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ENCYCLOPEDIA OFHEARTDISEASES

ENCYCLOPEDIA OFHEARTDISEASESM. GABRIEL KHAN, MD, FRCP[C], FRCP[LONDON], FACP, FACCCardiologistThe Ottawa HospitalOttawa, CanadaAssociate Professor of MedicineUniversity of OttawaOttawa, CanadaAMSTERDAM BOSTON HEIDELBERG LONDONNEW YORK OXFORD PARIS SAN DIEGOSAN FRANCISCO SINGAPORE SYDNEY TOKYOAcademic Press is an imprint of Elsevier

Elsevier Academic Press30 Corporate Drive, Suite 400, Burlington, MA 01803, USA525 B Street, Suite 1900, San Diego, California 92101-4495, USA84 Theobald’s Road, London WC1X 8RR, UKThis book is printed on acid-free paper.Copyright ß 2006, Elsevier Inc. All rights reserved.No part of this publication may be reproduced or transmitted in any form or by anymeans, electronic or mechanical, including photocopy, recording, or any informationstorage and retrieval system, without permission in writing from the publisher.Permissions may be sought directly from Elsevier’s Science & Technology RightsDepartment in Oxford, UK: phone: (þ44) 1865 843830, fax: (þ44) 1865 853333,E-mail: permissions@elsevier.com. You may also complete your request on-linevia the Elsevier homepage (http://elsevier.com), by selecting‘‘Customer Support’’ and then ‘‘Obtaining Permissions.’’Library of Congress Cataloging-in-Publication DataApplication submittedBritish Library Cataloguing in Publication DataA catalogue record for this book is available from the British LibraryISBN 13: 978-0-12-406061-6ISBN 10: 0-12-406061-7For all information on all Elsevier Academic Press publicationsvisit our Web site at www.books.elsevier.comPrinted in the United States of America05 06 07 08 09 10 9 8 7 6 5 4 3 2 1

To my wife Brigid who made this work possibleAndto our childrenSusanChristineYasminJacquelineStephenNatasha

CONTENTSAbout the AuthorPrefaceAcknowledgmentsxvxviixixAging and the Heart 1I. The Size of the Problem 1II. Effects of Aging on the Heart andVascular System 1III. Cardiovascular Therapy in the Elderly 2IV. Research Implications 3Bibliography 3Alcohol and the Heart 5I. Alcohol and Coronary Heart Disease 5II. Alcohol and Hypertension 6III. Alcohol and Heart Failure 6IV. Alcohol and Cardiomyopathy 6V. Alcohol and Abnormal Heart Rhythmsand Abnormal Electrocardiograms 7VI. Alcohol and Coagulation Factors and Stroke 7VII. Type of Alcohol Consumption 7VII. Perspective 8Bibliography 8Altitude and Pulmonary Edema 9I. Signs and Symptoms 9II. Mechanisms 9III. Management 10IV. Clinical Study 10V. Perspective and Research Implications 10Bibliography 11Anatomy of the Heart and Circulation 13I. Anatomic Features 13II. Circulation of Blood 21Bibliography 21Anderson-Fabry Disease 23Bibliography 23Anemia and the Heart 25I. Anemia and Heart Function 25II. Clinical Studies 25Bibliography 26Aneurysm 27I. Abdominal Aortic Aneurysm 27II. Thoracic Aortic Aneurysm 30III. Aortic Dissection 31IV. Berry Aneurysm 32Bibliography 32Angina 35I. Size of the Problem 35II. Pathophysiology 36III. Diagnosis 39IV. Disease Processes CausingAngina 40V. Stable and Unstable Angina 41VI. Nondrug Treatment 42VII. Drug Treatment 45VIII. Hypertension 53IX. Angina Patients with Heart Failure 53X. Silent Ischemia 53XI. Variant Angina(Prinzmetal’s Angina) 53XII. Unstable Angina/AcuteCoronary Syndrome 54Bibliography 55Angioplasty/Coronary Balloon 57I. Procedure 57II. Indications 58III. Contraindications and Limitations 58IV. Outcome of Angioplasty 59Bibliography 60

viiiAngiotensin-Converting EnzymeInhibitors/Angiotensin Receptor Blockers 61I. ACE Inhibitors 61II. Angiotensin II Receptor Blockers 65Bibliography 67Antihistamines 69I. Histamine Antagonists 69Bibliography 69Antioxidants 71I. Statins 71II. Vitamin E 72III. Vitamin C 73IV. Beta-Carotene 73V. Mediterranean Diet 74VI. Dietary Plant-Derived Flavonoids 74VII. French Red Wine 74VIII. Probucol 75Bibliography 75Antiphospholipid Antibody Syndrome 77I. Diagnosis 77II. Management 77Bibliography 77Antiplatelet Agents 79I. Mechanism of Action 79II. Indications 80III. Available Antiplatelet Agents 80Bibliography 83Arginine and the Heart 85I. Clinical Study 85Bibliography 85Arrhythmias/Palpitations 87I. Origin of the Heartbeat 87II. Palpitations, Premature Beats, andIrregular Beats 88III. Tachycardia 89IV. Antiarrhythmic Agents 95V. Automatic Implantable CardioverterDefibrillator 100VI. Conclusion 100Bibliography 100Arteriosclerosis 101I. Diseases Causing Arteriosclerosis 101II. Atherosclerosis 102Bibliography 103CONTENTSArtificial Heart 105I. Electric Total Artificial Heart 105II. Left Ventricular Assist Device 107III. Is There a Logical Role for VentricularAssist Devices? 108IV. New Frontiers 109Bibliography 109Aspirin for Heart Disease 111I. Historical Review 111II. Mechanism of Action 112III. Recognized Indications for Aspirin and Dose 113IV. Perspective 114Bibliography 114Atherosclerosis/Atheroma 117I. Introduction and Historical Background 117II. Pathology 119III. Pathogenesis 121IV. Vulnerable Atheromatous Plaques 127V. Clinical Studies 127VI. Perspective and Research Implications 128Bibliography 130Athletes and Sudden Cardiac Death 131I. Cardiac Causes of Sudden Death in YoungAthletes 132II. Sudden Death Not Associated withCardiac Disease 135III. Athlete’s Heart Versus HypertrophicCardiomyopathy 136Bibliography 137Atrial Fibrillation 139I. Epidemiology 140II. Diagnosis 140III. Causes and Research Implications 141IV. Pathophysiology 143V. Classification and Management 143VI. Anticoagulants 148VII. Electronic Pacing 149Bibliography 149Atrial Septal Defect 151I. Clinical Study 151Bibliography 152B-Type Natriuretic Peptide 153I. Clinical Studies 153II. Perspective 154Bibliography 155

CONTENTSixBeriberi Heart Disease 157I. Clinical Manifestations 157Bibliography 157Beta-Blockers 159I. Beta-Receptors 160II. Mechanism of Action 160III. Salutary Effects 160IV. Indications 161V. Clinical Trials 163VI. Adverse Effects and Cautions 164VII. Classification 164VIII. Subtle Differences and Research Implications 165IX. Individual Beta-Blockers 166Bibliography 167Blood Clots 169I. Causes of Blood Clots 169II. Nondrug Treatment 170III. Drug Treatment 170Bibliography 174Blood Pressure 175I. Historical Review 175II. Systolic and Diastolic Blood Pressure 178III. Classification 178IV. Normal Fluctuations in Blood Pressure 178V. Finger Cuff Method of Penaz 180VI. Technique and Pitfalls of Measurement 180VII. Effects of High Blood Pressure 180Bibliography 180Brugada Syndrome 183I. Clinical Features 183II. Perspective 184Bibliography 184Bundle Branch Block 185I. Right Bundle Branch Block 185II. Left Bundle Branch Block 187Bibliography 187Caffeine and the Heart 189I. Biochemistry 189II. Effects 190Bibliography 191Calcium Antagonists 193I. Mechanism of Action 193II. Available Calcium Antagonists 194III. Therapeutic Benefits 196IV. Next Generation Agents 196Bibliography 197Carcinoid Heart Disease 199I. Heart Damage 199II. Diagnosis 199III. Treatment 200IV. Clinical Study 200Bibliography 200Cardiogenic Shock 201I. Causes 201II. Pathophysiology 201III. Management 202IV. Perspective and Research Implications 202Bibliography 202Cardiomyopathy 203I. Hypertrophic Cardiomyopathy 204II. Sudden Death 207III. Dilated Cardiomyopathy 209IV. Restrictive Cardiomyopathy 211V. Specific Heart Muscle Disease 211Bibliography 212Cardiopulmonary Resuscitation (CPR) 215I. Causes of Loss of Consciousness 215II. Cardiac Arrest Rhythms 216III. Cardiopulmonary Resuscitation 216IV. Defibrillation 219V. Drugs for Cardiac Arrest 220VI. Perspectives and Research Implications 221VII. Outcomes of Out-of-Hospital Cardiac Arrest 221VIII. The Heimlich Maneuver 222Bibliography 222Chagas Disease 223I. Epidemiology 223II. Symptoms and Signs 223III. Diagnostic Investigations 225IV. Management 225Bibliography 225Chelation and Heart Disease 227I. Clinical Study 227II. Perspective 227Bibliography 228Abstract 228Chemotherapy-Induced Heart Disease 229I. Chemotherapeutic Agents 229II. Cardiac Damage from Anthracyclines 229

xiiXXIII. Risk Factors and Prevention 427XXIV. Heart Attack Prevention Diet 428Bibliography 429Heart Failure 433I. Incidence and Pathogenesis 433II. Basic Causes of Heart Failure 434III. Precipitating Factors 435IV. Pathophysiology 436V. Symptoms and Signs 437VI. Diagnosis 438VII. Drug Treatment 438VIII. Nondrug Therapy 444IX. What to Expect in the Hospitaland on Discharge 445Bibliography 446Hemochromatosis 449I. Incidence 449II. Genetics and Iron Overload 449III. Clinical Complications 450IV. Management 451Bibliography 451Herbal, Dietary Supplements, andCardiovascular Disease 453I. Historical 453II. Consumption and Regulation 453III. Benefits, Adverse Effects, andDrug Interactions 454IV. Substances Used by Athletes 460Bibliography 461HIV and the Heart 463I. Incidence 463II. Cardiac Complications of AIDs 463Bibliography 464Homocysteine and Cardiovascular Disease 465I. Homocysteine Metabolism 465II. Homocysteine and Vascular Disease 465III. Clinical Studies 465IV. Conditions Causing Hyperhomocystinemia 466V. Screening 466VI. Management of Hyperhomocystinemia 467VII. Benefits of Decreasing HomocysteineLevels 467VIII. Clinical Studies 467Bibliography 468Hypertension 469I. Measurement of Blood Pressure 469CONTENTSII. How High is High? 471III. Causes of Hypertension 471IV. Pathogenesis of Primary EssentialHypertension 474V. Complications 476VI. Symptoms 477VII. Investigations 477VIII. Nondrug Treatment 478IX. Drug Treatment 480Bibliography 490Hypertrophy of the Heart 493I. Pathophysiology 493II. Causes and Complications of HeartHypertrophy 495III. Diagnosis 495IV. Prevention and Management 497Bibliography 499Kawasaki Heart Disease 501I. Clinical Features 501II. Diagnosis 501III. Causation 502IV. Management 502Bibliography 502Miscellaneous Disorders 505I. Marfan Syndrome 505II. Cor Pulmonale 505III. Ehlers-Danlos Syndrome 506IV. Noonan Syndrome 506V. Ebstein’s Anomaly 507VI. Turner Syndrome 507VII. Fetal Alcohol Syndrome 507VIII. Holt-Oram Syndrome 507IX. Paget’s Disease 507X. Ankylosing Spondylitis 507XI. Rubella Syndrome 507XII. Pseudoxanthoma Elasticum 507XIII. Myotonic Muscular Dystrophy 508XIV. Takayasu 508XV. Lupus Erythematosus 508XVI. Sarcoidosis 509XVII. Syphilis 509XVIII. Atrial Myxoma 509Bibliography 509Murmurs and Heart Disease 511I. Clinical Cases 511II. Clinical Diagnosis of Heart Murmurs 512III. Investigative Tests 514Bibliography 514

ABOUT THE AUTHORDoctor M. Gabriel Khan is a cardiologist at the OttawaHospital and an Associate Professor of Medicine at theUniversity of Ottawa. Dr. Khan graduated MB, BCh, withFirst Class Honours at The Queen’s University of Belfast.He is a Fellow of the American College of Cardiology,the American College of Physicians, and the Royal Collegeof Physicians of London and Canada.He is the author of Cardiac Drug Therapy, sixth edition, 2003,W.B. Saunders/Elsevier, Philadelphia. On Call Cardiology, second edition, 2001,W.B. Saunders/Elsevier, Philadelphia. Rapid ECG Interpretation, second edition, 2003,W.B. Saunders/Elsevier, Philadelphia. Cardiac and Pulmonary Management, 1993, Lea &Febiger, Philadelphia. Medical Diagnosis and Therapy, 1994, Lea & Febiger,Philadelphia. Heart Attacks, Hypertension and Heart Drugs, secondedition, 1990, Bantam/Seal, Toronto. Heart Trouble Encyclopedia, 1996, Stoddart, Toronto. Heart Disease Diagnosis and Therapy, a PracticalApproach, second edition, 2005, Humana Press,New Jersey.His books are read worldwide, having acquired foreigntranslations: Chinese, French, Farsi, German, Greek,Italian, Japanese, Polish, Portuguese, Russian, Spanish,and Turkish.Here is an excerpt from the foreword, written by arenowned cardiologist and author, Dr. Henry J. L. Marriottfor the recent book, Heart Disease Diagnosis and Therapy:"Whenever I read Khan, I am affected as the rustics wereby Oliver Goldsmith’s parson:And still they gaz’d, and still the wonder grewThat one small head could carry all he knew.Khan’s knowledge is truly encyclopedic and, for hisfortunate readers, he translates it inot easily read prose.’’And for the book Cardiac Drug Therapy, fourth edition,a cardiologist reviewer states, ‘‘By far the best handbookon cardiovascular therapeutics I have ever had the pleasureof reading. The information given in each chapter isup-to-date, accurate, clearly written, eminently readableand well referenced.’’And from Clinical Cardiology a review of the fifthedition of Cardiac Drug Therapy, ‘‘This is an excellentbook. It succeeds in a very practical way while presentingthe major evidence in relation to its recommendations.From the trainee to the experienced consultant, all willfind it useful. The author stamps his authority very clearlythroughout the text by very clear assertions of his ownrecommendations even when these recommendations areat odds with those of official bodies. In such situationsthe ‘‘official’’ recommendations are also stated but clearlyare not preferred.’’

xviiiPREFACEremoved plaques of atheroma that obstructed arteries, andcutting the plaque of atheroma revealed a gelatinousporridge-like material. We still know little about thegrowth of atheromatous obstructions in arteries that causeheart attacks and strokes.This disease process is currently responsible for morethan 14 million deaths annually worldwide and it isbelieved that this will increase to about 25 million deathsin the year 2020 in a population of 7.4 billion people.This widespread disease causes more deaths than all formsof cancer, diabetes, infections, and asthma and lung diseases.Yet its prevention has defeated the medical professionbecause there is a relative paucity of research work done inthis area. We desperately need technologic instruments toprovide noninvasive detection of atheromatous obstructionin coronary arteries that presently can only be observedwith certainty by coronary angiography, and invasiveprocedure; electron beam CT scanning to determinecalcium scores is expensive and not sufficiently helpful.The text gives numerous illustrations to provide thereader with relevant insights and to render the materialmore user friendly. I trust that this volume will reach thehands and eyes of those who wish to quell the worldwideepidemic of cardiovascular disease.M. Gabriel KhanSeptember 2005

ACKNOWLEDGMENTSI am indebted to researchers worldwide whose works wereused to produce this fund of knowledge for futureresearchers in the field of cardiovascular medicine. I feelcertain that the names of many researchers have beenomitted because of my oversight and because referencesprovide only three names, et al.Hilary Rowe, my Publisher at Elsevier, had the foresightto accept my proposal to provide researchers in thetechnologic and medical field with an Encyclopedia ofHeart Diseases. I must express my thanks to her and herteam that includes: Erin LaBonte-McKay who assisted me with acquiringpermissions. Paul Gottehrer who faced the task of productionof the book without disappointing me. The printingstyle is what I requested. A text that is non-compressed,user-friendly, and with well-positioned illustrations.Few publishers are able to follow the whims of authors.There is little doubt, however, that without the love andcommitment of my wife Brigid, this daunting task of theproduction of a single-authored, 91-chapter book wouldnot have been possible.

Aging and the HeartI. The Size of the ProblemII. Effects of Aging on the Heart and Vascular SystemIII. Cardiovascular Therapy in the ElderlyIV. Research ImplicationsHeart failure has several causes including hypertension,and the prevention and management of heart failurewith old and new remedies require a concerted effort andrelevant new research.GLOSSARYcoronary heart disease obstruction of the coronary arteries withsymptoms such as chest pain, angina, or heart attacks.coronary thrombosis obstruction of a coronary artery by bloodclot.heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply ofblood reaches organs and tissues.hypertension high blood pressure.hypertrophy increase in thickness of muscle.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.myocardium the heart muscle.I. THE SIZE OF THE PROBLEMIn the year 2000 there were approximately 35 millionpeople in the United States who were 70 years and older.In the year 2030, the number will be approximately 70million. The world population of the elderly is approximately610 million and will grow to approximately 2billion by 2050. There is an epidemic of heart failure inthis aging population. In the United States, heart failure isthe most common diagnostic related group in thepopulation over 65. Coronary heart disease and strokeare very common. More than 60% of these individualshave hypertension, which is an important underlyingcause of heart failure. Atrial fibrillation, a serious abnormalheart rhythm, is common in the age group 70 to 85;this condition requires treatment with a blood thinner,warfarin, to prevent strokes. The main underlying causefor atrial fibrillation is hypertension.The prevention of morbidity and mortality in this agegroup requires the aggressive management of hypertension.II. EFFECTS OF AGING ON THE HEARTAND VASCULAR SYSTEMA. Gross AnatomyAging causes decreased elasticity and compliance of theaorta and great arteries arterial stiffness. This results inhigher systolic arterial pressures and increased impedanceof the propagation of blood from the left ventricle throughthe arterial system and the delivery of blood to organs andtissues. Mild left ventricular hypertrophy also occurs.B. Histological ChangesThese changes in the heart muscle include decreasedmitochondria and altered mitochondrial membranes.Increased collagen degeneration and interstitial fibrosiswith increased lipid and amyloid deposition causes the leftventricular muscle mass to become stiffer. Because of thisstiffness, after the systolic contraction of the ventricle ittakes longer for the ventricular mass to relax in diastole.This defect in relaxation and an abnormal dispensabilitycauses the ventricle to fail. Thus insufficient blood to meetthe demands of the tissues is propelled into the arterialsystem and heart failure ensues. This condition is referredto as diastolic heart failure. The exact underlying causes fordiastolic heart failure require further study. More knowledgewill improve today’s unsatisfactory therapy for thiscondition.Heart failure is commonly caused by systolic dysfunctionof the ventricle. The ventricular muscle mass isweakened by scarring from heart attacks and other cardiacdiseases. Failure of the muscle pump causes insufficientblood to be expelled from the ventricle into the arteries.Treatment for systolic heart failure has improved considerablysince 2000.1

2AGING AND THE HEARTC. Biochemical ChangesThese changes include decreased protein elasticity, changesin enzyme content that affect metabolic pathways,decreased catecholamine synthesis, and diminishedresponsiveness to beta-adrenergic stimulation.D. Electrical Conduction SystemSubstantial loss of pacemaker cells in the sinus node cause afall in heart rate and finally failure. This condition is calledsick sinus syndrome and is the most common reason forimplanting an electronic pacemaker. Increased fibrosisand calcification of the conduction system and loss ofspecialized cells in the His bundle and bundle branches canresult in failure of the electrical impulse to reach theventricles. This condition is called heart block and requiresa pacemaker. (See the chapter Pacemakers.)E. Valvular ChangesThese changes include fibrosis, thickening and calcificationof heart valves which leads to degenerative valvular disease.Calcified aortic stenosis may require valve surgery butthe statins, cholesterol-lowering agents, have been shownto decrease the rate of stenosis and may delay surgicalintervention. Mitral annular calcification occurs commonlyand occasionally causes mitral regurgitation, atrialarrhythmia, heart block, and infective endocurditis.Fibroproliferative lesions producing mitral regurgitationhas occured in elderly patients treated with antiparkinsoniandopamine receptor agonist pergolide.III. CARDIOVASCULAR THERAPYIN THE ELDERLYA. Thrombolytic TherapyPatients 70 years or older with an acute myocardial infarctare at high risk for serious events. Thrombolytic therapymay prevent death and further morbidity. Unfortunately,in patients older than 75 there is an increased risk ofintracranial bleeding. This excessive risk must be balancedagainst any possible benefit derived from thrombolytictherapy. The incidence of intracranial hemorrhage in thisage group is greater than 1.5% for alteplase (tissueplasminogen activator, t-PA) and tenectaplase, but greaterthan 0.5% for streptokinase.Although intracranial hemorrhage incidence is lowerwith streptokinase, it is not the drug of choice in NorthAmerica. Fortunately, in the UK, Europe, and worldwidethe less expensive agent streptokinase is still the mostwidely used pharmacologic reperfusion therapy. Thrombolyticagents that are effective but cause less intracranialbleeding than alteplase and tenectaplase in theelderly would be important additions to the therapeuticarmamentarium.B. Percutaneous InterventionBecause thrombolytic therapy carries a major risk ofintracranial hemorrhage and stroke in patients over age 75,randomized clinical trials have confirmed the beneficialeffects of primary coronary angioplasty with intracoronarystents. PCI is superior to thrombolytic therapy and ispreferred if skilled cardiologists and facilities are readilyavailable.In a randomized study of 87 patients older than 75 withacute myocardial infarction, the composite of death,reinfarction, or stroke at 30 days occurred in 4 (9%)patients in the percutaneous intervention (PCI) group ascompared with 12 (29%) in the patients receivingstreptokinase intravenously ( p ¼ 0.01). Patients olderthan 75 years of age with acute myocardial infarction orunstable angina obtain beneficial results with placement ofa stent in the culprit coronary artery, blocked by atheromaand thrombosis.C. Beta-Blocker TherapyBeta-adrenergic blocking drugs, beta-blockers, have provenbeneficial and save lives in patients with acute myocardialinfarction regardless of age. Some caution is requiredbecause the elderly over the age of 75 may have disease ofthe sinus node and slow heart rates may occur if the doseof the beta-blocking drug is excessive. Small doses ofthese agents are also beneficial in the elderly patientwith heart failure angina, atrial fibrillation, and hypertension.In the elderly hepertensive patient, a standing bloodpressure should always be taken to doucment posturalhypotension caused by vasodilatory anti-hypertensiveagents. Beta-adrenergic blockers do not cause posturalhypotension.D. Calcium AntagonistsThe calcium antagonists, or calcium entry blockers, arewidely used to treat hypertension. From 1990 to 2002, theWorld Health Organization (WHO) and the joint nationalcommittee for advice on hypertensive treatment in theUnited States recommended the use of calcium antagonistsas first line agents for management of hypertension in the

IV. RESEARCH IMPLICATIONS3elderly. Their recommendation is illogical and somewhatmisguided. These agents are well known to precipitateheart failure and should be used only in elderly patientswho have no evidence of left ventricular dysfunction.An epidemic of heart failure is occurring particularly inthe elderly. Calcium antagonists increase the incidence ofheart failure in the elderly because the aging heart loses itscontractile function and abnormal histologic, anatomic,and biochemical changes occur that increase the risk ofheart failure. Fortunately, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT) showed conclusively that the use of a diureticwas more beneficial than calcium antagonists in theprevention of stroke mortality and heart failure. Importantly,this study showed that the alpha blocker doxazosincaused an increased risk for the development of heartfailure and the use of alpha blockers should be curtailed.The result of this study will change recommendations andprescribing habits worldwide.IV. RESEARCH IMPLICATIONSThe following is a list of research implications.1. The processes that occur in the aging heart requireintensive studies. As outlined earlier, the populationof individuals 75 years and older is increasing and theincidence of heart failure and atrial fibrillation areincreasing by leaps and bounds. The pathophysiologyof the aging heart needs to be clarified. These answerswill surely result in improvement and changes intherapeutic strategies.2. It may be possible to prevent collagen degeneration andthe fibrosis that stiffens the left ventricular muscle wall.Agents such as spironolactone cause a more completeblock of aldosterone production than is achieved withangiotensin-converting enzyme (ACE) inhibition andreduce mortality and morbidity in patients with heartfailure. The salutary effects are not only related tosodium and water loss by this mild diuretic, but also toa decrease in cardiac fibrosis, retardation of endothelialdysfunction, and increased nitric oxide vasodilator production.Tissue collagen turnover and fibrosis appear tobe important facets of heart failure. Spironolactone mayattenuate deleterious structural remodeling in the agingheart. A derivative compound, eplerenone (Inspra), hasfewer adverse effects when compared with spironolactoneand has been shown in a well-run randomizedclinical trial to be an effective antihypertensive agent.3. Damage to mitochondria must be addressed.4. The use of beta-blocking drugs to treat hypertensionin patients prior to age 65 and from age 65 to 80 mayfavorably alter myocardial processes and decrease theincidence of heart failure. This hypothesis needs to betested. There are more than 12 beta-blocking drugscurrently available, but subtle differences exist andcarvedilol, bisoprolol, or metoprolol should be used inclinical trials for hypertension and heart failure and theuse of atenolol, propranolol, sotalol, acebutolol, andother beta-blockers that are not shown to be cardioprotectivein randomized clinical trials should beavoided.5. Polypharmacy is common in the elderly. The majorityof elderly patients take more than eight to 12 pills daily.Drug interactions occur commonly and results in asignificant number of deaths that should be avoidedby appropriate research and education to patients,physicaians and nurses who render care for the elderly.Renal dysfunction is a common occurence in theelderly, and importantly, a normal blood creatinine maybe present in patients with significantly compromisedrenal function that can lead to drug toxicity.BIBLIOGRAPHYBoer, M., Ottervanger, J., and Arnoud, W. Reperfusion therapy in elderlypatients with acute myocardial infarction. J. Am. Coll. Cardiol.,59:1723–8, 2002.Khan, M. G. Beta blockers the cornerstone of cardiac drug therapy.In Cardiac Drug Therapy, sixth edition, W.B. Saunders, Philadelphia,2003.Lakatta, E. G., Levy, D. et al. Arterial and cardiac aging: Majorshareholders in cardiovascular disease enterprises: Part I: Agingarteries: A "set up" for vascular disease. Circulation, 107:139–146,2003.Lakatta, E. G. et al. Arterial and cardiac aging: Major shareholders incardiovascular disease enterprises: Part III: Cellular and molecular cluesto heart and arterial aging. Circulation, 107:490, 2003.Major Cardiovascular Events in Hypertensive Patients Randomized toDoxazosin vs ChlorthalidoneMehta, R. H., Granger, C. B., Alexander, K. P. et al. Reperfusion strategiesfor acute myocardial infarction in the elderly: Benefits and risks. J. Am.Coll. Cardiol., 45:471–478, 2005.Pitt, B., Reichek, N., Willenbrock, R. et al. Effects of eplerenone,enalapril, and eplerenone/enalapril in patients with essential hypertensionand left ventricular hypertrophy. The 4E–left ventricularhypertrophy study. Circulation, 108:1831, 2003.The ALLHAT Officers and Coordinators for the ALLHAT CollaborativeResearch Group:The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) JAMA, 283:1967–1975. 2000.The ALLHAT Officers and Coordinators for the ALLHAT CollaborativeResearch Group:The Antihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT Major Outcomes in High-RiskHypertensive Patients Randomized to Angiotensin-ConvertingEnzyme Inhibitor or Calcium Channel Blocker vs Diuretic). JAMA,288:2981–2997, 2002.

Alcohol and the HeartI. Alcohol and Coronary Heart DiseaseII. Alcohol and HypertensionIII. Alcohol and Heart FailureIV. Alcohol and CardiomyopathyV. Alcohol and Abnormal Heart Rhythms andAbnormal ElectrocardiogramsVI. Alcohol and Coagulation Factors and StrokeVII. Type of Alcohol ConsumptionVIII. PerspectiveGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiomyopathy heart muscle disease.cardioprotection protection of the heart from serious eventsthat include coronary artery disease and its complications,angina, myocardial infarction and heart failure.HDL cholesterol high density lipid; the good cholesterol.heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hypercholesterolemia high levels of cholesterol in the blood.I. ALCOHOL AND CORONARY HEARTDISEASEThe regular consumption of small quantities of alcohol —two drinks per day for men and one drink per day forwomen — appears to be associated with lower rates ofcardiovascular events in most studies. These studies,however, do not have sound methodology. In most ofthese epidemiologic studies actual mortality rates are notstated and mainly relative risks are described.Study question: Let’s examine the relationship betweenalcohol intake and risk of coronary heart disease (CHD)among men with type 2 diabetes. Because type 2 diabetes isassociated with an increased risk of CHD, Tanasescu et al.studied the effect of alcohol on the risk of CHD.Methods: This included the study of 2419 men whoreported a diagnosis of diabetes at age 30 or older in thehealth professional’s follow-up study. Fifty new cases ofCHD (81 nonfatal myocardial infarction and 69 fatal) weredocumented during 11,411 person-years of follow up.Results: A questionnaire showed that alcohol use wasinversely associated with risk of CHD. After controllingfor body mass index (BMI), smoking, hypercholesterolemia,physical activity level, and other variables, relative risk(RR) was 0.78, 0.6, and 0.48 ( p for trend ¼ 0.03) correspondingto intake of less than 0.5 drinks per day, 0.5–2drinks per day, and greater than 2 drinks per day.Conclusions: The authors concluded that moderatealcohol consumption is associated with lower risk of CHDin men with type 2 diabetes. Results are consistent withthose of the four recent studies that focused on the effect ofalcohol on the occurrence of fatal or nonfatal myocardialinfarction (MI).Perspective: This is a limited study, and it is notsurprising that there is so much confusion about alcoholand cardioprotection.A. Alcohol and HDL CholesterolSeveral studies have confirmed that alcohol causes amodest increase in high density lipoprotein (HDL)cholesterol levels. There is a clear association betweenhigh levels of HDL cholesterol and longevity. Individualsaged 80 and older are often observed to have HDLcholesterol levels >1.8 mmol/L (>70 mg/dl). The majorityof individuals aged 30–50 have HDL cholesterol levelsbetween 0.9 to 1.5 mmol/L. The level

6ALCOHOL AND THE HEARTof liver dysfunction, increased blood pressure, worseningheart failure, behavioral disturbances, and in rare instances,damage to the heart muscle. Women, because of theirsmaller BMI and differences in liver metabolism, should beadvised not to exceed one drink a day if benefit is to beobtained without harm.B. Alcohol Consumption and HemostaticFactors1. Analysis of the Framingham Offspring CohortBecause cardioprotection is not fully explained by themodest increase in HDL cholesterol caused by alcohol,Mukamal et al. assessed the effects of alcohol onhemostatic factors.Methods: There were 3223 adults from the Framinghamoffspring study done in 1971 used. These offspringwere assessed 20 years later. Patients with coronary heartdisease were excluded. Alcohol use was rated as none,

VII. TYPE OF ALCOHOL CONSUMPTION7idiopathic dilated cardiomyopathy of unknown etiology.Myocytic hypertrophy, interstitial fibrosis, and disorganizationof mitochondria with large glycogen-containingvacuoles may be observed. Further research is required todefine the pathophysiology and therapeutic strategies toprevent this type of myocardial damage.V. ALCOHOL AND ABNORMAL HEARTRHYTHMS AND ABNORMALELECTROCARDIOGRAMSAlcohol is a major cause of atrial fibrillation, which is themost common abnormal heart rhythm encountered inmedical practice. This serious arrhythmia requires patientsto be treated with oral anticoagulants to prevent stroke.Moderate alcohol consumption can cause atrial fibrillation.(See the chapter Atrial Fibrillation). In some patients atrialor ventricular premature beats and palpitations may occur.Alcohol consumption for several years can cause theelectrocardiogram to show abnormal findings such as milddeformities of the ST segment and T waves.VI. ALCOHOL AND COAGULATIONFACTORS AND STROKEAlcohol consumption is associated with an increasedincidence of hemorrhagic stroke. Alcohol consumptionalters coagulation factors as outlined above in the analysisof the Framingham study.VII. TYPE OF ALCOHOL CONSUMPTIONA. Red Wine versus White WineMild alcohol consumption causes a modest reduction incardiovascular events. There has been considerable controversy,however, regarding what type of alcoholic beveragesprovides the greatest cardioprotection. Studies of theFrench population indicate that wine, particularly redwine, offers greater protection. Studies in the UK andother countries indicate that beer is as good or even slightlybetter. Studies in the United States indicate that spirits areas good as wine.In human volunteers a high-fat diet has been shown toinduce endothelial dysfunction while red wine counteractsit. Reportedly, the acute administration of red wine reducesthe increase in nuclear factor kB (NF-kB) responsible forpromoting the expression of several inflammatory genesresulting from a high-fat meal. This effect was notobserved for vodka.The French, who eat rich food and drink more heavilythan many other nationalities, have a much lower rate ofheart disease events, the so-called French paradox (see thechapters Atherosclerosis/Atherothrombosis and HeartAttacks). Their high consumption of red wine appears tobe the source of their cardioprotection. However, geneticfactors may also be involved.There appears to be significant differences between redand white wine. Red wine has a much higher content ofthe powerful antioxidants called polyphenols than whitewine. These polyphenols appear to mop up oxygen freeradicals that damage the arterial wall and may help toprevent damage caused by diabetes. French winemakershave recently increased levels of polyphenols in white wineby altering the wine-making process. They have done thisby using white grapes that have a high polyphenol contentand added more of the skins in which polyphenols areheavily concentrated. They softened the grapes for six daysand the mixture was heated. This straw-yellow winecontains polyphenol levels four times higher than normal.Unfortunately, a controlled clinical trial to study the resultsof this new process is unlikely to take place.B. French Red Wine versus GermanWhite WineInvestigative study: Because endothelial type nitric oxide(NO) synthase exerts vasoprotective effects and red wineconsumption has been associated with a reduction ofcardiovascular disease but without molecular basis,Wallerath et al. studied the effect of red wine onendothelial-type nitric oxide synthase (eNOS) expressionand eNOS activity in human endothelial cells.Methods: In the method used in this study, humanendothelial cells were treated with red wine and eNOSmessenger ribonucleic acid (mRNA) was measured byRNase protection assay and other techniques.Results: The results showed that incubation ofendothelial cells with red wines from France upregulatedeNOS mRNA and protein expression. In contrast, redwines from Germany showed little or no effect on eNOSexpression. No significant difference in eNOS mRNAexpression could be detected between ‘‘en barrique’’(matured in oak barrels) and ‘‘non-barrique’’ (maturedin steel attacks) produced French red wines. Endothelialcells treated with French red wines produced up to threetimes more bioactive NO than did control cells. Frenchred wines increased the activity of the eNOS promoter, andthe eNOS mRNA stability was also increased by red wine.

8ALCOHOL AND THE HEARTConclusions: This study concluded that the increase ineNOS expression and activity brought about by red winesfrom France may contribute to the beneficial effects onthe cardiovascular system. This observation provides aplausible and fascinating explanation for the differences inthe European and American observations on the cardioprotectiveeffects of different alcoholic beverages, butfurther research is required to resolve these importantcontroversies.Those who wish to take one drink or a maximum of twodrinks daily should enjoy the pleasure if they feel morerelaxed and enjoyment is derived. Individuals aged 45–80may obtain approximately 10% reduction in cardiacevent rates, but those who consume more than twodrinks daily may suffer the disadvantage of an increasedincidence of liver dysfunction, hemorrhagic stroke, andatrial fibrillation.VIII. PERSPECTIVEThe evidence that alcohol consumption is significantlycardioprotective is growing but inconclusive. If one or twodrinks daily provides some beneficial effects, then theseeffects are modest. Most important, only those athigher risk for coronary heart disease may benefit.Thus individuals aged 20–40 should not use alcohol forcardioprotection, because these individuals are at low riskfor heart disease. Individuals from age 40 to 80 with astrong family history of heart attack before age 60 andpresence of hypertension or diabetes may obtain someprotection, but studies have not provided a clear analysis.In any event the protection is expected to be approximately10% risk reduction versus approximately 33% with use ofstatins to lower LDL cholesterol levels. It is noteworthythat trials on antioxidants such as beta-carotene have beenshown to be noncardioprotective. The antioxidants inalcohol are unlikely to be sufficiently protective forindividuals at high risk. Individuals at risks for coronaryheart disease are advised to take medications that havebeen shown in randomized clinical trials (RCTs) todecrease mortality and cardiac events and not to rely onalcohol or herbal remedies that offer modest protection, ifany at all.BIBLIOGRAPHYAppeldoorn, C. C. M., Bonnefoy, A., Lutters, B. C. H. et al. Gallic acidantagonizes P-Selectin – mediated platelet – leukocyte interactions:Implications for the French paradox. Circulation, 111:106–112, 2005.Blanco-Colio, L. N., Valderrama, M., Alvarez-Sala, L. A. et al. Red wineintake prevents nuclear factor–kB activation in peripheral bloodmononuclear cells of healthy volunteers during postprandial lipemia.Circulation, 102:1020–6, 2000.Criqui, M. H., and Ringel, B. L. Does diet or alcohol explained theFrench paradox? Lancet, 44:1719–23, 1994.Cuveas, A. M., Guasch, V., Castillo, O. et al. A high fat diet induces andred wine counteracts endothelial dysfunction in human volunteers.Lipids, 35:143–8, 2000.Di Castelnuovo, A., Rotondo, S., Iacoviello, L. et al. Meta-analysis ofwine and beer consumption in relation to vascular risk. Circulation,105:2836–2844, 2002.Gronbaek, M., Becker. U., Johansen, D. et al. Type of alcohol consumedand mortality from all causes, coronary heart disease, and cancer. Ann.Intern. Med., 133:411–9, 2000.Mukamal, K. J., Jadhav, P. P., D’Agostino, R. B. et al. Alcoholconsumption and hemostatic factors. Analysis of the Framinghamoffspring cohort. Circulation, 104:1367–73. 2001.Szmitko, P. E., and Verma, S. Red wine and your heart. Circulation,104:1367–1373, 2002.Tanasescu, M., Hu, F. B., Willett, W. C. et al. Alcohol consumption andthe risk of coronary heart disease among men with type 2 diabetesmellitus. J. Am. Coll. Cardiol., 38:1836–1842, 2001.Wallerath, T., Poleo, D., and Li, H. Red wine increases the expressionof human endothelial nitric oxide synthase. J. Am. Coll. Cardiol.,41:471–8, 2003.

Altitude and Pulmonary EdemaI. Signs and SymptomsII. MechanismsIII. ManagementIV. Clinical StudyV. Perspective and Research ImplicationsGLOSSARYhypoxia; hypoxemia severe lack of oxygen in the blood.neutrophils white blood cells.pulmonary edema caused by heart failure and the heart fails toeject blood forward into the aorta. Fluid that contains salt andwater and components of blood flood the alveoli of the lungsand this results in severe shortness of breath.I. SIGNS AND SYMPTOMSHigh-altitude pulmonary edema, severe shortness of breathdue to accumulation of fluid in air sacs of the lungs, mayoccur in young, healthy, susceptible adults who ascendrapidly to altitudes in excess of 2500 m. The first symptomis usually dyspnea on exertion and a reduced exercisetolerance greater than expected for the altitude. A dry andannoying cough later becomes productive with bloodstainedsputum. Symptoms typically occur in the first twoto four days after arrival at these high altitudes.Symptoms may become much worse when theseindividuals engage in strenuous exercise at such highaltitudes before they become acclimatized. Cough, shortnessof breath, and reduced effort tolerance may increasewithin hours and progress to fulminant pulmonary edema,which is heralded by extreme shortness of breath, includingshortness of breath when the individual is lying in bed(orthopnea).On examination physical signs include fever, althoughthis rarely exceeds 38.5 C and crepitations or crackles(rales) are heard over the chest with the stethoscope. Highaltitudepulmonary edema is often accompanied bynonspecific cerebral symptoms including headache, anorexia,nausea, vomiting, fatigue, and sleep disturbance.Death may occur in young individuals who have nostructural heart disease. The risk for pulmonary edema isrelated to the rapidity of ascent, the level of exertion, andindividual susceptibility. The pulmonary symptoms maybe accompanied by severe cerebral symptoms such asaltered consciousness, ataxia, and brain herniation thatprogresses to coma and death. Thus individuals withsymptoms of acute mountain sickness (headache, anorexia,vomiting, dizziness, and fatigue) and high altitudepulmonary edema may progress rapidly to severe cerebralsymptoms and death.II. MECHANISMSVasoconstriction of pulmonary vessels causes an increase inboth alveolar capillary pressure and vascular fluid shearstress. Flooding of pulmonary capillaries and increasedcapillary permeability occur. Fluid and inflammatory cellsleak into the air sacs that are normally dry. Pulmonaryedema is caused by an imbalance between forces that drivewater into the air sacs and the physiologic mechanisms thatremove it.A reaction to lung injury brings about chemical mediatorsof inflammation, vascular endothelial growth factor,interleukin-1, and tumor necrosis factor. These are releasedfrom pulmonary structural cells and alveolar macrophages.Neutrophils and platelets are trapped in the pulmonarycapillaries. Fluid accumulates in the air sacs resulting inacute shortness of breath.Hypoxia increases pulmonary vascular resistance and thepulmonary artery pressures rise. Severe exertion furtherincreases pulmonary artery pressures.Sartori et al. determined that the nasal transepithelialpotential difference in persons who were susceptible tohigh-altitude pulmonary edema was 33% lower than thatin individuals who were not susceptible. The susceptibleindividuals appear to have a defect in transepithelialsodium and water clearance in the lungs, and this may be9

10ALTITUDE AND PULMONARY EDEMAgenetically determined. Severe sudden oxygen lack andexertion appear to render the alveolar-capillary boundaryleaky, in susceptible individuals, and fluid with inflammatorycells flood the alveoli.The process is the key to models of lung injury in whichcatecholamines alter sodium and fluid transport. Sartoriet al. hypothesized that a beta-adrenergic agonist such assalmeterol, commonly used in the treatment of asthma,may favorably alter the defective alveolar fluid and sodiumclearance. They showed that in susceptible mountaineerspretreated with inhaled salmeterol, the incidence of highaltitudepulmonary edema decreased 50% compared withcontrol subjects.III. MANAGEMENTThe best strategy to prevent pulmonary edema is toascend gradually to allow sufficient time for acclimatization.Descend to a lower altitude as quickly as possibleand administer a high inhaled concentration of oxygen.Simulated descent with a portable hyperbaric chamber canbe lifesaving.Prevention of pulmonary edema in people with a historyof high-altitude pulmonary edema may be achieved bythe use of nifedipine, a calcium antagonist that reducespulmonary artery pressures. Slow release nifedipine 20 mgevery 8 h has been shown to be effective in prevention afterrapid ascent to greater than 4000 m.Continuous positive airway pressure with a portabledevice is useful. Also, nifedipine 10 mg immediately, thenprovided that the systolic blood pressure is greater than100 mmHg, slow-release nifedipine 20–30 mg every12–24 h along with oxygen may be useful during descent.Nifedipine is a powerful vasodilator and antihypertensiveagent that may cause severe hypotension and caution isrequired. The high pulmonary artery pressure is caused byhypoxemia, which must be relieved by high concentrationsof inhaled oxygen.Acetazolamide, a mild diuretic and carbonic anhydraseinhibitor, causes elimination of bicarbonate by thekidney altering the blood pH and stimulating respiration.Acetazolamide should be commenced two days prior to aplanned trip to high altitudes. The drug does not preventhigh-altitude pulmonary edema, but it appears to be usefulin the prevention of acute mountain sickness and forhigh-altitude flights. The dosage should be 250 mg twiceor three times daily one day before ascent. A dose lowerthan 750 mg daily may be ineffective for some individuals.A combination of acetazolamide and dexamethasone8 mg daily is more effective than either drug alone.Ginkgo biloba at a dose of 80 mg twice daily has beenshown to be effective in a small study, but beneficial effectswere variable in other studies in preventing acutemountain sickness.Inhaled salmeterol commenced prior to the ascent andrepeated at 2000 m is advisable based on the work ofSartori et al. This drug has an excellent safety profileand has been used in asthmatics for more than 30 years.Serevent is a long-acting salmeterol that should also betried.IV. CLINICAL STUDYStudy question: Beta-adrenergic agonists upregulate theclearance of alveolar fluid and attenuate pulmonary edemain animal models. The study assessed effects of prophylacticinhalation of salmeterol, a beta-agonist, on theincidence of high-altitude pulmonary edema.Methods: These included a double-blind, randomizedplacebo-controlled study in 37 subjects susceptible tohigh-altitude edema who were assessed during exposure tohigh altitudes (4559 m). Nasal transepithelial potentialdifference was used as a marker of the transepithelialsodium and water transport in the distal airways of33 mountaineers prone to pulmonary edema and 33who were resistant.Results: Prophylactic inhalation of salmeterol decreasedthe incidence of high-altitude pulmonary edema by morethan 50%; the nasal transepithelial potential difference wasalso significantly changed.Perspective: Prophylactic inhalation of salmeterol, awell-known beta-adrenergic agonist used in the managementof asthma for more than 25 years, was shown to besufficiently effective in the study and is advisable.V. PERSPECTIVE AND RESEARCHIMPLICATIONSHigh-altitude pulmonary edema is preventable. Fortunately,very few mountain climbers are susceptible, butthose who are may have unpredictable recurrences whenthey are exposed to high altitudes. The susceptibleindividual must take prophylaxis including acetazolamide,nifedipine, inhaled salmeterol; ascend slowly; and avoidvigorous exertion. Considerable research is required in thisarea to further clarify the pathogenesis of high-altitudecerebral edema. This research would help refine morebeneficial treatment. Natural products including Ginkgobiloba and garlic may be useful for the amelioration ofbenign symptoms of high-altitude illness. Drugs includingsildenafil, which inhibits hypoxemia-induced pulmonary

Anatomy of the Heart and CirculationI. Anatomic FeaturesII. Circulation of BloodGLOSSARYatherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow of blood; theplaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).capillaries minute, thin-walled blood vessels which connect thearterioles and the venules, forming a network in nearly allorgans and tissues of the body.coronary arteries the arteries that supply the heart muscle andother parts of the heart with blood.heart the size of a closed fist, it lies within the chest cavity,directly under the breastbone (sternum); the shape of the heartis conical with the apex pointing downward to the left edge ofthe diaphragm.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.myocardium the heart muscle.tissues an aggregation of specialized cells which togetherperform certain special functions.I. ANATOMIC FEATURESMajor structural parts of the heart include the muscularwall (myocardium), the inner lining (endothelium), theouter lining (pericardium), and the blood vessels supplyingthe heart with blood. The coronary arteries andveins run along the surface of the heart through thepericardium and traverse the muscular wall. Anatomicalfeatures of the heart and circulation are illustrated inFigs. 1–10.A. Muscle Wall/MyocardiumThe wall of the heart consists of three layers: (1) a middlelayer of muscle fibers called the myocardium; (2) anouter thin covering, the pericardium (Fig. 2) and (3) aninternal lining called the endocardium that is smoothas silk. The blood of the heart rests momentarily on theendocardium before it is ejected from the heart into theaorta.B. PericardiumThe muscle wall of the heart is surrounded by a thin butdouble membrane, the pericardium. The innermost orvisceral layer of the pericardium is a secretory membranethat is closely attached to the surface of the heart muscle.The outer or parietal layer of the pericardium consistsof a thin but tough layer. Figure 1 shows the parietalpericardium (cut). The cells of the pericardium secreteminute quantities of a lubricating fluid that separatethe two layers of the pericardium. This pericardialfluid may be increased by diseases creating a pericardialeffusion.C. Chambers of the HeartThe thin-walled top chambers are called the right and leftatrium, see Fig. 3. Oxygenated blood passively enters theleft atrium from the lungs (Fig. 4) and deoxygenated bloodreturns from the lower extremities, abdomen, trunk, andthe head region and enters passively into the right atrium.The lower chambers are called the right and left ventricles.The left ventricle is thick-walled because the strong muscleis needed to pump the blood to all parts of the body. Theright ventricle is thin-walled because only a small amountof force is required to pump the blood from the rightventricle through the lungs and return the blood to the13

14ANATOMY OF THE HEART AND CIRCULATIONLeft common carotid arteryLeft internal jugular veinRight brachiocephalic veinRight subclavian arteryRight subclavian veinPerietal pericardium (cut)Left brachiocephalic veinLeft subclavian veinLeft subclavian arteryArch of aortaSuperior vena cavaRight lungRight auricleRight atriumCoronary sulcusPleura (cut)Right ventricleLeft lungPulmonary trunkLeft auricleRibs (cut)Anterior interventricular sulcusLeft ventricleApex of heartDiaphragmFIGURE 1 The heart in relation to surrounding structures. (Source: Gaudin, A.J., and Jones, K.C. (1989). ‘‘Human Anatomy and Physiology.’’Harcourt Brace Jovanovich, San Diego, p. 559. Reproduced with permission.)apex of pericardiumsuperior vena cavapericardium×rightauriclecoronarysulcusconusarteriosusrightventriclesuperior vena cavainnominate art.left common carotid art.left subclavian art.left branch ofpulmonary arteryarch of aorta superior vena cavaligament. arteriosumbifurcation of pulmonary art.left branch ofpulmon. art.right branch ofpulm. art.pulmonaryarteryleft auricleright pulmonaryveinspericardium×anterior longit.sulcusleftventricleaortapericardium×transversesinus ofparicardiumpulmonaryarteryrightauricleanteriorlongit.sulcuspericardium×pericardium×inferior venacavaapex of heartapex of heartFIGURE 2(Source: Sobotta, J., and McMurrich, J.P., Atlas of Human Anatomy, Philadelphia: W. B. Saunders, 1911. With permission.)

16ANATOMY OF THE HEART AND CIRCULATIONSuperior vena cavaAscending aorta Pulmonary trunkDescendingaortaRightpulmonary arteryAortic archLeftpulmonary arteryPulmonary veinsLobar branchesto left lungsPulmonary veinsLobar branchesto right lungInferior vena cavaRightatriumRightventricleLeftatriumLeftventricleOxygenated bloodUnoxygenated bloodFIGURE 4 Pulmonary circulation. (Source: Gaudin, A.J., and Jones, K.C. (1989). ‘‘Human Anatomy and Physiology.’’ Harcourt Brace Jovanovich,San Diego, p. 589. Reproduced with permission.)right coronaryarteryascending aortaleft superior pulmonaryveinright pulmonary veinsleft inferiorpulmonary veinright semilunarvalveposterior semilunar valvenodule of semilunar valveleft coronary arteryleft semilunar valve ×valve of foramenovaleposterior cuspgreat cardiacveinleft ventricle(muscularseptum)anterior cuspofbicuspid valveleft ventricle(muscular septum)chordaetendineaetrabeculaecarneaepapillary muscleleft ostiumvenosumpapillary musclesFIGURE 5(Source: Sobatta, J., and McMurrich, J.P., Atlas of Human Anatomy, Philadelphia: W. B. Saunders, 1911. With permission.)

I. ANATOMIC FEATURES17FIGURE 6(Source: Sobatta, J., and McMurrich, J.P., Atlas of Human Anatomy, Philadelphia: W.B. Saunders, 1911. With permission.)innominate arteryleft common carotid arteryleft subclavian arteryligamentum arteriosumpericardium ×right branch of pulmonary arterypericardium ×superior vena cavaleft branch ofpulmonary art.left branch ofpulmonary art.superior vena cavapericardium ×pericardium ×left auricleleft pulmonaryveinsleft auriclecoronarysulcusright pulmonaryveinssinus of thevenae cavaeterminalsulcuscoronarysulcusright atriuminferior vena cavaFIGURE 7anterior longitudinal sulcusapical notchleft ventricleapex of heartapical notchright ventricleposterior longitudinal sulcus(Source: Sobatta, J., and McMurrich, J.P., Atlas of Human Anatomy, Philadelphia: W.B. Saunders, 1911. With permission.)

18ANATOMY OF THE HEART AND CIRCULATIONLeft Main CoronaryArteryRight CoronaryArteryCircumflex ArteryFIGURE 8Left Anterior - DescendingCoronary ArteryCoronary arteries. (Source: Khan, M. Gabriel, Heart Trouble Encylopedia, Toronto: Stoddart, 1996. With Permission)Aortic sinusSemilunar valve cuspsLeft coronary arteryAortaRight coronary arteryLeft coronary arteryRight coronary arteryChordae tendineae ofbicuspid valveFIGURE 9 The aortic semilunar valve. (Source: Gaudin, A.J., and Jones, K.C. (1989). ‘‘Human Anatomy and Physiology.’’ Harcourt Brace Jovanovich,San Diego, p. 566. Reproduced with permission.)left atrium. The right and left atria are separated from eachother by a thin membrane called the atrial septum. Theright and left ventricles are separated by a thicker muscularstructure called the interventricular septum (see Figs. 2 and4). The right and left atria are separated from the right andleft ventricles by the tricuspid and mitral valves (mitralvalve ¼ bicuspid valve in Figs. 3 and 5), respectively. Theoutflow from the left ventricle is separated from the aortaby the aortic valve (Figs. 2, 5 and 9).The aorta, the largest artery in the body (Figs. 3, 5,and 7), leaves the heart and takes blood ejected from theheart to the rest of the body. The blood from the rightventricle is ejected through the pulmonary valve into thepulmonary artery, which traverses the lung (Figs. 3, 4, 6,

I. ANATOMIC FEATURES19To HeadCarotid Artery3SubclavianArtery to ArmTo intestine2Coronary ArterykidneyAtherosclerosis1Abdomen Aortadivides intoIliac Arteries to PelvisFemoral Arteryto Thigh and Legs41234Common Sites forAtherosclerosisFIGURE 10The heart and arteries.and 7). Blood is returned from the lungs to the left atriumvia the thin-walled pulmonary veins.The heart valves open and close to allow the heartchambers to fill with blood and to allow blood to beejected during systole or contraction of the heart. Theleaflets of the valves are smooth but may become thickenedby diseases such as rheumatic fever, which may lead toleaking or tight (stenotic) valves.D. Coronary ArteriesThere are two main coronary arteries, left and right, whichoriginate from the root of the aorta as it leaves the heart(see Figs. 5 and 8). Arteries are tubes which carry bloodfrom the heart. The channel within the tube is the lumenof the artery. The branches of the two main arteries carryoxygen and nutrients to the heart muscle and cells.As shown in Fig. 8, the coronary arteries run along theouter surface of the heart. The left main coronary arteryis very short, 0.2–4 cm, and divides almost immediatelyinto two branches. The first branch, called the anteriordescending artery, runs down the front surface of the heartnear the undersurface of the left margin of the breastbone.It supplies blood to a major portion of the left ventricle.The second branch, called the circumflex artery, circlesaround and feeds the back of the heart. The right coronaryartery leaves the aorta, veers sharply left, then is directedtoward the breastbone and curves downward to run alongthe border of the right ventricle. The right coronary arterysupplies branches to the electrical system, which involvesspecial cells that cause the heart to beat (the sinus node orpacemaker), and to the conducting bridge for electricaltransmission between the atrium and ventricle (atrioventricular(AV) node). The branches subdivide several timesand perforate the heart muscle at different points to bring

20ANATOMY OF THE HEART AND CIRCULATIONSuperior vena cavaExternal jugularInternal jugularBrachiocephalicSubclavianAxillaryInferior vena cavaHepatic veins from liverHepatic portal drainage to liverSuperior mesentericRenalTesticularCommon iliacInternal iliacExternal iliacCephalicBrachialBasilicMedian cubitalSplenicInferior mesentericRadialUlnarPalmarDigitalDeep femoralMiddle sacralFemoralGreat saphenousPoplitealSmall saphenousPeronealAnterior tibialPosterior tibialDorsal venous archDorsal digitalsFIGURE 11 Systemic veins. (Source: Gaudin, A.J., and Jones, K.C. (1989). ‘‘Human Anatomy and Physiology.’’ Harcourt Brace Jovanovich, San Diego,p. 598. Reproduced with permission.)nutrients to the muscle. These arteries have nothing todo with the blood flow inside the heart, which ispumped around the body. In addition, their internaldiameter is only about the size of a soda straw, thus, theyare easily obstructed. When the coronary arteries are completelyobstructed, a heart attack (myocardial infarction)results.Consider the heart as being supplied by four arteries,the left main coronary artery, the left anterior descending,the circumflex, and the right coronary artery (see Fig. 8).It is easy to visualize blockage of the left main coronaryartery as the most dangerous, as it would block offtwo major arteries. Fortunately, this occurrence israre. Most heart attacks block the right coronary artery,

II. CIRCULATION OF BLOOD21the anterior descending, and less common, the circumflexor smaller branches of all three arteries (see thechapters Heart Attacks and also Atherosclerosis/Atherothrombosis).II. CIRCULATION OF BLOODA. The Heart is a Simple PumpThe human heart is a muscular pump. Its function is topump blood containing oxygen, glucose, protein, fat, andsalts to every organ, tissue, and living cell of the body.The heart is divided into four chambers. The upperchambers are called the right and left atrium, and thelower chambers are called the right and left ventricles.Blood from all parts of the body drains into veins thatempty into the right atrium. Blood passes from the rightatrium through the tricuspid valve and reaches the rightventricle. During contraction of the right ventricle, bloodis pushed into the lungs where it gives off CO 2 , takes upoxygen, and returns via the pulmonary veins to the leftatrium (Fig. 4).During relaxation or diastole of the left ventricle, bloodpasses from the left atrium through the mitral valve(labeled bicuspid in Figs. 3 and 5) to reach the leftventricle. When the left ventricle contracts simultaneouslywith the right, about 70 ml of blood is ejected witheach heartbeat through the aortic valve into the aorta.The blood is then circulated through the branches of theaorta that form the arterial system supplying blood toorgans and tissues of the body.If the heart beats 70 times per minute, it produces anoutput from the heart of approximately 5 L of blood perminute. This is called the cardiac output. Each 70 mlof blood is propelled through approximately 100,000 kmof blood vessels. The heart beats about 2.5 billion timesduring an average lifespan, pumping more than 227million L of blood. Fortunately, the heart muscle is one ofthe strongest in the body. It can maintain efficient pumpingand life for more than 100 years provided the coronaryarteries that feed the muscle with blood do not becomeblocked by hardened plaques or a blood clot. Unfortunately,the coronary arteries are very narrow and are easilyobstructed by plaques containing cholesterol, calcium,and other constituents (see the chapter Atherosclerosis/Atherothrombosis).B. Systemic CirculationThe systemic circulation is the part of the vascular systemthat carries blood from the left ventricle to organs andtissues of the body. As outlined above, the aorta is themajor artery of the systemic circulation. It extends downthe length of the chest and abdomen and reaches the pelvisdividing into two branches, the iliac arteries (see Fig. 10).Veins collect blood from the capillaries of tissues andorgans (see Fig. 11). The large veins drain into the superiorand inferior vena cavae that return blood to the rightatrium.BIBLIOGRAPHYGaudin, A. J., and Jones, K. C. Human Anatomy and Physiology. HarcourtBrace Jovanovich, San Diego, 1989.

Anderson-Fabry DiseaseGLOSSARYhypertrophy increase in thickness of muscle.valvular pertaining to the heart valves.THIS DISEASE IS A RARE, INBORN X-LINKEDlysosomal storage disorder. The major substrate of thedeficient alpha-galactosidase A enzyme, globotriaosylceramide,accumulates in cells of the cardiovascularsystem. This leads to structural valvular abnormalitiesand enlargement of the heart with left ventricularhypertrophy, particularly in patients over age 40. Theheart muscle involvement includes cardiomyopathy, butit may be the only manifestation of this disease. Geneticabnormalities are X-linked and clinical manifestations infemale heterozygotes are rare. Serious clinical disease,fortunately, only affects less than 2% of heterozygousfemales.A new therapeutic strategy for treatment of lysosomalstorage diseases with enzyme replacement therapy hasbecome available.BIBLIOGRAPHYKampmann, C., Baehner, F., Whybra, C. et al. Cardiac manifestationsof Anderson Fabry disease in heterozygous females. J. Am. Coll.Cardiol., 40:1668–74, 2002.23

Anemia and the HeartI. Anemia and Heart FunctionII. Clinical StudiesGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiac dysfunction the normal function of the heart isreduced; abnormal heart function.creatinine breakdown of proteins excreted into the urine by thekidneys so that the composition in the bloodstream remainsrelatively constant.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%.heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hypotension marked decrease in systolic blood pressure,usually less than 95 mmHg (normal pressure range 100 to140 mm Hg)ischemia temporary lack of blood and oxygen to an area ofcells, for example, the heart muscle, usually due to severeobstruction of the artery supplying blood to this area of cells.myocardium the heart muscle.I. ANEMIA AND HEART FUNCTIONThe heart and the circulating system through arteries,veins, and capillaries must accomplish two goals: (1)delivery of oxygen and nutrients to organs and the peripheraltissues and (2) removal of metabolic waste productsthat accumulate throughout the body. Oxygen is carried byhemoglobin in red blood cells to the tissues. The normallevel of hemoglobin in circulating blood is 11.5–15.5 g/dl(115–155 g/L) in women and 15 to 17 g/dl in men.A normal structural heart with normal function cantolerate a hemoglobin of 7 g/dl for approximately one yearwithout causing cardiac damage or heart failure. Levels of6 g/dl or less may cause cardiac dysfunction after approximately6 months. In patients with angina, chest pain maybe precipitated because lack of oxygen to the myocardiumproduces myocardial ischemia that causes pain.Patients with sickle cell anemia commonly have ahemoglobin in the range of 7–8 g/dl. In these individualscardiac enlargement with dilation occurs early in thecourse of the disease. Because of the anemia and poordelivery of oxygen to tissues, cardiac output increases tocompensate and deliver the supply of nutrients. Thisentails more work for the heart. By age 40 these individualsmanifest symptoms of poor cardiac function.II. CLINICAL STUDIESStudy question: Mild anemia occurs commonly inpatients with heart failure, the detrimental effects of mildto moderate anemia on cardiac function and the effect ofcorrection has not been adequately addressed by controlledstudies. Many studies consider anemia to be a rareprecipitating cause of heart failure and of hospitalizationfor heart failure. Silverberg et al. studied the effect ofcorrecting anemia with erythropoietin (EPO) and intravenousiron.Methods: Patients (32) with moderate to severe heartfailure class III to IV, and left ventricular ejection fractionof less than 40%, despite optimal doses of heart failuremedications and with a hemoglobin level between 10and 11.5 g/dl were randomized. Group A receivedsubcutaneous EPO and intravenous iron to increase thehemoglobin level to >12.5 g/dl. Group B received notreatment for the anemia.Results: Over a mean follow up of 8 months, 4 patientsin group A died of heart failure. New York heartAssociation class improved by 42% in A and worsenedby 11% in B. The ejection fraction improved approximately5% in A and decreased approximately 5% in B.25

26ANEMIA AND THE HEARTThe serum creatinine did not change in A but increasedby 20% in B. Most important, the need for oral andintravenous furosemide decreased by 51 and 91%, respectively,in A, but increased 20%, respectively, in B. Lengthof hospital stay decreased significantly in A (79%), butincreased 57% in B.Horwich et al. analyzed a cohort of 1061 patients withsevere heart failure. The survival at one year was higher inpatients with increased hemoglobin levels. They concludedthat in chronic heart failure relatively mild degrees ofanemia are associated with worsened symptoms, functionalclass, and survival.Mozaffarian et al., using a prospective cohort design,evaluated the relationship between baseline serum hematocritand mortality among 1130 patients with a leftventricular ejection fraction less than 30% treated withACE inhibitors, diuretics, and digitalis. Follow up at 15months showed 407 deaths in those with a hematocrit of25–37%; these patients had a 52% higher risk of deathcompared with those with a normal hematocrit of 46–58%. In patients with severe heart failure, anemia is asignificant independent risk factor for death with a progressivelyhigher risk with increasing severity of anemia.The etiology, prevention, and treatment of anemia insevere heart failure require further investigation to improvesurvival rates.Correction of anemia in patients with heart failure hasbeen shown in this study to be most beneficial. Treatmentwith EPO and intravenous iron caused marked improvementin heart function and was associated with a significantreduction in hospitalization, renal impairment,and the need for diuretics. Correction of the anemiaalso enhances the standard therapy for heart failure.Silverberg et al. stated that it is surprising, judgingfrom the literature on heart failure, that such an obvioustreatment for improving heart failure is so rarelyconsidered.BIBLIOGRAPHYAnand, I., McMurray, J. J. V., Whitmore, J. et al. Anemia and itsrelationship to clinical outcome in heart failure. Circulation,110:149–154, 2004.Ezekowitz, J. A., McAlister, F. A., Armstrong, P. W. et al. Anemia iscommon in heart failure and is associated with poor outcomes:Insights from a cohort of 12,065 patients with new-onset heart failure.Circulation, 107:223–225, 2003.Horwich, T. B., Fonarow, G. C., Hamilton, M. A. et al. Anemia isassociated with worse symptoms, greater impairment in functionalcapacity and a significant increase in mortality in patients withadvanced heart failure. J. Am. Coll. Cardiol., 39:1780, 2002.Ishani, A., Weinhandl, E., Zhao, Z., Gilbertson, D. T., Collins, A. J.,Yusuf, S., Herzog, C. A. et al. Angiotensin-converting enzymeinhibitor as a risk factor for the development of anemia, and theimpact of incident anemia on mortality in patients with left ventriculardysfunction. JACC, 45:391–399.Mancini, D. M., Katz, S. D., Lang, C. C. et al. Effect of erythropoietin onexercise capacity in patients with moderate to severe chronic heartfailure. Circulation, 107:294–299, 2003.Mozaffarian, D., Nye, R., and Levy, W. C. Anemia predicts mortality insevere heart failure. J. Am. Coll. Cardiol., 41:19, 33–9, 2003.Schroecksnadel, Wirleitner, K. B., Fuchs, D. et al. Anemia and congestiveheart failureo response. Circulation, 108:41–42, 2003.Silverberg, D. S., Wexler, D., Sheps, D. et al. The effect of correctionof mild anemia in severe resistant congestive heart failure usingsubcutaneous erythropoietin and intravenous iron: A randomizedcontrolled study. J. Am. Coll. Cardiol., 37:1775, 2001.

AneurysmI. Abdominal Aortic AneurysmII. Thoracic Aortic AneurysmIII. Aortic DissectionIV. Berry AneurysmGLOSSARYaneurysm a ballooning of the wall of an artery or the heartcaused by severe weakening of the walls of the artery or theheart muscle.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow of blood; theplaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hypotension marked decrease in systolic blood pressure, usuallyless than 95 mmHg.intima the innermost lining of the vessel wall that is in contactwith flowing blood.media the middle wall of arteries.syncope temporary loss of consciousness caused by lack ofblood supply to the brain; fainting describes a simple syncopalattack.wall tension force exerted on the vessel or chamber wall actingto pull it apart in a circumferential direction; it is a function ofthe radius and the pressure within the lumen or chamber.THE LARGEST ARTERY IN THE BODY IS THEaorta, which takes blood from the heart and runs fromthe chest into the abdomen, lying against the spine untilit reaches the pelvis. It divides at that point into iliacarteries that supply blood to the pelvis, buttocks, and legs(see Fig. 1). Because the aorta takes the full force of bloodejected from the heart, it is the most likely artery in thebody to weaken.I. ABDOMINAL AORTIC ANEURYSMA. PathogenesisThe abdominal aorta is commonly affected by atheromaand the process of atherosclerosis (see chapter Atherosclerosis/Atherothrombosis).Atherosclerotic disease causesthickening of the intima. This thickening appears toreduce the diffusion of oxygen and nutrients from theaortic lumen to the strong middle wall of aorta. This causesdegeneration of the elastic elements and weakening of thewalls of the aorta. The elastic wall of the aorta may bestretched causing the vessel to dilate. Tension on thedilated aortic wall increases, thus, causing further expansionof the artery with aneurysmal formation. Tension inthe dilated vessel wall rises in accordance with Laplace’slaw, which states that wall tension is proportional to theproduct of pressure and radius; as the diameter of the aortaincreases its wall tension rises. The torrential blood flowimparts considerable hydrodynamic stress on the arterialwall, especially in the lower abdominal aorta.Most aneurysms occur in the abdomen just after theaorta branches to the kidney and before the aorta endsin its division into iliac arteries to the pelvis (see Fig. 1).Fortunately, aneurysms that occur before the aortabranches off to the kidney are rare; at this location repairof an aneurysm is fraught with danger as kidney failuremay occur. Other sites for aneurysmal formation are in thethoracic aorta, the iliac arteries in the pelvis, and thepopliteal artery at the back of the knee.Although hypertension, hyperlipidemia, and smokingare considered risk factors for the expansion of aneurysms,only smoking has been identified as a consistent risk factor;smoking increases the growth rate by 20–25%. Data froma study by Brady et al. including 1743 patients followedprospectively indicated that blood pressure and cholesterollevels did not predict the rate of expansion; aneurysmsexpanded significantly faster in current smokers than informer smokers. In addition, other studies indicated thatthe risk of rupture and the risk of death due to ruptureare higher among current smokers than among former27

28ANEURYSMCarotidArteryCoronaryArteryPlaque of atheromaAneurysmAbdominal Aortadivides intoIliac Arteriesto PelvisFIGURE 1Aneurysm.smokers and patients who never smoked by as much as afactor of 14 for smokers.Weakening of arteries may occur because of loss ofelasticity of the aortic wall due to aging. Another diseasethat affects the aortic wall is cystic medial necrosis, and thisappears histologically as smooth muscle cell necrosis anddegeneration of elastic layers within the media. The causeof the disease is unknown and mostly affects the thoracicaorta. Virtually all patients with Marfan syndrome developcystic medial necrosis disease and many, at a young age,develop aneurysms that occur mainly in the ascendingaorta, where the aorta originates from the heart.Studies indicate that there is a familial, genetic incidenceof abdominal aortic aneurysms. Screening of siblingsolder than 50 years of age of patients with aneurysmsrevealed an occult aneurysm in approximately 30% ofbrothers and less than 10% of sisters. The prevalence ofabdominal aortic aneurysms (3–6 cm) is approximately3 and 5% in individuals older than 55 and 65, respectively.The prevalence among men is about five times thatamong women. Studies suggest that one-time ultrasoundscreening of men at age 65 is sufficient to identify nearlyall those who are at risk. At this age men who have aorticdiameters less than 2.6 cm are all expected to be free fromsignificant aneurysm (less than 4 cm) 12 years later.B. Signs and SymptomsThe occurrence of abdominal aortic aneurysms is commonin men over age 55 and in women after age 70. Aneurysmsmay grow to more than 5 cm without causing symptomsand may go unnoticed by the individual. Abdominal aorticaneurysms, however, are not always asymptomatic. Backpain, abdominal pain, and particularly intermittent claudicationin men greater than age 65 may be the clue tothe presence of an abdominal aortic aneurysm. Selectivescreening for aneurysms in patients with intermittentclaudication nearly doubles the yield over screening in thegeneral population.The asymptomatic mass may be detected by deepmanual palpation of the central abdomen below or abovethe umbilicus. The majority of aneurysms are not detected

I. ABDOMINAL AORTIC ANEURYSM29by palpation and they are particularly obscured by bodyhabitus. Occasionally mild abdominal pain radiating tothe low back occurs. This mild pain usually has a constant,gnawing quality and may last for hours or days. Pain ofnew onset or progressive increase in the intensity of painmay indicate expansion of the aneurysm or impendingrupture. The rupture of an abdominal aneurysm is usuallyaccompanied by increasing severity of pain, lower bloodpressure, hypotension, and a pulsatile mass in the centralabdomen. The patient is usually anxious, sweaty, and indistress.A simple ultrasound of the abdomen detects allabdominal aneurysms and gives a good estimate of theirsize. Screening is recommended mainly in patients atrisk. The normal diameter of the aorta is 1.8–2 cm.Approximately 10% of men have an aortic diameter ofmore than 2.9 cm by age 65. An aneurysm is indicatedby an aortic diameter of 3 cm or greater. Aneurysms aresignificant when they are greater than 4 cm in diameterand from this stage must be followed closely every sixmonths with ultrasonography. A CT is even more accurateand can determine the size of aneurysms to within adiameter of 2 mm. Aneurysms more than 4 cm haveless than a 2% risk of rupture, but those larger than 5.5 cmhave a more than a 20% risk of rupture within 2 years;the risk is considered relatively low with aneurysms lessthan 5 cm.C. TreatmentPatients with aneurysms less than 4 cm are managedconservatively and should be given a beta-blocking drugthat reduces blood pressure and more important, decreasescardiac ejection velocity and hydrodynamic stress on thearterial wall. The systolic blood pressure should be keptlower than 140 mmHg, and diastolic less than 85 mmHgwith the use of a beta-blocker and other antihypertensiveagents. Propranolol should not be used in smokers becausethe drug is rendered ineffective.Aneurysmal repair is usually indicated when aneurysmsare greater than 5.5 cm because of the high risk of ruptureand an overall mortality rate of more than 80%. Only10–15% of patients survive the rupture. Patients whomanage to reach a hospital have a 50% mortality rate. Allvascular surgeons would recommend repair of aneurysms6 cm or larger.1. Surgical TreatmentRepair consists of opening of the aneurysm and insertinga synthetic prosthetic tube graft, usually fabricatedof Dacron or expanded polytetrafluoroethylene(Gore-Tex). Operative mortality is approximately 5%overall for effective repair, but it is less in low-risk patients.Operative mortality reaches 50% for repair of a rupturedaneurysm.2. Endovascular Stent GraftsDuring the past decade a noninvasive but costly technique,endovascular abdominal aortic aneurysm repair, has gainedsome acceptance following the first Russian descriptionof the experimental procedure in 1986. In 1991, Parodiintroduced this minimally invasive percutaneous approachused to exclude blood flow through abdominal aorticaneurysms. The bypass excludes blood flow through theaneurysm which shrinks over time, and the risk of ruptureis lessened. This technique involves minor surgery. Amodular, bifurcated endovascular graft is introducedthrough an artery in the leg and is advanced to occludeand bypass the aneurysm. Since Parodi’s description,several types of endovascular grafts have been tested inEurope and the United States with the Food and DrugAdministration’s (FDA) approval. The number of failuresindicates the preponderance of newer types of grafts.Endovascular graft deployment requires radiological andsurgical skills. A stent graft system is introduced throughthe femoral artery and either self- or balloon-expandingstents are used to trap a Dacron prosthesis with theproximal end precisely below the renal artery. Some devicesuse hooks and barbs to secure better fixation and preventdevice migration; stents in the wall facilitate fixation tothe iliac artery.This repair succeeds in excluding the aneurysm fromcirculation while allowing blood to flow through theprosthetic stent graft lumen to the distal aorta and iliacvessels to the legs. This represents a major breakthroughbecause many patients with aneurysms are elderly and haveother diseases, particularly prior heart attacks and heartfailure, which carry an increased risk for major surgicalintervention.Unfortunately, less than 50% of patients have aneurysmanatomy that is suitable for endovascular grafts. More than90% of females are rejected because of anatomical criteriathat include a smaller iliac artery diameter and aorticpathology, but the more common criteria is encroachmentof the aneurysm on the renal arteries. In addition, thereare several problems encountered that include a highincidence of endovascular leaks and approximately 5%of patients have aneurysms that continue to grow; 1%of patients may go on to rupture their aneurysm.Many devices have been introduced and have becomeobsolete within a couple of years because no engineer ormanufacturer has been able to resolve the issue of

30ANEURYSMendoleaks. Also biomaterial failure because of poor graftdesign leading to stent fractures, graft limb thrombosis,and iliac limb dislodgment may occur in modular grafts.The FDA issued a public health warning because of seriousadverse events that occurred with approved productsin 2002; a similar warning was given in the UK.At present there is no evidence from clinical trials thatthe risk of rupture of an aneurysm is reduced followingendovascular stent grafting. The risk of rupture is 1% peryear, similar to the risk in patients who have not undergonesurgery and are followed by ultrasonography. No largerandomized clinical trial has convincingly documentedthat this repair technique confers a mortality benefit eitherpreoperatively or long term compared to surgical repair.Most reports stem from single center, nonrandomizedstudies, but randomized trials comparing endovascularrepair with surgery are now in progress. This technologyrequires further refinement to be generally acceptable.When the refinements are made, it will be useful in theelderly and in patients with comorbid conditions who areat high risk for surgery.D. Clinical Studies1. Lederle et al.Study question: Does elective surgical repair of smallabdominal aneurysms improve survival?Methods: Patients 50–79 years old with abdominalaneurysms of 4–5.4 cm in diameter who did not have ahigh surgical risk (569 patients) underwent surveillance bymeans of ultrasonography or CT every six months withrepair reserved for aneurysms that became symptomatic orenlarged to 5.5 cm (567 patients).Results: After a mean of 4.9 years of follow up, deathfrom any cause in the two groups was not significantlydifferent. Trends in survival did not immediately favorany of the prespecified subgroups defined by age ordiameter of aneurysm of entry. These findings wereobtained despite a low total surgical mortality of 2.7%.Eleven patients, 0.6% a year, in the conservatively treatedgroup had rupture of aneurysms resulting in seven deaths.Conclusion: Survival is not improved by elective repairof abdominal aneurysms smaller than 5.5 cm, even whenoperative mortality is low.2. The UK Small Aneurysm Trial ParticipantsStudy question: Which therapy is best, immediate repairor surveillance of small abdominal aneurysms?Methods: In this study 1090 patients from age 60 to 76with small aneurysms of 4–5.5 cm were randomly assignedto undergo elective surgery or to undergo surveillance byultrasonography.Results: The mean duration of survival was not significantlydifferent: 6.5 years in the surveillance group versus6.7 years in the surgical group. The 30-day surgical mortalitywas 5.5%.Conclusions: Among patients with small abdominalaneurysms (< 5.5 cm), there appears to be no long-termdifference in mean survival between early surgery andsurveillance groups.II. THORACIC AORTIC ANEURYSMAneurysms of the aorta in the chest are much less commonthan abdominal aneurysms. They are classified as theascending, arch, or descending aortic aneurysms. Becauseof the etiology and natural history, treatment differs foreach of these aortic segments. Aneurysms of the descendingthoracic aorta are the most common and have similarcauses as those of abdominal aneurysms. Aneurysms ofthe descending aorta usually result from a cystic medialnecrosis; the etiology of which remains unknown. Also,cystic medial necrosis is observed in nearly all cases ofMarfan syndrome. Another rare connective tissue disorder,Ehlers-Danlos syndrome, may involve the aorta. Syphiliswas a common cause of ascending thoracic aneurysms,but is now rare because aggressive antibiotic therapy curesthe disease in its early stages. In these cases chest x-rayshowed typical linear calcification of the dilated ascendingthoracic aorta.A. Signs and SymptomsMore than 40% of patients are asymptomatic when firstdiagnosed mainly by routine chest radiography. A largeascending aortic aneurysm may compress the veins thatreturn blood from the head and neck to the heart via thesuperior vena cava. The aneurysm of the aortic arch ordescending aorta may compress the trachea and causecough, shortness of breath, wheezing, and hemoptysis.Posterior compression of the esophagus may cause difficultyin swallowing and compression of the recurrentlaryngeal nerve may produce hoarseness. Pain in the backand chest may occur; this is usually a constant deep, boringpain that can sometimes be severe.Diagnosis is usually obvious from the chest radiographyand aortography. A contrast-enhanced CT scan isaccurate in detecting and sizing thoracic aneurysms aswell as for monitoring growth. Magnetic resonance imaging(MRI) is also useful.

III. AORTIC DISSECTION31B. Treatment1. MedicalBecause surgical therapy carries a high mortality rate and isusually not advisable until ascending aneurysms are largerthan 5.5–6 cm or larger for descending aneurysms, medicaltreatment has an important role. A beta-blocking drug isstrongly recommended to reduce dP/dt and for the controlof blood pressure. Beta-blockers reduce cardiac ejectionvelocity and hydrodynamic stress. A randomized study of70 patients with Marfan syndrome treated with propranololversus no beta-blocker and monitored over a 10-yearperiod showed the following: the treated group showed asignificantly lower rate of aortic dilatation, aortic dissection,and aortic regurgitation; fewer deaths; aortic rootgreater than 6 cm; and significantly lower mortality ratesfrom the 4-year point onward. This study shows that bloodpressure must be aggressively controlled.2. SurgicalSignificant risks are associated with thoracic aortic surgery,particularly in the arch and descending aorta and surgeryis usually deferred for symptomatic patients or thosewith aneurysms greater than 6 cm. Aneurysms are usuallyresected and replaced with a prosthetic sleeve of appropriatesize. Postoperative complications include heartattacks, heart failure, stroke, renal failure, respiratoryfailure, and infection.skin is cold and clammy with impaired sensorium.Although the blood pressure may remain in the normalrange or sometimes be increased, hypotension may occurfrom external rupture; this is an ominous sign. Syncopeusually indicates a rupture into the pericardial sac withcardiac tamponade. A new loud aortic diastolic murmurmay be heard and the pulses may be lost in one ormore limb.The majority of patients with aortic dissection arehypertensive and older than 60. Normotensive youngerpatients usually have associated underlying disease of theaortic root that includes Marfan syndrome. This is aleading cause of aortic dissection in patients under 40.Other causes include giant cell arteritis, lupus erythematosus,Ehlers-Danlos syndrome, Noonan and Turner’ssyndrome, and relapsing polychondritis. Approximately15% of patients with coarctation of the aorta die fromaortic dissection.Urgent diagnosis is crucial. A clinical prediction studyindicates the following probabilities based on the threemost important diagnostic variables: (1)aortic pain withsudden onset, tearing or ripping character, or both; (2)widened mediastinum, aortic widening, or both; and (3)differential pulsations, differential blood pressure, orboth. The probability of dissection was high if isolatedpulse or blood pressures were found or all three variableswere present. Probability was intermediate with isolatedfindings of aortic pain or mediastinal widening. Theprobability of dissection was low with absence of allthree variables.III. AORTIC DISSECTIONAscending aortic aneurysms may undergo internal tearingor dissection resulting in an extremely high mortality ofup to 1% per minute and 60% in 60 minutes. Thus,time-consuming investigations that are not sufficientlysensitive or specific, such as CTscans, are usually not recommended.Emergency surgery carries the only hope of survivalfor patients with dissecting aneurysms, and immediateaccurate diagnosis is mandatory to guide therapy.A. Signs and SymptomsSudden onset of severe chest and interscapular pain iscommon in aortic dissection. The pain is sudden like agunshot, while heart attack pain builds up graduallyover several minutes. The pain is described as a tearingor ripping sensation that becomes rapidly unbearableresulting in a shock-like state. In this state the patient’sB. Diagnostic Testing1. Transesophageal EchocardiographyBecause of its low cost, accuracy, speed, and use at thebedside in very ill patients, further improvement indiagnostic features would likely establish transesophagealechocardiography (TEE) as the investigation of choice,especially in patients who are unstable and in hospitalswhere MRI is not available. The advantages of TEEinclude excellent sensitivity and specificity; rapid portability;the ability to be safely performed in critically illpatients including those on ventilators; and the ability todetect and quantify undefined mechanisms of aorticinsufficiency, the involvement of coronary orifices, pericardialeffusion, and the assessment of left ventricularfunction. The disadvantages include missing localizeddissection of the upper ascending aorta, not definingbranch vessel involvement, and the reverberation of artifactswhich can be misleading.

32ANEURYSM2. MRIMRI proved remarkably useful and safe even in unstablepatients with dissection in a blinded study by Nienhaberet al. In centers where new generation magnets areavailable, MRI may be the primary procedure of choice.New approaches to breath-hold magnetic resonanceangiography (MRA) allow rapid acquisition and producemarkedly improved images.3. New Generation CTSpiral or helical CT scan significantly reduces scanningtime, reduces respiration and motion artifact, and allowsmore images during peak levels of contrast enhancement.Newer scanners can image the entire aorta within secondsdisplaying three-dimensional images and appearing tohave a sensitivity and specificity comparable to that ofTEE and MRI.All three investigative methods, TEE, MRI, and CT,possess potential pitfalls in the evaluation of dissectionand are complimentary. Two imaging modalities may benecessary to correctly establish the diagnosis of this lifethreateningcondition.C. Management1. Urgent Medical ManagementUrgent medical management of aneurysm must be instituted.This includes immediate reduction in bloodpressure to 100–120 mmHg and elimination of pain.The force of left ventricular ejection (dP/dt), or ejectionvelocity, must also be reduced rapidly with the use of anintravenous beta-blocking drug such as esmolol, metoprolol,or propranolol. These agents are necessary evenwhen the blood pressure is in the low normal range of90–120 mmHg. If the blood pressure is severely elevated,labetalol, a beta-blocker with vasodilator activity, providesbetter control of the pressure and reduces dP/dt.2. Definitive Medical ManagementDefinitive medical therapy is indicated for uncomplicated,acute distal aortic dissection because survival rate in thisgroup of patients is greater than 90%. It is also indicatedfor stable, isolated arch dissection because surgery torepair the arch of the aorta is extremely difficult. Medicaltreatment is also advised for stable, uncomplicateddissection presenting more than two weeks after onsetof symptoms.3. Surgical ManagementSurgical risk is increased by age and the presence ofconcomitant diseases, particularly respiratory failure causedby severe chronic bronchitis and emphysema. Renal failure,cardiac tamponade, or cardiogenic shock also increasessurgical risk. Surgery is the treatment of choice for acuteproximal dissection, acute distal dissection complicated byrupture or impending rupture, and dissection in Marfansyndrome.IV. BERRY ANEURYSMA different type of aneurysm can occur at the base ofthe brain. The arteries at this site may have a developmentaldefect and form small berry-like aneurysms thatmay remain asymptomatic until a rupture occurs whenthe individual is between 20 and 50 years old. A subarachnoidhemorrhage at the base of the brain may damagethe brain substance and cause coma, death, or severedisability.These aneurysms may cause sudden intense headaches.Berry aneurysms are not related to high blood pressure,but coexisting hypertension may predispose them torupture. Patients with coarctation of the aorta or polycystickidney disease may have coexisting berry aneurysms, andthese individuals and family members should be screenedwith MRI. Fortunately, these aneurysms can be surgicallyclipped off prior to their rupture. A beta-blocking drugis useful during the perioperative period.BIBLIOGRAPHYAl-Omran, M., Verma, S., Lindsay, T. F., Richard, D., Weisel, Sternbach, Y.et al. Clinical decision making for endovascular repair of abdominalaortic aneurysm. Circulation, 110:e517–e523, 2004.Brady, A. R., Thompson, S. G., Greenhalgh, R. M. et al. Cardiovascularrisk factors and, abdominal aortic aneurysm expansion: Only smokingcounts. Br. J. Surg., 90:492–3, Abstract, 2003.Diethrich, E. B. Stent grafts for the treatment of abdominal aorticaneurysms. Am. Heart Hosp. J., 1:62–8, 2003.Ellegala, D. B., Day, A. L. et al. Ruptured cerebral aneurysms. N. Engl. J.Med., 352:121–124, 2005.Goldstein, S. A., and Lindsay, Jr., J. Aortic dissection: Non invasiveevaluation. Am. Coll. Cardiol. /ACC J. Rev. May/June 18, 2001.Isselbacher, E. M. et al. Thoracic and abdominal aortic aneurysms.Circulation, 111:816–828, 2005.Lederle, F. A., Wilson, S. E., Johnson, G. R. et al. For the AneurysmDetection and Management Veterans Affairs Cooperative Study

IV. BERRY ANEURYSM33Group. Immediate repair compared with surveillance of smallabdominal aortic aneurysms. N. Engl. J. Med., 346:1437–44, 2002.O’Gara, P. T. et al. Aortic aneurysm. Circulation, 107:e43–e45, 2003.Parodi, J. C., Palmaz, J. C., and Barone, H. D. Transfemoral intraluminalgraft implantation for abdominal aortic aneurysms. Ann. Vasc. Surg.,5:491–9, 1991.Powell, J. T., and Greenhalgh, R. M. Small abdominal aortic aneurysms.N. Engl. J. Med., 348:1895–1901, 2003.The United Kingdom Small Aneurysm Trial Participants. Longtermoutcomes of immediate repair compared with surveillanceof small abdominal aortic aneurysms. N. Engl. J. Med., 346:14,45–52, 2002.Upchurch, G. R., and Eagleton, M. J. Endovascular abdominal aorticaneurysm repair. J. Am. Coll. Cardiol. /ACC J. Rev. July/August1994–96, 2002.

AnginaI. Size of the ProblemII. PathophysiologyIII. DiagnosisIV. Disease Processes Causing AnginaV. Stable and Unstable AnginaVI. Nondrug TreatmentVII. Drug TreatmentVIII. HypertensionIX. Angina Patients with Heart FailureX. Silent IschemiaXI. Variant Angina (Prinzmetal’s Angina)XII. Unstable Angina/Acute Coronary SyndromeGLOSSARYafterload arterial impedance, restriction to blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of wall stress.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 50 to 75%; a lowejection fraction is less than 40%; often used as a markerof left ventricular contractility and function.electrocardiogram test used to diagnose myocardial infarction;EKG or ECG.heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.myocardium the heart muscle.palpitation rapid heart rate; the patient feels the heartbeat.preload the degree of ventricular muscle stretch present atthe onset of myocardial contraction; often expressed as enddiastolic volume or pressure.tachycardia increase in heart rate exceeding 100 beats perminute.PAIN OR DISCOMFORT IN THE CHEST, THROAT,jaw, or arms caused by severe, but temporary, lack of bloodand oxygen to a part of the heart muscle defines anginapectoris (see Fig. 1 in the chapter Heart Attacks). Angina iscaused by coronary artery disease (CAD) but often referredto as coronary heart disease (CHD). Because obstructivecoronary artery disease causes a lack of blood to reach theheart muscle (ischemia), the condition is also calledischemic heart disease (IHD). Angina affects men morecommonly than women, and the underlying disease conditionis not surprisingly referred to as ‘‘the widow-maker.’’I. SIZE OF THE PROBLEMAngina is caused by CAD. Atherosclerosis of the coronaryarteries causes obstruction to blood flow and deprivesthe heart muscle of blood. Obstructive atheroscleroticCAD leads to stable or unstable angina, fatal or nonfatalmyocardial infarction, sudden death, heart failure, arrhythmias,atrial fibrillation, and thromboembolism that maycause stroke. Approximately 15 million Americans haveCAD; approximately 7 million have angina and 8 millionhave had a heart attack. The approximate economic cost ofCAD and stroke in North America is approximately $350billion, with about $120 billion just for CAD.Although there has been a mild decrease in the incidenceof CAD in North America during the past decade, thedisease process and its complications are expected toincrease because of an aging population. Unfortunately,in developing countries the prevalence of CAD and itscomplications have increased in the past decade, andworldwide it is estimated that by 2025 cardiovasculardisease will reach epidemic proportions with approximately24 million deaths annually worldwide. Table 135

36ANGINATABLE 1Approximate [Rounded] Population and Incidence of Common Diseases and Death in 2020Population(Millions)Total deaths(Millions) CMPN InjuryNonCMPN,non CVDAllCVD IHD Stroke RHDOtherCVD1990World% Total deaths 5267 50.4 34.2 10.1 27.4 28.4 12.4 8.7 0.7 6.7EstME% Total deaths 798 7.12 6.4 6.2 42.8 44.6 23.4 11.1 0.3 12.0EmgME% Total deaths 346 3.8 5.6 10.3 29.5 54.6 27.1 16.9 0.7 10.0DevE% Total deaths 4124 39.5 41.9 10.7 24.3 23.0 9.0 7.5 0.7 5.72020World% Total deaths 7844 68.3 15.1 12.3 36.4 36.3 16.3 11.3 0.7 8.1EstME% Total deaths 905 8.6 6.2 5.2 46.3 42.3 22.5 10.6 0.2 9.1EmgME% Total deaths 365 4.8 2.9 8.6 34.8 53.7 27.0 16.3 0.5 9.9DevE% Total deaths 6573 54.8 17.6 13.7 34.9 33.8 14.3 10.9 0.8 12.1Note: EstMe ¼ established market economies USA, Canada, United Kingdom, Europe, Australia, and New Zealand;EmgMe ¼ emerging market ec ¼ Russian Federation, Ukraine [highest rates of CVD mortality];DevE ¼ developing ec ¼ China, India [1.2 billion], Asia, Africa, Latin America, Caribbean;CVD ¼ cardiovascular disease;CAD ¼ coronary artery disease;CPMN ¼ communicable maternal, perinatal, and nutritional.Modified from. Murray CJL, Lopez AD. The Global Burden of Disease, Cambridge MA: Harvard School of Public Health, 1996.gives the predicted (rounded) world population andincidence of common diseases and mortality rates.It is relevant that developing countries constitute morethan 80% of the world’s population and in theseregions, particularly in India and other Asian countries,the incidence of CAD is on the rise. The high incidenceof communicable, maternal, perinatal, and nutritionaldiseases in these countries will fall from approximately 41to 17%, but cardiovascular diseases will increase fromapproximately 20 to more than 33% over the next 20years. Japan is unique among the developed countries inthat although the stroke rates were the highest in the worldduring the 1960s, the incidence of stroke did not rise assharply as in other developed countries and has actuallyremained lower. In Japan cardiovascular disease rates havefallen more than 60% since the 1960s largely because ofa decrease in stroke rates. Life expectancy for men andwomen are the highest in the world reaching 77 years formen and 83 years for women.Table 2 shows cardiovascular and CAD mortality ratesper 100,000 people in some countries. Note the very lowmortality rates in France, Spain, and Italy, and the highrates in Finland, Scotland, Northern Ireland, and theUkraine.II. PATHOPHYSIOLOGYA. OverviewA high blood cholesterol and other factors including agenetic background, cause damage to arteries leading toblockage by atheroma. Obstruction by atheroma occursmost often in the coronary arteries that feed the heartmuscle with blood (see Fig. 1 in the chapter Heart Attacksand Fig. 1 in the chapter Atherosclerosis/Atherothrombosis).The heart muscle is one of the strongest in the body andas powerful as the muscles of the thigh and legs. The act of

II. PATHOPHYSIOLOGY37TABLE 2Cardiovascular and Coronary Artery Disease [CAD] Mortality per100,000 [Rounded]Country All causes CVD CHD StrokeEstablished Market EconomiesFranceMen 1361 330 142 67Women 552 122 36 35SpainMen 1323 399 181 93Women 578 180 52 57PortugalMen 1673 593 207 267Women 805 305 73 158FinlandMen 1691 834 631 110Women 1718 837 587 132ScotlandMen 1846 886 655 139Women 1103 441 273 107Economies in TransitionRussian FederationMen 2881 1343 767 409Women 1223 657 288 178UkraineMen 2940 1490 749 606Women 1379 830 342 408Note: Slovena has the lowest rates of the former Soviet and Eastern bloccountries: CVD mortality ¼ men 692, women300. Italy and Germanyhave low CVD mortality in men.walking or running requires contraction of the leg muscles.Such muscle work or activity requires efficient delivery ofoxygen, glucose, and other nutrients. These are broughtfrom the heart to the muscles by blood vessels calledarteries. The heart, our lifeline, functions as a simple pumpthat pumps more than 250 million liters of blood in anindividual’s average lifetime. It is surprising, therefore, thatthe muscle of this important pump receives a supply ofblood via only three small arteries that have a diameter ofa soda straw, ranging from 3 to 7 mm. The coronary arteriesrun along the surface of the heart and are branches of thelargest artery in the body, the aorta; the aorta commencesat the left ventricle, the main pumping chamber of theheart. In the chapter Anatomy of the Heart and Circulation,Fig. 8 shows the course of the coronary arteries andFigs. 5 and 9 show their origin close to the aortic valve.If the coronary arteries that feed the heart muscle withblood containing oxygen and nutrients become partiallyblocked, the muscle becomes painful when used. Thelack of blood to the heart muscle is called myocardialischemia, and it is typified by characteristic ECGfindings of ST-segment depression. (See the ECG inFigure 4.)As far back as the time of the Caesars, pain in the legsdue to obstruction of blood flow in arteries to the legswas labeled as intermittent claudication. The EmperorClaudius limped because of a painful leg, and the wordclaudication is derived from his name. Similarly, anginaoccurs because of a reduced blood supply.B. AtheromaAfter age 30 the coronary arteries become slowly obstructedby sludge consisting of cholesterol and smaller bloodparticles called platelets. The sludge forms a hardness, orplaque, which doctors call atheroma. These plaques bulgeinto the interior of the arteries, obstructing the freeflow of blood (see Fig. 1 and the chapter Atherosclerosis).The word atheroma is derived from the Greek ‘‘athere’’meaning porridge or gruel. When a plaque of atheroma iscut open, one can see a gelatinous, porridge-like materialwhich contains cholesterol. Fortunately, this porridge-likefatty material does not touch the blood that flows throughthe artery, because nature covers the fatty material with aprotective hard layer of cells called fibrous tissue. A plaqueof atheroma therefore consists of a central fatty core,covered by a fibrous cap (Fig. 1).Fibrous tissue is formed from special cells that areproduced everywhere in the body when a repair job isneeded; for example, a few days after a large cut or surgicalwound is stitched, fibrous tissue cells move in to form abridge, which transforms over the next few weeks into ascar. Some scars are smooth and some are bumpy andrough. Plaques of atheroma are also sometimes smooth orbumpy and rough. These tough scars in the inner wall ofthe arteries are perhaps nature’s way of patching andhealing. Because the vessel wall affected by atheroma getshardened and the medical word for hardness is sclerosis,the term used for this disease is atherosclerosis.Plaques of atheroma are most common in theabdominal aorta where it divides to form the vessels tothe pelvis and lower limbs, in the coronary arteries, inthe carotid arteries to the neck and brain, and in the vesselsof the lower limbs.When atherosclerosis in the coronary arteries causessymptoms, doctors use the term ‘‘atherosclerotic heartdisease,’’ coronary artery disease, or coronary heart disease(CHD). Many doctors use the term ischemic heart diseasebecause ischemia means a lack of blood and/or oxygen

38ANGINA2 413FIGURE 1 Obstruction of the coronary artery by plaques of atheroma that jut into the lumen and deprives the heart muscle of adequate bloodsupply ¼ myocardial ischemia manifested by chest pain [angina] and reflected on the ECG by characteristic ST segment depression. (1) Smooth lining ofvessel; (2) atheroma plaque filled with a variable amount of lipid material, foam cells and other substances [appearance of porridge-like gruel]; (3) a fibrouscap that may be firm and durable prevents rupture, or a thin fragile cap prone to rupture; and (4) rupture of the plaque initiatesthrombosis ¼ atherothrombosis. (From Khan, M. G., and Marriott, H. J. L. (1996). Heart Trouble Encyclopedia, p. 6, Toronto, Canada: StoddartPublishing Co.)caused by poor delivery of blood from arteries to the tissue.Angina, heart attacks, heart failure, and arrhythmias arethe main manifestations of CHD.C. Mechanism of PainWhen a coronary artery is severely obstructed with plaque,the heart muscle still receives an adequate amount ofoxygen when the heart is at rest and beating slowly at about72 beats per minute. During exertion or undue stress,however, the heart rate may increase from 72 to 90 or morebeats per minute. A faster heart rate entails more workfor the heart, which in turn requires more oxygen toaccomplish the work. The obstruction to the artery doesnot allow sufficient oxygenated blood to reach the heartmuscle. During those few moments, the lack of oxygencauses the heart muscle to become painful, and thissensation is perceived by the individual as pain or merelya mild but bothersome discomfort in the chest.Myocardial ischemia is a dynamic process. Three determinantsplay a major role in its pathogenesis:1. Obstruction of a coronary artery by atheroma occludesthe artery in a concentric process and is commonlyobserved in patients with stable angina, but in thosewith unstable angina the plaques are eccentric2. Increased myocardial oxygen demand by the vigorouslypumping heart muscle3. A release of catecholamine occurs at the onset of anginaand during the episode in most patients with stableangina; release of catecholamine may actually initiateischemia, which stimulates further catecholaminerelease, and the vicious circle perpetuates the lack ofoxygen by the myocardium, see Fig. 2This pathogenesis may manifest as the chest pain ofangina. Occasionally myocardial ischemia may occurwithout causing a sensation of chest pain; this conditionis called silent ischemia.When angina is present in an individual, it is certainthat at least one coronary artery will show a greater than70% obstruction or stenosis if a balloon angiogram is doneto visualize the coronary arteries. The obstructive plaque ofatheroma is often focal and usually occurs in the proximalportion of the coronary artery and not too distant fromthe origin of the aorta. Because the lesions are focal andproximal, they are easily reached with the balloon, whichdictates the success of angioplasty and bypass surgery.In some individuals and in many diabetics, lesions aremultifocal and longer with irregularities that produce adiffuse disease that is more difficult to treat with angioplasty,stents, or bypass surgery. A 25% decrease in theouter radius of a normal coronary artery results in abouta 60% decrease in a cross-sectional area. In an artery with75% stenosis, a 10% decrease in the outer radius wouldproduce a complete occlusion.During periods of exercise or exertion, catecholaminerelease causes an increase in heart rate, and an increase inthe velocity and force of myocardial contraction producesan elevation in blood pressure and an increase in myocardialoxygen demand. In the presence of significant coronaryartery stenosis, an oxygen deficit occurs. Myocardialischemia increases catecholamine release, resulting inan additional increase in heart rate and blood pressure

III. DIAGNOSIS39Exertional or emotional activity(Vicluous circle): StimulatesCatecholaminereleaseCoronary stenosesCoronary bloodflowDiastolic fillingperiodHeart rateForce and velocity cardiaccontractionblood pressureMyocardial oxygen supplyMyocardial oxygen demadMyocardial ischemiaFIGURE 2Pathophysiology of angina. ", increase; #, decrease.with further oxygen lack, and the vicious circle ensues(Fig. 2). In addition the coronary arteries fill during thediastolic period, which is shortened during an increase inheart rate.Fortunately, no damage happens to the heart muscleduring an attack of angina. Full recovery occurs withinminutes of the attack. Many patients have several episodesof this fleeting pain or discomfort a few times monthly forover 15 years and learn to cope with the minor restrictionsto their lifestyle. In some individuals, angina that is wellcontrolled or stable worsens causing unstable angina thatrequires special therapy; some patients go on to have heartattacks.III. DIAGNOSISA. Pain Pattern1. LocationThe pain of angina is usually felt in the center of the chestover the breastbone, and only rarely over the breasts (seeFig. 3 in the chapter Heart Attacks). Pain in the lower jawaccompanied by pain in the chest or arms during a walk orstrenuous activity is nearly always due to angina, especiallyif these symptoms recur during similar activities.Sometimes the discomfort is only in the upper arm with atingling feeling in the fingers; this pain comes mainlyon exertion as opposed to pain produced, for example,by a pinched nerve. A pinched nerve will cause similardiscomfort in the arms and fingers when the individualis at rest, but an activity, such as walking, makes littledifference.2. Severity and CharacterThe pain of angina may be mild to moderate and onlyoccasionally severe. Often it is just discomfort. Theindividual may even refuse to use the word pain to describethe peculiar sensation that feels like a tightness or aheavy weight on the breastbone. To some it is a burningsensation; to others it is a feeling of strangulation orsuffocation that fortunately disappears within one to five

40ANGINAminutes of rest, either with the individual standing orsitting. The pain of angina rarely lasts more than 10minutes. If an individual has pain similar to that describedand lasts more than 15 minutes, the patient should taketwo or three soft, chewable aspirins (80 mg each) and goimmediately to a hospital emergency room.William Heberden, in 1768 gave a detailed descriptionof a peculiar type of chest discomfort suffered by hispatients causing him to adopt the term ‘‘angina pectoris.’’His description was most appropriate.There is a disorder of the breasts marked with strongand peculiar symptoms, considerable for the kind ofdanger belonging to it, and not extremely rare whichdeserves to be mentioned more at length. The site of it,and the sense of strangling and anxiety with which it isattended, may make it not improperly called anginapectoris.They who are affected with it are seized whilethey are walking (more especially if it be uphill, andsoon after eating) with a painful and most disagreeablesensation in the breasts, which seems as if it were toextinguish life, if it were to increase or continue;but the moment they stand still, all this uneasinessvanishes.In all other respects, the patients are, at thebeginning of this disorder, perfectly well, and inparticular have no shortness of breath, from which itis totally different. The pain is sometimes situated in theupper part, sometimes in the middle, sometimes at thebottom of the breastbone, and often more inclined to theleft than to the right. It likewise very frequently extendsfrom the breasts to the middle of the left arm.Heberden recognized that the pain of angina always gotbetter within a minute or so after the precipitating activitywas stopped. For example, the individual might be quitewell, but on walking up an incline, especially againstthe wind, he or she developed discomfort in the chest.If the individual stopped the walk immediately and resteda minute, thus allowing the heart work to decrease, thediscomfort disappeared immediately.This concept of oxygen supply versus its demand by theheart muscle is the hallmark of angina. Make a long list ofwhat precipitates the pain and what relieves it, but the oneimportant clue to help the diagnosis is that the pain ordiscomfort is precipitated by a particular activity and,once the activity is stopped, the pain disappears withinminutes.B. Activities that Precipitate AnginaThese precipitating activities include:1. Walking up a hill2. Walking against the wind3. Running with some associated anxiety for a bus or to aplace, especially while carrying a bag; anxiety is mademore profound if the individual is late and must rush,thus, there is exertion and emotional stress4. A brisk walk or similar exertion soon after eating; thisdoes not include bending and stooping, which canprecipitate indigestion5. Unaccustomed exertion6. Emotional distress; for example, bad news, a scare,anger, rage, nightmares, etc.7. Pain may occur during overwhelming excitement; forexample, watching your team playing football, hockey,baseball, basketball, and similar exciting programsMost important, relief of pain in an individual withstable angina always occurs within minutes of cessation ofthe precipitating exertional or emotional activity. Reliefwith nitroglycerin occurs promptly within one to twominutes.IV. DISEASE PROCESSES CAUSINGANGINAAtherosclerosis Atheroma is the main cause of obstructionof coronary arteries and accounts for more than 90% ofcases of angina and coronary artery disease.Coronary artery spasm (variant angina) — This isa rare cause of angina in which spasm of the coronaryartery occurs often without identifiable stimuli. Thiscondition, also called Prinzmetal’s variant angina, ismore common in the Mediterranean and Italian population.In some patients, exposure to cold, smoking,emotional stress, aspirin ingestion, or cocaine use maytrigger coronary spasm. The coronary spasm is usuallyrelieved by nitroglycerin, nitrates, and calcium antagonists,and discontinuation of these medications may causeworsening of spasm. Beta-blocking drugs may increasecoronary artery spasm. The clinical hallmarks of coronaryartery spasm include pain usually occurring at rest, oftenduring sleep and described as chronic angina at rest, anECG during pain showing elevation of the ST segmentwhich is normalized by the use of nitroglycerin. The STsegment returns to normal on cessation of pain caused bycoronary spasm.

V. STABLE AND UNSTABLE ANGINA41Anomalous coronary artery — This rare occurrencemay go undetected, see the chapter Congenital HeartDisease.Aortic stenosis — Obstruction of blood flow from theleft ventricle through the aortic valve into the aorta may beimpeded by a tight stenotic valve. This severe obstructionto blood flow imposes a severe workload on the leftventricular myocardium that requires a greater demandfor oxygen. If the coronary arteries are mildly affectedby atheromatous obstruction, then angina occurs muchearlier than expected. Angina occurring in patients withsevere aortic stenosis carries a poor prognosis and requiressurgical intervention.Hypertrophic cardiomyopathy — The thickenedand severely hypertrophied left ventricular myocardiumrequires more oxygen and the supply may be outstrippedby the demand (see the chapter Cardiomyopathy).Severe anemia — In patients with moderate atheromatousobstructive disease severe anemia or loss of bloodcan further deprive the myocardium of blood and oxygen;this can precipitate angina or myocardial infarction.Kawasaki disease — In this rare disease of childhoodcoronary artery aneurysms occur and chest pain caused byangina may be bothersome (see the chapter KawasakiHeart Disease).Giant cell arteritis — This rare diseases of the walls ofthe artery, in particular the temporal artery, may affect thecoronary arteries. This process is called a vasculitis.Chemotherapeutic agents — The chemotherapeuticagent 5-fluorouracil is known to cause coronary arteryspasm in some patients that may lead to symptoms ofangina and occasionally myocardial infarction (see thechapter Chemotherapy-Induced Heart Disease).Syndrome X — This rare syndrome appears to affectmainly women, and in these patients angina-like symptomsmay occur in the presence of normal coronaryarteries. There is no evidence of obstruction or spasm inthese patients, and the exact cause for pain remainsobscure.V. STABLE AND UNSTABLE ANGINAThere are two types of angina: stable and unstable. Anginais described as stable if the condition has been present formore than two months, or if there has been no change inthe pattern of pain, particularly no change in the frequencyof attacks, severity, or duration of pain. Patients with stableangina only get pain at rest with sudden emotional stress.Angina is described as unstable when angina is present forless than 60 days, or when there is an increase in thefrequency, severity, and duration of pain and a change inthe known precipitating factors. If pain that normallyoccurs only on exertion or moderate activities starts tooccur on minimal activity or at rest but without emotionalstress, a patient should seek urgent attention in theemergency room.A. Case HistoryA 54-year-old man was late for a job interview. With somedifficulty, he found a parking space. It was a very cold andwindy January day, and he walked quickly for about twohundred yards toward the building. Suddenly, he felt astrange sensation in his chest. He kept on walking, butabout a minute later the discomfort felt like a heavy weighton his breastbone. His chest felt tight as he reached thebuilding, and he rested against the wall. He took a fewdeep breaths and felt better after about one minute. Hehad his job interview without any further discomfort andremained pain-free until a few months later when, whilewalking up an incline, he felt a similar pain. Again he hadto stop for a minute or two to get relief from the strangefeeling of suffocation or strangulation that accompaniedthe tight feeling in his upper chest. The next day he wasable to walk about a mile at a normal pace on a level gradewithout chest discomfort. A few days later he went golfing.During the first nine holes he felt well and had no chestdiscomfort, but walking upslope on the long 11 hole, hefelt pressure in his chest, a tightness across the shoulder,and a heaviness in his arms. He stopped pulling his golfcart and stood still for a minute. Somewhat embarrassedfor holding up the game, he searched his golf bag for someantacid tablets but, as he opened the package, he noticedthe pain had completely gone. He felt well that night.The next day when he walked quickly the discomfortreturned. His wife insisted on a visit to the doctor. Thedoctor found him to be slightly overweight with a normalECG reading. He was given nitroglycerin to be used underthe tongue and an oral nitrate called isosorbide dinitratein tablet form to help dilate the coronary arteries andrelieve pain.During the next three months, the man suffered fromsevere headaches that lasted a couple of hours after takinghis medication. His chest discomfort did not get worse,but his wife insisted on a referral to a cardiologist. Thecardiologist confirmed the diagnosis of stable angina andrecommended that the man follow a weight-reducing,low-cholesterol, low-saturated fat diet and that he stopsmoking. The cardiologist discontinued the oral nitrate

42ANGINAdrug and replaced it with timolol, a beta-blocking drug,which produced further relief of chest pain during thenext year.B. Tests Required to Confirm Diagnosis1. Resting ECGThe resting ECG may be normal in patients with angina,but during pain an ECG virtually always shows abnormalities.The ECG is the test most frequently used todiagnose angina, and it is the only test that can confirm theearly diagnosis of a myocardial infarction. The ECG showspositive abnormalities hours before damage to the heartmuscle is revealed by the tests for cardiac enzymes(troponins and CK–MB). In individuals with suspectedCHD, a baseline ECG that is normal or shows mildabnormalities can be used for comparison with futureECGs. A normal ECG is shown in Fig. 3. Duringmyocardial ischemia (angina), a diagnostic ECG findingshows a greater than 0.05-mm depression of the STsegment (see Fig. 4).2. Exercise Stress TestA treadmill exercise test using the Bruce protocol is usedworldwide to detect myocardial ischemia that is precipitatedby exercise. The ECG tracing during exerciseinducedischemia shows typical features that can be easilyrecognized. Although the test is of little value in screeningasymptomatic patients who are at low risk for CAD,it is most useful for patients who are symptomatic.False-positive tests are not uncommon in women.3. Cardiac Nuclear ScansCardiac nuclear scans performed following treadmillexercise or during myocardial-induced ischemia provokedby dipyridamole, adenosine, or dobutamine are particularlyuseful. These tests are not sufficiently sensitive orspecific, however, and further technologic advances arenecessary. Despite the use of these scans for more than 30years, further sophistication is necessary. There is roomhere for further research and development particularlybecause these tests are widely used and are often inaccurate.4. Coronary AngiogramsFor some patients, coronary arteriography may berequired. Arteriography is the gold standard for detectingobstruction of coronary arteries by atheroma. The exactsite and location of the obstruction can be identified forinterventional therapy with balloon angioplasty, stentimplantation, or bypass surgery. For a further descriptionof tests, see the chapter Tests for Heart Diseases.VI. NONDRUG TREATMENTA. Weight Reduction EffectsIf you have angina and you lose 10–25 lb, you willcertainly experience less pain, you will require a smallerdose of antianginal medication, and you may not requireangioplasty or surgery.Weight reduction, relief of stress, a low-saturated fatdiet, and avoidance of smoking are the most importantnondrug treatments for patients with angina. Weight lossdepends on eating less calories and burning off moreFIGURE 3Normal ECG.

VI. NONDRUG TREATMENT43FIGURE 4A. Abnormal ECG. B. Marked ST depressions and wave inversion anterior myocardial and left ventricular.calories during exercise. A combination of a low-caloriediet with some form of exercise program that increasescaloric expenditure must be followed, otherwise theweight gain that often occurs after stopping a low-caloriediet will ensue. All diets that are proven to cause weightloss over a period of years depend on reduced intake ofcalories. Calories do count, do not let anyone tell youotherwise.Weight loss occurs with reduction of calorie intake toless than 1000 calories daily and exercise to burn off morecalories. A meal should contain a moderate amount ofprotein, but a low-saturated fat content. Reduce yourintake of high-calorie foods containing refined sugars orstarches. A greater than 75% decrease in the usualconsumption of all products derived from wheat flour,potatoes, and rice along with 40 minutes of exercise daily isguaranteed to cause significant weight loss.Fish three times weekly, even canned tuna, salmon,sardines, and herring, will help to reduce the saturated fatin the diet. Many individuals may stick to these rules, butforget that alcohol, both mixes and beer, are high incalories. Avoid fast foods because they often high in

44ANGINAcalories and salt. An increase in salt increases the work ofthe heart muscle and puts a strain on the heart, which canlead to heart failure and shortness of breath. Thus, patientswith high blood pressure, heart failure, and angina areadvised to follow a low-salt diet.Lack of motivation often results in a failure to reduceweight. It is a tough battle for most overweight individualsto fight on their own, and success is more often obtainedby joining a weight-loss program or clinic. We stronglyadvise you to consult your physician or to contact yourHeart and Stroke Association for recommended publicationson weight loss. The Mediterranean style diet iscardioprotective and strongly recommended, see chaptersDiets and Heart Disease and Dyslipidemia.B. ExerciseWhat about exercise and angina? An exercise stress testusing a treadmill or bicycle under the supervision of aphysician should provide the answer to the question:‘‘How much exercise is safe for me?’’ Usually, a safe level ofexercise is that which will bring on only mild discomfort ormild shortness of breath. You should slow down for a fewseconds then stop for a minute or so before continuing theactivity (such as a quarter- or half-mile walk). Stretchingexercises and walking — including climbing two or threeflights of stairs daily — will improve your muscle tone.Exercise alone, however, cannot remove the obstructioncaused by plaques in arteries. Patients with angina do notjog because this activity often precipitates pain. For moreinformation, see the chapter Exercise and the Heart.C. SmokingNonsmoking men are 10 times less likely to have a fatal ornonfatal heart attack than heavy smokers. Sudden deathby heart attack is more common in heavy smokers thanin nonsmokers. Drugs that are effective in preventingangina and death lose their effectiveness in smokersbecause the by-products of cigarettes interfere with thebreakdown of the drugs in the liver. These drugs includethe frequently used beta-blocker propranolol and calciumantagonists such as nifedipine. Also, bypass grafts becomeblocked within a few years of bypass surgery in patientswho continue to smoke. If you have angina and chronicbronchitis, cigarette smoking will cause an increase inshortness of breath.Women between the ages of 35 and 50 who havefunctioning ovaries rarely suffer from angina or have heartattacks. Women who smoke and have an elevated bloodcholesterol level, unfortunately, increase their risk of havinga heart attack and angina prior to age 50.Perhaps, rather than quitting, changing to a differentbrand of cigarettes is considered. The bad news is thatfilter cigarettes and low-nicotine or low-tar brands ofcigarettes do not decrease the risk of heart attacks. In fact,filter cigarettes deliver more carbon monoxide to thesmoker’s system and cause more heart attacks than plaincigarettes.The oxygen supply to the heart muscle is low in patientswith angina. Angina patients who are smokers experiencepain at lower levels of exercise. Nicotine causes a slightincrease in the heart rate and a rise in blood pressure;therefore, the heart muscle demands more oxygen. Carbonmonoxide delivered from cigarettes steals oxygen awayfrom the heart muscle, which is already deprived ofoxygen. So the combination of carbon monoxide andnicotine is bad news. Regardless of the present conditionof your heart, do yourself a favor and quit smoking.Still, how do you stop smoking? It is easier said thandone. The first step is motivation. Consider the facts. Thedangers of carbon monoxide are well known. You wouldn’tstand around inhaling exhaust fumes from a car, especiallyif its engine was running in an enclosed garage; youknow that that situation would cause death. Yet, we haveinformation today that proves heavy cigarette smokers areexposed to eight times the level of carbon monoxideconsidered safe in industry, and it has been proven thatheavy cigarette smoking is a cause of heart attacks andsudden death.The addiction to nicotine is so powerful that nothingwill help if the smoker is not motivated to quit. Evenbronchitic patients continue to smoke because the addictionto nicotine is so great. To help you to quit smoking,enlist the assistance of stop smoking clinics; even hypnosisis a viable alternative. The American Cancer Society andthe National Cancer Institute provide several types ofprograms to help smokers quit. Local cancer societiesusually provide a list of programs that can help. Consulta physician for advice on nicotine tablets, patch, gum,or nasal spray. Most smokers who cannot motivatethemselves. Get help now!D. L-ArginineArginine increases nitric oxide availability in the arterialwall and this causes vasodilation and increases blood flow.Some clinical trials indicate modest improvement inangina symptoms with its use, but they are not consistent.Arginine is found in many foods and an arginine food baris also available.

VII. DRUG TREATMENT45VII. DRUG TREATMENTIn patients with stable angina treatment with drugs usuallyproduces about a 75% improvement in symptoms andquality of life. Three groups of drugs are usually employed:nitrates, beta-blockers, and calcium blockers (calciumantagonists). Aspirin is added to prevent coronary thrombosiswhich causes heart attacks.A. NitratesAngina sufferers are advised by their doctor to always carrynitroglycerin, even if the requirement is only two pillsa year. Nitroglycerin is a nitrate that is used under thetongue or in tablet or spray form. The tablets should bekept in a dark bottle and not in a pill box, because openingthe box lets in light, which will destroy the effectivenessof the drug within a few weeks. Remove the cotton woolfrom the bottle so the pills can be easily reached when ina hurry. Leave the cotton wool in a stock bottle kept in therefrigerator; these tablets will maintain their strength formore than one year. Tablets in a bottle that is opened oftenshould be good for three months.Oral isosorbide dinitrateHepatic metabolismMononitrate (ONO 2 )ONO 2Nitirc oxide (NO)SH* radiclesStimulatesGuanylate cyclaseConvertsGuanosine triphosphatetoCyclic guanosinemonophosphateCyclic (GMP)Lowers intracullularcalciumIsosorbidemononitrateMyocyte(vessel wall)1. Mechanism of ActionNitroglycerin dilates the veins, especially those in the lowerhalf of the body. Blood stays in these enlarged veinsand less blood reaches the heart. The heart then has lessblood to pump and the muscle works less, thus requiringless oxygen, and, as a result, the pain is relieved. Themechanism of action of nitrates and nitrate tolerance isillustrated in Fig. 5.Nitroglycerin tablets will work best if the lower half ofthe body is kept much lower than the head, that is, it isbetter to sit than to lie flat after taking them. You mayremain propped up in bed. Nitroglycerin causes expansionor dilatation of the blood vessels in the scalp, and thiseffect may produce a headache. The headache is not due toan increase in blood pressure; in fact, nitroglycerin dilatesthe arteries slightly and this causes a small fall in bloodpressure. Therefore, be careful not to take more than twodoses of nitroglycerin and not to walk right away. Unlessyou are accustomed to the dosage, you may become dizzyor feel faint and fall.Nitrate tablets that are swallowed are the oldestpreparations available in the treatment of angina. Thesedrugs are low in cost and have no serious side effects. Theycause frequent headaches, however, and are less effectivethan beta-blockers.Relaxation of vascular smooth muscle,vasodilation: maximal veins,minimal arteries at usual dosesFIGURE 5 Nitrates’ mechanism of action. * SH, sulfhydryl radiclesrequired for formation of NO, oxidized by excess exposure to nitratesbecome depleted. Leading to nitrate tolerance.a. Nitroglycerin—Glyceryl TrinitrateSupplied: Sublingual nitroglycerin tablets: 0.15 mg,0.3 mg, and 0.6 mg. Sublingual glyceryl trinitratetablets: 300 mg, 500 mg, and 600 mg. Also available asNitrolingual spray.Dosage: Patients are usually advised to start with 0.3mg. The tablet is placed under the tongue with the patientseated. The drug will not be as effective if the patient islying down, and if the patient is standing, dizziness orfaintness may occur. Thereafter, the usual prescribed doseis 0.3 mg or 0.6 mg of nitroglycerin or 500–600 mg ofglyceryl trinitrate.b. Cutaneous Nitroglycerins (Patches)Supplied: Comes as paste or ointment, which must not bemassaged into the skin. Slow-release cutaneous preparationsin the form of adhesive patches are clean and dry and

46ANGINATABLE 3NitratesGeneric sublingual Trade name or available as a Supplied and dosage bNitroglycerin Nitroglycerin 0.15, 0.3, 0.4, 0.6 mg (USA)Nitrostat0.3, 0.6 mg (C) cNitrostablin600 mg (C)Nitrolingual sprayMetered dose of 0.4 mgGlyceryl trinitrate (UK) Glyceryl trinitrate GTN 300, 500, 600 mgCoro-nitro spray400 mg/metered doseNitrolingual spray oral400 mg/metered doseNitroglycerin oral tablets Nitrong SR 2.6 mg (USA, C)Nitrostat SR, Nitrobid7 AM, 2PMBuccal tablets Nitrogard (USA) 1, 2, 3 mgSusadrin (USA)1, 2, 3 mgNitrogard SR (C)1, 2, 3 mgSuscard (UK)1, 2, 3, 5 mgIsosorbide dinitrate oral, tablets Isosorbide dinitrate 10, 20, 30, 40 mg (USA)10, 20, 30 mg (UK)10, 30 mg (C)Isordil10, 20, 30, 40 mg (USA)10, 30 mg (UK)10, 30 mg (C)Cedocard 10,10, 20 mg (UK)Cedocard 20,Cedocard Retard20 mgIsordil Tembids40 mg capsulesSorbitrate10, 20 mg (USA, UK)Isosorbide mononitrate Isosorbide mononitrate 20 mgElantan 2020 mgElantan 4040 mgIsmo20 mg b. i. d.,, 7 h apartImdur60–120 mg once dailya Several other trade names available.b For dosage see text.c C, Canada.can be used once daily. The paste or ointment starts towork in 30–60 minutes and lasts from 4 to a maximum of6 hours. The long-acting adhesive patches last from 16 to20 hours and must be removed every 12 h. The skinpreparations should not be applied to the forearms, hands,or lower legs, because it takes longer for the drug to reachthe general circulation. These preparations are usefulduring dental work and for minor or major surgery inpatients with CHD.Dosage: Skin preparations should be used only for 2–14days. These drugs are not meant to be used for more thana few weeks except if other drug therapy or surgicalintervention is inappropriate. They are less active if usedfor more than 12 h daily because of nitrate tolerance. Inaddition, these preparations must not be stopped suddenly;for example, after using them for a few weeks, the doseshould be tapered and reduced slowly over the next one totwo days. In some patients, when the drugs are stoppedsuddenly, angina can become worse. These preparationsare applied for 12 hand taken off for 12 h. Various nitratepreparations are listed in Table 3.c. Isosorbide Dinitrate (Isordil)Supplied: Sublingual tablets to be dissolved under thetongue: 5 mg. Tablets for oral use: 10 mg, 20 mg, and 30mg. Prolonged-action tablets: 40 mg. Prolonged-actioncapsules: 40 mg.

VII. DRUG TREATMENT47Dosage: A sublingual 5-mg tablet is dissolved underthe tongue before an activity known to produce chestdiscomfort. The 10-mg tablet is swallowed three timesdaily on an empty stomach, for example, one hour beforemeals. If headaches are not too severe, the drug can beincreased to 15 mg three times daily for a few days orweeks, then 30 mg three times daily. The prolonged-action40 mg preparation is taken once or twice daily. Nitratesare more effective taken at 7 a.m., 12 p.m., and 5 p.m.The 12-h gap without nitrates prevents the bodyfrom developing tolerance, which destroys the drug’seffectiveness.Advice and adverse effects: The sublingual 5-mgtablets take three to five minutes to become effective,somewhat longer than nitroglycerin; therefore, patients areadvised to use nitroglycerin during an attack of angina.The drug’s effect lasts from 20 to 60 minutes. Nitratescause headaches and dizziness. They should not be used asfirst choice in the treatment of angina pectoris, especiallysince beta-blockers have proven to be effective and reliable.In addition, beta-blockers can prevent death or favorablyalter the outcome of a heart attack. The use of oral nitrates,therefore, makes sense in patients who cannot take or donot respond to beta-blockers.d. Isosorbide Mononitrate (Imdur)Supplied: The 5-mononitrate of isosorbide dinitrate hasbecome available.Dosage: It is to be taken 20 mg after meals at 7 a.m. and2 p.m. daily.Maintenance: 20–40 mg twice daily. Imdur can betaken 60–120 mg once daily at 7 a.m.B. Beta-Blockers1. ActionsBeta-blockers are a group of drugs that reduce the action ofadrenaline (epinephrine) on the heart and arteries. Betablockersdecrease the heart rate so the pulse falls froma resting level of about 72 beats per minute to a range of50–60 beats per minute. Second, they reduce bloodpressure and third, they cause the heart muscle to contractless forcefully. All three effects cause the heart muscle torequire less oxygen, thus preventing angina.Beta-blockers block the effects of the stimulant stresshormones adrenaline and noradrenaline at the so-calledbeta-receptor sites present on the surface of cells in theheart and in arterial blood vessels. They therefore preventthe increase in heart rate, the force of heart musclecontraction, and the rise in blood pressure normallyproduced by these stimulants.Beta-blockers are recommended as a first-line oral drugtreatment in the management of angina pectoris. Table 4emphasizes the rationale for the use of beta-blocking drugsas first-line agents versus that of calcium antagonists andoral nitrates.In patients with angina, at least one coronary artery hasa block greater than 75%. At rest, sufficient blood reachesthe heart muscle; however, during moderate activities, theheart rate and blood pressure increase and the heart musclecontracts more forcefully to do the work because moreTABLE 4Beta-Blocker: First-Line Oral Drug Treatment in Angina PectorisEffect on Beta-blocker Calcium antagonist Oral nitrateHeart rate # "# "Diastolic filling of coronary arteries " — —Blood pressure ## ## —Rate pressure product # — a —Relief of angina Yes Yes VariableBlood flow (subendocardial ischemic area) b " # VariableFirst-line treatment for angina pectoris Yes No NoPrevention of recurrent ventricular fibrillation Proven No NoPrevention of cardiac death Proven No NoPrevention of pain from coronary artery spasm No Yes VariablePrevention of death in patient with coronary artery spasm No No Noa RPP variable decrease on exercise, but not significant at rest or on maximal exerciseb Distal to organic obstructionNote: #, decrease; ", increase; —, no significant change.From Khan, M. Gabriel. Cardiac Drug Therapy, sixth edition, Philadelphia, W. B. Saunders, 2003.

48ANGINAblood containing oxygen is required. The blockageprevents an adequate supply of oxygen from reaching themuscle. This oxygen lack causes the heart muscle tobecome painful, and the heart rate and blood pressuremay further increase during the stress of pain. Basically,beta-blockers cause the heart muscle to require less oxygento do the same amount of work. The heart rate multipliedby the systolic blood pressure gives an estimation of theamount of work and oxygen required by the heart muscle.Beta-blockers decrease both heart rate and blood pressure,therefore, less oxygen is required. They also cause the heartmuscle to contract less forcefully so that less oxygen isused. These drugs divert blood from the areas of the heartthat have an abundant supply to the deprived area.2. Indications and GoalsIf there are no contraindications to the use of betablockers,the treatment of angina should be sublingualnitroglycerin and aspirin plus a beta-blocker preferablygiven once and, at most, twice daily. Randomized controlledclinical trials have demonstrated that beta-blockertherapy is efficacious in reducing symptoms of anginaand episodes of ischemia and in improving exercisecapacity.The beta-blocker is always started at a very low doseand, over a period of days or weeks, increased to aneffective dose. A low dose of propranolol, for example, 20mg three times daily before meals increasing after a weekor two to 40 mg three times daily, is advisable. The doctorwill check to be sure that the pulse and blood pressureare stable and that there are no side effects from themedications. If necessary, the dose can be increased to 160mg long-acting (LA) capsule once daily, or 160 mg in themorning and 80 mg at bedtime. Atenolol is given 50 mgonce daily. The target pulse rate is 55–60 beats per minuteat rest and less than 100 beats per minute on moderateactivities that normally push the heart rate to greater than120 beats per minute.Some patients, 1 in 100, are very sensitive to betablockersand their pulse rate decreases to less than 48 beatsper minute. It is extremely rare to learn of patients whocome to harm because of a slow heart rate. A heart rate ofless than 42 beats per minute may cause dizziness, andthe individual may be forced to lie down. The bodyquickly compensates and the effects of a 40-mg tabletwear off in about four hours. The doctor usually reducesthe dose, or in very few cases, the drug is discontinued.In North America there are more than 12 millionindividuals who are taking beta-blockers for managementof their CAD. Many patients are, however, deprived ofsuch therapy because of inappropriate concerns regardingthe adverse effects of beta-blockers (see the chapterBeta-blockers).3. General CautionsThe list below outlines some general cautions regardingbeta-blockers.1. Do not suddenly stop taking beta-blockers. Betablockerscontrol the heart rate and oxygen requirementin just the same way as the reins that control a horse.If beta-blockers are stopped abruptly, it is similar tocutting the reins; the horse may gallop away. Therefore,the heart rate may increase from the accustomed 55–65beats per minute to 80–90 beats per minute. It isrelatively safe to miss one dose of a beta-blocker, or atthe most two doses per week. It is unadvisable to missany doses, but there are always unavoidable circumstances.No harm usually results from one missed dose;however, omitting the drug for two to three daysconsecutively may precipitate angina. Withdrawalshould be gradual over weeks and under the guidanceof your doctor.2. Report shortness of breath or wheezing to your doctoras soon as possible.3. Beta-blockers must not be used in combination withmonoamine oxidase (MAO) inhibitors, which are drugsused to treat different types of severe depression.4. Do not take decongestants or cold or cough remediescontaining epinephrine (adrenaline), phenylephrine,or phenylpropanolamine. These drugs can cause anincrease in blood pressure.5. The combination of beta-blockers and digitalis(digoxin) is safe.6. Metoprolol and propranolol are broken down in theliver more rapidly in smokers so that blood levels of thedrugs are reduced; thus, the drugs may be rendereduseless. Atenolol and nadolol are not broken down inthe liver and are not affected by smoking. Timolol hasbeen shown to prevent heart attacks or death in smokersas well as nonsmokers.7. Two pints of beer or 3 oz of liquor does not cause anyinteraction or alteration in effectiveness.4. ContraindicationsDo not take beta-blockers if you have any of the followingproblems.1. Severe heart failure: Few patients with angina have heartfailure. Beta-blockers can precipitate heart failure in

VII. DRUG TREATMENT49patients with very weak heart muscle function. It mustbe pointed out that the heart muscle is the strongestmuscle in the body; it does more work than any othermuscle during an individual’s lifetime. Many patientswho have had two heart attacks are still able to engagein a brisk two-mile walk or climb three flights ofstairs, and some can jog one to three miles. Theremaining heart muscle is stronger than the quadricepsmuscle of the thigh. The heart muscle is strongenough in about 90 out of 100 patients with anginato allow the use of beta-blockers. Patients with mildor moderate degrees of heart failure have benefitedby the use of beta-blocking drugs. Beta-blockersare indicated for mild-to-moderate heart failure,because a randomized clinical trial has shown thatthey prevent mortality and hospitalization in thiscategory of patients. See the chapter entitled ‘‘HeartFailure.’’2. Bronchial asthma, severe chronic bronchitis, oremphysema: Some patients with mild chronic bronchitisand for whom beta-blockers are deemed necessaryto control angina can use atenolol, bisoprolol, ormetoprolol, which has less effect on the lungs thannonselective beta-blockers. These three drugs arerelatively safe at low doses.3. Allergic rhinitis: Do not commence beta-blockersduring a flare-up of allergic rhinitis.5. Side Effectsa. The Heart and Vessels There can be precipitation of heart failure inpatients with a very weak heart muscle, as discussedabove.Severe slowing of the heart rate to less than 42 beats perminute in rare cases if the dose is not carefully adjusted;this is usually quickly spotted by the symptoms ofdizziness and ill feeling, and can be quickly rectified;hence, in practice this is not a problem. Extremely cold hands and feet can occur in about 10%of patients; the condition improves immediately ondiscontinuation of the beta-blocker.b. The LungsThere can be precipitation of wheezing and difficultbreathing in individuals who are known to have allergicasthma or severe bronchitis.c. The Nervous or Muscular System Dizziness due to excessive slowing of the pulse andreduction in blood pressure Vivid dreams in about 10% of patients takingpropranolol; these usually clear up when given analternative medication such as atenolol, timolol, ornadololMild depression occurring in less than 10% of patients,it is not a major problem in practice; because atenololand nadolol do not get into the brain like propranolol,they cause fewer problems Weakness and muscle fatigue of varying degree,occurring in about 10% of patients; a change frompropranolol to metoprolol, atenolol, or nadolol isadvisable; if symptoms persist and no other cause can befound, beta-blockers should be discontinuedReduction of libido and impotence that occurs in lessthan 5% of patients, it must be monitored by patientand physician; however, beta-blockers, by decreasingthe heart rate, blood pressure, and heart work can beuseful if pain is precipitated by intercoursed. Other Side EffectsIn some patients insomnia, altered sleep patterns,nervousness, muscle cramps, and muscle joint painscan be caused by pindolol6. Individual Beta-BlockersBeta-blockers are the most beneficial drugs used in thetreatment of angina. They have been in use in the UKsince 1964 and in the United States since 1969. The firstand most well-known drug in this group is propranolol(Inderal). Several other beta-blockers have also beenapproved by the FDA. Commonly used beta-blockersinclude acebutolol, atenolol, bisoprolol, carvedilol,nadolol, metoprolol, propranolol, and timolol.a. Atenolol (Tenormin)Supplied: Tablets: 25 mg (U. S.), 50 mg, and 100 mg.Dosage: Start 25 mg daily for about three days, thenone 50-mg tablet daily at any time of the day. If thecondition warrants, the doctor often starts with 50 mgdaily. Food does not interfere with the effectiveness ofatenolol. If angina is not controlled and especially if theblood pressure is elevated 100 mg may be necessary. This

50ANGINAbeta blocker is not as effective as the lipophilic betablockers carvedilol, bisoprolol, or metroprolol.calcium antagonist or an oral nitrate. As emphasized,smoking destroys the effectiveness of propranolol.b. Carbedilol (Coreg)Supplied: Tablets: 3.25 mg, 6 mg, 12 mg, and 25 mg.Dosage: 3.25 mg trial dose then twice daily increasingover weeks 12 to 25 mg twice daily. See the chapterentitled ‘‘Beta-Blockers.’’c. Bisoprolol (Zebeta, Monocor)Supplied: Tablets: 5 mg and 10 mg.Dosage: 5–10 mg once daily. This drug is a selectivebeta-blocker that spares the beta-blocking effect on thelungs. This salutary effect is more powerful than that ofatenolol and metoprolol.d. Metoprolol (Lopressor, Betaloc, Toprol XL)Supplied: Tablets: 50 mg and 100 mg.Dosage: 50 mg twice daily, before breakfast and atbedtime, increasing if necessary to 100 mg twice daily inthe majority of cases, and in a few cases to 200 mg twicedaily. This drug has advantages over propranolol inpatients with mild chronic bronchitis; if beta-blockersare deemed necessary to control angina, metoprolol upto 100 mg twice daily is safer than an equivalent dose ofpropranolol. Toprol XL has the advantage because it iseffective when taken once daily. It also has a low side effectprofilee. Nadolol (Corgard)Supplied: Tablets: 40 mg, 80 mg, 120 mg, and 160 mg.Dosage: 40–160 mg only once daily. As with atenolol,food makes no difference to absorption, and smoking doesnot alter effectiveness. After a few days or weeks at 40 mgdaily, the drug may be increased to 80 mg and in somepatients to 160 mg daily.C. Calcium Blockers (Antagonists)Normally, the muscle in the walls of arteries contractsunder the influence of the movement of calcium into thecells. Calcium blockers prevent calcium from moving intothe cell, thereby causing relaxation and dilatation of thearteries throughout the body. Calcium blockers are not aseffective as beta-blockers. The use of calcium blockers incombination with beta-blockers can improve the lifestyleof patients with angina (see the chapter CalciumAntagonists).1. ActionThe muscle in the heart and walls of arteries contractsunder the influence of a movement of calcium into thecells. Calcium is transported from the exterior to theinterior of cells through a system of tubules called slowcalcium channels. Calcium reaches the interior of musclecells and interacts with specialized proteins in the muscle,which then contract. Calcium blockers block the slowcalcium channels; this action prevents calcium from goinginto the cells, thereby causing the muscle of the heart andarteries to relax. These drugs are also known as calciumchannel blockers, calcium entry blockers, slow channelblockers, or calcium antagonists (see the chapter CalciumAntagonists).2. IndicationsIn variant angina (coronary artery spasm), all availablecalcium antagonists — amlodipine, nifedipine, verapamil,and diltiazem — are equally effective in this rarecondition. In stable angina pectoris calcium blockersshould be used in the following situations: if beta-blockersare contraindicated and if the response to adequate dosesof beta-blockers is good but not completely effective.f. Propranolol (Inderal)Supplied: Tablets: 10 mg, 20 mg, 40 mg, and 80 mg.Dosage: 20 mg three times daily before meals,increasing slowly, under a doctor’s supervision, to 120mg daily. After several weeks, an LA capsule of 80 mg or160 mg of propranolol may be preferable. Most patientswith angina should receive 160–240 mg before adding a3. Individual Calcium Blockersa. Amlodipine (Norvasc)Supplied: Tablets: 5 mg and 10 mg.Dosage: 5–10 mg once daily.Actions, advice, and adverse effects: Amlodipinestrongly blocks the slow calcium channels and causesdilatation of arteries. This drug, therefore, dilates the

VII. DRUG TREATMENT51coronary arteries and the arteries of the limbs andelsewhere. This action causes a reduction in the resistancein the arteries, blood pressure, and the work of the heart.By causing less work for the heart, along with dilatation ofthe coronary arteries, the pain of angina is relieved.Amlodipine has no effect on the electrical system of theheart, and it is safe in patients with electrical disturbances.There are no absolute contraindications to its use.Dizziness occurs in 3–7% of patients. If dizziness occurs,the drug is reduced. Dizziness can be made worse whennifedipine is combined with oral nitrates or nitrate preparationsplaced on the skin or drugs that lower bloodpressure. Edema of the legs occurs in about 5% of patients,but this does not indicate heart failure; instead it is due todilatation of capillaries in the legs. Headaches and athrobbing sensation in the head occur in 5–10% ofpatients, and occasionally the drug has to be discontinued.Patients should be reassured that the throbbing is not dueto an increase in blood pressure but to dilation of thearteries in the scalp. The action is similar to a tablet ofnitroglycerin put under the tongue. The headaches orthrobbing become less severe after a few weeks of treatment,and the majority of patients can tolerate amlodipineat 5 mg daily. Mild flushing and burning in the scalp andhead and occasional indigestion do occur.b. Verapamil (Isoptin)Supplied: Tablets: sustained release 120 mg, 180 mg, and240 mg.Dosage: 120–240 mg once daily.Indications: Verapamil can be used in variant angina(coronary artery spasm), which is rare. When chronicstable angina pectoris does not respond to beta-blockers,verapamil is an effective alternative. During severe palpitations(paroxysmal atrial tachycardia) verapamil givenintravenously in the emergency room is very effective andrestores the heart rhythm to normal.Actions, advice, and adverse effects: Verapamil is amoderately potent vasodilator. It causes a decrease in thecontraction of heart muscle; an action which can produceheart failure. Side effects include constipation, which maybe distressing, especially in the elderly. In women, secretionof milk from the breasts (galactorrhea) and a minordegree of liver disturbance may rarely occur. Verapamilis contraindicated in patients with a very slow pulse rate,heart block, sick sinus syndrome, heart failure, an enlargedheart, or poor heart muscle function.Drug Interactions: The combination of beta-blockersand verapamil may cause marked reduction of the pulserate to less than 42 beats per minute. Also, heart failure canbe precipitated. Interacting with digoxin, verapamil canincrease the level of digoxin in the blood, and when bothdrugs are used, the physician has to recheck levels ofdigoxin more frequently and may need to lower the doseof both drugs. Amiodarone is a drug that is used for thetreatment of serious forms of extra beats (ventriculartachycardia) and should not be combined with verapamil.When combined with tranquilizers, verapamil may have asedative effect. Verapamil also increases the effects ofanticoagulants (blood thinners).c. Diltiazem (Cardizem, Tiazac)Supplied: Controlled release (CD): 80 mg, 120 mg,240 mg, and 300 mg.Dosage: Diltiazem CD (Cardizem CD): 120 mg,180 mg, or 240 mg once daily. Maximum: 300 mg.Indications: These are the same as those listed forverapamil except that the drug is not used in the treatmentof paroxysmal tachycardia because its effect is very mild.Actions, advice, and adverse effects: Diltiazem has asimilar action to verapamil but is not as powerful. Thisdrug may cause headaches and dizziness. Disorientationand occasional, reversible elevation of liver enzymes(transaminases) have been seen in some patients.Constipation may be bothersome, although this is muchless than observed with verapamil. The combinationwith beta-blocking drugs is much safer than the combinationwith verapamil, but a few patients may developslow heart rates requiring the discontinuation or loweringof the dose.D. AspirinAspirin is the mainstay of antithrombotic therapy inpatients with CAD.1. A Life-Saving TherapyAngina leads to fatal or nonfatal myocardial infarction inmany patients. During onset of the chest pain that heraldsa myocardial infarction, thrombosis is occurring in thecoronary artery. This thrombus can be partly preventedand infarction or death can be averted in more than20% of individuals by the use of a quick-acting aspirinformulation such as chewable aspirin. Thus, two to four,80-mg chewable aspirins are recommended to individualswho sustain chest pain believed to be due to a heart attack.It is important to emphasize that the emergency use ofchewable aspirin can save morbidity and mortality from a

52ANGINAheart attack but that nitroglycerin in spray or tablet formdoes not prevent fatal or nonfatal infarctions. The use ofchewable aspirin is more important than the use ofnitroglycerin and worldwide education about this isessential.2. Preventive TherapyAn enteric-coated aspirin tablet is given to virtually allpatients with angina or CAD in an effort to prevent fatalor nonfatal infarction. A timely Veterans Administrationstudy utilizing 324 mg of aspirin in patients with unstableangina resulted in a 50% reduction in mortality rate andnonfatal myocardial infarctions. In another randomizedstudy, aspirin was shown to reduce the cardiac mortalityrate by 50% in patients with unstable angina. A Swedishstudy using 75 mg of aspirin in patients with stable anginashowed a 34% reduction in infarctions and death. Inpatients who are allergic or intolerant to the use of aspirin,clopidogrel bisulfate (Plavix) is recommended.E. StatinsStatins are well-known cholesterol-lowering agents thathave proved, in randomized controlled trials, to preventserious cardiac events in patients with CAD. Fatal andnonfatal infarctions are prevented in patients with stableor unstable angina.Available statins include atorvastatin, fluvastatin, pravastatin,simvastatin, and the recently introduced morepowerful statin, rosuvastatin. Statins are recommendedfor all patients with stable or unstable angina to maintainlow-density lipid (LDL) cholesterol levels at lessthan 80 mg/dl (2.0 mmol/L), see the section underDyslipidemia.F. Anti-Inflammatory AgentsAtheromatous plaque, whatever the causative factor, isexceedingly inflammatory in unstable angina, and reactivationof the process and plaque rupture may triggernew thrombus formation. There is minor evidencebut unproven role for Helicobacter pylori, Chlamydiapneumoniae and C. pneumoniae. Particularly high titers ofantibodies have been observed in patients with unstableangina as well as the presence of elementary bodies, DNA,and antigens in the atherosclerotic arterial wall.Gupta et al. screened 220 men after myocardialinfarction. Eighty patients with antibody titers greaterthan 1:64 were randomized to azithromycin or placebo for3 or 6 days. During the study the odds of an event inpatients with placebo were four times higher than those innonrandomized patients with negative titers or in treatedpatients with a positive titer.In the study of 200 patients with unstable angina andnon-Q-wave myocardial infarction, treatment with roxithromycinadministered for 30 days reduced the 6-monthmortality rate from heart attack from 4 to 0%, and the rateof death, infarction, or recurrent ischemia from 9 to 2%.Nonetheless, these are small studies and other clinicalstudies have been unsuccessful. Antibiotic therapy awaitsthe results of large randomized controlled trials.Aspirin’s salutary effect is caused by its antithromboticproperties, but its anti-inflammatory action appears toprovide some beneficial effects. In addition the use ofstatins has been shown to reduce levels of C-reactiveprotein and inflammatory response in atheromatousplaques. This beneficial effect of statins appears to beindependent from a lowering of LDL cholesterol.G. Newer Agents: NicorandilNicorandil is a nicotinamide ester with a dual mechanismof action. Its distinctive pharmacologic effect is to openATP-sensitive potassium channels, thus dilating peripheraland coronary resistance arterioles. In addition it has aunique feature — the drug possesses a nitrate moietywhich dilates systemic veins and epicardial coronaryarteries. This drug, therefore, increases coronary bloodflow which reduces pre- and afterload. Nicorandil hasbeen shown to have antianginal efficacy and a safetyprofile similar to that of oral nitrates and beta-blockers.Additionally, it appears that the drug has cardioprotectiveproperties. These effects are probably caused by the drug’sability to mimic the powerful ischemic preconditioningphenomenon by opening ATP-sensitive potassiumchannels.A randomized clinical trial in 5126 patients showedsignificant improvement in outcome due to a reduction inmajor coronary events caused by Nicorandil in patientswith stable angina. Mean follow up was 1.6 year.H. RanolazineRanolazine is an investigation treatment for angina.The drug is not Beta blocker, calcium antagonists ornitrate. Clarke et al. indicate that the drug appears to shiftadenosine triphosphate production away from fatty acidoxidation in favor of more oxygen efficient carbohydrateoxidation. In a small clinical trialin patients with chronicangina the drug at a dose 500–1000 mg twice daily was

XI. VARIANT ANGINA (PRINZMETAL’S ANGINA)53well-tolerated and increased exercise performance withoutsignificant decrease in blood pressure or increase in heartrate. The drug did not alter survival in the one year followup. The 1500-mg, twice daily dosing caused dizziness andnausea, ischemia, and constipation and rarely syncope. Thedrug should not be used in patients administered otheragents that increase the QT interval.VIII. HYPERTENSIONHypertension causes atheroma formation and atherosclerosis.A significant number of patients with anginahave hypertension: blood pressure greater than 140 orpressures in the high normal range of 135–140 systolicmmHg. Hypertension causes an increased thickness of theleft ventricular muscle, which requires more blood andoxygen to function. Hypertension must be aggressivelycontrolled. The best antihypertensive agents for patientswith angina are beta-blockers and ACE inhibitors.ACE inhibitors are particularly useful because theydilate the arterial circulation and rest the myocardiumwithout stimulating the heart to beat at a faster rate or torequire more oxygen. Other vasodilators that include 1 -adrenergic blockers, such as terazosin, increase heart rateand ejection velocity and are contraindicated in patientswith CAD. These agents may increase the incidence ofheart failure. A randomized clinical trial the HOPE study;see the Bibliography indicates that ACE inhibitors improvesurvival in patients with CAD.IX. ANGINA PATIENTS WITHHEART FAILURECoronary artery disease leads to myocardial infarctionwhich causes weakness of the heart muscle, and somepatients over time develop heart failure. These patientsare difficult to treat because they are not candidates forbypass surgery. Medical therapy must be used judiciously.Nitrates, in particular cutaneous nitrates, applied 14 hdaily, plus a small dose of a beta-blocking drug along withan ACE inhibitor and a diuretic, are beneficial for manypatients. Beta-blockers should be avoided in patients withsevere heart failure, but those with mild-to-moderate heartfailure gain major relief. Recent randomized clinical trialshave shown the beta-blockers, carvedilol, metoprolol, andbisoprolol effective in reducing mortality rates andhospitalization.In patients with an ejection fraction less than 35%,digoxin is indicated. Calcium antagonists should beavoided. Verapamil and diltiazem are contraindicatedbecause of reduced cardiac contractility and the possibilityof precipitating heart failure. Other calcium antagonistsincluding amlodipine and nifedipine should be avoidedbecause they may precipitate heart failure.X. SILENT ISCHEMIAMyocardial ischemia without pain or symptoms iscommon in patients with CAD. The incidence of silentischemia is high and the outcome unfavorable in patientswith unstable angina. Interventional therapy is oftenrecommended. Holter monitoring after noncardiac surgeryin patients with stable angina and post myocardialinfarction patients has documented a high incidence ofsilent ischemia within the second to fourth day aftersurgery.In the Total Ischemic Burden Bisoprolol Study, bothbisoprolol and nifedipine reduced the number andduration of transient ischemic episodes. Bisoprolol wassignificantly more effective than nifedipine and reducedthe morning peak of ischemic activity. This is in keepingwith other studies, which indicate that beta-blocking drugsare superior to calcium antagonists in producing salutaryeffects in patients with silent ischemia, especially inreducing early morning ischemia that may relate to thepeak incidence of early morning heart attacks and death.Patients with evidence of silent ischemia are recommendedto be treated with a beta-blocking drug, aspirin,and a statin and investigated with exercise stress testing.Those who show strongly positive exercise tests and/orejection fractions less than 45% should be submitted tocoronary angiography for consideration of an appropriaterevascularization procedure.XI. VARIANT ANGINA (PRINZMETAL’SANGINA)Prinzmetal’s variant angina is caused by coronary arteryspasm of undetermined etiology. Pain usually occurs atrest as opposed to typical stable angina occurring duringexertion. The ECG during pain shows ST-segmentelevation as opposed to typical angina showing ST-segmentdepression. An ECG is not necessary, however, to initiatetherapy.Beta-blockers can increase coronary artery spasmand cause chest pain so they are contraindicated inthese patients. Management includes cessation of smoking,avoidance of aspirin that may cause spasm, andthe use of high doses of nitroglycerin and calciumantagonists.

54ANGINAUnfortunately patients with variant angina, even whenthe syndrome is completely controlled by calciumantagonists, have died or have had myocardial infarctions.Although calcium antagonists are efficient in controllingthe pain of coronary artery spasm, they do not preventdeath. Coronary artery bypass surgery is indicated inpatients with significant atheromatous coronary arteryobstruction, which occurs coincidentally in some patientswith variant angina.XII. UNSTABLE ANGINA/ACUTECORONARY SYNDROMEA. Pathophysiology and SymptomsThe pathophysiology of unstable angina has beenidentified. In the majority of cases, disease-causing plaquesare asymmetric with irregular borders and a narrow neck.Platelets then aggregate on the surface of plaques formingsmall thrombi. Lipid-rich plaques have a predilection forrupture, and rupture of the plaque with an overlying thrombusis a common finding on angioscopy. Silent ischemiais fatal and observed in patients with unstable angina.Prognosis appears to be worse in this subset of patients.Unstable angina patients represent a heterogeneousgroup. Patients usually present with chest pain at restlasting from about 10 to 40 minutes; pain usually lastsmore than 20 minutes but less than hour. Patients withstable angina with chest pain only on exertion who developpain with much lower levels of activities or pain at restare a subset of unstable angina. Patients with new onsetangina occurring within the past 30 days have high-riskunstable angina.B. ManagementAll patients with unstable angina should proceed toan emergency room and be administered 160 mg ofchewable aspirin immediately if they have not alreadytaken the drug.1. Risk Stratification and New ClassificationDuring the past 50 years the three major complicationsof CAD associated with chest pain were classified asmyocardial infarction, severe chest pain without elevatedcardiac enzymes classified as unstable angina, and chestpain mainly on exertion labeled as chronic, stable angina.For more information, see the chapter Heart Attacks.Since 1998 national cardiac societies have altered thisclassification as follows:1. Patients with chest pain who have the characteristics ofa heart attack associated with typical ECG changedemonstrating ST-segment elevation are labeled as anST-segment elevation myocardial infarction (see thechapter Heart Attacks).2. Patients with chest pain and the characteristics of aheart attack associated with ECG changes demonstratingST-segment depression accompanied by elevatedtroponin or CK-MB enzyme elevations are labeled asnon-ST elevation myocardial infarction (formerly callednon-Q-wave myocardial infarction).Cardiac societies in the United States, Canada, and theUK have introduced a new terminology: acute coronarysyndrome in an attempt to identify high risk patients withacute chest pain. Classification of ischemic pain, acutecoronary syndrome includes:1. Subset of patients with ST-segment elevation myocardialinfarction2. Patients with non-ST elevation infarction (old term:non-Q-wave MI)3. Patients with typical features of unstable angina withelevated troponin levels are reclassified as non-STelevation infarction4. Patients with unstable angina: abnormal ECG changeswith normal troponin levels5. Patients with unstable angina, normal ECG changes,and normal troponins are classified as low riskPatients are stratified into low- or high-risk categoriesbased on:1. ECG changes done during pain showing ST-segmentdepression indicating ischemic changes; ST-segmentdepression greater than 0.05 mm (0.05 mV) indicateshigh risk.2. Patients with abnormal ECG and elevated troponinsare at high risk for serious events; elevated troponinlevels indicate necrosis of myocardial cells or a smallmyocardial infarct.3. Patients with evidence of recent onset of rest pain that isrecurrent, accompanied by ECG changes, are high risk.4. Patients without rest pain and absence of ECG changeswith normal troponin levels are at low risk.5. Diabetics with any of the above features are consideredhigh risk as are those patients who have had a previousinfarction.6. An elevated C-reactive protein is considered to beevidence of increased risk (see the chapter C-ReactiveProtein and the Heart).

XII. UNSTABLE ANGINA/ACUTE CORONARY SYNDROME552. Drug ManagementDrug management is an important aspect of treatingunstable angina/acute coronary syndrome.1. All patients are admitted to a coronary care unit or toan area where telemetry and blood pressure monitoringare available.2. Intravenous nitroglycerin is given to virtually allpatients to relieve chest pain.3. Morphine in small doses is given to stop pain thatcan stimulate autonomic responses that may increasecardiac arrhythmias and myocardial necrosis.4. A beta-blocking drug is begun provided there is nocontraindication such as asthma or bradycardia lessthan 50 beats per minute present.5. Chewable aspirin is usually administered in theemergency room followed by enteric-coated aspirin325 mg once daily.6. If A beta-blocking drug is contraindicated, a calciumantagonist such as diltiazem is administered.7. Heparin is given subcutaneously; low molecularweight heparin has been shown to be equally aseffective as intravenous heparin and easier to monitor.8. A statin is commenced to maintain LDL-cholesterollevels less than 2.0 mmol/L (80 mg/dl).9. Powerful antiplatelet agents are commenced, especiallyin high-risk patients. Clopidogrel followed by catheterizationand coronary angiography are used to definethe lesion.10. Glycoprotein IIb/IIIa receptor blockers such as:abciximab (ReoPro), Integrilin, or tirofiban areadministered to high-risk patients undergoing coronaryangiography and/or angioplasty with or withoutstent placement; several studies suggest that mainlydiabetics with acute coronary syndrome benefitfrom such therapy. Abciximab has been shown tohave beneficial effects in randomized clinical trialsin acute coronary syndrome patients undergoingangioplasty or stenting (see the chapter AntiplateletAgents).3. Interventional TherapyInterventional therapy such as coronary angioplasty withor without stenting or bypass surgery should be stronglyconsidered in patients with high-risk unstable angina/acutecoronary syndrome. These patients usually undergocoronary angiography within 24 h on admission to anemergency room.Coronary angiograms define the obstructive lesions, andballoon angioplasty and stent placement are done in themajority of patients. Balloon angioplasty with stenting hastransformed the management of unstable angina/acutecoronary syndrome (see the chapters Angioplasty andStents).In most categories of patients and in virtually alldiabetics, interventional therapy has advantages overmedical therapy for amelioration of angina, a return tonormal lifestyle, and probable prolongation of life.Coronary artery bypass surgery is indicated if angioplastyor stenting are not possible, particularly inpatients with an ejection fraction of less than 45%,and in diabetics.When coronary artery bypass surgery is selected,patients who can receive an internal mammary arterygraft are most fortunate. The arterial graft has a prolongedpatency of 15–20 years versus approximately 10–12 yearsfor saphenous vein grafts. Khot et al. have recently shownthat radial artery bypass grafts have an increased occurrenceof angiographically severe stenosis and occlusioncompared with left internal mammary artery grafts andsaphenous vein grafts (see the chapter Coronary ArteryBypass Surgery).BIBLIOGRAPHYCannon, C., and Braunwald, E. Unstable angina. In Heart Disease, sixthedition. E. Braunwald, D.P. Zipes, and P. Libby, eds. W.B. Saunders,Philadelphia, 1232–71, 2201.Chaitman, B.R., Skettino, S.L., Parker, J.O. et al. Anti ischemic effectsand long-term survival during ranolazine monotherapy in patientswith chronic severe angina. J. Am. Coll. Cardiol., 43:1375–1382,2004.Clarke, B., Wyatt, K.M., McCormack, J.G. et al. Ranolazine increasesactive pyruvate dehydrogenase in perfused rat hearts: Evidence for anindirect mechanism. J. Mol. Cell. Cardiol., 28:341–350, 1996.Goldman, S., Zadina, K., Moritz, T. et al. Long-term patency ofsaphenous vein and left internal mammary artery grafts after coronaryartery bypass surgery. J. Am. Coll. Cardiol., 44:2149–2156, 2004.Gupta, S., Leatham, E.W., Carrington, D. et al. Elevated Chlamydiapneumoniae antibodies, cardiovascular events, and Zithromycin inmale survivors of myocardial infarction. Circulation, 96:404, 1997.HOPE Investigators: Yusuf, S., Sleigh, P., Pogue, J. et al. Effects of anangiotensin converting enzyme inhibitor, ramipril, on death fromcardiovascular causes, myocardial infarction, and stroke in high-riskpatients. The Heart Outcomes Prevention Evaluation Investigators.N. Engl. J. Med., 342:145–153 2000,The IONA Study Group. Effect of the nicorandil on coronary events inpatients with stable angina: The impact of the nicorandil in angina(IONA) randomized trial. Lancet, 359:1269–75, 2002.Khan, M. Gabriel. Angina. In Cardiac Drug Therapy, sixth edition, WBSaunders, Philadelphia, 2003.Khan, M. Gabriel Unstable angina. In On Call Cardiology, second edition,WB Saunders, Philadelphia, 187–206, 2002.Kim, M.C., Annapoorna, K., and Sharma, S.K. Refractory anginapectoris: Mechanisms and therapeutic options. J. Am. Coll. Cardiol.,39:923–34, 2202.

56ANGINAKhot, U. N., Friedman, D. T., and Pettersson, G. Radial artery bypassgrafts have an increased occurrence of angiographically severe stenosisand occlusion compared with left internal mammary arteries andsaphenous vein grafts. Circulation, 109:2086–2090, 2004.Kramer, C. M. et al. The comprehensive approach to ischemic heartdisease by cardiovascular magnetic resonance imaging. J. Am. Coll.Cardiol., 44: 2182–2184, 2004.Lewis, H. D., Davis, J. W., Archibald, D. G. et al. Protective effects ofaspirin against acute myocardial infarction and death in men withunstable angina. Results of a Veterans Administration CorporativeStudy. N. Engl. J. Med., 309:396, 1983.Moreno, P. R., Fuster, V. et al. The year in atherothrombosis. J. Am. Coll.Cardiol., 44: 2099–2110, 2004.Nissen, S. E., Tuzcu, E. M., Schoenhagen, P. et al. For the reversalof atherosclerosis with aggressive lipid lowering (REVERSAL)investigators statin therapy, LDL cholesterol, C-reactive protein,and coronary artery disease. N. Engl. J. Med., 352:29–38, 2005.Park, S. J., Kim, Y. H., Lee, B. K. et al. Sirolimus-eluting stentimplantation for unprotected left main coronary artery stenosis. J. Am.Coll. Cardiol., 45:351–356, 2005.Petersen, S., Peto, V., Rayner, M. et al. Coronary heart disease statistics.London: British Heart Foundation, 2004.Raff, G. L., Gallagher, M. J., O’Neill, W. W., et al. Diagnostic accuracyof noninvasive coronary angiography using 64-slice spiral computedtomography. J. Am. Coll. Cardiol., 46: 552–557, 2005.Ridker, P. M., Cannon, C. P., Morrow, D. et al. For the pravastatin oratorvastatin evaluation and infection therapy-thrombolysis in myocardialinfarction 22 (PROVE IT–TIMI 22) investigator: C-reactiveprotein levels and outcomes after statin therapy. N. Eng. J. Med.,352:20–28, 2005.Rodriguez, A. E., Baldi, J., Carlos Pereira, F., et al. The ERACIII investigators five-year follow-up of the Argentine randomizedtrial of coronary angioplasty with stenting versus coronary bypasssurgery in patients with multiple vessel disease (ERACI II). J. Am.Coll. Cardiol., 46: 582588, 2005.Serruys, P. W., Ong, A. T. L., van Herwerden, Lex, A., et al. Five-yearoutcomes after coronary stenting versus bypass surgery for the treatmentof multivessel disease: The final analysis of the arterial revascularizationtherapies study (ARTS) randomized trial. J. Am. Coll.Cardiol., 46: 575-581, 2005.Steinhubl, S. R., Berger, P. B., Mann, J. T., III et al. For the CREDOInvestigators. Early and sustained dual oral antiplatelet therapyfollowing percutaneous coronary intervention: A randomizedcontrolled trial. JAMA, 2411–20, 2002.Sousa, J. E., Costa, M. A., Tuzcu, E. M., et al. New frontiers ininterventional cardiology. Circulation, 111:671–681, 2005.

Angioplasty/Coronary BalloonI. ProcedureII. IndicationsIII. Contraindications and LimitationsIV. Outcome of AngioplastyGLOSSARYangina pectoris short duration, recurrent chest pain or pressureoften accompanied by feelings of suffocation and impendingdoom; most frequently associated with lack of blood andoxygen to the heart muscle.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker of leftventricular contractility.ischemia temporary lack of blood and oxygen to an area ofcells, for example, the heart muscle, usually due to severeobstruction of the artery supplying blood to this area of cells.myocardial infarction death of an area of heart muscle causedby blockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.myocardium the heart muscle.I. PROCEDUREPTCA, percutaneous transluminal coronary angioplasty,is so named because the instrument is passed through theskin (percutaneously) and then through the lumen of theartery (transluminal) into the coronary artery, which ismolded into shape (angioplasty). The balloon-tippedcatheter is positioned next to the plaque of atheroma inthe artery (see Figure 1 in chapter entitled ‘‘Angina.’’).The balloon is inflated for 30–60 seconds and thenwidened by pressure (see Fig. 1). The narrowed arterybecomes dilated due to splitting (dissection) of the plaqueand overstretching of the middle wall (media) of the artery.Transient chest pain may occur during the inflation but isquickly relieved. Several inflations may be necessary toaccomplish dilation of the artery. The balloon is thendeflated, and dye is injected so that the cardiologist can seeif adequate dilation and flow of blood has been achieved.An optimal angiographic result (less than 20% residualTHE FIRST SUCCESSFUL CORONARY ANGIOPLASTYwas performed by the late Dr. Andreas Gruntzig in Zurich,Switzerland, in 1977. Dr. Gruntzig pioneered the modernera of interventional cardiology with his innovativepercutaneous transluminal coronary angioplasty (PTCA).Using a double-lumen balloon catheter, he performed thefirst PTCA by dilating the proximal left anteriordescending coronary artery and unblocking an atheromatousobstruction of a 37-year-old man with angina. Repeatangiograms on the 10th anniversary of this procedureshowed continued vessel patency; the patient has remainedsymptom-free for more than 20 years.FIGURE 1Coronary angioplasty.57

58ANGIOPLASTY/CORONARY BALLOONstenosis), is obtained in less than 25% of patients afterPTCA) is associated with a favorable late clinical outcome.Following angioplasty, the patient is monitored in thecoronary care unit for about 24 h.PTCA expands the coronary lumen by stretching andtearing the atherosclerotic plaque and vessel wall and to alesser extent, by redistributing atherosclerotic plaquealong its longitudinal axis. There is no evidence that theballoon compresses atheromatous plaques. PTCA hasbeen transformed in the past decade with the developmentof angioplasty to assist with lesions exhibiting complexcharacteristics. The term percutaneous coronary intervention(PCI), is now used to include angioplasty with orwithout stent deployment. More than 700,000 patients inthe United States had PCIs in 2004, far exceeding thenumber of patients who had coronary artery bypass graft(CABG) surgery. This method of treating coronary heartdisease (CHD) is available in most major medical centersworldwide.Atherosclerosis, however, usually affects several segmentsof the coronary arteries. As the disease advances, everyeffort must be made to halt its progress. All risk factors —smoking, high blood pressure, stress, cholesterol higherthan 200 mg (5.2 mmol), and LDL cholesterol higher than100 mg/dl (2.5 mmol) — must be controlled. Diet plusdrug therapy is usually necessary to achieve this goal (seechapter entitled ‘‘Dyslipidemia.’’)II. INDICATIONSA. Stable AnginaPatients with bothersome stable angina who do not achievesufficient relief with medical therapy are candidates forcoronary angioplasty, if they have any of the following:1. One coronary artery obstructed (greater than 75%) by adiscrete, preferably noncalcified atheromatous plaquewithout complex angiographic characteristics. Patientswith symptoms and obstruction of the left anteriordescending artery or right coronary artery before theartery gives off the first branch are the most idealcandidates. Procedural success rate exceeds 97% withthese candidates and is associated with a low risk ofearly complications.2. A broad range of obstructive lesions including obstructionsin two and three arteries. This is now possiblewith increased experience and new steerable cathetersystems. Success is less likely to occur in patients withobstruction in the circumflex artery or at lower points(distal) in the coronary arteries where there are irregularbends or turns.B. Acute Heart AttacksPatients with acute heart attacks may have the clotdissolved by drugs such as streptokinase or tissue-typeplasminogen activator (t-PA); or they may undergocoronary angioplasty to dilate the obstructed artery andinsertion of a stent. Often coronary angioplasty with stentimplantation is performed without the use of thrombolyticagents. Several randomized clinical trials indicate that thisaggressive interventional technique is superior to the use ofthrombolytic agents, and it is advocated in centers thathave facilities for rapid angiography and trained personnelfor PCI (see the chapter Heart Attacks).C. Unstable Angina and Non-ST ElevationMyocardial Infarction1. Clinical Study — RITA 3 InvestigatorsQuestion posed: We will test the hypothesis that PCI isbetter than a conservative strategy in patients with unstableangina or non-ST elevation myocardial infarction.Methods: A randomized multicenter trial of 1810patients with acute coronary syndromes was used. Patientswere assigned an early PCI or conservative strategy. Theantithrombin agent in both groups was low molecularweight heparin, enoxaparin. Primary end points were acombined rate of death, nonfatal infarction, or refractoryangina at four months and a combined rate of death ornon fatal infarction at one year.Results: At 4 months 86 (9.6%) of 895 patients in thePCI group had died or had a myocardial infarction orrefractory angina versus 133 (14.5%) of 915 patients in theconservative group, p ¼ 0.001. This difference was mainlydue to a halving of refractory angina in the interventiongroup. Death or infarction was similar in both groups atone year when symptoms of angina were improved withantianginal medications and significantly reduced withthe interventional strategy ( p ¼ 0.0001). The proceduralsuccess rate after PTCA was approximately 80% 20 yearsago compared with approximately 97% in recent years,including success in women.III. CONTRAINDICATIONS ANDLIMITATIONSBelow is a list of contraindications and limitations forangioplasty.1. A totally blocked artery cannot be cleared becausethe catheter cannot be positioned, and chronic total

IV. OUTCOME OF ANGIOPLASTY59occlusions are present in more than 20% of patientsand are particularly frequent in patients with multivesseldisease.2. Disease of the left main coronary artery before itdivides into the anterior descending presents too greata risk.3. The obstruction is in the terminal part of the artery andcannot be reached by the balloon catheter.4. A coronary artery bypass surgical team is not available;this is a relative contraindication; experienced operatorsin high-volume angiographic laboratories have lowcomplication rates when compared with low-volumemedical centers. The rare patient who requires bypasssurgery because of complications can be stabilized andtransported to an available surgical center. The recentavailability of bail-out coronary stents has reduced theemergency CABG rate after PTCA to less than 1%.5. Diabetics do not often obtain beneficial results; manydiabetics have lesions in the coronary arteries that areirregular, diffuse, and long and not amenable to PCI.Surgery is more beneficial in most diabetics.In greater than 25% of individuals with coronary arterydisease (CAD), the obstruction in the artery is such thatcoronary angioplasty cannot be done. Eccentric morphologyand ostial location increase the periprocedural risk.The presence of congestive heart failure or a low ejectionfraction less than 30%, cardiogenic shock, renal insufficiency,multivessel CAD, and diabetes dictate a pooroutcome, especially if a stent cannot be employed. Theprocedure is well tolerated in octogenarians, with singlevessel,discrete obstructive disease. Unfortunately, theincreased prevalence of multivessel and diffuse diseaseand left ventricular dysfunction in the elderly diminishesthe proportion of patients likely to have significant longtermbenefits in comparison to surgery. PTCA and surgeryare not competitive procedures and should be viewed ascomplementary.IV. OUTCOME OF ANGIOPLASTYSuccessful reopening of the artery is achieved in greaterthan 90% of cases, and with better blood flow, anginaimproves. The majority of patients return to work a fewdays later and have no recurrence of the angina for at leastsix months. Early complications are most often the resultof abrupt vessel closure, defined as sudden occlusion ofthe target vessel during or shortly after PCI. This occursin less than 2% of patients. The pathophysiology involveslocal vessel dissection with obstructive resection flapsaccompanied by thrombus formation. This process usuallyleads to myocardial infarction and need for bail-out stentor bypass surgery. The recent use of platelet IIb/IIIareceptor blockers and stenting has reduced the incidence ofadverse outcomes of acute vessel closure.Death occurs in less than 1% of cases. A heart attackoccurs in less than 2% of cases, because the crushing andsplitting of the plaque of atheroma exposes cells andsubstances that promote blood clotting. Thus clopidogrel,aspirin, or platelet receptor blockers are useful additionsto the drug armamentarium to assist with successfulPCI. In about 20% of patients, it is not possible to passthe catheter through the narrowed area. In about 10%, thedilation cannot be accomplished because the plaques arecalcified and rock-hard. These complications are similar tothose of CABG surgery.The main limitation of PTCA is narrowing of theartery (restenosis) at the site of angioplasty. This occursin approximately 33% of cases within 6 months of theprocedure. In these patients chest pain returns. This figurehas not changed much over the past 20 years. Despiteintensive research to prevent restenosis, the problem hasnot been overcome.The pathogenesis of restenosis in response to mechanicalinjury induced by balloon angioplasty is incompletelyunderstood and is multifactorial. Several, pharmacologicagents have been tested in randomized controlledtrials including aspirin, other antiplatelet agents, anticoagulants,antiproliferative agents, calcium antagonists,and folic acid. Only stent implantation has been shown tosignificantly decrease restenosis rates to approximately25% at 6 months (see the chapter Stents). In the stentrestenosis study (STRESS), restenosis rates were 32 and42% percent in the stent and PTCA groups, respectively.Fortunately, these stenoses can be dilated more easilyon the second procedure with relief of symptoms inmany, but CABG is still frequently required in subsequentyears. Additionally, the need for repeat revascularizationtapers off rapidly after the second year. Still,restenosis may be clinically silent in more than 30% ofpatients.Coronary angioplasty does not compete with CABGsurgery. Approximately 25% of individuals cannot havecoronary angioplasty or stents and must have CABG.Coronary angioplasty is much cheaper. The hospital stay isonly one day, and patients can usually return to workwithin a few days. Of those who undergo angioplasty,approximately 85% are angina-free and able to be moreactive. Most important, the procedure is done in patientswith stable or unstable angina mainly to relieve recurrentchest pain of angina. It has not been shown in randomizedclinical trials to prolong life significantly or reduce theoccurrence of myocardial infarction.

60ANGIOPLASTY/CORONARY BALLOONBIBLIOGRAPHYChieffo, A., Stankovic, G., Bonizzoni, E. et al. Early and mid-termresults of drug–eluting stent implantation in unprotected left main.Circulation, 111:791-795, 2005.Gersh, B. J., Braunwald, E., and Bonow, R. O. Chronic coronary arterydisease. In Heart Diseases, sixth edition. E. Braunwald and D. P. Zipes,eds. W.B. Saunders, Philadelphia, 1272–1343, 2001.Machecourt, J., Bonnefoy, E., Vanzetto, G. et al. Primary angioplasty iscost-minimizing compared with pre-hospital thrombolysis for patientswithin 60 min of a percutaneous coronary intervention center. J. Am.Coll. Cardiol., 45:515–524, 2005.RITA-2 Trial Participants. Coronary angioplasty versus medical therapyfor angina: the second randomized intervention treatment of angina[RITA-2] trial. Lancet, 350:461, 1997.RITA Investigators. Interventional versus conservative treatment forpatients with unstable angina or non ST elevation myocardialinfarction: The British Heart Foundation RITA 3 randomized trial.Lancet, 360:743–51, 2002.Serruys, P. W., Ormiston, J. A., Sianos, G. et al. Actinomycin-eluting stentfor coronary revascularization. A randomized feasibility and safetystudy: The ACTION trial. J. Am. Coll. Cardiol., 44:1363–1367, 2004.Sousa, J. E., Costa, M. A., Tuzcu, E. M. et al. New frontiers ininterventional cardiology. Circulation, 111:671–681, 2005.Spertus, J. A., Nerella, R., Kettlekamp, R. et al. Risk of restenosis andhealth status outcomes for patients undergoing percutaneouscoronary intervention versus coronary artery bypass graft. Circulation,111:768–773, 2005.van der Hoeven, B. L., Pires, N. M. M., Warda, H. M. et al. Int. J.Cardiol., 99:9–17, 2005.Vasan, R. S., D’Agostino, R. B., Sr. et al. Age and time need not andshould not be eliminated from the coronary risk prediction models.Circulation, 111:542–545, 2005.Vetrovec, G. W. et al. Optimizing percutaneous coronary interventionoutcomes: The next steps. Circulation, 111:125–126, 2005.Wurdeman, R. L., Hilleman, D. E., and Mooss, A. N. Restenosis, theAchilles’ heel of coronary angioplasty. Pharmacotherapy, 18:1024,1988.

Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor BlockersI. ACE InhibitorsII. Angiotensin II Receptor Blockers (ARB)GLOSSARYACE angiotensin-converting enzyme.afterload arterial impedance, restriction to blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of wall stress.aldosterone a hormone produced by the adrenal glands.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.converting enzyme the same as kininase II.heart failure a failure of the heart muscle to pump sufficientblood from the chambers into the aorta; inadequate supply ofblood reaches organs and tissues.hyperkalemia high levels of serum potassium.hypertrophy increase in thickness of muscle.hypotension marked decrease in blood pressure, usually lessthan 95 mmHg.infarct an area of cardiac necrosis caused by a disruption ofblood supply due to blockage of the supply artery.macula densa specialized cells in the kidney that control sodiumbalance.media the middle wall of the arteries.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.necrotic dead.nephropathy kidney disease.proteinuria a leak of protein from the kidney tubules into theurine.I. ACE INHIBITORSSince their introduction in 1980, angiotensin-convertingenzyme (ACE) inhibitors, because of their uniquepharmacologic properties, have proven superior to othervasodilators in the management of heart failure and havecome to play a key role in the therapy of hypertension.They are particularly useful in hypertensive patients withdiabetes and proteinuria.A. Mechanism of ActionThe sodium concentration in the distal kidney tubules,sensed by the macula densa, controls the release of reninfrom the specialized juxtaglomerular cells located in themedia of the afferent kidney arterioles. Renin is an enzymethat profoundly affects the cardiovascular system. It is aprotease that cleaves the leucine 10–valine 11 bond from thecirculating precursor angiotensinogen to form the decapeptideangiotensin I. ACE in the lungs cleaves histidineleucinefrom angiotensin I, resulting in the formation ofangiotensin II, which produces the effects listed below.1. Vasoconstriction that is more intense than that causedby norepinephrine. This vasoconstriction occursmainly in arterioles and, to a small degree, in veins.This action is more pronounced in skin and in thekidney but with some sparing of vessels in the brainand muscle.2. Renal effects that include marked sodium reabsorptionin the proximal kidney tubules.3. Adrenal effects that cause the release of aldosterone,which enhances sodium and water reabsorption andpotassium excretion in the renal tubule distal to themacula densa. Angiotensin II promotes release ofcatecholamines from the adrenal glands.4. There is an increase in sympathetic outflow thatfacilitates ganglionic stimulation of the sympatheticnervous system.Stimuli to the release of renin include: (1) a decrease inrenal blood flow, hypotension, and reduction of intravascularvolume; (2) sodium depletion or sodium diuresis;and (3) beta-adrenergic receptor activation.61

62ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/ANGIOTENSIN RECEPTOR BLOCKERSACE inhibitors are competitive inhibitors of angiotensin-convertingenzyme and therefore prevent theconversion of angiotensin I to angiotensin II. This actioncauses the salutary effects listed below.1. There is dilatation of arteries which causes a reductionin total systemic vascular resistance resulting in a fall inblood pressure and a reduction in afterload. This allowsthe left ventricle to pump blood more easily into thearterial system. Thus, the left ventricle has less work todo and this action prevents or improves heart failure(see the section Pathophysiology in the chapter HeartFailure).2. There is potentiation of sympathetic activity and therelease of norepinephrine is attenuated. This actioncauses further vasodilatation and reduction in afterload.The effect on the sympathetic nervous system andincreased vagal tone prevents the increase in heart ratethat is observed with other vasodilating agents. Thisimportant action is helpful in the management of heartfailure where tachycardia causes increased work for theheart, and in hypertensive patients it prevents hypertrophy.Other vasodilating drugs are deleterious in thesetwo conditions.3. There is a reduction in aldosterone secretion thatpromotes sodium excretion and potassium retention.This action also prevents or improves heart failure.Unfortunately, aldosterone secretion is not completelysuppressed. Agents that completely suppress aldosteroneare being investigated.4. Converting enzyme is the same as kininase II, whichcauses degradation of bradykinin to inactive peptides.The accumulation of bradykinin appears to stimulatethe release of the important vasodilator nitric oxide(NO) and prostacyclin, which protect the endotheliallining of arteries. This accumulation also contributes toarterial dilation and a further decrease in peripheralvascular resistance and afterload. Thus, ACE inhibitorsare more beneficial than angiotensin receptor blockersthat do not have this salutary effect on bradykinin.Excessive bradykinin, however, may cause angioedemain susceptible individuals.5. ACE inhibitors inhibit vascular superoxide production,and because superoxide reacts with nitric NO, ACEinhibitors appear to increase NO bioactivity. Thisaction, although modest, is important in patients withcoronary artery disease (CAD).6. The modulation and adequacy of the neurohormonalresponse to the long-term administration of ACEinhibitors in heart failure appear to be associated withACE gene polymorphism. Patients with heart failureand aldosterone escape have been shown to have ahigher prevalence of DD genotype compared withpatients who have normal aldosterone levels. A smallstudy indicated that the antihypertensive response toACE inhibition is more pronounced in subjects withACE DD genotype than in those with ACE II genotype.7. The ACE inhibitor captopril has been shown tomodestly reduce high blood uric acid levels. Thisaction may be important in an individual who is givendiuretics that increase uric acid levels. Captopril maycounteract some of this adverse effect.B. Available ACE inhibitorsBelow is a list of available ACE inhibitors.1. Captopril — dosage 12.5–50 mg two or three timesdaily for hypertension and heart failure. The discoveryof captopril, the first ACE inhibitor used in clinicalpractice, provided a major change in the managementof heart failure.2. Benazepril — dosage 5–30 mg daily3. Cilazapril — dosage 1.25–5 mg daily4. Enalapril — dosage 5–40 mg once daily5. Fosinopril — dosage 5–50 mg once daily6. Lisinopril — dosage 5–40 mg once daily7. Perindopril — dosage 2–8 mg once daily8. Quinapril — dosage 5–40 mg once daily9. Ramipril — dosage 2.5 mg or up to 15 mg once daily10. Trandolapril — dosage 0.5–4 mg once dailyAlthough there are more than ten ACE inhibitorscurrently available, it is unfortunate that their actions,indications, and adverse effects are similar. The neweragents have no beneficial effects over and above that of theolder agents captopril, enalapril, and lisinopril that wereavailable during the 1980s; thus the newer agents offer islittle added benefit to patients. Although there are subtledifferences in absorption, elimination by the liver or kidney,and duration of action, these differences do not causebeneficial effects and do not merit further discussion.C. Indications1. HypertensionThese agents are most effective in patients with high serumrenin activity. Younger white patients usually have a higherrenin activity followed by older white patients, and theseagents are particularly effective in the younger whitepatient. They are less effective in older white patients and,unfortunately, are not effective antihypertensive agents inpeople of African origin. The antihypertensive effects in

I. ACE INHIBITORS63patients of Asian and Oriental origin have not beenadequately studied. In addition, they cause effective bloodpressure lowering in less than 60% of white individuals.The addition of a diuretic stimulates renin activity andincreases the antihypertensive effects of ACE inhibitors.Nonetheless, it is not wise to use both agents in patients ofAfrican origin because a diuretic alone should suffice, andthe addition of an ACE inhibitor should be consideredsuperfluous (see the chapter Hypertension).2. Heart FailureThe effectiveness of ACE inhibitors in reducing mortalityand hospitalization in patients with severe heart failurewas first proven in 1987 by the Cooperative NorthScandinavian Enalapril Survival Study (CONSENSUS).The effectiveness of ACE inhibitors in reducing mortalityand hospitalization in patients with a moderate degreeof heart failure has been established in randomized clinicaltrials (RCTs) carried out during the 1990s. Worldwidethere is an epidemic of heart failure. ACE inhibitors areused in combination with diuretics, beta-blockers, anddigoxin in the majority of patients. Although these agentshave provided much relief for suffering patients and havesignificantly decreased mortality, the effect is still modestand newer agents must be sought (see the sectionPathophysiology in the chapter Heart Failure).3. Acute Myocardial InfarctionACE inhibitors are particularly useful in patients with anacute myocardial infarct and in whom the left ventricularfunction is moderately impaired. An infarct is an area ofcardiac necrosis caused by a disruption of blood supply dueto blockage of the supply artery. The necrotic muscleproduces an area of weak heart muscle that may impair theoverall contractile force of the powerful left ventricle andculminate in heart failure within days, months, or years.During the first few hours and days following an acutemyocardial infarct, probably because of weakness of theventricular muscle, there is stimulation of the reninangiotensinsystem resulting in increased stretch of theventricular muscle and mild-to-moderate cardiac enlargementoccurs. This deleterious process is called ventricularremodeling. The remodeling process is decreased significantlyby ACE inhibitor therapy and morbidity andmortality is also decreased. Studies that show the efficacyof ACE inhibitors in patients with acute myocardialinfarction are illustrated in the chapter Heart Attacks.ACE inhibitors are recommended in most patients whohave coronary heart disease, and particularly in diabetics.This is based on the Heart Outcomes PreventionEvaluation (HOPE) study, which showed that in highriskpatients ramipril 10 mg, given for 4.5 years, caused a22% reduction in the primary outcome of myocardialinfarction, stroke, or death from cardiovascular causes.The EUROPA study, which included 13655 patientswith previous myocardial infarction (64%), angiographicevidence of coronary artery disease (61%), and coronaryrevascularization (55%) were randomized to perindopril8 mg once daily or matching placebo. After a mean followup of 4.2 years, perindopril administration causedimprovement in outcome: about 50 patients needed tobe treated for a period of 4 years to prevent one majorcardiovascular event. Total mortality was 11% withperindopril, but this finding was not significant.D. Research ImplicationsAt the cellular level the renin-induced increased aldosteronelevels promote myocardial fibrosis and collagendeposition that lead to a stiff ventricle and progressivedecrease in normal left ventricular function. Treatmentwith ACE inhibitors appears to prevent nonmyocytecellular proliferation and collagen deposition improvingmyocyte contractile function. Direct aldosterone antagonistsare being investigated and research is needed in thisimportant area. Direct rennin inhibitors and analogsrequire further research. Candidate molecules for therapeuticuse have thus far been elusive.ACE inhibitor therapy appears to have a favorable effecton atherosclerosis, which is the major cause of obstructionto the flow of blood through arteries resulting in infarctsthat may occur in the heart or the brain (stroke). It appearsthat angiotensin II causes vasoconstriction and promotesthe growth and migration of vascular smooth muscle cellsinto the media. An increase in smooth muscle cell enzymecauses an increase in free radical production, whichpromotes the oxidation of low-density lipoprotein (LDL)cholesterol and the progression of the atheroscleroticprocess. Other favorable effects include an improvementin endogenous fibrinolytic function and vasodilatationproduced by bradykinins, prostaglandins, and the powerfulvasodilator NO (see the chapter Atherosclerosis/Atheroma).The incidence of sudden death appears to be reducedby ACE inhibitor therapy. Apart from a prevention ofthe deterioration in abnormal left ventricular function,patients treated with ACE inhibitors appear to have areduction in arrhythmias. This may be explained bythe decrease in the release of catecholamines that isincreased by angiotensin II. Excess catecholamines have

64ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/ANGIOTENSIN RECEPTOR BLOCKERSbeen documented to cause serious arrhythmias, and theirblockade by the beta-blocking drugs results in the provenbeneficial effects of these agents. Patients carrying the ACEDD genotype with angiotensin II type 1C allele appear tobe at higher risk for serious ventricular arrhythmias.ACE 2 has recently been defined. The renin-angiotensinsystem is obviously much more complicated than extensiveresearch over the past 20 years has suggested. The recentlydiscovered enzyme ACE 2 has beneficial effects on thefunction of the heart. ACE 2 converts angiotensin I toangiotensin 1–9 containing 9 amino acids that can beconverted by ACE to a shorter peptide angiotensin 1–7,a dilator of blood vessels whereas angiotensin II containing8 amino acids is a potent vasoconstrictor (see Fig. 1).Thus, ACE 2 appears to prevent the formation ofexcess angiotensin II, and this action is beneficial. Itappears that ACE 2 increases cardiac contractility, hascardioprotective properties, and may be an importantLIVERAngiotensinogenAngiotensinogenANGIOTENSIN IANGIOTENSIN IAdrenalsKIDNEYRENINACE 2*ANGIOTENSIN1−9ANGIOTENSIN1−7Arterial DilatorACELUNGSANGIOTENSIN II8 amino acidsArterial ConstrictorAldosteroneNa + andwaterReabsorptionAORTAAT 1 ReceptorsArteriesConstrictions=after loadBPCardiac workmuscle wall stressMyocardial fibrosisand subtle cardiac damageLeft ventricleFIGURE 1 Renin- angiotensin- aldosterone system: action on the heart and arterial system. * ACE 2 may counteract some of the effects of ACE activity.Angiotensin 11 action, however, must prevail to maintain adequate blood pressue to the brain and vital organs during catastrophic events: nature’s way ofsurvival. ACE ¼ angiotensin converting enzyme; AT1 ¼ angiotensin 11 activates two subtypes of angiotensin 11 receptors: AT1 and AT2, but only AT1mediates clinical effects of angiotensin 11.

II. ANGIOTENSIN II RECEPTOR BLOCKERS65regulator of cardiac function. Intensive research is requiredto obtain compounds that could increase the productionof beneficial ACE 2 and decrease the deleterious actionsof angiotensin II.E. Adverse EffectsBelow is a list of adverse affects of ACE inhibitors.1. Hypotension may occur if the dose of ACE inhibitoris excessive, particularly if a diuretic is used before theaddition off the ACE inhibitor. Lightheadedness,dizziness, and a faint feeling may occur. The initialdose should be small in elderly patients and in patientswith heart failure.2. Kidney failure may become worse if hypotensionoccurs or if the patient has severe obstruction in onerenal artery or tight renal artery stenosis. Fortunately,renal artery stenosis is uncommon.3. Hyperkalemia may occur if kidney failure is progressiveor if a potassium-sparing diuretic, potassiumsupplements, or salt substitutes are added to thetreatment regimen.4. Cough occurs in up to 20% of patients; it issufficiently bothersome to promote the discontinuationof medications in about 10% of treated patients.Cough occurs because of the accumulation ofbradykinin.5. Loss of taste has been reported in up to 7% ofpatients.6. Extensive skin rash with severe itching may occur ingreater than 10% of patients.7. Angioedema is a life-threatening complication thatoccurs in approximately 0.8% of patients. Bradykininand kallidin mediate hereditary angioedema. ACEinhibition results in the accumulation of bradykininwhich can cause angioedema. Swelling of the eyelids,lips, and tongue may occur. Most important, swellingof the upper airway may obstruct air entry to the lungand death can occur if treatment is not immediatelyavailable.F. InteractionsLithium levels may increase, and interactions may occurwith immunosuppressive agents and those that alter theimmune response.II. ANGIOTENSIN II RECEPTOR BLOCKERSAngiotensin II receptor blockers (ARBs) have beneficialeffects similar to those of ACE inhibitors, but angioedemaoccurs less, and cough rarely occurs compared to ACEinhibitors.A. Mechanism of ActionAngiotensin I can be formed by nonrenin enzymes such ascathepsin or tonin. Angiotensin I may be converted toangiotensin II by trypsin, cathepsin, or the heart chymase,but the exact contribution of these alternative pathwaysto the formation of angiotensin II remains unclear.Angiotensin II activates two subtypes of angiotensin IIreceptors, AT1 and AT2, but only the AT1 receptormediates all the known clinical effects of angiotensin IIdescribed above in Section I. AT1 receptors are present inthe heart, kidney, vascular smooth muscle cells, brain,adrenal glands, platelets, the placenta, and in adipocytes.The AT2 receptor affects the inhibition of cell growth,promotion of cell differentiation, tissue repair, apoptosis,and perhaps to a small degree, the production ofbradykinin, NO, and prostaglandins in the kidney. Othereffects may emerge with further research. The AT2receptors have been cloned and are present at a low levelin the adrenal gland, heart, brain, kidney, and uterus.ARBs were expected to have clinical effects that wouldbe equal to or superior to those observed with ACEinhibitors. Clinical trials during the past five years haveindicated that these agents reduce microalbuminuria andglomerulopathy and delay time to end-stage renal diseasein patients with type 2 diabetes. ACE inhibitors have beenshown to be useful in causing similar beneficial effectsin patients with type 1 diabetes, but evidence in type 2diabetic nephropathy is not convincing. Direct comparisonof ARBs with ACE inhibitors in this subset of patientshas not been tested. Head-to-head trials of ARBs and ACEinhibitors in diabetic nephropathy need to be conducted todetermine their respective place in renoprotection.Dual blockade of the renin-angiotensin-aldosteronesystem with both candesartan 16 mg once daily and lisinopril20 mg daily has been shown to be better than eithertreatment alone in reducing blood pressure and betterthen candesartan alone in reducing microalbuminuria.B. Available Angiotensin Receptor BlockersSeveral selective AT1 receptor blockers have becomeavailable. They have a high affinity for AT1 receptorsand negligible affinity for AT2 receptors. These include:1. Candesartan — dosage 4–16 mg daily, maximum32 mg once daily2. Irbesartan — dosage 150–300 mg once daily

66ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/ANGIOTENSIN RECEPTOR BLOCKERS3. Eprosartan — dosage 300–400 mg twice daily4. Losartan — dosage 25–100 mg once daily5. Telmisartan — dosage 28–80 mg once daily6. Valsartan — dosage 40–160 mg once dailyC. Clinical Trials1. The Losartan Heart Failure Survival Study ELITE IIStudy question: Is losartan superior to captopril inimproving survival?Methods: A double-blind RCT of 3152 patients withheart failure, was randomly assigned losartan (1578)titrated to 50 mg once daily or captopril (1574) titratedto 50 mg three times daily.Results: At a median follow up of 555 days there wereno significant differences in mortality or sudden deathbetween the two treatment groups.Perspective: Losartan was not superior to the ACEinhibitor captopril in improving survival in patientswith heart failure. Fewer patients in the losartan groupdiscontinued study treatment, however, because ofadverse effects (9.7 vs. 14.7%; p < 0.001).2. The Effect of Irbesartan on the Development ofDiabetic Nephropathy in Patients with Type 2 DiabetesStudy question: What is the effectiveness of irbesartan indelaying or preventing the development of diabeticnephropathy in hypertensive patients with type 2 diabetesand persistent microalbuminuria?Methods: 590 hypertensive patients with type 2diabetes and microalbuminuria were enrolled in thisRCT. One group received 150 mg irbesartan, while asecond group received 300 mg, and the placebo groupreceived other antihypertensive agents.Results: Ten of the 194 patients in the 300-mg group(5.2%) and 19 of the 195 patients in the 150-mg group(9.7%) reached the primary end point as compared with30 of the 201 patients in the placebo group (14.9%;p < 0.001). The primary end point was persistent withmore severe albuminuria with an albumin excretion ratethat was greater than 200 g per minute and at least50% higher than the baseline level. The 150-mg dose wasnot significantly different from the placebo. Thus, the 300-mgdosage is recommended.Perspective: ACE inhibitors have been shown to slowthe progression of diabetic nephropathy in patients withtype 1 diabetes and microalbuminuria. ACE inhibitorshave not been tested in patients with type 2 diabetes.Irbesartan is renoprotective in hypertensive patients withtype 2 diabetes and microalbuminuria, and the beneficialeffect is independent of the drug’s ability to lower bloodpressure. A similar RCT with another ARB showed similarbeneficial effects.3. CHARM Program of Trialsa. The CHARM–Alternative TrialMethods: In this study 2028 patients were used toexamine the effects of the ARB candesartan in patientswith reduced left ventricular ejection fraction less than40% who were intolerant of ACE inhibitors.Methods: Treated patients received candesartan 4–8 mgtitrated to 32 mg once daily plus the treatment given toplacebo patients. Standard heart failure therapy includesdiuretics, beta-blockers, digoxin, and spironolactone (85,54, 45, and 24%, respectively).Results: After 33.7 months follow up, patientsadministered candesartan were 23% less likely to experiencecardiovascular death or hospitalization for heartfailure compared with those who received placebo (40%vs. 33%; p ¼ 0.0004).b. The CHARM–Added TrialMethods: This trial examined the effect of candesartan onpatients who were already on ACE inhibitors, the majorityof whom were on a beta-blocker.Results: After 41 months of follow up, patientsreceiving candesartan were 15% less likely to experiencethe primary end point compared with those given placebo(42% vs. 37.9%; p ¼ 0.0011). This result occurredregardless of whether or not patients were on a betablockerand independent of the dose of ACE inhibitorused. The addition of candesartan to an ACE inhibitorplus a beta-blocker leads to further clinically importantreduction in cardiovascular death and hospitalizationfor heart failure. When the combination of candesartanand ACE inhibitors is administered, however, monitoringof serum creatinine and hyperkalemia is necessary.This is even more important if eplerenone or spironolactoneare used in the heart failure treatment regimen.There is no unfavorable interaction when candesartanand a beta-blocker are used in combination as opposed tothat shown with a losartan beta-blocker combination.Most important, ARBs like beta-blockers have subtleand important clinical differences that must be defined.

II. ANGIOTENSIN II RECEPTOR BLOCKERS67BIBLIOGRAPHYBourassa, M. G. et al. Angiotensin II inhibition and prevention of atrialfibrillation and stroke. J. Am. Coll. Cardiol., 45:720–721, 2005.Burnier, M. Angiotensin II type 1 receptor blockers. Circulation,103:904–91, 2001.CHARM: Granger, C.B., McMurray, J.J.V., Yusuf, S. et al. for theCHARM Investigators and Committees. Effects of candesartan inpatients with chronic heart failure and reduced left ventricular systolicfunction intolerant to angiotensin converting enzyme inhibitors; theCHARM-alternative trial. Lancet, 362:772–76, 2003.EUROPA: The European trial on reduction of cardiac events withperindopril in stable coronary artery disease investigators. Efficacy ofperindopril in reduction of cardiovascular events among patients withstable coronary artery disease: Randomized double-blind placebocontrolledmulticenter trial. Lancet, 362:782–88, 2003.Heagerty, A. M. et al. Influence of changes of blood pressure on vascularangiotensin II receptor subtype expression. Circulation, 111:956–57,2005.HOPE Investigators. Yusuf, S, Sleight, P, Progue, J. et al. The HeartOutcomes Prevention Evaluation Investigators: Effects of angiotensinconverting enzyme inhibitor, ramipril, on death from cardiovascularcauses, myocardial infarction, and stroke in high-risk patients. N. Engl.J. Med., 342:145, 2000.Ishani, A., Weinhandl, E., Zhao, Z. et al. Angiotensin-convertingenzyme inhibitor as a risk factor for the development of anemia,and the impact of incident anemia on mortality in patients with leftventricular dysfunction. J. Am. Coll. Cardiol., 45:391–399, 2005.Khan, M. Gabriel ACE Inhibitors in Cardiac Drug Therapy, sixth edition.W.B. Saunders, Philadelphia, 2003.Munzel, T., and Keaney, J.F. Are ACE inhibitors a ‘‘magic bullet’’ againstoxidative stress? Circulation, 104:1571–1574, 2001.Parving, H.-H., Lenhert, H., Brochner-Mortensen, J. et al. for theirbesartan in patients with type II diabetes and microalbuminuriastudy group: The effect of irbesartan on the development of diabeticnephropathy in patients with type II diabetes. N. Engl. J. Med.,345:870, 2001.Pitt, B., Poole-Wilson, P.A., Segal, R. et al. ELITE II — effect of losartancompared with captopril on mortality on patients with symptomaticheart failure: Randomized trial. The Losartan Heart Failure Study.Lancet, 255:1582, 2000.Wachtell, K., Lehto, M., Gerdts, E. et al. Angiotensin II receptor blockadereduces new-onset atrial fibrillation and subsequent stroke comparedto atenolol. J. Am. Coll. Cardiol., 45:712–719, 2005.

Antihistamines1. Histamine AntagonistsGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.palpitation rapid heart rate; the patient feels the heartbeat.THESE WELL-KNOWN ANTIALLERGY MEDICATIONSmay occasionally cause an increase in the pulse rate becausethey have an atropine-like effect. In some individuals, theheart rate may become rapid. These sensations, calledpalpitations and caused by arrhythmia, subside over timeand usually cause no harm. Patients with angina, however,should be cautious with the use of antihistamines, becausean increase in heart rate may trigger an attack of angina.Blood pressure is usually not increased by antihistamineuse, but many remedies containing antihistamines containthe decongestant phenylpropanolamine, which elevatesblood pressure. This should be avoided by patients withhypertension and angina.I. HISTAMINE ANTAGONISTSThese newer agents differ from the general group ofantihistamines in that they are more selective blockers ofspecific histamine H1 receptors. They do not produce thebothersome side effects usually noted with antihistamines,such as drowsiness and dry mouth. Unlike antihistamines,they are safe in patients with glaucoma or enlargement ofthe prostate. Older histamine H1 antagonists includeastemizole and terfenadine. These agents are generally safe,but abnormal heart rhythms, palpitations, transient lossof consciousness, and cardiac arrest have been reported.The electrocardiographic findings include an increase inthe QT interval. Agents that also increase the QT intervalshould not be taken concurrently with these H1antagonists.These agents are broken down in the liver. Thus,patients with liver disease or those using drugs thatinterfere with liver enzymes, such as the antibioticerythromycin, may be predisposed to arrhythmias. Patientstaking agents with a similar chemical structure —fluconazole, itraconazole, and metronidazole (Flagyl) —may have a greater predisposition to developing bothersome,and even serious, abnormal heart rhythms. Patientswith heart disease, those on diuretics or agents that reducethe levels of potassium in the blood, should not takeastemizole or terfenadine. The antibiotics erythromycin,azithromycin, and clarithromycin or similar types ofantibiotics should not be taken concurrently.Newer histamine antagonists such as cetirizine andloratadine have not been noted to cause serious arrhythmias,but surveillance and caution are needed in patientswith heart disease or in those taking diuretics and othersubstances that can lower blood potassium.BIBLIOGRAPHYKhan, M. Gabriel Effects of Drug Interactions. In Cardiac Drug Therapy,sixth edition. W. B. Saunders, Philadelphia, 2003.69

AntioxidantsI. StatinsII. Vitamin EIII. Vitamin CIV. Beta-CaroteneV. Mediterranean DietVI. Dietary Plant-Derived FlavonoidsVII. French Red WineVIII. ProbucolGLOSSARYatherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the flow of blood; the plaque ofatheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).cardioprotection protection of the heart from serious eventsthat include coronary artery disease and its complications,angina, myocardial infarction, and heart failure.flavonoid any of a large group of crystalline compounds foundin plants.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood and atheroma; medicalterm for a heart attack or coronary thrombosis.STEINBERG ET AL. WERE AMONG THE FIRST TOindicate that modified low-density lipoprotein (LDL)cholesterol could be responsible for the accumulationof lipid within macrophages, a crucial step in the earlyformation of atheromatous plaques.Only some antioxidants prevent the oxidation ofLDL cholesterol, which plays an important role in thepathogenesis of the atherosclerotic process and its progressionto blockage of arteries (see the chapter Atherosclerosis/Atherothrombosis).The harmful effect of LDLcholesterol is augmented by oxidized LDL cholesterolparticles. Prevention of the oxidation of LDL cholesterolparticles by chemical agents and natural products is an areaof intensive research. Natural substances and chemicalcompounds, which may protect lipids from attack byoxygen free radicals increase resistance to lipid peroxidation,reverse endothelial dysfunction, and increase nitricoxide (NO) mediated vasodilation will remain an interestingarea of research and development, despite thenegative results observed in many clinical trials.It is important to emphasize that it is not certain exactlywhere and how LDL cholesterol gets oxidized within thehuman body. More important, vitamin C is a water-solublevitamin and is thus confined to the extracellular fluids butvitamin E gains entry into lipoproteins. It is known thatlarge doses of beta-carotene do not prevent LDL oxidation.Thus, antioxidants have subtle and important differencesthat impact on their probable therapeutic benefits.After the past few years of conflicting results, the criticalquestion remains: Do antioxidants actually work? The roleof antioxidants in protecting people against heart diseaseremains controversial. There appears to be little doubt,however, that antioxidants present in the Mediterraneandiet possess cardioprotective effects; recent experimentalwork indicates that French red wines are cardioprotectivebeyond the effect on increasing HDL cholesterol. (Seechapter entitled ‘‘Alcohol and the Heart.’’)I. STATINSStatins are well-known, cholesterol-lowering agents. Theyare competitive inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, which is the keyenzyme catabolizing the early rate-limiting step in the biosynthesisof cholesterol within the hepatocyte. They lowerLDL cholesterol in blood and thus prevent heart attacksand death from myocardial infarction as well as strokes.More important, statins have been shown to prevent lipoproteinoxidation, and it is believed that some of theirsalutary effects may be related to this action. They appearto improve survival in patients with ischemic and nonischemicheart failure. Nitric oxide synthesis is diminishedin heart failure; statins enhance endothelial NO synthase(eNOS) activity and improve endothelial function (see thesection Statins in the Dyslipidemia chapter).71

72ANTIOXIDANTSII. VITAMIN EAntioxidant nutrients, particularly vitamin E, are stillwidely used with the hope of preventing cancer, heartdisease, and dementia. Although, clinical trials have notshown protection from cancer, the correct ‘‘protective’’dose may not have been used in some trials. Also, thepartially favorable effect of vitamin E on amyloid depositionin the brain and its effect on dementia remains tobe clarified.Vitamin E is a fat-soluble vitamin found in vegetablesand seed oils, particularly soybean and safflower, andsunflower seeds, corn, nuts, whole grains, and wheat germ.Increased dietary intake has not been shown to decrease theincidence of heart disease or cancer. With aging, however,the vitamin E content of blood platelets decreases; thisaction may predispose individuals to clumping of plateletsand cause a risk of clotting. The elderly may thus benefitfrom some vitamin supplements.A. Clinical Studies1. United States StudyA large-scale study in the United States showed a reductionin the relative risk of coronary heart disease only inmiddle-aged women who took vitamin supplements formore than two years. In men, a borderline beneficial effectwas observed for those taking above 100 IU daily forover two years.2. The Health Professionals Follow-Up StudyThis study included approximately 40,000 men. It showedthat males who consumed more than 400 IU daily had a40% reduction in the risk of heart disease compared withindividuals with the lowest intake of vitamin E. A studyinvolving 121,000 nurses reported a 34% decrease in riskof heart disease among women taking greater than 200 IUdaily.3. Cambridge Heart Antioxidant StudyThe Cambridge Heart Antioxidant Study (CHAOS)examined the effect of vitamin E in patients withangiographic-proven severe heart disease. This studyrandomized 2002 patients to vitamin E, 400–800 IU orplacebo. The mean age of the patients was 61.8 years.The baseline characteristics of patients are shown inTable 1. Most important, patients were enrolled immediatelyafter coronary angiography. More than 62% hadsevere triple- or double-vessel disease; more than 90%of patients had angina, evidence of reversible myocardialischemia, or both and approximately 9% were diabetics.Thus, this was a high-risk group of patients.After median follow up of 1.4 years, there was a benefitin the combined end point of nonfatal myocardialinfarction and cardiovascular death with a risk reduction of47% (41 vs. 64 events). Patients receiving vitamin E had aremarkable 77% reduction in myocardial infarction (41 inthe placebo vs. 14 in the vitamin E group). The powerfulcholesterol-reducing agents, statins, have not shown sucha decrease in nonfatal heart attacks. This study appearsto have been condemned because no effect on cardiacmortality was observed. The benefit was due mainly toreduction in risk of nonfatal myocardial infarction. It issurprising that this well-conducted study is unjustlydiscarded, mainly because of the results of the HOPEstudy (see Section I.A.6 below). It appears that someexperts believe that the prevention of nonfatal myocardialinfarction in high-risk patients is of no consequence. Thebeneficial effects of treatments that possess marginal butimportant beneficial effects may only be observed withcorrect dosing, and only after several years of intake of theparticular substance administered to patients at high risk.4. The SPACE StudyThe Secondary Prevention with Antioxidants of CardiovascularDisease in End-Stage Renal Disease (SPACE)study is a study of a small, high-risk group of patients:196 patients on hemodialysis with cardiovascular diseasefollowed for a median of 519 days. The vitamin E groupdecreased the relative risk for a composite primary endpoint of myocardial infarction, ischemic stroke, peripheralvascular disease, and unstable angina by 54%.A similar study involving a group of 40 cardiac transplantpatients treated for one year with 400 IU of vitaminE given twice daily for one year caused less coronaryprogression compared with those not given vitamins ( p ¼0.008). In cardiac transplant patients accelerated atherogenesiscommonly occur.5. Alpha Tocopherol Beta-Carotene CancerPrevention TrialIn this trial men were randomized to receive only 50 mgdaily of vitamin E, beta-carotene 20 mg daily, bothvitamins, or placebo. After mean follow up of 5.3 yearsthe four groups had similar rates of major coronary events,but there appeared to be an increased risk of hemorrhagicstroke in individuals administered vitamin E. The use of

IV. BETA-CAROTENE73low doses of different sources of vitamin E may haveaccounted for the differences in results between this studyand the CHAOS study.6. Heart Outcomes Prevention Evaluation TrialThe Heart Outcomes Prevention Evaluation (HOPE) trialenrolled a total of 2545 women and 6996 men 55 years ofage or older at high risk for cardiovascular events becausethey had cardiovascular disease or diabetes in addition toone other risk factor. Patients were randomly assigned toreceive either 400 IU of vitamin E daily from naturalsources or matching placebo and either an angiotensinconvertingenzyme (ACE) inhibitor or matching placebofor a mean of 4.5 years. The primary outcome was a compositeof myocardial infarction, stroke, and death fromcardiovascular causes. This remarkable study, however, wasnot an independent study of vitamin E. Most important,this widely quoted study included 38% diabetics (theaverage in most cardiovascular studies worldwide rangefrom 7 to 12%). This percentage of diabetics does notrepresent the population at large. In addition, there is onlya hypothetical risk for the study group; patients werenot selected after coronary angiograms as was done forthe CHAOS study; thus, the HOPE studied apples andoranges.In this study a total of 772 of the 4761 patients assignedto vitamin E (16.2%) and 739 of the 4780 (15%) assignedto placebo had a primary outcome event. There were nosignificant differences in the number of deaths fromvascular causes or fatal or nonfatal myocardial infarction.This large, widely touted randomized study, despite itsmethodology, unfortunately is likely to put an end tofurther clinical trials of vitamin E.Gotto et al. emphasized that ‘‘we cannot discountthe oxidation hypothesis in human atherosclerosis, andexperiments to date have only illustrated the difficultiesin testing this complex issue.’’III. VITAMIN CAlthough vitamin C, ascorbic acid, is one of the mostimportant antioxidants in extracellular fluids, it trapsperoxyl radicals and inhibits lipid peroxidation. Severalstudies indicate that there is no apparent benefit in theprevention of cardiovascular disease with use of vitamin C.1. The Nurse’s Prospective Observational Study of 87,000female nurses followed for a mean of 8 years andhealth professionals study in which 39,000 male healthprofessionals were followed for 4 years showed noreduced risk for coronary revascularization, myocardialinfarction, or death from coronary heart disease amongpersons using vitamin C.2. A randomized controlled trial carried out in Chinafound no reduction in total mortality or mortality fromcardiovascular diseases in 29,584 healthy adults givenvitamin C over 5 years.Vitamin C is known to have antioxidant properties, butits effects appear to be modest and may only be observed inpatients at very high risk; this includes patients with heartfailure in whom vitamin C has not been adequately tested,particularly in combination with vitamin E. Ascorbicacid has been shown to normalize endothelial functionby restoring NO-mediated vasodilatation of endotheliumin patients with hypertension, but it does not cause alowering of blood pressure.7. Vitamin E in Heart FailureRandomized trials to examine the benefits of vitamin Ehave not been carried out in patients with heart failure.A small study of patients with dilated cardiomyopathyshowed that the combination of vitamin E and C reducedplasma levels of malondialdehyde and superoxide anionand elevated the levels of antioxidant enzymes. The combinedtreatment with vitamin C and E has been shownto suppress neutrophil-mediated free radical productionand lower blood lipid peroxidation product in patientswith acute myocardial infarction. The role of vitamin Eeither alone or in combination with vitamin C in patientswith heart failure deserves to be further studied, particularlybecause oxidative stress is present in the failingheart.IV. BETA-CAROTENEResults of several clinical trials indicated that beta-carotenesupplementation is not beneficial in the prevention ofcardiovascular disease or its complications.1. The Carotene and Retinol Efficacy Trial (CARET) trialincluded 8314 men and women with a history ofcigarette smoking or occupational exposure to asbestosreceiving beta-carotene (30 mg per day), and retinol(25,000 IU per day). This trial was stopped earlybecause the incidence of mortality from lung cancerwas excessive. However, the population studied in thesetrials was already at high risk for lung cancer.2. The physician’s health study randomized 22071 malephysicians taking beta-carotene (50 mg per day),

74ANTIOXIDANTSaspirin 325 mg, both, or neither for 12 years. Therewere no cardiovascular benefits from beta-caroteneadministration.3. In the Alpha Tocopherol Beta-Carotene Cancer PreventionTrial (ATBC) the effects of daily doses of 50 IUof vitamin E, 20 mg of beta-carotene, both, or placebofor 5 to 8 years in 29133 smokers with a previousmyocardial infarct were monitored. The study foundno reduction in risk for major coronary events with anyof the antioxidants.V. MEDITERRANEAN DIETThe Mediterranean diet contains a substantial amountof antioxidants and has been shown to be substantiallycardioprotective. However, there are many other cardioprotectivefacets in this diet, including an abundance ofbeneficial alpha-linolenic acid (see the chapter Diets andHeart Disease).VI. DIETARY PLANT-DERIVEDFLAVONOIDSThese naturally derived products from several sourcesincluding red grape juice, red wine, soy products, andnuts (particularly almonds, walnuts, and hazel nuts), arereceiving attention for their antioxidant and cardioprotectiveproperties.A. Purple Grape Juice1. Freedman et al. StudyMethods: The effect of purple grape juice supplementationwas assessed in vivo in 20 healthy subjects. Welch’sgrape juice, 7 ml/kg, was administered for 14 days andused on isolated platelet preparations. Major polyphenoliccompounds in purple grape juice were isolated andseparated into four classes: flavonols (quercetin), cinnamicacids, anthocyanins, and polyflavan-3-ols (tannins).Results: Incubation of platelets with purple grapejuice led to reduced dependent inhibition of adenosinediphosphate induced aggregation and a dose-dependentdecrease in superoxide release, which was associated withan increase in platelet NO production. Similar in vivofindings occurred following two weeks of purple grapejuice consumption. Plasma antioxidant activity increasedby 50%.Conclusion: Both oral supplementation and in vitroincubation with purple grape juice decreases plateletaggregation, increases platelet-derived NO, and decreasessuperoxide production. The suppression of plateletmediatedthrombosis represents a potential mechanismfor the beneficial effects of purple grape products, independentof alcohol consumption.VII. FRENCH RED WINEFrench red wine appears to be more cardioprotectivethan wine from other countries. Although the data fordifferences in red and white wine remain controversial, andit appears that all alcoholic beverages carry somecardioprotective properties, it seems that French red winepossesses further cardioprotective properties.In a German study by Wallerath et al., three Germanand six French red wines were assessed. The study testedthe effect of red wine on endothelial-type NO synthaseexpression, eNOS expression, and eNOS activity inhuman endothelial cells. Incubation of endothelial cellswith red wines from France upregulated eNOS, mRNAand protein expression. In contrast, red wines fromGermany showed little or no effect on eNOS expression.Endothelial cells treated with French red wine producedup to three times more bioactive NO than control cells.French red wines increased the activity of other eNOSpromoters, with a transstimulated sequence located in theproximal 326 bp of the promoter sequence. The eNOSmRNA stability was also increased by red wine. Nosignificant difference in the Enos mRNA expressioncould be detected between the ‘‘en barrique’’ (maturedin oak barrels) and ‘‘non-barrique’’ (matured in steel tanks)produced French wines.Long-term, French red wine consumption in lowdoses could involve an upregulation of eNOS expression.This would lead to moderate, but sustained elevations ofvascular NO.The numerous phenolic acids, polyphenols, and flavonoidscontained in French red wines are likely constituentsprobably mediating the expressional upregulation ofEnos. French red wines contain high polyphenol levelscompared with wines from other regions leading to anenhanced production or bioactive NO. Apart from theother known beneficial effects of red wine on dyslipidemia,the enhanced NO activity could contribute to furthercardiovascular protection beyond that observed withother alcoholic beverages. In addition, the followingobservation may be relevant: red wine may have specificanti-inflammatory and antiproliferative effects. The acuteadministration of red wine reduces the increase in nuclearfactor kb (NF–kB) responsible for promoting the expressionof several inflammatory genes resulting from a

VIII. PROBUCOL75high-fat meal, a finding that has not been observed forvodka. This finding and the study by Cuveas et al.suggested that red wine may be particularly cardioprotectivein individuals consuming high-fat diets. These twoimportant findings may explain the French paradox(see the chapter Alcohol and the Heart).VIII. PROBUCOLTwo small studies have demonstrated that probucol, a drugused in the 1970s for lowering serum cholesterol, whichwas abandoned because of adverse effects, has importantadditional antioxidant properties. Probucol significantlyreduces restenosis when administered one month beforeand continued for six months after percutaneous transluminalcoronary angioplasty (PTCA). The small group,317 patients, used in these studies limits the conclusionsregarding the benefits of this drug.Because several clinical trials during the past 20 yearshave not altered the restenosis rate after PTCA, which stillremains at more than 33%, any agent or natural productthat reduces restenosis rates would be a welcome additionto the cardiologic armamentarium.BIBLIOGRAPHYAppeldoorn, C. C. M., Bonnefoy, A., Bianca, C. H. et al. Gallic acidantagonizes P-Selectin – mediated platelet – leukocyte interactions:Implications for the French paradox. Circulation, 111:106–112, 2005.ATBC: The Alpha Tocopherol Beta-carotene Prevention Study Group.The effect of vitamin E and beta-carotene on the incidence of lungcancer and other cancers in male smokers. N. Engl. J. Med.,330:1029–35, 1994.Blanco-Colio, L. N., Valderrama, M., Alvarez-Sala, L. A. et al. Red wineintake prevents nuclear factor-kB activation in peripheral bloodmononuclear cells of healthy volunteers during postprandial lipemia.Circulation, 102:1020–6, 2000.Brown, B. G., Crowley, J. et al. Is there any hope for vitamin E? JAMA,293:1387–1390, 2005.Cuveas, A. M., Guasch, V., Castillo, O. et al. A high-fat diet inducesand red wine counteracts endothelial dysfunction in humanvolunteers. Lipids, 35:143–8, 2000.Freedman, J. E., Parker, C., and Li, L. Select flavonoids and whole juicefrom purple grapes inhibit platelet function and enhance nitric oxiderelease. Circulation, 103:2792–8, 2001.GISSI-Prevenzione Investigatos (Gruppo Italiano per lo Studio dellaSopravvivenza nell’Infarto Miocardico). Dietary supplementation withn-3 polyunsaturated fatty acids and vitamin E after myocardialinfarction: results of the GISSI-Prevenzione trial. Lancet, 354:447–55,1999.Gotto, A. M. Antioxidants, statins and atherosclerosis. J. Am. Coll.Cardiol., 41:120, 5–10, 2003.Heart Protection Study Collaborative Group. MRC/BHF HeartProtection Study of antioxidant vitamin supplementation in 20,536high-risk individuals: A randomized placebo-controlled trial. Lancet,360:23–33, 2002.Henriksen, T., Mahoney, E. M., and Steinberg, D. Enhanced macrophagedegradation of low-density lipoprotein previously incubated withcultured endothelial cells: Recognition by receptors for acetylated lowdensitylipoproteins. Proc. Natl. Acad. Sci. U.S.A., 78:6499–503, 1981.Horwich, T. B., MacLelland, R., and Fonarow, G. C. Statin therapy isassociated with improved survival in ischemic and nonischemic heartfailure. J. Am. Coll. Cardiol., 43:642–648, 2004.Sacks, F. M. et al. Dietary phytoestrogens to prevent cardiovasculardisease: Early promise unfulfilled. Circulation, 111:385–387, 2005.Shite, J., Fuzhong, Q., Weike, M. et al. Antioxidant vitamins in dilatedcardiomyopathy. J. Am. Coll. Cardiol., 38:1734–40, 2001.Singh, R. B., Niaz, M. A., Rastogi, S. et al. Usefulness of antioxidantvitamins in suspected acute myocardial infarction (the Indianexperiment of infarct survival-3). Am. J. Cardiol., 77:232–6, 1996.Steinberg, D., Parthesarathy, S., Carew, T. E. et al. Beyond cholesterol:Modifications of low-density lipoprotein that increase its atherogenicity.N. Engl. J. Med., 320:915–924, 1989.Stephens, N. G., Parsons, A., Schofield, P. M. et al. Randomizedcontrolled trial of vitamin E in patients with coronary disease:Cambridge Heart antioxidant study (CHAOS). Lancet, 347:781–6,1996.Szmitko, P. E., Verma, S. et al. Red wine and your heart. Circulation,111:e10–e11, 2005.Tardif, J. C., Cote, G., Lesperance, J. et al. Probucol and multivitamins inthe prevention of restenosis after coronary angioplasty. N. Engl. J.Med., 337:365, 1997.The Heart Outcomes Prevention Evaluation [HOPE] Study Investigators.Vitamin E supplementation and cardiovascular events in high-riskpatients. N. Engl. J. Med., 342:154–60, 2000.The HOPE and HOPE-TOO Trial Investigators.* et al. Effects of longtermvitamin E supplementation on cardiovascular events and cancer arandomized controlled trial. JAMA, 293:1338–1347, 2005.Vogel, R. A. Vintners and vasodilators: Are French red wines morecardioprotective? J. Am. Coll. Cardiol., 41:479–81 2003.Wallerath, T., Poleo, D., Li, H. et al. Red wine increases the expressionof human endothelial nitric oxide synthase. J. Am. Coll. Cardiol.,41:471–8, 2003.Witztum, J. L., and Steinberg, D. The oxidative modification hypothesisof atherosclerosis: Does it hold for humans? Trends Cardiovasc. Med.,11:93-102, 2001.Yokoi, H., Daida, H., Kuwabara, Y. et al. Effectiveness of antioxidantin preventing restenosis after percutaneous transluminal coronaryangioplasty: The Probucol Angioplasty Restenosis Trial. J. Am. Coll.Cardiol., 30:855, 1997.Zitron, E., Scholz, E., Owen, R. W. et al. QTc prolongation by grapefruitjuice and its potential pharmacological basis: HERG channel blockadeby flavonoids. Circulation, 111:835–838, 2005.

Antiphospholipid Antibody SyndromeI. DiagnosisII. ManagementGLOSSARYanticoagulation to decrease the tendency of the blood to form aclot, thrombosis.lupus short for systemic lupus erythematosus (SLE).platelets very small disk-like particles that circulate in the bloodalongside red and white blood cells initiating the formation ofblood clots; platelets clump and form little plugs, thus causingbleeding to stop.thrombocytopenia a mild decrease in platelet counts.The principal autoantigen of antiphospholipid antibodysyndrome has been shown to be beta-2-glycoprotein 1(apolipoprotein H), a protein that binds cardiolipin andexposes an antigenic epitope. The antibody is calledcardiolipin, lupus anticoagulant, or anti-beta-2 glycoprotein1 depending on the test used. Two inexpensivetests, a standardized enzyme-linked immunosorbent assayfor anticardiolipin antibodies and a clotting test forlupus anticoagulant, rapidly rule out antiphospholipidsyndrome.The antiphospholipid syndrome and factor V Leiden arethe most common causes of thrombophilia accountingfor greater than 20% of cases of recurrent thrombosis inindividuals under age 40. Approximately 15% of womenwith recurrent pregnancy loss have this syndrome.I. DIAGNOSISThis complex syndrome actually is described as primary(not associated with another illness) and secondary (associatedwith SLE or another rheumatic disease). The antiphospholipidantibody (APLA) is detected in more thanone-third of patients with lupus.This syndrome is defined as the presence of eitherAPLA or a lupus anticoagulant accompanied by this listof clinical manifestations:1. Recurrent thrombosis of veins or arteries that areunexplained, that is, the usual causes of thrombosissuch as immobilization or postsurgical are lacking2. Frequent second- or third-trimester miscarriages3. Thrombocytopenia and livedo reticularis commonlyoccur; patients with SLE commonly show positive bloodserology for APLA, but the majority of these patients donot show clinical manifestations of the syndrome4. Heart valves may become involved with thromboticmasses that may embolize and cause stroke5. Ulcers of the lower legs around the ankle may resembleulcers caused by obstruction to the venous system andstasis ulcers, but ulcers caused by this syndrome areexquisitely painful and may resemble pyoderma gangrenosumII. MANAGEMENTThrombosis of veins or arteries should be treated withfull-dose oral anticoagulation with warfarin. A Canadianstudy indicated that using warfarin to keep the targetINR at 2–3 provides beneficial results that are equal tothat observed with high-dose anticoagulation with anInternational Normalize Ratio (INR) of 3.1–4.0. Aretrospective study in women in whom antiphospholipidantibody syndrome was diagnosed because of pregnancyloss (none of whom had a previous thrombotic event)suggests that treatment with low-dose aspirin providesprotection from thrombosis. An ongoing clinical trial inthe United States is comparing aspirin with placeboand a study in the UK is comparing aspirin with low-dosewarfarin plus aspirin.Fortunately, this syndrome is rare. Individuals whohave lupus and other autoimmune diseases may test positivefor the antiphospholipid antibody syndrome, but themajority usually do not manifest the symptoms, signs, andcomplications outlined above.BIBLIOGRAPHYLockshin, M. D., and Erkan, D. Treatment of the antiphospholipidsyndrome. N. Engl. J. Med., 349:1177–79, 2003.77

Antiplatelet AgentsI. Mechanism of ActionII. IndicationsIII. Available Antiplatelet Agentsveins. Antiplatelet agents are used in virtually all patientswith coronary artery disease to manage the acute andchronic phases of the disease as well as its complications.GLOSSARYacute coronary syndrome this syndrome defines patients withacute chest pain caused by myocardial infarction or unstableangina.aggregation platelet clumping.angina chest pain caused by temporary lack of blood to anarea of heart muscle cells, usually caused by severe obstructionof the artery supplying blood to the segment of cells.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atherosclerosis same as atheroma; raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and flow of blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma,medical term for heart attack or coronary thrombosis.PCI percutaneous coronary intervention; percutaneous transluminalcoronary angioplasty (PTCA), often involving the useof intracoronary stents.platelets very small disk-like particles that circulate in the bloodalongside red and white blood cells initiating the formationof blood clots; platelets clump and form little plugs calledplatelet aggregation, thus causing bleeding to stop.thrombi blood clots.ASPIRIN WAS THE ONLY ANTIPLATELET AGENTavailable from the 1970s to the 1980s. Today we nowhave more than five agents available. These cardioactivedrugs are useful in the prevention of thrombi in coronaryarteries and those arteries that supply the brain, but theyare much less effective in preventing thrombi that occur inI. MECHANISM OF ACTIONCoronary thrombosis is known to be the major cause ofcoronary artery occlusion resulting in fatal or nonfatalacute myocardial infarction. Antiplatelet agents arenamed this because they inhibit platelet aggregation,which plays a major role in coronary thrombosis, myocardialinfarction, and cardiac death.Platelets clump on to atherosclerotic plaques, causingocclusion of the artery, and/or embolize downstream.The occlusion of these vessels may induce fatal arrhythmiasand cardiac death. In patients with unstable angina,angioscopy has confirmed the presence of platelet clumpsattached to the surface of eccentric atheromatous plaquesthat jut into the lumen of arteries causing partial tonear complete occlusion. The atheromatous plaques maybecome fissured or rupture exposing a ‘‘porridge/gruel’’like substance or substances that are highly thrombogenic.(See also the chapter Atherosclerosis/Atherothrombosis.)However, antiplatelet agents are not expected to preventall forms of thrombotic events.After plaque rupture the formation of a platelet-richthrombus requires three essential steps:1. Platelet adhesion: This occurs shortly after an atheromatousplaque has ruptured and the process ofadhesion is mediated by the platelet glycoprotein IIbreceptor through its interaction with von Willebrandfactor.2. Platelet activation: The smooth discoid plateletassumes a spiculated form, thus increasing the surfacearea of the platelet membrane where thrombin is generated.Figure 1 illustrates the complex and orchestratedprocesses that lead to platelet aggregation along withstimulatory and inhibitory drugs and substances.79

80ANTIPLATELET AGENTSFIGURE 1 Platelet activation is an important early step in the pathophysiology of atherothrombosis. Platelet activation involves: (1) a shape change inwhich the platelet membrane surface area is greatly increased; (2) the secretion of pro-inflammatory, prothrombotic, adhesive, and chemotactic mediators(release reaction), that propagate, amplify, and sustain the atherothrombotic process; and (3) the activation of the glycoprotein (GP) IIb/IIIa receptor fromits inactive form. Multiple agonists including thromboxane A 2 (TXA 2 ), adenosine diphosphate (ADP), thrombin, serotonin, epinephrine, and collagen, canactivate the platelet and thus contribute toward establishing the environmental condition necessary for atherothrombosis to occur. Aspirin inhibits theproduction of thromboxane A 2 by its effect on the enzyme cyclooxygenase (COX) 1. The ADP receptor antagonists clopidogrel and ticlopidine prevent thebinding of ADP to its receptor. The effect of combining aspirin and clopidogrel is synergistic in preventing platelet aggregation. Antithrombins suchas unfractionated or low-molecular-weight heparin, hirudin, or bivalirudin are important in interfering with both thrombin-induced platelet activationand coagulation. The GP Iib/IIIa receptor antagonists act at a later step in the process by preventing fibrinogen mediated cross-linking of platelets, whichhave already become activated. ATP ¼ adenosine triphosphate; PAI ¼ plasminogen activator inhibitor; PDGF = platelet-derived growth factor; vWF ¼von Willebrand factor. (From Mehta, S.R., and Dphil, S.Y. (2003). Short- and long-term oral antiplatelet therapy in acute coronary syndromes andpercutaneous coronary intervention, J. Am. Coll. Cardiol., 41(4), 80S. With permission, American College of Cardiology Foundation.3. Platelet aggregation: Platelet activation converts theglycoprotein IIb/IIIa receptor into a form that canbind fibrinogen and aggregation occurs.II. INDICATIONSAntiplatelet agents are of proven value in the managementof non-ST segment elevation myocardial infarction;stable and unstable angina; post coronary artery bypassgraft (CABG), coronary artery stents, cerebral transientischemic attacks (TIAs); and lone atrial fibrillation inindividuals younger than 65.III. AVAILABLE ANTIPLATELET AGENTSCurrently used antiplatelet agents include aspirin, clopidogrel(ticlopidine still has a role, see Section III.B),dipyridamole plus aspirin, and platelet glycoproteinIIb/IIIa receptor blockers.A. AspirinAcetylsalicylic acid irreversibly acetylates the enzymecyclooxygenase. This enzyme is necessary for the conversionof platelet arachidonic acid to thromboxane A2,a powerful platelet-aggregating agent. Cyclooxygenase isinhibited by all nonsteroidal anti-inflammatory drugs(NSAIDs), aspirin transfers the acetyl group to theenzyme that is irreversibly inactivated. Other NSAIDssuch as ibuprofen act as reversible inhibitors of cyclooxygenase(see the chapter Nonsteroidal Anti-InflammatoryDrugs).Table 1 gives the clinically useful indications for aspirin.Most important, both the use of aspirin and the administrationof nitroglycerin sublingually also contribute to

III. AVAILABLE ANTIPLATELET AGENTS81CardiovascularTABLE 1Indications for AspirinCommentglycoprotein IIb/IIIa receptor to the form that bindsfibrinogen and links platelets. Clinical studies confirm thedrug’s effectiveness.1. Unstable angina Proven2. Stable angina Poven3. Acture-onset myocardialinfarctionthe prevention of fatal and nonfatal heart attacks. It isimportant for individuals to realize that a rapid-actingaspirin formulation such as two 80- to 81-mg chewableaspirins taken soon after the onset of chest pain has beenshown to cause a 25% reduction in fatal and nonfatalmyocardial infarction, whereas nitroglycerin has no effecton prevention. Nitroglycerin ameliorates the pain of stable,mild angina and its use has been overvalued.A recent study by Gum et al. demonstrated the naturalhistory of aspirin resistance and documented a greater thanthreefold increase in the risk of major adverse eventsassociated with aspirin resistance. Fortunately this formof resistance is rare and occurred in less than 5% of the326 stable cardiovascular patients administered aspirin.B. ClopidogrelProven, also enhances effectof thrombolytic agents4. Post-MI Proven effective5. Silent ischemia Strongly advisable6. Coronary artery bypass May prevent graft occulusionsurgery7. Post-coronary angioplasty Modest decrease in reocclusion8. Lone atrial fibrillation As good as oral anticoagulantst9. Bioprosthetic valves In combination with dipyridamole10. Transient cerebral ischemic Proven in both men and womenattacks11. Post-nonhemorrhagic strokes12. Patients over age 40 years Strongly advisableat risk13. Diabetics at high risk Advisablefor CHDCHD, coronary heart disease; MI, myocardial infarction.Clopidogrel is a thienopyridine derivative and an anologof ticlopidine; the drug inhibits platelet aggregationby inhibiting adenosine diphosphate (ADP) induced plateletactivation and inhibits platelet fibrinogen binding.Clopidogrel is more effective than ticlopidine, but isconsiderably less toxic. Clopidogrel prevents plateletdegranulation and the release reaction which producesprothrombotic substances. This drug selectively andirreversibly prevents ADP from binding to the plateletADP receptor and inhibits the transformation of the1. CAPRIE StudyIn the Clopidogrel versus Aspirin in Patients at Riskfor Ischemic Events (CAPRIE) study, the control wasmarginally better than aspirin ( p ¼ 0.045). Clopidogrelis recommended when aspirin is not tolerated.2. CURE TrialThe Clopidogrel in Unstable Angina Recurrent Events(CURE) trial was a double-blind placebo-controlledrandomized trial with clopidogrel versus placebo in additionto aspirin and other optimal therapy for patients withunstable angina and non-ST elevation acute myocardialinfarction (MI). Of the 12,652 patients, 16.5% (2072)had CABG surgery and 21% (2662) had percutaneouscoronary intervention (PCI). At follow up 12 monthslater clopidogrel treatment caused a 20% relative risk reductionin the outcome of MI, stroke, or cardiovasculardeath ( p ¼ 0.00009). Significant bleeding occurred in theclopidogrel group compared with the placebo group(3.7% vs. 2.7%; p ¼ 0.001), but there was no significantincrease in life-threatening bleeding: 135 bleeds (2.2%)for clopidogrel and 112 bleeds (1.8%) for the placebogroup ( p ¼ 0.13). The major risk of bleeding withclopidogrel has been noted in patients with acute coronarysyndromes scheduled for immediate CABG. In the CUREstudy most patients undergoing bypass surgery had thestudy drug stopped for a short period of time (days beforesurgery).3. PCI CUREThe PCI CURE study was a prospectively planned substudyof CURE. The study was confined to the 2658patients who underwent PCI and randomized to clopidogreland aspirin versus just aspirin. At 30 days there wasa significant benefit of clopidogrel over placebo. Mostimportant, the benefit of clopidogrel appeared identicalregardless of whether patients received PCI on anemergency basis or days after discharge.4. CREDO TrialThis trial randomized 2116 patients. Clopidogrel 300 mgor 600 mg plus aspirin was administered from 3 to 24 h

82ANTIPLATELET AGENTSbefore PCI. At one year patients who received clopidogrelplus aspirin greater than 6 h before PCI caused a 26.9%reduction in the risk of death, MI, or stroke ( p ¼ 0.02).Clopidogrel, 600-mg loading dose given 12–24 h (atleast 6 h) prior to PCI and stenting is a recommendedregimen. In this regard, clopidogrel has largely replacedticlopidine.Because of the major risk for bleeding with glycoproteinreceptor blockers, clopidogrel and aspirin combinationtherapy should be the preferred therapy for patientswith high-risk unstable angina or non-ST elevation acuteMI undergoing PCI. The combination is particularlyadvisable when intracoronary stents are used. Because ofthe major risk for bleeding with glycoprotein receptorblockers, clopidogrel and aspirin combination therapyshould be the preferred therapy for patients with high-riskunstable angina or non-ST elevation acute MI exceptin patients undergoing urgent CABG. Intermediate- andlow-risk patients not due to receive urgent PCI and inwhom further tests are necessary and when PCI is deferreddays to months after the acute event appear to be besttreated with the clopidogrel and aspirin combinationinstead of platelet receptor blockers. In patients scheduledfor urgent CABG, clopidogrel should be withheld toavoid bleeding.5. Clopidogrel versus TiclopidineBecause ticlopidine causes leukopenia and rarely agranulocytosis,it has been replaced by clopidogrel. A recentrandomized clinical trial, however, indicates superiorityof ticlopidine over clopidogrel after placement of coronaryartery stents. In a study by Muller et al. in 700 patientswith 899 lesions, cardiovascular death occurred in8 patients administered ticlopidine versus 26 patients withclopidogrel ( p ¼ 0.003). The combined end point of cardiovasculardeath or nonfatal MI occurred in 19 patientsreceiving ticlopidine versus 40 patients administeredclopidogrel ( p ¼ 0.005); after adjustment for covariables,ticlopidine reduced the risk of death by 63% comparedwith clopidogrel.Most important, clopidogrel will be a frequently usedcardioactive agent worldwide in patients undergoingPCI. Unfortunately, clopidogrel activation requires theCYP450 3A4 system; antiplatelet activity of the drug issubstantially inhibited by statins metabolized in the liverby the cytochrome pathway. These statins include thecommonly used atorvastatin, simvastatin, and fluvastatin.Pravastatin and rosuvastatin are excreted by the renalsystem and do not interact. Inhibitory effects have notbeen reported for ticlopidine. The high use of hepaticmetabolized statins in this study may explain the superiorityof ticlopidine over clopidogrel.C. Platelet Glycoprotein IIb/IIIa ReceptorBlockersThere are approximately 75,000 glycoprotein IIb/IIIareceptors on the surface of each platelet. Antagonism ofthese receptors blocks the final common pathway forplatelet aggregation — the binding or fibrinogen to theplatelet glycoprotein receptors; platelet aggregation causedby thrombin, thromboxane A2, ADP, collagen, and shearinducedplatelet aggregation is prevented. Unfortunately,these agents do not affect platelet activation and degranulation,unlike ADP receptor antagonists which are activeat much earlier stages of the atherothrombotic cascade.1. Abciximab (ReoPro)This widely used platelet receptor blocker inhibits bothalpha IIb3 receptor and alpha v beta 3 receptors. Severalrandomized clinical trials have documented the beneficialeffects when used for patients undergoing urgent PCI.This drug is not recommended for patients who are notscheduled for urgent PCI. Dosage would include 0.25 mg/kg IV bolus over at least 1 minute, immediately followedby IV infusion of 0.125 mgram/kg/minute for 18–24 h,concluding 1 h after PCI.2. Eptifibatide (Integrilin)This platelet receptor blocker has actions that are similarto abciximab. In a randomized clinical trial (PURSUIT), asignificant benefit was observed in patients who underwentPCI within 72 h with no benefit at 30 days in thosewithout PCI. In another large trial (TACTICS), eptifibatidewas beneficial only in patients with acute coronarysyndromes treated with early invasive PCI. In anothertrial (TARGET), the drug caused less protection frommajor ischemic events than abciximab. In the trial PRISM-PLUS, eptifibatide reduced events at seven days but notat six months. Dosage would be IV bolus of 135 mgram/kgfollowed by an infusion of 0.5 mgram/kg/minute for afurther 20–24 h after PCI.3. Tirofiban (Aggrastat)This platelet receptor blocker shows specificity towardalpha IIbb 3 receptor and has a shorter biological half-life

III. AVAILABLE ANTIPLATELET AGENTS83than abciximab and eptifibatide. Tirofiban and eptifibatideare indicated only in patients in whom immediate PCI isnot planned. In this population of patients the combinationof clopidogrel and aspirin may prove to be moreefficacious at 30 days and 1 year follow up. A meta-analysisof randomized clinical trials with these three agents withthe exception of abciximab used as indicated for PCIplanned within 24 h indicates that nondiabetic patientshad no survival benefit.In a large randomized trial (TACTICS) patients weretreated with tirofiban for 48 h plus aspirin and heparinand randomized to either invasive therapy (coronaryangiography and revascularization) or conservative strategy.It is claimed that at 6 months there was a significantreduction in death or MI ( p ¼ 0.0498; p ¼ 0.05) Thisp ¼ 0.05 is hardly the level of significance required torecommend a treatment strategy to the population atlarge. In clinical medicine it is essential to achieve a significancelevel of p < 0.02 to be meaningful in terms ofsaving lives.4. Oral AgentsSeveral randomized clinical trials have shown no benefitwith oral agents that included orbofiban (in the OPUStrial), sibrafiban (in SMPHONY, and xemilofiban (inthe EXCITE trial) caused excess mortality, usually suddendeath, and approximately a 30% increase in mortality.In five large randomized trials oral platelet receptorblockers showed a consistency toward increased mortalitywhen compared with placebo. A 37% increase in mortalitywas observed in a meta-analysis of four large trials.Thirty days after commencement of one trial there was a40% higher incidence of MI associated with these agents.Except for the proven beneficial defects of abciximab forpatients undergoing primary PCI, the IV agents, also havenot been a major success in terms of causing significantimprovement in survival at 6 months, and they cause asignificantly high excess in the incidence of major bleeding.The partial effectiveness of oral and IV agents may relateto the fact that they do not affect platelet activation anddegranulation; processes that occur very early in the stageof the platelet thrombotic process.Several randomized clinical trials in progress shouldindicate which platelet receptor blocker is best for acuteclinical situations and the role for clopidogrel combinedwith aspirin in patients stratified to receive PCI versusconservative therapy.BIBLIOGRAPHYCannon, C. Small molecule glycoprotein IIb/IIIa receptor inhibitorsas upstream therapy in acute coronary syndromes. Insights from theTACTICS TIMI-18 Trial. J. Am. Coll. Cardiol., 41:43–48S, 2003.Gum, P. A., Kottke-Marchant, K., Welsh, P. A. et al. A prospective,blinded determination of the natural history of aspirin resistanceamong stable patients with cardiovascular disease. J. Am. Coll. Cardiol.,41:961–5, 2003.Hans-Christoph, D., Bogousslavsky, J., Brass, L. M. et al. On behalf ofthe MATCH investigators: Aspirin and clopidogrel compared withclopidogrel alone after recent ischaemic stroke or transient ischaemicattack in high-risk patients (MATCH): Randomised, double-blind,placebo-controlled trial. Lancet, 364: 331–3, 200.Lange, R. A., and Hillis, L. D. Antiplatelet therapy for ischemic heartdisease. N. Engl. J. Med., 350:27–80, 2003.Khan, M. Gabriel. Cardiac Drug Therapy, sixth edition, W. B. Saunders,Philadelphia, 423, 2003.Mehta, S. R., and Yusuf, F. Short and long-term oral antiplatelet therapyin acute coronary syndromes and percutaneous coronary intervention.J. Am. Coll. Cardiol., 41:79–88S, 2003.Moliterno, D. J., and Chan, A. W. Glycoprotein IIb/IIIa inhibition inearly intent-to-stent treatment of acute coronary syndromes: EPIS-TENT, ADMIRAL, CADILLAC, and TARGET. J. Am. Coll. Cardiol.,41:49–54S, 2003.Mueller, C., Roskamm, H., Neumann, F.-J. et al. A randomizedcomparison of clopidogrel and aspirin versus ticlopidine and aspirinafter the placement of coronary artery stents. J. Am. Coll. Cardiol.,41:969–73, 2003.Schulman, S. P. et al. Antiplatelet therapy in non-ST-segment elevationacute coronary syndromes. JAMA, 292:1875–1882, 2004.Steinhubl, S. R., Berger, P. B., Mann, J. T. et al. Early and sustained dualoral antiplatelet therapy following percutaneous coronary intervention.A randomized controlled trial. JAMA, 288:2411–2420, 2002.SYMPHONY Investigators. A randomized comparison of sibrafiban, andoral platelet glycoprotein 11b/111a receptor antagonist, with aspirinfor acute coronary syndromes. Lancet, 355:337, 2000.The CURE Investigators. Effects of Clopidogrel in addition to aspirin inpatients with acute coronary syndromes without ST segment elevation.N. Engl. J. Med., 345:494–502, 2001.

Arginine and the Heart1. Clinical StudyGLOSSARYangina chest pain caused by temporary lack of blood supplyto an area of heart muscle cells, usually caused by severeobstruction of the artery supplying blood to the segment ofcells.brachial artery the artery of the arm and forearms that suppliesblood to the upper limb including the hands.endothelium the innermost part of the intima that comesin contact with circulating blood, a silky smooth layer ofepithelial cells.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severeobstruction of the artery supplying blood to this area of cells.I. CLINICAL STUDYStudy question: The many risk factors for coronary arterydisease are associated with reduced production of nitricoxide (NO) by the endothelium. L-arginine supplementationappears to have modest clinical benefits in patientswith angina. The effect of a medical food bar containingL-arginine, vitamin B 6 ,B 12 , vitamin C, folic acid, andniacin was evaluated.Methods: 36 patients with stable angina were randomizedand had two treatment periods of 2 weeks’ duration.Each group received two active bars or placebo bars.The brachial flow-mediated dilatation of the brachialartery in the arm was measured by ultrasonography.Results: The medical food bar improved flow-mediatedvasodilatation, treadmill exercise time, and quality of lifescores. However, electrocardiographic signs of ischemia ortime to onset of angina were not changed.Perspective: Two other studies, however, have shownno benefit to endothelial function and exercise performancein patients with coronary heart disease who werereceiving medical management with statins and otheragents. However, folic acid, vitamin B 6 ,B 12 , vitamin C,and niacin may increase vascular NO activity and mayhave contributed here. Strategies that increase endothelialNO synthase activity and thus, endothelial NObioactivity may lead to development of a new range ofantianginal medications. These strategies include provisionof cofactors for the enzyme NO synthase, enhancementof the transcription of the gene for this enzyme, andstabilization of messenger RNA (mRNA). Administrationof the substrate L-arginine does not appear to be useful,but further studies are required.BIBLIOGRAPHYCannon, R. O. Oral L-arginine (and other active ingredients) for ischemicheart disease? J. Am. Coll. Cardiol., 59:46–47, 2002.Maxwell, A. J., Zapien, M. P., Pearce, G. L. et al. Randomized trial ofa medical food for the dietary management of chronic stable angina.J. Am. Coll. Cardiol., 59:57–45, 2002.85

Arrhythmias/PalpitationsI. Origin of the HeartbeatII. Palpitations, Premature Beats, and Irregular BeatsIII. TachycardiaIV. Antiarrhythmic AgentsV. Automatic Implantable Cardioverter DefibrillatorVI. ConclusionGLOSSARYaction potential voltage changes generated across the membraneof a nerve or muscle cells when the cell is activated through avariety of stimuli (electrical, chemical, or mechanical).automaticity the ability to generate a spontaneous actionpotential.cardiomyopathy heart muscle disease.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.myocardium the heart muscle.Purkinje fibers the terminal branches of the cardiac conductingsystem that run along the subendocardium.ventricular fibrillation the heart muscle does not contractbut quivers, therefore there is no heartbeat (cardiac arrest); noblood is pumped out of the heart and death occurs withinminutes if the abnormal heart rhythm is not corrected.I. ORIGIN OF THE HEARTBEATArrhythmia is the term used for an irregularity or rapidityof the heartbeat or an abnormal heart rhythm. The patientexperiences the sensation as stronger, more forceful, orrapid heartbeats, or skipping of beats; this sensation iscommonly called palpitations. The sinus node, a verysmall group of specialized cells, is located in the upperright corner of the heart (see Fig. 1). The node is about30 3 mm thick. Through its genetic code and the influxand efflux of sodium and potassium into its cells, thisnatural pacemaker spontaneously fires infinitesimal electricaldischarges that are conducted through electric cablelikebundles to the atria and ventricles causing the heartmuscle to contract about 70 times a minute. The sinoatrial(SA) node’s spontaneous depolarization and repolarizationprovides a unique and miraculous automatic pacemakerstimulus that activates the atria and atrioventricular (AV)node, which conducts the activation current down thebundle branches to activate the ventricular muscle mass.Cardiac cells outside the SA node normally do not exhibitspontaneous depolarization. The SA discharge rate, usually50–100 beats per minute, is under autonomic, neural,chemical, and hormonal influence. The rate slows or getsfaster depending on the needs of the body. The sinus nodeis like a powerful generator and has complete control ofthe heart rate.Cells outside the sinus node pacemaker, for example,ventricular muscle cells, possess pacemaker activity thatis so weak that the normal electrical discharge from thesinus node suppresses them. Myocardial cells normallylack the ability for either spontaneous formation or rapidconduction of the electrical impulse. For these functionsmost cardiac cells are dependent on cardiac pacemakercells and the conduction system that consists of nodes,bundle branches, and a terminal branching network ofspecialized conducting tissue — the Purkinje fibers thatramify the myocardium. The sinus node undergoes spontaneousdepolarization and has no resting phase; myocardialtissue must be depolarized and have a resting potential (seethe chapter Electrocardiography). Occasionally, pacemakercells outside the SA node may interrupt the normal heartbeat,causing a premature beat, which is also called an extrabeat (see Fig. 1).The electrical conducting system of the heart is vital tolife. Damage to the electrical system can occur when thecoronary arteries are blocked and fail to supply sufficientblood to the electrical system as may happen after severalheart attacks. The electrical system can also be affected87

88ARRHYTHMIAS/PALPITATIONSSinus nodepacemakerAtrio-ventricularnode(super-highway)Right bundlebranchBeat comes too early=premature beatNormal distancebetweenheart beatExtrabeat orExtrasystoleLeft bundlebranchThe question is answered as follows:A heartbeat pause is due to an extra beat (extrasystole),medically termed a premature beat (see Fig. 1).Premature beats may originate in the top chamber ofthe heart. These are referred to as atrial prematurebeats, and they are of no significance if they occur in anormal heart. If they occur in the ventricle, they arecalled ventricular premature beats. Patients perceive theabnormal heart rhythm as either an extra beat or apause. An individual may state: ‘‘My heart skipped abeat.’’ The extra heartbeat nearly always becomes moreprominent when the heart slows while sitting or lyingdown. When the heart speeds up during walking orother activities, the extra beats are often suppressed bythe normal beats. Movement of the body also preventsthe sensation of the stronger heartbeat.Long heart pauseor skipped beatFIGURE 1 The electrical system of the heart. The electrocardiogrampicks up the heart’s electrical impulses transmitted through the skin of thechest. Premature beat is synonymous with terms extra beat, extrasystole,heart pause, or skipped beats. (From Khan, M. Gabriel, Heart TroubleEncylopedia, Toronto: Stoddart, 1996.)by certain degenerative diseases that cause calcificationand hardening (sclerosis) of the bundles.II. PALPITATIONS, PREMATURE BEATS,AND IRREGULAR BEATSA. DefinitionThe word ‘‘palpitation’’ is used by doctors and by somepatients to describe the heartbeat when it is fast, pounding,skipping, or irregular. A patient posed the followingquestion:I am 28 and have a problem with a heartbeat pause.This problem comes and goes and may result in 5–10pauses each minute. Sometimes my heart feels as if itmakes an extra beat. If I lie down, the irregularityseems more pronounced. I went to my family doctorwho found nothing wrong. My doctor concluded thatthese pauses were caused by too much adrenaline in theblood. Could you tell me more about this: the possiblecauses, cures, and long-term harm to the heart?B. CausesPremature beats may be due to either heart disease orextracardiac conditions, but often, they have no definablecause. Heart diseases that affect the heartbeat includedisturbance of the blood supply to the heart due tocoronary artery disease; diseases of the heart valves, usuallydue to prior rheumatic fever; and a common conditioncalled mitral valve prolapse. Valve problems are easilyexcluded by a physician, who can hear murmurs or clickswhen listening with the stethoscope. Echocardiography(cardiac ultrasound) can clarify the cause. Heart musclediseases (cardiomyopathy) are fortunately rare. Alcoholabuse can also cause cardiomyopathy. Viruses that causea flu-like illness can produce microscopic scars in theheart muscle (myocarditis) that may trigger extra beats.Myocarditis can be difficult to exclude if the patient is notseen during the acute phase.Investigations of extra beats should include bloodtests (to exclude anemia, a low serum potassium, or thyroidoveractivity), chest x-ray, echocardiography, Holtermonitor (24-h ECG recording), and a stress test.Extracardiac precursors include alcohol, smoking,stimulants such as caffeine, amphetamines (diet pills),and nicotinic acid in megavitamins and several drugs.In susceptible individuals, disturbances of the heartbeat(arrhythmias) are more common 12–24 h after alcoholconsumption. Other causes include thyroid overactivityand low oxygen in the blood due to lung diseases.Premature or extra beats commonly occur in youngindividuals with normal hearts and cause no harmfuleffects. In the normal heart, they bear no relation to heart

III. TACHYCARDIA89attacks, sudden cardiac death, or heart failure, and they donot harm the heart.Drug treatment is not indicated for patients with anormal heart because the side effects outweigh the benefits.Some patients, who are terribly bothered by numerousextra beats in the presence of a normal heart or mitralvalve prolapse, respond to beta-blockers (see the chapterBeta-Blockers). Five to 15 pauses or premature beats perminute in a normal heart is of no significance and requiresno drug treatment. Patients may have an extra beat thatoccurs after each normal heartbeat and more commonlyafter two normal beats. In the majority of individuals withpremature beats, there is no good reason why they shouldoccur at a particular time of the day or month. Severalstudies have utilized the 24-h Holter monitor to show thatmore than 66% of normal individuals studied haveventricular premature beats (VPBs). Unless serious heartdisease is present, all the bumpings, flutterings, thumpings,and irregular beats can be ignored.C. Diagnosis1. Atrial Premature BeatsPremature beats that arise from the atrium are called atrialpremature beats (APBs). An atrial premature P-wave hasa morphology different from that of the sinus P-waveand is usually followed a QRS complex similar to that ofthe normally conducted sinus beat (see Fig. 2). Atrialpremature beats may trigger atrial tachycardia or atrialfibrillation.2. Ventricular Premature BeatsPremature beats that arise in the ventricle are called ventricularpremature beats. These are bizarre looking beatswith a wide QRS complex and an ST segment sloping offin a direction opposite to the abnormal QRS complex (seeFig. 3). There is no preceding P-wave and the extra beatis followed by a fully compensatory pause before thenext normal sinus beat occurs. When this happens, theindividual may feel that the heart has stopped for a second.A VPB following each normal beat (termed ventricularbigeminy) is a common occurrence in healthy individuals,but pairs (couplets) or runs of three beats (triplets,nonsustained ventricular) are not uncommon in thosewith heart disorders (see Figs. 3 and 4).III. TACHYCARDIAThis is the term used by the medical profession to describea fast heart rate of greater than 100 per minute. Tachycardiasinclude:1. Sinus tachycardia2. Paroxysmal atrial tachycardia (PAT)3. Atrioventricular nodal reentrant tachycardia (AVNRT)4. Atrial fibrillation5. Atrial flutter6. Wolff-Parkinson-White syndrome (WPW)7. Ventricular tachycardiaThese tachycardias are usually differentiated for diagnosticpurposes into narrow QRS and wide QRS and theninto regular or irregular tachycardias (see Fig. 5).II5905 77FII5500 66F981 68MFIGURE 2 Premature atrial beats with bigeminal (A and B) and trigeminal (C) rhythm. B, the QRS complex of the premature atrial beats shows aberrantventricular conduction (From Chou, T.C., (1996). Electrocardiography in Clinical Practice, 4th ed., Philadelphia: W.B. Saunders, p. 344.)

90ARRHYTHMIAS/PALPITATIONSV1V4V2V5V3V6FIGURE 3ST segment elevation in V 1 through V 5 , poor R wave progression in V 2 through V 4 typical of recent anterior infarction.A. Sinus TachycardiaWhen the fast beat arises from the normal sinus nodepacemaker, it is called a sinus tachycardia. This is a normalphysiologic occurrence during exercise, infections causingfever, anxiety states, loss of blood, dehydration, andthyroid overactivity. This is one of the most commonabnormal tachycardias occurring in young healthy adults.B. Paroxysmal Atrial TachycardiaThose who have episodes of very fast heart beat, usually150–190 beats per minute, may have a condition knownas PAT. If episodes are frequent, drug treatment may benecessary. The term paroxysmal atrial tachycardia wasintroduced more than 50 years ago and was formerly usedto include AVNRT, but these two conditions have subtledifferences. Most cases called PAT are truly AVNRT.There is no conclusive evidence that excessive adrenalinetriggers PAT.In a few individuals, excessive adrenaline may play arole during stress or a heart attack. Excessive adrenalineis liberated in the heart muscle during a heart attack andincreases the occurrence of premature beats and otherabnormal heart rhythms. Pacemaker cells outside the sinusnode commence an electrical discharge and take over theheart rhythm for up to a few hours. The ECG reveals aP-wave that precedes the QRS and its contour is differentfrom the sinus P-wave; the rhythm may be regular orirregular. Some cases are caused by digoxin toxicity.C. Atrioventricular Nodal ReentrantTachycardiaThe most common type of paroxysmal narrow regulartachycardia is one originating in the AV node; it is called

III. TACHYCARDIA91V1V4V2V5V3V6FIGURE 4Sinus rhythm, rate 65. Run of ventricular premature complexes, abnormal ECG.atrioventricular nodal reentrant tachycardia. There isno conclusive evidence that excessive adrenaline triggersthis type of tachycardia. In a few individuals, excessiveadrenaline may play a role during stress or during a heartattack. Excessive adrenaline is liberated in the heartmuscle during a heart attack and increases the occurrenceof premature beats and other abnormal heart rhythms.Beta-blockers can be useful when excessive adrenaline fromstress or a heart attack precipitates tachycardias.A typical history of a 76-year-old patient is described:She can recall having PAT from age 22. Withoutwarning, she would feel a sudden pounding of theheart. The beats were so rapid that it was difficult tocount them. She would try certain maneuvers such aslying down, walking around, or taking a warm drink— all to no avail. Attacks would come on once or twicea year; in one year she had five episodes. The durationof the attacks was usually from several minutes to threeor four hours. She was age 38 when she presented at theemergency room because this particular episode hadgone on for more than three hours. The episode stoppeda few minutes after she came to the emergency room.She was informed that she had PAT, but she truly hadAVNRT. Her attacks had a typical sudden onset with arapid heart rate and abrupt cessation. Occasionally shefelt dizzy, as if she was about to faint, but she neverreally lost consciousness. This form of tachycardia nearlyalways occurs in a normal heart, and this was thesituation in this patient’s case.Additionally, in a normal heart AVNRT does not causeheart failure or angina, nor does it lead to a heart attack.At the time of her visit to the emergency room, the patientwas being treated with quinidine and had nausea anddiarrhea. The quinidine was discontinued and she wasadvised to suppress the attacks through the use of certainmaneuvers that increase the activity of the vagus nerve;the vagus nerve slows the heart and keeps it in check.Simple maneuvers to suppress AVNRT are (1) gaggingby putting a finger at the back of the tongue to causeretching, (2) holding both nostrils tightly and breathing

92ARRHYTHMIAS/PALPITATIONSANarrow QRS tachycardiaRegularSinus tachycardiaIrregularAtrial fibrillationAtrioventricular nodal reentranttachycardia (AVNRT)Atrial flutter (with fixed AVconduction)Atrial tachycardia (paroxysmaland nonparoxysmal)Atrial flutter (with variable AVconduction)Atrial tachycardia (variable AVblock or Wenckebach)Multifocal atrial tachycardiaWPW syndrome (orthodromiccircus movement tachycardia)BWide QRS tachycardiaRegularIrregularVentricular tachycardiaSupraventricular tachycardia(with preexisting or functionalbundle branch block)Atrioventricular nodal reentranttachycardiaWPW syndrome (orthodromic)Sinus tachycardiaAtrial tachycardiaAtrial flutter with fixed AVconductionWPW syndrome (antidromic,preexcited tachycardia)Atrial fibrillation (with bundlebranch block or with WPWsyndrome [antidromic])Atrial flutter (varying AVconduction, with bundle branchblock or WPW syndrome[antidromic])Torsades de pointesFIGURE 5 Method for rapid ECG interpretation. A, Step 11: The differential diagnosis of narrow QRS tachycardia. B, Step 11: The differentialdiagnosis of wide QRS tachycardia. (From Khan, M. Gabriel, (2005). Heart Disease Diagnosis and Therapy, second edition, New Jersey Humana Press.out against the resistance for about 30 seconds, and(3) holding the breath and immersing the face in coldwater for about 10 seconds. The patient was warned notto apply pressure on the eyeball because detachment ofthe retina may occur.On a few occasions the attack was stopped in theemergency room by massaging her right carotid artery(carotid sinus massage) for 3–6 seconds. This stimulatesthe vagus nerve and suddenly stops the abnormal fast heartrhythm in more than 50% of individuals. This techniqueshould not be tried until the patient is hooked up toa cardiac monitor or ECG. If these facilities are notavailable, someone needs to listen to the heartbeat whilethe doctor presses the carotid sinus. This technique isnot used in individuals over age 60 or in those whosecarotid arteries are known to be obstructed by atheromadue to the rare possibility of stroke.The above patient’s attacks became more frequentafter age 50. She was tried on digoxin, which was a 75%success for about two years. She later required a betablocker,which often helps in this situation. Very rarelya combination of digoxin and beta-blocker is necessary tosuppress attacks, and this was tried with success for abouttwo years. Finally, at age 51 she was tried on a beta-blockeralone and this was effective. At age 76, except for twoor three one-hour episodes per year, her heart remainednormal.The majority of patients with AVNRT get immediaterelief in the emergency room when given adenosine IVor IV verapamil. Verapamil cannot be used, however, in

III. TACHYCARDIA93individuals who have heart failure or who have a weakheart muscle, because it can precipitate heart failure insuch cases. Adenosine, is as effective as verapamil, but safer.Intravenous adenosine corrects the condition within afew seconds. Adenosine 6 mg is given, but the drug has ashort half-life of

94ARRHYTHMIAS/PALPITATIONSFIGURE 6AAV-nodal re-entrant tachycardia. Note the pseudo-s wave in lead III (arrow), and psuedo r 0 in V1 (arrow).ORAV Nodaltachycardia(common type)AtrialTachycardiaCircusmovementtachycardiaFIGURE 6B A representation of the sites of origin and mechanism of paroxysmal supraventricular tachycardia (SVT) as determined by the position andpolarity of the P waves in relation to the QRS complexes. In atrial tachycardia the P wave precedes the QRS; its polarity in lead III depends on its location.In AV notdal reentry tachycardia the P wave is buried within the QRS or may distort the end of the QRS: that portion of the QRS is then negative in leadIII. In circus movement tachycardia the P wave follows the QRS. (From Wellens, J.J.H., and Conover, M.B. (1992). The ECG in Emergency DecisionMaking. Philadelphia: W.B. Saunders, p. 75.)

IV. ANTIARRHYTHMIC AGENTS95FIGURE 7Sinus rhythm; supraventricular extrasystoles; WPW pattern; short PR and delta wave.abnormal heart rhythm and occurs mainly in patients withsevere coronary artery disease or severe cardiomyopathy.The heartbeat is regular but fast, between 120 and 200 perminute. Usually the diagnosis is made from an ECG thatshows a wide QRS complex and regular tachycardia (seeFigs. 8–10).During a heart attack, ventricular tachycardia mayoccur and is usually treated with a drug called lidocainefollowed by other drugs to suppress the rhythm. If successis not obtained, the patient’s abnormal heart rhythmis converted to normal sinus rhythm with the use of acardioverter, which delivers small electrical shocks to theheart. Such a cardioversion is carried out in the emergencyroom or the coronary care unit after the patient has beensedated. Frequent bothersome VPBs and nonsustainedventricular tachycardia are treated best with beta-blockers,and in some cases amiodarone may be necessary. Ventriculartachycardia may progress to ventricular fibrillation,which is usually the cause for sudden cardiac death. Animplantable defibrillator may be necessary in somepatients.G. Torsades de PointesThis is a pleomorphic form of ventricular tachycardia thatusually occurs in the presence of a prolonged QT interval.The RR interval is irregular and the QRS complex shows acharacteristic twisting of the points. The ventricular ratevaries from 200–300 beats per minute and is usually notsustained for more than a minute. Longer episodes degenerateinto ventricular fibrillation.Drugs and conditions that may precipitate torsades depointes include sotalol, amiodarone, and other antiarrhythmicagents; tricyclic antidepressants; antiviral and antifungalagents; antibiotics of the erythromycin-azithromycinseries; hypokalemia and hypomagnesemia; insecticide poisoning;congenital long QT syndrome; cocaine abuse; andchloroquine and pentamidine.IV. ANTIARRHYTHMIC AGENTSFigure 11 illustrates how myocardial cells generate anaction potential in phase zero through a fast influx ofsodium ions into cells. This increases the resting potentialand voltage of the cell (depolarization). During phase threethe cell returns to its resting potential with an efflux ofpotassium ions. Some antiarrhythmic agents produce theireffects by decreasing the rate at which sodium enters themyocardial cell during phase zero. Thus, generation of theaction potential of an abnormal impulse is dampened anddoes not reach sufficient magnitude to produce abnormalbeats. Quinidine, disopyramide, procainamide, flecainide,and propafenone decrease the rate at which sodium entersmyocardial cells. Beta-adrenergic blocking agents, lidocaine,and several antiarrhythmic agents decrease therate of automaticity of abnormal rhythms by depressingphase four of the action potential (as indicated by thearrow in Fig. 3). Amiodarone and a unique beta-blocker,sotalol, cause prolongation of the action potential (phasetwo) and retard the generation of an abnormal impulse.Most important, an increase in the absolute refractory

96ARRHYTHMIAS/PALPITATIONSV 1 **Predominantly-ve QRS V 4 −V 6 *QR complex inone or more of V 2 −V 6MorphologyV 1 and V 6LRV 2Left “rabbit ear”> right V 1V 3V 4V 5V 6QS or rsor net negative in V 6FIGURE 8 Electrocardiographic hallmarks of ventricular tachycardia (VT). * ¼ or concordant negativity in leads V 1 through V 4 . Positive concordance inleads V 1 through V 6 can be caused by VT or Wolff-Parkinson-White antidromic (preexcited) tachycardia. ** ¼ it is necessary to study the entire 12-leadtracing with particular emphasis on leads V 1 through V 6 ; lead II may be useful for assessment of P waves and AV dissociation. (From Khan, M. Gabriel(2001). On Call Cardiology, second edition. Philadelphia: W.B. Saunders, p. 141.)period(phases one and two), protects the heart fromdangerous impulse stimuli. During a 20–30 ms vulnerableperiod in phase three a strong electrical stimulusor ventricular ectopic beat can readily trigger ventriculartachycardia and ventricular fibrillation.A. Digoxin (Lanoxin)Digoxin is used to treat patients with atrial fibrillationto slow the fast heart rate. This drug may also be used toprevent recurrent attacks of AVNRT. It is used daily fora prolonged period to prevent recurrent attacks, butthe success rate may be low for some patients. The importantrole of digoxin in slowing the heart rate in patientswith atrial fibrillation is discussed in the chapter AtrialFibrillation.when they are associated with increased secretion ofcatecholamines and in individuals with mitral valveprolapse. These agents have a beneficial effect onVPBs produced during or following a heart attack. Betablockersare the only safe antiarrhythmic drugs that havebeen proven to prevent sudden cardiac death and heartattacks.Several other drugs are used to treat more difficultand serious heart rhythm disorders. Most of these drugshave serious side effects, are only 60–80% effective incontrolling the disturbance, and do not prevent death.Thus, doctors are not keen to treat premature beats unlessthey are associated with serious heart disease. In suchpatients, when premature beats are numerous with runs offour or more occurring together for more than 30 seconds,drugs are usually tried.B. Beta-BlockersBeta-blockers are occasionally used to treat AVNRT.These drugs can also be used to treat bothersome VPBsC. SotalolSotalol is unique in that it is the only beta-blockerthat has class III antiarrhythmic effects. It is the most

IV. ANTIARRHYTHMIC AGENTS97V 1V 2V 3V 4V 5V 6FIGURE 9 Onset of a tachycardia with negative precordial concordance. Negative precordial concordance indicates ventricular tachycardia, since such apatter does not occur during anterograde conduction over an accessory pathway. (From Wellens, J.J.H., and Conover, M.B. (1992). The ECG in EmergencyDecision Making. Philadelphia: W.B. Saunders, p. 60.)effective beta-blocker available for the treatment of seriousabnormal heart rhythms, particularly the prevention ofventricular tachycardia. This drug may prevent recurrencesof paroxysmal atrial fibrillation, although this effect ismodest.Sotalol is hydrophilic and is eliminated by the kidney.The action of the drug is prolonged, so it is effective whentaken once daily. It is not affected by smoking. Therecommended dosage is 80 mg once or twice daily for4 weeks, then 160 mg once daily with a maximum doseof 240 mg daily. The drug must not be used in patientswith a low serum potassium, and it must not be usedconcomitantly with drugs that increase the QT intervalbecause torsades de pointes may be precipitated.D. AmiodaroneThis drug is effective in suppressing life-threateningabnormal heart rhythms and is approved for treatingrecurrent episodes of sustained ventricular tachycardia.The drug’s major toxicity manifests deposits of granulesin the cornea, fibrosis of the lung in about 5%, andgrayish blue discoloration of the skin with prolonged

98ARRHYTHMIAS/PALPITATIONSaVFV 1V 2V 3V 4V 5V 684472FIGURE 10 Ventricular tachycardia. Note the monophasic R wave in lead V 1 and the deep S in lead V 6 , signs of ventricular tachycardia. The northwestaxis is also a helpful clue. (From Wellens, J.J.H., and Conover, M.B. (1992). The ECG in Emergency Decision Making. Philadelphia: W.B. Saunders, p. 51.)use at high doses. Neuropathy and thyroid disturbancesmay also occur. Amiodarone must not be used incombination with verapamil. Interaction may occurwhen used concomitantly with quinidine, digoxin,and oral anticoagulants such as warfarin. The drugshould be avoided in patients with a low serum potassiumand should not be used with agents that prolong theQT interval because torsades de pointes may be precipitated.It is also contraindicated in patients with sick sinussyndrome.E. DisopyramideThis drug has effects similar to quinidine. It is useful inthe emergency treatment of ventricular tachycardia whengiven intravenously. Disopyramide should not be usedin patients with heart failure or poor heart muscle functionbecause it can precipitate heart failure. It is contraindicatedin individuals with glaucoma, kidney failure, low bloodpressure, and enlargement of the prostate because urinaryretention can be precipitated. The drug must not be usedin combination with verapamil.F. LidocaineThis drug is used intravenously in emergency situationsand is effective in suppressing ventricular tachycardia andserious premature beats (see the chapter Heart Attacks).G. MexiletineThis drug is more effective than disopyramide. It suppressescomplex abnormal heart rhythms, but it has notimproved survival rate. Mexiletine is contraindicated inpatients with low blood pressure. The dose must bereduced if kidney failure is present. Side effects includeslowing of the pulse, stomach problems, confusionalstates, double vision, and disturbance in walking (ataxia).The drug is therefore reserved for the treatment of lifethreateningarrhythmias.H. ProcainamideProcainamide has similarities to the well-known quinidine.It is of value when given intravenously in the emergency

IV. ANTIARRHYTHMIC AGENTS99FIGURE 11 Antiarrhythmic drug action. (From Khan, M. Gabriel. Cardiovascular system pharmacology, Encylopedia of Human Biology, second edition.San Diego: Academic Press, 1997.)management of ventricular tachycardia that is not responsiveto lidocaine. When used orally it has a variableeffect. It is less effective than quinidine or disopyramideand when used for longer than six months, patients candevelop joint pains and fever (lupus erythematosus).Although very rare, white blood cells can be damaged(agranulocytosis) with its use. The drug should not be usedin patients with low blood pressure, severe heart failure,and myasthenia gravis.I. QuinidineThe use of quinidine has greatly decreased since the adventof other antiarrhythmic agents. Quinidine suppressespremature beats in about 60% of cases, but it is onlypartially effective with life-threatening arrhythmias.Because of rare but serious side effects, the use of thedrug is questionable. Quinidine can precipitate ventricularfibrillation, which is the most dangerous abnormal heart

100ARRHYTHMIAS/PALPITATIONSrhythm, and cardiac arrest. It does not seem reasonable togive priority to a drug that may increase the risk ofventricular fibrillation and death. This agent increases thelevel of digoxin in the blood and when used concomitantly,care is necessary with digoxin and anticoagulants such aswarfarin.V. AUTOMATIC IMPLANTABLECARDIOVERTER DEFIBRILLATORWhen life is severely threatened by the recurrence ofabnormal heart rhythms that have caused cardiac arrestor recurrent sustained ventricular tachycardia, the automaticimplantable cardioverter defibrillator can play a rolein the health of selected patients. Recent advances in thisarea allow a ray of hope. Dr. Saksena in New Jersey hasintroduced a nonsurgical technique for implanting theautomatic cardioverter defibrillator. Clinical trials haveshown this to be highly successful.VI. CONCLUSIONWe have a long way to go in the management of simplepremature beats, more complex extra beats, ventriculartachycardia, and the prevention of ventricular fibrillation,which is the cause of death in many heart patients.Questions still to be answered include the following:1. Are the drugs effective in suppressing the abnormalrhythm?2. Do they prevent ventricular fibrillation and prolonglife, especially during and after a heart attack?3. How serious are their side effects, including the precipitationof more dangerous heart rhythms?4. Is their use justified in the given individual?At present, partial success with the use of complexdrug combinations in the seriously ill has been achieved,yet life has not been prolonged. In addition to toxicity,several visits to the doctor and cost must be justified.BIBLIOGRAPHYACC AHA/ESC Guidelines for the management of patients withsupraventricular arrhythmias — Executive summary. J. Am. Coll.Cardiol., 42:1494–1529, 2003Alboni, P., Bott, G. L., Bald, N. et al. Outpatient treatment of recentonsetatrial fibrillation with the ‘‘Pill-in-the-Pocket’’ approach.N. Engl. J. Med., 351:2384–2391, 2004.Becker, R. C. et al. Novel constructs for thrombin inhibition. AM. HEAR.J., 149:S61–S72, 2005.Bourassa, M. G. et al. Angiotensin II inhibition and prevention of atrialfibrillation and stroke. J. Am. Coll. Cardiol., 45:720–721, 2005.Eckardt, L., Probst, V., Smits, J. P. P. et al. Long-term prognosis ofindividuals with right precordial ST-segment-elevation Brugadasyndrome. Circulation, 111:257–263, 2005.Ferguson, J. D., and DiMarco, J. P. Contemporary managementof paroxysmal supraventricular tachycardia. Circulation, 107:1096,2003.Gaita, F., Riccardi, R., Caponi, D. et al. Linear cryo ablation of the leftatrium versus pulmonary vein cryo isolation in patients with permanentatrial fibrillation and valvular heart disease: Correlation ofelectro-anatomic mapping and long-term clinical results. Circulation,111:136–142, 2005.Halperin, J. L. et al. Ximelagatran: Oral direct thrombin inhibition asanticoagulant therapy in atrial fibrillation. J. Am. Coll. Cardiol.,45:1–9, 2005.Hanna, I. R., Langberg, J. J. et al. The shocking story of azimilide.Editorial. Circulation, 110:3624–3626, 2004.Hazel SJ , Paterson HS, Edwards JRM et al. Treatment of AtrialFibrillation via Energy Ablation. Circulation, 111:e103–e106, 2005.Jongbloed, M. R. M., Bax, J. J., Lamb, H. J. et al. Multi-slice computedtomography versus intracardiac echocardiography to evaluate thepulmonary veins before radiofrequency catheter ablation of atrialfibrillation. J. Am. Coll. Cardiol., 45:343–350, 2005.Khan, M. G. In Heart Disease Diagnosis and Therapy, second edition.Humana Press, New Jersey, 2005.Khan, M. Gabriel. Cardiac Drug Therapy, sixth edition, W. B. Saunders,Philadelphia, 2003.Khan, M. Gabriel. Rapid ECG Interpretation, second edition,W. B. Saunders, Philadelphia, 2003.McMurray, J., Køber, L., Robertson, M. et al. Anti-arrhythmic effect ofcarvedilol after acute myocardial infarction. J Am. Coll. Cardiol.,45:525–530, 2005.Montenero, A. S., Bruno, N., Antonelli, A. et al. Long-term efficacy ofcryo catheter ablation for the treatment of atrial flutter. J. Am. Coll.Cardiol., 45:573–580, 2005.Packer, D. L., Keelan, P., Munger, T. M. et al. Clinical presentation,investigation, and management of pulmonary vein stenosis complicatingablation for atrial fibrillation. Circulation, 111:546–554, 2005.Page, R. L. et al. Newly diagnosed atrial fibrillation. N. Engl. J. Med.,351:2408–2416, 2004.Rossenbacker, T., Mubagwa, K., Jongbloed, R. J. et al. Novel mutation inthe Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome. Circulation, 111:961–968, 2005.Saksena, S. Nonpharmacologic therapy for cardiac arrhythmias, cardiacpacing, implantable cardioverter defibrillators, catheter, and surgicalablation. In Heart Disease Diagnoses and Therapy, M. Gabriel Khan, ed.Williams & Wilkins, Baltimore, MD, 1996.Saksena, S., Prakash, A., Ziegler, P. et al. Improved suppression ofrecurrent atrial fibrillation with dual-site right atrial pacing andantiarrhythmic drug therapy. J. Am. Coll. Cardiol., 40:1140, 2002.Singer, I., Hussein, A., Niazi, P. T. et al. Azimilide decreases recurrentventricular tachyarrhythmias in patients with implantable cardioverterdefibrillators. J. Am. Coll. Cardiol., 43:39, 2004.Wachtell, K., Hornestam, B., Lehto, M. et al. Cardiovascular morbidityand mortality in hypertensive patients with a history of atrialfibrillation. J. Am. Coll. Cardiol., 45:705–711, 2005.

ArteriosclerosisI. Diseases Causing ArteriosclerosisII. AtherosclerosisGLOSSARYadventitia the outermost lining of the vessel wall.epistaxis hemorrhage from the nose.hyperplasia abnormal increase in the number of normal cellsin normal arrangement in an organ or tissue which increasesits volume.intima the innermost lining of the vessel wall that is in contactwith flowing blood.media the middle wall of arteries.retinopathy noninflammatory disease of the retina, particularlycaused by diabetes or hypertension.THERE HAS BEEN MUCH CONFUSION IN THE USEof the terms arteriosclerosis and atherosclerosis. Arteriosclerosisis a diffuse lesion which often affects longsegments of the arterial tree in which there is usually acombination of hypertrophic and fibrous changes in theentire thickness of all layers of the arterial wall. The mediaand adventitia are commonly affected by this diseaseprocess. Atherosclerosis is the term used for atheromaof arteries. It is typically patchy with a focal lesion ofthe intima with degeneration. There are also plaques ofatheroma jutting into the lumen of the vessel obstructingthe flow of blood. (See chapter entitled ‘‘Atherosclerosis/Atheroma.’’)I. DISEASES CAUSING ARTERIOSCLEROSISA. Hypertensive ArteriosclerosisProlonged hypertension causes the walls of the affectedarteries to become firmer and thicker, and the lumen areoften wider than normal. Arteries appear to be generallyenlarged and they may become somewhat tortuous. Thesechanges can be seen especially in the retinal arteries(hypertensive retinopathy), kidneys, pancreas, and otherorgans. The lumen of minute arterial branches, however,are often diminished owing to thickening of the intima.Microscopic examination shows that the arterial wallis generally thickened with a proliferation of connectivetissue cells and formation of new tissue both in theintima and the media. There is a considerable amountof concentric fibrous thickening, often without atheromaformation. In the thickening of media there may bedistinct evidence of muscular increase, but in most casesthe muscle fibers are found to be undergoing replacementby fibrous tissue leading to distinct fibrosis of the media.There is, however, true muscular hypertrophy. In youngsubjects with severe kidney disease and severe hypertension,hypertrophy of the media occurs before secondaryfibrosis has appeared. This hypertrophy is similar tohypertrophy of the myocardium in response to theincreased workload imposed by the high pressures. In thethickened intima, there is distinct hypertrophy andhyperplasia of the longitudinal muscle layer next to theinternal elastic lamina. A reactive increase in the supportingelements of the vessel wall occurs in both muscle andelastic tissue. This occurs in response to increased bloodpressure. This type of musculoelastic hyperplasia can bearrested by some antihypertensive agents.With hypertensive arteriosclerosis the walls of smallvessels become swollen and hyaline and its lumen may bediminished. These changes may be observed in end-stagekidney disease caused by severe hypertension and nephritis.In advanced cases there are lesions of a more severe typein which patchy necrosis of the arterial wall occursalong with fibrous infiltration and thrombosis. A typicalfinding in patients with malignant hypertension is fibrinoidnecrosis of arteries in the kidney and other organs.These hemorrhagic changes are classically observed in theretinal arteries that are severely damaged by malignanthypertension and reflect the extensive pathologic changesthat occur in other organs including the kidney and brain.Cerebral hemorrhage may also occur. Epistaxis is notuncommon and red blood cells exuding from kidneylesions are also found in the urine.101

102ARTERIOSCLEROSISB. Monckeberg’s Sclerosis — Calcificationof the MediaCalcification is frequent in the arterial system. A strikingdegree of calcification is that which occurs in the mediaof arteries, particularly in the elderly. Calcification ofthe media is far more common in large arteries such as theiliac and femoral arteries. Lime salts are deposited in themiddle media in these patients and elevated blood pressuremay be recorded, but the mean arterial pressure is normal.This condition is not caused by hypertension nor does itcause hypertension. This is essentially a senile change thatrarely leads to senile gangrene.C. Endarteritis ObliteransEndarteritis obliterans is a reaction of the arterial wall toan irritant which approaches it from the outermost liningof the adventitia. This process may be initiated by syphilisin which the main lesions are endarteritis and periarteritisof the small arteries in association with infiltration oflymphocytes and plasma cells around them.These lesions affect the vasa vasorum, the small arteriolesthat feed the media with blood. The aortic arch is alsocommonly affected by syphilitic lesions. The arch immediatelyabove the aortic valve is usually involved leading toweakness of the arterial wall and aneurysm formation ofthe ascending part of the aortic arch. Syphilis commonlydamages the aortic valve and dilates the aortic valve ringcausing severe aortic regurgitation. The aortic arch showsthickened plaques and irregularity of the surface withformation of aneurysmal depressions. Narrowing of theorifices of the coronary artery at their origin from theaorta (ostia) may occur and cause angina. Syphilitic lesionsmay also affect the pulmonary arteries causing right heartstrain and heart failure. The arterial damage by syphilis istherefore not considered a true form of arteriosclerosisand is regarded as a specific disease of the arteries thatincludes vasculitis.D. Thromboangiitis ObliteransThis disease process is a segmental vasculitis that affectsthe peripheral arteries, veins, and nerves of the arms andlegs. The renal, coronary, and cerebral vessels may also beinvolved. Thromboangiitis obliterans is sometimes calledBuerger’s disease as he was the first to described it in 1908in 11 amputated limbs.The pathologic process of this disease is distinct fromatheroma and arteriosclerosis. This condition is fortunatelyrare and occurs in young persons usually less than age 40who are cigarette smokers. The pathologic process consistsof highly cellular thrombi composed of polymorphonuclearleukocytes forming micro abscesses. Occasionallymultinuclear giant cells are observed. The inflammatoryinfiltrate affects the vascular wall, but the internal elasticlamina remain intact. There is usually considerable fibrosisof the media and adventitia. Similar changes may bepresent in the accompanying veins and phlebitis of thesuperficial veins of the arms and legs may be a prominentfeature. It is important to note that atherosclerosis andarteriosclerosis are two distinct diseases that cause disturbancesin arteries, not veins.Thromboangiitis obliterans is common in Asia andrare in North America and western Europe. Most patientshave symptoms before age 40 and more than 80% occurin men. Patients may complain of cold hands and feet(Raynaud’s phenomenon) and develop digital ulcerationsand gangrene. Several diseases may cause similarsymptoms and signs including scleroderma, lupus erythematosus,mixed connective tissue disease, and antiphospholipidantibody syndrome. These diseases must beexcluded before considering thromboangiitis obliteransas the diagnosis.Diagnosis is based on the age of onset before age of40, history of tobacco use, physical examination demonstratingdistal limb ischemia, and exclusion of other conditionsmentioned above. Angiography may show segmentallesions.Treatment includes cessation of cigarette smoking.Biopsy of lesions may prove difficult to heal and reconstructivesurgery is often not feasible because of thesegmental lesions that may be present.II. ATHEROSCLEROSISThe word ‘‘atheroma’’ is derived from the Greek stem‘‘athere,’’ meaning porridge or gruel. When a plaque ofatheroma is cut, one can see a gelatinous, thick, porridgelikematerial that contains cholesterol and other fattymaterial. The plaque of atheroma involves the intimaand the middle wall of the artery. Apart from a rich fatcontent, the plaque has a preponderance of smooth musclecells that are derived from the media. These smoothmuscle cells are believed to be very important in theformation and growth of the plaque. Substances such ascholesterol and products released from blood plateletsstimulate the smooth muscle cells to proliferate, thusenlarging the plaque.

II. ATHEROSCLEROSIS103The intima of the artery in contact with the blood issmooth. When atherosclerosis occurs, a plaque of atheromajuts into the lumen of the artery. The silky smoothlining of the arteries is damaged by the force of blood as itmoves through arteries that are elastic and constantlymoving in pulsation. With every pulse wave, the arterialwall yields and stretches; over many years some damagemust occur. The damage is partially repaired by smallblood particles (platelets), which clump together andplug the damaged surface. These platelet plugs form atemporary patch, just like the plug of coagulated bloodthat forms when you nick yourself and a very small clotforms. In the coronary arteries or aorta, small clots arecommonly formed on the lining. Presumably, these clotsare involved in the repair of injuries to the smooth liningof the arteries. These small blood clots are somehowwelded into the lining as hard, thickened areas (fibrousplaques). The artery tries to strengthen its wall duringthis repair job.The plaques of atheroma are sometimes smooth,bumpy, large, rough, and even ulcerated. Because thevessel wall gets hard (sclerosed), the term used for thedisease is atherosclerosis (see the chapter Angina). A heartattack is caused by blockage of a coronary artery, and sucha blockage is usually due to one or more of the following:A blood clot forms on a plaque of atheroma. Lipidrich plaques are prone to rupture but can be fissuredor ulcerated and this often leads to clotting; the termatherothrombosis describes this serious complication ofatheroma. See the chapter Atheroma/Atherosclerosis.A large plaque of atheroma nearly completely blocksthe artery.Small blood particles (platelets) may stick to the surfaceof the plaque in clumps similar to sludge in pipes; theclumped material may dislodge and be moved downstreamby the blood and may block a smaller artery.A coronary artery may go into spasm, especially at thesite of a plaque, blocking the vessel for a few minutes ora few hours (coronary artery spasm).An increase in adrenaline can be produced under theinfluence of stress or other inciting factors causingclumping of platelets that may lead to clot formation;excess adrenaline from any source can also produceelectrical disturbances in the heart, especially ventricularfibrillation; in fibrillation the heart muscle stops contractingand quivers therefore no blood is pumped,causing cardiac arrest.The exact mechanism that leads to the formation ofblockage by atheroma has defied medical research forthe past 60 years; it is certain that a high level of LDLcholesterol, particularly oxidized LDL (bad) cholesterol,initiates and perpetuates atheroma formation andprogression.Atherosclerosis causes blockage of arteries and is thecause of heart pain, angina, heart attacks, and deathfrom coronary heart disease; blockage of arteries byatherosclerosis is the basic cause of heart attacks,stroke, aneurysm of the aorta, and poor circulation inthe legs.In the western world, the UK, Europe, Ireland, andRussia atherosclerosis is the most common disease affectingmen aged 35–80 and women after age 55. Death dueto atherosclerosis is several times more common than allforms of cancer. The underlying atherosclerotic disease ofthe coronary arteries leads to more deaths than any otherdisease in industrialized countries. This disease is muchmore common in young men than women. Womenare fortunately protected from atherosclerosis up to age 55because of estrogens. Because men commonly die fromheart attacks between age 40 to 60, the disease in theleft anterior coronary artery has been appropriately labeled‘‘the widow-maker.’’BIBLIOGRAPHYBickerstaff, L. K., Pairolero, P. C., Hollier, L. H. et al. Thoracic aorticaneurysms: A population based study. Surgery, 92:1103, 1982.Forrester, J. S. Toward understanding the evolution of plaque rupture.J. Am. Coll. Cardiol., 42:1566–1568, 2003.Lie, J. T. The rise and fall and resurgence of thromboangiitis obliterans(Buerger’s disease), Acta Pathol. Jpn., 39:153–58, 1989.

Artificial HeartI. Electric Total Artificial HeartII. Left Ventricular Assist DeviceIII. Is There a Logical Role for Ventricular Assist Devices?IV. New FrontiersGLOSSARYatherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.left ventricular assist device a device that can replace a leftventricle that is no longer able to pump blood into the aorta.New York Heart Association class IV heart failure the worststage, end-stage, severely symptomatic at rest.thromboembolic clots or thrombi that break off from theinterior lining of the heart; they are propelled by the bloodand become lodged in an artery supplying blood to an organor to the extremities.CARDIOVASCULAR DISEASE IS THE MAIN CAUSEof death in the United States, Canada, UK, Ireland, andEurope. It accounts for more than 40% of total deathsin these countries. Many of these deaths are due to heartfailure. Heart failure affects approximately five millionAmericans with more than half a million new cases diagnosedannually. The aggregate five-year survival rate ofpatients with heart failure is approximately 50%, but theone-year mortality rate is close to 50% for patients withsevere heart failure (New York Heart Association class IVheart failure). Patients who remain in class IV heart failurefor several months despite optimal medical therapy mayrequire heart transplantation.There is no doubt that cardiac transplantation has arole and provides beneficial relief of suffering in selectedindividuals. The one-year survival rate is more than 80%and the 10-year survival rate is close to 50% fortransplantation. This far exceeds the dismal survival rateobtained with the left ventricular assist devices that at twoyears is less than 20%. Following left ventricular assistdevice a transplant is necessary within one to six months.This calls for two operations within six months in verysick individuals. This is a major disadvantage of assistdevices. Most important, there are fewer than 4000 donororgans available worldwide per year. The cost of twooperations within six months is prohibitive as well asphysically and mentally traumatic. A functional total artificialheart would be a dream come true.I. ELECTRIC TOTAL ARTIFICIAL HEARTThe first artificial heart implant was carried out byDr. Denton Cooley in Houston, Texas, in a 47-year-oldman with intractable heart failure using the Liotta artificialheart developed by Domingo Liotta. This artificial heartwas based upon the laboratory work of Dr. MichaelDeBakey.The electric total artificial heart was designed forpermanent use and was completely implantable. Pneumatictotal artificial hearts have not proved successful insmall group studies. The Jarvik-7-100 artificial heart,a pneumatic system developed by the physician-engineer,Robert Jarvik, was tried in four patients as a permanentimplant. All four patients died because of infectious,hematologic, and thromboembolic complications. Onepatient lived for 20 months. This device was first useby Dr. William DeVries who implanted the device inBarney Clarke in 1982. The presence of percutaneousdrive lines causes infectious complications and the bulkyexternal drive unit makes pneumatic artificial hearts unsuitablefor permanent implantation.From 1970 to the present much investigational workhas been done in the development of left ventricular assistdevices as opposed to the development of a total artificialheart. This setback has delayed the development of thetrue total artificial heart. During the past decade, through105

106ARTIFICIAL HEARTa contract program established by the National Heart andLung Institute, two research teams have been developingan electric total artificial heart that is undergoingclinical testing in selected areas in the United States.A. AbioCorA completely novel approach to the artificial heart wasconceived by engineers from the Abiomed company.The AbioCor is a totally implantable artificial heartthat is electric as opposed to the failed Jarvik-7, which isa pneumatic system.AbioCor is the Abiomed (Danvers, MA) total artificialheart. It has been tried in a few patients (see Fig. 1). Theprosthesis replaces the right and left ventricles of therecipient and is an electrohydraulically triggered devicethat can provide a cardiac output of 4–8 L/minute withAortaPulmonaryarterya maximum of 10 L/minute. The design allows forphysiologic flow in a pulsatile manner, and has been shownto provide satisfactory end organ perfusion. This devicehas the potential to provide a satisfactory outcome forpatients suffering from end-stage heart failure who are notsuitable for transplantation or when donor hearts are notavailable.1. Implantable ComponentsA chest unit containing two blood-pumping sacs filland empty alternately, supplying pulsatile blood flowthrough the aorta and pulmonary arteries, respectively.An artificial septum is situated between the two bloodsacs and contains a miniaturized centrifugal pump thatrotates at 5000–90,000 rpm. The pump then transportsthe hydraulic fluid alternatively to the right and leftsides. Blood flows through artificial plastic trileaflet valveswhich act as atrioventricular and ventriculoarterial valves.Rechargeable lithium ion cells provide energy to thepump for up to 30 minutes. The internal rechargeablebatteries allow patients freedom for 15–30 minutes asthe batteries are constantly charged from an externalsource. A microprocessor in the chest unit provides physiologicparameters: beat rate, motor speeds, and balancebetween the right and left pressures that control thepumping function of the heart. A disk-shaped internaltranscutaneous energy transfer (TET) coil is placed in thesubpectoral region.VenaecavaeArtificialright ventricleHydraulicpumping systemArtificialleft ventricleFIGURE 1 An artificial heart (Abiocor) shown implanted in arecipients’s mediastinum. The prosthesis replaces the right and leftventricles of the recipient. (From Jessup, M. (2001). N. Engl. J. Med.,345(20), p. 1492. With permission.)2. External ComponentsThe internal TET receives magnetic waves from an externalTET coil, which transfers energy across the skin to theimplanted device by a process of inductive coupling thatconverts the external energy to electrical energy. Thus, thedevice is totally internal with no cables through the skin.A console the size of a laptop computer houses a batterythat powers the device for approximately 45 minutes.The external TET coil attaches to the console and providesa constant power supply. The console is plugged into a walloutlet and is disconnected for activities and travel.B. Lionheart1. Chest SizeSize constraints remain the most important hurdle.Patients must have an adequate chest cavity size or anteroposteriorthoracic dimension.

II. LEFT VENTRICULAR ASSIST DEVICE1072. Power SourceThe Lionheart (Arrow, Reading, PA) electrical artificialheart uses a single, implantable energy converter to driveboth ventricles that are implanted within the pericardium.It avoids the problem of using a separate external driveunit for each ventricle as is done with the pneumaticsystem. The electrical unit uses a single implantable energyconverter to drive both ventricles and requires a minimumenergy of 14 W. Unfortunately, implanted batteriesare not capable of supplying the power that is required.The development of high-energy density batteries hopefullyshould eliminate the need for the present use ofa primary external power source as this is a major hurdlestill left to overcome.II. LEFT VENTRICULAR ASSIST DEVICEA. SystemsLeft ventricular assist devices are implanted only inpatients who are eligible for cardiac transplantation.These devices are used as bridges to transplantation.There are three left ventricular assist devices presentlyavailable:Thoratec, the HeartMate, and Novacor.The Thoratec system is paracorporeal: the pneumaticpump resides externally on the surface of the abdomen andis connected by cannulas to the heart and the ascendingaorta. Figure 2 is taken from the Rose et al. study whichreviewed long-term use of left ventricular assist devices.In the second and third systems the device is placedentirely within the chest cavity and abdomen. The energyconduit and vent, a drive line, is brought through theskin to the external energy source. Major problems withthese systems include: a high incidence of infection of thedevice that usually occurs between 3 and 6 months, a highrate of bleeding by 6 months, and a probability of devicefailure greater than 33% at 2 years.B. Clinical Study: Rose et al.Study question: Does long-term use of left ventricularassist devices enhance survival and the quality of life?Methods: Patients (129) with end-stage heart failureand eligible for cardiac transplantation were randomizedto receive a left ventricular assist device (68 patients) oroptimal medical management (61). All patients hadsymptoms classified as of New York Heart Associationclass IV heart failure.FIGURE 2 Components of the left ventricular assist device. The inflowcannula is inserted into the apex of the left ventricle, and the outflowcannula is anastomosed to the ascending aorta. Blood returns from thelungs to the left side of the heart and exits through the left ventricular apexand across an inflow valve into the prosthetic pumping chamber. Blood isthen actively pumped through an outflow valve into the ascending aorta.The pumping chamber is placed within the abdominal wall or peritonealcavity. A percutaneous drive line carries the electrical cable and air vent tothe battery packs (only the pack on the right side is shown) and electroniccontrols, which are worn on a shoulder holster and belt, respectively.(From Rose, E.A., et al. (2001). N. Engl. J. Med., 345(20), p. 1437. Withpermission.)Results: The device caused a significant reduction inrisk of death as compared with the medical therapy groupp ¼ 0.001). Figure 3 shows the rates of survival at oneyear: 52% for the device group and 25% in the medicalgroup ( p ¼ 0.002). The primary end point was 48% lowerin the device group. Importantly, at 2 years survival wasnot significantly different: 23 and 8%, respectively( p ¼ 0.09).C. PerspectiveThis remarkable study is the first randomized study toascertain whether a left ventricular assist device couldprovide long-term benefits and enhance survival in patientsawaiting transplantation. The study clearly shows that thedevice can prolong life beyond optimal medical therapyin desperately ill New York Heart Association class IV

108ARTIFICIAL HEARTbridged to transplantation, and 19 were well 30 days aftertransplantation.Adverse events were: Reoperation for bleeding (n ¼ 8, 27%) Hemolysis (n ¼ 3, 10%) Device-related infection (n ¼ 2, 6.7%) Pump thrombus (n ¼ 4,13%) Stroke (n ¼ 3, 10%)FIGURE 3 Kaplan-Meier analysis of survival in the group that receivedleft ventricular (LV) assist devises and the group that received optimalmedical therapy. Crosses depict censored patients. Enrollment in the trialwas terminated after 92 patients had died; 95 deaths had occurred by thetime of the final analysis. (From Rose, E.A., et al. (2001). N. Engl. J.Med., 345(20), p. 1439. With permission.)patients, but only for up to 6 months. The device wasa failure at 24 months. In addition, complications andsuffering remain intolerable and perhaps not justifiable:few patients who received the assist device survived longerthan 2 years, the incidence of infection was 28% at3 months, the incidence of bleeding by 6 months was42%, and a probability of device failure was 35% at twoyears. Pulsatile ventricular assist device (VAD) hasrecently been approved by the FDA as a suitable alternativetreatment for patients who are not candidates forheart transplantation. The drawbacks of these VADsinclude:Large size and noisyHigh incidence of device-related infection.MalfunctionGoldstein et al. reported on the safety and feasibility trialof the MicroMed DeBakey ventricular assist device as abridge to transplantation (J. Am. Coll. Cardiol. 45:2005).The MicroMed DeBakey VAD is a miniaturized, implantable,electromagnetically actuated titanium axial flowpump with a single moving impeller. ‘‘The rotatingmotion of the impeller produces continuous flow. Anultrasonic flow probe provides direct measurements ofpump flow. Wiring from the pump and the flow probeexit the skin and connect to a portable controller.’’The 30 subjects were class IV patients who were inotropeand/or intra-aortic balloon pump dependent, andwere accepted as candidates for cardiac transplantation.All 30 patients survived the operation. There was nodevice failure. Twenty patients (67%) were successfully‘‘As a result of this initial feasibility trial, the FDA hasapproved an expanded multicenter evaluation of theMicroMed DeBakey pump as a bridge to transplantation.’’Advantages of the device include:MiniaturizationA limited blood-contacting surfaceIII. IS THERE A LOGICAL ROLE FORVENTRICULAR ASSIST DEVICES?There are approximately fewer than 3000 donor organsavailable worldwide per year. In the United States alone,in 1999, 2184 patients with heart failure underwent hearttransplantation. When a left ventricular assist device isimplanted a donor heart must be available within approximately3 months for the patient to maintain survival andquality of life.Published data by treating teams indicate that patientswho have received a device implant must be given priorityfor the next available donor heart. Thus virtually allindividuals who can afford the expense (approximately$150,000. for the device plus approximately $50,000 forhospitalization) incurred in acquiring an assist devicewill receive the highest priority for obtaining the nextavailable donor heart. The treating team recognizes thatif the patient with the assist device does not undergotransplantation within a few months of device implantation,complications and death are to be expected withina year. Therefore, the availability of a donor heart isnecessary for the success of the assist device, but as stressedabove, there are limited donor hearts available.In a study at the Montreal Heart Institute 16 patientsreceived an assist device as a bridge to transplant. Thirteenof the patients underwent heart transplantation. Threedied while waiting for a transplant. During this sameperiod, 20 patients had a heart transplant without theuse of an assist device. The time spent waiting for atransplant, however, was longer for those without an assistdevice: 87 days compared to only 17 days for patients whoreceived an assist device.

IV. NEW FRONTIERS109FIGURE 4 AbioFit. Three-dimensional reconstruction of patient’s cardiothoracic anatomy with virtual implant of AbioCor. (From Samuels, L. (2003).Am. Heart Hosp. J., p. 93. With permission.)It appears that an assist device ensures heart transplantationwhich improves survival. This treatment selectionbias may be unethical and does not solve the transplantproblem in North America or worldwide. Extensiveresearch and funding for the development of a totalartificial heart is a more logical strategy for the managementof end-stage heart failure in patients. Both theprevention of the underlying disease, atherosclerosis, thatcauses coronary artery disease and aggressive managementof hypertension to prevent the occurrence of heartfailure carries the key to future survival.IV. NEW FRONTIERSA ray of hope has been generated by the work ofDr. M. H. Yacoub, who describes a novel strategy: a combinationof surgery and physiologic hypertrophy. Thesurgical process involves implantation of a left ventricularassist device and medical therapy with a drug, clenbuterol,a beta-2-agonist which induces reverse remodeling of theleft ventricular myocardium and subsequent physiologicmyocardial hypertrophy. This strategy improves left ventricularcontractility and ejection fraction sufficiently toallow explantation of the assist device (the Harefieldprotocol).The small study of 19 patients resulted in 4 deaths.Among the 15 patients, 11 had sufficient recovery fromheart failure and had the left ventricular assist deviceexplanted. Ten patients are alive at two and a half yearsfollow up and showed excellent exercise capacity withremarkable improvement in ejection fraction and leada relatively normal life.Clenbuterol changes phenotype, genotype, and geneexpression in myocytes; in animal studies the agent hasbeen shown to improve pressure volume relationships,increase myocyte size, and enhance organization ofmyofibrils. Dr. Yacoub indicates that not all hypertrophyis maladaptive. The strategy is to rest the heart andmake it as small as possible, then activate the genesassociated with the fetal heart and make it matureagain. Once the heart is atrophied it is appropriate toenhance physiologic hypertrophy with clenbuterol orsimilar agents, which leads to improved left ventriclefunction.BIBLIOGRAPHYBrown, B. G., Crowley, J. et al. Is there any hope for vitamin E? JAMA,293:1387–1390, 2005.Goldstein, D. J., Zucker M., Arroyo L. et al. Safety and feasibilitytrial of the MicroMed DeBakey ventricular assist device as a bridge totransplantation. J. Am. Coll. Cardiol., 45:962–963, 2005.Hon, J. K. E., and Yacoub, M. H. Bridge to recovery with the use ofleft ventricular assist device and clenbuterol. Ann. Thorac. Surg., 75(Suppl.) S36–S41, 2003.

110ARTIFICIAL HEARTJessup, M. Mechanical cardiac support devices — dreams and devilishdetails. N. Engl. J. Med., 345:1490–92, 2001.Nielsen, J. C., Powell, A. J., Gauvreau, K., Marcus, E. N., Prakash, A.,Geva, T. et al. Magnetic resonance imaging predictors of coarctationseverity. Circulation, 111:622–628, 2005.Pagani, F. D., and Aaronson, K. D. LVAD therapy: The future is upon us.ACC Curr. Rev., Sept/Oct 90–94, 2002.Rose, E. A., Gelijns, A. C., Moskowitz, A. J. et al. Long-term use ofa left ventricular assist device for end-stage heart failure. N. Engl. J.Med., 345:1435–43, 2001.Samuels, L. The AbioCor totally implantable replacement heart. Am.Heart Hosp. J., 1:91–6, 2003.The HOPE and HOPE-TOO Trial Investigators.* et al. Effects oflong-term vitamin E supplementation on cardiovascular eventsand cancer a randomized controlled trial. JAMA, 293:1338–1347,2005.Wentzel, J. J., Corti, R., Fayad, Z. A., Wisdom, P., Macaluso, F.,Winkelman, M. O., Fuster, V., Badimon, J. J. et al. Does shear stressmodulate both plaque progression and regression in the thoracicaorta?: Human study using serial magnetic resonance imaging[Clinical research]. J. Am. Coll. Cardiol., 45:6:846–854.Yacoub, M. H. A novel strategy to maximize the efficacy of left ventricularassist devices as a bridge to recovery. Eur. Heart J., 22:534–540,2001.

Aspirin for Heart DiseaseI. Historical ReviewII. Mechanism of ActionIII. Recognized Indications for Aspirin and DoseIV. PerspectiveGLOSSARYatheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).myocardial infarction death of an area of heart muscle causedby blockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.platelets very small disk-like particles that circulate in the bloodalong with red blood cells initiating the formation of bloodclots; platelets clump and form little plugs called plateletaggregation, thus causing bleeding to stop.and in 1899, Felix Hoffman, a Bayer chemist, used aspirinto treat his father’s rheumatism.C. Lawerence Craven, 1953The first clinical trial of aspirin in patients occurredfrom 1948 to 1956 when a general practitioner, LawrenceCraven, treated 1500 relatively healthy, overweight, sedentarymen between the ages of 40 and 65. The result ofthe study reported in the Mississippi Valley Journal concludedthat one aspirin a day was sufficient, because noneof Lawrence Craven’s 1500 patients experienced a heartattack over the five-year course of treatment. This smallstudy, however, did not influence physicians to prescribeaspirin to patients for heart problems.I. HISTORICAL REVIEWYou do not have to believe in Adam and Eve to recognizethe significance of an apple. The old saying ‘‘an applea day keeps the doctor away’’ has been changed to ‘‘anaspirin a day keeps the doctor away’’ (see Fig. 1).A. Hippocrates, 400 BC and BeyondAs early as BC 350, Hippocrates tried to relieve the painof his patients by asking them to chew willow bark, anatural substance which contains salicylic acid. In 1763,Reverend Stone of Chipping Norton, England, showedthe benefit of willow bark for individuals with ague andfever. Today pain can be relieved by aspirin, which alsocontains salicylic acid.B. Von Gerhardt, 1853The use of salicylic acid, however, did not become commonuntil 1853 when Von Gerhardt of Bayer developed aspirinFIGURE 1111

112ASPIRIN FOR HEART DISEASED. John Vane, 1971Credit for influencing physicians to prescribe aspirinfor heart problems must be given to John Vane. He showedthat aspirin blocks the action of special substances in thebody called prostaglandins. This action prevents bloodplatelets from clumping together to produce a clot. Thus,aspirin is referred to as an antiplatelet agent that is a mildblood thinner. A study in the UK by Elwood et al. foundaspirin to be of no significant benefit when taken for a fewyears following a heart attack. Unfortunately, patients wereenlisted at various durations after their heart attacks (from3 to 6 months). Aspirin was not administered immediatelyfollowing the myocardial infarction. This flaw in methodologyand controversies delayed the use of aspirin for thenext 10 years.E. Lewis et al., 1983The timely 1983 study by Lewis et al. in the United Statesheralded a new era, and aspirin became widely known asa life-saving drug. This study showed that one Alka-Seltzercontaining 325 mg of acetylsalicylic acid, given to patientswith severe angina (heart pains, unstable angina), causeda 49% reduction in nonfatal and fatal heart attacks.A Canadian study testing aspirin, sulfinpyrazone, or bothin unstable angina confirmed Lewis’ observation thataspirin given immediately to patients who presented to theemergency room with severe chest pain or unstable anginaprevented serious events.F. ISIS-2, 1988This landmark study is the first to show the remarkablebenefits of aspirin when given immediately followingthe onset of chest pain caused by myocardial infarction.The second International Study of Infarct Survival(ISIS-2), a study mounted in the UK, confirmed a markedincrease in survival in a large group of patients given160 mg of plain aspirin (noncoated) within 6 h of theonset of chest pain causing a heart attack. In that study,aspirin greatly improved the life-saving effects of streptokinase,a drug used to dissolve clots soon after the occurrenceof a heart attack.G. Primary Prevention, 1988Finally, in 1988, a trial with 22,071 male U.S. physiciansaged 40–84 given 325 mg of aspirin on alternate daysfor five years demonstrated that aspirin use resulted ina 44% reduction in the risk of nonfatal myocardialinfarction. This trial endorsed the use of small-dose coatedaspirin preparations in normal individuals deemed at riskfor coronary artery disease and its complications.H. Swedish Trial, 1992The Swedish angina pectoris aspirin trial studied 2035patients with chronic stable angina without infarction.Aspirin, 75 mg, reduced the occurrence of infarction andsudden death by 34% in the treated patients versusplacebo.II. Mechanism of ActionAcetylsalicylic acid irreversibly acetylates the enzymecyclooxygenase found in platelets. This enzyme is necessaryfor the conversion of platelet arachidonic acid to thromboxaneA2. The latter is a powerful platelet-aggregatingagent and vasoconstrictor. The conversion to thromboxaneA2 and platelet aggregation can be initiated by severalsubstances, especially those released following the interactionof catecholamine or platelets with subendothelialcollagen. Endothelial and smooth muscle cells, whenstimulated by physical or chemical injury, cause cyclooxygenaseto convert membrane arachidonic acid to prostacyclinwhich is then released. Prostacyclin is a powerfulinhibitor of platelet aggregation as well as a potent vasodilator.Aspirin reduces the formation of prostacyclin inthe vessel wall and its undesirable effects. Low-dose aspirininhibits thromboxane A2 synthesis and platelet aggregation,but does not appear to inhibit prostacyclin productionsignificantly.Cyclooxygenase is also inhibited by all nonsteroidalanti-inflammatory drugs (NSAIDs), aspirin transfers andacetyl group to the enzyme irreversibly inactivating theenzyme (see Fig. 2). Other NSAIDs such as ibuprofen, actas a reversible inhibitors of cyclooxygenase and thus cannotbe depended on to cause sustained cardioprotection.Antiplatelet agents are not expected to prevent allforms of thrombotic events. Thrombi occurring in arteriesare rich in platelets, so antiplatelet agents are partiallyeffective. In obstructed arteries, with slow flow, the thrombusconsists mainly of red cells within the fibrin meshand very few platelets. This situation is similar to venousthrombosis where platelets are not predominant. Thecontents of a ruptured plaque are highly thrombogenic.Aspirin is only partially effective in preventing coronarythrombosis following plaque rupture, the usual cause ofa heart attack. Thus, antiplatelet agents are not sufficientlybeneficial in the prevention of coronary thrombosisoccurring at the site of a ruptured atheromatous plaque.

III. RECOGNIZED INDICATIONS FOR ASPIRIN AND DOSE113AcetylCOO − O=O C−CH 3Acetylsalicylate(aspirin)a heart attack. The immediate use of 2–4 chewable aspirinsmay prevent a heart attack or death. For this protection160–320 mg immediately then a 325-mg enteric coatedaspirin daily for a lifetime is necessary.PlateletSer OHActivecyclooxygenaseCOO − OHSerOInactivecyclooxygenaseO=C−CH 3[Irreversible inactivation]C. Stable AnginaStable angina is characterized by mild-to-moderate chestpain that recurs usually on exertion; stable angina mayexist for 1–10 years without culminating in a heart attack.Aspirin is used in these patients to prevent heart attackor death. The recommended dosage is 80–160 mg daily.For many years a 325-mg enteric-coated aspirin daily hasbeen recommended.SalicylateOthercauseNSAIDs [e.g., ibuprofen] Reversible inactivationFIGURE 2 Irreversible inactivation of platelet cyclooxygenase byacetylsalicylate (aspirin).III. RECOGNIZED INDICATIONS FORASPIRIN AND DOSEA. Life-Saving MeasuresBased on the proven benefits observed in ISIS-2, takingaspirin is a life-saving measure when taken within a fewhours of chest pain or symptoms resulting from a developingheart attack. The dose should be one plain325-mg tablet of aspirin, chewed and swallowed, or preferably,2–4 chewable aspirins (80 mg each, a dose of160–320 mg). It is important for the public at large torecognize that chewable aspirin taken immediately duringthe pain of heart attack can either prevent a heart attackor prevent death in a significant number of individuals.Most important, the nitroglycerin tablet or spray usedunder the tongue commonly prescribed and used bypatients is of no value in preventing a heart attack or deathwhen the process of myocardial infarction has begun.After a heart attack has been stabilized, an enteric-coatedpreparation of aspirin is then continued for several yearsand sometimes indefinitely.B. Unstable AnginaUnstable angina is characterized by the occurrence ofchest pain lasting 10–40 minutes, rarely more than anhour. Pain may wax and wane and eventually culminate inD. After Coronary Artery Bypass SurgeryA recent study has confirmed the protective benefits ofaspirin use following bypass surgery. It is used to preventblockage of the bypass graft. A dose of 325 mg daily isuseful for the first few years following surgery. Becausethe atherosclerotic disease is still present in other coronaryarteries, complications such as angina and fatal or nonfatalmyocardial infarction may occur and aspirin is continuedto prevent these episodes.E. Prevention in Normal Individuals at RiskMen over age 45 or women over age 60 with risk factorsincluding: family history of heart attacks before age 60;high cholesterol levels greater than 5.5 mmol/L, or LDLcholesterol greater than 160 mg/dl (4 mmol); hypertension;or diabetes are at risk for the development ofatherosclerotic coronary artery disease and its complications.The dose of one enteric-coated 80- to 81-mg aspirindaily is recommended for these patients. For dosages toprevent stroke, see the chapter Stroke/CerebrovascularAccident.A study reported (N. Engl. J. Med., April 2005)indicated that in healthy women age 45–64, with one orno risk factors, low dose aspirin (100 mg alternate day) didnot significantly reduce risk of heart attacks but preventednonfatal stroke risk. I must point out that there is nogender difference in the efficacy of aspirin as some maybelieve.In women age 35–55 heart attacks are rare compared tomen. The result of the study is not surprising, therefore,because one cannot prevent heart attacks if they do notoccur in that age group. The study was underpowered. Thereason why strokes occur in women 45–55 when heart

114ASPIRIN FOR HEART DISEASEFIGURE 3attacks are uncommon at this age has as yet, not beenclarified.Most important, in the above study, aspirin did notprevent fatal stroke rates. The pathophysiologic mechanismcausing fatal stroke and heart attack is similar. Anatheromatous plaque undergoes erosion or ruptureliberating a porridge like material that is intenselythrombogenic and the thrombus cannot be amelioratedby aspirin or other antiplatelet agents that do not affect theculprit thrombotic factors. In the study transient ischemicattacks (TIAs) were significantly reduced, however. Thisfinding is not surprising because TIAs are caused byplatelet emboli and platelet thrombi have been shown inrandomised clinical trials to be significantly prevented byantiplatelet agents such as Plavix or the combination ofaspirin and dipyrimadole. A small stroke represents thecontinuation process of a transient ischemic attack some ofwhich can be prevented therefore by aspirin or otherantiplatelet agent.Women ages 45–64 who have more than one cardiovascularrisk factor should benefit significantly in theprevention of nonfatal strokes and TIAs with the use ofsmall dose aspirin, 75–81 mg enteric-coated daily. Thosewith two or more risk factors may benefit from risk ofheart attack. The above study used 100 mg alternate dayand this may not be an adequate dose to prevent non fatalheart attacks. (See the chapter entitled Stroke/CerebrovascularAccident.)IV. PERSPECTIVEMany individuals who fall into the above categories arenot treated with aspirin by their physicians. In particular,individuals are not advised regarding the proven life-savingvalue of chewable aspirin taken immediately during anepisode of chest pain presumed to be due to an impendingheart attack or episode of unstable angina. Individualsshould be informed that chewable aspirin cansave a life or prevent a heart attack, but that nitroglycerinunder the tongue used in tablet or spray form doesnot prevent the occurrence of fatal or nonfatal myocardialinfarction.It is remarkable that after many years of research andwith the expenditure of several billion dollars, only 4 of themore than 100 drugs administered by mouth to treat heartdiseases cause prolongation of life. These agents arechewable aspirin, beta-blockers, ACE inhibitors, and thecholesterol-lowering drugs, statins. Thus an aspirin a dayis now better than an apple a day. Two 80- to 81-mg softchewable aspirin taken at the onset of a heart attack canprevent death or decrease the size of heart muscle damage(see Fig. 3).BIBLIOGRAPHYCairns, J. A., Gent, M., Singer, J. et al. Aspirin and sulfinpyrazone orboth in unstable angina. N. Engl. J. Med., 313:1369, 1986.Craven, L. L. Experiences with aspirin (acetylsalicylic acid) in thenonspecific prophylaxis of coronary thrombosis. Miss. Val. Med. J.,75:38, 1953.Elwood, P. C., Cochrane, A. L., Burr, M. L. et al. A randomizedcontrolled trial of acetyl salicylic acid in the secondary prevention ofmortality from myocardial infarction. BMJ, 1:436, 1947.Ferrari, E., Benhamou, M., Cerboni, P. et al. Coronary syndromesfollowing aspirin withdrawal. J. Am. Coll. Cardiol., 45:456–459, 2005.Gavaghan, T. P., Gebski, V. G., and Baron, D. W. Immediate postoperative aspirin improves vein graft patency early and late aftercoronary artery bypass surgery. Circulation, 83:1536, 1991.

IV. PERSPECTIVE115ISIS-2 (Second International Study of Infarct Survival) CollaborativeGroup. Randomized trial of intravenous streptokinase, oral aspirin,both or neither among 17187 cases of suspected acute myocardialinfarction. Lancet, 11:349, 1988.ISIS-2 (Second International Study of Infarct Survival) CollaborativeGroup. Randomized trial of intravenous streptokinase, oral aspirin,both or neither among 17187 cases of suspected acute myocardialinfarction. Lancet, 11:350, 1988.Juul-Moller, S., Edvardsson, N., Jhnmatz, B. et al. Double-blind trialof aspirin in primary prevention of myocardial infarction in patientswith stable chronic angina pectoris. Lancet, 340:1421, 1992.Lewis, H. D., Davis, J. W., Archibald, D. G. et al. Protective effectsof aspirin against acute myocardial infarction and death in men withunstable angina: Results of a Veterans Administration CooperativeStudy. N. Engl. J. Med., 309:396, 1983.Mangano, D. T. for the Multicenter study of Perioperative IschemiaResearch Group: Aspirin and mortality from coronary bypass surgery.N. Engl. J. Med., 347:1309, 2002.Ridker, P. M. and Others et al. A randomized trial of low-dose aspirin inthe primary prevention of cardiovascular disease in women. N. Engl. J.Med., 352: April ??, 2005.Steering Committee of the Physicians Health Study Research Group:Final report on the aspirin component of the ongoing PhysiciansHealth Study. N. Engl. J. Med., 321:129–135, 1989.

Atherosclerosis/AtheromaI. Introduction and Historical BackgroundII. PathologyIII. PathogenesisIV. Vulnerable Atheromatous PlaquesV. Clinical StudiesVI. Perspective and Research ImplicationsGLOSSARYangiogenesis functional new blood vessel growth.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood; theplaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).atherothrombosis when a plaque of atheroma is fissured orruptures, the contents of the plaque are highly thrombogenicand a clot (thrombus) forms rapidly causing complete occlusionof arteries leading to myocardial infarction, stroke, orother cardiovascular events (atheroma plus thrombosis ¼atherothrombosis).diapedese the passage of blood cells through intact vessel walls.endothelium the innermost part of the intima that comes incontact with circulating blood, a silky smooth layer of epithelialcells.hemodynamics the study of the movement of blood and theforces involved in the circulation of the blood.hydrodynamics a branch of the science of mechanics whichtreats liquids.intima the innermost lining of the vessel wall that is in contactwith flowing blood.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severe obstructionof the artery supplying blood to this area of cells.leukocytes white blood cells.monocytes scavenger white blood cells.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.pathogenesis the development of morbid conditions or ofdisease, particularly the cellular events and reactions andother pathologic mechanisms occurring in the developmentof disease.platelets very small disk like particles that circulate in the bloodalongside with red blood cells initiating formation of bloodclots; platelets clump and form little plugs called plateletaggregation,, thus causing bleeding to stop.thrombogenic causes clotting of the blood.I. INTRODUCTION AND HISTORICALBACKGROUNDA. IncidenceAtherosclerosis dates back to ancient civilization andlesions have been found in arteries of Egyptian mummies.Obstruction of arteries by plaques of atheroma (atherosclerosis)is the basis for cardiovascular disease whichaccounts for approximately 40% of all deaths in westernworld and Europe. This single disease is the most commoncause of death, particularly premature death, in industrializedcountries. During the past decade the incidenceof coronary artery disease has declined a little in mostdeveloped countries, still, there has been an increasedincidence in many countries in eastern Europe and Asia.The geographic variation in deaths from coronary arterydisease is shown in Fig. 1 and Table 1 in chapter entitled‘‘Angina.’’ In 1990, the annual mortality from cardiovasculardisease worldwide was 14.3 million in a populationof 5.3 billion; this mortality will exceed 25 million in2025, approximately 37% of the total 68 million deaths ina population of about 7.8 billion.Of the estimated 1.1 million Americans who have amyocardial infarction annually, 650,000 are first-time117

118ATHEROSCLEROSIS/ATHEROMAFIGURE 1 Mortality rates from coronary heart disease in selectedcountries. (Data are age-standardized rates per 100,000 (rounded)).(From 1997–1999 World Health Statistics Annual, 2001.)events and 450,000 are recurrences. More than 45% ofthese events are fatal and associated with ventricularfibrillation.B. HistoricalRokitansky, a famous pathologist, performed more than30,000 autopsies causing him to postulate that atheromawas due to slow deposition of small thrombi at focalpoints on the arterial intima with subsequent organizationinto the wall of the artery. He publicized his theoryin 1841.The German pathologist Virchow, in 1858, recognizedthe participation of cells and the proliferative nature ofatheroma formation. He used the term endarteritis deformans,indicating and that reactive fibrosis in response toinjury was due to a repair mechanism.In 1933 after fatty lesions were produced in the arteriesof rabbits fed with a high-cholesterol diet, Anitschkowemerged as one or the influential figures in the fieldof experimental atherosclerosis. He considered atherosclerosisan infiltrative rather than a degenerative processthat begins with the accumulation of lipid substances inthe deep intima. He warned, however, that cholesterol wasnot the only factor.In 1938, Winternitz indicated that atheroma occurpartly from rupture of small capillaries of the arterialwall; hemorrhage into the plaque and organization ofthis material increased the size of atheroma. In 1949,Dugid revised the older theory of Rokitansky. He theorizedthat atheromatous lesions of the aorta and coronary arteriesmay result from the slow deposition of thrombus at focalpoints on the intima with subsequent organization andinfiltration with lipids. Dugid pointed out that smallthrombi on the arterial lining are more common thanrealized, and that they are quickly incorporated into theintima by growth of the endothelium over the surface.Later they are converted into fibrous tissue in whichvariable degrees of fatty degeneration occur in the deeperlayers.The characterization of lipoprotein particles in the1950s strengthened the cholesterol concept. Cholesterol,as the culprit for atheroma formation and coronary arterydisease, still remained controversial in the minds ofmany cardiologists, researchers, and the public worldwide.In 1953, Lober provided the earliest provocative proofthat diet could cause coronary artery disease. Ross andGlomsett, in 1976, merged the concepts of earlier investigatorsthat atherosclerotic lesions develop only afterchronic injury of the endothelial lining. The mechanismsof injury could be derived from three sources: hemodynamic(turbulence), immunologic, and biochemical. Laterin 1986 Ross summarized the pathogenesis of atherosclerosiswith this idea. Fluid dynamics, at certain sites,create an area of turbulence which in turn injuresthe endothelial lining so that it becomes more permeableto circulating lipoproteins. Circulating platelets clumptogether at the denuded site to form a micro clot; smoothmuscles proliferate in this area probably under the stimulusof platelet-derived growth factor.In 1994 the Scandinavian Simvastatin Study reviewedthe controversial question: How important is the involvementof cholesterol, particularly LDL cholesterol? Thisquestion was only adequately answered in 1994, whenstatins were shown, in the hallmark Scandinavian SimvastatinSurvival Study (4S), to cause a significant decreasein coronary artery disease mortality based on the reductionof total cholesterol and LDL cholesterol blood levels. Thisended a 60-year-old controversy and ushered in the startof a new era in the prevention of atherosclerosis.C. PerspectiveCurrent evidence from extensive research indicates thatall the pathogenic concepts outlined above are involved inthe generation of atherosclerosis that causes coronary arterydisease and other cardiovascular diseases including strokeand peripheral vascular disease. After 100 years of research,including the past 50 years of intensive research, we haveonly uncovered the tip of the iceberg. Cardiovasculardisease remains rampant in Finland, Scotland, NorthernIreland, the Ukraine, the United States, Canada, Europe,

II. PATHOLOGY119Outerwall= ADVENTITIAInner walldisorganizedBloodclotRuptureof atheromaNormalsmooth inner wall=INTIMAIntima is the lining nextto the blood and is smoothMiddle wall=MEDIAContains smooth muscle cells,contract and constrict arteryPlaque of AtheromaJust into the LumenSmooth muscle cells of mediamigrate to intimaPlatelet clumpsCholesterol crystalCholesterol - lipid - fatCalciumDead cells - debrisFibrous capFIGURE 2 Atherosclerosis of the artery. (From Khan, M. Gabriel, Heart Trouble Encylopedia, Toronto: Stoddart, 1996.)and England and is increasing worldwide in the developingworld. See Tables 1 and 2 in the chapter entitled ‘‘Angina.’’II. PATHOLOGYA. Definition of Atheroma and AtherosclerosisThe word atheroma is derived from the Greek ‘‘athere’’meaning porridge or gruel. When a plaque of atheromais cut open one sees a gelatinous, porridge-like materialwhich contains globules of cholesterol fat, neutral fat,saturated sterols, protein granules, crystals of cholesterol,fatty acids, calcium, and other cells. The amount ofcalcium in the lesion (calcification) is extremely variable.Fortunately, the porridge-like material does not touch theblood that flows through the artery, because nature coversthe fatty material with a protective hard layer of cellscalled fibrous tissue. The atheromatous material forms aplaque, an opaque yellowish-white patch of thickening,that juts into the lumen of the artery. An atheromatousplaque therefore consists of a central fatty core that hasa variable amount of lipids and calcium covered by afibrous cap. Because the cap is hard and the medical wordfor hardness is ‘‘sclerosis,’’ the disease is commonly calledatherosclerosis. The fibrous cap, however, may be quitethin and fragile and prone to fracture and rupture or showerosion in some individuals. The exposed material is highlythrombogenic. Figure 2 gives a simplified representationof an atheromatous plaque and the subsequent ruptureand blood clot that completely obstructs the artery.B. Arteries InvolvedSites of predilection for atherosclerosis are illustrated inFig. 3. Why some arteries are spared and others are severelyinvolved is of particular concern to the author and appearsto have received small attention from research workers.Scientific literature shows a paucity of research in this areaversus a great amount of research related to lipoproteinsand inflammation.1. AortaThe aorta is virtually always involved in cardiovasculardisease. There must be a reason for this that has notreceived sufficient attention. As seen in the aorta, theprocess begins with the appearance of yellowish areas in theintima, which become distinctly raised. These focal areasincrease in extent and thickness and become confluent.If a well-formed patch is incised, it is seen that a yellowlipid-rich pulpy material occupies the deeper part of theintima next to the media separated from the lumen by

120ATHEROSCLEROSIS/ATHEROMATo HeadCarotid Artery3SubclavianArtery to ArmTo intestine2Coronary ArterykidneyAtherosclerosis1Abdomen Aortadivides intoIliac Arteries to PelvisFemoral Arteryto Thigh and Legs41234Common Sites forAtherosclerosisFIGURE 3The heart and arteries.connective tissue layers of varying depths. Sometimes thislayer is thick, and the patches show a whitish coloron surface view. ok he focal patches of atheroma areconspicuously related to the orifice of branches of arteriesthat stem from the aorta. Involvement of the aorta isusually most marked at the lower end before bifurcationinto the iliac arteries (see Fig. 3).Microscopic examination shows the lesions start firstand are always more advanced in the deeper part of theintima, the fibers of which may be saturated with fattymaterial. When atheroma of the aorta is advanced, it maylead to weakening of the media of the artery resultingin expansion and dilatation of the wall. This is called ananeurysm.2. Coronary ArteriesThe coronary arteries are commonly involved in cardiovasculardisease (see Figures in the chapter entitled‘‘Anatomy of the Heart and Circulation’’). This leads toangina and culminates in fatal or nonfatal heart attacks.Sudden cardiac death commonly occurs in asymptomaticindividuals. Why the coronary arteries are involved sooften as opposed to arteries in the upper limbs intriguesthis author and will be discussed in Section III. Also, thecoronary arteries are affected by severe atheroma in mensome 10 years before women are affected. Men thereforebetween the ages of 40 and 55 commonly suffer heartattacks. Heart attacks are uncommon in women until afterthe age of 60.3. Carotid ArteriesThe carotid arteries and their medium-sized branches asthey enter the brain are commonly involved in atheromatousdisease; this is the cause of stroke. The incidence ofstroke in men and women ages 50–60 are similar however,and this difference between carotid artery atheroma andcoronary atheroma remains unclear. The normal hormonal

III. PATHOGENESIS121status in women between ages 40 to 50 is believed tocontribute to their cardioprotection.has to contend with further turbulent blood flow andfurther injury to the intima.4. Iliac and Leg ArteriesThe iliac arteries as they leave the aorta and pelvis areprone to atherosclerosis as are the femoral arteries in thethighs and the popliteal arteries behind the knees. Obstructionin these arteries causes lack of circulation to the calfmuscles. This lack of blood supply causes intermittent painin the calf muscle during a brisk walk, and this condition isreferred to as intermittent claudication. The EmperorClaudius limped because of a painful leg and, the wordclaudication is the derived from his name.5. Other Arteries Rarely AffectedThe renal arteries that supply the kidney with blood arefortunately only occasionally affected by atheroma. Whythe arteries supplying the upper limbs, the liver, and lungsare spared and the spleen and the entire small and largeintestine are rarely affected is intriguing. Little attentionhas been given to this disparity over the last 20 years.Pulmonary arteries are involved only when there is highpressure in the pulmonary circulation; thus turbulencecaused by a change in blood pressure is of importance.Individuals with constant, long-term systolic blood pressurein the normal range of 115–130 mmHg who showa change of 20 mmHg to reach borderline hypertensivel levels of 135–150 mmHg may be at risk for developmentof progressive atherosclerosis.III. PATHOGENESISThe precise cause and pathogenesis of atheroma formationremains unknown.A. Current Pathogenic Theories1. The Initial LesionThe initial lesion is a small focus of injury of the intimacaused by increased turbulence of blood at special arterialsites such as the orifice of branches — particularly thatof the aorta as mentioned above — bifurcations, andcurvatures that cause characteristic alterations in bloodflow. This small area of injury incites a unique protective,nonspecific inflammatory response, but nature’s healing2. The Accumulation of Lipoprotein ParticlesFrom observations in young adults dying of trauma and inrabbits fed a diet high in cholesterol and saturated fat, theaccumulation of small lipoprotein particles in the intimahas been noted to be one of the first ultrastructuralalterations. This observation was noted in the 1950s andstill finds space in major cardiology textbooks printed in2002. The search of a 1958 Muir’s textbook of pathology,provides similar lines: ‘‘fatty degeneration usually occurs inthe intima. On microscopic examination they are found tobe due chiefly to fatty material in stellate cells of the intimaand macrophages, and to a certain extent in the endothelialcells. This fatty deposit is cholesterol and glycerol fat. Suchpatches have been found in children dying acutely oftrauma. They indicate that fat is prone to accumulatewithin the intimal cells but the reason for this is obscure.’’It appears that much remains to be clarified regarding thepathogenesis of atheroma formation.This author attempts to simplify the pathogenesis ofatherosclerosis as follows: atheroma is the result, of hemodynamicforces that cause patchy arterial injury. Thisprovokes a healing response which involves a nonspecificinflammatory reaction with the unfortunate accumulationof lipid substances from circulating blood. The damagedarea is walled off by nature’s band-aid, a protective fibrouscap. Smooth muscle cells play a major role in the healingprocess.3. Endothelial Activation and LeukocyteRecruitment/Inflammatory ResponseA nonspecific inflammatory response is central to theatherosclerotic process from the beginning to its complicationof vessel occlusion which results in cardiovascularevents.Endothelial injury, or activation, is followed by aninflammatory process that commences with adherenceof leukocytes to the endothelium and diapedese betweenendothelial cell junctions to enter the intima where theybegin to accumulate lipids and transform into foam cells.Monocytes as well as T lymphocytes tend to accumulate.The following molecular mediators play a major role inthe development of atheroma:1. Vascular cell adhesion molecule-1(VCAM-1) facilitatesattraction of leukocytes to the endothelial surface.Studies indicate that rabbits given a normal diet showed

122ATHEROSCLEROSIS/ATHEROMAno expression of VCAM-1 but greatly increasedexpression of VCAM-1 and adherent leukocytes whenthe rabbits were fed a high-cholesterol diet.2. Monocyte chemoattractant protein-1 (MCP-1) producedby the intima and smooth muscle cells from themedial wall of the artery assist monocyte transfer acrossthe endothelium.3. Monocyte activation results in the expression ofscavenger receptors by macrophages and transformationof macrophages into foam cells. Macrophage-colonystimulating factor (M-CSF) has a key role in foamcell formation because it acts as a potent monocyteactivator. Animal studies indicate that M-CSF deficiencycauses decreased atheroma formation in LDLreceptor-deficientmice.Figures 4 and 5 give a simplified portrait of howthe hidden key, turbulence of blood, initiates endothelialinjury and dysfunction. This calls forth activated macrophagesto the scene of injury followed by accumulationof oxidized LDL cholesterol and a nonspecific inflammatoryresponse occurs. This response is similar to thatobserved following allergic reactions, autoimmune processes,and trauma, but with the unique features imposedby the silky, smooth endothelial lining of arteries that hasa protective, strong media (see Fig. 2). The media containssmooth muscle cells which migrate into the injured areato assist in healing the minute wound. Much researchhas been done on the smooth muscle cell and its importantcontribution to the atherosclerotic process. Thecontribution of the smooth muscle cells, however,commences after the injury has been inflicted. Figure 5illustrates further details.It has been noted that increased turbulence of bloodat specific arterial sites causes rolling and adherence ofmonocytes and T cells. This is believed to be the result ofthe upregulation of adhesion molecules on both theendothelium and on leukocytes.4. Intracellular Lipid Accumulation and FoamCell FormationMonocytes once trapped in the arterial intima imbibelipid substances. This lipid-laden macrophage is calleda foam cell. These macrophages are stimulated to divideunder the influence of a co-mitogen, M-CSF, andinterleukin-3.5. The Smooth Muscle Cell Migration and ProliferationTough smooth muscle cells migrate from the mediainto the intima probably to strengthen the injured area.The chemoattractants for smooth muscle cells appear tobe platelet-derived growth factor secreted by activatedmacrophages. The smooth muscle cells also divide vigorously,but some cell death occurs.6. LDL Cholesterol InvolvementLDL activates foam cells and causes injury to these cellswithin the intimal lesion. It appears that LDL cholesterolis chemotactic for other monocytes. This enhances theinflammatory response by stimulating the replication ofmonocyte-derived macrophages and the attraction of newmonocytes into the early atheromatous lesion. This activityfurther stimulates migration and proliferation of smoothmuscle cells into the intimal area of injury. The toughsmooth muscle cells, along with other cellular and noncellularcomponents, assume a protective role in anendeavor to form a fibroproliferative barrier that thickensthe arterial wall at the site of injury. This is nature’s wayof healing, but occasionally the healing process is incomplete,which results in a thin, fragile protective cap proneto erosion and rupture.7. InfectionThere is unconvincing evidence that certain infectiousorganisms including Chlamydia pneumoniae, cytomegalovirus,Helicobacter pylori, and others may be involved inthe inflammatory process and evolution of plaque rupture.Increased antibody titers to these organisms have beenused as predictors of further cardiac events in patientsfollowing a heart attack. Examination of atheromatouslesions has occasionally identified C. pneumoniae. Clinicaltrials using antibiotics have thus far not been beneficial,but this organism may contribute to destabilization ofatheromatous plaques and may play a role in initiatingplaque rupture. Clarification of this is necessary.A recent study by Agmon et al. indicated that C. pneumoniaeIgG antibody titers are not associated with thepresence or severity of aortic atherosclerosis in the generalpopulation. This observation does not support a rolefor infection by this organism in the initiation or progressionof atherosclerosis.The levels of circulating markers of inflammation suchas C-reactive protein, a marker of nonspecific inflammatoryprocesses, are higher in patients with unstable coronaryartery disease than in those with stable coronarydisease. Persistent elevation of C-reactive protein inpatients with unstable angina strongly predicts furtherserious cardiac events. The precise mechanisms by whichearly plaque formation initiates an inflammatory response

III. PATHOGENESIS123LDLturbulence ofblood/shear stressundetermine factors/toxins elementshomocysteinecigarettesmokingviral infectionshypertensionsimmunecomplexesENDOTHELIAL INDJURY/DYSFUNCTIONmonocytes adhereand migrate into intimaLIPID PERMEABILITYOXIDIZED LDLActivated macrophagesengulf and metabolize oxidized LDLrelease products of lipid oxidationfree radicals/toxic productsDENUDATION OF ENDOTHELIUMplatletadhesionrelease growth factors, cytokinesMigration and proliferation ofsmooth muscle cells produceGENETICSUSCEPTIBILITYFIBROUS CAP COVERING CENTRALVARIABLY LIPID-RICH CORE=ATHEROSCLEROTIC PLAQUEmacrophages, colagenase Idigest extra cellular matrixhydraulic stress, catecholamines,angiotensin IIPlaque rupturerelease thrombogenic materialTHROMBOSISFIGURE 4 Pathogenesis of atherosclerotic (atheroma) plaque. (From Khan, M. Gabriel, Heart Disease Diagnosis and Therapy, second edition.New Jersey: Humana Press, 2005.)

124ATHEROSCLEROSIS/ATHEROMAInitial process : Injury to endothelial Liningcause probablyhydrodynamic: blood flowturbulence at focal sites of artery wallArea of injury of endothelialcells: denudation of endotheliumEndothelial cellliningIntimaInternalelasticlaminaMediathickmusclewallSmoothmuscle cellsActivated leukocytes: mococyte* adhesionLipoprotein particlesPlatelet particlesSmoothmuscle cellsActivated whiteblood cells, utilizetheir pseudopodia and crawlinto the intimaTrappedLDL particlesFoam cell: leukocytes, monocytesthrough scavenger receptors engulfLDL particles; oxidation + accumulationof cholesterolSmooth muscle cells migrate intothe media and proliferate to repairthe injury “Band-aid”AdeventitiaFIGURE 5the intima.Simplified concepts: atheroma plaque formation in the early stages. * ¼ activated white blood cells, utilize their pseudopodia and crawl intoin the absence of infection by microorganisms remainsunclear. (see the chapter C-Reactive Protein.)B. Hydrodynamic Forces/Pulsatile Blood FlowMechanical forces on the walls of arteries consist of threetypes:(1) the tangential fictional force from the flow of bloodacross the endothelial surface, (2) the transmural pressure(the direct effect of pressure), and (3) wall stress as a resultof pressure-induced wall deformation and subsequentcyclic strain. Increased blood pressure appears to promoteatherogenesis through biomechanical effects of pulsatileblood flow, or cyclic strain, which has been observedto affect endothelial cell gene expression and function.Okada et al. have shown that changes in shear stressregulate endothelial production of several factors includingvasodilators such as nitric oxide (NO) and prostacyclin andvasoconstrictors such as endothelin-1. They also showedthat increased cyclic stretch augments production of IL-8and MCP-1 in a dose-dependent fashion.Linear shear stress forces appear to be atheroprotectiveand associated with reduced production of reactive oxygenspecies (ROS). Oxidative stress results from the productionof ROS, superoxide anion, and hydrogen peroxide.These are molecules that cause oxidative damage andtrigger intracellular signaling cascades. The muscular wallof arteries is a rich source of ROS; the constituents ofatheromatous plaques produce and use ROS. Hypercholesterolemiainduced in rabbits causes an increase inROS in rabbit aortas. Treatment with the antioxidantpolyethyleneglycol superoxide appears to reverse impairedendothelial-dependent relaxation observed in rabbit aortictissue. Dietary lowering of cholesterol reduces ROSproduction in rabbits.Low shear stress and disturbed flow are associatedwith increased production of ROS and redox sensitive

III. PATHOGENESIS125upregulation of chemoattractant adhesion molecules(VCAM-1). Cyclic strain increases s1CAM-1 expressionby human endothelial cells in a time- and strain-dependentmanner resulting in increased monocyte adhesion.In vitro studies with animal models of hypertensionhave shown increased production of ROS in arterialtissues. Increased cyclic biomechanical strains modifymacrophage function by increasing expression of scavengerreceptors that participate in the deposit of lipid in thearterial wall.C. Arteries of PredilectionAs described in Section II, several arteries are spared atheromatouslesions.1. VeinsAtheroma does not occur in veins because the thin-walledveins do not contain an appreciable media, and they arenot exposed to the same hemodynamic stress and turbulenceof blood that occurs in arteries.2. Pulmonary ArteriesAtheroma is virtually never seen in the pulmonary arteriesand pulmonary veins. These arteries are large and mediumsized.The pulmonary artery receives blood that is ejectedfrom the right ventricle and circulates the blood to thelungs. It is similar to blood being ejected from the leftventricle into the aorta. The only difference is that the leftventricle pumps blood more vigorously and at higherpressures and velocity therefore submitting arteries toturbulent flow. Thus, the tendency for atheroma to bemost marked in the lower part of the aorta is probably dueto the increased hydrostatic pressure in that position. Theright ventricle ejects blood into the pulmonary artery at alow pressure (25 mmHg vs. greater than 120 mmHg in theaorta). The resistance to flow of blood through the lungs islow, thus the right ventricle ejects blood at a much lowervelocity than the left ventricle. Atheroma in the pulmonaryarteries is virtually absent except in the presence of severepulmonary hypertension. This author was intrigued by thisfinding more than 25 years ago. The finding seemsto support the hypothesis that turbulent flow may initiatethe lesions of atheroma in arteries at points in whichmaximum turbulence occur.Vulnerable areas are present in the aorta which haveto withstand the force of cardiac ejection velocity.Branches of the aorta, particularly the carotid, iliac, andfemoral-popliteal arteries are vulnerable. More important,the coronary arteries have a unique flow pattern as they areempty during cardiac systole and fill only during diastole.This spurt-flow phenomenon may perhaps explain theirpredilection to hemodynamic injury.3. Arteries of the Upper LimbsThe arteries of the upper limbs include the subclavianand brachial arteries and medium-sized arteries similar tothe ones in the legs or the carotid arteries of the head.Atheroma is not usually seen in these arteries. The reasonwhy these arteries are not involved may hold the key tothe puzzle of atheroma formation. The kidney arteriescirculate the entire blood volume to be filtered by thekidney. Atheromatous lesions in these arteries were relativelyrare compared to the involvement of the coronaryand carotid arteries.4. Aorta and Iliac VesselsThese vessels withstand the entire hemodynamic forcetransmitted directly by ejection of blood into the aortafrom the powerful heart muscle. The velocity and turbulenceis excessive at branching points including thebifurcation of the aorta and iliac arteries and in individualswho have high circulating LDL cholesterol lesions areexpected to be more aggressive.5. Coronary ArteriesThe coronary arteries are commonly involved and this isnot surprising. These are unique arteries. They aredifferent from the arteries in the rest of the body. It isimportant to stress that these arteries collapse during thesystolic contraction of the heart. They fill intermittentlyduring diastole when the heart is relaxed. This intermittentflow to cardiac muscles that work harder and longer thanany muscles in the body probably cause hemodynamicinjury to the coronary arterial wall.Agents that reduce turbulence and velocity of flow,particularly the beta-blocking drugs, may prove beneficialin clinical trials when used in conjunction with statins toreduce LDL cholesterol levels to less than 80 mg/dl inyounger individuals at risk. It is of interest that in themanagement of patients with ruptured aortic aneurysmsor dissecting aneurysms a beta-blocking drug is givenimmediately to quell the ejection velocity of blood thatfurther tears the ruptured artery.

126ATHEROSCLEROSIS/ATHEROMA6. Angiogenesis in PlaquesDuring the past decade therapeutic angiogenesis has comeinto vogue. The use of angiogenic peptides is believed toproduce therapeutic angiogenesis in the heart to improveblood supply and oxygen to muscles deprived of blood.Unfortunately, this may not be such a good therapeuticstrategy. Muir’s textbook of pathology from 1958 states:Winternitz has shown that atheromatous patches maycontain new capillaries, and these delicate vessels areexposed to the fluctuations in pressure within thearteries. It is not surprising, therefore, that thesecapillaries may rupture causing hemorrhage into suchpatches; hemorrhage into a plaque sometimes followsexertion with its consequent rise of blood pressure.Thereafter thrombosis often occurs during sleep.It appears that old and important information has beenlost amongst recent researchers. In some cases ofmyocardial infarction and sudden death, sudden occlusionof the artery occurs because of hemorrhage into the plaquefollowed by rupture of the plaque and subsequentthrombosis. The initiating event in these cases is not theusual cause of a heart attack — Unfortunately, becausemicro vessels within the plaque are friable and prone toburst, attempts to augment myocardial blood flow byenhancing new vessel growth by transfer of angiogenicproteins or their genes might have deleterious effects onlesion growth. They may initiate hemorrhage and plaquerupture, a disaster that researchers are trying desperately toprevent. See the section below, Vulnerable AtheromatousPlaques.D. Other Risk Factors1. DiabetesThe importance of diabetes as the cause of acceleratedand progressive atherosclerosis is described in the chapterDiabetes and Cardiovascular Disease. The role of hypertension,elevated LDL cholesterol, and low levels of HDLcholesterol are discussed above. These factors in diabeticpatients cause aggressive atheromatous obstruction ofarteries at many sites in the body.2. Cigarette SmokingAntioxidant stress and other deleterious effects caused bycigarette smoking are believed to play a role in cardiovasculardisease, but the exact mechanisms have not beenclarified yet.3. Familial PredispositionUndefined genetic factors play a major role in the predispositionfor the development of atheromatous coronaryartery disease and its complication of myocardial infarctionand sudden cardiac death. A family history of suddencoronary death before age 50 places the individual athigh risk.4. Stressful LifestyleA stressful lifestyle in individuals with other risk factorsincreases the likelihood of atheromatous coronary disease(see the chapter Stress and Heart Disease).5. AgeAge is an overwhelming factor in cardiovascular disease.It is well known that atheroma formation is more prevalentin the elderly. Realistically the disease starts fromapproximately age 25 and increases gradually culminatingin most populations between the age of 40 and 50. It takes10–15 years for lesions to grow sufficiently to obstructvessels, except when an asymptomatic plaque that iscausing less than 60% occlusion of an artery acceleratesand ruptures for reasons that are presently obscure andassociated thrombosis occludes the artery. This commonlyoccurs in diabetics and in patients with high LDLcholesterol levels. In many patients the disease advancesslowly between the age of 50 and 70 without causingsymptoms. In women often after age 75 cardiovasculardisease culminates in obstruction of an artery, myocardialinfarction, or death. Men, unfortunately, are weaker anddie earlier.6. HomocysteineThere has been much talk in the past decade aboutthe influence of elevated plasma homocysteine, atheromaformation and risk for cardiac events. The evidence linkingelevated homocysteine levels and atherosclerosis is indeedweak. In a randomized clinical trial the administration ofpyridoxine and folic acid caused a reduction of homocysteinelevels, but resulted in a greater number of occlusionsto intracoronary stents. In the Vitamin Interventionfor Stroke Prevention (VISP) randomized controlled trialreduction of total homocysteine after nondisabling cerebralinfarction had no effect on vascular outcomes during the2 years of follow up.

V. CLINICAL STUDIES127IV. VULNERABLE ATHEROMATOUSPLAQUESA. Rupture of the PlaqueUneven thinning and fracture or fissuring of the plaque’sfibrous cap leads to rupture. The porridge-like substancesexposed to the flowing blood are highly thrombogenicand trigger thrombosis that blocks the lumen of the artery.This is the main underlying cause of a myocardial infarct(see Fig. 2). Fracture of the fibrous cap occurs often atthe shoulders of a lipid-rich plaque where macrophagesenter. The processes and mechanisms that underlie thinningfracture and rupture of plaques are unclear, and theyare presently a subject of extensive research.The provision of durable collagenous tissue processedby smooth muscle cells is important in maintaining theexistence of the plaque’s fibrous cap. Collagen providesmost of the biomechanical resistance to disruption ofthe fibrous cap. Substances found in degranulatingplatelets appear to increase smooth muscle cell collagensynthesis that may reinforce the strength and viability ofthe fibrous cap. Additionally, in some lesions there is amarked decrease in the presence of smooth muscle cellsor increased smooth muscle cell death within the plaqueoccurs, and this reduces collagen production. It is possiblethat the new capillaries and vessels within the plaquemay be important for the survival of smooth muscle cells.Thus, angiogenesis may be hazardous.Platelets play an important role in initiating clottingin arteries and arterioles. They form an initial plug orclot and are followed by the deposit of a fibrin mesh thatforms a firm clot. Platelets are trapped by the materialexposed by the fractured plaque and the first phase ofthrombosis is initiated. Aspirin or platelet glycoproteinIIa/IIIb receptor blockers are used to prevent this deleteriousplatelet aggregation. Platelets are intriguing bloodparticles that require much research in order to uncovertheir therapeutic potential.B. Superficial Erosion of the Endothelial LiningCovering the PlaqueEvidence of superficial erosion of the intimal lining hasbeen observed in approximately 25% of patients who havesustained a myocardial infarction and died within a fewhours. Endothelial cell desquamation through activation ofbasement membrane degrading metalloproteinases appearsto be involved, but the mechanisms are unclear.C. Hemorrhage into the PlaqueNew capillaries and small vessels grow into the plaqueand provide a useful function in that they may providenutrient material for smooth muscle cells that formcollagen necessary to strengthen the fibrous cap. Thesenew vessels are, however, fragile and may burst causinga minute hemorrhage within the plaque. The pressurewithin the plaque may cause disruption of the fibrous cap,and thrombosis completes the occlusion of the artery.V. CLINICAL STUDIESA. Maehara et al.Study question: What are the clinical and angiographiccorrelates of plaque rupture detected by intravascularultrasound?Methods: Three hundred plaque ruptures in 254patients were assessed by angiographic and intravascularultrasound.Results: Plaque rupture occurred in 46% of patientswith unstable angina and 33% of patient with myocardialinfarction, but it was also observed in 11% of patientswith stable angina and 11% of patients with no symptoms.The tear the fibrous cap occurred at the shoulder in63% and occurred in 37% in the center of the plaque.Thrombi were common in patients with unstable angina.The plaque rupture site contained the minimum lumenarea site in only 28% of patients; rupture sites had largerarterial and luminal areas and more positive remodelingthan minimum luminal area sites.Conclusions: Surprisingly, plaque ruptures usually donot cause lumen compromise.B. Varnava et al.Study question: Is there a relationship between the morphologiccharacteristics of coronary plaque vulnerability,lipid core size, and macrophage count, and coronary arterypositive remodeling (no lumen narrowing), or increasedconstrictive adventitial fibrosis and thickening with negativeremodeling (lumen narrowing)?Methods: The hearts of 88 male patients with suddencardiac death were assessed.Results: When 108 plaques were studied, 59% hadpositive remodeling and 40% had negative remodeling.Plaques with positive remodeling had a larger lipid core(39% vs. 22%, p ¼ < 0.001) and a higher macrophagecount. Plaques with negative remodeling were associated

128ATHEROSCLEROSIS/ATHEROMAwith greater thinning of the medial and adventitial wallopposite the plaque.Conclusions: Plaques with positive remodeling havea high lipid content and macrophage count. This mayexplain why plaque rupture often occurs at sites withonly modest lumen stenosis.Perspective: M. J. Davies is well known for his workon atherosclerosis and its relationship to sudden death andmyocardial infarction. The authors of this study includeDr. Davies who states: ‘‘Both pathologic studies andintravascular ultrasound studies suggest adventitial fibrosisand thickening influence negative remodeling (lumennarrowing). This may result in a more concentric lesionand stabilization of the site. Why lipid content varies withplaque remodeling is not all clear.’’C. ApoA Milano; Nissen et al.Study question: Low levels of HDL-C increase risk foratheromatous coronary artery disease. Can the administrationof HDL-C or an HDL mimetic reduce atheromavolume?Objective: ApoA-I Milano is a variant of apolipoproteinA-I that is isolated in individuals in rural Italy whoexhibit very low levels of HDL and are atheroma free.Infusion of recombinant ApoA-I Milano/phospholipidcomplexes has been shown to produce regression of atherosclerosisin animal models. The effect of intravenousrecombinant ApoA-I Milano/phospholipid complexes(ETC-216) on atheroma burden in patients with acutecoronary syndromes was assessed.Results: A recombinant ApoA-I Milano/phospholipidcomplex (ETC-216) administered intravenously for fivedoses at weekly intervals produced a mean (SD) percentatheroma volume decrease by 1.06% (3.17%) in thecombined ETC-216 group as measured by IVUS. In theplacebo group, percent atheroma volume increased by0.14%. Although promising, these results require confirmationin larger clinical trials where the absolute reductionin atheroma volume in the combined treatmentgroups was 14.1 mm 3 or a 4.2% decrease from baseline(P < 0.001). . Confirmation in large randomized trials isrequired.D. Brousseau et al. TorcetrapibStudy question: Torcetrapib is a new investigational agent,which is a potent inhibitor of cholesteryl ester transferprotein (CETP). Inhibition of CETP raises HDL cholesterollevels. The effect of torcetrapib was assessed.Results: In a small study of 19 patients with LDLcholesterol < 40 mg/dl (1 mmol/L) torcetrapib 120 mgdaily administered with atorvastatin increased HDL-Cby 61% (P < 0.001) and 46% (P ¼ 0.001) without atorvastatin.The 120-mg, twice daily dosage increased HDL-C106 % (P < 0.001). Also, in the atorvastatin arm torcetrapibsignificantly reduced LDL-C by 17% (P ¼ 0.02).Clinical trials in patients at high risk are underway.E. Nissen et al. Reversal StudyStudy question: Reversing atherosclerosis with aggressivelipid-lowering (REVERSAL) was done in a randomizedtrial study which compared the effects of an aggressivelipid-lowering regimen (atorvastatin 80 mg) daily and amoderate lipid-lowering regimen, (pravastatin 40 mg) oncoronary atheroma burden as measured by intravascularultrasound in 654 patients.Results: Administration of atorvastatin resulted in areduction from 3.9 mmol/L to a mean LDL-C 2.0 mmol/L (80 mg/dl), with no change in atheroma volume versuspravastatin reduction to 2.8 mmol/L (110 mg/dl) anda 2.7% increase in atheroma volume. The C-reactiveprotein decreased 35% with atorvastatin versus 5% withpravastatin.VI. PERSPECTIVE AND RESEARCHIMPLICATIONSAfter 100 years of research and controversies the pathobiologyof the most common cause of death, atherosclerosis,is stated by renowned researchers to be rapidlychanging, but this author believes it remains elusive.Positive answers regarding the pathogenesis and the evolutionof beneficial treatment strategies can only be resolvedin the distant future, perhaps another 25 years, unlessaggressive and extensive research is carried out. The numerousstudies that relate to plaque rupture and vulnerabilityof plaques, although important, will not resolve thepathogenesis of atherosclerosis or its prevention. Angiographicstudies are numerous and intravascular ultrasound,computerized tomography that assesses calcium content ofplaques, or the use of PET scans and MRI scans will notproduce answers.Substances that could strengthen and stabilize thefibrous cap would provide a major beneficial therapeuticstrategy that may prevent plaque fissuring and rupture orerosions. Angiogenesis and gene therapy may promotehemorrhage into plaques, and caution is required by thosewho currently propose this investigational therapy.The reason why atheroma virtually never occurs in arteries

VI. PERSPECTIVE AND RESEARCH IMPLICATIONS129of the upper limbs, and the hepatic artery that suppliesthe liver and has a predilection for the descending aorta,coronary arteries, and carotid arteries must be thoroughlyaddressed. This author presumes that hemo- and hydrodynamicfactors produce excessive turbulence at sites inarteries where the atheromatous lesion occurs. These forcescreate minute focal areas of injury to the endotheliumof arteries. If this is the initial lesion, then it must beprevented if the problem of atherosclerosis is to be arrested.This hypothesis must be tested.Therapeutic strategies that can be tried in the meantimeinclude the use of a beta-blocking drug that has provensuccessful in reducing mortality in cardiac patients. Only 3of the available 20 beta-blocking drugs meet this criterion:bisoprolol, carvedilol, and metoprolol. These agents mayreduce turbulence at sites of atheroma induction. Theyshould be tried in individuals at high risk at age 30,before major atheroma has formed. Treatment may berequired for greater than 10 years in young individuals athigh risk; that is preventive treatment similar to that ofasymptomatic hypertension. Individuals at risk includethose with a family history of heart attack (fatal nonfatal)or angina prior to age 60; LDL cholesterol greater than100 mg/dl; HDL cholesterol less than 0.9 mg; and itshould be prescribed at the initial diagnosis of diabetes. Inaddition beta-blockers have been shown to preventsudden death in patients with coronary artery diseaseand may prevent plaque rupture. The salutary effects ofbeta blockade are given in Fig. 1, the chapter Beta-Blockers. Figure 6 summarizes the major factors involvedin the genesis of atheroma and the resultant cardiovascularevents.Prevention of atheroma formation and its dangerousconsequences require treatment of the initiating factor,turbulent blood flow and optimal treatment of the fivereasons that cause progression of the atheromatous lesion.Today’s medicine does not address the treatment ofturbulent blood flow (hyper- and hydrodynamic) factorsthat in all probability initiate the atheromatous lesion. Acombined strategy of reduced turbulence in arteries andANGINASUDDEN DEATHHEARTATTACKFatalNon fatalAORTICANEURYSM(abdominal)STROKEHEART FAILUREPERIPHERALVascular Disease(intermittent claudication)FIGURE 6Consequences of obstruction of arteries.ATHEROMATOUS, ATHEROSCLEROTICObstruction of ArteriesPromotersofAtheromaformationandprogression1. Dyylipidemia 2. Diabetes 3. Hypertension 4. Age5. Stress (volatile)Contributing factors: Cigarette smoking? homocysteine. ? microorganismsATHEROMAPLAQUEInjury to Innerwallof ArteryHydrodynamic factors:TurbulentBlood flow.Injury to internal lining,endothelium of arteryFIGURE 7Major factors in the formation of atheroma and its progression and clinical complications.

130ATHEROSCLEROSIS/ATHEROMAthe reduction of LDL-C to less than 2.0 mmol/L (80 mg/dl) with an increase in HDL-C to greater than 1.5 mmol/L(60 mg/dl) may have salutary effects.BIBLIOGRAPHYAgmon, Y., Khandheria, B. K., Meissner, I. et al. The association betweenChlamydiae pneumaoniae seropositivity and aortic atherosclerosis.J. Am. Coll. Cardiol., 41:1482–7, 2003.Aikawa, M., Sugimaya, S., Hill, C. et al. Lipid lowering reduces oxidativestress and endothelial cell activation in rabbit atheroma. Circulation,106:1390–96, 2002.Ambrose, J. A., Barua, R. S. et al. The patho-physiology of cigarettesmoking and cardiovascular disease: An update. J. Am. Coll. Cardiol.,43:1731–37, 2004.Ambrose, J. A., D’Agate, D. J. et al. Plaque rupture and intracoronarythrombus in non-culprit vessels. J. Am. Coll. Cardiol., 45:959–660,2005.Brousseau, M. E., Schafer, E. J., Wolfe, M. L. et al. Effects of an inhibitorof cholesteryl ester transfer protein on HDL cholesterol. N. Engl.J. Med., 350:1505–1515, 2004.Cheng, J.-J., Wung, B. S., Chao, Y. J. et al. Cyclic strain enhancesadhesion of monocytes to endothelial cells by increasing intercellularadhesion molecule-1 expression. Hypertension, 28:386–91, 1996.Corti, R., Fuster, V., and Badimon, J. J. Pathogenetic concepts of acutecoronary syndromes. J. Am. Coll. Cardiol., 41:7S–14S, 2003.Forrester, J. S. Toward understanding the evolution of plaque rupture.J. Am. Coll. Cardiol., 42:1566–1568, 2003.Fuster, V., Moreno, P. R., Fayad, Z. A. et al. State-of-the-art paperAtherothrombosis and high-risk plaque. Part I: Evolving concepts.J. Am. Coll. Cardiol., 46:937–954, 2005.Goldstein, J. A. Angiographic plaque complexity: The tip of the unstableplaque iceberg. J. Am. Coll. Cardiol., 39:1464–1467, 2002.Griendling, K. K., Sorescu, D., and Ushio-Fukai, M. NAD[P] H oxidase;role in cardiovascular biology and disease. Circ. Res., 86:494–501,2000.Hedblad, B., Ögre, M., Engström, G. et al. Heterogeneity of cardiovascularrisk among smokers is related to degree of carbon monoxideexposure. Atherosclerosis, 179:177–183, 2005.Khan, M. Gabriel. Beta blockers: The cornerstone of cardiac drug therapy.In Cardiac Drug Therapy, sixth edition, W. B. Saunders, Philadelphia,2003.Khunti, K., Samani, N. J. et al. Coronary heart disease in people of south-Asian origin: Important minority ethnic populations in manycountries worldwide are people of south-Asian origin. Lancet,364:2077, 2004.Lusis, A. J., Fogelman, A. M., Fonarow, G. C. et al. Genetic basis ofatherosclerosis: Part II: Clinical implications. Circulation, 110:2066–2071, 2004.Maehara, A., Mintz, G. S., Bui, A. B. et al. The morphologic andangiographic features of coronary plaque rupture detected byintravascular ultrasound. J. Am. Coll. Cardiol., 40:904–10, 2002.Moreno, P. R., Fuster, V. et al. The year in atherothrombosis. J. Am. Coll.Cardiol., 44:2099–2110, 2004.Okada, M., Matsumori, A., Ono, K. et al. Cyclic stretch upregulatesproduction of interleukin-8 and monocyte chemotactic and activatingfactor/monocyte chemoattractant protein-1 in human endothelialcells. Arterioscler. Thromb. Vasc. Biol., 18:894–901, 1998.Petersen, S., Peto, V., Rayner, M. et al. Coronary heart disease statistics.London: British Heart Foundation, 2004.Reilly, M. P., Lehrke, M., Wolfe, M. L. et al. Resistin is an inflammatorymarker of atherosclerosis in humans. Circulation, 111:932–939,2005.Sakamoto, H., Aikawa, M., and Hill, C. C. Biomechanical straininduces class A scavenger receptor expression in human monocyte/macrophages and THP-1 cells. Circulation, 104:109–14, 2001.Shah, P. K. Mechanisms of plaque vulnerability and rupture. J. Am. Coll.Cardiol., 41:15S–22S, 2003.Steven, E., Nissen, T., Tsunoda, E., Murat, T. et al. Effect of recombinantApoA-I Milano on coronary atherosclerosis in patients withacute coronary syndromes. A randomized controlled trial. JAMA,290:2292–2300, 2003.Takano, M., Inami, S., Ishibashi, F., et al. Angioscopic follow-up studyof coronary ruptured plaques in non-culprit lesions. J. Am. Coll.Cardiol., 45:652–658, 2005.Taylor, W. R. Hypertensive vascular disease and inflammation: mechanicaland humoral mechanisms. Curr. Hypertens. Rep., 1:96–101, 1999.Varnava, A. M., Mills, P. G., and Davies, M. J. Relationship betweencoronary artery remodeling and plaque vulnerability. Circulation,105:393–43, 2002.Wong, ND. Detection of subclinical atherosclerosis: implications forevaluating cardiovascular risk. ACC Current J. Rev. March 2004.Yonemura, A., Momiyama, Y., Zahi, A., Fayad, Z. A. et al. Effect of lipidloweringtherapy with atorvastatin on atherosclerotic aortic plaquesdetected by non-invasive magnetic resonance imaging. J. Am. Coll.Cardiol., 45:733–74, 2005.

Athletes and Sudden Cardiac DeathI. Cardiac Causes of Sudden Death in Young AthletesII. Sudden Death not Associated with Cardiac DiseaseIII. Athlete’s Heart Versus Hypertrophic CardiomyopathyGLOSSARYanomaly marked deviation from normal, especially as a result ofcongenital or hereditary defects.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow of blood; theplaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).Holter monitor a machine, the size of a handbook, that iscapable of recording 24–48 h of continuous electrocardiographicmonitoring; the tracing is used to assess abnormalheart rhythms, particularly serious arrhythmias.hypertrophy increase in thickness of muscle.myocardium the heart muscle.sarcomere the contractile unit of a myofibril; sarcomeres arerepeating units, delimited by the Z bands, along the length ofthe myofibril that make up the myocardium of the heart.sudden cardiac death A death from cardiac cause that occursinstantaneously or within the hour of the onset of symptoms;the hallmark features are an instantaneous and unexpectedtime and mode of cardiac death.syncope temporary loss of consciousness caused by lack of bloodsupply to the brain; fainting describes a simple syncopal attack.ventricular cavity the chamber of the ventricle.ventricular fibrillation the heart muscle does not contract butquivers; therefore, there is no heartbeat (cardiac arrest) anddeath occurs within minutes if the abnormal heart rhythm isnot corrected.ATHLETES AND SUDDEN CARDIAC DEATH CREATESa dilemma for most clinicians involved in sports medicine.Athletes may have unsuspected serious heart diseaseand still be relatively asymptomatic. Although rare, thesediseases may result in sudden death in young athleteswith the catastrophic event emotionally impacting familymembers, friends, and classmates. In young athletes(median age 17 years), the frequency of cardiac suddendeath occurs in approximately 1:70,000 individual studentathletes during a 3-year career. Older athletes, particularlymale joggers and marathon runners, however, have a muchhigher rate of exercise-related sudden death — reportedlyapproximately 1:30,000 per year. More than 90% ofathletic field deaths occur in males and about 60% are atthe median age of 17. Most important, Maron et al.indicated that the trigger for sudden death in athletes withunsuspected cardiac disease coincides with peak periods ofcompetition training, particularly for organized teamsports. In this setting, sudden death or major collapsehas been associated with peak exercise training in 90% ofathletes in the late afternoon and evening hours. Thischapter deals mainly with sudden death in trained athletes,but similar deaths can occur in male high school studentsduring training for team sports. The exact prevalence ofthis occurrence is unknown because of the lack of studiesin this population group. The incidence of hypertrophiccardiomyopathy and other diseases discussed below shouldbe similar in both trained and untrained athletes.Causes of sudden death in young athletes include:1. Hypertrophic cardiomyopathy, approximately 28%2. Commotio cordis, approximately 20%3. Coronary artery anomalies, approximately 14%4. Myocarditis, approximately 5%5. Unexplained left ventricular hypertrophy, approximately5%6. Marfan syndrome causing aortic dissection orruptured aneurysm7. Arrhythmogenic right ventricular dysplasia, approximately3%; more common in some regions of Italy8. Severe aortic stenosis, approximately 3%9. Coronary artery disease, approximately 3%10. Myxomatous mitral valve disease, less than 3%11. Dilated cardiomyopathy, less than 3%12. Less than 12% are represented by the long QTsyndrome, cocaine and other drug abuse, heat stroke,131

132ATHLETES AND SUDDEN CARDIAC DEATHcardiac sarcoidosis, ruptured Berry aneurysm causingsubarachnoid hemorrhage, and asthma or otherpulmonary disorderI. CARDIAC CAUSES OF SUDDEN DEATHIN YOUNG ATHLETESA. Hypertrophic CardiomyopathyMaron et al. have contributed greatly to our understandingof the athlete and heart disease and indicated thathypertrophic cardiomyopathy is the single most commoncause of sudden death in young athletes. This is all themore devastating to affected families and to perturbedphysicians because of the frequent absence of symptomsprior to death. Hypertrophic cardiomyopathy accounts formore than 33% of these deaths.1. DefinitionHypertrophic cardiomyopathy is defined and diagnosed bythe demonstration of unexplained left ventricular hypertrophyassociated with nondilated ventricular cavities.Figure 1 illustrates morphologic components of the diseaseprocess. Note the conspicuous hypertrophy of the interventricularseptum (labeled VS) that separates the leftand right ventricle. The left ventricle cavity is reduced toa slit-like form as it merges with the aorta (AO), and theblood flow delivery from the left ventricle into the aortaFIGURE 1 Morphological components of the disease process in hypertrophic cardiomyopathy (HCM), the most common cause of sudden death inyoung competitive athletes. A, Gross heart specimen sectioned in a cross-sectional plane similar to that of the echocardiographic (parasternal) long axis; leftventricular wall thickening shows an asymmetrical pattern and is confined primarily to the ventricular septum (VS), which bulges prominently into theleft ventricular outflow tract. The left ventricular cavity appears reduced in size. FW ¼ left ventricular free wall. B–D, Histological features characteristicof left ventricular myocardium in HCM. B, Markedly disordered architecture with adjacent hypertrophied cardiac muscle cells arranged at perpendicularand oblique angles. C, An intramural coronary artery with thickened wall, due primarily to medial hypertrophy, and with apparently narrowed lumen.D, Replacement fibrosis in an area of ventricular myocardium adjacent to an abnormal intramural coronary artery, and probably a consequence of ischemia.Ao ¼ aorta; LA ¼ left atrium; RV ¼ right ventricle. (From Maron, J. (1997). Hypertrophic cardiomyopathy. Lancet, 350, pp. 127–133. With permission.)

I. CARDIAC CAUSES OF SUDDEN DEATH IN YOUNG ATHLETES1332.5 µmMyosin FilamentActin FilamentZ disk20% shortening2.0 µmElectrostatic Linear Actuator Simulatedwith Sarcomere StructureSarcomere UnitFIGURE 2 The structure of sarcomere looks like that of an electrostatic linear motor. S.C. Jacobsen proposed the structure of a musclelike actuator.(From Micromechanical Devices.)is obstructed. Thus, initially the disease was appropriatelycalled idiopathic hypertrophic subaortic stenosis (IHSS),then in the 1970s, it was renamed hypertrophic obstructivecardiomyopathy (HOCM). In the 1980s it became wellknown that many patients did not develop obstructivefeatures, and the designation hypertrophic cardiomyopathybecame used worldwide.2. GeneticsHypertrophic cardiomyopathy is a familial cardiac abnormalityand is a relatively common genetically transmitteddisease occurring in approximately 0.2% (1 in 500) of thegeneral population. To date, 9 culprit genes and well over100 specific mutations have been identified. Each of theculprit genes encodes sarcomeric contractile proteins in theheart muscle (see Fig. 2, the structure of the sarcomere, andfigures in the chapter Cardiomyopathy).The most prevalent of these genes is the beta myosinheavy chain (MYH7) that occurs in approximately 35% ofcases. Cardiac troponins-T (TNNT2) occur in approximately15% and cardiac myosin binding protein C inapproximately 15%. Alpha cardiac actin (ACTC) is seen inless than 5% of cases. For further genetic details see thechapter Cardiomyopathy.3. Risk of DeathYoung athletes with asymptomatic, undetected hypertrophiccardiomyopathycan die unexpectedly. The group athighest risk are those few patients who have survived anepisode of sustained ventricular tachycardia or ventricularfibrillation. These patients have about an 11% chance offurther serious event within 5 years and are managed withan implantable cardioverter defibrillator.Risk assessment may be employed in a few individuals,but the fundamental problem with most proposed riskmarkers is that individually they appear to be onlymodestly predictive of medium-term risk of sudden death.Despite clinical experience suggesting that adversefamily history and syncope are harbingers of suddendeath, most large studies, however, indicate that they areno more predictive of sudden death risk than nonsustainedventricular tachycardia on Holter monitoring and anabnormal exercise blood pressure response. Still, recurrentsyncope associated with exertion in the young should beconsidered serious and assessed further.McKenna et al. pointed out that ‘‘over the past fourdecades a number of clinical features have been proposedas markers of sudden death risk in patients withhypertrophic cardiomyopathy. Their application in clinicalpractice has, however, remained unsystematic and haphazard.’’Genotyping is currently problematic in prognosticassessment and the physician does not have genotypingavailable as a routine clinical test. McKenna et al. suggestedthat future studies may confirm the observation ofAckerman et al., that selected MYH7 and TNNT2 mutationsdo confer increased risk of disease and relatedcomplications. In the Ackerman et al. study, however, amalignant mutation was only found in 3 (1%) of the 293patients who had the following features: 24% had a familyhistory of sudden cardiac death prior to age 40; 6% hadextreme hypertrophy greater than 30 mm; and 8.5% hadreceived an implantable cardioverter defibrillator. Thus,the group all had significant hypertrophic cardiomyopathy.

134ATHLETES AND SUDDEN CARDIAC DEATHMost agree that asymptomatic patients with mild leftventricular hypertrophy less than 20 mm, a normal exerciseblood pressure response, and absence of arrhythmia onHolter monitor with no family history of prematuresudden death have a low risk of sudden death. Massivedegrees of left ventricle hypertrophy greater than 30 mm inassociation with other risk factors are suggested by some tobe a marker of risk. McKenna et al., however, pointed outthat the majority of sudden deaths occur in patients with awall thickness of less than 30 mm.C. Coronary Artery DiseaseAlthough coronary artery disease occurs commonly in menafter age 40, it can also occur in individuals between theages of 25 and 40. In one study of sports-related suddendeaths, not limited to competitive athletes, atheromatouscoronary artery disease (as well as hypertrophic cardiomyopathy)was the leading cause of sudden death. Ruptureof an atheromatous plaque may cause sudden death inyoung athletes, albeit rarely.4. Advice to Athletes with HypertrophicCardiomyopathyAthletes with an unequivocal diagnosis of hypertrophiccardiomyopathy should refrain from engaging in competitivesports and all forms of intensity training.Dehydration must be avoided because this furtherdecreases the narrowed left ventricular cavity and obstructionof blood flow. All competitive athletes older than age12 should have a thorough cardiac examination done bya family physician and an ECG. A positive family historyof premature sudden cardiac death before age 40, theobservation of a cardiac murmur, or an abnormal ECGmay alert the physician to the diagnosis of hypertrophiccardiomyopathy or other cardiac disease that may herald aserious cardiac event.B. Coronary Artery AnomaliesCongenital coronary artery anomalies account for approximately20% of sudden cardiac death in young competitiveathletes. As an example of one anomaly, the left maincoronary artery should arise from the left sinus of Valsalva,but instead, in these patients, it arises from the right sinus.The left ventricle muscle mass consequently is deprived ofan adequate blood and oxygen supply (see the sinus ofValsalva in the figures in the chapter Anatomy of the Heartand Circulation).Unfortunately death may occur without manifestingsymptoms such as exertional syncope or chest pain, andwithout abnormalities on the ECG at rest or on exercisetesting. Symptoms such as exertional syncope, markedfatigue, and pallor observed soon after exertion require adiligent search for coronary artery anomalies. Investigationsshould include a transesophageal echocardiogram.Most important, these anomalies can be corrected bybypass surgery. Unfortunately, participation in athleticscreening does not reliably identify patients with coronaryartery malformations (for more information see thechapter Congenital Heart Disease).D. Ruptured AortaRupture of the aorta accounts for approximately 5%of deaths in athletes, although the death may not besudden. Rupture of the aorta is a characteristic of Marfansyndrome, a condition in which the strong muscular elasticmiddle wall of the aorta has a decreased number of elasticfibers and becomes weakened and prone to rupture.E. Aortic StenosisCongenital malformations of the aortic valve may producesevere obstruction to the flow of blood from the leftventricle into the aorta. The abnormal architecture of thevalves causes turbulent flow of blood that traumatizes thevalves and causes fibrosis, rigidity, calcification of valveleaflets, and narrowing of the aortic orifice. This conditionusually becomes symptomatic in young adults. Because ofsymptoms such as shortness of breath on exertion, syncope,tiredness, and fatigue, the condition is usually discoveredand is easily diagnosed. Diagnosis is made when a loudmurmur is heard over the aortic valve area with thestethoscope. The ECG and chest x-rays clarify theabnormality and surgery corrects the defect. Thus, theseindividuals do not often succumb to sudden death. Thiscondition is reported to cause about 5% of deaths inathletes, but it is not related specifically to highly trainedcompetitive young athletes whose defect would normallybe picked up by screening.F. Other CausesOther causes include those listed below.1. MyocarditisThis is usually caused by viral infections and is often adifficult diagnosis to establish. Chest pain, shortness ofbreath, palpitations, and abnormal heart rhythms mayoccur. A mild flu-like illness may be followed by an

II. SUDDEN DEATH NOT ASSOCIATED WITH CARDIAC DISEASE135asymptomatic phase in which no symptoms of heartdisease are manifested, but during the next few months oryears weakness of the myocardium may result in a cardiacevent usually associated with malignant arrhythmias:ventricular tachycardia, ventricular fibrillation.2. Mitral Valve ProlapseThis causes approximately 2% of cardiac deaths in athletes.Not all of the deaths are sudden. Mitral valve prolapse is acommon condition, but serious complications are rarebefore age 45.3. Arrhythmogenic Right Ventricular DysplasiaThis is a familiar condition usually associated with very fastheart rates (ventricular or supraventricular tachycardias).It can cause sudden death in young individuals includingathletes. The disease accounts for less than 4% of suddendeath in athletes. In a region in Italy this condition is thesingle most common cause of sudden death in competitiveathletes and is reportedly more common than hypertrophiccardiomyopathy. The ECG and echocardiogram usuallyshow abnormal features; the right ventricle muscle bundlesare replaced by fibrous and fatty tissue.4. Disturbances in the Electrical Conduction SystemThese disturbances of the heart rarely cause sudden deathin athletes and other young people. In these cases,individuals are observed to have very slow heart rates andcomplete heart block.5. The Brugada SyndromeThis can be a cause of sudden death, but is not oftenassociated with sudden death in competitive athletes. Inthese cases, the ECG is always abnormal and is used todetect this very rare condition. For more information seethe chapter Brugada Syndrome.6. WPW and Long QT SyndromeSudden death in individuals with apparently normal heartsaccounts for approximately 3% of deaths. Conditions thatdo not causes structural abnormalities and are thereforenot detected on pathological examination at autopsyinclude: Wolff-Parkinson-White (WPW) syndrome andfamilial long QT syndrome. In WPW there is ananomalous or accessory conduction pathway that allowsrapid heartbeats in the range of 220–280.A congenital abnormality of electrical conduction, thefamilial long QT syndrome, may escape detection becausethere is no structural abnormality to be found at autopsy.Sudden death in athletes age 35–50 is common, becauseat this age asymptomatic and undetected coronary arterydisease may be present. The coronary arteries may beinvolved with obstructive atherosclerotic disease that maycause a fatal or nonfatal heart attack or sudden death.Athletes over age 45 commonly have known atheroscleroticdisease, undetected dyslipidemia or diabetes, andthose who persist as recreational joggers, marathonrunners, or engage in high-intensity squash or tennismay succumb to sudden death.II. SUDDEN DEATH NOT ASSOCIATEDWITH CARDIAC DISEASEA. Commotio CordisBlunt, nonpenetrating blows to the chest are known toproduce ventricular fibrillation, albeit rarely, withoutassociated injury to the ribs, sternum, or heart. Thiscondition is a more common cause of sudden death inathletes than all other conditions except hypertrophiccardiomyopathy. Commotio (disturbance, concussion)cordis is most common in individuals less than 16 yearsof age, because at this age the chest wall is still pliable andprobably enhances transmission of the energy from thechest blow to the myocardium. Survival after commotiocordis occurs in less than 15% and may be achievedif cardiopulmonary resuscitation and defibrillation arereadily applied.In commotio cordis the blow may not be consideredintense enough to cause death. Blows of sufficient magnitudemay be produced by a blow from sports projectileslike a pitched baseball, hockey puck, or lacrosse ball;a karate blow or a blow delivered to relieve hiccups,or a collision between outfielders during baseball. Otherinjuries include a nonpenetrating blow to the neck thatmay rupture a vertebral artery and result in death fromhemorrhage.B. Cocaine, Anabolic Steroids, and HerbalStimulantsThe use of cocaine, anabolic steroids, and dietary supplements,particularly those containing ephedrine/ephedra(ma huang), are potent cardiac stimulants and mayprecipitate life-threatening arrhythmias.

136ATHLETES AND SUDDEN CARDIAC DEATHIII. ATHLETE’S HEART VERSUSHYPERTROPHIC CARDIOMYOPATHYA. DifferentiationThere is little doubt that young, highly trained athletesdevelop physiologic thickening of the muscular wall of theleft ventricle. This is similar to the enlarged biceps of abodybuilder or a blacksmith. This normal physiologicenlargement of the heart muscle (hypertrophy), can bedifficult to differentiate from a mild form of hypertrophiccardiomyopathy. Maron et al. observed that athleteswithin this hypertrophic gray zone presented an importantand common difficult problem in which the differentialdiagnosis between hypertrophic cardiomyopathy andathlete’s heart must be resolved by noninvasive testing.Such testing often resolves the problem.The athlete heart may show segmental thickening ofthe ventricular septum of 13–15 mm, which can beobserved on echocardiography. The ECG in these athletesmay show signs of ventricular hypertrophy, abnormal STsegment, and T-wave changes that may appear highlyabnormal.Differentiation can be observed in a number of ways.1. The ECG shows the bizarre patterns seen in hypertrophiccardiomyopathy.2. The echocardiogram usually shows asymmetric hypertrophyin hypertrophic cardiomyopathy, whereas theathlete’s heart shows similar changes in both the leftand right ventricle mass or a balanced enlarged heart.The left ventricular cavity is usually less than 45 mm inhypertrophic cardiomyopathy and in an athlete’s heartthere may be dilatation of the cavity to greater than55 mm.3. Left atrial enlargement is common in patients withhypertrophic cardiomyopathy, but it is not usually seenin an athlete’s heart.4. It is rare to find the athlete’s heart in women.5. Family history, gene mutation for hypertrophic cardiomyopathy,and changes seen on ECG and echocardiogramusually confirm the diagnosis. In more difficultcases an MRI may be used to differentiate the twoconditions.B. Clinical Studies1. Scharhag et al.Study question: Is the athlete’s heart characterized bysimilar left and right ventricular hypertrophy?Methods: Left and right ventricle mass, volume,and function in 21 male endurance athletes (27 4years), with a weight of 70 kg, were compared with21 matched untrained control subjects and analyzedby MRI.Results: All of the cardiac dimensions were significantlydifferent between the endurance athletes and the controlsubjects.Conclusions: Regular and extensive endurance trainingresults in nearly identical changes that can be observedin the left and right ventricle muscle mass and in theirvolume and function. This leads to the conclusion thatthe athlete’s heart is a balanced enlarged heart. Inhypertrophic cardiomyopathy, however, the hypertrophyis usually asymmetric; if the left ventricular shows amore uniform (concentric) hypertrophy, then the rightventricle shows relatively little hypertrophy or an unbalancedhypertrophy.2. Sharma et al.Study question: High-endurance sports training maycause increased left ventricular wall thickness and mayconflict with the diagnosis of hypertrophic cardiomyopathy.Information on echocardiographic dimensions inathletes age 14–18 is lacking. What echocardiographicmeasurement of hypertrophy would be considered importantfor the diagnosis of hypertrophic cardiomyopathy inyoung athletes?Methods: Included were 720 elite athletes, (75% male,age 15–16) participating in endurance sports and 250healthy sedentary control individuals who underwentechocardiography.Results: Compared to controls, athletes had greaterabsolute left ventricular wall thickness (LVWT). No femaleathlete had an LVWT greater than 11 mm and only 3trained male athletes had an absolute thickness greater than12 mm. Each of the 38 athletes with LVWT exceedingpredicted limits also showed enlarged left ventricular cavitydimensions of 50–60 mm.Conclusions: Trained young athletes show greaterabsolute LVWT compared with non-athletes. Only asmall proportion of athletes exhibited an LVWT exceedingupper limits, very rarely greater than 12 mm, and thenalways accompanied with left or right ventricular chamberenlargement. Hypertrophic cardiomyopathy, however,should be considered strongly in any trained youngmale athlete with an LVWT of greater than 12 mm and(females greater than 11 mm), and with a nondilated leftventricle.

III. ATHLETE’S HEART VERSUS HYPERTROPHIC CARDIOMYOPATHY137BIBLIOGRAPHYAckerman, M. J., Van Driest, S. L., Ommen S. R. et al. Prevalence andage dependence or malignant mutations in the beta myosin heavychain and troponin T genes in hypertrophic cardiomyopathy:A comprehensive outpatient perspective. J. Am. Coll. Cardiol.,39:2042–8, 2002.Burke, A. P., Farb, A., Virmani, R. et al. Sports related and nonsports related sudden cardiac death in young athletes. Am. Heart J.,121:568–75, 1991.Corrado, D, Basso, C., Rizzoli, G. et al. Does sports activity enhance therisk of sudden death in adolescents and young adults? J. Am. Coll.Cardiol., 42:1959–1963, 2003.Lim, M. J., Forsberg, M., and Kern, M. J. Provocable pressure gradientacross an anomalous left main coronary artery: A unique diagnostictool. Circulation, 111:e108–e109, 2005.Maron, B. J. Sudden death in young athletes. N. Engl. J. Med., 349:1064–75, 2003.Maron, B. J. Sudden death in young athletes: Lessons from the HankGathers affair. N. Engl. J. Med., 329:55–57, 1993.Maron, B. J., Pellica, A., and Spirito, P. Cardiac disease in young trainedathletes: Insights into methods for distinguishing athlete’s heart fromstructural heart disease with particular emphasis on hypertrophiccardiomyopathy. Circulation, 91:1596–1601, 1995.Maron, B. J., Shirani, J., Poliac, L. C. et al. Sudden death in youngcompetitive athletes: Clinical, demographic and pathological profiles.JAMA, 276:199–204, 1996.McKenna, W. J., Mogensen, J., and Elliott, P. M. Role of genotyping inrisk factor assessment for sudden death in hypertrophic cardiomyopathy.J. Am. Coll. Cardiol., 39:2049–51, 2002.Nishimura, R. A. and Holmes, Jr., D. R. Hypertrophic obstructivecardiomyopathy. N. Engl. J. Med., 350:1320–1327, 2004.Scharhag, J., Schneider, G., Urhausen, A. et al. Right and left ventricularmass and function in male endurance athletes and untrainedindividuals determined by magnetic resonance imaging. J. Am. Coll.Cardiol., 40:1856–63, 2002.Sharma, S., Maron, B. J., Whyte, G. et al. Physiologic limits of leftventricular hypertrophy in elite junior athletes: Relevance todifferential diagnosis of athlete’s heart and hypertrophic cardiomyopathy.J. Am. Coll. Cardiol., 40:1431–6, 2002.

Atrial FibrillationI. EpidemiologyII. DiagnosisIII. Causes and Research ImplicationsIV. PathophysiologyV. Classification and ManagementVI. AnticoagulantsVII. Electronic PacingGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiomyopathy heart muscle disease.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood and atheroma; medicalterm for a heart attack or coronary thrombosis.tachycardia increase in heart rate exceeding 100 beats perminute.torsades de pointes a very serious, life-threatening ventriculararrhythmia.valvular disorders disease of heart valves, particularly mitralstenosis, mitral regurgitation, aortic stenosis, and aorticregurgitation.Wolff-Parkinson-White syndrome characterized by prematureexcitation of the ventricles due to an anomalous conductionbypass tract between the atria and ventricles; often leads torapid heart rates.THE TERM ATRIAL FIBRILLATION IS USED TOdescribe an abnormal rhythm of the heartbeat; instead ofbeating regularly, the heart beats very erratically. Theirregular heartbeats may speed up, and the heart ratemay be as fast as 120–180 beats per minute. These fastand strong beats may be sensed as palpitations. Atrialfibrillation is the most common persistent heart rhythmabnormality observed in medical practice.The adequate management of atrial fibrillation hasresisted the major advances in cardiology that have beenmade in the past 40 years. This stubborn and bothersomearrhythmia has increased to epidemic proportions over thepast 20 years, particularly because of an aging populationand beneficial treatments for many other heart diseaseprocesses that are complicated by atrial fibrillation. Theonly test available for the diagnosis of atrial fibrillation isthe simple, an inexpensive ECG, a clinical test that hasremained virtually unchanged since its inception in the1940s.Figure 1 shows the electrical system of the heart, theconduction system that transports the current of energyinitiated in the sinus node which is then delivered to theventricular structures to initiate the heartbeat. The ECGpicks up the heart’s electrical impulses transmitted throughthe skin of the chest. The normal physiologic processshould be understood in order to recognize the clinicalfeatures and electrocardiographic findings observed inatrial fibrillation.The sinoatrial (SA) node is unique and has no steadyresting potential. After repolarization, slow spontaneousdepolarization occurs. Thus, this unique pacemakerprovides individuals with an automatic, infinitesimalcurrent that sets the electrical activity and contraction ofthe heart. The SA discharge rate, usually 50–100 perminute, is under autonomic, chemical, and hormonalinfluence.In the electrical system the atrioventricular (AV ) nodeprovides a necessary physiologic delay of the electricalcurrents. This allows the atria to fill the ventricles withblood before ventricular contraction or systole from theAV node, a physiologic ‘‘tollgate,’’ the electrical currentrapidly traverses the right and left bundle branches, thespecialized conductive tissues of the ventricles, and theentire ventricular myocardium is depolarized. The transienthalt and slowing of conduction through thespecialized AV node fibers play an important protectiverole in patients with atrial flutter and atrial fibrillation.In these conditions, a rapid atrial focus fires at a rate of300–600 beats per minute and these rapid beats reach theAV node; fortunately, this AV tollgate reduces the electrical139

140ATRIAL FIBRILLATIONSinus nodepacemakerAtrio-ventricularnode(super-highway)Left bundlebranchRight bundlebranchFIGURE 1Electrical system of the heart.traffic that reaches the super highway which traverses theventricles at approximately 80–180 beats per minute, andserious life-threatening events are prevented as the rapidrates are slowed. (See the chapter Electrocardiography.)I. EPIDEMIOLOGYAtrial fibrillation is a common arrhythmia found in greaterthan 1% of persons older than 60 years. This rate rises toabove 5% in people older than 69, and increases to morethan 10% in people older than 79. Prevalence of thisdisorder increases dramatically with age, but it is alsobecoming more prevalent with time, even after adjustmentfor age and underlying structural heart disease. More than85% of patients with atrial fibrillation are older than 65.In the elderly this disorder causes substantial morbidityincluding stroke, heart failure, and hospitalization. Patientsrequire an anticoagulant to prevent stroke; this therapyoccasionally causes cerebral hemorrhage and requiresbothersome laboratory testing every 2 weeks.Younger patients between the ages 25 and 50 areoccasionally affected with atrial fibrillation because ofthe presence of underlying heart diseases that includecongenital heart disease, cardiomyopathy, rheumatic heartdisease, mitral stenosis, mitral regurgitation, and othervalvular disorders. In more than 30% of cases in youngerindividuals with paroxysmal atrial fibrillation no obviousstructural heart disease was detected on examination of theindividual or on tests such as echocardiography and cardiacnuclear scans.Because of its high prevalence in the worldwidepopulation, hypertension is responsible for more than14% of cases of heart disease, and it is responsible for morecases of atrial fibrillation than any other disorder. Somepatients have atrial fibrillation without evidence ofstructural heart disease or hypertension; this disorder islabeled lone atrial fibrillation. Data from the Framinghamstudy indicate that lone atrial fibrillation is responsible forgreater than 15% of all cases with a peak prevalence inindividuals 60–80 years of age.II. DIAGNOSISDiagnosis of atrial fibrillation is based on history, clinicalexamination, and confirmation with an ECG. The patientmay experience rapid and irregular heartbeats usually fromone to several hours. Associated symptoms include mildshortness of breath that can become severe if seriousunderlying heart disease is present. During atrial fibrillationthe atrium does not contract normally and blood istherefore not delivered rapidly into the left ventricle. Poorfilling of the ventricle and the fast ventricular rate maycause a fall in blood pressure resulting in lightheadednessand dizziness. Because the atrium is fibrillating and not

III. CAUSES AND RESEARCH IMPLICATIONS141contracting, there is stasis of blood in the atrial appendage.Stasis predisposes the patient to clot formation and thesethrombi may be dislodged and fly into the circulation andtravel to other organs (embolize). The embolus can blockan artery in the brain and cause a stroke.Atrial fibrillation may last several hours to a couple ofdays and then disappear for several days to weeks; thiscondition is referred to as paroxysmal atrial fibrillation.These patients may have no symptoms from 6 monthsup to 2 years and then fibrillation may recur. Atrialfibrillation, therefore, does not always cause symptoms andthe disease can be misdiagnosed. In the CardiovascularHealth study, 12% of new cases of atrial fibrillation werediagnosed on the basis of ECG screening alone and theseindividuals presumably had no symptoms.In patients presenting with atrial fibrillation it isimperative to exclude structural heart disease, particularlymitral stenosis which has a typical murmur that can bemissed because of the fast heart rate. The echocardiogramdoes not help with diagnosing atrial fibrillation, but it isuseful when detecting underlying structural heart disease.III. CAUSES AND RESEARCHIMPLICATIONSDiseases or disorders that cause atrial fibrillation are shownin Fig. 2. Due to the vast number of both serious diseasesand disorders that cause atrial fibrillation, it is not surprisingthat a definitive cure is rarely possible. This hasbecome most frustrating for cardiologists and technologistswho strive to provide advances in technologic equipmentand strategies for the management of atrial fibrillation.Valvular heart diseaseHypertensionMitral valveAortic valvePulmonaryvalveAtrialfibrillationHeart failureCoronary artery Disease (CAD)— myocardail infarction— unstable angina— chronic CADCongenital Heart DiseaseWPW syndromeCardiomyopathiesPericarditis/myocarditisConstrictive pericarditisCor pulmonalePulmonary embolismPneumothoraxSick sinus syndrome(sinus node dysfunction)Extra cardiac– Thyrotoxicosis– Alcohol– Post thoracotomy syndrome– Ruptured esophagus– Esophago jejunostomy– Carbon monoxide poisoningFIGURE 2Lone Atrial fibrillation: Idiopathic - No Structuralor functionalheart disease*Foci located in theproximal pulmonary veinsUnderlying causes or risk factors for atrial fibrillation. *Ablation therapy in patients with paroxysmal atrial fibrillation.

142ATRIAL FIBRILLATIONThe prevention of atrial fibrillation is therefore of paramountimportance. There has been little focus in the past20 years on the prevention of this abnormality.A. HypertensionBecause the cure and management of atrial fibrillation ismost often difficult, it is necessary to prevent theoccurrence of atrial fibrillation by aggressive managementof conditions that cause atrial fibrillation. The aggressivemanagement of hypertension is very important. Unfortunately,despite more than 50 years of extensive research bynational bodies and pharmaceutical firms and the majoradvertisement of new drugs available for the managementof hypertension, only four antihypertensive agents areavailable.These agents include diuretics, beta-blockers, calciumblockers, and ACE inhibitors. The recently added newagents, angiotensin receptor blockers, are really nodifferent from ACE inhibitors but appear to have a lesserincidence of adverse effects. There are more than 12diuretics, 15 beta-blockers, 10 calcium antagonists, 14ACE inhibitors, and 6 angiotensin receptor blockersavailable, but these represent only 4 active agents.In addition diuretics, beta-blockers, or ACE inhibitorsachieve the goal blood pressure of less than 140 mmHg inless than 50% of patients. Often two drugs must be usedfor control, thus reducing patient compliance. Calciumantagonists are effective in approximately 65% of patients,but they are not cardioprotective and carry increased riskfor the causation of heart failure in the elderly and inpatients with heart disease.Excellent control of hypertension, therefore, has notbeen achieved worldwide and this will not occur until themedical profession and pharmaceutical firms recognize theroot of the problem. Only four antihypertensive agents areavailable and they are only mildly beneficial. The fifthgroup of antihypertensive agents is the alpha-blockers.They have been shown to increase the incidence of heartfailure in the recently completed ALLHAT trial.All editorials in clinical medical journals purport the ideathat available antihypertensive agents are all beneficial andwith combination therapy control is possible.B. Heart FailureThere is a worldwide epidemic of heart failure. It is causedby most of the conditions listed above, but it has othercauses and precipitating factors. Heart failure causesthe left atrium to enlarge even further and this enlargementenhances the occurrence of atrial fibrillation. Earlyaggressive treatment of mild heart failure, New York HeartAssociation class I and II, with beta-adrenergic blockingdrugs and ACE inhibitors may prevent progression to classIII heart failure and may prevent atrial fibrillation in somepatients.C. Valvular Heart DiseaseDiseases of heart valves, particularly mitral stenosis, mitralregurgitation, aortic stenosis, and regurgitation, arecommonly associated with atrial fibrillation. Many patientsfollowing valvular heart surgery develop atrial fibrillation.D. Chronic Coronary Artery DiseaseThe prevention of coronary artery disease would obviouslylead to a decrease in the prevalence of atrial fibrillation.Atrial fibrillation occurs in more than 15% of patientsduring the first few days of acute myocardial infarction.Chronic coronary artery disease does not commonly causeatrial fibrillation, but because the disease is common it isresponsible for more than 5% of cases of atrial fibrillation.Coronary artery disease is caused by obstruction of arteriesby atheroma. After more than 50 years of research it is stillimpossible to prevent atheroma formation in arteries.Treatment with statins, aspirin, ACE inhibitors, and all thenew wonder drugs proclaimed by manufacturers andmedical experts only prevent complications of atheroma inapproximately 25% of patients, but they do not preventthe disease process. It is obvious that more extensiveresearch is required to halt the epidemic of atheromatouscoronary artery disease worldwide (see the chapterAtherosclerosis/Atheroma).E. Sick Sinus SyndromePatients with sick sinus syndrome (sinus node dysfunction)have degenerative disease of the sinus node. The naturalgenerator that emits an electrical impulse causing theheartbeat is diseased in sick sinus syndrome. Bradycardia ofless than 45 beats per minute along with greater than4-second pauses may result in loss of consciousness. Inaddition, because of the slow heart rate foci in the atrialtakeover the electrical circuit and cause rapid heart beats,tachycardia, ranging from 120 to 160 beats per minute.The slow regular rhythm may change to atrial fibrillationoften at a fast heart rate, (tachycardia) followed withinhours by slow heart rates (bradycardia) — thus the termbradytachy syndrome. These patients are best managed byimplantation of a pacemaker.

V. CLASSIFICATION AND MANAGEMENT143F. ThyrotoxicosisThyrotoxicosis is caused by hyperthyroidism. The thyroidglands produces excessive amounts of thyroxine withresultant stimulation of the heart and tachycardia. Atrialfibrillation is a well-known complication and bothersomepalpitations with tachycardia of 120–180 beats per minutemay occur. The tachycardia is controlled with betablockingdrugs such as propranolol, and the thyroidgland is treated with medications or radioactive iodine.G. Idiopathic Atrial FibrillationIt is not uncommon for atrial fibrillation to occur in theabsence of an abnormal structural or functioning heart.This condition is called lone atrial fibrillation. Data fromvarious countries are not available, but in the United Statesapproximately 15% of patients are found to have loneatrial fibrillation. In some of these patients, and particularlyin those with paroxysmal atrial fibrillation, recentinvestigations have revealed foci located in the proximalpulmonary veins that may cause ectopic atrial activation.IV. PATHOPHYSIOLOGYDuring the past 50 years different theories have beenproposed to explain the mechanism underlying atrialfibrillation, but many controversies surrounded thesemechanisms. In the past decade it seems well acceptedthat both focal and reentrant mechanisms are involved,playing a different role in the initiation and perpetuationof the arrhythmia. Several recent human multielectrodemapping systems and other studies indicate that in atrialfibrillation the dominant mechanism incorporates multiplemeandering wavelets, both in the acute and chronic formof this condition. Multiple wavelengths of excitationpropagate around the atrial myocardium and the arrhythmiais perpetuated because of an abnormal atrial tissuesubstrate, particularly in patients with structural heartdisease and permanent atrial fibrillation. Patients withparoxysmal atrial fibrillation with no evidence of structuralheart disease appear to have a trigger-predominantmechanism, but the two basic mechanisms reflect a largeoverlap. After very long periods of permanent atrialfibrillation, if sinus rhythm is restored, reverse remodelingusually fails to occur. This may explain why in patientswith persistent atrial fibrillation for more than 12 monthsit is difficult to maintain sinus rhythm followingcardioversion.Atrial fibrillation may be triggered by focal initiators.Recent experimental work indicates that ectopic atrialactivation may emerge from one more foci located in themuscular sleeves of the proximal pulmonary veins as singlebeats or repetitive bursts of activity. This focal-triggeredatrial fibrillation is often paroxysmal in its early stages, andit may be observed in individuals with structurally normalhearts. The focal-triggered mechanism may also underliesome cases of persistent atrial fibrillation in the presence orabsence of structural heart disease. It appears that thepresence of atrial foci functioning as triggers localized inthe pulmonary veins is a finding in many patients withlone or idiopathic and paroxysmal atrial fibrillation. In thisgroup of patients, segmental or circumferential pulmonaryvein ablation has an emerging role.V. CLASSIFICATION AND MANAGEMENTA. Acute Atrial FibrillationAn episode of atrial fibrillation observed within 48 h of itsonset is described as acute. If the ventricular rate is greaterthan 160 beats per minute and results in acute cardiovasculardecompensation manifested by hypotension,shortness of breath, chest pain, confusion, or heart failure,the rhythm should be converted to normal sinus rhythm.DC cardioversion is usually the initial treatment of choice.Figure 3A shows the ECG tracing of a patient with acuteatrial fibrillation and a fast ventricular rate of 160 beats perminute. Figure 3B shows the same patient hours later afterthe rate had been decreased by a beta-blocking drug. It alsoshows spontaneous reversion to normal sinus rhythm.The diagnostic points of the ECG are as follows: therhythm is completely irregular, the R-to-R intervals areirregular, there are no visible P-waves, and the baselineshows irregular undulations.If there are no signs of cardiovascular decompensationand the arrhythmia is well-tolerated, diltiazem (a calciumantagonist), esmolol, or other beta-blocking drugsadministered intravenously can be used to slow theventricular response to less than 110 beats per minute,with the hope that normal sinus rhythm may returnspontaneously within 12–24 h of onset. Sinus rhythm mayreturn spontaneously if atrial fibrillation is due to anextracardiac cause that is corrected or if the left atrium isnot enlarged. If spontaneous sinus rhythm does not occur,conversion to sinus rhythm may be attempted withpharmacologic agents such as ibutilide.Ibutilide should not be used in patients with a lowserum potassium level or prolonged QT interval becausetorsades de pointes may be precipitated. There is a 5%

144ATRIAL FIBRILLATIONFIGURE 3AAtrial fibrillation; fast ventricular rate 165 beats per minute.FIGURE 3Bper minute.Atrial fibrillation. Note the completely irregular rhythm, RR intervals irregular, absent P waves; slow ventricular response of 80 beatsincidence of torsades in patients with ischemic heartdisease. This drug should not be used concomitantly withdrugs that increase the QT interval.Patients with atrial fibrillation for more than 48 hrequire oral anticoagulation with warfarin for at least 3weeks before cardioversion can be safely attempted.Anticoagulants are continued after conversion for at least8 weeks to prevent thromboembolism and stroke.Alternatively heparin is administered intravenously, andif no thrombi are observed by transesophageal echocardiographicassessment, cardioversion may be attempted ifdeemed absolutely necessary.

V. CLASSIFICATION AND MANAGEMENT145FIGURE 3CNormal ECG: normal RR intervals, regular sinus rhythm, P waves visible.If there is no hemodynamic compromise and the patientis stable in the presence of acute atrial fibrillation, thereasons for conversion to sinus rhythm should be stronglyexamined. Although electrical cardioversion may establishsinus rhythm in more than 90% of patients, after 6 monthsless than 30% of patients remain in sinus rhythm.If atrial fibrillation occurs with very fast heart rates of200–240 per minute, Wolff-Parkinson-White syndromemay be the underlying cause. This disease is caused by ananomalous pathway that is capable of conducting rapidly.Drugs that are commonly used to manage chronic atrialfibrillation such as digoxin, beta-blockers, and calciumantagonists are contraindicated (see Wolff-Parkinson-White syndrome in the glossary).B. Paroxysmal Atrial FibrillationThese patients experience intermittent, recurrent, and selfterminatingepisodes of atrial fibrillation. Episodes areconsidered paroxysmal atrial fibrillation if they terminatespontaneously. Some patients tolerate these short bouts ofirregular, abnormal heart rhythms without symptoms,especially if they are in the range of 100–140 beats perminute. Many elderly patients tolerate atrial fibrillationwell without therapy or with minimum therapy, becausethe ventricular rate is slow (80–120 beats per minute) andbecause they have concomitant atrioventricular (AV ) nodaldisease. AV nodal disease blocks conduction from theatrium to the ventricle slowing the ventricular responseand heart rate. This slow ventricular response happensbecause several of the drugs used (digoxin, beta-blockers,calcium antagonists) to control the fast heart rates cause apartial blockage of the electrical impulse as it traverses theAV node to reach the ventricle (see Fig. 1).Other patients experience rapid heart rates of 160–190beats per minute that may recur twice a year or two orthree times weekly for a few months then recur monthslater. Paroxysmal atrial fibrillation of this type is extremelybothersome to many patients who may have to attendemergency rooms or must receive antiarrhythmic drugs orpacemaker therapy.Paroxysmal atrial fibrillation accounts for 35–50% of allcases of atrial fibrillation. It is most common in patients intheir 50s and 60s with prevalence peaking between the agesof 50 and 70. This condition is three times more commonin men than in women. The probability that lone atrialfibrillation will progress from paroxysmal to permanent isapproximately 20%. Paroxysmal atrial fibrillation occurs inpatients with structurally normal hearts, but it also occursin patients with structural heart disease.Paroxysmal atrial fibrillation remains a difficult problemto manage. The rapid heart rates are difficult to controlwith available agents, which include beta-blockers, calciumantagonists, digoxin, and amiodarone. Sotalol 160–240 mgdaily may cause maintenance of sinus rhythm in less than50% of patients. Breakthrough atrial fibrillationcommonly occurs and anticoagulation with warfarin or

146ATRIAL FIBRILLATIONximelagatran becomes necessary to prevent stroke (see thechapter Blood Clots).Paroxysms with a ventricular rate of 140–180 beats perminute can be managed with diltiazem or esmololintravenously to reduce the rapid heart rate to less than110 beats minute until spontaneous revision to sinusrhythm occurs. Digoxin is usually not effective in reducingrapid ventricular rates during paroxysms and is notadvisable in patients with paroxysmal atrial fibrillationexcept when combined with a beta-blocking drug.The combination of a beta-blocking drug with the calciumblocker diltiazem plays a role in controlling rapidventricular rates.In patients with paroxysmal atrial fibrillation resistant todrug therapy there are three options: Complications ofthese procedures must be outlined in detail to the patient.1. Pulmonary Vein AblationIn pulmonary vein ablation percutaneous catheters areused to identify the location of arrhythmogenic foci withinall four pulmonary veins. Either segmental pulmonary veinisolation or circumferential pulmonary vein ablationtechniques are used at different centers. In skilled handsand in patients with one focus, the success rate approaches80%. The success rate is low in patients with persistentatrial fibrillation and lower in those with structural heartdisease than in those without. Left atrial ablation toencircle the pulmonary veins has been shown to improvesurvival, reduce the risk of heart failure and stroke, andimprove quality of life when compared with medicaltherapy.Patients not suitable for pulmonary vein ablationinclude those with a large left atrium of greater than60 mm, patients with contraindications to anticoagulants,and the elderly over 75 years of age. Before consideringpulmonary vein ablation, sinus node dysfunction (sicksinus syndrome), thyrotoxicosis, AV nodal reentranttachycardia, and Wolff-Parkinson-White syndrome mustbe excluded.a. Clinical StudiesIn a published series (San Raffaele University Hospital,Milan, Italy), 251 patients underwent circumferentialpulmonary vein ablation: 179 patients with paroxysmalatrial fibrillation and 72 patients with persistent atrial fibrillationpresent for more than 3 months. At a mean followup of 310 days, 86% of the patients with paroxysmalatrial fibrillation and 76% of patients with chronic atrialfibrillation, respectively, were free of recurrent atrial fibrillationin the absence of antiarrhythmic drugs.In a study from the University of Michigan (AnnArbor), segmental pulmonary vein isolation was performedin 93 patients with paroxysmal atrial fibrillation and 17with persistent atrial fibrillation. At a mean follow up of208 days 28 and 70% of the paroxysmal and persistentatrial fibrillation patients, respectively, experienced recurrentepisodes of symptomatic fibrillation in the first 2weeks after ablation. The only independent clinicalpredictor of the ablation was the presence of persistentatrial fibrillation before the procedure.Good clinical results were achieved in patients withvalvular disease, cardiomyopathy, and coronary arterydisease with or without left ventricle dysfunction. Becauseof these encouraging results, an algorithm has beenproposed by the American Heart Association/AmericanCollege of Cardiology, see Fig. 4.2. Specific Linear Left Atrial Lesionsa. Clinical study, Kottkamp et al.Study question: Curative treatment for patients withrefractory atrial fibrillation is among the main challengesof interventional electrophysiology. A specific left atriallinear lesion concept for treatment of paroxysmal andpermanent atrial fibrillation was tested using intraoperativeablation with minimally invasive surgical techniques.Method: Seventy patients with drug-refractorypersistent and paroxysmal atrial fibrillation underwentintraoperative radiofrequency ablation using video-assistedminimally invasive techniques via minithoracotomy.Results: Mean follow up was 18 months. Six monthsfollowing ablation, 93% of patients were in sinus rhythmin both groups and at 12 months 96% were in sinusrhythm.Conclusions: A pure linear lesion line concept confinedto the left atrium specifically targeting elimination ofanatomically defined left atrial ‘‘anchor’’ reentrant circuitseliminated atrial fibrillation over a mean follow up of 18months in greater than 90% of patients.Research implication: The linear lesion line concept isnot yet practicable when applied percutaneously. Thepathophysiologic concept is the prevention of anatomicallydefined left atrial reentrant circuits without mass reductionand without treatment of potential triggers. It is possiblethat in the future this intraoperatively validated strategiclinear left atrial lesion line concept might be transferredto catheter ablation; new navigation and catheter technologiesshould allow the transfer to percutaneous ablationtechniques.

V. CLASSIFICATION AND MANAGEMENT147FIGURE 4 Algorithm for the management of atrial fibrillation based on its clinical presentation. AF ¼ atrial fibrillation; SND ¼ sinus node dysfunction;WPW ¼ Wolff-Parkinson-White syndrome; AVNRT ¼atrioventricular nodal reentrant tachycardia; HF ¼ heart failure; SR ¼ sinus rhythm; TEE ¼transesophageal echocardiography; CV ¼electrical and/or pharmacological cardioversion; PV ¼ pulmonary vein; LA ¼ left atrium; LV ¼ left ventricular;SHD ¼ structural heart disease; AADs ¼ antiarrhythmic drugs; AE ¼ adverse events; PKR ¼ pacemaker. *According to the American Heart Association/American College Cardiology guidelines. (From (2003). ACC Curr. J. Rev. with permission from the American College of Cardiology Foundation.)C. Persistent Atrial FibrillationThis form of atrial fibrillation will not self-terminate, butit can be effectively cardioverted to sinus rhythm with DCcardioversion or pharmacologic agents. Some patients withvalvular heart disease may be converted easily providedthat the left atrium is not large. A large left atrium greaterthan 5 cm is a risk factor for the causation of atrialfibrillation and often predicts a recurrence in a few monthsfollowing cardioversion to sinus rhythm.A major randomized clinical trial involving more than4500 patients, randomized to either rate control ofpersistent atrial fibrillation or rhythm control (suppressionof atrial fibrillation), showed no significant differences inmortality, morbidity, or quality of life between the twostrategies.Patients with drug-refractory persistent atrial fibrillationmay require intervention that includes pulmonaryvein ablation or intraoperative radiofrequency ablationutilizing a specific left atrial linear lesion line concept, asdescribed above.1. Synchronized DC CardioversionAttempting DC conversion of atrial fibrillation is alwaysconsidered carefully. Immediate DC cardioversion isindicated for patients who are hemodynamically unstable.It is usually contraindicated in permanent atrial fibrillationwith a duration of greater than one year because sinusrhythm is usually not maintained and in patients with aleft atrial size greater than 5.5 cm. Patients with atrialfibrillation of less than one week’s duration usually regainatrial function after conversion. Embolization occurs inabout 2% of patients and anticoagulation is necessarybefore cardioversion. Conversion should not be attemptedin patients with suspected digitalis toxicity because of therisk of precipitating ventricular fibrillation. Patients with

148ATRIAL FIBRILLATIONsick sinus syndrome (sinus node dysfunction) should notbe considered as conversion may cause prolonged pauses.Anticoagulants are not used in DC conversion if the atrialfibrillation has been present for less than 24 h; patientswith valvular heart disease, particularly mitral stenosis, mayhave thrombus in the left atrial appendage and transesophagealechocardiography is warranted to exclude thrombi.In patients with a duration over 24 h but less than 48 h,IV heparin may be used for anticoagulation to allowconversion within 24 h. Patients with atrial fibrillation forgreater than 48 h should be anticoagulated for at least3 weeks prior to conversion and anticoagulation shouldbe continued for more than three weeks followingconversion. Light anesthesia with a standby anesthesiologistis necessary during the procedure.D. Permanent Atrial FibrillationAtrial fibrillation that cannot be terminated by cardioversion,that can be terminated only for brief intervals, or thatlasts longer than one year without cardioversion havingbeen attempted is classified as permanent. Chronic atrialfibrillation implies continuing atrial fibrillation and doesnot address the important clinical distinction betweenpersistent and permanent atrial fibrillation.In the vast majority of patients with permanent atrialfibrillation, slowing of the ventricular response to 70–90beats per minute will be helpful. A beta-blocking drug suchas metoprolol, bisoprolol, or atenolol should slow downthe ventricular response. These agents are also a goodchoice in patients with concomitant congestive heartfailure New York heart Association class I–III. Digoxinwas commonly used for this condition from the 1950s to1990, but during the past decade beta-blockers havebecome the agents of choice, mainly because it becameapparent that digoxin does not achieve the control of a fastventricular rate associated with exercise. In patients inwhom beta-blockers cannot be used safely, the ventricularrate can be slowed sufficiently with the inexpensive digoxinadministered once daily. Occasionally a combination of abeta-blocker and digoxin becomes necessary.All of the available beta-blocking drugs can be usedsafely with the exception of sotalol. This drug must not beused in the management of permanent (chronic) atrialfibrillation because it carries a risk of torsades de pointes.Other beta-blockers do not have this adverse side effect.A recent clinical trial confirmed that it is safer to managepatients with permanent atrial fibrillation by controllingtheir ventricular rate (heart rate) rather then attempting tocardiovert to sinus rhythm or use pharmacologic agents tomaintain sinus rhythm. Patients after conversion do notoften remain in sinus rhythm and pharmacologic agents(amiodarone, flecainide, propafenone, sotalol, and quinidine)necessary to maintain sinus rhythm are usually notsuccessful and produce life-threatening adverse effects.VI. ANTICOAGULANTSA. WarfarinPatients with atrial fibrillation considered high risk forstroke require anticoagulation with warfarin to maintainan INR of 2–3 to prevent stroke. An INR of 1.4–1.9 hasbeen shown to be associated with a stroke or mortality ratesimilar to that for an INR of less than 1.5. The loss ofatrial contraction leads to stasis of blood in the atrium andis more marked in the left atrial appendage, the mostcommon site for clot formation. Stasis is accompanied byhypercoagulability and there is increased concentrationsof fibrinogen and fibrin D-dimer and increased concentrationsof von Willebrand factor. These derangements allcontribute to the development of a prothrombotic stateand embolization. Five randomized clinical trials indicatethat warfarin anticoagulation reduces the risk of strokeby 68% and lowers mortality by 33%. The risk ofhemorrhagic complications, particularly cerebral hemorrhage,rises greatly when the INR exceeds 3.9. Patients onoral anticoagulants should have blood tests every 2–3weeks to maintain an INR of 2–3 in order to preventserious hemorrhagic events. In patients over 80 years of ageand in those with small risk of bleeding, the INR ismaintained at 1.8–2.8. Patients at high risk for bleedingare not given anticoagulants.Aspirin is only recommended for patients with loneatrial fibrillation who are younger than 65 and with noother risk factors for thromboembolism and for those whoare intolerant to warfarin administration. Aspirin’s riskreduction of stroke is less than 20%. Patients with loneatrial fibrillation who are younger than 65 have a lowstroke rate of approximately 1% versus patients over age 75with one or more additional risk factors for thromboembolismwho have a stroke rate of greater than 8%. Loneatrial fibrillation is indicated by the absence of hypertensionand valvular and other heart disease.B. New Anticoagulant: XimelagatranThis direct thrombin inhibitor has been shown to be aseffective as warfarin in preventing stroke and does notrequire monitoring with blood tests. The drug represents amajor breakthrough for management of atrial fibrillation

VII. ELECTRONIC PACING149and control of thromboembolism. The stroke preventionwith the oral direct thrombin inhibitor ximelagatran,compared with warfarin in patients with nonvalvular atrialfibrillation (SPORTIF) III and V randomized trials,studied patients at moderate risk. Patients with mitralstenosis, significant valve disease, or previous valvular heartsurgery were excluded. Thus the new agent if approvedshould be used only in patients similar to those in theSPORTIF trials. Caution: in both trials the new drugcaused substantial but usually transient increases in liverenzyme concentrations in 6% of patients. Enzyme elevationsreached greater than five times the upper limits ofnormal in 3.4% of ximelagatran-treated patients (see thechapter Blood Clots). Hepatotoxicity limits the use of thedrug and similar agents should be sought.VII. ELECTRONIC PACINGIt is known that conversion of atrial fibrillation to sinusrhythm does not improve survival. The reason for trying tomaintain sinus rhythm is mainly to control symptoms.Neither antiarrhythmic drugs nor atrial pacing alone havebeen successful in suppressing atrial fibrillation.A. Atrial PacingRecently, dual-site right atrial pacing has been shown insmall studies to achieve partial suppression of arrhythmiain patients with bradycardia and atrial fibrillation onantiarrhythmic drugs. The trials, however, do not supportthe use of atrial pacing as monotherapy in symptomaticatrial fibrillation.B. Ablation of the AV node and Implantation ofa Permanent PacemakerThis procedure is a last resort for patients with bothersomeatrial fibrillation refractory to other treatments. Theablation of the AV node produces rate control and regularventricular contractions, but the atria continue to fibrillateand the risk of stroke remains. Mortality is not improvedby this procedure. The combined incidence rate of suddendeath and malignant ventricular arrhythmias is approximately7%.1. Clinical Study, Ozcan et al.In a study of 334 consecutive patients with atrialfibrillation who underwent AV node ablation, 9 patientshad sudden death after the ablation, 4 patients had suddendeath likely related to the procedure, and in 3 patientsarrest occurred within 48 h and 1 patient arrested 4 daysafter the procedure. In three other patients sudden deathwas possibly related to the procedure, because the eventoccurred within 3 months afterward.The risk of sudden death is highest within 2 days afterprocedure. The annual rate of sudden death ranges from2 to 4%. The high risk of death is unacceptable in acondition that does not cause sudden death and in whichmortality is low in patients treated with anticoagulants.BIBLIOGRAPHYALLHAT: Major outcomes in high-risk hypertensive patients randomizedto angiotensin converting enzyme inhibitor or calcium channel blockerversus diuretic; the antihypertensive and lipid lowering treatment toprevent heart attack trial. JAMA, 288:2981–97, 2002.Alboni, P., Bott, G. L., Bald, N. et al. Outpatient treatment of recentonsetatrial fibrillation with the "Pill-in-the-Pocket" approach. N. Engl.J. Med., 351:2384–2391, 2004.Bourassa, M. G. et al. Angiotensin II inhibition and prevention of atrialfibrillation and stroke. J. Am. Coll. Cardiol., 45:720–721, 2005.Executive Steering Committee on Behalf of the SPORTIF IIIInvestigators. Stroke prevention with the oral direct thrombininhibitor ximelagatran compared with warfarin in patients withnonvalvular atrial fibrillation (SPORTIF III), a randomized controlledtrial. Lancet, 362:1691–1698, 2003.Gaita, F., and Riccardi, R. Lone atrial fibrillation; transcatheter orminimally invasive surgical approaches? J. Am. Coll. Cardiol., 40:481–83, 2002.Gaita, F., Riccardi, R., Caponi, D. et al. Linear cryo-ablation of the leftatrium versus pulmonary vein cryo-isolation in patients withpermanent atrial fibrillation and valvular heart disease: Correlationof electroanatomic mapping and long-term clinical results. Circulation,111:136–142, 2005.Halperin, J. L. et al. Ximelagatran: Oral direct thrombin inhibitionas anticoagulant therapy in atrial fibrillation. J. Am. Coll. Cardiol.,45:1–9, 2005.Hazel, S. J., Paterson, H. S., Edwards, J. R. M. et al. Treatment of atrialfibrillation via energy ablation. Circulation, 111:e103–e106, 2005.Hylek, E. M., Go, A. S., Chang, Y. et al. Effect of intensity of oralanticoagulation on stroke severity and mortality in atrial fibrillation.N. Engl. J. Med., 349:1019–26, 2003.Jongbloed, M. R. M, Bax, J. J., Lamb, H. J. et al. Multi-slice computedtomography versus intra-cardiac echocardiography to evaluate thepulmonary veins before radiofrequency catheter ablation of atrialfibrillation. J. Am. Coll. Cardiol., 45:343–350, 2005.Khan, M. Gabriel. Arrhythmias. In. Cardiac Drug Therapy, sixth edition,W. B. Saunders, Philadelphia, 2003.Kottkamp, H., Hindricks, G., Autschbach, R. et al. Specific linear left atriallesions in atrial fibrillation. J. Am. Coll. Cardiol., 40:475–80, 2002.Lauer, M. R. Dofetilide: Is the treatment worse than the disease? J. Am.Coll. Cardiol., 37:1106–10, 2001.Marza, I., James, S., and Holt, P. Biatrial pacing for paroxysmal atrialfibrillation. J. Am. Coll. Cardiol., 40:457–63, 2002.Montenero, A. S., Bruno, N., Antonelli, A. et al. Long-term efficacy ofcryo catheter ablation for the treatment of atrial flutter. J. Am. Coll.Cardiol., 45:573–580, 2005.

150ATRIAL FIBRILLATIONOzcan, C., Jahangir, A., Friedman, P. A. et al. Sudden death afterradiofrequency ablation of the atrioventricular node in patients withatrial fibrillation. J. Am. Coll. Cardiol., 40:105–10, 2002.Pappone, C., Rosanio, S., Augello, G. et al. Morbidity and mortality andquality of life after circumferential pulmonary vein ablation for atrialfibrillation. J. Am. Coll. Cardiol., 42:185–197, 2003.Packer, D. L., Keelan, P., Munger, T. M. et al. Clinical presentation,investigation, and management of pulmonary vein stenosiscomplicating ablation for atrial fibrillation. Circulation, 111:546–554,2005.Page, R. L. et al. Newly diagnosed atrial fibrillation. N. Engl. J. Med.,351:2408–2416, 2004.Peters, N. S., Schilling, R. J., Kanagaratnam, P. et al. Atrial fibrillation:Strategies to control, combat, and cure. Lancet, 359:593–603, 2002.Saksena, S., Prakash, A., Ziegler, P. et al. Improved suppression ofrecurrent atrial fibrillation with dual site right atrial pacing andantiarrhythmic drug therapy. J. Am. Coll. Cardiol., 40:1140–50, 2002.Wachtell, K., Hornestam, B., Lehto, M. et al. Cardiovascular morbidityand mortality in hypertensive patients with a history of atrialfibrillation. J. Am. Coll. Cardiol., 45:705–711, 2005.

Atrial Septal DefectI. Clinical StudyGLOSSARYembolization encrusted material, particularly small clots orbacterial vegetation on the heart valves, heart chambers, orveins which may dislodge and fly off into the circulation; theyare swiftly carried to other organs, for example, pulmonaryembolism.murmur a blowing sound heard with a stethoscope usuallycaused by obstruction of heart valves or leaking valves.which leads to further investigations. Because oxygenatedblood is pumped from the left atrium into the right side ofthe heart, the organs of the body including the skin receiveoxygenated blood. Thus, the individual does not becomeblue in the face, a condition described as cyanosis. Becauseof this, atrial septal defect is a cause of noncyanoticcongenital heart disease.The ECG usually shows evidence of an incomplete rightbundle branch block. This is a clue for the treatingphysician. A transesophageal echocardiogram (TEE) isusually diagnostic. Closure of the hole in the heart iscurative and should be done if symptoms are present.ATRIAL SEPTAL DEFECT, A HOLE IN THE SEPTUMdividing the right and left atrium, is the most commoncongenital heart defect observed after age 12 and in adults,because the lesion is usually so small that it causes littledisturbance in infants. Atrial septal defect accounts forapproximately 10% of all congenital cardiac defects. Withthis defect oxygenated blood is shunted from the leftatrium into the right atrium and traverses the pulmonaryarteries and lungs and returns to the left side of the heart(Fig. 1). This circulatory disturbance is called a left to rightshunt. The shunt is usually small but if the hole is largeenough the right ventricle works harder to pump theextra blood delivered to it, from the left side, into thepulmonary arteries and through the pulmonary circulationback to the left side of the heart. The right ventricle overtime is subjected to more strenuous work than normal.The muscle of the right ventricle becomes weaker and failsto expel sufficient blood from the chamber, and acondition referred to as right heart failure occurs. Theatrial septal defect most often involves the fossa ovalis inthe mid septal region; this is called an ostium secundumtype of defect.With a small hole in the heart, the infant or young childis relatively asymptomatic. With larger defects tiredness,shortness of breath on exertion, and frequent infection ofthe lungs may occur. These symptoms are more obvious asheart failure worsens. A soft heart murmur is usually heardI. CLINICAL STUDYStudy question: A study by Attie et al. assessed weathersurgical treatment of atrial septal defects in patients overage 40 improves their long-term outcome.Methods: The study included 521 patients over age 40with atrial septal defect who were randomly assigned tosurgical closure or medical treatment.Results: After approximately seven years of follow-up,surgical closure was superior to medical treatment inimproving the composition of major cardiovascular eventsand overall mortality. Closure of the defect is advisable inpatients over age 40 with pulmonary artery pressures lessthan 70 mmHg and a pulmonary/systemic output ratiogreater than 1.7. Sudden death was more common in themedical group than the surgical group. This study showsthat nonsurgical closure of the defect is not an option.A nonrandomized analysis of 442 patients undergoingclosure with the Amplatzer septal occluder (ASO) wascompared with 154 patients in the surgical group. TheASO consists of two expandable round disks with a 4 mmlong connecting waist that is delivered to the site in the leftatrium via a catheter threaded through the left upperpulmonary vein. The early primary and secondary benefitsfor surgical versus device closure were not significantlydifferent. The complication rate, however, was lower andhospital stay was shorter for device closure versus surgical151

152ATRIAL SEPTAL DEFECTFIGURE 1 Transesophageal echocardiograms in two patients with atrial septal defects. In each case there is a distinct loss of tissue in the atrial septum,allowing direct communication between the left atrium and right atrium. (From Braunwald, E., Heart Disease. A Textbook of Cardiovascular Medicine,sixth edition, Philadelphia: W. B. Saunders, 197, 2001.)FIGURE 2 Transesophageal two-dimensional images from patients with an ostium secundum (A) and superior sinus (B) atrial septal defect. In (A) thedefect is seen in the mid-portion of the inter-atrial septum in the fossa ovalis. In (B) the superior sinus defect (SSD) can be seen to be an ‘overriding’ of thesuperior vena cava (SVC) rather than a defect in the inter-atrial septum itself. (From Camm, J.D., Fox, A.J., Hall, R.J.C., and Poole-Wilson, P.A., Eds.,Diseases of the Heart, second edition. London: W. B. Saunders, 327, 1996.)repair. The complication rate was 7.2% for the devicegroup and 24% for the surgical group.In a 417-patient study by Chessa et al., the Cardio-SEAL/STARFlex was used in 159 patients and the ASO in258 patients. Thirty-four patients experienced 36 complications.Ten patients underwent elective surgical repairbecause of device malposition or embolization. Twentyfourpatients experienced 25 minor complications, unsatisfactorydevice position, or embolization. One patient hadperipheral embolization one year after implantation andsudden death occurred in one patient 1.5 years later. Theauthors of the study concluded that the ASO devicebecame their first choice for closing defects larger than18 mm. Transcatheter closure of the hole in the atrialseptum has evolved successfully over the past 20 years, butappropriate patient selection and expertise for deploymentof the seal is crucial.BIBLIOGRAPHYAttie, F., Rosas, M., Granados, N. et al. Surgical treatment for secundumatrial septal defects in patients greater than 40 years old. J. Am. Coll.Cardiol., 58: 2035–4, 2001.Chessa, M., Carminati, B., Margherita, B. et al. Early and latecomplications associated with transcatheter occlusion of secundumatrial septal defect. J. Am. Coll. Cardiol., 39:1061–5, 2002.Du, Z.-D., Hijazi, Z. M., Kleinmann, C. S. et al. Comparison betweentranscatheter and surgical closure or secundum atrial septal defect inchildren and adults. J. Am. Coll. Cardiol., 39:1836–44, 2002.Roman, K. S., Masaki, N., Fraser, G. et al. Real-time subcostal3-dimensional echocardiography for guided percutaneous atrialseptal defect closure. Circulation, 109:320–321, 2004.

B-Type Natriuretic PeptideI. Clinical StudiesII. PerspectiveGLOSSARYheart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.dyspnea shortness of breath, usually on exertion.edema accumulation of fluidmyocardium the heart muscle.THE NATRIURETIC PEPTIDE SYSTEM INCLUDESatrial (ANP) and brain or B-type (BNP) natriureticpeptide. Brain natriuretic peptide (BNP) is a 32 aminoacid cardiac natriuretic peptide that was originally isolatedfrom porcine brain tissue. The human BNP gene is locatedon chromosome 1 and encodes the 108 amino acidprohormone pro-BNP which circulates with the 32 aminoacid biologically active BNP and the N terminal 76 aminoacid component of the prohormone (NT-proBNP). Thesethree components can be measured by immunoassay.BNP is released by cardiac myocytes of the ventricles inresponse to myocardial wall stress. This is brought on byincreased transmural wall tension and elevations of enddiastolic pressure, ventricular volume expansion andpressure overload. The secretion of this important peptideserves to regulate sodium and water balance by the kidneysand causes vasodilatation of arteries, which benefits thefailing heart.Elevated BNP levels are detected in the blood of patientswith heart failure but levels are normal in patients withshortness of breath caused by pulmonary disease. Therapid measurement of levels of BNP in the blood hasproved useful in the diagnosis of heart failure.More important, in emergency rooms the BNP testrapidly clarifies whether severe shortness of breath iscaused by heart failure or by pulmonary disease. Heartfailure is readily diagnosed by the symptoms of severeshortness of breath on minimal effort, shortness of breathin bed, and swelling of the ankles caused by accumulationof fluid. Confirmation is obtained on clinical examinationand from a chest x-ray (see the chapter Heart Failure).Although NT-pro BNP levels are 2 to 10 times higher thanthe BNP levels in patients with heart failure, NT-proBNPis eliminated from the blood by the kidneys and is notreliable in patients with coexisting renal insufficiency,a condition that is often associated with heart failure.Clearance of BNP is not dependent on kidney function.I. CLINICAL STUDIESA. Maisel et al.Methods: A study was done of 1586 patients who visitedthe emergency with acute shortness of breath, dyspnea, andwhose BNP level was measured with a bedside assay. Thediagnosis of heart failure was confirmed by two independentcardiologists.Results: Dyspnea was caused by heart failure in 744patients, 47%, with shortness of breath due to noncardiaccauses; in 72 patients with a history of left ventriculardysfunction, 5%; and no finding of heart failure in 770patients, 49%. The BNP levels were more accurate thanhistorical or physical findings in establishing the diagnosisof heart failure. At a cut-off of 100 pg/ml, the diagnosticaccuracy of BNP was 83%. A level of BNP less than50 pg/ml indicates the absence of heart failure. Patientswith the diagnosis of heart failure had mean BNP levelresults of 675 50 pg/ml.B. Mueller et al.Methods: A prospective randomized controlled study of452 patients who presented to the emergency departmentwith acute dyspnea. The study randomly assigned 225patients to BNP assay and 227 were assessed by a153

154B-TYPE NATRIURETIC PEPTIDEAorta*Release of ANPRelease of BNPModest suppressionof Renin-aldosteronesystemAtriumVent ricledilates arteries, BP (smalleffect because of powerful)Renin-Angiotensin II actionsKidneyAdrenalsaldosteronenatriureticeffect: excretionNa + and waterNatriuretic peptideseffectsNa + ReabsorptionRenin-angiotensinaldosterone systemconsiderably more powerfulthan natriuretic peptidesactionsFIGURE 1 Effects of atrial, A-type, and ventricular, B-type natriuretic peptides. * ¼ C-type natriuretic peptides released from vascular endothelium: asmall effect. ANP ¼ A-type natriuretic peptide. BNP ¼ B-type natriuretic peptide. Note that the effects of the renin angiotensin aldosterone system isconsiderably more powerful than that of the natriuretic peptides so as to maintain adequate blood pressure during catastrophic events that profoundlydecrease blood pressure (see Figure 1, in chapter entitled Angiotensin-Converting Enzyme Inhibiters/Angiotensin Receptor Blockers).physician. Primary end points were the time to dischargethe total cost of treatment.Results: The use of BNP measurements reduced theneed for hospitalization and intensive care: 75% of patientsin the BNP group were hospitalized versus 85% assessedby a physician. The mean time to discharge was 8 days and11 days in the BNP and control groups, respectively. Thetotal cost of treatment was $5410 and $7264 in the BNPand control group, respectively.C. Pierre-Yves et al.Objectives: During stress and exercise BNP levels riseand lower cardiac workload. That benefits patientswith coronary artery disease (CAD). This study soughtto identify determinants of exercise rise in BNP levels inpatients with CAD.Methods: BNP and ANP levels were estimated at restand peak exercise.Results: Treatment with beta-blockers was a strongindependent predictor of an increase in natriuretic peptideconcentrations at exercise. Patients with CAD show amuch higher exercise release of ANP and BNP whenadministered beta-blockers. These high levels of peptidesappear to protect diseased hearts against stress.II. PERSPECTIVERapid measurement of BNP is useful in establishing orexcluding the diagnosis of heart failure in patients withacute severe shortness of breath. BNP levels can confirmthe diagnosis of heart failure when the cause of acute severeshortness of breath remains uncertain after assessment ofthe history, physical findings, and chest x-ray. The severity

II. PERSPECTIVE155of heart failure appears to be reflected by the height ofBNP levels. The discovery that A-type (atrial), natriureticpeptide is secreted by the atrium (atrial natriuretic factor),was a major breakthrough that paved the way for therevelation of BNPs.BIBLIOGRAPHYAdams, J., Apple, F. et al. New blood tests for detecting heart disease.Circulation, 109:e12–e14, 2004.Baughman, K. L. B-type natriuretic peptide — a window to the heart.N. Engl. J. Med., 347:158–9, 2002.Lindahl, B., Lindbðck, J., Jernberg, T., Johnston, N., Stridsberg, M,Venge, P., Wallentin, L. et al. Serial analyses of N-terminal pro-B-typenatriuretic peptide in patients with non-ST-segment elevation acutecoronary syndromes. pages 533–541.Maisel, A. S., Krishnaswamy, P., Nowak, R. M. et al. Rapid measurementof the B-type natriuretic peptide in the emergency diagnosis of heartfailure. N. Engl. J. Med., 347:161–7, 2002.Mueller, C., Scholer, A., Laule-Kilian, K. et al. Use of B-type natriureticpeptide in the evaluation and management of acute dyspnea. N. Engl.J. Med., 350:647–654, 2004.Pierre- Yves, M., Mertes, P. M., and Hassan-Sebbag, N. Exercise release ofcardiac natriuretic peptides is markedly enhanced when patients withcoronary artery disease are treated medically by beta-blockers. J. Am.Coll. Cardiol., 43:353–359, 2004.Takeshi Soeki, Ichiro Kishimoto, Hiroyuki Okumura, TakeshiTokudome, Takeshi et al. C-type natriuretic peptide, a novel antifibroticand antihypertrophic agent, prevents cardiac remodeling aftermyocardial infarction.

Beriberi Heart DiseaseI. Clinical ManifestationsGLOSSARYcardiogenic shock extremely low blood pressures in the arteriescaused by failure of the heart to eject blood; systolic bloodpressure is usually less than 90 mmHg.effusions accumulation of fluid.pulmonary edema fluid in the air sacs and alveoli; the lungsbecome congested and severe shortness of breath occurs.BERIBERI HEART DISEASE IS CAUSED BY SEVEREthiamine deficiency. This disease is most prevalent in theFar East, however, in the past decade its prevalence hasmarkedly decreased. It occurs mainly in individuals whosestaple diet consists of polished rice that is deficient inthiamine but high in carbohydrates.Diets with a high carbohydrate content require a greaterintake of thiamine. White bread enriched with thiaminehas helped in this respect. Because alcohol is high in carbohydratecontent but deficient in thiamine, some alcoholicsbecome thiamine deficient and weakness of the heart musclemay occur. The disease is also common in fad dieters.I. CLINICAL MANIFESTATIONSSwelling of both legs is caused by edema and may becomesevere. Pitting edema of both legs may extend up to thethighs and over the trunk. The heart becomes dilated andweakness of the muscle progresses to heart failure. Beriberiheart disease may cause sudden cardiac dysfunction withindays of onset of symptoms. This condition is accompaniedby low blood pressure, tachycardia, and lacticacidosis. Patients may die within hours or within days ofcardiogenic shock and pulmonary edema.On laboratory diagnosis for Beriberi heart disease serumpyruvate and lactic acid levels are increased. The ECGshows low-voltage QRS complex and prolongation of theQT interval. Chest x-ray usually shows dilatation of bothventricles and congestion of the lungs with pleuraleffusions.Treatment including administration of 100 mg of IVthiamine, then 25 mg daily for about 2 weeks causesdramatic improvement. Although the initial treatmentdoes not require digoxin and diuretics, a few days afterstarting thiamine therapy digoxin and diuretics areindicated and produce beneficial results. Disturbance ofnerves in the legs often accompanies the heart symptomsand thiamine replacement improves this type of polyneuropathy.BIBLIOGRAPHYGivertz, M. M., Colucci, W. S., and Braunwald, E. Clinical aspects ofheart failure, high output failure; pulmonary edema. In. Heart Disease,sixth edition. E. Braunwald, D. P. Zipes, P. Libby, and R.O. Bonow,eds. W. B. Saunders, Philadelphia, 2005.157

Beta-BlockersI. Beta-ReceptorsII. Mechanism of ActionIII. Salutary EffectsIV. IndicationsV. Clinical TrialsVI. Adverse Effects and CautionsVII. ClassificationVIII. Subtle Differences and Research ImplicationsIX. Individual Beta-Blockerspulmonary edema a condition in which heart failure causesmarked congestion of blood in the lungs, and fluid escapesinto the air sacs and alveoli preventing the oxygenation ofblood, this is associated with severe shortness of breath at rest.systole period of contraction of the heart muscle especially ofthe ventricles; blood is ejected from the ventricles.ventricular fibrillation the heart muscle does not contract butquivers; therefore there is no heartbeat (cardiac arrest) and noblood is pumped out of the heart; death occurs within minutesif the abnormal heart rhythm is not corrected.GLOSSARYafterload arterial impedance, restriction to blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of wall stress.angina short duration, recurrent chest pain or pressure oftenaccompanied by feelings of suffocation and impending doom;most frequently associated with lack of blood and oxygen tothe heart muscle.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).dyslipidemia the same as hyperlipidemia, elevated blood cholesterol,LDL cholesterol, triglycerides, or low HDL cholesterol.heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severe obstructionof the artery supplying blood to this area of cells.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.preload the degree of ventricular muscle stretch present at theonset of myocardial contraction; often expressed as enddiastolic volume or pressure.THE SURFACES OF CELLS IN VARIOUS ORGANSand tissues have receptor sites. Hormones and otherchemicals act at their respective receptor sites to bringabout a particular action in the cell. Adrenaline andnoradrenaline are called catecholamines and are releasedfrom sympathetic nerve endings and as hormones from theadrenal glands. They have their major actions on receptorsites called beta-receptors. Stimulation of the sympathetic–adrenal system during danger or severe stress, for example,causes an outpouring of adrenaline and noradrenaline intothe blood circulation and at nerve endings.Catecholamines (adrenaline and noradrenaline) arestimulants and cause an increase in the force of contractionof the heart increasing heart rate, blood pressure, andblood sugar. An outpouring of catecholamines is necessaryto prepare the body for a fight-or-flight response.Therefore, we need this surge of adrenaline if we haveto flee from a charging bull. Although adrenaline andnoradrenaline have positive effects, in excess they can causeovercharging of the cardiovascular system, which can precipitateventricular fibrillation.It is well documented that during a heart attack largequantities of noradrenaline are released into the heartmuscle, which can precipitate abnormal heart rhythms,particularly, ventricular fibrillation. Adrenaline causes anincrease in heart rate and an increase in blood pressure,thus causing the heart to work harder. Because a coronaryartery is blocked during a heart attack, the increased workwith less available oxygen causes further damage to the159

160BETA-BLOCKERSheart muscle and increases the size of the muscle damage,causing a larger heart attack.Beta-blocking drugs were originally discovered bySir James Black of Imperial Chemical Industries. Sincethe introduction of the prototype, propranolol, for themanagement of hypertension in 1964, more than 12 betablockingdrugs have become available. Beta-adrenergicblocking drugs have become the cornerstone of cardiacdrug therapy.I. BETA-RECEPTORSBy definition, beta-blockers block beta-receptors. Structurallythey resemble the catecholamines (adrenaline andnoradrenaline) and block the action of these catecholaminesat their receptor sites. The beta-receptors aresituated on the cell membrane and are believed to be a partof the adenyl cyclase system. An agonist acting on itsreceptor site activates adenyl cyclase to produce cyclicadenosine-5-monophosphate, which is believed to be theintracellular messenger of beta stimulation. There are twotypes of beta-receptors, beta-1 and beta-2.A. Beta-1 ReceptorsThe beta-1 receptors are present mainly in the heart,renin-secreting tissues of the kidney, parts of the eyeresponsible for the production of aqueous humor, and to alimited degree in bronchial tissue of the lung. Beta-1-adrenergic receptors regulate heart rate and myocardialcontractility, but in situations of stress with the provocationof epinephrine release stimulation of cardiac beta-2receptors contribute to additional increases in heart rateand contractility.B. Beta-2 ReceptorsThese are predominant in the bronchial tissues of the lung,vascular smooth muscle, insulin-secreting tissues of pancreas,gastrointestinal tract, and to a limited degree inthe heart and coronary arteries. None of these tissuesexclusively contains one subgroup of receptor. The populationdensity of receptors decreases with age. In addition,the beta-receptor population is not static, and duringlong-term therapy with beta-adrenergic blocking agentsthe number of receptors is increased.The heart contains beta-1 and beta-2-adrenergicreceptors in the proportion 70:30. In heart failure, cardiacbeta-1 receptors are reduced in number and population.II. MECHANISM OF ACTIONBlockade of cardiac beta-1 receptors causes a decrease inheart rate, myocardial contractility, and velocity of cardiaccontraction. Beta-blockers cause the heart muscle to workless, thus requiring less oxygen; in time of oxygen lack,such as during a heart attack or severe angina, this actioncan be life-saving. Because of the reduction in the oxygenrequirement of the heart muscle, the beta-blocking drugsare effective in preventing the chest pain of angina pectoris.Because patients with angina have a high risk of developinga heart attack over ensuing years, beta-blockers areimportant for both pain and prevention.An increase in adrenaline such as that produced duringstress or vigorous exercise causes an increase in (1) thenumber and stickiness of blood platelets, (2) clotting factorVIII (the hemophilic factor), and (3) the viscosity ofthe blood. Beta-blockers block some harmful effects ofadrenaline.Beta-blockers have antiarrhythmic effects; they depressphase 4 diastolic depolarization and are effective inabolishing arrhythmias caused by increased catecholamines.This action is particularly important in patientswith ischemic heart disease. The electrical impulse trafficthrough the AV node in reduced with beta-blockers andthe rate of conduction is slowed. This important actionslows the heart rate in patients with rapid heart ratescaused by atrial fibrillation. There is also a favorable effecton ventricular arrhythmias, particularly those induced byincreased sympathetic activity observed in patients withoxygen lack to the myocardium because of obstructivecoronary artery disease. Blockade of beta-1 receptorsreduces activity of the renin–angiotensin system in thekidney by reducing renin released from the juxtaglomerularcells; this action causes some lowering of bloodpressure.Pierre-Yves et al. have shown that patients with stablecoronary artery disease exhibit much higher exercisereleases of atrial and ventricular natriuretic peptides(ANP and BNP) when they are treated with beta-blockersthese authors postulated that increased secretion of potentvasodilating and natriuretic agents constituted a mechanismfor protecting diseased hearts against stress.III. SALUTARY EFFECTSBeta-blockers have been shown to prevent fatal and nonfatalheart attacks and sudden cardiac death. (The salutaryeffects of beta-adrenergic blockade are depicted in Fig. 1.A decrease in heart rate increases the diastolic intervalduring which the coronary arteries are filled with blood.

IV. INDICATIONS161VFthresholdImprovesdiastoliccoronaryperfusionBETA-ADRENERGIC BLOCKERSHeart rateBlock effects ofcatecholamine surgesDoubleproductBPMyocardial O 2requirementISCHEMIACatecholaminereleaseMyocardialcontractilityEarly a.m.plateletaggregabilityEjection velocityHydraulic stressIncidence ofplaque fissuring?CoronarythrombosisNonfatal orFatalmyocardial infarctionEarly a.m.Sudden deathIncreaseDecreaseFIGURE 1 Salutary effects of beta-adrenergic blockade. (From Khan,M. Gabriel, (2003). Cardiac Drug Therapy, sixth edition, Philadelphia:W.B. Saunders, p. 3. With permission.)The coronary arteries are squeezed during systole and bloodflow is restricted. Thus beta-blockers increase oxygensupply to the myocardium. This major beneficial effect hasnot been given prominence by workers in the field.Beta-blockers decrease the force and velocity of cardiaccontraction and decrease the heart rate pressure product(RPP). This action decreases myocardial oxygen demandand is important in the relief of angina.It is interesting to note the good effect of beta-blockerson the arterial system. The thousands of miles of arteriesare constantly under pressure from the pulsatile force andvelocity of blood as well as blood pressure. The decrease incardiac ejection velocity and a decrease in hemodynamicstress on the arterial wall, especially at the branching ofarteries, may decrease the atherosclerotic process andplaque rupture. Atherosclerosis is commonly seen wherearteries divide. Beta-blockers reduce blood pressure aswell as the force and velocity of blood flow at thesedividing points of mechanical stress and provide someprotection from vessel wall injury. This favorable effect isof paramount importance in patients with high bloodpressure. Mechanical injury from the velocity and force ofblood is the prime cause of vessel wall injury, which leadsto atherosclerosis, dissection of the plaques of atheromaand subsequent thrombosis, as well as rupture of ananeurysm (see the chapter Aneurysm).A decrease in the fatal arrhythmias, an increase inventricular fibrillation threshold, and amelioration ofventricular and supraventricular arrhythmias have beendocumented with beta-blockers. They decrease earlymorning platelet aggregation and arrhythmias inducedby catecholamines. By doing this, they decrease theearly morning peak incidence of heart attack and suddendeath.IV. INDICATIONSA. AnginaBeta-blockers are first-line therapy for the management ofstable angina. They have been shown to be more effectivethan oral nitrates and calcium antagonists. They reduce therecurrence of chest pain in more than 66% of patients.Many patients with angina manifest little pain, but theymay have several episodes of ischemia during the day ornight.These episodes can be adequately suppressed bythe use of beta-blocking drugs (see the chapter Angina).In patients with unstable angina these drugs are usedimmediately with aspirin when the patient arrives in theemergency room.B. Acute Myocardial InfarctionBeta-blockers are strongly recommended as therapy foracute myocardial infarction and are administered withinminutes of arrival in the emergency room to virtually allpatients who present with acute chest pain believed to becaused by a heart attack. As soon as an ECG confirms thediagnosis, an aspirin, a beta-blocker, and a thrombolyticagent are administered. In patients with acute myocardialinfarction beta-blockers have been shown to preventcardiac death and reduce infarct size. In these patients,beta-blockers are often continued for several years (seeFig. 2).C. HypertensionBeta-blockers and diuretics remain first-line agents for themanagement of virtually all patients with hypertension.Beta-blockers are the drugs of choice in younger and olderwhite patients. Contrary to the opinion of some experts,beta-blockers have been proven effective in older whitepatients. Beta-blockers are particularly indicated in allindividuals with hypertension and concomitant coronary

162BETA-BLOCKERSTotal patientpopulationTotal no.of patientsin trialNo. of patientsin differentgroupsNo ofdeathsMortalityContinued670Timolol945Withdrawn27536471884Continued718Placebo937Withdrawn21967 31 117 3510% 11% 16% 16%E. Heart FailureThe harmful effects of overactivation of the sympatheticnervous system in heart failure are ameliorated significantlyby beta-blockers. The judicious use of titrated doses ofbeta-adrenergic blockers has been shown to improvequality of life, recurrence of heart failure, and mortalityin patients with various grades of heart failure. TheCOPERNICUS study involved 2289 patients with severeheart failure and ejection fractions of less than 20%.The treatment drug carvedilol caused significant reductionsin mortality and hospitalization for heart failure. TheCOMET study randomized 1511 patients with chronicheart failure (ejection fraction less than 35%) to treatmentwith carvedilol and 1518 to metoprolol. Follow up at58 months showed all-cause mortality to be 34% forcarvedilol and 40% for metoprolol, p ¼ 0.0017.Totalmortality9810.4%P

V. CLINICAL TRIALS163that should be shut and flows from the left ventricle intothe left atrium. The left ventricle becomes enlarged andfinally weakens causing heart failure. In an animal study ofmitral regurgitation, the ACE inhibitor, lisinopril, reducedpre- and afterload, but its effect on the left ventricularcontractility was insignificant. Atenolol, when added tolisinopril, achieved a maximum hemodynamic benefitand also restored left ventricular contractility. Moderateto-severemitral regurgitation is an extremely difficultcondition to manage; the timing for surgery in patientswith severe disease is often a dilemma. Any cardioactiveagent that causes amelioration of the disease process is awelcome addition to the drug armamentarium.Beta-blockers are the cornerstone of treatment forpregnant patients with moderate-to-severe mitral stenosis.These agents slow the heart rate which allows filling of theleft ventricle and prevents life-threatening pulmonaryedema. In mitral stenosis the mitral valve opening isstenosed or tight, and blood flow from the left atriumis restricted. This flow is further decreased when theheart rate is fast. Patients with mitral valve prolapseand bothersome palpitations respond favorably to betablockers.I. Hypertrophic CardiomyopathyAlthough medical treatment with beta-blockers does notcause a decrease in mortality, symptoms are often significantlyrelieved with a beta-blocking agent. See chapterentitled ‘‘Cardiomyopathy.’’J. Perioperative MortalityBeta-blockers have been shown to decrease morbidity andmortality in patients undergoing coronary artery bypasssurgery and in cardiac patients undergoing other types ofsurgery. Beta-adrenergic blockade allows safer induction ofanesthesia and prevents the hypertensive response toendotracheal intubation. These agents reduce the occurrenceof arrhythmias in the intra- and postoperativeperiods. Both atenolol and bisoprolol have been shownin randomized clinical trials to reduce morbidity andmortality when given perioperatively and for one weekpostoperatively.L. Diabetic PatientsDeath in the majority of patients with type 2 diabetes iscaused by cardiovascular disease. Both fatal and nonfataland sudden heart attacks are common in diabetics.Unfortunately, the usual optimal treatment of diabeteswith insulin or oral agents does not significantly preventcardiovascular complications. Beta-adrenergic blockers areusually considered by experts to be relatively contraindicatedin diabetics, particularly those with dyslipidemias.This expert advice is illogical. These are the onlycardioactive agents along with aspirin that could protectthe heart from serious events and dyslipidemia can becontrolled with statins. (See the chapter Diabetes). Also,beta-blockers appear to have a renoprotective effect. In theSOLVD heart failure study, surprisingly in contrast to theACE inhibitor enalapril, beta-blockers were renoprotectivein both the ACE inhibitor and the placebo groups. See thelater discussion of the UKPDS beneficial results indiabetics treated with a beta-blocker in Section V.D.M. Other IndicationsProlonged QT interval syndromes may cause syncope orsudden death and beta-blockers provide some benefit inthese patients. An electrical storm in the heart mayprecipitate multiple episodes of ventricular tachycardia orventricular fibrillation and repetitive ventricular fibrillationresistant to therapy. The beneficial effect of the betablockerpropranolol on recurrent ventricular fibrillationcaused by electrocution was documented in 1970s, butlittle attention was given to this report. Recent studieshave documented the role of beta-blockers in electricalstorms and today propranolol is used for the managementof repetitive ventricular fibrillation resistant todefibrillation.V. CLINICAL TRIALSClinical trials have documented that beta-blockers significantlyprevent death in patients who are given the drugfrom the first week of the heart attack and for an additionaltwo years.K. Marfan SyndromeThis disease often causes dilatation of the ascending aorta,which results in aortic dissection. Prophylactic betaadrenergicblockade slows the rate of aortic dilation andretards the development of aortic complications.A. Norwegian Postinfarction Timolol TrialThis hallmark clinical trial was the first to document thelife-saving effects of beta-blockers in patients following aheart attack (see Fig. 2). In this superbly well-conductedNorwegian study, 1884 patients were randomized to two

164BETA-BLOCKERSgroups. The first group of 942 patients was started on abeta-blocker, timolol, 7 days after a heart attack. The othergroup received a placebo. At the end of two years, thetreated group had a 35% reduction in heart death,28% reduction in new heart attack, and 67% reductionin sudden death ( p < 0.001). The impressive resultswere observed in smokers and nonsmokers; they werepublished in 1981 (see Fig. 2).B. The American Beta-Blocker HeartAttack TrialThe Beta-Blocker Heart Attack Trial (BHAT) gave similarif not just as impressive results. In 16,400 randomizedpatients, propranolol, 120–240 mg, administeredto patients 14 days after myocardial infarction and followedfor 2 years showed a significant 26% reduction inmortality rate. Propranolol was not effective in smokers,however, because of the interactions in the liver; cigarettesmoking lowers the blood levels of propranolol anddecreases cardioprotective effects.C. The CAPRICORN StudyIn this recent, large multicenter study, patients from 1 to21 days after acute myocardial infarction and ejectionfraction less than 40% were randomized. The controlgroup received optimal medical therapy including the useof ACE inhibitors. The treated group received carvedilol6.25 mg increased progressively to 25 mg twice daily.Carvedilol caused a significant 23% reduction in all-causemortality in patients observed for 2.5 years; the mortalitywas 116, (12%) in the treated versus 151 (15%) in theplacebo group. The absolute reduction in risk was 2.3%.Forty-three patients need to be treated for one year to saveone life. This reduction is virtually the same as thatobserved in a meta-analysis of three ACE inhibitor trials.Most important, the reduction observed with carvedilol isin addition to those of ACE inhibitors alone.D. The UKPDS ResultsThe UKPDS results confirm that in type 2 diabetes, betablockerssignificantly reduced all-cause mortality, risk forheart attack, stroke, and importantly peripheral vasculardisease as well as microvascular disease. Over a follow up ofnine years the change in albuminuria and serum creatininewas the same in both the ACE inhibitor (captopril), andthe beta-blocker groups.E. ImplicationsBeta-blockers and aspirin are proven by studies to preventdeath from heart attack. About 450,000 heart attackpatients survive to leave hospitals in the United States andCanada annually, and about 100,000 of these patients willhave another heart attack in the following year. Betablockerscan prevent a heart attack in approximately 20%(30,000) of these patients and prevent death in about25%. Yet these cardioprotective drugs that can prolonglife are not advocated and prescribed by many internistsand family physicians because of the rare incidence ofimpotence and fatigue. Many practitioners continue to usenewer agents, particularly, calcium antagonists, nitrates,and other agents that have not been shown to prolong lifein randomized clinical trials.VI. ADVERSE EFFECTS AND CAUTIONSBeta-blockers are safe cardioactive agents if the warningsand contraindications are followed. They are not advisablein patients with severe class IV heart failure. They are indicated,however, in class I–III heart failure. Class IV patientswho have been stabilized and are no longer decompensatedcan be started on very small doses of carvedilol (3.5 mg).Beta-blockers are contraindicated in patients withbronchial asthma and in patients with severe chronicobstructive pulmonary disease including emphysema.Patients with mild chronic bronchitis may be given acardioselective beta-1 agent and may require supplementalsalbutamol. Other contraindications include:1. Complete heart block and varying grades of heart block2. Severe bradycardia less than 48 beats per minute3. Allergic rhinitis4. Insulin-dependent diabetics who are prone to hypoglycemia5. Raynaud’s phenomenonAdverse side effects of beta-blockers include tirednessand fatigue in about 10% of patients, erectile dysfunctionin about 10%, precipitation of heart failure in patientswith poor left ventricular function, slowing of the heartrate causing bradycardia less than 50 beats per minute,depression in less than 5%, very cold extremities in lessthan 10%, and vivid dreams. Switching to a hydrophilicdrug excreted by the kidney may decrease vivid dreams.VII. CLASSIFICATIONA classification of beta-blockers is given in Fig. 3. Cardioselectivityindicates that the drug chiefly blocks beta-1

VIII. SUBTLE DIFFERENCES AND RESEARCH IMPLICATIONS165receptors in the heart and partially spares beta-2 receptorsin the lungs and blood vessels. Large doses of all betablockingagents block beta-2 receptors, thus, cardioselectivedrugs are not cardiospecific. Bisoprolol is morecardioselective than metoprolol or atenolol. The classificationinto cardioselective and nonselective is important, butoversimplified.VIII. SUBTLE DIFFERENCES ANDRESEARCH IMPLICATIONSThe subtle differences that exist among the available betablockingdrugs are often overlooked. Figure 3 gives aworking classification. Cardioselective agents are safer thannonselective beta-blockers in diabetic patients and inthose with mild-to-moderate chronic obstructive pulmonarydisease. This information appears to be well knownworldwide. Agents with beta-agonist activity (intrinsicsympathomimetic activity, ISA) are not cardioprotective,e.g., pindolol, and should become obsolete. Of the cardioselectiveagents only metoprolol has been shown inrandomized clinical trials to significantly reduce coronaryheart disease mortality and events. Bisoprolol has not beentried in trials of infarction patients but was beneficial inheart failure trials. Atenolol, a popular cardioselectiveagent, is used worldwide but has never been tested in arandomized trial of post myocardial infarction patients orISA(beta agonist)#AcebutololCeliprololNon ISABeta-blockersCardioselective?Yes [β 1 ] Yes [β 1 β 2 ]AtenololBetaxolol*Bevantolol (E)BisoprololEsmololMetoprololxx NebivololISAAlprenolol (E)CarteololOxprenololPenbutololPindololAll available in the United States except if labeled (E)Non ISAPropranololNadololSotalolTimololTeratolol (E)*CarvedilolBucindololISA = Intrinsic sympathomimetic activityE = Europe* added weak alpha-blockerItalic = lipid soluble# weak β 1 selectivity, weak ISAxx = vasodilatory beta-blockerFIGURE 3 Classification of beta-blockers. All available in the UnitedStates except if labeled (E). ISA ¼ intrinsic sympathomimetic activity;E ¼ Europe; * ¼ added weak alpha-blocker; italic ¼ lipid soluble;# ¼ weak ß 1 selectivity, weak ISA; xx ¼ vasodilatory beta blocker.in patients with left ventricular dysfunction or heartfailure. It should not be assumed that this agent has similarcardioprotective properties as metoprolol, carvedilol,propranolol, bisoprolol, and timolol (see earlier discussionof clinical trials in Section IV).Of the cardioselective agents only bisoprolol andmetoprolol have been shown to decrease cardiac mortality.Both of these drugs have lipophilic properties. Lipophilicityallows a high concentration of drug in the brain.This appears to block sympathetic discharge in the hypothalamusand elevate central vagal tone to a greater extentthan water-soluble, hydrophilic agents. This may relateto the prevention of sudden cardiac death. Abal et al., ina rabbit model, showed that ‘‘although both metoprolol(lipophilic) and atenolol (hydrophilic) caused equal betablockade, only metoprolol caused a reduction in suddencardiac death.’’ It appears that this information has notreached clinicians or researchers.In addition, only carvedilol, metoprolol, timolol, andpropranolol — all lipophilic agents — have been shown toreduce mortality and morbidity in postinfarction patients.Atenolol is nonlipophilic and probably provides lesscardioprotection than proven agents. It has not beenadequately tested in randomized trials. Sotalol and oxprenolol,both nonlipophilic, have been tested in randomizedclinical trials and have not been shown to significantlyreduce mortality or morbidity. Oxprenolol has some betaagonistactivity that negates cardioprotection.Both nonselectivity and lipophilicity may providecardioprotection. It is possible that cardioselective agentsare not as cardioprotective as beta-1 and beta-2 blockingagents. Large, randomized clinical trials in the postmyocardial infarction patients with long-term follow uphave only been carried out with the nonselective agentstimolol, propranolol, and recently with carvedilol. Eachagent proved beneficial in reducing cardiac mortality andmorbidity. The cardioselective metoprolol reduced mortalityand morbidity in a postinfarction trial but follow upwas three months. Metoprolol was also successful in aheart failure trial (MERIT). The cardioselective bisoprololreduced mortality and morbidity in a heart failure trial(CIBIS II), but this agent is partially lipophilic. Atenololwas used in an early acute myocardial infarction trialand the result was only modestly significant. The methodologywas unsound in this trial; patients were admitted 4,6, and 12 hours post infarction, so this was not a genuinetrial of a beta-blocker during the first few hours ofinfarction. Unfortunately atenolol is the beta-blockingdrug most often used in antihypertensive trials comparingbeta-blockers with diuretics, calcium antagonists, andACE inhibitors. A nonselective, lipophilic drug such ascarvedilol that is proven effective in postinfarction patients

166BETA-BLOCKERSand in patients with severe heart failure should be tested inhypertensive patients. The cardioselective agent bisoprololhas lipophilic properties and also deserves testing inhypertensive trials.Beta blockade causes a mild increase in serum potassiumbecause of blockade of the beta-2-mediated epinephrineactivation of the Na K þ ATPase pump which transportspotassium from extracellular fluid into the cells. Duringstress, serum potassium has been observed to decrease1.0 mEq/L; this can be prevented by blockade of beta-2receptors. Nonselective beta-blockers are superior toselective agents in preventing fluctuations of serum potassiumconcentration during stress and possibly during acutemyocardial infarction. It may also be more cardioprotectivethan cardioselective agents.Carvedilol has important differences from atenolol,metoprolol, and other beta-blockers. This lipophilic, beta-1,beta-2 blocking agent is a very mild alpha-1 blocker andcauses arteriolar dilatation. Antioxidant and antiproliferativeproperties have also been noted. Carvedilol also lowersplasma endothelin levels.IX. INDIVIDUAL BETA-BLOCKERSA. AcebutololThis relatively cardioselective, partially hydrophilic andlipophilic agent possesses mild beta-agonist activity.A dosage of 200–300 mg twice daily is given for hypertension.Because of the presence of beta-agonist activity,this drug is not indicated for the management of angina ormyocardial infarction.B. AtenololThis beta-1 cardioselective agent is water-soluble, hydrophilic,and eliminated by the kidneys. It has a low sideeffect profile and is therefore widely used. As outlinedabove, the drug has not been shown to decrease mortalityin randomized trials. A dosage of 25–50 mg once daily isgiven, but a dose of 75 mg is required in some patientswith angina or hypertension.C. BisoprololThis agent is highly beta-1 selective and is more cardioselectivethan metoprolol and atenolol. It is 50%lipophilic and metabolized in the liver. The water-soluble,hydrophilic component is excreted by the kidneys. Theconcentration of unchanged bisoprolol in rat brain is lowerthan that of metoprolol or propranolol, but higher thanthat of atenolol after dosing. This agent has a low sideeffect profile. A dosage of 5–10 mg once daily, and amaximum of 15 mg daily is recommended.D. CarvedilolThis noncardioselective agent is a beta-1, beta-2 receptorblocker with very mild alpha-1 vasodilating activity.A recent randomized trial has shown the drug to beeffective in reducing mortality in patients with acutemyocardial infarction with an ejection fraction of lessthan 40%. In a large, randomized trial the drug significantlydecreased mortality and morbidity in patientswith moderate and severe heart failure. Patients are given adosage of 3.125 mg daily for heart failure, titrated slowlyover weeks to 12.5–25 mg twice daily. For hypertensionthe dosage is 12.5 mg then 25 mg, if necessary, with amaximum of 50 mg daily.E. MetoprololThis beta-1 cardioselective agent has been used extensively.It is commonly used in the management of angina,hypertension, and heart failure; clinical trials have shownthe drug to be effective in reducing morbidity andmortality in patients with a moderate degree of heartfailure. Metoprolol is commonly prescribed to reduce therapid heart rate in patients with atrial fibrillation, butother beta-blockers have similar effects.F. NebivololNebivolol is a new, highly selective beta-1 receptorantagonist with antioxidant properties that has beenshown to cause vasodilatation in humans. This agentreverses endothelial dysfunction in hypertensive patients.It appears that the drug causes vasodilatation through anendothelial beta-2-adrenergic receptor mediated nitricoxide production. Nitric oxide formed in arteries causessalutary vasodilatation. The vascular release of superoxideis increased in atherosclerotic arteries and oxygen caninactivate nitric oxide; oxidative inactivation of nitricoxide is a cause of endothelial dysfunction. Cominaciniet al. has shown that nebivolol increases nitric oxide by alsodecreasing its oxidative inactivation.G. OthersOther agents include the well known propranolol, but itsefficacy is questionable and should become obsolete for the

IX. INDIVIDUAL BETA-BLOCKERS167management of hypertension, angina, and followingmyocardial infarction, because the other agents describedabove cause less adverse effects. Sotalol is indicated mainlyfor the management of some patients with paroxysmalatrial fibrillation to maintain sinus rhythm (see the chapterAtrial Fibrillation).BIBLIOGRAPHYAbald, B., Bjorkman, J. A., Edstrom, T. et al. The role of central nervoussystem beta-adrenoreceptors in the prevention of ventricular fibrillationthrough augmentation of cardiac vagal tone (abstract).J. Am. Coll. Cardiol., 17:165A, 1991.Bakris, G. L., Fonseca, V., Katholi, R. E. et al. Metabolic effects ofcarvedilol versus metoprolol in patients with type 2 diabetes mellitusand hypertension. A randomized controlled trial for the GEMINIInvestigators. JAMA, 292:2227–2236, 2004.Billinger, M., Seiler, C., Fleisch, M. et al. Do beta-adrenergic blockingagents increase coronary flow reserve? J. Am. Coll. Cardiol.,38:1866–1871, 2001.Carlberg, B., Samuelsso, O., Lindholm, L. H. et al. Atenolol in hypertension:Is it a wise choice? Lancet, 364:1684–89, 2004.CAPRICORN investigators: Effect of carvedilol on outcome aftermyocardial infarction in patients and with left ventricular dysfunction.Lancet, 357:138, 2001.CIBIS-II: The cardiac insufficiency bisoprolol study II. A randomizedtrial. Lancet, 353:9–13, 1999.COMET: Comparison of carvedilol and metoprolol on clinical outcomesin patients with chronic heart failure in the carvedilol or metoprololEuropean trial (COMET). A randomized controlled trial. Lancet,362:7–13, 2003.Cominacini, L., Pasini, A. F., Garbin, U. et al. Nebivolol and its4-keto derivative increase nitric oxide in endothelial cells byreducing its oxidative inactivation. J. Am. Coll. Cardiol., 42:1838–1844, 2003.Cruickshank, J. M. Beta-blockers continue to surprise us. Eur. Heart J.,21:355, 2000.Khan, M. Gabriel. Beta-blockers, the cornerstone of cardiac drug therapy.In Cardiac Drug Therapy, sixth edition, W. B. Saunders/Elsevier,Philadelphia, 2003.Marie, P.-Y., Mertes, P. M., Hassan-Sebbag, N. et al. Exercises release ofcardiac natriuretic peptides is markedly enhanced when patients withcoronary artery disease are treated medically by beta blockers. J. Am.Coll. Cardiol., 43:353–359, 2004.McMurray, J., Køber, L., Robertson, M. et al. Antiarrhythmic effect ofcarvedilol after acute myocardial infarction. J. Am. Coll. Cardiol.,45:525–530, 2005.MERIT–HF Study Group. Effect of metoprolol CR/XL in chronic heartfailure. Metoprolol CR/XL randomized trial in congestive heart failure(MERIT–HF). Lancet, 353:2001–2007, 1999.Nemoto, S., Hamawaki, M., DeFreitas, G. et al. Differential effects of theangiotensin-converting enzyme inhibitor lisinopril versus the betaadrenergic receptor blocker atenolol on hemodynamics and leftventricular contractile function in experimental mitral regurgitation.J. Am. Coll. Cardiol., 40:149–54, 2002.Packer, M., Coast, J. S., Fowler, M. B. et al. COPERNICUS: Forthe carvedilol prospective in randomized cumulative survival studygroup. Effect of carvedilol on survival in severe chronic heart failure.N. Engl. J. Med., 344:1651, 2001.Pratt, C. M. et al. Three decades of clinical trials with beta-blockers.JACC, 45:531–532.SOLVD Investigators. Effect of enalapril on survival in patients withreduced ventricular ejection fractions and congestive heart failure.N. Engl. J. Med., 325:293, 1991.

Blood ClotsI. Causes of Blood ClotsII. Nondrug TreatmentIII. Drug Treatment3. Clot-dissolving drugs (thrombolytic agents)4. Agents that prevent clot formation (anticoagulants andantiplatelet drugs).GLOSSARYacute coronary syndrome this syndrome defines patients withacute chest pain caused by myocardial infarction or unstableangina.anticoagulants blood thinners.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma,medical term for heart attack.PCI percutaneous coronary intervention; percutaneous transluminalcoronary angioplasty (PTCA), often involving the useof intracoronary stents.platelets very small disk-like particles that circulate in the bloodalongside red and white blood cells initiating the formationof blood clots; platelets clump and form little plugs calledaggregation, thus causing bleeding to stop.IN 90% OF CASES, THE CAUSE OF A FATAL OR Anonfatal heart attack is a blood clot in a coronary artery(coronary thrombosis). The clot often occurs on thesurface of a plaque of atheroma that is partially obstructingthe lumen of the coronary artery. Patients may have manylarge atheromatous plaques and yet not develop a clot overa 5- to 15-year period. There is no test that can tell uswhen and where a clot will occur. Cholesterol, hypertension,exercise, and cigarette smoking have little to do withthe clotting of blood; therefore, we must look elsewhere.Reduction in fatal and nonfatal heart attacks requiresthe prevention and therapeutic strategies outlined below.1. Prevention of atheroma formation in arteries2. Prevention of erosion or rupture of atheromatousplaques in the coronary arteries and cerebral circulationI. CAUSES OF BLOOD CLOTSBlood clots are believed to occur in the coronary arteriesbecause of platelets that become sticky when they comein contact with the damaged lining of blood vessels, whereatheroma formation has commenced. Platelets interactwith the damaged surfaces, and chemicals that areproduced at the site cause the platelets to clump (plateletaggregation) and form a clot. Chemicals in the body thatcause platelets to clump or sludge include collagen fromthe damaged vessel wall, adrenaline, and a very powerfulplatelet-clumping chemical called thromboxane A2.Platelets are small particles present in the blood andcirculate as elliptical flat disks. They are the body’s firstdefense against excessive bleeding. At the site of bleeding,platelets accumulate and stick together to form a clump toplug the seepage of blood. When the platelets clumptogether, other clotting factors contribute to the finalconversion of a blood protein, fibrinogen, which turns intoa mesh of fibrin strands that traps red cells and additionalplatelets, thus forming a firm clot.Platelets are most sticky when they are newly releasedfrom the bone marrow. This may occur 4–10 days afterany type of surgery; for example, there is a higher incidenceof clots in veins of the legs after surgical operations.The lack of movement of the legs causes a slowing of thecirculation in veins and increases the chances of a clot inthe deep veins of the legs.Mild cooling and chilling of the body without hypothermiacan lead to an increase in the total number andstickiness of platelets and may increase clotting. Thismay influence the incidence of coronary thrombosis inwinter. During stress, or in early morning, adrenaline andother chemicals increase the number and stickiness ofplatelets, which may clump onto an atheromatous plaqueand cause a coronary thrombosis and myocardial infarction169

170BLOOD CLOTS(MI). It is not surprising, therefore, that most fatal heartattacks occur in the early morning hours between 5 and8 a.m. Certain foods, especially high-fat foods, increase thestickiness of platelets and influence other blood-clottingfactors, but to a small extent.Atheromatous plaques produce turbulence and slow theblood flow in the coronary artery. The force of blood andincreases in blood pressure can cause fissures or rupture ofplaques. Platelets stick to these areas on the plaque and canstart clot formation. Prevention of clots will be achieved ifthe formation of atheromatous plaques and their ruptureare prevented. Plaque rupture liberates highly thrombogenicsubstances that rapidly cause clotting and blockageof arteries.Nicotine and carbon monoxide, which are by-productsof cigarette smoking, increase platelet stickiness and maybe important factors. Carbon monoxide from cigarettesmoke and exhaust of motor vehicles increase atheromaformation. Some foods have a high vitamin K content andincrease the concentration of a clotting factor made inthe liver (prothrombin). In addition, fibrinogen, the finalprotein involved in the formation of clots, is manufacturedin the liver; it has been shown that the mean fibrinogenconcentration and viscosity in the blood is increased inpatients who have had heart attacks. Thus, it is importantto recognize that certain foods other than those involved inelevating blood cholesterol may be important in increasingor decreasing clot formation. Some foods have propertiesthat may prevent clot formation, albeit with a modesteffect. (see Section VII in the chapter Cholesterol).II. NONDRUG TREATMENTAs a nondrug treatment, these dietary measures arestrongly advised. Eat less fatty meals, which reducessaturated fat and hydrogenated fat intake. Saturated fatsform LDL (bad) cholesterol in the body. Try to increasethe intake of foods that may prevent blood clotting,particularly onions, garlic, and foods containing alphalinolenicand eicosapentaenoic acids; the latter are derivedfrom fish and cod liver oil. The polyunsaturated acids inthe diet of the fish-eating Japanese and Inuit preventclumping of platelets and have favorable effects on theblood-clotting system. These foods decrease platelet clumpingas well as increase vessel wall prostacyclin (prostaglandin),a compound that helps to keep the lining of theartery clean. Try to increase your consumption of fish, forexample, mackerel and salmon, which have a high contentof the polyunsaturated fatty acids. Linolenic acid has beenproven valuable in the prevention of plaque (see SectionVII in the chapter Cholesterol).Avoid or sparingly use alfalfa, turnip greens, andbroccoli, which are very high in vitamin K, and lettuce,cabbage, and spinach, which have a moderate content ofvitamin K. The concentration of prothrombin, a bloodclottingfactor, can be increased by foods containing highamounts of vitamin K. If the anticoagulants warfarin orCoumadin are prescribed, use these foods in moderation,for example, the same quantities four days weekly ratherthan two days of heavy consumption. It is more difficult tothin the blood and more frequent blood tests may benecessary if these foods are not used in moderation.III. DRUG TREATMENTA. Thrombolytic AgentsRentrop reported successful recanalization of coronarythrombotic occlusion with intracoronary infusion of streptokinasein patients. Streptokinase was the first thrombolyticagent employed, and its usefulness was firstdocumented in the Italian trial of intravenous streptokinase(GISSI). This drug remains in use today because it isthe least expensive of the available thrombolytic agents andhas a low risk for intracranial hemorrhage compared withother agents that are modestly better in dissolving clots.The internationally run British trial, the InternationalStudy of Infarct Survival (ISIS–2), showed that anintravenous infusion of 1.5 million units of streptokinaseadministered over 1 h is not particularly expensive ortroublesome to give routinely, and it provides significantreduction in mortality and morbidity in patients seenwithin 3 hof onset of chest pain. Most important, intravenousor subcutaneous heparin is not necessary whenstreptokinase is used; this reduces the risk for intracranialhemorrhage.The American run international trial, Global Utilizationof Streptokinase and t-PA for Occluded Coronary Arteries(GUSTO), demonstrated a modest 14% mortality reductionover streptokinase. Despite an increased risk ofintracranial hemorrhage and the cumbersome use ofintravenous heparin for several days, t-PA was establishedas the thrombolytic drug of choice for the managementof acute MI and gained widespread acceptance in theUnited States. Steptokinase continued to be the main agentused in the UK, Europe, and developing countries witht-PA used for selected cases and for patients allergic tostreptokinase.

III. DRUG TREATMENT171The ASSENT–2 study compared single bolus tenecteplasewith front-loaded t-PA. At 30 days mortality rateswere almost identical, but in patients treated after 4 h themortality rate was 7% with tenectaplase and 9.2% witht-PA. Additionally, tenectaplase is given as a bolus versusintravenous infusions for t-PA, thus, tenectaplase hasreplaced t-PA as the agent of choice. Intracranial hemorrhagein patients over age 75 remains a problem with theuse of these powerful thrombolytic agents. The risk islower with streptokinase. It has been established that it isnot the selection of thrombolytic agent that matters, butthe time the agent is used. It is more important to give anythrombolytic agent up to 3 hof symptom onset. There aresome life-saving properties from 4 to 6 h, and between 6and 12 hours there is a modest reduction in mortalityrate that must be weighed against the risk of intracranialhemorrhage, particularly in patients over age 75.In hospitals worldwide when a patient is admittedwith a heart attack within 3 h of onset of chest pain, thedoctor will inject a thrombolytic drug. Depending onavailability and costs, tenecteplase, streptokinase, t-PA, orreteplase are used because they have all been shown in largerandomized controlled trials to be effective in dissolvingfreshly formed clots. When a clot prevents blood fromreaching part of the heart muscle, this area of the heartmuscle dies within an hour. Patients must get to a hospitalas quickly as possible within a half hour of chest pain. After6 h, dissolving the clot may not help. To prevent MI, it isnecessary to prevent the clot from forming in the firstplace.In patients presenting within 4 h of symptom onset,speed of reperfusion is important. In more than 6% ofpatients admitted to U. S. hospitals, the door-to-needletime is in excess of 30 minutes, which is still inexcusablyhigh. The door-to-needle time should be kept to less than15 minutes.B. Antiplatelet AgentsAntiplatelet agents include aspirin; clopidogrel, which hasreplaced ticlopidine; dipyridamole; and the newer agents,platelet glycoprotein receptor blockers. These drugs preventplatelet clumping (aggregation). They are not anticoagulantsand do not cause spontaneous bleeding.1. AspirinSupplied: Aspirin blocks an enzyme (cyclooxygenase)within the blood platelets and prevents the formation ofthromboxane A2, which causes clumping of platelets.A dose of aspirin as low as 80 mg daily, a quarter of anordinary aspirin, is capable of blocking the formation ofthromboxane A2. A dose of 325 mg (one ordinary aspirin)stops platelet clumping for 2–5 days. Clinical trials haveconfirmed that a small dose of aspirin, 160–325 mg dailysoon after a heart attack, can prevent heart attacks anddeath.Dosage: For coronary artery disease or those at risk,a 325-mg coated or 80- to –81-mg aspirin daily is recommended.This therapy provides modest protection fromcoronary thrombosis. More important is that patients taketwo or three chewable aspirin (80 to 81 mg) immediatelyat the onset of chest pain, because this may prevent a heartattack or death in up to 20% of patients. This strategy ismore important than the use of nitroglycerin under thetongue, which does not prevent a fatal or nonfatal heartattack (see the chapter Aspirin for Heart Disease).2. DipyridamoleSupplied: Tablets 50 mg, 75 mg.Dosage: 50 to 75 mg three times daily one hour beforemeals.This drug is not beneficial when used alone, but incombination with aspirin it has been shown to reduce theincidence of clotting of coronary artery bypass grafts(CABG). In animal experiments, dipyridamole has beenshown to be effective in preventing platelet clumping. Ratsstressed with electric shocks developed platelet clumpingin the coronary arteries, which produced small areas ofdamage to the heart muscle (MIs). This damage can beprevented in more than 80% of animals when pretreatedwith dipyridamole. The combination of aspirin and sulfinpyrazonehas similar benefits.During the 1970s a clinical trial called the Paris-1 Studyevaluated the usefulness of dipyridamole combined withaspirin in about 2000 patients who had heart attacks. Thisstudy, unfortunately, included patients with old and veryold heart attacks, ranging from six months to three years.Only patients with less than a six-month-old heart attackshowed a significant reduction in death rate; this is notacceptable scientific evidence.The combination of dipyridamole and aspirin wasreevaluated in a clinical trial that ran from 1980 to 1984.Three thousand patients were treated within 30 days oftheir heart attacks and followed for 2 years. Thiscombination was not of value in preventing deaths dueto heart attacks, but it caused a 37% reduction in therecurrence of heart attacks. The combination of aspirinand dipyridamole prevents formation of blood clots in vein

172BLOOD CLOTSgrafts of patients who have had CABG. Recent trialshave shown that 325 mg of aspirin is as good as thecombination of aspirin and dipyridamole. Dipyridamole isnot effective when used without aspirin.Dipyridamole combined with aspirin (Aggrenox), hasbeen shown to provide beneficial effects for secondaryprevention after stroke. Dipyridamole should be added toaspirin if transient ischemic attacks (TIAs) occur duringaspirin therapy. A randomized controlled trial indicatedthat a slow-release dipyridamole formulation of 200 mgplus aspirin 50 mg twice daily resulted in a highly significantreduction in the occurrence of stroke (P ¼ 0.001).The reduction for aspirin and dipyridamole for strokewas 37% versus 15% for dipyridamole alone and 18% foraspirin alone. Presently, the combination of aspirin anddipyridamole or clopidogrel appears to be the most effectiveand safest therapy for secondary prevention of stroke.3. ClopidogrelThe drug action of clopidogrel is similar to ticlopidine, butwith fewer adverse effects.Dosage: 75 mg once daily.Clopidogrel has been well tested in large randomizedclinical trials such as CAPRIE, CURE, and CREDO. It isindicated for the reduction of cardiovascular events such asTIAs, stroke, MI, and vascular death. The CREDO trialshowed that clopidogrel 300 mg administered from 6 to24 h before percutaneous coronary intervention (PCI)caused a significant reduction in the risk of death, MI, orstroke.4. TiclopidineTiclopidine inhibits platelet clumping and can decrease thefrequency of chest pain as well as correct abnormal ECGchanges in patients with attacks of angina due to coronaryheart disease. Studies implicate platelets as a majorculprit in the causation of complications of coronaryheart disease, including fatal or nonfatal heart attacks orangina. Ticlopidine was used in patients to prevent strokeif aspirin was not tolerated, but because of damage to whiteblood cells and serious platelet abnormality, the drug isnow obsolete and replaced by clopidogrel.5. Platelet Glycoprotein IIb/IIa Receptor BlockersThere are numerous glycoprotein receptors on the surfaceof each of platelet (> 75,000). Antagonism of thesereceptors blocks the final common pathways of activation-bindingof fibrinogen to the platelet glycoproteinreceptors. This action prevents the platelet aggregationcaused by thrombin, thromboxane A2, ADP, and collagen.These agents administered intravenously and by infusionprevent mortality and morbidity in patients withacute coronary syndromes who are undergoing PCI.They cause significant bleeding, however (see the chapterAntiplatelet Agents). Oral agents have a systemic effect andare generally counteracted only with hemodialysis. Thisis a major defect of new oral agents that so far have notshown beneficial effects.C. Oral Anticoagulants (Warfarin, Coumadin)1. IndicationsAnticoagulants are not significantly effective in preventinga first or recurrent heart attack. They were used for thispurpose from 1955 and abandoned in 1968. A recent trialhas shown some beneficial effects, and they are usedsuccessfully for the treatment of clots in veins, particularlythrombi in the lower limbs (see the chapter Deep VeinThrombosis). Anticoagulants are also used to treat clots inthe lungs (pulmonary embolism) and the heart chambers(atrium or ventricle) preventing such clots from movingfrom the heart and blocking an artery elsewhere in thebody such as in the legs or brain. Warfarin is commonlyused for the prevention of stroke in patients with atrialfibrillation.2. ActionsWarfarin, a 4-hydroxy coumarin compound, is the agentmost widely used in the North America because of itspredictable onset, duration of action, and excellentbioavailability. Warfarin is rapidly absorbed and reachesmaximum plasma concentrations in about 90 minutes.It has a half-life of 36–42 h and circulates bound to plasmaproteins with accumulation in microsomes of the liver.Warfarin and other anticoagulants induce their anticoagulanteffect by interfering with the cyclic interconversionof vitamin K and its 2, 3 epoxide, vitamin K epoxide.The posttranslation carboxylation of glutamate residueson the N-terminal regions of vitamin-K-dependent proteinsto y-carboxyglutamates is induced by the essentialcofactor vitamin K. A decrease in vitamin KH2 limits they-carboxylation of the vitamin-K-dependent coagulantproteins (prothrombin, factor VII, IX, and X) andanticoagulant proteins (protein C and protein S). It alsoimpairs their biologic function in blood coagulation.Inherited resistance to warfarin anticoagulation has beendescribed in humans, albeit rarely.

III. DRUG TREATMENT1733. InteractionsPatients on long-term warfarin therapy are sensitive tofluctuating levels of dietary vitamin K found in the greenvegetables and nutritional fluid supplements that are richin vitamin K. These reduce anticoagulant effects. Drugsthat interact with warfarin are numerous and some arelisted in Table 1. Drugs may influence the pharmacokineticsof warfarin by altering its metabolic clearanceor its rate of absorption. They may further influencewarfarin activity by inhibiting the synthesis of vitamin-K-dependent coagulation factors or increasing theirmetabolic clearance.4. DosageA dose of warfarin 5 mg daily usually achieves adequateanticoagulant effect in 5 days. If more rapid anticoagulationis required a first dose of 10 mg followed by5 mg daily until the INR is in the therapeutic range isrecommended. It is desirable to administer the drug atnight so that dosage changes can be made by a physicianduring the early or late afternoon following a morningblood test.The anticoagulant effect of warfarin occurs within 24 hbecause of the inhibition of factor VII, which has a half-lifeof about 7 h; peak activity is delayed for about 84 hbecause of the longer half-lives of factors II, IX, and X. It isimportant to recognize, however, that reduction of anticoagulantactivity may be counteracted by the thrombogeniceffect of reduced protein C activity during the first48 hof warfarin activity. Therefore, in patients administeredheparin intravenously warfarin therapy should overlapfor at least two days until the INR is within the desiredrange. A dose of 10 mg each night for two nights wasoriginally advocated, but rare gangrene of the limbs hasbeen noted.Adjustment of dosage was originally regulated by thedetermination of the prothrombin time. This was replacedby the INR more than a decade ago. The INR is maintainedat 2–3 for most cases of thrombosis. Bleeding due tooral anticoagulant activity is reversed by vitamin K1.D. Heparin1. Unfractionated HeparinHeparin is a glycosaminoglycan composed of chains ofalternating residues of D-glucosamine and uronic acid.Heparin has a molecular weight of 15,000 with approximately50 monosaccharide chains.This well known intravenous anticoagulant has beenused worldwide for many years and has now been partiallyreplaced by low molecular weight heparin (LMWH) givensubcutaneously. These new preparations have shown to beas effective as unfractionated intravenous heparin. Theysubstantially reduce hospitalization costs because patientsare able to administer these agents subcutaneously at homeand avoid hospitalization.The anticoagulant activity of heparin requires a cofactor,antithrombin III. A pentasaccharide sequence randomlydistributed along one-third of the heparin chains mediatesthe interaction between heparin and antithrombin.The heparin antithrombin complex inactivates thrombinand thus prevents thrombin-induced activation of factorsV and VII.The dosage recommended is IV heparin 5000 to10,000 U (100 U/kg) bolus then a continuous infusionof 12–25 U/kg for pulmonary embolism or deep veinthrombosis. For MI, a lower dose is recommended of60 U/kg bolus and infusion, 12 U/kg to maintain a PTTof 50–70 seconds.The main complication of heparin therapy is hemorrhage,but between 5 and 10 days of heparin therapyheparin-induced thrombocytopenia may develop. Whenadministered for more than one month, heparin may causeosteoporosis.2. Low Molecular Weight HeparinLMWHs are fragments of unfractionated heparin producedby chemical or enzymatic depolymerization processesthat yield glycosaminoglycan chains with a meanmolecular mass of approximately 5000. Because binding toendothelial cells and to plasma proteins is chain-lengthdependent with longer heparin chains having greateraffinity than shorter chains, LMWHs have a much longerhalf-life than IV heparin. The absence of protein bindingin the LMWHs contributes to the excellent bioavailabilityversus IV heparin. They also have a more predictableanticoagulant response when administered in fixed doses.Beneficial effects of LMWHs on mortality and morbidityin patients with acute coronary syndrome are equal to thatof unfractionated heparin.Dosage: Enoxaparin 1 mg/kg subcutaneously every 12h or 1.5 mg/kg once a day. Dalteparin 120 IU/kg subcutaneously(but not more than 10,000 IU) every 12 h.LMWHs should be avoided in patients with significantrenal dysfunction (serum creatinine > 2 mg/dl),176 mmol/1, because these drugs are excreted by the kidney.3. Direct Thrombin InhibitorsThese include bivalirudin, hirudin, argatroban, and anoral agent ximelagatran. These agents bind thrombin

174BLOOD CLOTSand block its interaction with substrates, thus preventingfibrin formation, thrombin-mediated activation ofclotting factors, and thrombin-induced platelet aggregation.These agents have distinct advantages over heparin:they produce a more predictable anticoagulant effectbecause they do not bind to plasma proteins, they arenot neutralized by platelet factor IV, and they inactivatefibrin-bound thrombin in addition to the fluid phase ofthrombin.Hirudin is a naturally occurring specific thrombininhibitor. It is a 65-amino-acid polypeptide that wasisolated from the saliva of the leech Hirudo medicinalismore than 30 years ago. Recombinant techniques haveprovided the agent for clinical use.The GUSTO IIb trial indicated that a combination ofhydrogen and streptokinase is a promising alternative tot-PA with heparin. Death or reinfarction occurred in 8.6%of patients treated with hirudin versus 14.4% of patientstreated with heparin (P ¼ 0.004). Hirudin is eliminatedby the kidneys and should not be used in patients withimpairment of renal function.Bivalirudin had beneficial effects that were similar ormodestly better than heparin in small clinical trials inpatients with acute coronary syndrome and those undergoingPCI, but superiority over heparin needs to be testedin large randomized trials. This agent binds reversibly tothrombin, which may explain the lower adverse effectscompared with hirudin and heparin.The plasma half-life of intravenous administration ofbivalirudin is 24 minutes. This short half-life is anadvantage over hirudin. Also, the drug is only partiallyexcreted by the kidneys, and this allows a greater measureof safety. In a randomized clinical trial in patientsundergoing PCI, bivalirudin reduced the risk of deathor MI 30% at 50 days with 60% reduction in majorbleeding.Ximelagatran is the first in a new class of oral directthrombin inhibitors under investigation for prevention andtreatment of thromboembolic events. After oral administrationthe drug is rapidly metabolized to its active form,melagatran, a direct thrombin inhibitor of soluble andfibrin bound thrombin.In the ESTEEM trial, a placebo-controlled, doubleblindrandomized multinational study of 1883 patientswith acute ST segment elevation or non-ST segmentelevation MI was undertaken. The drug significantlyreduced the risk for the primary end point (all-causedeath, nonfatal infarction, and severe recurrent ischemia)compared with placebo from 16.2% to 12.7%, p ¼ 0.036.All patients received aspirin. No serious clinical adverseoutcomes were observed but mild elevation of liverenzymes occurred rarely with ximelagatran administration.In the SPORTIF III trial alanine aminotransferaseelevations reached greater than five times the upper limitof normal in 3.4% of patients, and caution is required.Patients should be carefully monitored for hepatotoxicitywhich limits general application of this drug. Similaracting agents should be sought (see chapter AtrialFibrillation).BIBLIOGRAPHYAbrams, J., Frishman, W. H., Bates, S. M. et al. Pharmacologic optionsfor treatment of ischemic disease. In Cardiovascular Therapeutics,second edition. E. M. Antman, ed. W. B. Saunders, Philadelphia,2002.Becker, R. C. Novel constructs for thrombin inhibition. Am. Heart J.,149:S61–S72, 2005.ESTEEM: Wallentin, L., Wilcox, R. G., Weaver, W. D. et al. For theESTEEM Investigators. Oral ximelagatran for secondary prophylaxisafter myocardial infarction: The ESTEEM randomized controlledtrial. Lancet, 362:789–97, 2003.Executive Steering Committee on the Behalf of the SPORTIF IIIInvestigators. Stroke prevention with oral direct thrombin inhibitorximelagatran compared with warfarin in patients with non-valvularatrial fibrillation (SPORTIFF III): Randomized controlled trial.Lancet, 362:1691–1698, 2003.Halperin, J. L. Ximelagatran: Oral direct thrombin inhibition asanticoagulant therapy in atrial fibrillation. J. Am. Coll. Cardiol.,45:1–9, 2005.Hirsh, J., Warkentin, T. E., Raschke, R. et al. Heparin and low molecularweight heparin: Mechanisms of action, pharmacokinetics, dosingconsiderations monitoring, efficacy and safety. Chest, 114:489S–506S,1998.Rentrop, K. P., Blanke, H., Karsch, K. R. et al. Subjective intracoronarythrombolysis in acute myocardial infarction and unstable anginapectoris. Circulation, 63:307, 1981.Steinhubl, S. R., Berger, P. B., Mann, J. T. et al. Early and sustained dualoral antiplatelet therapy following percutaneous coronary intervention.JAMA, 288:2411–20, 2002.Topol, E. J. Aspirin with bypass surgery-from taboo to new standard ofcare. N. Engl. J. Med., 347:1359, 2002.

Blood PressureI. Historical ReviewII. Systolic and Diastolic Blood PressureIII. ClassificationIV. Normal Fluctuations in Blood PressureV. Finger Cuff Method of PenazVI. Technique and Pitfalls of MeasurementVII. Effects of High Blood PressureGLOSSARYaneurysm a severe weakening of the wall of an artery or heartmuscle leading to ballooning of the wall of the vessel or heartchamber.arrhythmia general term for irregularity or rapidity of theheartbeat, an abnormal heart rhythm.arteriosclerosis loss of elasticity and hardening of the artery dueto several causes, particularly age change and deposits ofcalcium; an artery with pipe-like rigidity.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack.THE HEART PUMPS BLOOD DIRECTLY INTOblood vessels called arteries, which are like a series ofpipes. The narrower the artery, the greater the resistance orimpedance to the flow of blood; therefore, the heart mustpump with greater force. The amount of force the blood ispumped from the heart through the arteries is the bloodpressure.I. HISTORICAL REVIEWA. The Beginning of SphygmomanometryReverend Stephen Hales is the father of sphygmomanometry.During his seven-year course in theology at CorpusChristi (Bene’t College), Cambridge in 1733, mathematicsand science were added to basic theology and philosophy.It was at Cambridge where he initially experimented onpressure, resistance, and flow. He later became curate ofTeddington outside of London, received his BA, and wasawarded an MA at Cambridge and Bachelor of Divinityfrom Oxford.Some years later he commenced his experimental scientificwork on the circulation of blood. He conductedmore than 25 experiments on dogs and horses. Figure 1 isan artist’s impression of Hale’s experiments to determinethe blood pressure of a horse. His observations were publishedin Volume II of the Statical Essays in 1733:...in the summer I caused the mare to be tied downalive on her back; having laid open the left crural arteryabout three inches from her belly, I inserted into it abrass pipe whose bore was one sixth of an inch indiameter.... I fixed a glass tube of nearly the samediameter which was 9 feet in length: then untying theligature of the artery, the blood rose in the tube 8 feet 3inches perpendicular above the level of the left ventricleof the heart;... when it was at its full height it wouldrise and fall at and after each pulse 2, 3, or 4inches ....’’Figure 2 is a page from Haemastatics showing hismeasurement for correlating blood volume with the bloodpressure. After this, it appears that there were no advancesfor the next 100 years.B. Further AdvancesPoiseuille was a physician and a physicist who introducedthe mercury manometer to the world in 1833. He won thegold medal of the Royal Academy of Medicine for hisdoctoral designation of the management of arterial bloodpressure by means of the mercury manometer connectedto a cannula that was inserted directly into an artery.Around 1881 Samuel von Basch further advanced bloodpressure measurements with the use of an inflatable175

176BLOOD PRESSUREFIGURE 1 Rev. Stephen Hales and an assistant measuring the blood pressure in a horse. (From the National Library of Medicine. Literary source,Medical Times, 1944. Courtesy of National Library of Medicine.)

I. HISTORICAL REVIEW177FIGURE 3 A later sphygmomanometer by Von Basch (1883). (Photosource, National Library of Medicine. Literary source, Basch, S.S.R., von(1883). Ein-Metall-sphygmomanometer. Wien. Med. Woch., 33(22), 674.Courtesy of National Library of Medicine.)FIGURE 2 A page from Hale’s ‘Haemastatics’. (From the NationalLibrary of Medicine. Literary source, Original. Courtesy of NationalLibrary of Medicine.)rubber bag with water (see Fig. 3). In 1889, Potain substitutedair for water and used a rubber bulb for compressionof the pulse. He recorded the pressure with aportable aneroid manometer, but the measurements wereunreliable.C. Advancements Leading to CurrentMethodsScipione Riva-Rocci, in 1896, reported a noninvasivemethod of obtaining blood pressure that led to our currenttechnique (see Fig. 4). He reported the appearanceof definite and pronounced oscillations in the columnof mercury which coincided with the appearance of theradial pulse. This was taken as the systolic pressure. TheFIGURE 4 Riva-Rocci’s sphygmomanometer. (Photo source,University of Central Florida. Literary source, Burch, G. and DePasquale,N. (1962). Primer of Clinical Measurements of Blood Pressure, Fig. 14, p.29, St. Louis: C.V. Mosby. With permission.)diastolic pressure was recorded when the level of themercury column changed from large to small oscillations.A major defect in Riva-Rocci’s technique was the use ofa narrow 5-cm arm band. German pathologist FriedrichVon Recklinghausen later corrected this defect by introducinga 12-cm wide arm band in 1901.By 1905, Nicolai Korotkoff further advanced Riva-Rocci’s ideas. In 1898 Korotkoff obtained his medicaldegree from the University of Moscow and pursueda career in vascular surgery. As a surgeon, he often useda stethoscope to differentiate between a solid mass andarterial aneurysm. He was therefore concerned with soundsmade by arteries.

178BLOOD PRESSUREHis main conclusions were derived from the simpleobservation that a perfectly constricted artery undernormal conditions does not emit any sounds. Thus, heproposed the sound method for measuring blood pressureon humans. He used the Riva-Rocci sleeve on the middlethird of the arm. At first he observed no sounds, but as themercury in the manometer dropped to a certain heightthe first short faint tones appeared. He called these tonesthe maximum blood pressure. When all sounds disappeared,the manometer reading reflected the minimumblood pressure. The accuracy of Korotkoff’s ‘‘soundmethod’’ has stood the test of time. It is presently usedworldwide with acceptable clinical accuracy; nothing haschanged except for a varied cuff size relative to the armwidth.II. SYSTOLIC AND DIASTOLICBLOOD PRESSUREEveryone has a blood pressure, but what does that mean?The pressure in the arteries when the heart contracts(systole) is called systolic blood pressure. This is usuallyless than 140 millimeters of mercury (mmHg). Thepressure in the arteries when the heart is relaxed (diastole)is called diastolic pressure, and this is usually less than90 mmHg in adults.Here is another way of looking at blood pressure. Eachcontraction of the heart causes blood to be pushed(propelled) through the arteries in the form of a pulsewave; thus the flow of blood in the arteries is pulsatile.A wave must have a crest and a trough. The crest is causedwhen the heart contracts (systole) and is the highestpressure. Systolic blood pressure coincides with the firstKorotkoff sounds heard with the stethoscope over thebrachial artery at the cubital fossa just below the level ofthe inflated cuff on the arm. The trough is caused whenthe heart relaxes (diastole), producing the lowest pressure,or diastolic pressure at which instant all Korotkoff soundsdisappear, and no sounds are heard with the stethoscope.Resistance in the arteries against which the heart mustpump is called the total vascular resistance. If the totalvascular resistance increases, blood pressure increases. Thisvascular resistance is increased when the arteries areconstricted by disease, aging, drugs, or naturally occurringchemicals in the body such as adrenaline and noradrenaline.Sudden alarming stress, fright, and situations thatprovoke sudden anxiety may cause secretion of excessadrenaline and noradrenaline, which causes sudden andconsiderable elevation in systolic blood pressure. In thesesituations the systolic blood pressure, which may have been135 mmHg, may shoot up suddenly, and within minutesbe 175–200 mmHg.The amount of blood expelled by the heart into thearteries in one minute is called the cardiac output and isabout 5 L/minute. Blood pressure is equal to the totalvascular resistance multiplied by the cardiac output.Hypertension is the medical term for high blood pressureand has nothing to do with excessive nervous tension.High blood pressure in individuals older than age 18is defined as a systolic blood pressure of greater than140 mmHg and/or a diastolic blood pressure of greaterthan 90 mmHg based on the average of two or morereadings taken at each of two or more visits after an initialscreening (average of at least four readings taken days orweeks apart).III. CLASSIFICATIONThe classification of blood pressure (BP) for adults age18 years and older as given in the Seventh Report of theJoint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure(JNC 7) is as follows: Normal: BP < 120 systolic; diastolic 160; >100IV. NORMAL FLUCTUATIONS INBLOOD PRESSUREA. Marked VariabilityMarked variability in blood pressure is normal. It variesfrom minute to minute and from day to day like the wavesof a sea, fluctuating with the force of the prevailing winds.Blood pressure is different at night, during sleep, and theearly morning, fluctuating considerably during the day.The systolic pressure may differ from 5 to 15 mmHgduring these moments.Ambulatory blood pressure recordings may be needed insome individuals to verify the correct levels of hypertension.The blood pressure readings in a doctor’s office orclinics are often higher than they are in a home setting.Blood pressure readings taken at home are important,but it is necessary to have the pressure recorded outsidethe home in different settings to arrive at conclusivedocumentation that high blood pressure is indeed present.The variability of the blood pressure recorded on repeatedmeasurements, both at a single visit and on separateoccasions at a clinic or physician’s office, is much greaterthan most doctors and patients realize. Individuals are

IV. NORMAL FLUCTUATIONS IN BLOOD PRESSURE179often falsely labeled normotensive or hypertensive. Becauseof the lifelong commitment to antihypertensive medications,the diagnosis must be carefully established, particularlywith borderline hypertension. Because of this markedvariability in recorded blood pressure from day to day,individuals with borderline hypertension may requireobservation for up to two years before a correct diagnosisis made and the commencement of medications.B. Daytime and Nighttime VariabilityDaytime blood pressure is mainly determined by thedegree of physical and mental activity and is under thecontrol of baroreflexes that operate through adjustments inheart rate and peripheral vascular resistance. The usual fallin blood pressure at night is a result of sleep and inactivityrather than the time of day; pressure falls during theday if an individual sleeps. Blood pressure may fall10–20 mmHg during sleep as the baroreflex sensitivitydecreases sympathetic nervous activity.There is a usual abrupt rise in blood pressure withinminutes of arising in the early morning caused bycatecholamine release; it is a critical period that coincideswith an increased incidence of sudden cardiac death,stroke, and myocardial infarction. An increase in catecholaminesincreases blood pressure, which causes increasedstickiness of platelets that may aggregate and predisposethe formation of clots in coronary arteries or arteries thatsupply the brain. The activity of the heart increases as moreoxygen is required to cope with the stimulation caused bythe release of catecholamines.Beta-blocking drugs counteract the deleterious effects ofcatecholamines, and they have been shown in sound,randomized clinical trials to decrease the early morningincidence of sudden deaths and fatal and nonfatal myocardialinfarction. These sudden deaths are not preventedby aspirin or antiplatelet agents. This information is probablyknown to less than 25% of practicing doctorsworldwide.C. White-Coat HypertensionThe definition of white-coat hypertension awaits clarification.The prevalence in a population of untreated hypertensivepatients has been reported to vary from 12% to ashigh as 53%. It is estimated, however, that about 10% ofthese individuals have genuine hypertension; they do notrequire medication and their hypertension should bedefined by blood pressures taken outside the physician’soffice. Home measurements and the use of finger bloodpressure measurements should be used.The acute elevation of blood pressure in the officesetting is presumably a conditional reflex that increasessympathetic nervous arousal each time the blood pressureis taken by the physician. In a study of 292 patients withdiastolic blood pressures ranging from 90 to 104 mmHgduring multiple physician’s visits over a period of6 years, 21% had persistently normal readings during a24-hambulatory recording.White-coat hypertension has been observed in morethan 20% of individuals diagnosed as hypertensive,including elderly patients with systolic hypertension.In one study approximately 50% of patients who werenot believed to be responding to medications based onphysician’s blood pressure readings were shown onambulatory monitoring to have controlled blood pressures.Overuse of medications in this large population ofindividuals is a real problem.D. PseudohypertensionPseudohypertension is a false reading of high blood pressure.It is not unusual for this to occur in patients witharteriolosclerosis, calcification, and diffuse hardening ofthe arteries, particularly in the upper limbs. With hardeningof the arteries, the rigid, pipe-like arteries resistcompression by the sphygmomanometer cuff, and thepressure in the cuff wrapped around the arm fails toconstrict and collapse the brachial artery. Because of this,blood continues to flow through the artery into theforearm causing a false high reading. A reading in the rangeof 180 to 220 is not unusual.Pseudohypertension should be excluded in elderlyindividuals whose brachial arteries characteristically feelrigid and pipe-like and in individuals who have no effectsof hypertension after several years of abnormal readingssuch as evidence of hypertension in the retina or cardiovascularor renal disease. Pseudohypertension may alsobe suspected in these individuals with blood pressureapparently resistant to therapy and in those who developdizziness and lightheadedness related to change in posture.Recordings over a period of weeks in the home, particularlywith a simple finger blood pressure measurement,should resolve the diagnosis of pseudohypertension invirtually all patients. An automatic oscillometric recordermay be required to verify the blood pressures, and rarely,a direct intra-arterial reading may be necessary.E. Home MeasurementsHome measurements of blood pressure are crucial for theadequate management of hypertension in more than 33%

180BLOOD PRESSUREof hypertensives. A record of home measurements verifiedby measurements outside the physician’s office is animportant strategy to prevent overmedication.Measurements in the home have been shown to givevirtually all of the information provided by ambulatoryblood pressure monitoring. The home or ambulatoryreadings have been shown in studies to be comparable,reproducible, and considerably lower than office readings.Home blood pressure measurements are strongly indicatedfor the following:To assist the physician with the diagnosis of borderlineor stage 1 hypertension (see stages given above inSection III)To exclude short term hypertension that may occur fora few months because of stressful situations at work orat home and do not require lifelong medicationsTo exclude white-coat hypertensionTo exclude pseudohypertension in the elderlyTo monitor response to therapy to avoid the additionof another antihypertensive agent to achieve control,thus preventing overmedication for so-called uncontrolledblood pressure in an office settingV. FINGER CUFF METHOD OF PENAZThis method works on the principle of the unloadedarterial wall. Arterial pulsation in a finger is detectedby a photoplethysmograph under a pressure cuff. Theplethysmograph’s output drives a servoloop which changesthe cuff pressure to maintain constant output so that theartery is held in the partially opened state. The pressureoscillations in the cuff are measured and resemble theintra-arterial pressure wave in most individuals tested.Finometer and Portapres recorders are available and areuseful for the diagnosis of pseudohypertension that mayoccur in the elderly who may be overmedicated becauseof the finding of high blood pressure readings obtainedwith the usual cuff method.VI. TECHNIQUE AND PITFALLS OFMEASUREMENTThe cuff size must the appropriate for the blood pressuremeasurement to be accurate. The arm and the mercury oraneroid manometer must be at the same level as the heart.The patient should be seated for about 5 minutes withthe back supported and with the arm supported at heartlevel. If the arm is not supported than readings areapproximately 8 mmHg higher than those taken witharm supported. If the back is not supported, readings maybe as much as 10 mmHg higher because of the isometricexertion needed to support the body and arm.Inflate the bladder quickly to a pressure about20 mmHg above the systolic pressure as recognized bydisappearance of the radial pulse. Inflating the bladder tooslowly may cause errors. Deflate at a rate of 2–4 mmHgper second; a slower rate of deflation may cause false highreadings. If a second blood pressure reading is to be taken,the cuff must be completely emptied of air and the armband removed and reapplied. Many erroneous readings areobtained if proper technique is not stringently applied.VII. EFFECTS OF HIGH BLOOD PRESSUREA moderate degree of hypertension for more than fiveyears causes severe damage to vital organs. Complicationsinclude:1. Hypertrophy or enlargement of the heart2. Heart failure that causes fluid to accumulate in thelungs and the legs manifested by severe shortness ofbreath3. Myocardial infarction4. Atrial fibrillation, a serious arrhythmia which causespalpitations, leads to stroke, and requires a bothersomecommitment to anticoagulation with blood thinners5. Stroke that may be thrombotic or hemorrhagic6. Damage to the kidney that leads to renal dysfunctionand renal failure7. Aortic aneurysm prone to ruptureSee the chapter Hypertension for causes of hypertensionand drug and nondrug treatment.BIBLIOGRAPHYAram, V., Chobanian, M. D., Bakris, G. L., and the National HighBlood Pressure Education Program Coordinating Committee et al.The seventh report of the joint national committee on prevention,detection, evaluation, and treatment of high blood pressure. The JNC7 Report. JAMA, 289:2560–2571, 2003.Clarke-Kennedy, A. E., Stephen Hales, D. D., F.R.S. Br. Med. J., 2:1656,1977.Editorial. Stephen Hales: Father of hemodynamics. Med. Times, 72:315,1944.James, G. D., Pickering, T. G., Yee, L. S. et al. The reproducibilityof average ambulatory, home and clinic pressures. Hypertension,11:545–49, 1988.Julius, S. Home blood pressure monitoring: Advantages and limitations.J. Hypertens., 9 (Supplement 3):S41–S46, 1991.Kaplan, N. M. Measurement of blood pressure. In Clinical Hypertension,Williams & Wilkins, Baltimore, MD, 1994.

VII. EFFECTS OF HIGH BLOOD PRESSURE181Khan, M. Gabriel Hypertension. In Cardiac Drug Therapy,W. B. Saunders, Philadelphia, 2003.Mejia, A. D., Egan, B. M., Schork, N. J. et al. Artifacts in measurementof blood pressure and lack of target organ involvement in theassessment of patients with treatment-resistant hypertension. Ann.Intern. Med., 112:270–77, 1990.Messerli, F. H., White, W. B., and Staessen, J. A. If only cardiologists didproperly measure blood pressure. J. Am. Coll. Cardiol., 40:2201–3,2002.Penaz, J. Photoelectric measurement of blood pressure, volume and flowin the finger. Digest 10th International Conference Med. Biol. Eng.Dresden, Germany. p. 104, 1973.Pickering, T. G. Ambulatory monitoring in the definition of hypertensionJ. Hypertens., 10:401–9, 1992.Pickering, T. G. Blood pressure measurement issues. In Hypertension.S. Oparil and M. A. Weber, eds. W. B. Saunders, Philadelphia, 306,2000.Pickering, T. G., James, G. D., Boddie, C. et al. How common is whitecoat hypertension? JAMA, 259:225–28, 1988.Stewart, M. J., and Padfield, P. L. Blood pressure measurement: Anepitaph for the mercury sphygmomanometer? Clin. Sci., 83:1–12,1992.Zweifler, A. J., and Shahab, S. T. Pseudohypertension: A new assessment.J. Hypertens., 11:1–6, 1993.

Brugada SyndromeI. Clinical FeaturesII. PerspectiveGLOSSARYBrugada P. Brugada described the syndrome and its electrocardiographicchanges.sodium cardiac channels cardiac cells possess channels throughwhich sodium and potassium flow inward and outward; theexchange of positive and negative charge produces a smallcurrent.syncope temporary loss of consciousness caused by lack of bloodsupply to the brain; fainting describes a simple syncopal attack.ventricular fibrillation the heart muscle does not contract butquivers; therefore, there is no heartbeat (cardiac arrest) and noblood is pumped out of the heart; death occurs within minutesif the abnormal heart rhythm is not corrected.PEDRO AND JOSEP BRUGADA DESCRIBED Acardiac condition in 1992 characterized by a typicalECG pattern and a high incidence of sudden death particularlyin younger individuals. The Brugada syndrome is acongenital disorder of sodium cardiac channel function. Itis prevalent in Southeast Asia. Rare deaths have occurredduring sleep sometimes associated with nightmares. Thesyndrome has variety of names in different countries:Bangungut (scream followed by sudden death) in thePhilippines, Lai Tai in Thailand, and Pokkuri (unexpecteddeath at night) in Japan. Apparently in Thailandunexplained sudden cardiac death is the leading cause ofdeath in young men, and approximately 40% of thesepatients have a family history of sudden deaths; anestimated incidence of 1 sudden death per 1000 personsper year. The Brugada VCG phenotype has been estimatedto be up to 1.4% in Japan The typical ECG patternmay be intermittent, and is found in 0.15% of Japaneseadults, which is associated with a greater then 50-foldincrease in the risk of unexpected death; the incidenceis reportedly ninefold higher in Japanese men than inwomen.Although much less common than in south–eastern Asiathis syndrome is not rare in western countries and in NorthAmerica.I. CLINICAL FEATURESSymptoms, particularly syncope and sudden death, usuallyappear between the ages of 40 and 50. These symptomsoccur with no warning. In one study of 163 patients inwhich ventricular fibrillation occurred in 22% percent, thefollowing observations were made: 12:1 male to femaleratio, 58% of Asian origin, and mean age at first abnormalheart rhythm detected was 22–65, but occurred more oftenin the 40–50 age group. Most of these patients had afamily history of syncope, sudden death, or abnormalECG changes.In Brugada syndrome sudden cardiac death is oftenpreceded by several episodes of syncope. Brugada syndromeis believed to cause approximately 30% of all casesof ventricular fibrillation of unknown cause. Remme et al.reported that the vast majority of patients showed noevidence of structural heart disease but the electrical systemhas a minor derangement, probably in the bundle ofHis–Purkinje electrical conducting system that in someindividuals can trigger ventricular fibrillation and death.In these patients the ECG is diagnostic and shows adistinctive type of right bundle branch block. The STsegment is elevated in chest leads V1, V2, and V3 wherethe right bundle branch pattern is usually seen. Figures 1–5show the ECG tracing in a patient with Brugada syndrome.The elevated ST segment has a curious convexcurve or a coved and saddle back shape. The ECG isabnormal but the heart is structurally normal. Antiarrhythmicagents are not effective in preventing ventricular183

184BRUGADA SYNDROMEsyndrome is a disorder of sodium cardiac channel functionthat triggers the electrocardiographic changes andmalignant arrhythmias, particularly ventricular fibrillation.Mutations in a gene responsible for the sodium channelhave been identified in some families with this syndrome.More than three different mutations on the cardiacsodium channel gene SCN5A on chromosome 3 have beendescribed. Mutations on other genes are being sought.Further research is required in this area and its resultsare of extreme importance to prevent deaths in youngindividuals.FIGURE 1 Twelve-lead electrocardiogram (ECG) of a patient withBrugada syndrome. The ECG is characterized by a right bundle branchblock pattern and persistent ST elevation in V 1 through V 3 . (FromBrugada, J., and Brugada, P., (1998). Circulation, 97:457–460.By permission of the American Heart Association, Inc.)fibrillation in these patients and implantation of a cardioverterdefibrillator is advisable to prevent sudden death.II. PERSPECTIVEThe exact mechanism of the electrocardiographic changesand the development of ventricular fibrillation and suddendeath remain undetermined. Electrically active cardiac cellspossess sodium channels; an outward sodium current iscounterbalanced by an inward sodium current. It appearsthat in this syndrome the inward current is attenuatedand some of the electrocardiographic features can be partlyexplained based on changes in sodium currents. TheBIBLIOGRAPHYAntzelevitch, C., Brugada, P., Brugada, J., Brugada, R., Towbin, J. A.,and Nademanee, K. Brugada syndrome: 1992–2002: A historicalperspective. J. Am. Coll. Cardiol., 41:1665–1671, 2003.Antzelevitch, C., Brugada, P., Borggrefe, M. et al. Brugada syndrome:Report of the second consensus conference: Endorsed by the HeartRhythm Society and the European Heart Rhythm Association.Circulation, 111:659–670, 2005.Belhassen, B., Viskin, S., and Antzelevitch, C. The Brugada syndrome:Is ICD the only therapeutic option? Pacing Clin. Electrophysiol.,25:1634–1640, 2002.Brugada, P., and Brugada, J. Right bundle branch block, persistentST-segment elevation and sudden cardiac death: A distinct clinicaland electrocardiographic syndrome. J. Am. Coll. Cardiol., 20:1391–96,1992.Eckardt, L., Probst, V., Smits, J. P. P. et al. Long-term prognosis ofindividuals with right precordial ST-segment-elevation Brugadasyndrome. Circulation, 111:257–263, 2005.Ikeda, T., Sakurada, H., Sakabe, K. et al. Assessment of noninvasivemarkers in identifying patients at risk in the Brugada syndrome:insight into risk stratification. Journal American college cardio 37:1628–34, 2001.Makita, N., Shirai, N., Wang, D. W. et al. Cardiac sodium channeldysfunction in Brugada syndrome is aggravated by beta [1]-subunit.Circulation, 101:54–60, 2000.Matsuo, K., Akahoshi, M., Nakashima, E. et al. The prevalence, incidenceand prognostic value of the Brugada-type electrocardiogram. J. Am.Coll. Cardiol., 38:765–770, 2001.Naccarelli, G. V., and Antzelevitch, C. The Brugada syndrome:Clinical, genetic, cellular and molecular abnormalities. Am. J. Med.,110:573–81, 2001.Remme, C. A., Wever, E. F. D., Wilde, A. A. M. et al. Diagnosisand long-term follow-up of Brugada syndrome in patientswith idiopathic ventricular fibrillation. Eur. Heart J., 22:400–409,2001.

Bundle Branch BlockI. Right Bundle Branch BlockII. Left Bundle Branch BlockGLOSSARYheart failure failure of the heart to the pump sufficient bloodfrom the chambers into the aorta; inadequate supply bloodreaches organs and tissues.hypertrophy increase in thickness of muscle.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot in and atheroma;medical term for a heart attack or coronary thrombosis.sudden cardiac death death from cardiac causes that occursinstantaneously or within the hour of the onset of symptoms;the hallmark features are an instantaneous and unexpectedtime and mode of cardiac death.EACH CONTRACTION OF THE HEART IS PRECEDEDby excitation waves of electrical activity that originate ina unique pacemaker called the sinoatrial (SA) node,which provides individuals with an automatic, infinitesimalcurrent that sets the electrical activity and contractionsof the heart. The electrical discharge from the SA nodepasses across the atrium and reaches the atrioventricular(AV) node, see Fig. 1. From the AV node the current isconducted to the ventricle through two bundles, a largeleft bundle and a thinner right bundle (see the chapterAnatomy of the Heart and Circulation).Many myocardial diseases are associated with bundlebranch block. The prognosis of bundle branch blockreflects the underlying myocardial disease and is thereforevariable. Mass electrocardiographic surveys indicate thatmany apparently healthy individuals have bundle branchblock.I. RIGHT BUNDLE BRANCH BLOCKThe right bundle branch is the continuation of thepenetrating AV bundle and runs as a single discrete bundlebeneath the endocardium of the ventricular septum to thebase of the anterior papillary muscle. The bundle thenruns in the moderator band to form a rich anastomosingnetwork of conducting fibers throughout the rightventricle. The subepicardial location and discrete natureof the bundle branch of the rim of the right ventricularoutflow makes it vulnerable to trauma from catheters.Because of its discrete nature, the bundle is easily damagedby several diseases including focal hypoplasia that causescongenital right bundle branch block, anteroseptal myocardialinfarction that commonly affects the ventricularseptum, and right ventricular hypertrophy associated withdiffuse subendocardial fibrosis.The electrical bundles that take the electrical impulsesto the right ventricle are damaged or do not conduct theimpulse; the electrical impulses fail to reach the rightventricle. Complete right bundle branch block occurswhen there is a complete interruption of conduction tothe right ventricle through the right bundle branch.Diagnosis is made only from the ECG. Figure 2 shows theelectrocardiographic genesis of the QRS complex in rightbundle branch block (RBBB). Figures 3A, and B show anormal ECG compared with one that depicts the featuresof RBBB. Note that the QRS complex is wide and canhave a duration of greater than 120 ms, whereas in anormal tracing the QRS duration is 80–110 ms. Thishappens because it takes more time for the electricalcurrent to be conducted from the AV node through theleft bundle then for the right ventricle to receive thecurrent.A. ECG Criteria for Diagnosis of RightBundle Branch BlockThe ECG criteria necessary for diagnosis include QRSduration greater than 120 ms, M-shaped complex inchest leads V1 and V2, and slurred S wave in lead I andV6 with an amplitude greater than the R wave in lead Iand V6.185

186BUNDLE BRANCH BLOCKB. Causes of Right Bundle Branch Blockand Associations1. In Normal IndividualsRight bundle branch block is a normal finding in adults ofall ages. Many individuals with RBBB have no evidence ofstructural heart disease and isolated RBBB occurs morecommonly than isolated left bundle branch block (LBBB).An incidence of about 2% per 1000 was observed in astudy of 122,000 apparently normal Air Force personneland applicants age 16–55; at age 40–55 the incidence wasabout 3%. The cause all of RBBB in otherwise healthyindividuals remains unclear. It is clear that in individualsage 15–50 with RBBB and no evidence of structural heartdisease the prognosis and the survival time are not muchdifferent from individuals in the general population withoutRBBB. Apparently there is an increased incidence ofRBBB among individuals who live at high altitude.In a follow up of 855 men 50 years or older, the prevalenceof bundle branch block increased from 1% at age50–17% at age 80, with RBBB in 13% and LBBB in about7%. This suggests that the occurrence of bundle branchblock after the age of 45 is caused by slowly progressivedegenerative conduction tissue disease; the long slenderright bundle is vulnerable to processes related to aging.RBBB, therefore, is common and when observed inindividuals with structurally normal hearts it is nonprogressive.This condition does not affect the patient’slifestyle and causes no symptoms. It does not lead to heartattacks or heart failure and requires no treatment. Apacemaker is never required in patients with structurallynormal hearts.2. In Individuals with Coronary Artery DiseaseAcute and chronic coronary artery disease (angina and oldor acute myocardial infarction) are common causes ofRBBB, and reportedly it is the most common perioperativeconduction defect observed after coronary artery bypasssurgery.In patients with acute myocardial infarction, RBBBhas been observed in greater than 10% (3–29%) and iscommonly associated with another conduction block, leftanterior hemiblock. This is associated with an adverseoutcome of a large area of infarction, with an in-hospitalmortality of greater than 20% and one-year mortality ofgreater than 45%.3. Congenital Heart DiseaseRBBB is often associated with an atrial septal defect,ventricular septal defect, Ebstein’s anomaly, and tetralogyof Fallot. A common treatment for RBBB in childrenis open heart surgery to correct tetralogy of Fallot or ventricularseptal defect.4. Valvular and Hypertensive Heart DiseaseValvular lesions that cause right ventricular hypertrophymay cause RBBB. Other causes include:1. Coarctation of the aorta2. Pericarditis3. Myocarditis4. Chagas disease5. Pulmonary embolism6. Cor pulmonale7. Cardiomyopathy8. Brugada syndromeC. Right Bundle Branch Block and theLeft Anterior HemiblockRBBB may be associated with a block of the anteriorbranch of the left bundle. This branch or fascicle is thinand long and has a single blood supply. It is commonlydamaged by ischemic chronic coronary artery disease orduring acute myocardial infarction as outlined above.Fibrosis, Chagas disease, and other pathologic processesmay cause damage to this thin fascicle resulting in a minorblock. This minor block was first described by Rosenbaumas a left anterior hemiblock, but now it is called leftanterior fascicular block.The diagnosis of the left anterior fascicular block ismade when there is left axis deviation, a small Q wave inlead I, and small R wave in lead III (see Fig. 3). Whenpatients develop RBBB and left anterior hemiblock duringacute myocardial infarction some patients require theinsertion of a pacemaker to prevent complete heart block.When RBBB and left anterior hemiblock are observedin patients who have never had a heart attack and havestructurally normal hearts as determined by echocardiography,ECG, and other methods, the prognosis is good.D. Incomplete Right Bundle Branch BlockIn incomplete RBBB, the QRS duration is 90–115 ms,causing other symptoms similar to complete RBBB. It iscommonly associated with atrial septal defect. IncompleteRBBB is a common ECG finding in normal individuals.Straight back syndrome, pectus excavatum, coarctation ofthe aorta, right ventricular volume overload, and musculardystrophy may also be associated with incomplete RBBB.

II. LEFT BUNDLE BRANCH BLOCK187II. LEFT BUNDLE BRANCH BLOCKLeft bundle branch block (LBBB) is common after age60 and is due to a block of the conduction in the bundlethat receives impulses from the atrium and conductsthe electrical current through the left ventricle (Fig. 1). TheECG is typical, and the physician makes the diagnosisonly after looking at the ECG.A. ECG Diagnostic CriteriaIn LBBB the QRS complex is wide and bizarre lookingwith a duration of greater than 120 ms (see Fig. 4). Othercriteria include notched R wave in lead I, aVL, V5, or V6;leads V1 and V2 have small or no R waves; and the STsegment in V1 and V2 is elevated.B. Causes of Left Bundle Branch BlockRBBB is often seen in normal individuals. LBBB, on theother hand, is more often due to subtle diseases of theheart, including coronary artery disease, valvular heartdisease, muscle scars, cardiomyopathies, fibrosis, degenerativedisease (Lev and Lenegre disease), and all causesof left ventricular hypertrophy. Approximately 15% ofpatients with aortic stenosis that causes severe left ventricularhypertrophy exhibit LBBB.Although LBBB is a serious conduction disturbance, theelectrical current gets to the left ventricular myocardiumvia the right ventricular conduction system. This activatesthe left ventricle with a time delay that is observed as anincreased duration of the QRS complex of the ECG.It does not cause disturbance of the heart rate and virtuallynever requires an artificial pacemaker.C. PrognosisIn patients younger than age 50 with LBBB and structurallynormal hearts there is no adverse prognostic significance;these individuals have idiopathic LBBB or earlydevelopment of degenerative disease of the conductionsystem. New LBBB appearing after age 50 requiresinvestigation. In the Framingham study 55 individualsdeveloped new LBBB at about 62 years with cardiovasculardisease manifested in 89%, and 50% died within 10 years.A marker of favorable prognosis is the ECG and echocardiographicabsence of left atrial enlargement, which ifpresent indicates severe left ventricular hypertrophy andsignificant disease. In patients with coronary artery disease,heart failure, hypertension, valvular heart disease, andcardiomyopathy the prognosis depends on the severity ofthe heart disease. In patients with underlying heart disease,greater than 25% are expected to die within 2 years andgreater than 50% die suddenly. The prognosis is poor inindividuals with LBBB who develop myocardial infarctionor those in whom acute infarction causes LBBB. In thesecases thrombolytic therapy or percutaneous coronary interventionis necessary.BIBLIOGRAPHYHiss, R. G., and Lamb, L. E. Electrocardiographic findings in 122,043individuals. Circulation, 25:947, 1962.Khan, M. Gabriel Rapid ECG Interpretation, second edition, W. B.Saunders, Philadelphia, 2003.Schneider, J. P., Thomas, H. E., Kreger, B. E. et al. Newly acquiredleft bundle branch block, the Framingham study. Ann. Int. Med.,90:303. 1979.Surawicz, B., and Knilans, T. K. Chou’s Electrocardiography in ClinicalPractice, W. B. Saunders, Philadelphia, 2001.

Caffeine and the HeartI. BiochemistryII. EffectsGLOSSARYarrhythmia general term for irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiac output the volume of blood pumped by the ventricleper unit time expressed in liters per minute; it is a function ofthe stroke volume multiplied by the heart rate.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.CAFFEINE IS A PSYCHOACTIVE DRUG THAT OCCURSnaturally in many foods and beverages including coffee,tea, chocolate, and cocoa. It has found its way into manycommercial soft drinks because of its proven mildstimulant effect and relative safety when consumed insmall amounts. But caffeine can produce beneficial effectsin one individual and potentially harmful effects inanother. Many pain relievers contain caffeine added toaspirin or acetaminophen to potentiate the effects of theseagents. Levels of caffeine in common beverages and foodsare shown in Table 1 and levels of caffeine in commondrugs are listed in Table 2.Caffeine is the most widely used psychoactive substance.More than 100 billion doses of caffeine are consumedannually in North America. Caffeine occurs naturally inmore than 60 plant species worldwide, and the drinking oftea in China dates back to around 2500 BC.I. BIOCHEMISTRYCaffeine is a xanthine derivative — 1, 3, 7-trimethylxanthine.Other naturally occurring xanthines include thewell-known theophylline (the major constituent in tea)and theobromine. Coffee is a major source of caffeine andTABLE ILevels of Caffeine in Common Beverages and FoodsBeverage/foodServing size(oz)Approximate mgcaffeine/servingCoffeeDrip 5 150Percolated 5 110Instant, regular 5 50–100Instant, flavored mix 5 25–75Decaffeinated coffee 5 1–6Black tea1-min brew 5 10–203-min brew 5 20–355-min brew 5 25–35Instant tea 5 30–60Cocoa beverage 5 2–20Soft drinksJolt 12 70Caffeinated cola drinks 12 30–65Mountain Dew, 12 40–50Mello Yello,Sunkist Orange7-Up, Sprite, RC-100,12 0Fanta Orange,Hires Root BeerChocolateCake1/16 of149-inch cakeIce cream 2/3 cup 5Mr. Goodbar 1.65 6Special dark, Hershey 1.02 23From Blount, J.P., and Cox, W.M. (1997), Caffeine, Encyclopedia ofHuman Biology, Vol. 2, 2nd Ed., San Diego: Academic Press, p. 275.chlorogenic acid and also contains a substantial amountof magnesium and other micronutrients. Caffeine is apowerful central nervous stimulant and moderate dosesof 200 mg contained in two cups of coffee activate thecerebral cortex sufficiently to slow changes in an individual’selectroencephalogram (EEG). Caffeine is also a mildcardiac stimulant.189

190CAFFEINE AND THE HEARTTABLE IILevels of Caffeine in Common DrugsDrugStandardadultdoseII. EFFECTSA. CardiovascularApproximate mgcaffeine/standarddosePrescription painkillersDarvon compound capsule 1 32Cafergot tablet (migraine) 1 100Nonprescription(over-the-counter) painkillersAnacin, Midol, Vanquish 2 65Plain aspirin 2 0Cold/allergy medicineDristan 2 30Coryban-D, Sinarest, 1 30TriaminicinStimulantsNo-Doz 2 200Vivarin 1 200From Blount, J.P., and Cox, W.M. (1997), Caffeine, Encyclopedia ofHuman Biology, Vol. 2, 2nd Ed., San Diego: Academic Press, p. 275.Caffeine has mild and variable effects on the heart rate,the heart muscle, blood pressure, blood flow, and bloodcholesterol.1. Heart RateCaffeine generally increases the heart rate. After ingestionof caffeine a mild decrease in heart rate may be observedwithin the first hour followed by an increase in heart rateduring the following two hours. Chronic caffeine useelevates the resting heart rate and significant reductions inheart rate are observed upon cessation of caffeine intake.Caffeine also stimulates the medullary vagal nerve nucleiand thus causes a mild decrease in heart rate depending onthe dose and time of ingestion.A genuine tachycardia, heart rate greater than 100 beatsper minute, is not often observed. Arrhythmias that cause asensation of palpitations may be precipitated, however, bytwo or three cups of coffee daily in susceptible individuals.Patients with paroxysmal atrial tachycardia, (AV nodalreentrant tachycardia) and those with atrial or ventricularpremature beats may note an increase in the frequency ofthese beats and pronounced increase in heart rates maybe precipitated. In these individuals cessation of caffeineintake is often beneficial. However, the most commonarrhythmia encountered in medical practice, atrial fibrillation,is not adversely affected by caffeine intake (see thechapter Arrhythmias/Palpitations).2. Heart MuscleCaffeine has a direct stimulant effect on the heart muscleand causes an increase in the force of myocardialcontraction (i.e., an inotropic effect). The inotropic effectsare, however, minimal compared to that of digoxin, themild inotropic agent commonly used to treat heart failure.Because of the increase in the force of myocardialcontractility and increase in the heart rate, the cardiacoutput increases slightly. This effect is important inpatients with heart failure in whom two cups of coffeedaily may induce a minimal benefit without harm.3. Blood PressureEffects of caffeine on blood pressure are controversial.Single doses can cause a small increase in blood pressurein users; the increase in blood pressure appears to besomewhat greater in nonusers who occasionally consumecoffee. One or two cups of coffee can increase bloodpressure slightly in habitual users, they have no effect onchronic coffee drinkers. Significant reduction in bloodpressure has been observed in chronic users who abstain,but the methodology in several studies on hypertensionand caffeine use has been questioned. It is not knownwhether caffeine interacts unfavorably with antihypertensivemedications.4. Heart AttacksThe link between caffeine consumption and heart attacksremains controversial. The studies done in 1980 failed toimplicate coffee consumption, but two studies since 1985have shown an apparent link between heavy coffee useand heart attacks. Carefully organized studies with soundmethodology are required to clarify this important issue.5. Blood Flow and Blood VesselsCaffeine dilates systemic blood vessels, small arteries, andarterioles, but it constricts extracranial vessels that arebelieved to aid in the relief of migraine headaches.Cafergot, a drug used for migraines, contains 100 mg ofcaffeine and 1 mg of ergotamine.

II. EFFECTS1916. CholesterolChronic caffeine intake appears partially responsible forincreased blood cholesterol levels. Although this effectis controversial, discontinuing coffee moderately reducestotal blood cholesterol levels less than 7%.B. Diabetes, Coffee, and the HeartMost diabetics succumb to a fatal or nonfatal heart attack,or heart failure (see the chapter Diabetes and CardiovascularDisease). A recent study in The Netherlands hasshown that heavy coffee consumption was associated witha substantially lower risk of clinical type 2 diabetes. It isunfortunate that such a large intake of caffeine is requiredto produce such a beneficial effect.The phenol chlorogenic acid reduces glucose absorptionand oxidative stress in vitro and inhibits hydrolysisof glucose-6-phosphate, which could reduce glucoseoutput in the liver. Coffee contains substantial amountsof magnesium that could improve insulin sensitivity andinsulin secretion and has been associated with a lowerrisk of type 2 diabetes. The epidemic of diabetesworldwide continues and any strategy that can be addedto the armamentarium to prevent diabetes would bewelcome.1. Clinical Study: van Dam et al.van Dam investigated the association between coffee consumptionand risk of clinical type 2 diabetes in 17,111Dutch men and women aged 50–60. During 125,774person-years of follow up, 306 new cases of type 2 diabeteswere reported.After adjustment for potential confounders, individualswho drank at least 7 cups of coffee daily were 0.05 times aslikely as those who drank 2 cups of coffee daily to developtype 2 diabetes ( p ¼ 0.0002). Higher coffee consumptionwas associated with a lower risk of type 2 diabetes.It is known that caffeine acutely lowers insulin sensitivity.In a small intervention study, increased coffeeconsumption for two weeks reduced fasting blood glucose,whereas the substitution of decaffeinated coffee for caffeinatedcoffee for 3 weeks did not affect blood glucose.BIBLIOGRAPHYBlount, J. P., and Cox, W. M. Caffeine. Encyclopedia of Human Biology,Vol. 2, second edition, Academic Press, San Diego, 1997, p. 275.Keijzers, G. B., De Galan, B. E., Tack, C. J. et al. Caffeine can decreaseinsulin sensitivity in humans. Diabetes Care, 25:364–69, 2002.Pincomb, G. A. Acute blood pressure elevations with caffeine in menwith borderline hypertension. Am. J. Cardiol., 77:270–74, 1996.van Dam, R. M., and Feskens, E. J. M. Coffee consumption and riskof type 2 diabetes mellitus. Lancet, 360:1477–78, 2002.

Calcium AntagonistsI. Mechanism of ActionII. Available Calcium AntagonistsIII. Therapeutic BenefitsIV. Next Generation AgentsGLOSSARYangina pectoris short duration, recurrent chest pain or pressureoften accompanied by feelings of suffocation and impendingdoom; most frequently associated with lack of blood andoxygen to the heart muscle.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker ofleft ventricular contractility.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; an inadequate supply of bloodreaches organs and tissues.inotropic an effect that affects the force of muscular contractions;negative inotropic refers to decreased myocardial contractilitythat may lead to poor pumping of blood, reducedejection fraction, and heart failure.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.myocytes single muscle cells.pulmonary edema fluid in the air sacs and alveoli; the lungsbecome congested and severe shortness of breath occurs.I. MECHANISM OF ACTIONCalcium movement into cells is mediated by severalmechanisms. Albrecht Fleckenstein showed that thecalcium channels can be selectively blocked by a classof agents. He called these agents calcium antagonists.Calcium movement into the cells is mediated by severalmechanisms. Calcium antagonists act at the plasmamembrane to inhibit calcium entry into cells by blockingvoltage-dependent calcium channels.Calcium ions play an important role in the contractionof cardiac, skeletal, and smooth muscle. Myoplasmiccalcium depends on calcium entry into the cell. Calciumbinds to the regulatory protein troponin, removing theinhibitory action of tropomyosin. In the presence ofadenosine triphosphate this allows the interaction betweenmyosin and actin with consequent contraction of themuscle cell.There are at least three different types of calciumchannels designated as L, T, and N types. The L-typechannels, once activated, remain for a long period of timeand have a large calcium-carrying capacity. The T channelshave a brief opening time and N channels havecharacteristics that are neither of the L nor T type. Onlythe L-type channels are sensitive to the action of calciumantagonists. The effect of the calcium antagonists is torestrict calcium entry, and over a given period of timefewer calcium ions are available for participation inintracellular events such as muscle contraction and neuronalactivity. Thus some have labeled these compoundscalcium channel blockers, calcium channel antagonists,calcium entry blockers, and slow calcium blockers.Calcium antagonists differ from one another in termsof their potency, tissue selectivity, and duration of action.The calcium antagonists available for clinical use aremainly L-type channel blockers. The T channel appears atmore negative potentials and seems to play a role in theinitial depolarization of the sinus node and atrioventricular(AV) node tissue. Mibefradil, a T channel blocker, causedbradycardia and a host of adverse effects that caused thedrug’s premature withdrawal from the market.The three major calcium antagonists include nifedipine,diltiazem, and verapamil (see Fig. 1 for their structuralformulas). Dihydropyridine, the prototype of whichis nifedipine, appears to act by plugging the calcium193

194CALCIUM ANTAGONISTSTABLE 1Hemodynamic and Electrophysiologic Effects of CalciumAntagonistsNifedipine a Diltiazem VerapamilCoronary dilation þþ þþ þPeripheral dilation þþþþ þþ þþþNegative inotropic þ þþ þþþAV conduction# $ þþþ þþþþHeart rate "$ #$ #$Blood pressure# þþþþ þþ þþþSinus node depression $ þþ þþCardiac output" þþ $ $a Or other dihydropyridines.þ¼minimal effect; þþþþ ¼ maximal effect; $¼ no significantchange; #¼ decrease; "¼ increase.From, Khan, M. G. (2003). Cardiac Therapy, 6 Ed., Philadelphia:W. B. Saunders, p. 3.electrophysiologic effects of calcium antagonists are givenin Table 1.II. AVAILABLE CALCIUM ANTAGONISTSFIGURE 1 Structural formulas of the three calcium antagonist prototypes:verapamil (a phenylalkylamine), nifedipine (a dehydropyridine),and diltiazem (a benzothiazepine). (From Nayler, W.G. (1997). Calciumantagonists, Encyclopedia of Human Biology, Vol. 2, 2 nd Ed., San Diego,Academic Press, p. 295.)channels. These agents cause dilation of coronary arteriesand marked peripheral arteriolar dilatation resulting in aprofound fall in blood pressure. There is little or no actionon the sinoatrial (SA) node and conducting tissue.Verapamil and diltiazem are phenylalkylamines andbenzothiazepines. They cause distortion of calcium channelsand coronary artery dilation, but there are additionaleffects on the SA and AV nodes. These agents also have anegative inotropic effect and decrease myocardial contractility.Thus, the dihydropyridines, phenylalkylamines, andbenzodiazepines have vastly different actions. For example,only amlodipine and felodipine, of the dihydropyridinefamily, have proved relatively safe in patients with leftventricular dysfunction and heart failure. Other agentsmay precipitate heart failure. The hemodynamic andA. DihydropyridinesThese agents cause dilation of arteries throughout thebody including mild dilatation of coronary arteries. Theyalso cause a variable decrease in myocardial contractilitythat may lead to heart failure in susceptible individuals.Dihydropyridines include amlodipine, felodipine, and,nifedipine. They are indicated for the management ofhypertension. They may also be used for the treatmentof stable angina, but only in combination with a betablockingdrug that prevents an increase in heart rate andthe increase in cardiac workload that may be caused bydihydropyridines. The common adverse effects includeedema of the ankles, flushing, headaches, and rarely,hypertrophy of the gums. Other dihydropyridines includeisradipine, nicardipine, nimodipine, nitrendipine, andniludipine.1. Amlodipine (Norvasc)This dihydropyridine has a long half-life of 35–50 h andpeak blood levels are reached after 6–12 h. Amlodipine isan effective antihypertensive agent that is used worldwide.It has a good safety profile but pulmonary edema (heartfailure) may be precipitated in patients with severe leftventricular dysfunction and ejection fraction of less than

II. AVAILABLE CALCIUM ANTAGONISTS19530%. Edema of the ankles, feet, and lower leg may bebothersome in about 10% of treated patients. This drug isoften combined with a beta-blocker in the managementof angina. The dose for angina or hypertension is 5–10 mgonce daily.2. Felodipine (Plendil)This dihydropyridine has actions, effects, and indicationsthat are similar to amlodipine. The dose for hypertensionis 2.5–5 mg daily with a maximum dose of 10 mg.3. Nifedipine (Procardia, Adalat XL)Nifedipine is the first calcium antagonist used in clinicalpractice. It was introduced during the early 1980s for themanagement of hypertension, angina, and particularlycoronary artery spasm (variant angina) and is still usedworldwide. The drug is an excellent antihypertensiveagent. Headache, edema of the ankles, and facial flushingoccur in about 15% of patients. Although introduced forthe management of angina, like other dihydropyridines,the drug should be used only for stable angina in patientswho are also administered a beta-blocker. For the managementof coronary artery spasm (Prinzmetal variantangina), the drug can be used without beta-blockers, whichare contraindicated in this condition.Short-acting capsule or tablet formulations of nifedipineare no longer recommended because an increase inmorbidity and mortality has been reported in patients withcoronary artery disease. The slow-release once dailyformulation is now used worldwide at a dose of 30–60mg once daily. The maximum dose of 90 mg should beused with caution.B. Benzothiazepines1. DiltiazemDiltiazem is a mild arteriolar vasodilator. It is a widely usedcalcium antagonist because its safety profile is good. Theblood pressure lowering effect of this benzothiazepine isnot as powerful as the dihydropyridines, and a large doseis usually required to obtain a satisfactory antihypertensiveeffect. Diltiazem has a milder action than the dihydropyridinesand causes less vasodilatation of arteries; thus itis a week antihypertensive agent. The drug causes somedecrease in myocardial contractility and heart failure maybe precipitated in patients with left ventricular dysfunctionor in patients who are administered a beta-blocking drugconcomitantly.Most important, the drug inhibits electrical conductionthrough the AV node. It is useful for the management ofsupraventricular tachycardias by slowing rapid heart ratesthat may occur with atrial fibrillation.Unfortunately, this drug causes some suppression of thesinus node and normal pacemaker activity and may causebradycardia. It should be avoided in patients with sicksinus syndrome and heart failure. Adverse effects includeincreased liver function tests, increased transaminases, andconstipation, but headache and edema of the ankles are lesscommon than with the dihydropyridines.Important interactions occur with digoxin, and digoxinlevels may be increased by about 33%. Diltiazem combinedwith amiodarone may produce deleterious effectson the sinus pacemaker causing arrest and hypotension.Interactions have been noted with cyclosporine, cimetidine,and carbamazepine.The short-acting tablet formulation of diltiazem is notrecommended. Long-acting and slow-release formulationsare administered 180 mg to a maximum of 300 mg oncedaily.C. Phenylalkylamines1. VerapamilVerapamil is a moderately potent vasodilator. Two majordifferences between the actions of verapamil and thedihydropyridines include a major depressant effect on theAV node and a mild depressant effect on the SA node.Also, depression of myocardial contractility for verapamilis considerably more than the maximum effect observedfor dihydropyridines. This marked negative inotropiceffect may precipitate heart failure in patients with leftventricular dysfunction and an ejection fraction less than40%. Because of this effect, verapamil should not becombined with a beta-blocking agent.The electrophysiologic effect of mild depression ofconduction through the AV node makes the drug effectivein the management of supraventricular tachycardia. Givenintravenously, verapamil was used worldwide for themanagement of this condition from 1984 to 1996 andhas now been relegated to second choice behind adenosine.Verapamil is indicated for the management of hypertensionand for angina, particularly when beta-blockersare contraindicated. It is also used for the managementof coronary artery spasm. The intravenous preparationis indicated for supraventricular tachycardia. Doses of120–240 mg sustained-release, long-acting preparationsare advised once daily.Verapamil is contraindicated in patients with bradycardia( a heart rate of

196CALCIUM ANTAGONISTSsinus and AV nodes. This drug may precipitate heartfailure and is contraindicated in patients with left ventriculardysfunction or an ejection fraction less than 40%.It is also contraindicated in patients with acute myocardialinfarction.Adverse effects include severe constipation that may beparticularly bothersome in the elderly. Interactions occurwhen combined with beta-blockers and may cause severebradycardia, heart block, or heart failure. Caution isnecessary because interactions have been noted with amiodarone,oral anticoagulants, guanidine, and tranquilizers.Other phenylalkylamines include anipamil, ronipamil,devapamil, fendiline, and tiapamil.III. THERAPEUTIC BENEFITSCalcium antagonists are indicated for the conditionsoutlined below. Isolated hypertension without organ damage or coexistingdisease benefits from calcium antagonists. These agents are particularly useful for isolatedhypertension in older people of African origin andusually achieve the blood pressure goal; they have beenshown in randomized clinical trials to be more effectivethan ACE inhibitors, beta-blockers, and diuretics. In younger people of African origin a clinical studyshowed that diltiazem was effective in 64% comparedwith 47% for atenolol and 40% for diuretics. Patients with severe stage II and III hypertensionrequire the combination of several antihypertensiveagents and calcium antagonists are appropriate exceptin patients with left ventricular dysfunction. Calcium antagonists are a critical part of combinationtherapy in hypertensive patients with a variety of underlyingdisorders (comorbidities) in whom blood pressurecontrol at more aggressive goals has been deemedessential but remains elusive. Calcium antagonists are used to treat hypertensionassociated with renal disease or renal failure if ACEinhibitors are contraindicated or poorly effective. Calcium antagonists have shown benefits in hypertensivediabetic patients; the large SYST-EUR and theSystolic Hypertension in China (SYST-China) trialsdemonstrated more than a 50% reduction in totalmortality in the diabetic subgroup. In patients with stable angina the addition of a calciumantagonist, particularly a dihydropyridine or diltiazem,has been shown in clinical trials to cause significantamelioration of recurrent chest pain. In patients with severe aortic regurgitation, theunloading effect of nifedipine has been shown in aclinical trial to cause significant reversal of the leftventricular dilatation and hypertrophy, and surgicaltherapy may be appropriately delayed from 1 to 2years. Patients with cold fingers and Raynaud’s phenomenonmay find some benefit with calcium antagonists. The dihydropyridine nimodipine, in a clinical trial, wasshown to be useful in the management of cerebralarterial spasm caused by subarachnoid hemorrhage withcontrolled blood pressure. Following coronary artery bypass graft using the radialartery as a conduit, dihydropyridine calcium antagonistsare used for an indefinite period to prevent spasmand occlusion of the arterial graft.IV. NEXT GENERATION AGENTSSeveral dihydropyridine calcium antagonists have beenintroduced during the past 25 years. First degenerationdihydropyridines are the naturally short-acting agents thatinclude felodipine, isradipine, nifedipine, and nitrendipine.These rapid-acting vasodilators are powerful antihypertensiveagents, but their fast onset of action results inmarked vasodilation that causes reflex stimulation of thesympathetic nervous system and hemodynamic adverseeffects that include increased heart rate, increased cardiacworkload, and an increased incidence of heart failure inpatients with left ventricular dysfunction. These adverseeffects have become controversial and the short-actingformulations of dihydropyridines such as verapamil anddiltiazem are no longer recommended. They have largelybeen removed from the marketplace.Second generation agents such as verapamil SR,nifedipine XL, felodipine ER, and diltiazem SR and CDwere developed with modified release properties to slowtheir onset of action. Adverse effects are still high, particularlyedema and constipation, and heart failure is precipitated,albeit rarely.Third generation agents include amlodipine. Theseagents have a naturally occurring long plasma half-life(over 24 h) but are washed out from the receptor relativelyfast. Equilibrium is essentially between the plasma proteinbounddrug and the calcium L channel. Amlodipine movesquickly onto the calcium channel to provide a quick onsetof action and thus vasodilatation, which results in modestsympathetic stimulation and unwanted mild tachycardiaor an increase in heart rate of about 10 beats per minute

IV. NEXT GENERATION AGENTS197from baseline. These agents may precipitate pulmonaryedema in patients with left ventricular dysfunction.Next generation agents include lercanidipine, lacidipine,and manidipine. These dihydropyridines have importantand subtle differences when compared with second andthird generation dihydropyridine calcium antagonists.Lercanidipine has been shown to have major advantagesover amlodipine. Because the drug dilates both afferentand efferent arterioles, the high incidence of peripheraledema caused by older calcium antagonists is reducedmore than 50%. The balanced effect of lercanidipine andmanidipine on efferent and afferent arterioles is importantin renal protection. The older calcium antagonists listedabove dilate only afferent arterioles. The COHORT studyof elderly hypertensive patients concluded that lercanidipineand lacidipine are much better tolerated thanamlodipine.Recent investigations indicate that lercanidipine administeredto hypertensive diabetic patients is more effectivethan the angiotensin receptor blocker, losartan, in reducingleft ventricular hypertrophy and left ventricular mass.These third generation dihydropyridines represent animportant addition to the therapeutic armamentarium.Their place in clinical practice will increase further ifthey are shown to be devoid of the major adverse effectof all calcium antagonists — the precipitation ofheart failure in patients with significant left ventriculardysfunction.BIBLIOGRAPHYKhan, M. Gabriel. In Cardiac Drug Therapy, sixth edition, W. B.Saunders, Philadelphia, 2003, p. 81–101.Khan, M. G. In Heart Disease Diagnosis and Therapy: Cardiogenic Shock,second edition. Humana Press, New Jersey, 2005.Messerli, F. H. Evolution of calcium antagonists: Past, present, and future.Clin. Cardiol. 26 (Suppl. 11), 12–16, 2003.Tuomilehto, J., Rastenyte, D., Birkenhager, W. H. et al. Effects ofcalcium channel blockade in older patients with diabetes and systolichypertension. Systolic hypertension in Europe Trial Investigators.N. Engl. J. Med., 34:677–84, 1999.Wang, J. G., Staessen, J. A., Gong, L. et al. Chinese trial on isolatedsystolic hypertension in the elderly. Systolic hypertension in China(Syst-China) Collaborative group. Arch. Intern. Med., 160:211–20,2000.Zanchetti, A. Emerging data on calcium channel blockers: TheCOHORT study. Clin. Cardiol., 26: (Suppl. 11), 17–20, 2003.

Carcinoid Heart DiseaseI. Heart DamageII. DiagnosisIII. TreatmentIV. Clinical StudyGLOSSARYendocardium internal lining of the heart.malignant tumor the tumor that invades and spreads to adjacentand distant organs.tricuspid regurgitation tricuspid valve leaks and blood is propelledbackwards from the right ventricle into the right atriumand into the neck veins.CARCINOID HEART DISEASE MAY OCCUR INpatients with carcinoid syndrome. The main symptomsof flushing, diarrhea, and occasional wheezing are causedmainly by 5-hydroxytryptamine or serotonin, that is liberatedfrom carcinoid tumors that originate from chromaffincells (neuroendocrine cells) of the terminal ileum.These tumors of the small intestine contain neurosecretorygranules that release a variety of biogenic amines thatinclude serotonin, histamine, bradykinins, tachykinins,and prostaglandins. Involvement of the heart occurs inabout half of carcinoid syndrome cases. It is seen mainly inpatients with malignant tumors that have metastasized tothe liver.I. HEART DAMAGEBioactivity amines, principally, serotonin, liberated from amalignant tumor causes deformation of the tricuspid valvethat leads to tricuspid regurgitation. The pulmonary valvebecomes deformed by the plaque-like material resulting ina leaky, incompetent valve (pulmonary regurgitation) ora tight, stenotic valve (pulmonary stenosis). In a clinicalstudy of carcinoid heart disease, 97% of patients hadright-sided valvular involvement; severe tricuspid valveregurgitation occurred in all patients and severe pulmonaryvalve regurgitation in 72%.A whitish colored plaque forms mainly on the right sideof the heart and only in less than 3% of cases are the mitraland aortic valves of the left heart affected. The lesions ofthe valves and endocardium are caused by serotonin thatreaches a high concentration in the right heart. Minimalquantities reach the left side of the heart because5-hydroxytryptamine is destroyed in the lungs by monoamineoxidase. Some serotonin is destroyed in the liverand in the brain.The anorectic drugs fenfluramine and dexfenfluramineexert their effects through interference in serotonin metabolism.It is interesting that they were associated withlesions identical to that seen in carcinoid syndrome.II. DIAGNOSISCarcinoid tumors are rare. They arise from enterochromaffincells typically located in the gastrointestinal tract.At the time of diagnosis, more than 30% of patients havedisseminated disease characterized by cutaneous vasomotorflushing, secretory diarrhea, and mild bronchospasm.In carcinoid heart disease, 5-hydroxytryptamine is metabolizedto 5-hydroxyindoleacetic acid (5-HIAA). Elevatedlevels of 5-HIAA in the urine confirm the diagnosis.Echocardiography confirms thickening of the tricuspid andpulmonary valves with tricuspid and pulmonary valveregurgitation and in some cases, pulmonary valve stenosis.The lesions in the heart may cause right-sided heart failure.Because the blood cannot be ejected adequately throughthe pulmonary valve, the right ventricle work is increased.Because the tricuspid valve leaks, blood regurgitates intothe veins of the neck and back toward the liver, whichbecomes pulsatile with each heartbeat.The malignant tumor may spread to involve the muscleof the heart. These metastatic carcinoid tumors of the heartare about 2 cm and can be detected by echocardiography.199

200CARCINOID HEART DISEASEIII. TREATMENTThere are no specific treatments for carcinoid heart disease.The noncardiac symptoms may be controlled with somatostatin,but the action of this drug is only minutes.Octreotide has been shown to be much more effective inreducing flushing diarrhea and urinary levels of 5-HIAA.IV. CLINICAL STUDYMoller et al. studied the poorly understood factorsassociated with the progression of carcinoid heart disease.They studied 71 patients who underwent serial echocardiographicstudies performed more than one year apartand 32 patients referred directly for surgical intervention.These workers concluded that high serotonin levels arerelated to the progression of carcinoid heart disease, andthe risk of progressive heart disease is higher in patientswho receive chemotherapy.Somatostatin is a potent inhibitor of many processesincluding serotonin. In this nonrandomized study itappears that somatostatin was ineffective in preventingdevelopment of carcinoid heart disease. Findingssuggested that although serotonin is related to developmentof carcinoid disease, neither somatostatin therapynor hepatic dearterialization prevents the progression ofchronic lesions. Patients in the study who receivedcytotoxic chemotherapy had the highest risk of progressivecarcinoid heart disease. The exact mechanism involvedin the progression of carcinoid disease requires furtherclarification.BIBLIOGRAPHYHoward, R. J., Drobac, M., Rider, W. D. et al. Carcinoid heartdisease: Diagnosis by two-dimensional echocardiography. Circulation,66:1059–65, 1995.Moller, J. E., Connolly, H. N., Rubin, J. et al. Factors associated withprogression of carcinoid heart disease. N. Engl. J. Med., 348:1005–15,2003.Pandya, U. H., Pellikka, P. A., Enriquez-Sarano, M. et al. Metastaticcarcinoid tumor to the heart: Echocardiographic — pathologic studyof 11 patients. J. Am. Coll. Cardiol., 40:1328–32, 2002.

Cardiogenic ShockI. CausesII. PathophysiologyIII. ManagementIV. Perspective and Research ImplicationsGLOSSARYatheromatous same as atherosclerotic, a plaque that juts intothe lumen and obstructs the flow of blood in arteries.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack of coronary thrombosis.revascularization procedures that include coronary artery bypasssurgery to bypass obstructive atheromatous plaques or percutaneouscoronary intervention (PCI) using balloon angioplastywith or without stents.tissues aggregation of similarly specialized cells which togetherperform certain special functions.CARDIOGENIC SHOCK IS CAUSED BY A DECREASEDpumping ability of the heart that results in a shock-likestate with insufficient blood perfusion to organs andtissues. During cardiogenic shock, systolic blood pressure isless than 90 mmHg for greater than one hour and notresponsive to IV fluids. The cardiac index is less than2.2 L/minute/m 2 , and the pulmonary capillary wedge pressureis greater than 18 mmHg. Patients usually haveclouded consciousness and cold extremities.I. CAUSESAcute myocardial infarction is the most common cause ofcardiogenic shock. Other causes of cardiogenic shock aregiven in Table 1. The complete occlusion of a coronaryartery by a clot causes death of an area of heart muscle thatis supplied by that blood vessel and its branches. If a verylarge area of heart muscle is involved, the general pumpingcapability of the heart is severely compromised. Becausedead myocardium cannot contract, blood cannot beeffectively ejected out of the left ventricle into the aorta[see Fig. 1 in the chapter Anatomy of the Heart andCirculation). Blood is held up in the lungs and fluidaccumulates in air sacs causing pulmonary edema whichresults in severe shortness of breath. Because blood cannotbe ejected from the heart, the blood pressure fallsdrastically. When more than 40% of the heart muscle isinvolved, cardiogenic shock often occurs.II. PATHOPHYSIOLOGYIn general terms shock is a clinical state in which targetorgan–tissue perfusion is inadequate to supply vital substratesand remove the metabolic waste. Inadequate cellularoxygenation leads to marked generalized impairment ofcellular function and multiorgan failure.The heart tries to contract more vigorously in the face ofthis catastrophic event; the renin–angiotensin–aldosteronesystem is activated and causes severe vasoconstrictionin an attempt to increase blood pressure (see Fig. 1 inthe chapter Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers), but over time the hypercontractilityof the heart ceases. This occurs because thereis utilization of glucose over fatty acids, loss of Krebscycle intermediates, and depletion of substrate required forATP production.Figure 1 illustrates the pathophysiology of shock.Because forward flow of blood is severely retarded, bloodreturned to the heart from veins of the body and from thelungs cannot be accommodated in a heart that is alreadyfull of blood. Blood then backs up into the venouscirculation of the neck and in the lungs. This pressure ofblood returning to the heart is referred to as an increasedfilling pressure (Fig. 1). It is easy to visualize that the shockstate may occur if there is no filling pressure as wouldoccur in severe dehydration or severe blood loss (i.e., thetank has no gas).Basically cardiogenic shock results from profoundreduction in cardiac output. This is usually caused by201

202CARDIOGENIC SHOCKmarked reduction of left or right ventricular systolic function,despite adequate ventricular filling pressures, andthere is a failure of compensatory vasoconstrictive mechanismsthat are overwhelmed by inappropriate vasodilationin large, nonvital vascular beds. Thus this deprivescriticalareas like the heart ,brain, and kidney of perfusion.Hochman points out that data from the shock trial andregistry indicate that cardiogenic shock is often notsimply due to extensive myocardial infarction with pumpfailure, ‘‘but also involves inflammatory mediators. Thesemediators induce nitric oxide synthase (iNOS) expression,increasing nitric oxide (NO) and peroxynitrite levels,resulting which results in further myocardial dysfunctionand failure of an appropriate peripheral circulatoryresponse.’’III. MANAGEMENTMost patients require an intra-aortic balloon pump andIV vasopressor drugs to support blood perfusion to organsand tissues. The opening of the obstructed artery usingballoon angioplasty with the insertion of stents hasimproved survival. Because approximately 40% of cardiogenicshock patients have occlusions in three coronaryarteries, emergency coronary artery bypass surgery is theonly measure that has improved survival in this group.In the SHOCK trial, the overall 30-day mortality ratewas 47% in patients undergoing emergency revascularizationversus 56% in the medical stabilization group.This improvement was maintained at the six-monthfollow up.IV. PERSPECTIVE AND RESEARCHIMPLICATIONSThe incidence of cardiogenic shock will not decrease untilthe main cause, which is obstruction to coronary arteriesby atheromatous plaque and thrombosis, is arrested.Thrombolytic therapy is of little value and revascularizationwith balloon angioplasty and coronary bypass surgerycan only be undertaken in special centers. The SHOCKtrial only studied 300 patients. More research is requiredto assess if we could develop cardioactive agents to protectthe myocardium from necrosis during an occlusion ofa coronary artery.BIBLIOGRAPHYHasdal, D., Topol, E. J., Calif, R. M. et al. Cardiogenic shockcomplicating acute coronary syndromes. Lancet, 356:7.9–26, 2000.Hochman, J. S. Cardiogenic shock complicating acute myocardialinfarction. Expanding the paradigm. Circulation, 107:2998–3002,2003.Khan, M. Gabriel, Cardiogenic shock, In Heart Disease Diagnosis andTherapy, second edition, New Jersey: Humana Press, 2005.Sanborn, T. A., Sleeper, L. A., Webb, J. G. et al. Correlates of oneyear survival in patients with cardiogenic shock complicatingacute myocardial infarction. J. Am. Coll. Cardiol., 42:1373–1379,2003.

CardiomyopathyI. Hypertrophic CardiomyopathyII. Sudden DeathIII. Dilated CardiomyopathyIV. Restrictive CardiomyopathyV. Specific Heart Muscle DiseaseGLOSSARYheart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hemodynamics the study of the movement of blood and theforces involved in the circulation of blood.mutations a permanent transmissible change in the geneticmaterial.outflow tract gradient marked thickness of the left ventricularseptum obstructs the blood flow from the left ventricle that isto be delivered into the aorta.paroxysmal nocturnal dyspnea patient awakens at night fromsleep with severe shortness of breath and must dangle the legsor walk to an open window; relief occurs only after severalminutes.sarcomere the contractile unit of a myofibril; sarcomeres arerepeating units, delimited by the Z bands, along the length ofthe myofibril that make up the myocardium of the heart.CARDIOMYOPATHY IS A RARE FORM OF HEARTdisease that affects only the heart muscle. The termcardiomyopathy is derived from the word cardio, the heart,and myopathy, which indicates a weakness or disturbanceof the muscle. Heart muscle diseases of unknown cause areclassified under the term cardiomyopathy.In one form of heart muscle disease, the muscle of theventricle becomes considerably thickened to the point thatthe cavity of the left ventricle becomes nearly filled withmuscle mass; thus less blood enters the chamber and lessblood is expelled into the circulation. Because the muscle isenlarged, or hypertrophied, the disease is called hypertrophiccardiomyopathy. This is a disease of young adults.See chapter entitled ‘‘Athletes and Sudden Cardiac Death.’’The muscle enlargement may be so severe that itobstructs the flow of blood into the aorta, and death mayoccur suddenly, particularly in individuals from age 12 to36 years. Some athletes who have died suddenly have hadthis disease. In some families, hypertrophic cardiomyopathyis caused by mutation in the cardiac myosin gene.Approximately 60% of cases occur in families with anautosomal dominant pattern and 40% of cases aresporadic.In another form of heart muscle disease, the heart dilateswithout increasing the size of the muscle. The chambersare swollen, and the muscle becomes weak. This conditionoften results in failure of the heart to pump blood, whichresults in heart failure. Heart transplants are required insome of these patients (see the chapter Heart Failure).Other types of heart muscle diseases may be caused byviruses. Patients with AIDS have had HIV viral infectionof the heart muscle. The heart muscle may also bedamaged by cocaine, an overload of iron (hemochromatosis),and some inherited conditions.With different varieties of involvement of the heartmuscle, classification became necessary. In the 1970s and1980s cardiomyopathy was defined as heart muscle diseaseof unknown cause. The current classifications are:1. Hypertrophic cardiomyopathy2. Dilated cardiomyopathy3. Restrictive cardiomyopathy4. Arrhythmogenic right ventricular cardiomyopathy(right ventricular dysplasia)5. Unclassified cardiomyopathy: diseases that do not havefeatures of 1through 4 and include fibroelastosis andmitochondrial disease6. Specific cardiomyopathies (specific heart musclediseases formerly called secondary cardiomyopathy).Each of these cardiomyopathies will be discussed. Mostof these diseases are rare, but hypertrophic cardiomyopathy203

204CARDIOMYOPATHYhas become well-known because it is one of the causes ofsudden death in young athletes and young individuals.I. HYPERTROPHIC CARDIOMYOPATHYHypertrophic cardiomyopathy (HCM) is found throughoutthe world with a prevalence in North America of0.2%. Before the diagnosis of HCM is considered hypertensiveheart disease, a major cause of the left ventriclehypertrophy, and other causes of hypertrophy must beexcluded. In practice HCM is defined and diagnosedby the demonstration of unexplained left ventricularhypertrophy.Hypertrophic cardiomyopathy is a disease caused by awide variety of mutations in genes encoding cardiacsarcomeric proteins, which leads to inappropriate andoften severe hypertrophy of the myocardium.A. GeneticsApproximately 60% of cases are familial and are inheritedin a Mendelian single gene autosomal dominant fashion.More than 150 mutations in 10 culprit genes that encodesarcomeric proteins are implicated in this disease. Themost common of these culprit genes include:1. Beta myosin heavy chain (MYH7), approximately 35%2. Cardiac troponin-2 (TNNT2), approximately 15%3. Myosin binding protein C genes, approximately 15%4. Alpha tropomyosin5. Essential myosin light chain6. Troponins-I7. Alpha cardiac actin8. Regulatory myosin light chain.Familial HCM can be caused by genetic defects at morethan one locus, therefore, it is a genetically heterogeneousdisease. The mutations of the troponins-T and somemutations of the beta myosin heavy chain appear to beassociated with sudden death more often than othermutations. Some mutations may be associated with a highincidence of sudden cardiac death, whereas others appearto have a more benign course. This has led to the hypothesisthat genotyping may facilitate the identification ofindividuals at risk for sudden death. But there is extremevariability and even mutations that were considered bysome to be malignant, MYH7 and TNNT2, often run abenign course. In a study by Ackerman et al. so-called‘‘malignant’’ mutation was found in only 1% of 293 studypatients. The authors concluded that given the lowprevalence of malignant MYH7 and TNNT2 mutationsin a large study, genetic testing was unlikely to contributesignificantly to risk assessment.Mutations of the troponins-T gene usually result in onlymild or no heart muscle hypertrophy. Some of the sporadicforms of the disease are caused by spontaneous mutations.It is of interest that in some patients with an abnormalgene and normal echocardiography, the most diagnosticand least expensive test is the ECG.B. Macroscopic FeaturesThere is a marked increase in myocardial mass and theventricular cavity is encroached upon such that theventricular cavity becomes smaller and narrowed (seeFig. 1). The marked thickening of the interventricularseptum obstructs the free flow of blood from the leftventricle into the aorta, (outflow tract gradient). The leftventricle tends to be involved much more than the right.The degree of hypertrophy and the parts of the heartthat are involved are extremely variable. See Figure 1 in thechapter entitled ‘‘Athletes and Sudden Cardiac Death.’’Hypertrophy can be patchy, involving the septum only,the apex of the anterior, and the lateral walls. This type ofhypertrophy is often referred to as asymmetric hypertrophy.(Fig. 1). Occasionally the hypertrophy of the heartmuscle that is seen in HCM and that observed in highlytrained male athletes may be difficult to differentiate.Hypertrophy of the apex of the heart (apical HCM) ismore common in Japan than in other parts of the world.In apical HCM the ECG shows a highly abnormal patternof giant negative T waves in the precordial ECG leads.Despite the frightfully abnormal looking ECG, patientsare often asymptomatic and the disease runs a benigncourse. Figure 2 shows the ECG in a patient with apicalHCM. Figure 3 shows a patient with HCM, mildhypertrophy of the septum, and mild free wall hypertrophybut without significant obstruction of the outflow tractthat leads from the left ventricle to the aorta as depictedin Fig. 1.C. Microscopic FeaturesMicroscopically in HCM the myocytes are hypertrophiedand in disarray and there is abundant interstitial fibrosis.Individual myocytes demonstrate disarray in the orientationor their myofibrillar architecture. The disorganizationin the alignment of cardiac myocytes is oriented aroundloose connective tissue. Large areas of fibrosis are observedthroughout the affected muscle. This microscopic picturemay also be seen in muscle where there is no obvioushypertrophy.

I. HYPERTROPHIC CARDIOMYOPATHY205To Head and ArmsFrom Headand ArmsAorta (To Body)Superior Vena CavaPulmonary ArteryPulmonary VeinRight ArtiumPulmonary ValveLeft AtriumMitral ValveAortic ValveTricuspid ValveInferior Vena CavaLeft VentricleRight VentricleFrom BodyHeart MuscleFIGURE 1Ap. 267.)Oxygenated BloodDeoxygenated BloodAorta(to Abdomen)HeartMuscleNormal heart. (From Khan, M.G. and Marriott, H.J.L. (1996). Valve diseases, Heart Trouble Encyclopedia, Toronto: Stoddart Publishing,To Head and ArmsFrom Headand ArmsAorta (To Body)Superior Vena CavaPulmonary ArteryPulmonary VeinRight ArtiumPulmonary ValveTricuspid ValveInferior Vena CavaRight VentricleFrom BodyLeft AtriumMitral ValveXAortic ValveXXLeft VentricleSeptal HypertrophyHeart MuscleOxygenated BloodDeoxygenated BloodAorta(to Abdomen)HeartMuscleFIGURE 1BAdjacent mitral valve (X) leaflet impinges on the hypertrophied septum (XX).

206CARDIOMYOPATHYFIGURE 2Giant T-wave inversion leads v2–v6 in a patient with apical hypertrophic cardiomyopathy.FIGURE 3Hypertrophic cardiomyopathy simulating inferolateral infarction. Q waves leads 2, 3, aVF, V 4 to V 6 ; note the positive T waves.

II. SUDDEN DEATH207D. Pathophysiology1. Most patients show asymmetric hypertrophy of theseptum and a hypertrophied nondilated left and orright ventricle. The septum may be diffusely hypertrophiedor only in its upper, mid, or apical portion.Hypertrophy extends to the free wall of the leftventricle.2. There is decreased compliance and incomplete relaxationof the thickened and stiff left ventricular musclethat causes impedance to filling of the ventricles duringdiastole (diastolic dysfunction)3. The rapid powerful contraction of hypertrophied leftventricle expels most of its contents during the firsthalf of systole. This hyperdynamic systolic functionis apparent in most patients with HCM.4. The anterior leaflet of the mitral valve is displacedtoward the hypertrophied septum. Mitral regurgitationis virtually always present in the obstructive phase ofthe disease.5. Because of the obstruction overflow from the leftventricle into the aorta and outflow pressure gradientat rest, HCM is much worse during exercise in morethan 40% of patients.6. Disease of small branches of the coronary arteriesmay occur, but the major coronary arteries are notobstructed.E. Clinical Features1. Shortness of breath commonly occurs but may not benoticeable in many patients until the obstruction tooutflow of the left ventricle becomes severe.2. Fainting, syncope, or presyncope during exercise orduring normal activities is a warning signal.3. Chest pain may occur because of restricted flow to thecoronary arteries.4. Abnormal heart rhythms causing palpitations mayoccur.5. On examination, hypertrophy of the heart is reflectedby a thrusting and forceful apex beat of the heartthat can be seen or felt with the palpating hand. Amurmur is heard with the stethoscope and has typicalcharacteristics, but the entire examination may reveallittle or no abnormalities depending on the stage of thedisease.6. The ECG is usually abnormal with pathologic Qwaves in leads I, II, III, aVF, V5, and V6, as shown inFig. 3.7. Signs of heart failure are observed in the end stagesof the disease. Figure 4 gives an outline of variousprocesses that lead to the end stages which culminate inheart failure or death.II. SUDDEN DEATHDeath is most often sudden in HCM and unfortunatelythis may occur in asymptomatic patients, in those whowere unaware that they have the disease, or in individualswith an otherwise stable course.The mechanisms that result in sudden death remainunresolved. The identification of patients at high risk ofsudden death presents great difficulties for the average andexpert clinicians.A. GenotypingGenotyping is not available as a routine clinical test, andmost important, it is currently problematic in prognosticassessment. The findings of Ackerman et al. of only 1%malignant mutation in 293 patients is important and isin keeping with several other observations. Even withinso-called high-risk families there is a variable diseaseexpression and prognosis. Watkins et al. described a largeScottish family with mutation in TNNT2 in which 8 diedsuddenly before age 30, but 8 others lived to be 70–80years old. Several other reports of this type have beennoted.B. Clinical EvaluationBecause the promise held for genotyping is not likely tomaterialize, assessment of risk is based mainly on clinicalevaluation and specific investigations. Clinical parametersthat may assist in the assessment of risk for sudden death,however, remain unsystematic and haphazard. Mckennaet al. made the point that at best, clinical risk markers areonly modestly predictive of short-to-medium term risk ofsudden death. The presence of a severe outflow tractgradient does not correlate with the risk of sudden death.C. Marked Left Ventricular HypertrophyCurrent evidence indicates that marked left ventricularhypertrophy should not be relied upon for diagnosis. Somestudies indicate that left ventricular wall thickness greaterthan 30 mm significantly increases the risk of sudden

208CARDIOMYOPATHYDisorganized myofibrillar muscle elements [myofibrillar disarray]Hypertrophy of the septum and other areas of the ventricle [asymmetric hypertrophy]Obstruction to flow from the ventricle into the aorta [hypertrophic obstructive]cardiomyopathyMitral regurgitationAtrial fibrillationVery small chamber cavity of the left ventriclePoor relaxation of the ventricle leads to poor filling of the chamberReplacement of myocytes with collagen and extensive fibrosisHypercontractile* heart [hyperdynamic heart requires more oxygen]Necrosis [death] of heart muscle cellsWeakened heart muscleSystolic and diastolic dysfunctionPump failure [left ventricular failure]FIGURE 4*Each contraction of the heart is vigorous even with normal heart rates of 70 to 80beats per minuteHypertrophic cardiomyopathy: processes that lead to end stage disease and heart failure.death. In a study by Spirito et al. sudden death occurredin less than 1% of patients with maximal thickness lessthan 20 mm and in 16% of patients with maximalthickness greater than 30 mm over the average follow up of7 years. Unfortunately at least 10% of patients in mostsurvival studies show a left ventricular wall thicknessgreater than 30 mm. Most important, the majority ofsudden cardiac death in patients with HCM occurs inthose with a wall thickness of less than 30 mm.Survivors of cardiac arrest make up a high-risk groupthat is easy to define. These are individuals who havesurvived an episode of sustained ventricular tachycardia.These patients have about an 8% chance of further cardiacevent in five years.A history of sudden death in the family or syncope inan individual is worrisome, and there is considerableanecdotal evidence to suggest that these two features carrya sizable predictive risk. The worry to the family andindividual is understandable. The outcome statisticalanalyses in large series show that syncope and a previoushistory of sudden death are not reliable indicators,however, for the prediction of future sudden death.Syncope is more sinister in children with HCM than inadults.Findings of nonsustained ventricular tachycardia onHolter electrocardiographic ambulatory monitoring andan abnormal blood pressure response on exercise alongwith clinical evaluation (massive left ventricular hypertrophy)and family history (unexplained syncope, familyhistory of sudden death) are useful toward a diagnosis. In aprospective study in which these parameters werepresent, there was an annual sudden death risk ofapproximately 3%.A group at low risk for sudden death may be identifiedas asymptomatic patients with left ventricular thicknessless than 20 mm, absence of nonsustained ventriculartachycardia on Holter monitoring, normal exercise bloodpressure response, and no family history of sudden death.D. Management1. MedicalBeta-blockers are the mainstay of medical therapy. Drugmanagement is used mainly in patients who are symptomaticand in patients who present with chest pain, mildshortness of breath, or presyncope. A marked increase invigorous contractions of the heart muscle (hypercontractility)dictates the need for more oxygen by the thickenedmuscle; beta-blocking drugs such as metoprolol, whichdecreases the force and velocity of contraction of theventricle, and decreases oxygen requirement, have beenused successfully for more than 30 years to achievesubjective and objective benefit in a significant number of

III. DILATED CARDIOMYOPATHY209patients. Also, in patients with HCM the heart rate is slowand this leads to improved filling of the ventricle duringdiastole and increased filling of the coronary arteries thatsupply the thickened muscle with blood and oxygen. Betablockingagents, however, have not been shown to preventsudden death and clinical trials are difficult in patientswith HCM. Other agents used in selected cases includeverapamil, which may precipitate heart failure and hypotensionin some. Verapamil improves relaxation of theventricle and allows for better filling of the left ventricle,but it should be avoided in patients who are at risk fordevelopment of heart failure.Diuretics may cause dehydration because of the removalof salt and water from the body. This effect decreases thevolume of blood returned to the heart, and this may haveserious consequences in patients who already have poorfilling of the left ventricle.2. Chemical Septal AblationThis technique is used mainly in highly symptomaticpatients who have contraindications or are resistant to drugtreatment. In these patients the outflow tract gradientat rest should be greater than 30 mmHg or greater than60 mmHg with provocation. The septum usually measuresgreater than 18 mm thick. Catheterization of the targetvessel (the most important proximal septal artery thatsupplies the septum with blood) and ablation of the areawith the use of alcohol appears to produce satisfactoryresults in selected patients. Complications include completeheart block, damage to a coronary artery, myocardialinfarction, and pericardial tamponade. Hospital mortalityranges from 1 to 4%.3. Surgical MyomectomySurgical removal of excess muscle tissue in the region ofthe thickened septum is a logical solution to reduceoutflow tract gradient and promote better flow of bloodfrom the left ventricle into the aorta. In 1957 Brockadvanced this method, and subsequently Morrow popularizedthe technique. A portion of the thickened interventricularseptum is excised; often the mitral valve is replaced.Symptoms are definitely improved, but the mortality rateranges from 2 to 5%. Surgical intervention is usuallysatisfactory; long-term improvement in symptoms andexercise capacity is observed in most patients.4. Dual-Chamber PacemakerDual-chamber pacemaker insertion is based on the observationthat excitation of the septum by pacing causes theseptum to contract away from the opposing wall reducingthe obstruction to outflow of blood from the ventricle(reduces the left ventricular outflow tract gradient). Thisstrategy appeared useful in the European trial, but severaltrials in the United States have failed to show significantbenefit.III. DILATED CARDIOMYOPATHYHeart failure is rare in individuals younger than age 20.If congenital heart disease is excluded, the most commoncause of heart failure in the young is idiopathic dilatedcardiomyopathy (DCM). More than 50 known specificdiseases of heart muscle can produce the signs, symptoms,and manifestations of idiopathic DCM. Some of thesediseases include the following:1. Infectious: Coxsackie, cytomegalovirus, HIV, Chagasdisease, tuberculosis, acute rheumatic fever, toxoplasmosis,trichinosis, echinococcus, schistosomiasis, andLyme disease2. Endocrine: Thyroid diseases (thyrotoxicosis and,hypothyroidism), diabetes, and acromegaly3. Infiltrative diseases: Amyloidosis, hemochromatosis,and sarcoidosis4. Alcoholic cardiomyopathy5. Collagen vascular disease: Lupus erythematosus, scleroderma,mixed connective tissue disease, polyarteritisnodosa, and rheumatoid arthritis6. Toxic: Cocaine, heroin, amphetamines, cancer chemotherapeuticagents, arsenic, cobalt, lead, phosphorus,and ethylene glycol7. Nutritional: Thiamine, protein, and selenium8. Others: Endomyocardial fibroelastosis, peripartum, andsleep apneaIdiopathic DCM is transmitted in an autosomaldominant manner although X-linked, autosomal recessive,and mitochondrial inheritance also have been observed.A. GeneticsShaw et al. stated in an editorial that the geneticheterogeneity of DCM is illustrated by the autosomaldominant form with several foci and gene mutationsidentified that include Iq32 (cardiac troponin-T), 14q11(beta myosin heavy chain), 4q12 (beta –sarcoglycan), and15q14(actin). Figure 5 shows some proteins involved inDCM and their cellular location.The mechanisms by which individual mutations causeidiopathic DCM require further clarification. The end

210CARDIOMYOPATHYFIGURE 5Cardiomyocyte showing some proteins involved in development of DCM. (From The Lancet, 360, 654, 2002. With permission.)result of the disease is a weakened heart muscle that leadsto heart failure. Abnormalities in force transmission andvelocity of contraction of the heart muscle appear toresult from mutations of contractile proteins, actin, alphatropomyosin,and desmin. Cardiac beta myosin heavychain and troponins-T mutations are believed to resultin reduced force generation by the sarcomere. Mutationsin both sarcoglycans are believed to cause DCM.Mutations in the mitochondrial respiratory chain alsocan lead to DCM.B. Clinical Features1. Progressive shortness of breath on exertion appears overweeks or months. This then progresses to shortness ofbreath in bed (orthopnea) and paroxysmal nocturnaldyspnea.2. Signs and symptoms of right and left heart failurebecome evident.3. On auscultation gallop sounds are typically present.C. Investigations1. Chest x-ray shows enlargement of the heart with fluidin the lungs (pleural effusions) and evidence of heartfailure.2. Echocardiogram shows enlargement of all four chambersand the entire muscle wall contracts poorly (globalhypokinesis). A pericardial effusion (excess fluid in thepericardial sac) can be seen.

V. SPECIFIC HEART MUSCLE DISEASE211D. ManagementTransplantation has a role in selected individuals but doesnot benefit patients worldwide. Aggressive treatment forheart failure carries the only hope for improved survivaland must include the following medications:1. Diuretics: Furosemide in a dosage to prevent fluidretention, edema, signs of heart failure, and particularlyfor the relief of shortness of breath.2. ACE inhibitor therapy: Enalapril or lisinopril or similarACE inhibitor, see the chapter Heart Failure.3. Beta blockers: The use of metoprolol or carvedilol isnow recognized as essential. These agents have recentlybeen shown to be effective in relieving symptoms aswell as improving cardiac function. Lowes et al.reported the study of 53 patients treated with metoprololor carvedilol and observed significant improvementthat was associated with changes in myocardialgene expression. A study by Cice et al. in 114 dialysispatients with dilated cardiomyopathy treated withcarvedilol showed a reduction in left ventricularfunction, left ventricular volumes, and clinical status.4. Spironolactone: Added to the above beta-blockersfurther improves clinical status survival and decreaseshospitalization for heart failure.5. Dual-chamber electronic pacing: In patients with heartfailure and intraventricular conduction delay (IVCD),this has shown significant benefit, reduced hospitalization,and probably will delay the time to transplantationin individuals on waiting lists.6. Anticoagulants: These may be required to reduce therisk of embolism that occurs frequently in patients withdilated hearts.7. Antiarrhythmics: In some of these patients implantationof an IVCD may become necessary.IV. RESTRICTIVE CARDIOMYOPATHYRestrictive cardiomyopathy is rare in the western worldand in Europe. Diseases that cause damage to the muscleand restrict the flow of blood into the ventricle includeamyloidosis, sarcoidosis, hemochromatosis, scleroderma,Adriamycin toxicity, and heart involvement by infectiousagents. The most common cause of restrictive cardiomyopathy,especially in tropical regions, is endomyocardialfibrosis.The damage to the muscle in these diseases causes theventricular walls to become excessively rigid and the mainabnormality is impaired relaxation and compliance thatimpedes the filling of the ventricle. Less blood is heldwithin the ventricle and thus less blood is expelled into theaorta and systemic circulation. When the supply of bloodto organs becomes inadequate, heart failure is diagnosed.This situation is due mainly to poor diastolic filling ofthe ventricle rather than to a decrease in the force ofcontraction of the ventricular muscle (systolic dysfunction)which is the most common cause for heart failure.A. Clinical FeaturesIn the tropics endomyocardial fibrosis may result inintermittent fever, shortness of breath, cough, palpitations,edema, and tiredness. Symptoms and signs of heart failuremust be differentiated from constrictive pericarditis.Endomyocardial fibrosis may mimic the hemodynamicand clinical features of constrictive peritonitis. Chest x-rayor fluoroscopy may show calcification of the right andleft ventricular apical myocardium due to thrombusformation, calcification of all fibrosis, and calcification ofthe endocardial region. The apex of the heart may becompletely obliterated. Blood tests may reveal increasedeosinophils (hypereosinophilia). Echocardiogram typicallyshows obliteration of the apices of the ventricle withechogenic masses. Also, extensive myocardial calcificationmay be detected.B. Management1. Steroids may be helpful to subdue inflammatorychanges.2. Anticoagulants are advisable to prevent thromboembolism.3. Arrhythmias may respond to small doses of a betablockersand occasionally some beneficial responsemay be obtained with ACE inhibitors.4. Diuretics are usually not beneficial, but may berequired for symptomatic relief of shortness of breathand other manifestations of heart failure.V. SPECIFIC HEART MUSCLE DISEASESpecific heart muscle disease usually produces a dilatedform of cardiomyopathy with impaired systolic function.Restrictive physiology is seen with amyloid, sarcoid,neoplasm, radiation, scleroderma, hemochromatosis, andeosinophilic endomyocardial disease, in which eosinophiliais usually present. Rarely, myocardial tuberculosis ispresent with restrictive features. Amyloid heart disease andEMF are usually considered examples of RCM, but when

212CARDIOMYOPATHYTABLE 1Principal Causes of Specific Heart Muscle DiseaseBacterial:Parasitic:Viral:Collagen vascular:Metabolic and dietary disorders:Toxic:Chemotherapeutic agents:Neuromuscular:Endocrine:Granulomata:Others:Diphtheria, tuberculosisChagas’ disease, toxoplasmosis, trichinosis, Echinococcuscoxsackie, cytomegalovirus, HIV, Epstein-Barr Kawasaki diseaseLupus erythematosus, scleroderma, mixed connective tissue disease,polyarteritis nodosa, rheumatoid arthritisThiamine, selenium deficiency; glycogen storage diseaseAdriamycin, doxorubicin, cocaine, cobalt, ethanol, leadMercury, prednisone, zidovudine, X radiation, and allergic reactionsDuchenne’s muscular dystrophy, myotonic dystrophy, Friedreich’s ataxiaThyroid heart disease, pheochromocytoma, Addison’s diseaseSarcoidosisAmyloid (see text), hemochromatosiscardiac involvement is associated with multiple organdisease, they qualify as specific heart muscle disease (seeTable 1).Endomyocardial biopsy is often required but may notbe helpful in patchy disease such as sarcoid. The presenceof systemic disease of other organs, especially the liver,lymph nodes, and skin, which can be easily submitted tobiopsy, assist in defining the underlying cause.Amyloidosis causes deposition of specific proteins asinsoluble fibrils in the extracellular space of several organsincluding the heart. The disease affects individuals in thefifth and sixth decade of life. The heart muscle is weakenedand mainly right heart failure ensues in more than 40%of patients.BIBLIOGRAPHYAckerman, M. J., McKenna, W. J., Thierfelder, L. et al. Mutations in thegenes for cardiac troponins T and alpha tropomyosin in hypertrophiccardiomyopathy. N. Engl. J. Med., 332:1058–64, 1995.American College of Cardiology/European Society of Cardiology ClinicalExpert Consensus Document on Hypertrophic Cardiomyopathy.J. Am. Coll. Cardiol., 42:1688–1713, 2003.Boriani, G., Maron, B. J., Win-Kuang, S. et al. Prevention of suddendeath in hypertrophic cardiomyopathy: But which defibrillator forwhich patient? Circulation, 110:e438–e442, 2004.Braunwald, E., Seidman, C. E., and Sigwart, U. Contemporary evaluationand management of hypertrophic cardiomyopathy. Circulation,106:1312–1316, 2002.Brock, R. Functional obstruction of the left ventricle. Guy’s Hospital Rev.,106:221, 1957.Canon, R. O. Assessing risk in hypertrophic cardiomyopathy. N. Engl.J. Med., 349:1016–18, 2003.Cice, G., Ferrara, L., Benedetto, A. D. et al. Dilated cardiomyopathy indialysis patients. Beneficial effects of carvedilol, a double-blind,placebo-controlled trial. J. Am. Coll. Cardiol., 57:47–11, 2001.Elliott, P. M., Blanes, G., Mahon, J. R. et al. A relation between theseverity of left ventricular hypertrophy and prognosis in patients withhypertrophic cardiomyopathy. Lancet, 357:420–24, 2001.Eriksson, M. J., Sonnenberg, B., Woo, A. et al. Long-term outcomein patients with apical hypertrophic cardiomyopathy. J. Am. Coll.Cardiol., 39:638–45, 2002.Kühl, U., Pauschinger, M., Noutsias, M., Seeberg, B., Bock, T., Lassner, D.,Poller, W., Kandolf, R., Schultheiss, H. P. et al. High prevalenceof viral genomes and multiple viral infections in the myocardiumof adults with ‘‘idiopathic’’ left ventricular dysfunction. Circulation,111:887–893, 2005.Lowes, B. D., Gilbert, E. M., Abraham, W. T. et al. Myocardial geneexpression in dilated cardiomyopathy treated with beta blockingagents. N. Engl. J. Med., 346:1357–65, 2002.Maron, B. J., Dearani, J. A., Ommen, S. R. et al. The case for surgeryin obstructive hypertrophic cardiomyopathy. J. Am. Coll. Cardiol.,44:2044–2053, 2004.Maron, B. J., Seidman, J. G., Seidman, C. E. et al. Proposal forcontemporary screening strategies in families with hypertrophiccardiomyopathy. J. Am. Coll. Cardiol., 44:2125–2132, 2004.Maron, B. J. Sudden death in young athletes. N. Engl. J. Med.,349:1064–1075, 2003.Maron, B. J., Estes, N. A., III, Maron, M. S., Almquist, A. K., Link,M. S., and Udelson, J. E. Primary prevention of sudden death as anovel treatment strategy in hypertrophic cardiomyopathy. Circulation,107:2872–2875, 2003.McKenna, W. J., Mogensen, J., and Elliott, P. M. Role of genotype in riskfactor assessment for sudden death in hypertrophic cardiomyopathy.J. Am. Coll. Med., 39:249–51, 2002.Morrow, A. G. Hypertrophic subaortic stenosis: operative methodsutilized to relieve left ventricular outflow obstruction. J. Thorac.Cardiovasc. Surg., 76:423–430, 1978.Nishimura, R. A., and Holmes, D. R. Hypertrophic obstructivecardiomyopathy. N. Engl. J. Med., 350:1320–1327.Ommen, S. R., and Nishimura, R. A. Hypertrophic cardiomyopathy:Echocardiographic basis of therapy. Am. Coll. Cardiol. J. Rev., January/February 46–49, 2001.Reisinger J, Dubrey SW, Falk RH. Cardiac Amylodosis. Cardiology inReview.5: [6], 317-24, 1997.Roberts, R., and Sigwart, U. New concepts in hypertrophic cardiomyopathies,part II. Circulation, 104:2249–52, 2001.

V. SPECIFIC HEART MUSCLE DISEASE213Scheinman, M. M., Crawford, M. H. et al. Echocardiographic findingsand the search for a gold standard in patients with arrhythmogenicright ventricular dysplasia. J. Am. Coll. Cardio., 45:6:866–867.Shamim, W., Yousufuddin, M., Wang, D. et al. Nonsurgical reduction ofthe interventricular septum in patients with hypertrophic cardiomyopathy.N. Engl. J. Med., 347:1326–33, 2002.Shaw, T., Elliott, P., and McKenna, W. J. Commentary. Dilatedcardiomyopathy: A genetically heterogeneous disease. Lancet,360:654–655, 2002.Spirito, P., Bellone, P., Harris, K. M. et al. Magnitude of left ventricularhypertrophy and risk of sudden death in hypertrophic cardiomyopathy.N. Engl. J. Med., 1778–85, 2000.Watkins, H., McKenna, W. J., Thierfelder, L. et al. Mutations in the genesfor cardiac troponins T and alpha tropomyosin in hypertrophiccardiomyopathy. N. Engl. J. Med., 332:1058–64, 1995.Wigle, E. D., Schwartz, L., Woo, A. et al. To ablate or operate? That is thequestion. J. Am. Coll.Cardiol., 38:1707–1710, 2001.Yoerger, D. M., Marcus, F., Sherrill, D. et al. Echocardiographicfindings in patients meeting task force criteria for arrhythmogenicright ventricular dysplasia: New insights from the multidisciplinarystudy of right ventricular dysplasia. J. Am. Coll. Cardio.,45:6:860–865.

Cardiopulmonary Resuscitation (CPR)I. Causes of Loss of ConsciousnessII. Cardiac Arrest RhythmsIII. Cardiopulmonary ResuscitationIV. DefibrillationV. Drugs for Cardiac ArrestVI. Perspectives and Research ImplicationsVII. Outcomes of Out-of-Hospital Cardiac ArrestVIII. The Heimlich ManeuverGLOSSARYcardiac output the volume of blood pumped by the ventriclesper unit of time expressed in liters per minute: it is a functionof the stroke volume multiplied by the heart rate.cardiac tamponade compression of the heart by fluid in thepericardial sac causing hemodynamic compromise that leads tocardiogenic shock and death if not immediately corrected.hyperkalemia high levels of serum potassium.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.syncope temporary loss of consciousness caused by lack of bloodsupply to the brain; fainting describes a simple syncopal attack.ventricular fibrillation the heart muscle does not contract butquivers; therefore, there is no heartbeat (cardiac arrest) and noblood is pumped out of the heart; death occurs within minutesif the abnormal heart rhythm is not corrected.PERHAPS YOU MAY HAPPEN TO BE NEARsomeone who falls to the ground and stops breathing.You may be alone or someone summons you to help. Canyou help? If you have never learned how to do CPR, youwill not know what to do to save a life. Thus it is wise forall individuals to attend a practical course in CPR or atleast read and practice the drill until it becomes automatic.Since its description more than 43 years ago, thefundamentals of CPR have undergone minimal changes.The technique is quite simple. The main goal in applyingCPR is trying to get oxygen to the individual’s brain tokeep it alive until expert help arrives. Mouth-to-mouthventilation oxygenates the blood, and chest compressionscause forward flow of blood, albeit a small flow, that resultsin some cardiac output into the circulation so thatoxygenated blood reaches vital organs.In this chapter the relevant points of CPR are summarizedso that if you are faced with an individual who has‘‘dropped dead’’ or appears to have lost consciousness inyour presence, you may be able to render assistance.I. CAUSES OF LOSS OF CONSCIOUSNESSPatients may lose consciousness and fall because of severalreasons such as syncope, seizure, stroke, or cardiac arrest.A. Syncope/FaintingWith syncope the patient has a pulse, does not stop breathing,and has no shaking of the limbs. Simply keeping thehead down, preferably with the individual lying flat, andraising the legs up in the air above the patient’s hips willcause blood to flow from the legs. In about one minute theindividual will recover completely.B. Seizure/EpilepsyDuring a seizure the patient’s limbs exhibit jerky, movements,the limbs get rigid, or there is a combination ofrigidity and jerking of one or more limbs. The patient isbreathing, but saliva and foam bubble from the mouth.Some individuals pass urine or stool. Recovery is typical.C. StrokeDuring a stroke, circulation to part of the brain is cut offbecause of a blood clot in an artery in the brain. Strokesusually occur in individuals over age 60. It is rare for the215

216CARDIOPULMONARY RESUSCITATION (CPR)patient to fall suddenly to the floor without some warning.The patient will have a pulse and breathing will be present.There is no reason to do CPR because the heartbeat,circulation, and respirations have not stopped.D. Cardiac ArrestDuring cardiac arrest, the heart stops beating completelyand is at a standstill (asystole) in about 25% of individuals.In about 60–75%, cardiac arrest is due to ventricularfibrillation. Ventricular fibrillation can be treated by anelectrical shock, which defibrillates the heart and replacesthe ventricular fibrillation with a normal heartbeat.In standstill or asystole, there is no electrical current inthe heart, and using electrical shock is of no value. In a fewcases, the heart may commence beating on its own. Thiscondition is called a Stokes-Adams attack, named after thedoctors who first described it. A few individuals can besaved by the insertion of a pacemaker if the attack occursin the hospital.It is wise for a family member of a heart patient to knowhow to give CPR. It reassures the patient that somethingcan be done. The knowledgeable individual also feels somesense of confidence, which promotes hope.Each year approximately a quarter million individualsdie suddenly in the United States from coronary arterydisease before reaching a hospital; more than half amillion have a cardiac arrest and receive CPR duringhospitalization.II. CARDIAC ARREST RHYTHMSThere are only two cardiac arrest rhythms to consider:ventricular fibrillation and pulseless ventricular tachycardia(VF/VT).The American Heart Association (AHA) Guidelines2000 for CPR and emergency cardiovascular care advisesthat in patients with cardiac arrest it is advisable to alwaysassume that the rhythm is VF or pulseless V T. Becauseindividuals who can be saved from cardiac arrest areusually in VF or pulseless V T, the earliest possible deliveryof defibrillation is the single most effective intervention.A recent study in Norway, however, indicates that the useof three minutes of CPR prior to defibrillation, rather thanimmediate defibrillation, resulted in better outcomesamong VF patients who received attention more thanfive minutes after symptom onset. In patients who receiveddefibrillation immediately, 46% achieved a spontaneouspalpable pulse on admission versus 56% of those withinthree minutes of CPR. Further studies are necessary toclarify this finding.B. Automated External DefibrillatorThe distribution of automatic external defibrillators hasbeen widespread. The AHA recommends that all firstrespondingemergency personnel such as physicians,nurses, emergency medical technicians, paramedics, firefighters,and volunteer emergency personnel be trainedand permitted to operate a defibrillator. The defibrillatorshould be available in all emergency ambulances thatengage in the care or transit of cardiac patients.The automated external defibrillator automaticallyinterprets the cardiac rhythm and, if VF is present, advisesthe operator to provide a shock. Because most cardiacarrests occur in the home, a case can be made for homedefibrillators for patients at high risk. Their size, that ofa notebook laptop computer, and costs of approximately$3000 should both decrease considerably over the nextdecade.A. Ventricular Fibrillation/PulselessVentricular TachycardiaVF is defined as a pulseless chaotic disorganized rhythmwith an undulating irregular pattern that varies in size andshape and has a ventricular waveform greater than 150 beatsper minute. V T is an irregular wide QRS complex tachycardia(see the chapter Arrhythmias/Palpitations). Patientswith V Tmay remain stable, alert, and have a pulse. Patientswith unstable ventricular tachycardia are hemodynamicallyunstable with a blood pressure of less than 90 mmHg, chestpain, shortness of breath, clouding of consciousness, orrapid loss of consciousness.III. CARDIOPULMONARY RESUSCITATIONCPR is only a temporary measure. The aim is to get bloodcontaining a fresh supply of oxygen to the brain.Therefore, it is necessary to breathe enough air into thepatient’s lung, then compress the chest to cause thenonbeating heart to expel blood into the arteries. Thisproduces circulation of the blood to the brain. Rarely, thepatient may be revived, and the heart begins to beatspontaneously. In patients with ventricular fibrillation,death will occur unless the heart is defibrillated. The hopeis that the ambulance has a portable defibrillator and ateam that can defibrillate the patient.

III. CARDIOPULMONARY RESUSCITATION217A. How to Recognize Cardiac ArrestFirst, the patient’s level of responsiveness must be determined.If the patient is unresponsive, he is unconsciousand oblivious to shaking or commands. Second, determineif the patient is breathing. Within 30 seconds you shouldhave arrived at a conclusion that a cardiac arrest hasoccurred. Speed of diagnosis is critical. Within three tofour minutes of cardiac arrest, irreversible brain damagecan occur because of lack of oxygen. The intention is toprovide basic life support until advanced life support in theform of expert technical help arrives. When CPR is startedwithin four minutes after collapse, the probability ofsurvival doubles.In a King’s County survey, 46% of patients with VFsurvived CPR versus only 7% for presumed asystole andpulseless electrical activity (PEA). The incidence of VF inthat survey was 45% and asystole/PEA 41%. Thus close to50% of patients with VF can be resuscitated with efficientCPR, but less than 10% with other rhythms can beresuscitated.B. The Steps of CPRAHA Guidelines provide the following steps for CPR(see Fig. 1): Check responsiveness Open the airway Check breathing Give two effective breaths Access the circulation Compress the chest (see Fig. 2)1. Responsiveness — AirwayCPR should be commenced immediately. First, turn thevictim flat on the back on a hard surface (preferably thefloor). Quickly assess head tilt for responsiveness and lossof consciousness. Figure 2 shows the use of the head tilt/chin lift maneuver to open the airway. One hand is placedon the victim’s forehead and firm backward pressure isapplied with the palm to tilt the head back. The index andmiddle finger of the other hand are placed under the bonyparts of the lower jaw. The chin is lifted forward and thejaw is supported. Avoid pressing the fingers into the softtissue under the chin. This maneuver should bring theteeth almost together and maintain dentures in position.2. BreathingPlace your ear over the victim’s mouth and nose. If you donot hear or feel the flow of air escaping and the chest doesnot rise and fall, the victim is not breathing. Pinch thevictim’s nostrils closed, using your thumb and index fingerof the hand on the forehead. Then take a deep breath,make a tight seal over the victim’s mouth with yourmouth, and blow into the victim’s mouth. Blow air intothe victim’s mouth to fill the lungs (ventilate) rapidly twotimes allowing the chest to deflate totally between eachbreath.C. Circulation1. The PulseThere is no pulse if cardiac arrest has occurred. Check for apulse by feeling the carotid artery in the neck. The rightcarotid artery is felt one inch from the angle of the jaw.Place the index finger in a straight line parallel with thewind pipe (trachea) so that the entire length of the firstfinger pad is touching the skin. The tip of the index fingershould be approximately opposite the Adam’s apple. Startby feeling the most prominent part of the Adam’s applewith the tips of two fingers, then slide the finger outwardto reach the groove between the hard cartilage of the windpipe and the muscle of the neck. The carotid artery liesonly a few millimeters under the skin, and the pulsation iseasily felt. Practice feeding this pulse so that you can find itin a hurry, taking no more than 10 seconds.Evidence has accumulated from the European ResuscitationCouncil and other international expert panels thatthe pulse check is not a good diagnostic test for thepresence or absence of a beating heart. The pulse is not asatisfactory check for lay responders and they should checkfor signs of circulation such as any movement includingswallowing or breathing that consists of more than anoccasional gasp.2. Chest CompressionPlace the heel of one hand over the lower half (see Fig. 1)of the breastbone, but at least one inch (2 cm or twofingerbreadths) away from the end of the breastbone(xiphoid process). Position the heel of your other hand onthe top of the first. Keep the fingers off the rib cage. If yourhands are too high, ineffective chest compression mayresult, and fracture of the ribs may occur. Keep your armsstraight at the elbow (locked elbows) and apply pressure asvertically as possible. Your shoulders should be directlyabove the victim’s breastbone. Chest compressions are theneasily carried out by forceful movements of the shouldersand back, thus the maneuver is less tiring. Depress the

218CARDIOPULMONARY RESUSCITATION (CPR)• Person collapses• Possible cardiac arrest• Assess responsivenessUnresponsiveBegin Primary ABCD Survey 1(Begin BLS Algorithms)• Activate emergnecy responsesystem• Call for defibrillator• A Assess breathing (openairway, look, listen, and feel)Not Breathing• B Give 2 slow breaths 1• C Assess pulse, if no pulse →• C Start chest compressions• D Attach monitor/defibrillatorwhen availableNo Pulse• CPR continues• Assess rhythmVF/VTNon-VF/VTAttempt defibrillation(up to 3 shocks if VF persists)2 Non-VF/VT(asystole or PEA)3FIGURE 1CPR for1 minuteSecondary ABCD Survey 4, 5• Airway: attempt to place airway device• Breathing: confirm and secure airway device,ventilation, oxygenation• Circulation: gain intravenous access; give adrenergicagent; consider → antiarrhythmics, buffer agents,pacingNon-VF/VT patients:—Epinephrine 1 mg IV, repeat every 3 to 5 minutesVF/VT patients:—Vasopressin 40 U IV, single dose, 1 time onlyor—Epinephrine 1mg IV, repeat every 3 to 5 minutes(if no response after single dose of Vasopressin, mayresume epinephrine 1 mg IV push; repeat every3 to 5 minutes)• Differential Diagnosis: search for and treat reversiblecausesCPR up to3 minutesComprehensive ECC algorithm. (From Circulation, 200:102(8) Supplement I-142–I-165. Copyright 2000 American Heart Association, Inc.)breastbone one to two inches (3–5 cm) toward the spine;alternately compress and relax.The compression rate should be about 90–100 compressionsper minute. At the end of the 15th compressiontwo full breaths are given. CPR should never be interruptedfor more than five seconds, and it should be continueduntil skilled help arrives. Endotracheal intubationshould be accomplished within 30 seconds of cessationof CPR.Note that the victim’s mouth should be almost completelyclosed, however, depress the lower lip a bit so thatthe mouth remains slightly open. If dentures cannot bemanaged in place, remove them after first giving the veryimportant first two breaths. You must see the chest rise and

IV. DEFIBRILLATION219FIGURE 2 Basic life support. (From Khan, M. Gabriel, Cardiopulmonary resuscitation, in Cardiac Drug Therapy, sixth edition, Philadelphia:W. B. Saunders.)fall. If the first two breaths meet with resistance and thechest fails to rise when you breathe air into the patient’smouth, make sure that the airway is properly opened bythe head tilt/chin lift method and that the seal around themouth is airtight. Then clear the airway with your fingersif necessary. The fact that the patient suddenly dropped tothe ground and was not choking while eating is sufficientto persuade you not to waste time searching for meat orvomitus.IV. DEFIBRILLATIONThe first shock setting should be 200 joules followed bya second shock of 300 joules. One defibrillator paddleis positioned to the right of the sternum below the clavicle.The other paddle is placed to the left of the left nipplewith the center of the paddle in the mid-axillary line.An appropriate gel is one that has a low impedance.Because gel spreads during chest compression, shocks mayarc across the chest surface thus, the gel must be toweledoff. Conducting gel pads should be used but must bechanged between shocks. Heavy arm pressure should beapplied to each paddle applied to the chest anddefibrillation should take place when the victim’s phaseof ventilation is in full expiration. In the UK the lowerpaddle is placed over the points designated as V4 and V5for the ECG, that is, a little outside the position of thenormal apex beat. The paddle should be placed at least fiveinches away from a pacemaker generator.The area around the patient should be checked so thatno personnel are directly or indirectly in contact with thepatient. The operator must not touch the patient whenthe shock is delivered. Deliver countershock by depressingboth paddle discharge buttons simultaneously. Ifno skeletal muscle contraction is observed, check theequipment.After countershock reassess the cardiac rhythm. If VFpersists repeat the shock as soon as possible and continueCPR during any delays. If an organized rhythm is restored,check immediately for a pulse. If no pulse is presentresume CPR.Ventricular asystole causing cardiac arrest indicatesa poor prognosis. After CPR is initiated epinephrineis given. Occasionally VF may masquerade as asystole.

220CARDIOPULMONARY RESUSCITATION (CPR)The monitoring electrodes should be repeated from theoriginal positioned to ensure that VF is not present.Asystole or electromechanical dissociation is usually causedby irreversible myocardial damage that is extensive with apoor prognosis.A. Errors in DefibrillationEisenberg and Mengert emphasized the following commonerrors in CPR. Defibrillation errors may occur if thesynchronized mode is accidentally selected before defibrillationis attempted, thus no shock is delivered. Asystolemay be falsely displayed when the selection is set forpaddles and the rescuer believes that rhythm lead II isbeing displayed. In addition, if a vast amount of chest hairis present it should be shaved off where the paddles are tobe placed; smeared gel across the chest should be toweledoff before defibrillation.Oxygen at 100% concentration is given as soon aspossible through a bag-valve mask or endotracheal tube.Plastic face masks may provide 50–60% oxygen with anoxygen flow rate of 10 L/min.randomized trials in patients with cardiac arrest however,showed no significant benefit. The higher dose regimen isno longer recommended.B. VasopressinVasopressin, a clonal substance antidiuretic hormone,becomes a powerful vasoconstrictor when used at muchhigher doses than normally present in the body. This drugpossesses effects that duplicate the positive effects ofepinephrine, but does not duplicate the adverse effects ofepinephrine. Only one dose of vasopressin is required.This is less frequent than epinephrine because the 10- to20-minute half-life of vasopressin is much greater thanthe 3- to 5-minute half-life of epinephrine. Vasopressinis recommended only for VF/VT; there is no evidence tosupport its usefulness in asystole or PEA.Vasopressin is to be administered IV single-dose onetime only. If there is no response 5–10 minutes after asingle dose of vasopressin, it is advisable to resumeepinephrine 1 mg IV push every 3–5 minutes.V. DRUGS FOR CARDIAC ARRESTA. Epinephrine (Adrenaline)For more than 40 years epinephrine has been a key agentused during cardiac arrest. Epinephrine is both an alphaandbeta-adrenergic agonist; therefore, it stimulates spontaneouscardiac contractions, increases systemic vascularresistance resulting in an increased aortic diastolic perfusionpressure, and improves coronary blood flow. It isrelevant that epinephrine constricts peripheral vessels butpreserves flow to vital organs causing coronary arterydilation.Epinephrine is indicated for fine VF, which is renderedmore amenable to removal by countershock and for VFthat does not respond to electrical countershock. Asystoleand pulseless idioventricular rhythms and electromechanicaldissociation may respond to this drug, albeit rarely.A dose of 1 mg IV push every 3–5 minutes (0.01 mg/kg)is recommended. A 20-ml IV fluid flush should be administeredto ensure delivery of the drug centrally. A dose of1 mg/10 ml of a 1:10,000 solution may be given via thetracheobronchial tube.A higher dose of epinephrine was advocated by the AHAin 1992 based on studies. If the 1-mg IV dose wasineffective, escalating doses of 3 and 5 mg or 5 mg per doserather than 1 mg were advised; the result of 8 largeC. AmiodaroneAmiodarone is a complex drug which effects sodium,potassium, and calcium channels as well as alpha- andbeta-adrenergic blocking properties (see the chapterArrhythmias/Palpitations). This drug is recommendedafter defibrillation and epinephrine in cardiac arrest withpersistent VT or VF.The recommended dose is 300 mg IV push. If VF/pulseless VT recurs, consider administration of a seconddose of 150 mg IV.D. Beta-Adrenergic Blocking AgentsThe actions and beneficial effects of beta-blockers are givenin the chapter Beta-blockers. Atenolol, metoprolol, andpropranolol have been shown to reduce the incidenceof VF significantly in post-MI patients who did notreceived fibrinolytic agents. Beta-blockers have been shownto prevent recurrent VF. VF is unique among cardiacarrhythmias because management with immediate countershockantifibrillatory drugs can be useful. Beta-blockersincrease VF threshold and have been shown to be useful inpatients who have repetitive VF precipitated by electrocution.Although these agents have a negative inotropiceffect, they are not helpful in patients in cardiac arrest.

VII. OUTCOMES OF OUT-OF-HOSPITAL CARDIAC ARREST221Metoprolol is administered 5 mg by slow IV pushover 5 minutes, at 5-minute intervals for a total 15 mg.Propranolol has been used worldwide and its use continuesat a dose of 0.1 mg/kg by slow IV push divided into threeequal doses at 2- to 3-minute intervals. The rate ofadministration should not exceed 1 mg/minute. Esmolol isa short-acting beta-blocking agent with a short half-life of2–9 minutes. The drug is metabolized by erythrocyteesterases and requires no dose adjustment in patients withrenal or hepatic impairment. The dosing regimen iscomplex and requires an IV infusion pump (see thechapters Beta-Blockers and Arrhythmias/Palpitations).E. Sodium BicarbonateThis agent is no longer recommended for routine useexcept for pre-existing hyperkalemia. Prompt ventilation ofthe lungs is essential for excretion of carbon dioxide and isthe most effective method for combating acidosis.Sodium bicarbonate may be used to combat bicarbonateresponsive acidosis, tricyclic overdose, and after about 10minutes of ventilation including intubation, defibrillation,and use of epinephrine. If CPR is still necessary, sodiumbicarbonate may be used. The drug may also be used onreturn of circulation after long cardiac arrest, but itsuse should be guided by arterial pH measurements.The recommended dose is an IV bolus of 1 mEq/kg( 50 mEq).F. AtropineThis drug is of value in the management of severebradycardia associated with cardiac arrest. Patients withasystole or PEA may respond to atropine while preparationsare made for pacing. Patients with a high degreeatrioventricular block, slow idioventricular rates, and severesinus bradycardia with hypotension should be given a trialof atropine IV.A dose of 1 mg IV repeated in 3–5 minutes is recommended.If asystole persists, the maximum of 3 mg can beadministered (0.04 mg/kg).G. Magnesium SulfateMagnesium sulfate is reported to expedite ventriculardefibrillation and is indicated for polymorphic ventriculartachycardia, torsades de pointes, and management ofhypomagnesemia. A dose of 1–2 mg IV is recommended.H. BretyliumBretylium has been dropped from the VF/pulseless VTalgorithm. This drug was used in the 1980s and 1990s forrecurrent VF, but was only partially successful and neverproven. In the late 1990s, severe problems with obtainingthe raw materials curtailed manufacture. The world sourcesof bretylium appear to be nearly exhausted. Bretylium hasa high incidence of side effects including hypotension. Ithas been replaced by amiodarone and beta-blockingagents.VI. PERSPECTIVES AND RESEARCHIMPLICATIONSAutomated external defibrillators are now increasinglyplaced where people congregate such as shopping malls,stadiums, casinos, exercise facilities, airports, and airplanes.They should be in the homes of patients at risk, becausethe majority of cardiac arrests occur in the home. Mostimportant, a bag-valve mask and an artificial airway shouldbe provided with the defibrillator. This would assistconsiderably with mouth-to-mouth resuscitation, whichhas its disadvantages. A miniature apparatus to compressthe chest more adequately than the use of the arms wouldbe an advantage.Intravenous epinephrine has played an important roleduring the last 40 years and is the main vasopressor usedin the management of cardiac arrest. Isoproterenol iscontraindicated. Vasopressin is indicated only for VFand pulseless VT with a restriction to one dose. Neo-Synephrine and other agents have also been tried. Newvasoactive agents are needed to cause cardiac contractionsand produce adequate blood flow to vital organs.VII. OUTCOMES OF OUT-OF-HOSPITALCARDIAC ARRESTBunch et al. conducted a population-based analysis of thelong-term outcome and quality –of life of survivors of outof-hospitalcardiac arrest from ventricular fibrillation.Methods: All patients who had an out-of-hospitalcardiac arrest and received early defibrillation wereincluded.Results: Cardiac arrest occurred in 330 patients, VFin 200 (61%), pulseless electrical activity in 58 (18%),and asystole in 72 (22%). Of the 200 VF patients 145survived to admission, 61 died in hospital, and 84 (42%)were discharged from the hospital – 79 neurologicallyintact and 5 neurologically impaired.

222CARDIOPULMONARY RESUSCITATION (CPR)Among patients who were considered candidates forantiarrhythmic therapy 10 patients received amiodaronealone and 35 (50%) of all neurologically intact survivorsreceived an implantable cardioverter defibrillator. Ofthe 79 survivors 19 died after hospital discharge. Of 60patients at five-year follow up 45 were able to return towork and 50 completed the health questionnaire.Conclusions: Of 330 cardiac arrest victims only 50patients (15%) were alive and well 5 years later, with 70%having an implantable cardioverter defibrillator.VIII. THE HEIMLICH MANEUVERThis maneuver is used for removing foreign bodies fromthe airway. You must stand behind and wrap your armsaround the waist of a conscious victim. Then place thethumb side of your fisted hand above the victim’s naveland well below the lower tip of the breastbone. Using theother hand, forcefully push the fist with a quick upwardthrust into the victim’s abdomen. Repeat the thrust a fewtimes if necessary. An unconscious victim is placed faceupward. The rescuer kneels and places the heel of one handabove the navel and with the second hand on top pushesinto the abdomen with a quick upward thrust.BIBLIOGRAPHYAbella, B. S., Sandbo, N., Vassilatos, P., Alvarado, J. P., O’Hearn, N.,Wigder, H. N., Hoffman, P., Tynus, K., Vanden Hoek, T. L.,Becker, L. B. et al. Chest compression rates during cardiopulmonaryresuscitation are suboptimal: A prospective study during in-hospitalcardiac arrest. Circulation, 111:428–434, 2005.Bunch, T. J., White, R. D., and Gersh, B. J. Long-term outcomes of outof hospital cardiac arrest after successful early defibrillation. N. Engl.J. Med., 348:2626–33, 2003.Cummins, R. O., and Eisenberg, M. S. Prehospital cardiopulmonaryresuscitation: Is it effective? JAMA, 253:2408–12, 1985.Eisenberg, M. S., and Mengert, T. J. Cardiac resuscitation. N. Engl.J. Med., 344:1304–13, 2001.Guidelines 2000 for Cardiopulmonary Resuscitation and EmergencyCardiovascular Care. The AHA in collaboration with the internationalliaison committee on resuscitation. Circulation, 102 (8 Suppl.):1–142,2000.Kouwenhoven, W. B., Jude, J. R., and Knickerbocker, G. G. Closed chestcardiac massage. JAMA, 173:1064–7, 1960.Safar, P. Ventilatory efficacy of mouth to mouth artificial respiration:Airway obstruction during manual and mouth to mouth artificialrespiration. JAMA, 167:355–41, 1958.Sanders, A. B., Ewy, G. A. et al. Cardiopulmonary resuscitation inthe real world: When will the guidelines get the message? JAMA.,293:363–365, 2005.Wenzel, V., Krismer, A. C, and Arntz, H. R. A comparison of vasopressinand epinephrine for out-of-hospital cardiopulmonary resuscitation.N. Engl. J. Med., 350:105–113, 2004.Wik, L., Kramer-Johansen, J., Myklebust, H., Sørebø, H., Svensson, L.et al. Quality of cardiopulmonary resuscitation during out-of-hospitalcardiac arrest. JAMA, 293:299–304, 2005.

Chagas DiseaseI. EpidemiologyII. Symptoms and SignsIII. Diagnostic InvestigationsIV. ManagementGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiomyopathy heart muscle disease.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker ofventricular contractility.hypokinesis decreased myocardial contraction usually caused bydamage and weakness of the heart muscle due to coronaryartery disease and cardiomyopathies.myocardium the heart muscle.I. EPIDEMIOLOGYThe protozoan Trypanosoma cruzi causes Chagas disease,which affects more than 30 million individuals, withapproximately 100 million at risk in Latin America.Figure 1 shows the distribution of Chagas disease in theAmericas. This disease is prevalent only in Central andSouth America, particularly in Argentina, Chile, Brazil,and Bolivia. It also occurs in the southern United States,however, where more than 90,000 Latin Americans arebelieved to be infected. The risk of transmission in theUnited States is mainly by blood transfusion by thisimmigrant population.A. TransmissionChagas disease is transmitted to children and young adultsless than age 20 through the bite of a bug (reduviid,subfamily Triatominae). The bug becomes infected byfeeding on infected animals such as the armadillo,opossum, raccoon, and skunks. Domestic dogs and catsalso provide an extensive reduviid reservoir for infectingentire families.The biting bug unfortunately dwells in the roofs andwalls of houses. During the night the bug drops onto thesleeping individual and inflicts bites around the eyes.Infection is transferred when the trypanosomes in theanimals excrement enters the wounded skin or penetratesthe conjunctiva. The protozoa multiplies and thenmigrates through most organs of the body including themyocardium, pericardium, liver, spleen, and brain. Chagasdisease is primarily transmitted through blood transfusions,and unfortunately screening of blood is financiallynot possible in the affected countries. The simpleaccomplishment of screening blood, building betterhomes, and screening cats and dogs would prevent themajority of infections.II. SYMPTOMS AND SIGNSA. Acute PhaseThe bite of the bug around the eyes allows thetrypanosomes to gain entry through the conjunctiva.This often results in one-sided swelling around the eye(periorbital edema) and swelling of the eyelid (Romanasign). If the entry is through the skin, a lesion called achagoma appears. The initial lesion may go unrecognized,however, and no symptoms may appear until after morethan 15 years when symptoms of chronic disease emerge.In about 10% of infected individuals acute symptomssuch as muscle aches and pains, fever, sweating, andenlargement of the liver and spleen occur. If the parasiticinfection involves the cardiac muscle, an acute myocarditisand heart failure may supervene causing death. Lesionsmay spread to involve the endocardium and stimulate theflowing blood to form a clot that may embolize. Thepericardium may be involved causing pericardial effusions.Young children become more seriously ill than youngadults, and in more than 10% the acute disease is fatal.Many patients recover, however, and symptoms disappear223

224CHAGAS DISEASEFIGURE 1 Distribution of Chagas disease in the Americas. (From Acquatella, H. (1995). Atlas of Heart Diseases, Vol. 2. (Abelmann, W.H., Braunwald,E., eds.). p. 8.1–8.18, Philadelphia: W.B. Saunders.)over 1–2 years. More than 40% of infected patients aftera relatively symptom-free interval of several years revealsigns and symptoms of chronic Chagas disease.B. Latent and Chronic PhaseCardiac involvement is mainly due to a cardiomyopathythat manifests about 20 years after the trypanosomalinfection. At this point, the heart muscle is uniformlydestroyed and replaced by fibrous tissue. The weakenedheart muscle is stretched, the left ventricular chamberdilates, the pumping function is severely deranged, andheart failure supervenes. Heart failure produces changesin the heart, circulation, and veins that can be detectedon examination by the physician. A chest x-ray confirmsdilation of the heart and presence of fluid in thespongework of the lungs and fluid within the pleuralspace (pleural effusions).The main manifestation of heart failure is increasingshortness of breath on mild activity and with severe heartfailure, shortness of breath occurs at rest. Heart failuredescribes the signs and symptoms that occur when the leftor right ventricles are unable to eject an adequate amountof blood into the aorta to fulfill the needs of organs andtissues. Thus blood remains longer in the lungs and saltand water escapes into the air sacs (the alveoli), causingoxygen lack and severe shortness of breath. In heartfailure, salt and water are retained by the kidneys as acompensatory mechanism and extra fluid exudes intotissues in dependent parts of the legs causing bilateralleg edema. The legs are not waterlogged, they are brinelogged (see the chapter Heart Failure).The pathologic findings include hypertrophy anddilatation of cardiac chambers in keeping with a dilatedcardiomyopathy. The left ventricle apex becomes thin andbulges into an aneurysm. Clot formation often occurswithin the aneurysm and thromboembolism to otherorgans occurs.The electrical bundles of the heart, particularly the rightbundle branch and the anterior fascicle of the left bundlebranch, are commonly involved by the inflammatoryprocess causing the ECG to show a typical pattern ofright bundle branch block and left anterior fascicularblock hemiblock. The large left bundle branch is reallyinvolved.Symptoms of cardiomyopathy include shortness ofbreath, chest pain, syncope, and sudden death caused byheart block due to involvement of the electrical conductingsystem. In many patients the left ventricle fails, butmanifestations are mainly of right heart failure. Thus, theshortness of breath from left ventricular failure maydiminish and signs of right heart failure may become more

IV. MANAGEMENT225prominent. These signs include fluid retention that causesswelling of the abdomen (ascites) and bilateral leg edema.The trypanosome in Brazil often involves the esophagus,stomach, and colon resulting in a dilated esophagus(megaesophagus and megacolon). This is uncommon inCentral America and Mexico because it is caused by adifferent strain of trypanosome.In the acute phase of the disease, trypanosomes arefound in the cardiac fibers accompanied by marked cellularinfiltrate around cells that have ruptured and released theparasites. It is not unusual, however, to be unable to findparasites in the cardiac tissue at autopsy. An autoimmunemechanism is believed to explain the lack of correlationof parasitemia with disease severity. T. cruzi antigen isfrequently found in biopsy specimens.III. DIAGNOSTIC INVESTIGATIONSA. Chest X-rayThe chest x-ray shows a dilated heart that increases tosevere proportions as the disease progresses. The lungsmay show evidence of fluid accumulation with pleuraleffusions, but the lung fields may be relatively clear ifmainly right heart failure occurs.B. Blood TestsIn Chagas disease the serum aldolase is usually elevated.A complement fixation test (Machado-Guerreiro test) thathas high specificity and sensitivity is used to identifychronic Chagas disease. Xenodiagnosis is the preferred testin endemic areas. With this test reduviid bugs bred in thelaboratory are allowed to bite the patient. The parasites arethen found in the intestine of the insect proving infectionin the patient.C. EchocardiographyEchocardiography shows enlargement of all four heartchambers in Chagas patients. There is also a reduction inthe ejection fraction. On echo, the appearance of Chagas isdistinctive: there is hypokinesis, poor contractility of theleft ventricular posterior wall, relatively preserved intraventricularseptal wall motion, and poor movement of theapical segment of the heart with dilatation and aneurysmalformation.IV. MANAGEMENTA. PreventionVector control and interruption of transmission of theparasites to humans remain crucial. In endemic areasindividuals should avoid having dogs or cats in the home.Improved housing conditions, repair of walls and ceilings,and added fresh paint should deter bugs from these areas.The use of nets for sleeping should prevent bugs fromfalling from ceilings onto the exposed face at night.B. MedicationsAntiparasitic agents such as benzimidazole, itraconazole,and nifurtimox reduce parasitemia in the acute phase, butthey do not have any effect on the autoimmune-mediatedchronic form of the disease. Anticoagulants are necessary inpatients with left ventricular aneurysm or thrombi detectedin the ventricle and those who have sustained embolism.Arrhythmias often require treatment with antiarrhythmicssuch as amiodarone. This drug is used for symptomaticrelief and does not appear to prolong life.BIBLIOGRAPHYApt, W., Aguilera, X., Arribada, A. et al. Treatment of chronic Chagasdisease with itraconazole and allopurinol. Am. J. Trop. Med. Hyg.,59:133, 1998.Parada, H., Carrrasco, H. A., Anez, N. et al. Cardiac involvement is aconstant finding in acute Chagas disease: A clinical parasitologicaland histopathological study. Int. J. Cardiol., 60:49, 1997.Wynne, J., and Braunwald, E. In Heart Disease, sixth edition.E. Braunwald, D. P. Zipes, and P. Libby, eds. W. B. Saunders,Philadelphia, 1789, 2001.

Chelation and Heart DiseaseI. Clinical StudyII. Perspectivetherapy. Controversies have raged in the last 30 yearsregarding the value of chelation therapy.GLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells usually caused by severe obstruction of theartery supplying blood to the segment of cells.atherosclerosis same as atheroma, raised plaques on the innerwall filled with cholesterol, calcium, and other substances onthe inner wall of the arteries that obstruct the lumen and theflow blood; the plaque of atheroma hardens the artery, hencethe term atherosclerosis (sclerosis ¼ hardening).myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.plaque of atheroma same as atherosclerotic, a plaque that jutsinto the lumen and obstructs the flow of blood in arteries.OBSTRUCTION OF CORONARY ARTERIES BYcholesterol, calcium deposition, and fibrotic tissuefollowed by accumulation of blood particles, platelets,and finally thrombosis is the cause for angina, heart attack,heart failure, and sudden death. After more than 50 yearsof considerable research on the cause and prevention ofobstruction to coronary arteries by plaques of atheroma,we are still a moon ride away from preventing obstructionto arteries. Chelation, a method for clearing the obstruction,is analogous to using Drano to clean obstructedpipes. Treatments cost approximately $4000 per year and,surprisingly, during the 1980s and 1990s was used by morethan half a million patients in the United States annually.It appears that in Canada approximately 8% of patientsundergoing coronary angiography have tried chelationI. CLINICAL STUDYStudy question: Does chelation therapy with EDTAimpact exercise-induced ischemia or quality of life inpatients with stable coronary artery disease?Methods: A double-blind randomized clinical trial of84 patients with stable angina (stable coronary arterydisease) on the usual recommended medical therapy andsignificant electrocardiographic ST segment depressionwere studied. EDTA 40 mg/kg or placebo was administeredfor three hours per treatment twice weekly for15 weeks and then once monthly for three months. Malepatients represented 84% of the study group, average age65 years, multivessel disease was present in approximately55%, 50% of patients were asymptomatic, and 60%had significant angina.Results: At baseline there was no difference in the timeof onset of ischemia on electrocardiographic treadmilltesting. After treatment there was no difference to supporta beneficial effect of calcium chelation therapy withEDTA. There was no difference in exercise time to induceischemia on the treadmill and no difference in exercisecapacity or quality of life.II. PERSPECTIVEKnudtson et al. concluded: ‘‘physicians can now informpatients that there is no scientific evidence to support theclaim that $4000 per year for chelation therapy withEDTA is money well spent.’’ The fact that controversialchelation therapy is still practiced indicates that we donot have treatment that provides satisfactory beneficial227

228CHELATION AND HEART DISEASEeffects for the majority of patients treated for obstructivecoronary artery disease and that more research is required.The idea of chelation should not be abandoned. EDTAhas had its day but perhaps other molecules that candissolve plaques of atheroma should be sought.BIBLIOGRAPHYKnudtson, M. L.,Wyse, K. G., Galbraith, P. D. et al. Chelation therapyfor ischemic heart disease. A randomized controlled trial. JAMA,287:481–6, 2002.Merrill, L. K.,Wyse, G., Galbraith, P. D., Brant, R., Hildebrand, K.,Paterson, D., Richardson, D., Burkart, C., and Burgess, E. for theProgram to Assess Alternative Treatment Strategies to Achieve CardiacHealth (PATCH) Investigators. JAMA, 287:481–486, 2002.ABSTRACTContext Chelation therapy using EDTA is an unprovenbut widely used alternative therapy for ischemic heartdisease.Objective To determine if current EDTA protocols havea favorable impact on exercise ischemia threshold andquality of life measures in patients with stable ischemicheart disease.

Chemotherapy-Induced Heart DiseaseI. Chemotherapeutic AgentsII. Cardiac Damage from AnthracyclinesIII. CyclophosphamideIV. 5-FluorouracilGLOSSARYafterload arterial impedance, restriction of blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of wall stress.endocardium internal lining of the heart.heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hypotension marked decrease in blood pressure, usually lessthan 95 mmHg.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severe obstructionof the artery supplying blood to this area of cells.metastases distant spread of cancer to various organs.myopericarditis specific or nonspecific infection of both thepericardium and the myocardium.necrosis cell death.DURING THE PAST DECADE THERE HAVE BEENconsiderable advances in the use of chemotherapy for thetreatment of the various cancers such as Hodgkin’s andnon-Hodgkin’s lymphoma, acute leukemias, colorectal andlung cancer, and local tumor control particularly withbreast cancer. Metastases to various organs causes untoldsuffering and pain. Chemotherapy is effective in manypatients, but its toxic effects on the heart, particularly onthe myocardium, often limit their use in patients whomay need these agents the most. Most important, cardiomyopathycaused by chemotherapeutic agents causes deathin a significant number of patients. Further research isrequired to provide new effective agents with less toxicity.I. CHEMOTHERAPEUTIC AGENTSIt is common for chemotherapeutic agents to be associatedwith myocardial damage reduction in ejection fraction andheart failure.The toxic effects of anthracyclines on the heart are wellknown. Doxorubicin, in a total toxic dose range of greaterthan 550 mg/m 2 , causes heart failure and arrhythmias.Daunorubicin in a total toxic dose range of greater than550 mg/m 2 , has the same toxicity as doxorubicin. Theanthracenedione mitoxantrone causes significant decreasein left ventricular ejection fraction and heart failure.Amsacrine at conventional doses causes ventriculararrhythmias. Cyclophosphamide at a dose of greater than100–120 mg/kg over 2 days may cause heart failure, hemorrhagicmyocarditis, pericarditis, and necrosis of themyocardium. Ifosfamide has similar cardiotoxic effectsand can cause heart failure. 5-Fluorouracil at conventionaldoses may cause chest pain and coronary artery spasm thatcauses anginal pain and rarely, myocardial infarction.Busulfan at conventional doses may cause fibrosis of theendocardium. Cisplatin at conventional doses may causechest pain and myocardial ischemia. Vincristine andvinblastine at conventional doses may cause myocardialinfarction. Mitomycin C in conventional doses causesmyocardial damage that is similar to radiation-inducedinjury. Interferons in conventional doses may exacerbateunderlying cardiac disease. Interleukin-2 in conventionaldoses causes abnormal heart rhythms, hypotension, andmyocardial damage.II. CARDIAC DAMAGE FROMANTHRACYCLINESAnthracyclines contain an aromatic ring structure thatintercalates in between DNA base pairs. The mechanism ofcardiotoxicity appears to be inhibition of the function oftopoisomerase II. This enzyme is critical in allowing DNA229

230CHEMOTHERAPY-INDUCED HEART DISEASEto undergo efficient repair. Most important, these agentsgenerate free radicals that can damage cell membranespartly by lipid peroxidation. Amsacrine and mitoxantroneproduce lower quantities of free radicals and cause lesscardiotoxicity and cardiomyopathy compared with thedoxorubicin, daunorubicin, idarubicin, and epirubicin.Cardiac tissues possess a low ability to detoxify these freeradicals because of the presence of only small amounts ofcatalase that converts hydrogen peroxide to water.In addition, anthracyclines chelate iron. These anthracycline–ironcomplexesproduce cardiac-damaging hydroxylradicals. Research is required in this area to find moleculesthat may modify these toxic effects. One agent, dexrazoxane,undergoes hydrolysis to a carboxylamine that is capableof removing iron from the anthracycline–iron complex.It is partly effective in protecting the myocardium fromdamage.Listed below are electrocardiographic manifestations ofanthracycline cardiac damage.1. Prolongation of the QT interval may occur in somecases following the first or subsequent doses. Thus,other drugs that may increase the QT interval shouldnot be administered concurrently because arrhythmiasmay be precipitated.2. Increased heart rate, sinus tachycardia, and abnormalheart rhythms may arise from the atrium such assupraventricular tachycardia.3. Electrical conduction disturbances such as atrioventricularblock and bundle branch block may occur.4. ST segment elevation and T-wave changes thatreflect pericarditis or myopericarditis may occur. Thedamage to the heart may culminate in heart failureand death during the first 2 weeks of therapy, albeitrarely.Most of the cardiac toxic effects of anthracyclines arecaused by prolonged therapy and the cumulative dose ofthe drug. There is loss of cardiac myocytes with increasingdoses of these agents. Vacuolation of cells and myofibrillardropout cause weakness of muscle elements that lead todilatation of the ventricular muscle, which constitutesa chronic dilated cardiomyopathy that may appear andprogress many years after cessation of anthracyclinetherapy.A. Signs and SymptomsMain symptoms of cardiotoxicity are shortness of breathand fatigue caused by cardiomyopathy that causes poorejection of blood from the heart (ejection fraction) into thearteries. These are symptoms of heart failure. Physical signsinclude edema, enlargement of the liver, and accumulationof fluid in and around the lungs, and pleural effusions.The veins in the neck may be distended with blood thatthe heart is unable to pump forward (indicating jugularvenous pressure). The chest x-ray may show signs of heartfailure. Abnormal heart rhythms are common.There are several diagnostic tests to reveal anthracyclinecardiotoxicity. Patients are usually followed with radionuclideventriculography, which gives a good assessmentof the left ventricular ejection fraction. A decrease in theejection fraction to less than 40% is a signal for thedevelopment of heart failure. An ejection fraction below45% indicates that myocardial damage has already takenplace. Echocardiographic assessment is not as accurateas radionuclide ventriculography for determination of theejection fraction, but it gives the best assessment overmyocardial wall abnormalities and regional cardiac relaxation.These subtle abnormalities as well as the echocardiographicfindings described above may be the firstsignals of cardiac damage.B. Management of CardiotoxicityArrhythmias are one symptom of cardiotoxicity. They aremanaged with administration of beta-blockers. Supraventriculartachycardia and bothersome sinus tachycardiacan be controlled with atenolol, 25–50 mg once daily ormetoprolol, extended-release 50 mg once daily. A majorcontraindication to beta-blockers is the precipitation ofwheezing and severe asthmatic attacks in susceptibleindividuals. They are, however, safe in patients with mildchronic bronchitis (see the chapter Beta-Blockers). Patientswith ejection fractions less than 45% should be commencedon an afterload reducing agent such as an ACEinhibitor: enalapril 5 to 10 mg once daily or similar dosageof another ACE inhibitor (see the chapter Angiotensin-Converting Enzyme Inhibitors/Angiotensin ReceptorBlockers).Patients with heart failure should be managed withoptimal therapy with diuretics such as furosemide20–60 mg once daily, an ACE inhibitor, digoxin, and asmall dose of a beta-blocker. If heart failure persists,spironolactone should be added to the regimen (see thechapter Heart Failure). Changes in dose schedules toweekly intravenous infusions rather than a larger doseevery 3 weeks appears to afford some cardioprotection.C. Research ImplicationsIn the prevention of cardiotoxicity, the use of liposomeencapsulatedanthracyclines appears to be controversial.

IV. 5-FLUOROURACIL231Dexrazoxane is capable of accepting the iron from theanthracycline–iron complex that generates tissue-damaginghydroxyl radicals and provides some cardioprotection.However, this agent may increase the incidence ofmyelosuppression and has not been shown to increasedisease-free survival. Its use is limited to oncologists.Agents that require further clinical testing includecoenzyme Q10, melatonin, probucol, beta-blockers, calciumantagonists, and glutathione. A transgenic mouseoverexpressing the human complementary DNA for multipledrug resistance, driven by an alpha-cardiac myosingene, has been developed. These transgenic mice appearto be resistant to anthracycline-mediated cardiac-myocytedropout. Newer agents that can be of value to manypatients who suffer from cancer worldwide are beingresearched and developed.III. CYCLOPHOSPHAMIDECyclophosphamide and ifosfamide high-dose therapy maycause severe cardiomyopathy and heart failure in patientsundergoing stem cell transplantation. Acute myocytenecrosis, with damage to the endothelial lining of theheart, and hemorrhagic myopericarditis may occur with a30% mortality rate. The ECG shows abnormal patternsand the chest x-ray is a good test for detecting heart failure.An echocardiogram is not a test used for the detection ofheart failure, but it is useful in revealing weakness of theheart muscle, pericarditis, or pericardial effusions. Seriouscomplications are more common in patients with preexistingheart disease, particularly in those with leftventricular dysfunction and an ejection fraction of lessthan 45%.Interferon alfa is a drug used in the management ofchronic myelogenous leukemia, hairy cell leukemia, andKaposi’s sarcoma. It may cause severe dilated cardiomyopathywith symptoms and signs of heart failure that arereversible when the drug is discontinued.Interleukin-2 is a drug that has been noted to causehypotension, rarely myocardial infarction, noncardiogenicpulmonary edema, and kidney failure.IV. 5-FLUOROURACILThis is a frequently used agent and its associated cardiotoxicitymay be more common than previously thought.Cardiotoxic effects occur when the drug is administeredas a continuous infusion and within 5 h of infusion.Symptoms and signs are usually reversible within afew days. 5-Fluorouracil should be discontinued whencardiotoxicity arises and reinstitution is not advisable dueto high incidence of recurrence. The overall incidence ofcardiotoxicity ranges from 2 to 18% with a mortality of2–15%. Unfortunately, there is no method to predictwhich patients are risk, because it has been noted thatpre-existing heart disease, dose and route of administration,age, and chest radiation do not consistently correlatewith associated toxicity. In a study of 1083 patients,however, those with a prior history of heart disease had asignificantly increased risk (4.5 vs. 1.1%) of developingchest pain compared with patients without known heartdisease (

232CHEMOTHERAPY-INDUCED HEART DISEASEarrhythmias that include atrial fibrillation, ventricularpremature beats, nonsustained ventricular tachycardia, andrarely, ventricular fibrillation have been reported. Echocardiographymay reveal left ventricular wall motionabnormalities, hypokinesia, and reduced ejection fraction.BIBLIOGRAPHYStone, R. M., Bridges, K. R., and Libby, P. Hematological-oncologicaldisorders and cardiovascular disease. In Heart Disease, seventh edition.E. Braunwald, D. P. Zipes, and P. Libby, eds. W. B. Saunders,Philadelphia, 2005.

CholesterolI. The Magnitude of the ProblemII. Historical and Clinical TrialsIII. Causes of HypercholesterolemiaIV. Types of CholesterolV. Blood TestsV1. Coronary Artery Disease RiskVII. Diets and CholesterolVIII. Cholesterol-Lowering DrugsGLOSSARYangina chest pain caused by temporary lack of blood to an areaof the heart muscle cells, usually caused by severe obstructionof the artery supplying blood to the segment of cells.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).coronary heart disease obstruction of the coronary arteries withsymptoms such as chest pain, angina, or heart attacks.dyslipidemia the same as hypercholesterolemia, elevated bloodcholesterol, LDL cholesterol, triglycerides, or low HDLcholesterol.myocardial infarction death of an area of heart muscle dueto blockage of a coronary artery by blood clot and atheroma,medical term for a heart attack or coronary thrombosis.of scientific evidence proving that lowering elevated bloodcholesterol in humans prevents fatal or nonfatal heartattacks was missing.I. THE MAGNITUDE OF THE PROBLEMIf cholesterol is the major cause of atheroma that obstructsthe flow of blood in arteries of the heart and brain,significant morbidity and mortality from cardiovasculardisease would be prevented by the aggressive lowering oftotal serum cholesterol and low-density lipoprotein (LDL)cholesterol. The complete occlusion of a coronary artery orcerebral artery is virtually always caused by a combinationof atheromatous obstruction of the artery and subsequentrupture of the plaque of atheroma with thrombusformation on the ruptured material. Thus, the termatherothrombosis (see the chapter, Atherosclerosis/Atherothrombosis).Atherothrombotic cardiovascular disease causes morethan 14 million deaths per year worldwide in a populationof about 6 billion people. This is expected to increase tomore than 25 million deaths by the year 2020 in apopulation of about 7.4 billion people. It is estimatedthat worldwide interventions could prevent more thanone million deaths annually. The prevention of atheromais obviously more important to world health thanthe expensive production of so-called left ventricular assistdevices, which are a bridge to heart transplantation.CHOLESTEROL IS A LIPID, OR FAT-LIKE SUBSTANCE,made by animal cells. The role of an elevated bloodcholesterol in causing a blockage to arteries by atherosclerosisand a subsequent myocardial infarction was acontroversial issue from 1900 to 1994. Advice to patientsduring those 90 years was often half-hearted. Until recentlywe were not able to put the blame firmly on cholesteroland convince physicians and patients worldwide toaggressively lower serum cholesterol levels. The key pieceII. HISTORICAL AND CLINICAL TRIALSA. 1900–1983Few physicians believed that cholesterol was a majorfactor in the development of atherothrombosis. Supportiveevidence was based mainly on investigations in cholesterolfed,hypercholesterolemic rabbits that showed thedevelopment and progression of atheroma formation233

234CHOLESTEROLrelative to the elevation in blood cholesterol. Anecdotalreports and small clinical studies supported this notion. The Seven Countries Study included more than 12,000men from Finland, Greece, Italy, The Netherlands,Japan, the United States, and Yugoslavia. The Finns hadthe highest intake of saturated fat, the highest bloodcholesterol levels (greater than 280 mg), and the highestnumber of fatal and nonfatal heart attacks, about900 per 100,000. The Japanese, with an average bloodcholesterol of 140 mg, had the lowest heart attack deathrate of 102 per 100,000. The United States, with anaverage of 220 mg, had a heart attack death rate of670 per 100,000. The death rate was also low in Greeceand Italy. Japanese immigrants to the United Stateswho adopt an American diet have an incidence of coronaryartery disease ten times that of their countrymenin Japan. The Framingham epidemiologic studies contributedgood evidence to support the view that a high bloodcholesterol greatly increases the risk of developingcoronary artery disease. People who have a rare, inherited genetic defect thatprevents the body from getting rid of cholesterol mayhave blood cholesterol levels as high as 900–2000 mg(23–50 mmol/L) from early childhood. These patientsdevelop cholesterol-containing lumps and bumps,especially on the knees, elbows, and tendons of thewrists and the Achilles tendon. These individuals mayhave a heart attack from the age of 1 to 10. Fortunatelythe condition, homozygous type II hyperlipoproteinemia,only occurs in one per million.Because of these studies, more than 60% of physiciansbelieved that an elevated serum cholesterol was a majorfactor, but proof from randomized clinical trials was stilllacking.B. 1984The Lipid Research Clinics Program reported the resultsof a successful trial in the United States over a periodof 10 years at a cost of $150 million. The trial showedthat a reduction in blood cholesterol resulted in a smallbut significant reduction in fatal and nonfatal heartattacks.This study was randomized and scrupulously conductedin many centers in the United States and in two centersin Canada. More than 480,000 men aged 35–59 werescreened to find subjects who had a cholesterol level greaterthan 265 mg (6.9 mmol), but were otherwise healthy andhad no evidence of heart disease or hypertension. The3806 men found suitable for the trial were asked to followa cholesterol-lowering diet. A random group of half themen was given a drug to lower cholesterol (cholestyramine,24 g daily); the other half was given an identical-lookingbut nonmedicinal preparation (placebo). The cholesterolloweringdrug caused an 8% lowering of the bloodcholesterol. After follow up for an average of 7.4 years,there were 187 fatal or nonfatal heart attacks in the controlgroup and 155 in the drug-treated group. Unfortunately,cholestyramine is a powder that is mixed with fruit juiceand is unpleasant to taste. Patients do not comply withtaking it two or three times daily, and it is not surprisingthat the reduction in cholesterol was 8% rather thanthe expected 25%. Nevertheless, the study showed thatlowering of cholesterol by a special drug reduces theoccurrence of heart attack. Thus a reduction of bloodcholesterol by diet should have a similar good effect, buta strict diet only reduces total serum cholesterol from7 to 10%.C. 1994The Hallmark Scandinavian Simvastatin Survival Study(4S) was undertaken in 1994 (see Table 1).Methods: This large multicenter study randomized4444 patients with mean cholesterol levels of 261 mg/dl(6.7 mmol/L) and LDL cholesterol levels of 172 mg/dl(4.87 mmol/L) to treatment with either simvastatin 20 mgor a matching placebo. The patients had angina or previousmyocardial infarction. The therapeutic goal of 4Swas to reduce total cholesterol to approximately 200 mg/dl; 37% of individuals required 40 mg per day to achievethis goal.Results: Total cholesterol was reduced 25% and LDLconcentrations were reduced 35% . HDL levels increased8%. At 5.4 years median follow up there was a highlystatistically significant decrease in total mortality rate of30%.There were 256 (12%) deaths in the placebo groupversus 182 (8 %) in the simvastatin group (P ¼ 0.0003).The placebo group had 189 coronary deaths comparedwith 111 in the simvastatin group, a 42% reduction in therisk of coronary deaths.Also in 1994 the Multicenter Anti-Atheroma Study(MAAS) was undertaken. This was a study of 381 patientswith coronary artery disease treated with 20 mg ofsimvastatin for four years. Results showed a decrease innew obstructions in coronary arteries, and fewer treatedpatients required angioplasty or surgery.D. 1995In 1995 the West of Scotland Coronary Prevention Studytrial randomly assigned 6595 apparently healthy Scottish

III. CAUSES OF HYPERCHOLESTEROLEMIA235men 45–64 years of age with a mean plasma cholesterollevel of 272 23 mg/dl. (7.0 0.6 mmol/L) to receive thepravastatin 40 mg or placebo. After 4.9 years follow uptotal mortality was not significantly decreased: deaths fromany cause were 135 in the placebo group and 106 in thetreated group (P ¼ 0.051, nonsignificant). Deaths fromall cardiovascular causes were 73 in the placebo and 50 inthe pravastatin group (P ¼ 0.033). There was a significantdecrease in nonfatal myocardial infarction (MI), however,with 204 nonfatal MIs in the placebo group and 143 in thetreated group (P ¼ 0.001).Thus, lowering elevated cholesterol in healthy men withelevated serum cholesterol in the range 250–300 mg/dl wasnot shown to decrease total mortality or total cardiovasculardeaths in this trial. Treatment decreased totalcholesterol and LDL cholesterol by 20 and 26%, respectively,compared with placebo. It is possible that morethan a 33% decrease in the levels are required to showa benefit. HDL cholesterol was increased by 5% in thetreated group, and this had no effect on mortality. Anincrease in HDL cholesterol greater than 10% should bethe goal, but this needs further testing in clinical trials.E. 1996The Cholesterol and Recurrent Events (CARE) trialrandomized 4159 patients with MI and angina to 40 mgof pravastatin treatment or placebo with a mean serumcholesterol level of 209 17 and LDL cholesterol 139 15. After follow up of 5 years there were no significantdifferences in overall mortality or mortality from noncardiovascularcauses. Yet, this study is described by someexperts as a landmark study. The number of fatal MIs was38 in the placebo group versus 24 in the treated group( p ¼ 0.07, nonsignificant). There was a modestly significantreduction in the number of coronary bypass surgeriesrequired in the pravastatin group compared to the placebo.Breast cancer occurred in 12 of the 290 women treatedwith pravastatin and one case of cancer occurred in thecontrol group (P ¼ 0.002).F. 1988In 1988 the Long-Term Intervention with Pravastatin inIschemic Disease (LIPID) study group was undertaken.Methods: This randomized clinical trial compared theeffects of pravastatin 40 mg with those on placebo in 9014patients 31–75 years of age. Patients had a history of MI orunstable angina and mean cholesterol level of 218 mg/dl(6.1 mmol/L) and median LDL cholesterol level of150 mg/dl.Results Over a mean follow-up period of 6.1 yearsoverall mortality was 14.1% in the placebo group (633deaths) and 11% in the pravastatin group (498 deaths;P < 0.001). Deaths from coronary artery disease occurredin 8.3% in the placebo group and 6.4% in the pravastatingroup (P < 0.001). The trial randomized 1216 womenand cancers including breast cancer were similar in bothgroups.This significant decrease in overall mortality andcardiovascular deaths in patients with severe coronaryartery disease and mean cholesterol levels representativeof the population of patients at risk for coronary arterydisease events confirms the beneficial effects observed in the4S study. It is important to recognize that most patientswith coronary artery disease have cholesterol levels that arenot markedly elevated with a mean of about 225 mg/dl(5.8 mmol/L).A strict, low-saturated-fat diet that will lower bloodcholesterol by 10% percent is feasible, but it may alsolower the good high-density lipoprotein (HDL) cholesterol.Whereas strict dieting can decrease total cholesterol7–10%, the statin drugs (HMG-CoA reductase inhibitors)have been documented in the clinical trials outlinedabove (4S, CARE, LIPID) and in more recent trials todecrease total cholesterol and LDL (bad) cholesterol from20–50%. It requires this aggressive lowering of totalcholesterol and LDL cholesterol to achieve a reduction ofatheroma development and its complications.About 20% of the population have all the luck. Theycan eat a high-cholesterol, high-saturated-fat diet andviolate all dietary rules, yet never get significant coronaryheart disease and live beyond 79.III. CAUSES OF HYPERCHOLESTEROLEMIAA. Familial HypercholesterolemiaThis is a primary genetic abnormality. In very rare cases,marked elevation of cholesterol (800–1500 mg/dl) is causedby a genetic defect. A receptor on the surface of cells (LDLreceptors) removes LDL cholesterol from the blood. Inthis disorder there is decreased production or function ofthe LDL receptor. This autosomal disorder may involveabnormalities in the synthesis, transport, or clustering ofthe LDL receptor.Homozygous familial hypercholesterolemia fortunatelyis rare and occurs in approximately one per millionindividuals in the United States. These patients have nofunctioning LDL receptors and have markedly elevatedLDL cholesterol as high as 1200 mg/dl (31 mmol/L)and extensive coronary and peripheral atherosclerosis.

236CHOLESTEROLAcute MI may occur within the first one to two years ofchildhood.Heterozygotes have a reduction of 50% of the circulatingLDL receptors and may have serum cholesterollevels in the range of 300–800 mg/dl and manifest coronaryartery atherothrombosis, peripheral vascular disease,or atheromatous obstruction to the abdominal aorta inthe third or fourth decade. Racial differences may determinethe number of LDL receptors, and thus the abilityto remove LDL cholesterol gradually from the bloodstreamis affected.Familial combined hyperlipidemia is a common conditionthat occurs in more than 1% of the North Americanpopulation. This disorder may cause elevation of totalcholesterol or triglycerides or both.B. Polygenic HypercholesterolemiaIn this condition there is a genetic predisposition anddietary factors. In susceptible individuals with a decreasednumber of LDL receptors, high saturated fat andcholesterol intake causes substantial elevation of serumcholesterol with levels in range of 260–320 mg/dl(6.5–8.3 mmol/L). Approximately 3% of the populationin the United States appears to be affected. Althoughelevation in total cholesterol is less severe than in heterozygousfamilial hypercholesterolemia, the elevation of totaland LDL cholesterol increases risk for coronary arterydisease and drug therapy with statins is advisable.C. Other Causes for HypercholesterolemiaType 2 diabetes occurs in approximately 7% of the NorthAmerican population and nearly all of these individualshave some form of dyslipidemia. Their serum cholesterol isusually in the range of 240–290 mg/dl (6.2–7.5 mmol/L).Hypothyroidism is a relatively common condition thatdecreases the metabolism with increases in serum cholesterolin the range of 240–320 mg/dl.Renal disease can also affect cholesterol levels. A form ofglomerulonephritis causes marked loss of protein in theurine, diffuse edema, and hypercholesterolemia. Biliarycirrhosis with its prolonged obstructive jaundice causesmarked elevation in serum cholesterol. Other causes includepancreatitis, monoclonal gammopathy, and porphyria.IV. TYPES OF CHOLESTEROLCholesterol is a member of a class of naturally occurringcompounds called sterols. It is an essential part of thefatty sheath that insulates nerves and the outer membraneof all animal cells, and is a component of chemicals thatinclude steroids (cortisone) and sex hormones such asandrogens and estrogens. Cholesterol acts as a precursorof bile acids and occurs in high concentrations in thebrain, nerves, and adrenal glands; cholesterol concentrationis greater than 3 g per 100 g in the brain. Body cellssatisfy their cholesterol requirements for maintenanceand growth by intracellular synthesis of cholesterol andthe receptor-mediated uptake from the external mediumof cholesterol-rich LDL particles.Dietary cholesterol is absorbed from the jejunum inan unesterified form. Within the small intestine cholesterolis esterified with fatty acids and incorporated into thetriglyceride core of chylomicrons that are secreted intothe intestinal lymphatics and reach the blood circulation.Within the bloodstream chylomicrons are convertedinto remnant particles through the action of lipoproteinlipase. Triglycerides are liberated and virtually all the cholesterolparticles are carried to the liver via the portal vein.Less than half the cholesterol in the diet is absorbed. It isinteresting that after many years intensive drug research,ezetimibe, the newest agent, has been shown to localize inthe distal and at the brush border cells of the small intestineand inhibit cholesterol absorption. This drug is,therefore, an important addition to our therapeutic armamentariumbecause it can be combined safety with thepowerful acting statins that interfere with the manufactureof cholesterol in the liver.The human body and contains approximately 1 g ofcholesterol per kilogram body weight. About 1 g of cholesterolis lost from the body by the conversion to bileacids and steroid hormones. This loss is balanced by endogenoussynthesis from saturated fats and fecal excretion ofunabsorbed dietary cholesterol.Some of the cholesterol in blood is derived from thefood you eat, but the major part, greater than 70%, ismanufactured in the liver, mainly from saturated fats.Thus, if we had no cholesterol in the diet, the liver wouldmanufacture more cholesterol to compensate. Some excesscholesterol is excreted in the bile. Cholesterol is presentonly in foods of animal origin, in particular, eggs, milk,butter, cheese and meats, and a very high concentrationis present in gland meats, such as liver, brain, kidney,heart, and sweetbreads. Plant-based foods such as potatoes,wheat, rice, vegetables, fruits, grains, and beans contain nocholesterol.In order to understand the changes that may be requiredin your diet, it is important to learn the differencebetween the types of cholesterol: total cholesterol, LDLcholesterol, and HDL cholesterol. Individuals shouldbecome familiar with the different types of fats in foods

IV. TYPES OF CHOLESTEROL237such as triglycerides, saturated fats, monounsaturated fats,and polyunsaturated fats (see Section VII).A. Total CholesterolCholesterol is a fat (lipid) that is insoluble in water. It isabsorbed by the intestine or released from the liver intothe bloodstream. Cholesterol does not circulate freely insolution but is attached to a protein carrier, forming amolecule called a lipoprotein. Lipoproteins vary in sizeand density; the smaller the size, the higher the density.Cholesterol may be transported in a low-density lipoprotein;thus the term ‘‘low-density lipoprotein (LDL) cholesterol.’’There is also a high-density lipoprotein (HDL)cholesterol (see the chapter Dyslipidemia).When a doctor states that your cholesterol is 250 mg(6.5 mmol), he is giving you the total amount of cholesterolin your blood, which includes LDL and HDLcholesterol. The total figure is not broken down unlessspecifically requested by the doctor. The values given inmilligrams are the amount in each 100 ml of blood ornumber of millimoles in one liter of blood.B. Low-Density Lipoprotein (Bad) CholesterolThe low-density lipoprotein is small and contains most ofthe cholesterol that is transported to cells. About 75%of the blood cholesterol is carried as LDL cholesterol.The LDL cholesterol particle is the one responsible foratheroma formation and progression. The higher the levelof LDL cholesterol in the blood, the greater the risk ofcoronary heart disease; thus the term ‘‘bad’’ cholesterol.Oxidation of LDL cholesterol is believed to be animportant process in the formation and progression ofatheroma. It appears that oxidative modification of LDLcauses an increase in foam cell formation and increasedrates of LDL accumulation within developing atheromatousplaques. In addition, oxidized LDL appears to havedirect cytotoxic effects on the endothelium of arteries atthe site of injury.Oxidative stress causes oxidation of LDL cholesterol.Oxidative stress results from the production of reactiveoxygen species, superoxide anion, and hydrogen peroxidemolecules that cause oxidative damage and trigger intracellularsignaling cascades. The constituents of the atheromaplaque produce and use reactive oxygen species. LDLcholesterol reduction appears to reduce the production ofdeleterious reactive oxygen species.This author believes that it is unlikely that LDL particlescause direct injury to normal healthy endothelium,because the same blood level of LDL cholesterol is presentin veins that virtually never develop atheroma exceptwhen they are exposed to high blood pressure, such as insevere pulmonary hypertension. It is more likely that shearstress caused by turbulence of blood at particular focalpoints in arteries, particularly at branching areas, andother factors cause endothelial injury; LDL particles thenjust partake in the orchestration of accelerated atheromatousplaque growth. Increased blood pressure appearsto promote atherogenesis through the mechanical effectsof pulsatile blood flow (see the chapter Atherosclerosis/Atheroma).A plasma level of LDL cholesterol greater than160 mg/dl is associated with a high risk for coronaryartery disease events in susceptible individuals and levelsless than 100 mg/dl confer a low risk. When an individualis documented as having very-high-risk LDL cholesterollevels (>200 mg/dl) associated with premature coronaryartery disease, all available first-degree relatives should betested.C. High-Density Lipoprotein (Good)CholesterolMuch interest has been focused on HDL cholesterol,so-called because it is very small in size and very high indensity. HDL cholesterol is believed to carry cholesterolaway from body cells such as the lining of arteries helpingto keep the artery wall clean; thus the term ‘‘good’’cholesterol.As discussed earlier most heart attacks occur in individualswith total cholesterol levels between 210 and 240mg/dl (5.5 and 6.2 mmol/L), and more than 50% of adultAmericans have cholesterol levels in this range. In theseindividuals with borderline high blood cholesterol, a lowlevel of HDL cholesterol further increases the risk forcoronary artery disease. Figure 1 shows the incidence ofcoronary heart disease in four years by HDL cholesteroland total plasma cholesterol level for men and womenolder than 49 and free of cardiovascular disease.The HDL system comprises a variety of small lipoproteinssmaller than LDL, but both HDL and LDLparticles contain mostly cholesteryl ester. Virtually all HDLparticles contain apoA-1 as their major apolipoprotein andthe particles vary a little in size; the largest particles is HDL2 and the predominant smaller particle HDL 3.1. MetabolismThe many steps involved in HDL metabolism are notfully understood. Small HDL 3 particles accumulate cholesterylester and expand to HDL 2; an important step isfurther transformation by interaction with cholesteryl ester

238CHOLESTEROLtransfer protein (CETP). At each step of the HDL metaboliccycle some apoA-1 is lost. High levels of CETP turnup the cycle at a high rate and this diminishes the totalpool size of HDL that is manifested as a lowered HDLcholesterol level.It appears that CETP is an important enzyme involvedin HDL biology. Inhibiting this key enzyme that modulatesHDL can raise HDL levels. Vaccines and cardioactiveagents that may increase HDL levels significantly are beinginvestigated, and there is great hope that major increases inHDL cholesterol would cause significant protection fromatherothrombosis and its serious impact on morbidity andmortality worldwide.2. Effect on AtherosclerosisSeveral epidemiologic studies indicate an inverse relationshipbetween HDL cholesterol levels and risk for coronaryartery disease (see Fig. 1). A low HDL cholesterol levelgreater than 35 mg/dl (0.9 mmol/L) has been designated asa major risk factor for coronary artery disease. It is statedthat every 1% increase in HDL cholesterol decreases coronaryartery disease risk by about 2%, and each 1% reductionin total cholesterol should produce a 2% reduction incoronary artery disease risk. In Finland where HDL bloodcholesterol levels are among the highest in the world, thecardiovascular death rate is the highest of all Europeancountries (see the chapter Heart Attacks).Some scientists suggest that HDL promotes reversecholesterol transport, that is, the removal of cholesterolfrom tissues including removal of unesterified cholesterolin atheromatous plaques so that it can be transported tothe liver and excreted. But proof is required. Most important,HDL is believed to prevent LDL from oxidationand aggregation and thus protect against formation andprogression of atheroma. This important area requiresfurther intensive investigation for clarification.3. Variability of HDL LevelsAbout 25% of blood cholesterol is carried as HDLcholesterol. People with high levels of HDL cholesterol,greater than 60 mg (1.6 mmol), appear to live longer andhave less coronary artery disease. People with levels lessthan 31 mg (0.8 mmol) have an increased risk of coronaryartery disease. It is not clear why some people should havehigh values and others very low. It appears that about halfof the variation in HDL levels in the general population isexplained by genetic factors. Fortunately not all individualswith low HDL levels get heart attacks.Nongenetic factors that are known to be associated withlow levels of HDL are diabetes, obesity, smoking, and lackof exercise.Most females and males prior to puberty have about thesame cholesterol levels. Boys, however, at puberty haveabout a 20% drop in HDL and a rise in LDL cholesterol.The decrease in HDL cholesterol may be due to anincrease in androgens. In men the HDL level stays fairlyconstant up to age 55, then starts to rise between 55–65.It is possible that this rise might be due to a decreaseof androgens, which occurs during the male climactericperiod. In women there is a gradual rise in HDL cholesterolfrom age 25 onward. Women are believed to beprotected until post menopause by this increase in HDLand by their hormonal status. Why women are protectedfrom coronary heart disease until menopause and yet notprotected from strokes is not easily explained, especially ifatherosclerosis is the basis of both diseases.There is a relationship between HDL cholesterollevels and population groups, foods, alcohol, exercise,and drugs.a. Population GroupsThe Japanese and Inuit men and the black population inEngland, Jamaica, South Africa, and the United Statesappear to have higher HDL cholesterol levels than whites.The exact reason for this finding is unknown. It may bedue to a combination of genetic or environmental factorsand diet. In Finland HDL cholesterol blood levels areamong the highest in the world, but it is not cardioprotective.Thus there are discrepancies that must be resolvedby intensive investigative research.b. Foods and BeveragesA low-saturated-fat, low-cholesterol diet modified to beacceptable to patients may cause a small fall in HDLcholesterol levels. A very low-saturated-fat diet causesa significant reduction in HDL cholesterol. A highcarbohydratediet produces a mild fall in HDL cholesterol.A vegetarian diet may cause a slight decrease inHDL and this may be due to an increased carbohydrateintake.A diet rich in the saturated fats increases HDL levels.The intake of saturated fats is very high in Finland wherelevels of HDL cholesterol are believed to be the highestin the world. This fact is stressed because despite thehigh blood HDL cholesterol, the highest cardiovasculardisease rates in Europe exists in Finland (greater than 800deaths per 100,000 for men and 500 deaths per 100,000for women). Northern Ireland and Scotland hold thesecond and third spots. The United States and the UKhave slightly lower rates. The rates per 100,000 men(and women) in France, Spain, Portugal, Russia, Ukraine,and Slovenia are approximately 330, (120), 400, (180),

IV. TYPES OF CHOLESTEROL239600 (305), 1340 (657), 1490 (830), and 700 (310),respectively.The French death rate from cardiovascular disease isthe lowest in developed countries. The exact reason for thisremains unclear. The French consumption of red winewhich increases HDL cholesterol is believed to play acardioprotective role. The mechanism by which alcoholincreases HDL blood levels is unclear, but high consumptionof alcohol may inhibit the activities of CETP andhepatic triglyceride lipase. If this action proves to becorrect, then blood HDL cholesterol levels should increase.There are, however, factors other than increased HDL thatare produced by alcohol consumption and appear to becardioprotective and vascular protective. Products presentin French red wines that are not present in German redwines have been shown to produce beneficial vasculareffects (see the chapter Alcohol and the Heart).c. ExerciseDaily moderate exercise such as long-distance running(2–3 miles) can increase HDL levels approximately 5–12%(2–4 mg/dl). Strenuous and vigorous aerobic exercise cancause a 15–20% increase (6–8 mg/dl), but it is difficult formany to sustain a vigorous aerobic exercise program formore than 10 years. Often when this is performed fromage 20 to 35 it is relinquished from age 45 onward, thetime it is most needed. It is unfortunate that mild-tomoderateexercise five times weekly to produce the trainingeffect (cardiovascular fitness) may increase HDL levelsonly 1–3 mg.No one has documented that a rise in HDL cholesterolfrom low levels of less than 34 mg/dl to high levels ofgreater than 45 mg/dl and sustained for greater than 5years reduces cardiovascular risk. Jogging one to two milesdaily or every other day will produce the training effect,but appears to have a little or an inconsistent effect onHDL levels. A randomized clinical trial of exercise inducedan increase in HDL-C and its protective effect was notseen. Thus we await randomized clinical trials of drugs thatincrease HDL significantly.d. DrugsThere are a few drugs that alter HDL levels slightly. Niacincauses a mild increase (5–10%) in HDL levels, but thedrug causes many adverse effects. The beta-adrenergicblocking agents may cause mild reduction in HDLcholesterol from 1 to 7%, but these agents are knownto decrease cardiac mortality and morbidity because ofcardioprotective mechanisms. Pharmaceutical companiesare busy developing HDL-increasing compounds, but theywill require several years of testing, especially with regardsto safety.e. ObesityA body mass index (BMI equals the weight in kilogramsdivided by the square of the height in meters) of 25–30is considered overweight and a BMI of greater than 30 isobese. More than 50% of Americans are graded asoverweight with a BMI greater than 25, and about 18 %are obese. The prevalence of obesity is the same inAustralia and New Zealand. Obesity among children isalso on the rise. Obesity causes insulin resistance, anincrease in triglycerides on fasting glucose, a loweredHDL cholesterol, and an increase in blood pressure.Abdominal obesity, waist circumference greater than 40inches (102 cm) in men and 35 inches in women is morehighly correlated with the metabolic risk factors than anelevated BMI.Obese individuals have been noted to have HDLcholesterol levels that are 5–10 mg/dl lower and triglyceridelevels 35–110 mg/dl higher than subjects who arelean. The Framingham study indicates that for every10-lb. weight gain, the total cholesterol level increases7 mg/dl in men and 5 mg/dl in women.f. DiabetesVirtually all type 2 diabetics have dyslipidemia manifestedby mild-to-moderate elevation in serum cholesterol(230–280 mg/dl), elevated triglycerides (300–500 mg/dl), and a low HDL cholesterol (

240CHOLESTEROLh. Clinical TrialsThe Veterans Affairs Cooperative studies program High-Density Lipoprotein Cholesterol Intervention trial(VA-HIT) studied individuals with atherosclerotic disease.Subjects had a low HDL cholesterol level of 32 mg/dl(0.82 mmol/L) associated with a low LDL cholesterol of111 mg/dl (2.8 mmol/L), total cholesterol 175 mg per dl(4.5 mmol/L), and triglycerides 161 mg/dl (1.8 mmol/L).Then 1267 patients were randomized to placebo and 1264were randomized to gemfibrozil. Mean age was 64 years,the mean BMI was 29, and participants were characterizedby abdominal obesity.At five-year follow up there were 219 coronary arterydisease deaths and nonfatal MIs in the gemfibrozil groupcompared to 274 events in the placebo group, a relativerisk reduction of 22%, an absolute risk reduction of4.2% in favor of the active treatment group (P ¼ 0.006).The important total mortality was not reported. Thebenefit of the VA-HIT study was associated with a minimalincrease in HDL cholesterol of only 7.5%. Total cholesteroldecreased by 2.8% and triglycerides decreased by24.5%.In a similar study of 10,000 patients with major typesof dyslipidemia, micronized fenofibrate 200 mg administeredfor 12 weeks reduced total cholesterol 20%, LDL by25%, triglycerides by 28%, and increased HDL by 23%.The LDL/HDL ratio was lowered from a mean of 5.3 atbaseline to 3.2 after 12 weeks of treatment.D. Very-Low-Density LipoproteinThe very-low-density lipoprotein (VLDL) is very large andlow in density. It transports triglycerides, which are usedmainly as a fuel; for example, in exercising muscle. Theevidence linking elevated blood triglyceride levels withcoronary heart disease is very weak and unclear. Thus, anelevated blood triglyceride level alone is not of importance.Weight reduction or cessation of alcohol intake alwayscauses a marked reduction in triglyceride levels but doesnot alter LDL cholesterol levels.V. BLOOD TESTSA. Total CholesterolWhat is a normal blood cholesterol, and when does thelevel produce a risk of coronary heart disease? Bloodcholesterol is not necessarily very high, that is, greater than265 mg (6.9 mmol), in those who have heart attacks. Infact, most heart attacks occur in individuals with bloodcholesterol around the average of 220–250 mg (5.7–6.5mmol). In the LIPID study described above, only 3806men with a blood cholesterol greater than 265 mg could befound from a screening of 480,000. The remainder hadcholesterol levels of less than 265 mg and most likely in therange of 200 to 250 mg.Between 1970 and 1989, laboratories in North Americareported a normal cholesterol as between 150 (3.9 mmol)and 250 (6.5 mmol). But it is now established thatindividuals with so-called normal cholesterol in the rangeof 220–250 are at increased risk, and heart attacks arecommon in individuals with such levels. A blood cholesterolof 220–250 mg (5.7–6.5 mmol) is considered highby world standards. Most doctors now talk about anoptimal safe total cholesterol level of less than 190 mg/dl(4.9 mmol/l) or LDL less than 120 mg (3 mmol). Heartattacks are uncommon in individuals with a cholesterollevel less than 160 mg (4.2 mmol).If we treat patients with a cholesterol level greaterthan 250 mg (6.5 mmol), we will be excluding more than80% of the population who are at high risk for coronaryheart disease. To reiterate, most heart attacks in NorthAmerica occur in people with blood cholesterol between220 and 260 mg. Individuals with a blood cholesterolless than 180 mg (4.7 mmol) obviously deal withcholesterol by their own natural process. They are amongthe fortunate; no dietary modification is necessary, andblood cholesterol only needs to be rechecked about everyfive years.The blood cholesterol measurement gives the totalblood cholesterol, that is, LDL cholesterol plus HDLcholesterol. Food eaten within hours does not have animmediate effect on total blood cholesterol and HDLcholesterol measurements, so fasting is not necessary forthis test. Triglyceride level is not an independent riskfactor and therefore widespread screening for elevatedtriglycerides is not warranted. It is also an expensiveinvestigation. If your doctor thinks that triglyceride determinationis necessary, you must fast for 14 h beforeblood is taken. Blood tests for glucose, diabetes, andtriglycerides are the only tests for which it is necessary tofast for 12–14 h before the test.B. Blood LDL Cholesterol LevelsDetermination of LDL cholesterol is not done routinely,because it is a difficult, time-consuming, and expensivetechnique. It must be done fasting because it iscalculated by a formula that requires a triglyceride bloodlevel, which must be done after fasting 12 hours. The

V1. CORONARY ARTERY DISEASE RISK241formula for calculating the blood LDL cholesterol levelis as follows:LDL cholesterol¼ total cholesterol HDL cholesterolðtriglyceride divided by 5Þ¼ mg=dl; for the value in mmol=L divide by 2This formula does not apply if the triglycerides exceed 250mg/dl.In individuals age 15–75 optimal LDL cholesterol levelsare less than 115 mg/dl (3 mmol/L). In North America,the UK, and Europe the vast majority of individualshave an LDL cholesterol in the range of 130–200 mg/dl(3.4–5.2 mmol/L). In patients with coronary heart disease,the level of LDL is of paramount importance and shouldbe maintained at less than 100 mg/dl (2.6 mmol).C. HDL Cholesterol Blood LevelBlood testing for HDL cholesterol levels can be done in thenonfasting state. Levels less than 35 mg/dl (0.9 mmol/L)are considered low and less than 27 mg/dl (0.7 mmol/L) isconsidered unacceptably low. Levels greater than 54 mg/dl(1.4 mmol/L) are considered optimal.V1. CORONARY ARTERY DISEASE RISKA. Based on LDL CholesterolA high LDL cholesterol level is considered the mostimportant major risk factor for coronary artery disease.The relationship between LDL cholesterol and coronaryartery disease risk is continuous over a broad range ofblood levels from low to high (110 mg/dl to greater than190 mg/dl) and LDL cholesterol is the primary target oftherapy.Patients with established coronary artery disease areconsidered to have a 10-year risk greater than 20%. It isexpected that more than 20% of such individuals willdevelop a recurrent coronary artery disease event within 10years. In these individuals LDL cholesterol levels greaterthan 130 mg/dl greatly increase the risk. Most nationalguidelines state that in patients with proven coronaryartery disease or CAD risk equivalent, particularlydiabetes, drug treatment is strongly indicated to maintainthe level to less than 100 mg/dl (2.6 mmol/L)(see Table 2). This author advises a level less than 80 mg/dl(2 mmol/dl).individuals without coronary artery disease or evidenceof cardiovascular disease should be assigned a risk based onthe following:1. Their levels of LDL cholesterol: risk is increased if theLDL-C is >190 mg/dl, and the goal should be 20 with a goal LDL

242CHOLESTEROLThe total cholesterol is used by the NCEP to determine10-year risk assessment because of a larger and more robustFramingham database for total cholesterol than for LDLcholesterol. Nonetheless, the executive summary states thatthe LDL cholesterol is the primary target of therapy.C. Based on the Total Cholesterolto HDL Cholesterol RatioThe total cholesterol to HDL cholesterol ratio is used toindicate risk. An individual with a total cholesterol of220 mg/dl (5.7 mmol/L) and HDL cholesterol of 46 mg/dl(1.2 mmol/L) has a ratio of 4.7, the average risk forcoronary heart disease. This ratio is not recommended bythe author because it does not give a true estimate of risk.A 50-year-old male with a serum cholesterol of 220 mg/dl,with a strong family history of heart disease occurringbefore age 55, is at high risk. The same individual with aratio of 4.7 but with diabetes is also at high risk forcoronary artery disease events.The total cholesterol to HDL ratio risk for coronaryheart disease is as follows:10 ¼ much above average riskThe NCEP Adult Treatment Panel III stronglyadvocates the concept of global risk assessment alongwith the focus on LDL cholesterol as the primary targetof therapy. The panel does not mention total to HDLcholesterol ratio in their 2001 guidelines. The global riskassessment is essential for identifying patients who willmost benefit from risk factor modification and drugtherapy. This statement does not underestimate the potentialcardioprotective value of high HDL cholesterol levelsexceeding 50 mg/dl. Adverse outcomes appear to beassociated with HDL cholesterol levels less than 30 mg/dl(0.8 mmol/L), but clinical proof from randomized trials isrequired to clarify the dangers of very low HDL cholesterollevels.VII. DIETS AND CHOLESTEROLA. Saturated Fats and CholesterolAll animal fat is saturated and solid at normal roomtemperatures. The degree of hydrogenation of a fatdetermines how solid and saturated it is. Saturated fatsare broken down in the body and increase blood cholesterol.Therefore, the most effective dietary method oflowering blood cholesterol is to reduce intake of saturatedfats. High-cholesterol foods are few, therefore, we do notuse the term low-cholesterol diet.Vegetable fats are unsaturated and almost all are liquidat room temperatures. There are three vegetable oils thatshould be avoided: coconut, palm, and peanut. Coconutoil contains a high amount of saturated fat and is usedfor cooking in several countries. It is also used in NorthAmerica in nondairy cream substitutes, for example,coffee cream. Palm oil contains significant amounts ofsaturated fat, and peanut oil, though mainly unsaturated,has certain fatty acids that produce plaques of atheromain animals. The only vegetable that contains a littlesaturated fat is the avocado; therefore, low-cholesterol,low-fat diets often recommend that you avoid avocados.You will note from Table 1, however, that although a largeavocado contains a significant amount of fat, only a littleof it is saturated, and no cholesterol is present. Therefore,one avocado a week is an excellent food, especially if ahigh potassium intake is required.B. Polyunsaturates and Linolenic AcidThe replacement of some saturated fats in the diet bypolyunsaturated, monounsaturated, and other unsaturatedfats found in abundance in vegetable oil reduces bloodLDL cholesterol. The saturated and polyunsaturated fatcontents of commonly used foods are given in Table 1.Oils recommended for the preparation of meals includecanola, olive, and soybean because they contain alphalinolenicacid, very low cholesterol levels, and a minimumof saturated fat. For example, ‘‘cholesterol-free’’ canola oilcontains 6% saturates and will produce a small amountof cholesterol in the body. Not all vegetable oils claim tobe cholesterol free but contain significant saturated fats.Because vegetable margarines contain a small amount ofsaturated fat and hydrogenation remains controversial,they should be used in moderation (see the chapter Dietsand Heart Disease). Some products may have palm orcoconut oil added to enhance hardening; these two oils arenot recommended (see Table 4). Olive oil is recommendedfor salads, but olive oil margarines may contain palm oilto enhance hardening so read labels carefully. Some margarinesclaim that they contain no cholesterol and arenonhydrogenated yet they contain palm oil.It is important to note that many recipes developed forweight reduction diets tend to cut out carbohydrate foodsin order to decrease weight and may even introduce foodsthat increase blood clotting and cholesterol. Therefore,be careful in choosing ‘‘popular’’ weight reduction diets.Consult Table 4 and the instructions given in the chapteron Heart Attacks.

VII. DIETS AND CHOLESTEROL243TABLE 4Saturated Fat, Polyunsaturated and Cholesterol Content of FoodsITEM* Cholesterol Total Fat Sat/ Recom Sparinglymg g g Fat not recMEATSBeef liver 395 10 3 XKidney 725 11 4 XSweetbread 420 21 — XLean beef 82 5 2 Roast beefRib 85 33 14 X Rump 85 21 9 XStewing 82 27 11 X Lean 82 9 4 Ground 85 18 8 X SteakSirloin 85 25 10 X Lean 85 5 2 Veal 90 12 5 LambLean 90 7 4 Chop & fat 110 33 18 XHamFat roasted 80 28 7 XBoiled, sliced 80 18 5 Pork chop 80 30 12 XChickenBreastand skin 72 6 1 DrumstickFried 80 9 2 Turkey 80 5 2 FISHSole 45 1 trace Trout 50 13 3 Tuna 60 7 2 Butter 30 11 9 trace 7Lard 12 13 5 1 XOILSCanola 0 14 5 8 Corn oil 0 14 1 7 Rapeseed 0 14 1 3 XSafflower 0 13 1 10 Sunflower 0 14 1 9 Soybean 0 14 2 7 Coconut 0 14 12 2 XPalm olive 0 7 2 .2 X0 14 1 Peanut 14 2 4 XTABLE 4(Continued)ITEM* Cholesterol Total Fat Sat/ Recom Sparinglymg g g Fat not recCheese 1 ozBrick 27 8 6 trace Blue 24 trace Cheddar 30 10 6 trace Cottage skim milk 2.6 .5 trace Processed 0 trace trace trace NUTS [1 oz 30 g]Almonds [24nuts] 0 14 1.5 3 [P] 10 [M] **Brazil nuts 0 19 5 7 [P] 7 [M] XCashews [18 nuts] 0 13 2.5 2.5 [p] 8 [M] XCoconut 0 13 11 trace XHazelnuts [12] 0 18 1 2[p] 15 [m]Peanuts [35] 0 14 2 5 [P] 7 [M] XButter pecans 0 19 2 5 [P] 12 [M] XWalnuts 0 18 [7nuts] 2 11 [P] 5 [M] *Quantity is 3 oz, 90 g unless specified, 15 ml ¼ one tablespoon.**Foods recommended contain less than 5 g saturated fat per 3 oz.Total Saturated Polyunsat- Not Use ITEM* Cholesterol Fat Fat uratedRecom.Recom.’’ Sparingly P ¼ polyunsaturated, M ¼ monounsaturatedC. Nuts and Cholesterol and RiskMost nuts contain no cholesterol and very little saturatedfats, but the exceptions include coconut and Brazil nutswhich have high saturated fat content and their productsshould be avoided (see Table 4). Cashew nuts and peanutshave significant saturated fats, and although they containan adequate amount of monounsaturated and polyunsaturatedfatty acids, they are not recommended and shouldbe used sparingly. Additionally, it appears that peanutsmay have atherogenic potential. Nuts that contain littlesaturated fat and a high amount of monounsaturated fatsinclude almonds, walnuts, and hazelnuts and their intakeis highly recommended.D. General Advice on DietsDiets to reduce atherosclerosis or heart attacks must betailored to meet the needs of the individual, because eachfamily has different eating habits. Special recipes and dietsheets may be misleading and difficult to follow for alifetime and individuals should consult Table 4, or similarinformation.It is recommended that the general population use foodsthat contain a low amount of saturated fat and cholesteroland make an effort to increase intake of polyunsaturated

244CHOLESTEROLand monounsaturated fat, linolenic acid, and foods thathave a favorable effect on blood clotting (see the chapterBlood Clots). Reduction in the intake of cholesterolalone is not sufficient because saturated fat is convertedinto cholesterol in the body; therefore, reduction insaturated fat intake is essential. Most important, theintake of trans fat must be curtailed (see chapter Diets andHeart Disease).The recommendation made by the American HeartAssociation is as follows:Total fat intake should be reduced from the average40% of calories to 30%. Polyunsaturated fat shouldprovide up to 10% of calories and the polyunsaturatedfat to saturated fat (P/S) ratio should be about 1:1.Carbohydrate intake should be increased from anaverage of about 45%–55% to maintain averagebody weight, and protein intake should remain atabout 12–14%.Scotland has not shared, however, in the slight declinein mortality that has been experienced in Australia,Belgium, Canada, Finland, Norway, and the UnitedStates. Scotland has moved up in the world league ofcoronary deaths to second for men, and Northern Irelandhas moved to third for men and second for women. In theUK, fat intake has remained the same for the past 30 yearsat about 40% of food energy and even increased between1974 and 1982 to 41% of food energy. The Departmentof Health and Social Security made the followingrecommendations to physicians and the general public inthe UK:Reduce the total fat intake to 35% of food energy withsaturated fats making up no more than 11%. Increasethe polyunsaturated to saturated ratio from the present0.27 to about 0.45. The intake of polyunsaturatedacids presently at 5% of food energy should reach 7%,which is less than the American and World HealthOrganization’s suggestion of 10%.The UK panel claims that the effects on the populationof a P/S ratio of 1.0 and beyond are unknown. Individualswho are considered to have a high risk of developingcoronary heart disease are advised to cut fats to 30% offood energy, with saturated fats contributing no morethan 10%, i.e., identical to the recommendation in theUnited States. Thus there is consensus on both sides of theAtlantic.A Mediterranean style diet that contains an abundanceof linolenic acids is strongly recommended by the author;see the chapter Diets and Heart Disease.The reduction in dietary saturated fat intake as wellas the cessation of smoking by many individuals has provideda decline in the incidence of coronary heart diseasemortality.VIII. CHOLESTEROL-LOWERING DRUGSA. HMC-CoA Reductase Inhibitors (Statins)The statins, atorvastatin, fluvastatin, lovastatin, pravastatin,and simvastatin, are cholesterol-lowering agentsthat are effective and have few side effects. They cause a20–40% reduction in total, or LDL, cholesterol. They maycause a small, 1–6%, increase in HDL cholesterol, butthis effect is variable. Clinical trials have shown that theseagents decrease LDL cholesterol levels and reduce the riskof heart attack and death from heart attacks. The newestagent, rosuvastatin, is even more powerful than Lipitorin reducing LDL levels to goal. Randomized clinical trialsthat document the effectiveness of these agents are giventhe chapter Dyslipidemia.Mild side effects from statins include headaches, muscleaches, and pain in the upper abdomen without gastritis,ulcers, or bleeding. An increase in the liver enzymes maybe detected on blood test, but the risk subsides when thedrug is discontinued. Caution: Do not take with niacinor fibrates such as gemfibrozil or fenofibrate. Statins arecontraindicated in pregnancy.1. AtorvastatinSupplied: Tablets: 10, 20, 40, 60 mg.Dosage: 10–40 mg once daily; the author’s maximumdose is 60 mg daily. The 80 mg dose is rarely required andmore adverse effects may occur at the maximal dose ofthe drug.2. FluvastatinSupplied: Capsules: 20 mg.Dosage: 20–40 mg after the evening meal or bedtime.3. LovastatinSupplied: Tablets: 10, 20, 40 mg.Dosage: 10–40 mg after the evening meal.4. PravastatinSupplied: Tablets: 10, 20, 40 mg.Dosage: 10–40 mg after the evening meal or bedtime.

VIII. CHOLESTEROL-LOWERING DRUGS2455. RosuvastatinSupplied: Tablets: 10, 20, 40 mg.Dosage: 10 mg once daily is more effective in loweringLDL cholesterol than 40 mg of Lipitor or simvastatin.It causes a better increase in HDL cholesterol. The author’smaximum suggested dose is 20 mg daily.6. SimvastatinSupplied: Tablets: 5, 10, 20 40, 60 mg.Dosage: 10–40 mg after the evening meal.B. Cholesterol Absorption Inhibitors1. EzetimibeSupplied: Tablets 10 mg.Dosage: 10 mg once daily. This drug has a low sideeffect profile and can be combined with a statin.C. Resins1. CholestyramineSupplied: Powder in packets or in cans with a scoop.Dosage: 12–24 g daily in liquid a half hour before to ahalf hour after meals. Start with 4 g (one scoop) twice dailyfor one week, then 4 g three times daily for one month,and if necessary, thereafter increase to 8 g three times daily.Cholestyramine and colestipol are not absorbed fromthe gut and act by binding bile salts in the intestine. Thisaction causes the liver to increase the conversion ofcholesterol to bile acids, which are excreted in the bile.Cholestyramine has no serious side effects. Constipation,nausea, bloating, gas, and abdominal cramps mayoccur. High doses taken for several years can cause poorabsorption of certain vitamins. It may interfere with theabsorption of digoxin and blood thinners (anticoagulants).The recent introduction of ezetimibe as an effective drugwill render bile acid resins such as cholestyramine andcolestipol obsolete.D. Fibrates1. GemfibrozilSupplied: Capsules: 300 mg.Dosage: 300 mg taken about a half hour before themorning and the evening meal for one to two weeks, then300 mg twice daily.Gemfibrozil is the first fibrate to be introduced in theseventies since the discontinuation of clofibrate in thelate sixties. This drug causes a 5–10% reduction in serumcholesterol, 30% reduction in triglycerides, and a 5–10 %increase in HDL cholesterol. Side effects include stomachpain and bloating in less than 5% of patients. Gallstonesmay occur.In the VA-HIT study gemfibrozil caused a 31% decreasein triglycerides, but only a 6% increase in HDL cholesterolcompared with placebo. This negligible increase in HDL isclaimed to have caused a beneficial reduction in cardiacevents. There was no reduction in all cause mortality or intotal cardiac mortality; there was a small, 22% reductionin total cardiac death and nonfatal myocardial infarction(MI) (P

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Coenzyme Q10I. ActionsII. Clinical StudyIII. Prospective and Research ImplicationsNADHFMN:Fe-nhGLOSSARYheart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; and inadequate supply of bloodreaches organs and tissues.pulmonary edema fluid in the air sacs and alveoli; the lungsbecome congested and severe shortness of breath occurs.I. ACTIONSThe enzyme Q10 (ubiquinone), a quinine, was discoveredin 1957, and since that time there has been considerablecontroversy regarding its use in heart failure and otherforms of heart disease. This enzyme serves as a mitochondrialenzyme supplement and appears to improvedefective myocyte energetics in patients with heart failure.Coenzyme Q10 plays an intermediary role in the electrontransport chain during the oxidation of reduced nicotamideadenine dinucleotide (NADH) or succinate, with theconversion of oxygen to water within the mitochondria(see Fig. 1). This enzyme is involved in electron protontransfer during oxidative phosphorylation. Also, coenzymeQ10 possesses antioxidant, free radical scavenging, andmembrane stabilizing properties.There is no doubt that myocyte energetics andmitochondrial function is severely deranged in patientswith heart failure and salutary cardioactive agents arewanting. There have been major advances in the managementof heart failure during the past decade, but theepidemic of heart failure continues worldwide. To stop thisepidemic, it is crucial that new cardioactive agents arefound.COQ 10FMN:Fe-nhCyto bCto c 1Fe-SCyto c Cyto a-a 3SuccinateFIGURE 1 The role of coenzyme Q 10 (CoQ 10 ) in electron transport.CoQ 10 plays an intermediary role in the electron transport chain duringthe oxidation of reduced nicotinamide adenine dinucleotide (NADH) orsuccinate, with the ultimate conversion of oxygen to water within themitochondria. Cyto Cytochrome; FAD Flavin adenine dinucleotide;Fe-nh Nonheme iron; Fe-S Iron disulfide; FMN Flavin mononucleotide.(From Raj, S.R., Weisel, R.D., and Verma, S. (2002). Can. J. Cardiol.,18(10), 1054.)II. CLINICAL STUDY1/ 2 O 2H 2 OSeveral small clinical studies of coenzyme Q10 that havenot been randomized indicate an improvement in physicalactivity. A nonrandomized, nonblinded, four-week studyof 1715 patients reported improvement in symptoms andquality of life. A longer study using 100 mg daily for over6 years reported improvement in ejection fraction. A smallstudy suggested degeneration in symptoms and hemodynamicfeatures on discontinuation of the enzyme. Arandomized study without placebo control in 806 patientsshowed improvement in functional class and heart failuresymptoms over a 6-month follow up.The results of a few small double-blind, randomizedplacebo-controlled trials are given in Table 1. In most ofthe studies involving less than 50 patients no reasonableconclusion can be drawn. In 1993 the largest double-blind,randomized study involving 591 patients followed forone year showed hospitalizations were decreased withthe enzyme; 40% versus 20% for placebo ( p < 0.001).247

TABLE 1Double-blind, Placebo Controlled, Randomized Trials of Coenzyme Q 10 (CoQ 10 ) for Congestive Heart FailureFirst author (reference) Year Design nEtiologyof heartfailureNYHAclass(enrolment)CoQ 10dose(mg/day)CoQ 10treatmentduration(weeks) ResultsTrials enrolling 20 or fewer patientsLangsjoen (12) 1985 Xover 19 DCM III-IV 100 12 "SV by IC, "EF, "general activityJudy (13) 1986 Xover 14 DCM IV 100 12 "CO, "SV, "EF by ICMazzola (15) 1987 Xover 20 Mixed II-III 60 4 Improved NYHA scoreRossi (14) 1991 Parallel 20 CAD N/A 200 12 "Exercise capacityNo change in EF by echoNo change in CO by ICPogessi (16) 1991 Xover 18 Mixed II-III 100 8 "EF by echo (45.7% to 49.1%)"FS by echo (26.6% to 29%)Morisco (17) 1994 Xover 6 Mixed II-III 150 4 "CO, "EF, "SV by radionuclide assessmentTrials enrolling more than 20 patientsPermanetter (20) 1992 Xover 25 DCM I-III 100 16 No change in EF by MUGANo change in CO or SV by ICNo change in exercise toleranceMorisco (18) 1993 Parallel 641 Mixed III-IV 100-150 52 #CHF hospitalizations"Functional capacityNo change in moralityHofman-Bang (19) 1995 Xover 79 Mixed II-IV 100 12 No change in EF by MUGANo change in NYHA classMinimal increase in work capacityMinimal increase in QOLWatson (21) 1999 Xover 27 Mixed II-III 100 12 No change in LV dimensionsNo change in CO (thermodilution)No change in QOLKhatta (22) 2000 Parallel 46 Mixed III-IV 200 26 No change in EF by MUGANo change in peak oxygen consumptionNo change in exercise durationNote: #Decrease; "Increase. CAD Coronary artery disease; CHF Congestive heart failure; CO Cardiac output; DCM Nonischemic dilated cardiomyopathy; echoEchocardiography; EF Ejection fraction; FS Fractional shortening; IC Impedance cardiograph; LV Left ventricular; MUGA Gated radionuclide assessment; n Number of patients;N/A Not available; NYHA New York Heart Association; QOL Quality of life; SV stroke volume; Xover Cross-over. (From Raj, S.R., Weisel, R.D., and Verma, S. (2002). Can. J.Cardiol., 18(10), 1056.)

III. PROSPECTIVE AND RESEARCH IMPLICATIONS249The enzyme group had fewer patients with pulmonaryedema, 20 versus 51, and cardiac asthma, 97 versus 198( p < 0.001). There was no difference in survival betweenthe two groups. More recently studies with less than 55patients receiving optimal heart failure therapy showedno differences.III. PROSPECTIVE AND RESEARCHIMPLICATIONSA small study indicated that statin therapy reduces plasmalevels of coenzyme Q10, which may have adverse effects onheart failure states. Further studies are needed to determinewhether ubiquinone reductions are limiting the maximumfavorable effects of statin therapy on the microcirculation.The use of enzyme Q10 carries only one disadvantage —neglect of approved heart failure remedies. Further studiesare clearly indicated because the enzyme appears to causeno harm and appears to alter parameters that are derangedin heart failure that are not corrected by the excellentcardioactive agents available for the management of heartfailure. These agents include ACE inhibitors, diuretics,beta-blockers, digoxin, spironolactone, and eplerenone.Intensive research is required to obtain new cardioactiveagents to manage heart failure (see the chapter HeartFailure).BIBLIOGRAPHYRaj, S. R., Weisel, R. D., and Verma, S. Coenzyme Q10 and congestiveheart failure: What is the verdict? Can. J. Cardiol., 18:1054–57,2002.Strey, C. H., Young, J. M., Molyneux, S. L. et al. Endotheliumamelioratingeffects of statin therapy and coenzyme Q10 reductions inchronic heart failure. Atherosclerosis, 179: Issue 1 201–206, 2005.

Congenital Heart DiseaseI. Incidence and ClassificationII. Ventricular Septal DefectIII. Patent Ductus ArteriosusIV. Aortic StenosisV. Bicuspid Aortic ValveVI. Coarctation of the AortaVII. Other Congenital AnomaliesVIII. Congenital Cyanotic Heart DiseaseIX. Pregnancy and Congenital Heart DiseaseGLOSSARYautograft a tissue graft transferred from one part of the patientsthe body to another part.commissures a site of union of corresponding parts, especiallythe sites of junction between the adjacent cusps of the heartvalves.cyanosis purplish-blue discoloration of the lips, tongue, mucousmembranes, ear lobes, extremities, fingers, and toes.endocarditis infection on deformed or damaged valves in theheart, or at the site of a hole in the heart (ventricular septaldefect).heterograft a graft of tissue taken from a donor of one speciesand grafted into a recipient of another species, also called axenograft.homograft a graft of tissue taken from a donor of the samespecies as the recipient.hypoxemia severe lack of oxygen in the blood.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severe obstructionof the artery supplying blood to this area of cells.murmur a blowing sound heard with a stethoscope usuallycaused by obstruction of heart valves or leaking valves.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot or atheroma;medical term for a heart attack or coronary thrombosis.oligohydramnios Deficiency in the amount of amniotic fluid.syncope temporary loss of consciousness caused by lack of bloodsupply to the brain; fainting describes a simple syncopal attack.I. INCIDENCE AND CLASSIFICATIONThe incidence of moderate and severe forms of congenitalheart disease (CHD) is about 6 per 1000 live births, butit is 19 per 1000 live births if the potentially seriousbicuspid aortic valve is included. If very small muscularventricular septal defects (VSDs) are included, all formsincrease to 75 per 1000 live births. Although severalclassifications are used, the oldest and most meaningful isthe division into cyanotic and noncyanotic CHD.Cyanotic CHD involves right-to-left shunts. Thearterial circulatory system receives an overflow of deoxygenatedblood from the right side of the heart resulting in adiscoloration of the tongue, lips, and mucous membranes.Organs and tissues receive blood low in oxygen.Noncyanotic CHD mainly involves left-to-right shuntsand valvular defects. In individuals with left-to-rightshunts oxygenated blood flows from the left side of theheart into the right atrium or ventricle and is returned tothe lungs. Usually there is no significant hypoxemia, exceptin children with severe defects. Fortunately noncyanoticCHD is much more common than cyanotic disease.The noncyanotic group includes the following:1. Ventricular septal defect, incidence 30%, more than80% close before age 2–32. Patent ductus arteriosus, 10%3. Atrial septal defects (ASD of the fossa ovalis secundumdefects), 10%4. Atrioventricular septal defects (endocardial cushiondefects, a common atrioventricular canal)5. Pulmonary stenosis, 7%6. Aortic stenosis, 6%7. Bicuspid aortic valves, common8. Coarctation of aorta, 7%9. Mitral regurgitation, rare10. Anomalous origin of coronary arteryThe cyanotic group includes the following:1. Tetralogy of Fallot, 6%2. Persistent truncus arteriosus, 2%251

252CONGENITAL HEART DISEASE3. Hypoplastic right heart includes tricuspid stenosis,pulmonary atresia with an intact ventricular septum,and Ebstein anomaly 16%4. Total anomalous pulmonary venous connection, 16%5. Critical pulmonary stenosis, 16%6. D-transposition of great arteries, 16%There are few definite differences in the incidence ofsome forms of CHD in different populations. There is ahigh proportion of subarterial VSDs in China and Japan35% versus 5% in Caucasians. In Malta there is anexcessive incidence of tetralogy of Fallot. Aortic stenosisand coarctation are more common in Caucasians than inthe black or Hispanic population in the United States.II. VENTRICULAR SEPTAL DEFECTVentricular septal defects are the most common form ofcongenital heart disease. If all newborns are examinedabout 3% would reveal tiny muscular VSDs. Spontaneousclosure occurs by age 3 in greater than 50% of patientsborn with VSDs. Still, VSDs after age 2 represent the mostcommon lesion if bicuspid aortic valves are not includedin the equation. Occasionally children, however, may notexperience spontaneous closure up until age 10.A. Clinical FeaturesSmall VSDs are usually asymptomatic. Oxygenatedblood rushes from the left ventricle through a hole in theseptum that separates the right and left ventricles (seeFig. 1). The blood traverses this hole at high velocity andsets up turbulence that is heard as a murmur with astethoscope. The murmur is produced as the left ventriclecontracts in systole. A harsh systolic murmur is heardwith maximal intensity at the left lower sternal borderand is well heard to the left and right of the sternumwith less intensity at the apex of the heart. The murmurradiates from the point of maximal intensity like thespokes of a wheel. A thrill may be felt with the palm ofthe hand in the region where the murmur was bestheard with the stethoscope. Because of these typicalfeatures the diagnosis can usually be made with thesimple stethoscope.aortaPumonaryto lungsAortic valve at outflowof left ventricleVentricularseptal defectRight ventriclechamberTricuspidvalveVentricularmuscleFIGURE 1Papillarymuscle (see plates underanatomy of the heart)Ventricular septal defect. See Figures 5 and 6 in the chapter entitled Anatomy of the Heart and Circulation.

III. PATENT DUCTUS ARTERIOSUS253B. Clinical Study, Gabriel et al.Study question: The study is to assess long-term outcomeof patients with small VSDs in whom surgical closure isnot usually recommended.Methods: A total of 229 children with VSDs consideredtoo small to require surgery, i.e., less than 50% shunt withnormal pulmonary artery pressure. Follow up is to meanage of 30 10 years.Results: Spontaneous closure was observed in 14 patients(6%). No patient died, 4 patients developed endocarditis,and only one patient required surgical closure. Surgicalclosure does not appear to be required during childhood aslong as the left-to-right shunt is less than 50% and signs ofleft ventricular volume overload are absent, pulmonaryartery pressure is not elevated, and there are no symptomsrelated to aortic regurgitation. The outcome in wellselectedpatients with small VSDs is good. The studyfindings are in agreement with current practice.C. PerspectiveWith a VSD blood flows from the left ventricle with ahole in the septum into the right ventricle. If this left-torightshunt is greater than 50%, symptoms such asshortness of breath and fatigue may occur and these mayincrease in severity. It is of utmost importance to identifypatients who may develop irreversible pulmonary vascularobstructive disease (Eisenmenger’s syndrome). An increasein the resistance of the pulmonary circulation causesincreased workload and strain on the right ventricle withsubsequent heart failure. The shunt of blood from the leftventricle to the right ventricle through the hole in theseptum may be reversed so that blood then flows fromthe right ventricle into the left ventricle. This reversal ofthe shunt from right to left must be prevented, and surgicalcorrection must be employed long before this complicationoccurs. This condition may occur with large shunts or withcomplicated defects associated with pulmonary stenosis,aortic regurgitation, and other lesions.Echocardiography identifies and quantifies the VSD.If the shunt is significant or symptoms are present, catheterizationshould be performed to determine the pressureand blood flow in the pulmonary artery. With largershunts, elective surgery is usually advised before the childenters school.In all patients with VSDs, it is necessary to enforceprophylactic antibiotic therapy before dental and otherminor surgical procedures. Antibiotics prevent the growthof organisms that attach to the wall of the heart at the siteof the VSD. This dangerous condition is called infectiveendocarditis. Although small defects cause no symptomsand may never require surgery, endocarditis can occurat the site of the defect and prophylaxis is lifesaving.III. PATENT DUCTUS ARTERIOSUSPatent ductus arteriosus is a common lesion occurringin approximately 10% of infants, about the same incidenceas ASD. In the fetus a widely opened, patent vesselconnects the pulmonary trunk to the descending aorta.This patent vessel is called a patent ductus arteriosus,(see Fig. 2). Thus, the output of deoxygenated blood fromthe right ventricle bypasses the unexpanded lungs of thefetus. Blood is propelled form the right ventricle into thepulmonary trunk and through the patent ductus and entersthe descending aorta where it is carried to the fetal organof oxygenation, the placenta.Sensitive studies have shown that in the term infantthe ductus is almost always closed by 4–7 days and in someinstances several weeks after birth. It was a long heldview that the ductus, no longer required as a vital conduit,closes soon after birth because of the abrupt rise in arterialoxygen that accompanies the first breath of the baby.The closure of the ductus is not only related to the suddenincrease in the pressures of oxygen that accompany theventilation in the newborn, but also related to the actionsof vasoactive compounds that stimulate proliferation ofcells and fibrosis that produce a complete closure. Preterminfants have an increased incidence of a patent ductusbased on abnormal physiology rather than on a structuralFIGURE 2aortaPatent ductus arteriosusoxygenated blood to lungsPulmonary artery to lungsPatent ductus arteriosus: left to right shunt.

254CONGENITAL HEART DISEASEabnormality. In the preterm infant the patent ductusmay cause minor problems, but if other serious congenitalmalformations coexist the shunting of blood throughthe ductus provides a unique mechanism that can belifesaving.A. Clinical FeaturesIn the term infant with a patent ductus oxygenatedblood flows from the aorta backward into the pulmonarytrunk, because the blood pressure and aorta is severaltimes higher than that in the pulmonary circulation. Thisshunting of blood is called a left-to-right shunt that issimilar to that described above with VSDs and ASDs. Leftto-rightshunts are noncyanotic congenital heart lesionsthat are usually well tolerated by the body and give rise toproblems only when they are very large shunts or otherlesions coexist.Examination of the infant by the physician reveals aloud continuous machinery-like murmur that is best heardat the upper left after breastbone (sternum). The openingof the palm of the hand placed in this area may detecta vibratory sensation called a thrill. A typical findingis bounding peripheral pulses that can be felt at thewrist and the top (dorsum) of the feet (the dorsalis pedisartery).B. TreatmentThe presence of a patent ductus necessitates its closure,which can be done at low risk. Surgical ligation is simple,but the newer techniques using transcatheter closureappear promising. A patent ductus may coexist withother malformations such as coarctation of the aorta andvalvular aortic stenosis, and these lesions must be excludedbefore simple ligation of the ductus. A patent ductus isa potential site of endocarditis and prophylactic antibioticsare required.With an ASD, however, because the flow across this leftto-rightshunt is small, endocarditis is extremely rare andantibiotic prophylaxis is usually not recommended. It isone of the few heart lesions in which a murmur is heardand deformities are present for which prophylaxis is notrequired.the commissures, which results in obstruction to the valveso that blood flow from the left ventricle into the aorta isrestricted, (see figures in the chapter Anatomy of theHeart and Circulation for normal aortic valve and heartstructures). Severe or moderate degrees of aortic stenosiscan be life threatening and surgical correction is necessary.Percutaneous balloon aortic valvuloplasty may delaysurgical correction of the deformity in some individuals.Bacterial endocarditis must be prevented with antibioticcoverage.V. BICUSPID AORTIC VALVEBicuspid aortic valve is important because it is the mostcommon congenital heart lesion and often remainsundetected until aortic stenosis develops in adults betweenage 25 and 40. Also, the valve may become incompetentwith blood flowing from the aorta back into the leftventricle, a condition called aortic incompetence or aorticregurgitation. A study designed to determine the incidenceof CHD reported CHD excluding bicuspid nonstenoticaortic valves as 9596 defects per million live births and13,556 bicuspid aortic valves per million live births.The majority of bicuspid valves are well toleratedthroughout adult life, but individuals harbor a risk forbacterial endocarditis and antibiotic prophylaxis is required.The diagnosis of bicuspid valve is simple: a murmur iseasily heard at the stethoscope in the aortic valve area andthe second right intercostal space. The murmur mayradiate and may be heard over the neck vessels.Echocardiography confirms the diagnosis.A. Management and Research ImplicationsDuring young adult life the aortic valve may becomeobstructed or incompetent and must be replaced. Thevalve has a predilection for calcification which furtherobstructs the flow of blood. A mechanical valve is superiorto a bioprosthetic valve that may only last 12–20 years.A pulmonary autograft, an aortic homograft, or otherdevice may be selected depending on the age of the individualand the preference of the surgical team.Further research for new valvular structures that arelong-lasting but carry no risk of thrombosis is needed.IV. AORTIC STENOSISThe normal aortic valve has three leaflets. With congenitalaortic stenosis the valve is often bicuspid (two leaflets). Theaortic valve leaflets are thickened and fusion occurs atVI. COARCTATION OF THE AORTACoarctation of the aorta is a congenital narrowing ofthe aorta as the artery winds its way from the top of

VII. OTHER CONGENITAL ANOMALIES255the heart. The condition may be discovered when the childis an infant if the coarctation is severe or if an astutephysician correctly interprets the signs. About 80% ofchildren with coarctation have a mild coarctation ordevelop an extensive corollary system of vessels that carryblood past the coarctation. These children may have nosymptoms until they reach adolescence; some childrenhave no symptoms until they reach the age of 15–30.Early diagnosis of coarctation of the aorta is essential toensure timely surgical or nonsurgical correction. Althoughthere are remarkable specific physical signs that makediagnosis straightforward in the doctor’s office, it isone of the most commonly overlooked diagnoses inchildren. A diagnosis can be made within minutes if thephysician feels the femoral pulses and finds them absentor weak. There is also accompanying high blood pressurein the arms and low pressure in the legs. More than 80%of coarctations are situated just beyond the ductusarteriosus and, fortunately, beyond the beginning of theleft subclavian artery, which supplies blood to the leftupper limb.Because the aorta is constricted, the limbs are bloodstarved. There is hypertension in the upper part of thebody and the blood pressure is low in the legs. Symptomsresult from lack of adequate blood supply to the lowerlimbs, causing coldness, numbness, heaviness of the legsand feet, pain in the muscles, intermittent claudication,and leg cramps. Other symptoms include dizziness, headaches,nosebleeds, shortness of breath, and palpitations.Complications from coarctation of the aorta includeangina, heart failure, aortic rupture, and cerebral hemorrhagefrom associated berry aneurysms at the base of thebrain. All patients should be screened to exclude berryaneurysms, polycystic kidney disease, and bicuspid aorticvalve. Endocarditis of a bicuspid valve or the aorta inthe arch or just distal to the coarctation may occur.Treatment is best achieved with surgery. Balloon dilatationis recommended for recurrent coarctation and hashad a success rate of about 80%. Results from theValvuloplasty and Angioplasty of Congenital AnomaliesRegistry indicate a success rate that is comparable withsurgery for recurrent coarctation. As first-step therapy,however, balloon dilatation is considered investigational.Protection from a rupture during the procedure is ofconcern because the coarctation area is not surroundedby scar tissue as occurs after surgery. Because dilatationof the artery causes tears in the wall (intima and media),long-term follow up is required to exclude the possibilityof aneurysm formation. Continued evaluation and longtermassessment are necessary before the procedure can beconsidered first choice. Fawzy et al, however, reportedon successful long-term outcome [up to 15 years] ofballoon angioplasty of discrete native coarctation of theaorta in adolescents and adults.After correction of the coarctation, the blood pressuremay increase over the ensuing years. Thus close follow upis necessary. Because constriction of the aorta causesreduced blood flow to the kidney, the renin–angiotensinsystem is stimulated and this increases blood pressure.ACE inhibitors constitute rational therapy for the managementof hypertension, but are not always successful.VII. OTHER CONGENITAL ANOMALIESA. Coronary Artery Anomalies in AdultsAnomalies are found in less than 1% of patientsundergoing coronary angiography and in less than 0.3%of autopsies. Most of these are, however, benign.Anomalies can originate from the coronary artery fromthe contralateral coronary sinus. The left main and rightcoronary artery may arise from the left aortic sinus andcause about 8% of serious coronary anomalies. (Seecoronary ostia in Figures 5 and 9 in the chapter entitledAnatomy of the Heart and Circulation.) This anomaly isassociated with sudden death. Some of these individualsare asymptomatic until they exercise. Another type ofanomaly may originate from a single coronary artery ora coronary artery from the pulmonary artery.1. Clinical FeaturesAngina, transient loss of consciousness, syncope, myocardialinfarction, heart failure, and sudden death may occurwith coronary artery anomalies. Sudden cardiac death inyoung individuals, particularly athletes, has drawn attentionto these anomalies which account for about 15%of these catastrophic events in young adults. Sudden deathis more common when the anomalous artery is dominantand supplies a larger part of the heart muscle.Common causes of sudden cardiac death in young adultsinclude hypertrophic cardiomyopathy (see the chapterAthletes and Sudden Cardiac Death), Brugada syndrome(see the chapter Brugada Syndrome), and coronary arteryanomalies. Usually these defects cause symptoms becauseof a steal phenomenon — areas of heart muscle deprivedof blood with oxygen and nutrients. Chest pain, angina,myocardial infarction, shortness of breath, and syncopemay occur. Anomalous origin of the left main coronaryartery from the right coronary sinus is more frequentlysymptomatic than when the right coronary artery arisesfrom the left coronary sinus.

256CONGENITAL HEART DISEASEThe origin of the left main coronary artery from thepulmonary trunk is a serious condition that usually causesdeath during early childhood. The ECG shows broad, deepQ waves in leads I, aVL, V5, and V6, and signs ofischemia. Deep Q waves in lead I are rarely seen except inhypertrophic cardiomyopathy. Survival may occur topuberty in a few cases if myocardial collaterals developfrom the normally arising right coronary artery. Apart fromthe ominous electrocardiographic findings that shouldlead to immediate investigations, auscultation with thestethoscope may reveal a continuous murmur that servesto differentiate the rare condition from all other cardiacabnormalities. Only a patent ductus arteriosus causesa continuous murmur that is usually very loud andmachinery-like. These individuals usually present withsyncope, undue shortness of breath, angina, myocardialinfarction, or sudden death.Arteriovenous malformations (AVMs) are anomalouslesions of concern that occur in the brain where hemorrhagecan cause devastating effects. The usual presentationis a hemorrhage, seizures, progressive neurologic deficits,and headache. Recently great advances have been madein the application of endovascular embolization techniques,stereotactic radiosurgery, and microsurgery for themanagement of AVMs that were previously thoughtuntreatable. The finding of an AVM in one site in thebody demands a search for one in other vital organs ofthe body, particularly the lungsAnother congenital anomaly is dextrocardia. With thisthe left chambers of the heart are on the right and the rightchambers are on the left. The apex of the heart isformed by the left ventricle and points to the right. Thereis similar transposition of the abdominal organs so that thespleen is on the right and the liver is on the left. The ECGshows typical features. Figure 3A shows a normal tracing(A) compared with the mirror image of dextrocardia (B).Chest x-ray and echocardiography are diagnostic. Patientsusually have no other heart defects and are usuallyasymptomatic. In patients with dextrocardia but with theabdominal organs in the normal position, other cardiacanomalies coexist and patients may be symptomatic.See other cardiac anomalies in the chapters Atrial SeptalDefect, Patent Foramen Ovale, and Athletes and SuddenCardiac Death.VIII. CONGENITAL CYANOTIC HEARTDISEASECongenital heart disease is a general term that refers todefects of the heart that occur during the development ofthe fetus. They are present at birth but may be discoveredmuch later. The exact causes of congenital heart disease,which occurs in about 0.8% of live births, is unknown.Approximately 10% of all congenital cardiac defects canbe accounted for by chromosomal aberrations or geneticmutations or transmission. Down syndrome is the mostcommon chromosome aberration and occurs in about 1in every 700 births; the risk rises steeply if the motheris over age 35 and is as high as 4% for women over age 44.In this condition, an atrial septal defect (ASD), a hole inthe septum dividing the top chambers of the heart iscommon.Congenital defects associated with prenatal exposureto teratogens, which adversely affect embryonic or fetaldevelopment, include infectious vectors such as rubella,and drugs and chemicals including radiation, ACE inhibitors,alcohol, hydantoin, lithium, phenylalanine, thalidomide,trimethadione, valproic acid, vitamin D, andanticoagulants as well others. Because so little is knownabout the causes of the majority of congenital heart defects,and teratogens are strongly implicated in many, it mustbe emphasized that no medication should be taken duringthe first six months of pregnancy without prior consultationof a knowledgeable physician.Some babies born with congenital heart defects mayappear blue (cyanotic) at birth or during early childhood,and during exertion and exercise, some children maybecome cyanotic. In severe cases, the child is blue even atrest and the ends of the fingers appear club-like. This formof congenital heart disease is called congenital cyanoticheart disease and is caused by blood which is deoxygenatedflowing from the right side of the heart to the left side. It isusually caused by a hole in the heart combined with anobstruction to blood flow through one of the valves.A. Tetralogy of FallotThis is the most common form of cyanotic CHD observedafter one year of age, with an incidence of about 6% ofall forms of CHD.Several defects are involved in this condition. A ventricular septal defect (VSD) causes a hole in theseptum between the two ventricles. Right ventricular outflow obstruction in the area ofthe pulmonary valve causes hypertrophy of the rightventricle and a higher pressure in the right ventricle.Thus, deoxygenated blood flows through the hole in theheart from the right to the left ventricle. This deoxygenated,or blue blood, is pumped from the left ventricleinto the arteries and general circulation. A bluediscoloration is imparted to the lips, tongue, earlobes,and other areas.

VIII. CONGENITAL CYANOTIC HEART DISEASE257Lead I II III aVR aVL aVFV 1 V 2 V 3 V 4 V 5 V 6Lead I II III aVR aVL aVFV 1 V 2 V 3 V 4 V 5 V 6FIGURE 3 Mirror-image dextrocardia with situs inversus. The patient is a 15-year-old girl. There is no evidence of organic heart kisease. (A) Tracingrecorded with the conventional electrode placement. (B) Tracing obtained with the left and right arm electrodes reversed. The precordial lead electrodes alsowere relocated in the respective mirror-image positions on the chest. The tracing is within normal limits. (From Chou, T.C. (1996). Electrocardiography inClinical Practice, 4 th ed., Philadelphia: W.B. Saunders.) There is a dextraposed aorta that is overriding theseptal defect. Other anomalies, such as an ASD, VSD, or patentductus, can cause a right-to-left-shunt and cyanoticproblems if they are associated with pulmonary hypertensionand enlargement of the right ventricle thatmarkedly increases the right ventricular pressures.The majority of congenital heart defects, however,result in blood flow from the left side of the heart carryingoxygenated blood into the right side, thus no bluishdiscoloration is observed. These children may have a completelynormal childhood, and the defect is discoveredin adolescence or young adulthood. In both congenitalcyanotic heart disease and noncyanotic heart disease, ifthe defects are large enough, children may showstunting of growth and are predisposed to frequent chestinfections.The four defects that comprise the tetralogy are1. A large VSD2. An obstruction of the outlet of the right ventricle thatrestricts the flow of blood into the pulmonary artery(see Fig. 4).3. The entrance to the aorta overrides the right ventricularoutlet and the large hole in the septum; thus, deoxygenatedblood flows into the aorta and the systemiccirculation to organs and tissues with cyanosis of thelips, mucous membranes, and the periphery4. Right ventricular muscular wall enlargementAdditionally, these defects coexist in about 40% ofpatients with other cardiac defects including patent ductusarteriosus and peripheral pulmonary artery stenosis.1. Clinical FeaturesThe majority of children with tetralogy of Fallot aresymptomatic and cyanotic. Most are observed to be cyanoticfrom birth or develop cyanosis before age 1 indicatingsevere pulmonary outflow obstruction and a largeVSD. Severe shortness of breath on mild exertion, fatigue,and in some cases syncope that occasionally terminates inconvulsions may occur. The child at rest often resorts to asquatting position or may lie with knees drawn to thechest, a most comfortable position that results in lesscardiac burden.

258CONGENITAL HEART DISEASEFIGURE 4 Tetralogy of fallot with infundibular and valvular pulmonic stenosis. The arrows indicate direction of blood flow. A substantial right-to-leftshunt exists across the ventricular septal defect. RA ¼ right atrium; LA ¼ left atrium; RV ¼right ventricle; LV ¼ left ventricle; Ao ¼ aorta; PA ¼ pulmonaryartery. (From Friedman, W.F., and Silverman, M., in Heart Disease, A Textbook of Cardiovascular Medicine, sixth edition, Braunwald, E., Zipes, D.P., andLibby, P. Eds. Philadephia: W.B. Saunders, 1559, 2001. With permission.)On examination the infant reveals some underdevelopment.After one year the ends of the fingers have acurious clubbed shape and the toes may also be clubbed.A systolic thrill is palpable along with a loud systolicmurmur heard along the lower left sternal border.Echocardiography confirms diagnosis but delineationof complex pulmonary and other abnormalities usuallyrequire combined angiography and three-dimensional CT.2. ManagementUsually correction of the lesion is essential to preventsevere hypoxemia and delayed growth and development.Palliative measures are employed in infants and totalcorrection is then carried out at low risk later in childhood.IX. PREGNANCY AND CONGENITALHEART DISEASEPregnancy should be avoided if possible in most patientswith CHD. Patients with cyanotic CHD, Eisenmenger’ssyndrome, Marfan syndrome, coarctation of the aorta,VSD with shunt greater than 50% and others with rightto-leftshunts, and moderate aortic stenosis must avoidpregnancy.A. Research ImplicationsBecause genetic causes of CHD are far more commonthan previously realized, there has recently been a vastamount of new genetic research. A single gene mutationappears to be the causative factor in familial forms ofASD. Much has been learned from the rubella syndrome inwhich abnormalities such as cataracts, deafness, microcephaly,patent ductus, pulmonary stenosis, and ASDsoccur.The genes responsible for many defects have beenmapped and identified. Figure 5 gives cardiovascularmanifestations associated with chromosome aberrations.B. TeratogensTeratogens and congenital heart disease require intensiveresearch. The thalidomide effects are well-known, however,there are several drugs that have teratogenic effects andare used occasionally worldwide during the first 16 weeksof pregnancy. Many drugs including alcohol and otherunknown substances are used within the first three weeksof pregnancy often before the mother is aware that pregnancyhas occurred. Electrical impulses in the developingembryo produce a heart impulse as early as the 22nd day.During the first 28 days the developing fetus may beexposed to alcohol, antidepressants, caffeine, nicotine, and

IX. PREGNANCY AND CONGENITAL HEART DISEASE259FIGURE 5 Chromosomal location of human genes associated with some disorders of the cardiovascular system. These genes affect the structure,function, and metabolism of the heart and blood vessels and hemostasis and have been identified by the deleterious effects of mutations. Numerousadditional genes that encode structural proteins important to the cardiovascular system have been identified but not yet associated with disease. In the figure,brackets next to the chromosome show the regional localization of the gene causing a particular disorder. Brackets next to two or more disorders indicatedthat all the genes causing the disorders map to the same region. Disorders surrounded by boxes are caused by different mutations a the same gene. (FromPyeritz, R.E. (2001). Heart Disease, 6 th ed., Braunwald, E., Ed., Philadelphia: W.B. Saunders, pp. 1983–1984. With permission.)

260CONGENITAL HEART DISEASEFIGURE 5Continued

IX. PREGNANCY AND CONGENITAL HEART DISEASE261TABLE 1Cardiovascular Defects Associated with Prenatal Exposure to TeratogensTeratogenEthanolHydantoinLithiumPhenylalanineRetinoic acidRubellaTrimethadioneValproic acidVitamin DWalfarinCardiovascular Abnormalities a50% have CHD: VSD (50% close spontaneously),TOF, ASD, ECD, absence of a pulmonary artery10% have CHD: VSD, ASD, PS50% have CHD: TGA, TOF, VSD, IAA>50% have CHD: PDA with or without ASD, VSD, PPS, IAA50% have CHD: complex combinations most frequent(involving VSD, ASD, PDA, AS, PS), VSD, TOF>50% have CHD: left- and right-sided flow lesions: CoA, HLH,ASD, VSD, pulmonary atresiaSupravalvular aortic stenosis is the cardinal manifestation; PPS10% have CHD: PDA, PS; rarely, intracranial hemorrhage.CHD ¼ congenital heart defect(s); VSD ¼ ventricular septal defect; TOF ¼ tetralogy of Fallot; ASD ¼ atrialseptal defect; ECD ¼ endocardial cushion defect; PS ¼ valvular pulmonic stenosis; TGA ¼ transposition of greatarteries; IAA ¼ interrupted aortic arch; PPS ¼ peripheral pulmonic stenosis; PDA ¼ patent ductus arteriosus;AS ¼ aortic stenosis; CoA ¼ coarctation of aorta; HLH ¼ hypoplastic left heart.a Among patients with the full clinical spectrum associated with each teratogen; cardiovascular defects listed indecreasing order of prevalence. From Pyeritz, R.E. (2001). Genetics and cardiovascular disease. In Braunwald, E.,Zipes, D. P., and Libby, P., Eds., Heart Disease, 6 th ed., Philadelphia: W.B. Saunders, p.1993.other products that may alter the development of theunique human heart. The study of the embryo heart atweeks 2 through 8 is crucial and more research is needed inthis area (see the chapter Embryology).More than strict animal testing of new and old drugsthat may be teratogenic must be done. It is necessary todetermine which animals are the best representation of thehuman fetus. Development of the chick embryo is similarto that of the human embryo and much of our understandingof the heart’s early development comes fromstudies of chick embryo. Perhaps a different model isrequired to test the effect substances on developmentalinjury in the human embryo.Cardiovascular anomalies associated with prenatalexposure to teratogens are given in Table 1. Cardiovasculardrugs that are contraindicated particularly duringthe first 16 weeks of pregnancy include angiotensinconvertingenzyme (ACE) inhibitors and angiotensinreceptor blockers. These agents may adversely affect fetaland neonatal blood pressure control and renal function.They may cause defects and oligohydramnios. Theseagents are teratogenic in animals and are associated witha high incidence of intrauterine death. They are used inthe management of hypertension and are contraindicatedin women of childbearing age. Calcium antagonists such asdiltiazem, verapamil, nifedipine, amlodipine, and similardihydropyridines must also be avoided.BIBLIOGRAPHYFawzy, M. E., Awad, M., Hassan, W. et al. Long-term outcome (up to15 years) of balloon angioplasty of discrete native coarctation of theaorta in adolescents and adults. J. Am. Coll. Cardiol., 43:1062–1067,2004.Fleetwood, I. G., and Steinberg, G. K. Arteriovenous malformations.Lancet, 359:863–73, 2002.Gabriel, H. M., Heger, M., Innerhofer, P. et al. Long-term outcome ofpatients with ventricular septal defect considered not to requiresurgical closure during childhood. J. Am. Coll. Cardiol., 59:1066–71,2002.Hoffman, J. I. E., and Kaplan, S. The incidence of congenital heartdisease. J. Am. Coll. Cardiol., 39:1890–900, 2002.Lim, M. J., Forsberg, M., and Kern, M. J. Provocable pressure gradientacross an anomalous left main coronary artery: A unique diagnostictool. Circulation, 111:e108–e109, 2005.Taylor, A. J., and Virmani, R. Coronary artery anomalies in adults:Which are high-risk? AAC Curr. J. Rev., September/Oct 1992–95,2001.

Contraception and Cardiovascular DiseaseI. Oral ContraceptivesGLOSSARYembolism sudden blocking of an artery by a clot or foreignmaterial which has been brought to its site of lodgement bythe circulating blood. Pulmonary embolism is often causedby a clot (thrombus) that dislodges from a vein in the thigh orpelvis and shoots into a pulmonary artery.myocardial infarction death of an area of heart muscle due toblockage of the coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.thromboembolism formation of a blood clot and a subsequentdislodgment; the thrombus is carried in the circulating bloodand obstructs an artery.I. ORAL CONTRACEPTIVESA. RisksThe risk of cardiovascular disease among women attributedto the use of oral contraceptives became immediatelyapparent following the use of these agents more than40 years ago. The risk was alarming in women older thanage 30 who smoked cigarettes. The use of third generationoral contraceptives is purported to have a lower risk ofmyocardial infarction compared with second generationoral contraceptives. Recent studies do not indicate thatthird generation contraceptives possess a lower risk forinfarction and most important, the studies indicate asignificantly increased risk for deep vein thrombosis(DVT) and pulmonary embolism compared with usersof second generation contraceptives. Because the risk formyocardial infarction in women before age 35 is extremelylow, studies are confounded.The risk of heart attack has not been minimized bythe use of third generation oral contraceptives. Cigarettesmoking continues to be the major factor for increased riskof heart attacks in older, childbearing women aged 33–45and second or third generation contraceptives increase thatrisk. Most important, the increased risk for DVT andthromboembolism has not been removed.1. Increased Coagulation FactorsThe identification of a poor anticoagulant response toactivate protein C (aPC) has far reaching consequencesand has provoked new directions in the field of prothromboticmarkers. Individuals with aPC resistance haveinadequate partial thromboplastin time (PTT) prolongationwhich increases hypercoagulability. The PTT givesa measure of clotting factors except the factor caused byprothrombin. Normal levels of PTT range from 30 to 40seconds. When heparin, the well-known intravenousanticoagulant, is administered to thin the blood the PTTgoal is set at 1.5–2.3 times the mean control range, whichcorresponds to a PTT of 50–80 seconds. At these levelssome clots are partly dissolved and further clotting isprevented.Most important, aPC resistance occurs more frequentlywith DVT as seen from two studies. This incidence isconsiderably higher than that observed with well-knowncoagulation protein deficiencies which include protein Cat 3%, protein S at 4%, antithrombin at 2%, and plasminogenat 1%.Normally, a specific amount of aPC added to plasmacauses a calculated prolongation of the PTT, but in patientswith aPC resistance inadequate PTT prolongation isobserved.The factor V Leiden mutation is an important risk forDVT. In a case control study of premenopausal womenwho developed DVT, the risk of thrombosis among usersof oral contraceptives was increased fourfold. The riskfor DVT was eightfold among carriers of the factorV Leiden versus noncarriers. Women with the factorV Leiden mutation who used oral contraceptives had a30-fold increase in risk.263

264CONTRACEPTION AND CARDIOVASCULAR DISEASE2. Deep Vein ThrombosisThe phenotype of aPC resistance is associated with a singlepoint mutation, designated factor V Leiden in the factorV gene. Factor V Leiden mutation results from a singlenucleotide substitution of adenine for guanine 1691. Thus,the amino acid arginine is replaced with glutamineat position 506. This unfortunate change eliminates theprotein C cleavage site in factor V. The frequency of thismutation was found to be about 3% in healthy malephysicians in the United States and did not appear toincrease the risk of stroke or heart attack in the PhysiciansHealth Study. But the incidence of the factor V mutationwas observed to be three times higher among men whodeveloped DVT. Thus coagulation and clotting in veins ofthe lower limbs and pelvis and veins that drain into theright atrium is a different phenomenon from that observedin the coronary arteries supplying the heart with bloodand the branches of the aorta that circulate blood to thehead and lower limbs. A good example is set forth bythe proved fact that aspirin and other antiplatelet agentsare useful in preventing clots in the coronary arteries andin the prevention of strokes, but they are of little or novalue in the prevention of clot formation in the veins of thelower limbs.Thus it is advisable to screen for factor V Leiden inwomen older than age 35 who take oral contraceptives.This advice is particularly important if there is concomitanthypertension, hyperlipidemia, cigarette smoking, or afamily history of DVT.3. Myocardial InfarctionSecond and third generation oral contraceptives generallycontain a small dose of synthetic estrogen and a syntheticprogestin. The risk of myocardial infarction is currentlybelieved to be low, but the risk is increased in women olderthan age 35 and in those with hypertension, hyperlipidemia,and in those who are cigarette smokers.The estrogenic contents of the pill modestly increasesgood cholesterol HDL levels, lowers LDL cholesterol(bad) levels, and mildly increases serum triglycerides.The progestin component increases LDL levels, causes adecrease in HDL levels, and may increase coagulopathy.Agents such as desogestrel, gestodene, norgestimate, andnorethindrone may have modest beneficial effects onlipoprotein levels, but they are associated with an increasein DVT and thromboembolism which includes pulmonaryembolism.4. HypertensionAlthough second and third generation oral contraceptivesrarely cause an increase in blood pressure in youngerwomen, in those over 35 a mild increase in blood pressurethat returns to normal has been observed. The incidenceof increased blood pressure is low, but it is increased inindividuals who are overweight or who have had hypertensionin previous pregnancies, and perhaps in those whoabuse alcohol. In rare instances blood pressure may acceleraterapidly and cause renal damage. Thus, caution isnecessary and adequate follow up is essential. In addition,plasma insulin levels are increased reflecting peripheralinsulin resistance, a harbinger for subtle cardiovasculardamage.a. Clinical Study: Tanis et al.Methods: This study consisted of 248 women who had afirst myocardial infarction and were identified and enrolledin a nationwide population-based case control study and925 control women who had not had a heart attack andwho were matched for age and calendar year of the indexevent. Subjects supplied information on all contraceptiveuse and cardiovascular risk factors.Results: The alteration for heart attack among womenwho used any type of combined oral contraceptive ascompared with nonusers was 2.0. The adjusted alterationwas 2.5 among women who used second generation and1.3 among those who used third generation oral contraceptives.Conclusions: The authors of the study concluded:‘‘the risk of myocardial infarction was increased amongwomen who used second generation oral contraceptives.Results with respect to use of third generation oralcontraceptives were inconclusive but suggested that therisk was lower than the risk associated with secondgeneration oral contraceptives.’’B. PerspectiveAlthough the majority of patients with a heart attack inthe study quoted above were between the age of 35 and49 (72%), only 74 patients with acute myocardialinfarction were using oral contraceptives and 134 werenot. The wide confidence interval observed in the studyhighlights the low statistical power of the study and

I. ORAL CONTRACEPTIVES265indicates that random variation is an alternative explanationfor the results. It is interesting that the authors ofthe study offered the following rebuttals to criticisms ofthe study:‘‘The lower risk of myocardial infarction that weobserved in association with third generation contraceptives(desogestrel or gestodene) as compared with secondgeneration contraceptives (levonorgestrel) may beexplained by random variation around equivalence,also, the study performed in the United Kingdom foundthe risk associated with third generation contraceptiveswas 1.8 times that associated with secondary generationcontraceptives.’’Combined results of the two studies suggest:third generation contraceptives increase the risk ofmyocardial infarction, and the difference in secondgeneration contraceptives, if any, is small. Third genetioncontraceptives double the risk of venous thrombosisassociated with second generation contraceptives whichare already associated with a fourfold increase in riskrelative to non-use of oral contraceptives.Tanis and Rosendaal agreed with my admonitions givenabove and further stated that ‘‘there are prothrombotic,hemostatic changes that are more pronounced with thirdgeneration preparations than with older preparations.’’Clearly this study is too small to generate credibleanswers for individuals who may be at risk and mostimportant, policymaking remains at a standstill.On the basis of several studies that were in progressin 1995, the British committee on safety of medicineswarned general practitioners of a potentially increased riskof venous thromboembolism among users of third generationcontraceptives. This advice was not given in theUnited States. Policymakers must be warned that theymust differentiate the risk for myocardial infarction thatis totally different from thromboembolism caused byDVT. Complications from DVT are as important as myocardialinfarction because they may cause life-threateningpulmonary embolism.BIBLIOGRAPHYChasan-Taber L., and Stampfer, M. Oral contraceptives and myocardialinfarction — the search for the smoking gun. N. Engl. J. Med.,345:1841–2, 2001.Tanis, B. C., and Rosendaal, F. R. Oral contraceptives and the risk ofmyocardial infarction. N. Engl. J. Med., 346:1828, 2002.Tanis, B. C., van den Bosch, M. A. J., Kemmeren, J. M. et al. Oralcontraceptives and the risk of myocardial infarction. N. Engl. J. Med.,345:1787–93, 2001.Vessey, M., Painter, R., and Yeates, D. Mortality in relation to oralcontraceptive use and cigarette smoking. Lancet, 362:185–91, 2003.

Coronary Artery Bypass SurgeryI. The Coronary ArteriesII. IndicationsIII. Types of GraftsIV. OutcomesV. ComplicationsVI. Surgery in the ElderlyVII. ContraindicationsVIII. MedicationsIX. Coronary Bypass Surgery versus PCIGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of the cells.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).atrial fibrillation the most common, persistent arrhythmia thatis seen in medical practice; it may precipitate thromboembolicstroke.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker ofleft ventricular contractility.embolism, embolus a blood clot that forms in an artery, a vein,or the heart that breaks off and is carried by the circulatingblood, finally lodging and blocking the artery that suppliesan organ with blood; for example, pulmonary embolism isan embolus blocking the artery in the lung.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.I. THE CORONARY ARTERIESDr. Rene Favoloro of Argentina performed the first coronaryartery bypass graft (CABG) in 1967 at the ClevelandClinic. He used a vein from a patient’s leg to bypass theobstruction in the coronary artery. Since that time, severalmillion bypass operations have been performed worldwide.Coronary artery bypass grafting is a simple procedure:A vein from the patient’s leg is removed and inserted intothe aorta as it leaves the heart and the other end of thevein is joined to the coronary artery below the blockage.Blood then flows from the aorta through the vein graftbeyond the blockage to the coronary artery and to theheart muscle (see Fig. 1). When possible, surgeons preferto use the internal mammary artery instead of using avein graft to bypass the blockage in the important leftanterior descending (LAD) artery.AortaVein graft(vein from patients leg)Obstruction byatheroma(atherosclerosis)CoronaryarteryFIGURE 1 Coronary bypass graft. Blood flows from the aorta to acoronary artery bypassing the blockage.267

268CORONARY ARTERY BYPASS SURGERYII. INDICATIONSA. Stable AnginaIf stable angina is not adequately relieved by the combinationof a beta-blocker, a nitrate, and a calcium blockerand lifestyle is deemed unacceptable by the patient orthe physician, coronary artery bypass surgery is usuallyrecommended. The main aim of surgery is to relieve pain.The complete relief of pain is certainly most satisfying andthis is achieved in 90% of patients, whereas drugs achievethis goal in less than 50%. Drugs lessen the frequency ofangina by about 60% in approximately 60% of patientstreated. Some patients are satisfied with medical therapyand surgery is not indicated. About 40% of patients withangina are not satisfactorily controlled with medical therapy;these patients are recommended to have coronaryarteriography with a view to CABG.Patients with mild anginal symptoms may have severeatheromatous obstruction of the coronary arteries. Stresstesting and nuclear scans may risk-stratify these patients;those with positive tests at a workload that is low areusually submitted to coronary arteriography.Patients with mild stable angina with compromised leftventricular function as indicated by an ejection fraction(EF) of less than 45% and patients with diabetes mayobtain improvement in survival with a revascularizationprocedure. The revascularization procedure may be bypasssurgery or PCI. In addition, beta-blockers are contraindicatedin patients with asthma and they may requirerevascularization at an early stage.B. Unstable AnginaPatients with unstable angina are identified by the following:a change in pattern, increasing frequency, severityand/or duration of pain, and a lesser degree of knownprecipitating factors. Pain may occur on exertion and atrest. Also, new onset of angina present for less than 60 daysis classified as unstable angina.The majority of patients with unstable angina shouldundergo coronary arteriography. Depending on the extentand site of lesions, they are offered PCI or surgery if nomajor contraindication exists.C. Left Main Coronary Artery DiseaseThe left main coronary artery is a short segment before itdivides into the LAD and circumflex arteries (see Fig. 2).Severe disease of the left main is fortunately uncommonFIGURE 2Coronary arteries.but is obviously a serious situation when it occurs, becauseit supplies blood to most of the heart. Thus, CABG isadvisable regardless of the severity of symptoms or leftventricular dysfunction. Patients with triple-vessel diseasewhich includes atheromatous obstruction of the proximalLAD are at high risk for coronary events and bypasssurgery is usually recommended.D. Diabetes MellitusPatients with diabetes and stable or unstable angina withtriple- or double-vessel disease, especially if this involvesthe LAD, are usually offered surgery because its benefitssupersede those of PCI.III. TYPES OF GRAFTSA. Saphenous VeinThe saphenous vein is ideal for bypass of occlusions ofthe right coronary and circumflex coronary arteries andfor their diagonal branches. A saphenous vein graft iseasily harvested and is used in emergency situations. Theseinclude bypass of the LAD because the internal mammaryartery is more difficult to mobilize in emergencysituations. Saphenous vein grafts are superior or equalto radial artery grafts, but are much more vulnerable toocclusion compared with the internal mammary artery.

III. TYPES OF GRAFTS269Approximately 10% of saphenous grafts becomeobstructed during the perioperative period. At 1 yearapproxmately 22% are obstructed and at 5 and 10 years,approximately 30% and greater than 55%, respectively,of these grafts become occluded. During the first yearafter implantation of the vein graft, there is proliferationand migration of smooth muscle cell into the intima. Themigration of smooth muscle cells is nature’s method ofhealing and strengthening damaged vascular endotheliumand is an early stage of atheromatous formation. In theselesions there are lipid-laden form cells, cholesterol clefts,and areas of calcification and thrombosis that are featuresof atherosclerosis. Late occlusions are due to acceleratedatherosclerosis that occurs in saphenous vein grafts. Thesaphenous vein in the leg never develops atherosclerosisand the atheromatous process occurs only after the graftis exposed to the high arterial pressure that is present inthe coronary and systemic circulation; the low pulsatilepressure in veins protects the vessel from the developmentof atherosclerosis. Beta-blocking agents decrease cardiacejection velocity and pulsatile blood flow, and along withmarked blood LDL cholesterol reduction, may favorablyinfluence saphenous vein graft occlusion. Fortunately,atherosclerosis is rare in internal mammary artery grafts.B. Internal Mammary ArterySince the late seventies use of internal mammary arterygrafts became popular and the current standard for bypassgrafting is the routine use of the left internal mammaryartery graft to the LAD, with supplemental saphenousvein grafts to other arteries. Figure 1 shows saphenous veingrafts and Fig. 2 shows an internal mammary artery graftto the LAD.It is not known why the internal mammary artery rarelydevelops atheroma. It is one of the few arteries in the bodythat is relatively free from atheromatous obstruction exceptafter age 70. The endothelium of this artery produces moreof the vasodilator prostacyclin than the endothelium of thesaphenous vein. This is one explanation that is given for thedifferences in atheroma formation.Fibrointimal proliferation that is different fromatheroma formation rarely develops in internal mammaryartery grafts resulting in late graft closure. But a greaterthan 80% patency at 10 years provides a decreased riskof late death, myocardial infarction, and reoperation overa 20-year period. Patency rates are 95, 90, and 83% at 1, 5,and 10 years, respectively.The internal mammary artery is, however, delicateand great care is required during mobilization to avoidtrauma to the vessel. Because the procedure takes considerabletime, this graft is not often used for emergencysurgery. The use of bilateral internal mammary arterygrafts provides superior protection from long-term occurrenceof myocardial infarction and angina, but harvestingis time-consuming and causes a high rate of postoperativecomplications such as bleeding, wound infection,and prolonged ventilatory support. Bilateral internal mammarygrafting is not an acceptable choice for diabeticsbecause of the increased occurrence of sternal woundinfections.C. Radial ArteryThe radial artery is readily accessible in the forearm, andit is used frequently by some surgeons. Spasm and thrombosisof the artery have been minimized by carefulmanipulation of the vessel and the use of long-termcalcium antagonists. The patency rate for radial grafts at5 years is approximately 80% versus 90% for internalmammary artery graft. Khot et al. have recently shown thatradial artery bypass grafts have an increased occurrenceof angiographically severe stenosis and occlusion comparedwith left internal mammary arteries and saphenous veingrafts.When coronary artery bypass surgery is selected, patientswho can receive an internal mammary artery graft are mostfortunate. The arterial graft has a prolonged patency of15–20 years versus approximately 10–12 years for saphenousvein grafts.D. Robotic Bypass SurgeryRobotic coronary bypass surgery using a left internalmammary artery graft to the LAD along with balloonangioplasty and stenting to non-LAD vessels that requiretreatment has proven successful in a small a study of150 patients. Follow up after three years shows 100% ofthe mammary grafts to be patent; 3.8% of the PCI vesselswere occluded, and 15% were narrowed; 10 patients hadrepeat PCI, and none had repeat surgery. Importantly,96% of the patients treated with this hybrid procedurewere free of symptoms at three years. Because the goldstandard treatment for obstructive coronary artery diseaseremains a left internal mammary artery graft, there is hopethat this hybrid procedure using robotic bypass surgeryto the LAD and angioplasty with stent for other vesselscould prove a major management strategy for the reliefof symptomatic, obstructive coronary artery disease.

270CORONARY ARTERY BYPASS SURGERYIV. OUTCOMESA. SurvivalOverall mortality of bypass surgery is approximately 3%.The operative mortality in patients over age 70, especiallyin women, is high — 6.3% versus 3.8% for men. Low-riskpatients may have a mortality as low as 1%, but in patientswith left ventricular dysfunction and an EF of 30% or less,mortality is as high as 9%. Survival at one month and 1, 5,10, and 15 years is 97, 95, 87, 76, and 60%, respectively(see Table 1).B. Prolongation of LifeImproved survival may be achieved in patients with stableor unstable angina and serious blockage of arteries in thefollowing types:1. Individuals who have severe narrowing of the leftmain coronary artery before it divides; this is theanatomical lesion for which surgery is universallyaccepted and is fortunately rare2. Individuals who have triple-vessel disease, that is, severeobstruction of the right coronary, the LAD, and thecircumflex arteries, especially in patients with decreasedfunction of the left ventricular muscle3. If the LAD is blocked before its first branch, plus twoother vessels have more than 80% obstruction andangioplasty is not possible4. Left ventricular dysfunctionThe EF, the amount of blood the ventricle puts outinto the aorta with each beat, is an important measure ofthe strength of the heart muscle. Its value is expressed asa percentage. A normal EF is more than 50%, an EF of lessthan 30% carries a bad prognosis, and less than 25% isa very poor prognosis. Surgery is highly beneficial inpatients with an EF between 30 and 45%. Thereforepatients with triple- or double-vessel disease that includesthe LAD and left ventricular dysfunction are best managedwith bypass surgery rather than angioplasty with stent ormedical therapy.Some studies indicate that viable dysfunction in themyocardium may improve after coronary revascularization.Although bypass surgery in patients with left ventriculardysfunction may provide relief of angina and improveleft ventricular function in some. There is lack of evidencefrom randomized controlled trials and the mortality ofsurgery should not be underestimated. An EF of lessthan 35% predicts an operative mortality of approximately7%; a recent study in patients with an EF of less than30% showed an in-hospital operative mortality of 8.4%.A recent study with the beta-blocking agent carvediloldemonstrated improvement in symptoms, occurrence ofheart failure, and survival in patients with myocardialinfarction and depressed left ventricular function.Most important, the aforementioned clinical trials ofbypass surgery in patients with left ventricular dysfunctiondid not compare patients medically treated with adrug as effective as carvedilol. The recent CAPRICORNand COPERNICUS studies show conclusively that thebeta-blocker carvedilol improves survival in patients withTABLE 1Results and Complications of Coronary Artery Bypass SurgeryOccurrence 1 Week (%) 1 Year (%) 5 Years (%) 10 Years (%) 15 Years (%)Survival (vein graft) 99 95 87 76 60 a –69 dPerioperative myocardial infarction (MI) 7–12MI fatal, nonfatal 5 15 35Reoperation for bleeding 1–4OcclusionVein graft occlusion 6–10 b 12–20 b 30 50–55 >60Internal mammary graft 17Internal mammary anastomosis c 17Symptomatic improvement 90 80Asymptomatic angina free 90 50a ACC/AHA Task Force Report, J Am Coll Cardiol, 1991; 17:543.b Aspirin 1 hour postoperative ¼ 1.6 and 5.8% (see Table 4.12.)c Preferred technique.d Internal mammary graft, J Am Coll Cardiol, 1996; 334:216.

V. COMPLICATIONS271coronary artery disease and severe left ventricular dysfunctionwith an EF of less than 30%; (see these studies givenin the Bibliography).which provides relief from angina. Discontinuation ofsmoking is necessary to prevent the recurrence of anginaand improvement in survival.C. Symptomatic ReliefApproximately 90% of patients get complete relief ofangina for the first year after saphenous vein grafts.At the end of 5 years approximately 30% of patientshave obstruction of their grafts and in some patientsangina recurs. The approximate freedom from angina is80% at 5 years and 50 and 25% at 10 and 15 years,respectively.Presently, with the addition of medication such asaspirin, fewer grafts become blocked. After five years,about 80% of patients are still pain-free, lead active lives,and enjoy life to the fullest — a situation that does notmaterialize with the use of drug treatment in patients withfrequent episodes of angina.Bypass surgery is simple to perform and there are fewcomplications. Cardiac surgeons can be proud of thisoperation, which provides major relief for suffering andcan prolong life in a selected few. We can visualize manysuccessful operations using angioplasty, stents, and lasertherapy during the next 20 years, but unless atherosclerosisis prevented, and this seems to be out of reach for thenext 50 years, coronary artery bypass surgery will playa substantial role for longer than some experts predict.Bypass surgery will be necessary for the left main coronaryartery disease and triple-vessel disease with left ventriculardysfunction that generally cannot be treated with angioplastyand stent.Patients who have had surgery must understand, however,that the other arteries and points in the coronaryartery below the graft can develop further atherosclerosisbecause the operation does not cure the disease. In addition,a blood clot (coronary thrombosis) can form in anyindividual at any time at the site of atheromatous obstructionwithout warning. Therefore, coronary bypass surgerydoes not prevent a second or third heart attack, althoughit may prevent death in a few.D. Other Factors Affecting Mortality andMorbidityApproximately 50% of grafts become blocked after 10years, particularly in patients who smoke or have hypertension,diabetes, or an LDL cholesterol level greater than120 mg/dl (3 mmol/L). Thus most patients require treatmentwith statins to achieve an LDL goal of less than80 mg/dl (2.0 mmol/L) to maintain patency of graftsV. COMPLICATIONSA. Acute Myocardial InfarctionAlthough intraoperative myocardial protection withimprovements in surgical techniques has advanced duringthe past decade, perioperative myocardial infarction (listedin Table 1) occurs in 7–12% of patients. Causes of perioperativemyocardial infarction include incomplete revascularization,thrombosis of the native coronary artery,diffuse atheromatous formation of the coronary arterydistal to the bypass graft, technical problems with thesurgical anastomosis, inadequate myocardial preservationintraoperatively, increased myocardial oxygen needs duringsurgery, hypotension caused by bleeding or medications,and tachycardia and abnormal heart rhythms such as atrialfibrillation that increase myocardial oxygen demand.The diagnosis of perioperative myocardial infarctionis difficult because there is virtually always elevation ofmyocardial creatine kinase (CK–MB) following surgery;nonspecific ECG changes occur postoperatively and theseimportant diagnostic tests of acute myocardial infarctionbecome nondiagnostic. The ECG still remains themost useful test, however, for diagnosis of perioperativeinfarction. The presence of new Q waves accompaniedby evolutionary ST or T-wave changes should suggestinfarction.Bedside echocardiography may reveal new regionalwall motion abnormalities compared with the preoperativebaseline echocardiogram. The new sensitive cardiacenzymes, troponins, are not useful because these enzymesbecome elevated postoperatively in virtually all patientswho undergo bypass surgery.A perioperative infarction increases in-hospital mortality(12%) when compared with patients who have notsustained infarction (mortality is approximately 2%).Predictors of perioperative infarction include left maincoronary artery disease; three-vessel disease, and perioperativeangina.B. Heart FailureHeart failure may be precipitated in patients with leftventricular dysfunction, especially in those with an EF ofless than 30%. Arrhythmias with a fast ventricular ratesuch as atrial fibrillation and other supper ventricular

272CORONARY ARTERY BYPASS SURGERYarrhythmias occur during surgery and in the early postoperativestate. These tachycardias increase left ventriclework and strain that may precipitate heart failure. Theavoidance of drugs that depress cardiac contractility suchas calcium antagonists, the use of ACE inhibitors for theleft ventricular strain, and the judicious use of small dosesof beta-blocking agents provide benefits. Furosemide aswell as other diuretic agents are used to relieve shortnessof breath.C. Atrial Fibrillation and Other ArrhythmiasAtrial fibrillation is a common complication of bypasssurgery and occurs in approximately 40% of patients,mainly within the first three days of surgery. Atrialfibrillation increases the incidence of heart failure; athrombus may form in the left atrium and embolizationmay result in stroke. It is remarkable that althoughatrial fibrillation is an extremely common arrhythmiaprecipitated by cardiac surgery, management strategies thatcan significantly prevent its occurrence have not beenestablished.The pre- and perioperative administration of betaadrenergicblocking agents reduce the incidence of heartfailure to about 30% in patients following bypass surgeryand in approximately 50% of patients following valvularsurgery. When atrial fibrillation occurs during surgerythe administration of intravenous beta-blocking agentssuch as metoprolol or esmolol reduces the fast ventricularrate from greater than 130 beats per minute to less than90 beats per minute.Supraventricular tachycardia occurs infrequently. Thisresponds rapidly to intravenous administration of adenosine6 mg in more than 60% of patients. A repeated doseof 12 mg can be administered if necessary and thisterminates the tachycardia in virtually all patients. Ventriculararrhythmias such as ventricular premature beatsoccur frequently and when needed are managed with asmall doses of a beta-blocking agent.D. NeurologicNeurologic complications occur in approximately 6%of bypass patients. Confusional state, stupor, coma, andsome deterioration in intellectual function and memorymay occur, albeit rarely. Intellectual dysfunction in theearly postoperative period occurs in greater than 50% ofpatients. Causes of neurological defects include embolizationof mobile atherosclerotic plaques in the aorta. Intraoperativemanipulation of the aorta is a major cause ofatheroemboli. Emboli from the cardiopulmonary bypassmachine circuit and its tubing can also cause neurologicaldefects. Cardiac surgery carried out on the beating heartwith the avoidance of cardiopulmonary bypass largelyovercomes these defects and its use is being developed.E. BleedingReoperation for hemorrhage is needed in approximately3% of bypass patients. The risk of bleeding is increasedin the elderly and also during bilateral internal mammaryartery grafting. The preoperative use of aspirin, heparin,and platelet receptor blockers in the management of acutecoronary syndromes increases the risk for hemorrhage.F. InfectionMediastinitis and/or infection of the wound with dehiscenceoccurs in about 1% of patients. This is increased inobese individuals, diabetics, or with the use of bilateralinternal mammary artery grafts.G. HypertensionPostoperative hypertension occurs in approximately 50%of patients and is easily controlled with nitroprusside,intravenous nitroglycerin, beta-blocking agents, or calciumantagonists.VI. SURGERY IN THE ELDERLYSurgery in relatively healthy patients between the age of70 to 80 in the absence of diabetes, left ventriculardysfunction, and other cardiovascular atherothromboticdisease undergo bypass surgery with a small added riskcompared to younger patients. In a large series of patientsintraoperative mortality was 3.8% in men versus 6.2%in women. The presence of the above conditions and othercomorbid conditions increases the risk considerably tomore than 7%.A. Octogenarian StudyStudy question: Is there a difference in outcomes amongoctogenarians undergoing bypass surgery using cardiopulmonarybypass or surgery without cardiopulmonarybypass.Methods: Bypass surgery was performed in patients80 years or older using cardiopulmonary bypass in 63 and62 surgeries were without cardiopulmonary bypass. Baselineleft ventricular EF and comorbidity were similar in thegroups preoperatively and the mean number of grafts inpatients did not differ.

VIII. MEDICATIONS273Results: The operative mortality was higher in thecardiopulmonary bypass group, 15.9 versus 4.8% in thosewithout bypass (P ¼ 0.04). More patients in the cardiopulmonarybypass group required blood transfusion, 92%versus 73% ( p ¼ 0.01). Postoperative myocardial infarctionwas similar, 11% versus 15%. This remarkable studyshould prompt a large randomized trial to confirm theresults.VII. CONTRAINDICATIONSSevere damage to the heart muscle as manifested byrecurrent heart failure or other indications of left ventriculardysfunction and an EF of less than 30% is a majorcontraindication for bypass graft surgery. Such patientsare very short of breath and often have fluid in thelungs. Shortness of breath cannot be relieved by surgery,and the heart muscle is not significantly strengthened forsurgery.Several heart attacks cause large areas of scarring, andthe scar tissue is weak. Scar tissue is dead and not suppliedwith blood; therefore, a bypass graft does not feed bloodto that area. Heart failure in the presence of an acuteheart attack that clears within the first seven days is nota contraindication to bypass surgery several months later,because the heart muscle recovers more than 75% of itsfunction.VIII. MEDICATIONSA. Perioperative1. AspirinAspirin given perioperatively has been shown to reducegraft occlusion.for 30 days postoperatively. There were two deaths andno myocardial infarctions versus nine deaths and nineinfarctions in the untreated group.B. Postoperative MaintenanceMaintenance medications that are given after coronarybypass surgery include aspirin, beta-adrenergic blockers,statins, and calcium antagonists.1. AspirinCoated aspirin 325 mg daily is given to patients indefinitelyto prevent graft occlusion and to prevent recurrentfatal or nonfatal myocardial infarction.2. Beta-Adrenergic BlockersThese are recommended in virtually all patients unlesscontraindicated by the presence of asthma or significantbradycardia with a heart rate less than 50 beats per minute.These agents assist with maintenance of blood pressure inthe normal range, decrease cardiac ejection velocity,prevent tachycardia, and are known to prevent fatal ornonfatal myocardial infarctions and sudden death inpatients with coronary artery disease.3. StatinsStatins such as simvastatin, rosuvastatin, or atorvastatin areadministered and recommended to virtually all patientsto maintain an LDL cholesterol of less than 80 mg/dl(2.0 mmol/L). This step is necessary to prevent graftocclusion and prevents fatal or nonfatal myocardialinfarction.2. Beta-Adrenergic BlockersBeta-blockers have been shown to decrease morbidityand mortality following cardiac surgery and other formsof surgery. These agents quell the effects of catecholaminesand allow safer induction of anesthesia and help to preventthe hypertensive response to endotracheal intubation. Theyalso prevent recurrent arrhythmias and have been shownto improve morbidity and mortality. Atenolol has beenshown in a randomized controlled trial to reduce morbidityand mortality when given before operation and oneweek postoperatively. In a randomized controlled trial of1351 high-risk patients undergoing vascular surgery, bisoprololsignificantly reduced events ( P < 0.001). Bisoprololwas commenced one week preoperatively and continued4. Calcium AntagonistsDrugs such as oral nitrates and calcium antagonists are notusually required except if angina recurs. Many patients arecontinued for years on these unproven and costly drugs.Calcium antagonists are strongly recommended toprevent spasm of the artery if a radial graft is used.Hypertension is best managed with an ACE inhibitor,a beta-blocker, or a small dose of a diuretic rather thanwith a calcium antagonist.C. Other AdvicePatients are strongly advised to stop smoking. They areencouraged to engage in an exercise program and maintaina low-cholesterol, low-saturated-fat diet. Blood pressure

274CORONARY ARTERY BYPASS SURGERYshould be checked every four months to be sure that it isnot elevated because this may aggravate the problems ofblockage in the graft.Patients must be strongly advised that atheroscleroticdisease is not cured by surgery. Coronary thrombosis canstill occur. The vein graft can develop atherosclerosis overa period of 10–15 years as veins are not usually subjectedto the blood pressure found in arteries. The averagepressure found within veins is normally about 5–7 mmHgas compared to the normal pressure in arteries of about110–150 mmHg. One study showed that at 10 yearspost surgery more than half of the grafts were narrowedor blocked, particularly in individuals who continued tosmoke cigarettes or in those with hypertension andincreased cholesterol levels. Clinical trials done from 1994to 1995 have established that the use of statins to maintainLDL cholesterol at less than 80 mg/dl (2.0 mmol/L)prevents the progression of atheroma and reduces the needfor angioplasty and repeat bypass surgery (see the chapterCholesterol).IX. CORONARY BYPASS SURGERYVERSUS PCICoronary artery bypass surgery is not in competitionwith PCI (coronary angioplasty with intracoronary stent).The two methods of treatment are complimentary. Manyof the surgical studies listed were done without the use ofinternal mammary artery grafts. Also, the PCI studiesconsist mainly of coronary angioplasty with only somepatients receiving stents. Most important, the new drugelutingstents are superior to older stents and produce upto 90% reduction in stent stenosis (a restenosis rate of

IX. CORONARY BYPASS SURGERY VERSUS PCI275Results: At the median follow up of two years patientsundergoing PCI were more likely to require additionalrevascularization compared with the surgery group (21%vs. 6%; p ¼ 0.0001). The combined end point of deathand Q-wave infarction was similar. Most important, fewerpatients in the bypass group died compared with the PCIgroup (2% vs. 5%; p ¼ 0.01).The ERAC1 II trial was a small study of only 450patients followed for 18.5 months; a high percentage ofunstable patients were enrolled in this study compared toothers and this may relate to poorer surgical outcomes.Hoffman et al. performed a meta-analysis of 13 recentrandomized trials on 7964 patients comparing PCI andbypass surgery. Bypass surgery was associated with a lowerfive-year mortality, less angina, and fewer revascularizationprocedures. For patients with multivessel disease bypasssurgery provided a survival advantage at 5–8 years. Theaddition of stents reduced the need for repeat revascularizationby about half.BIBLIOGRAPHYAbizaid, A., Costa, M. A., Centemero, M. et al. Clinical and economicimpact of diabetes mellitus on percutaneous and surgical treatmentof multivessel coronary disease patients: Insights from the arterialrevascularization therapy study (ARTS) trial. Circulation, 104:533–3821 2001.Acar, C., Ramsheyi, A., Pagny, J. Y. et al. The radial artery for coronaryartery bypass grafting: Clinical and angiographic result at five years.J. Thorac. Cardiovasc. Surg., 116:981, 1998.Anonymous. Coronary angioplasty versus coronary artery bypass surgery.the randomized intervention treatment of angina (RITA) Trial. Lancet,341:573, 1993.BARI Investigators. Influence of diabetes on 5-year mortality and morbidityin a randomized trial comparing CABG and PTCA in patients withmultivessel disease. The Bypass Angioplasty Revascularization Investigation(BARI) trial. Circulation, 96(6):1761–69, 1997.Barner, H. B., Standeven, J. W., and Reese, J. 12 year experience withinternal mammary artery for coronary artery bypass. J. Thorac.Cardiovasc. Surg., 90:668, 1985.Bell, M. R., Gersh, B. J., Schaff, H. V. et al. Effect of completenessof revascularization on long-term outcome of patients with threevessel disease undergoing coronary artery bypass surgery. A reportfrom the Coronary Artery Study (CASS) Registry. Circulation, 86:446,1992.CAPRICORN Investigators: Effect of carvedilol on outcome aftermyocardial infarction in patients with left ventricular dysfunction:The CAPRICORN randomized trial. Lancet, 357:1385–90,2001.COPERNICUS: Carvedilol prospective randomized cumulative survivalstudy group one effect of carvedilol on survival in severe chronic atrialfibrillation. N. Engl. J. Med., 344:1651–58, 2001.Demaria, R. G., Carrier, M., Fortier, S. et al. Reduced mortality andstrokes with off-pump coronary artery bypass grafting surgery inoctogenarians. Circulation, 106:1–10, 2002.Elefteriades, J. A., Tolis, G., Jr., Levi, E. et al. Coronary artery bypassgrafting in severe left ventricular dysfunction. Excellent survival andfunctional status. J. Am. Coll. Cardiol., 22:1411, 1993.Favoloro, R. G. Saphenous vein autograft replacement of severe segmentalcoronary artery occlusion. Ann. Thorac. Surg., 5:334, 1968.Garrett, H. E., Dennis, E. W., and DeBakey, M. E. Aortocoronary bypasswith saphenous vein graft. Seven year follow-up. JAMA, 223:792,1973.Green, G. E., Spencer, F. C., Tice, D. A. et al. Arterial and venousmicrosurgical bypass grafts for coronary artery disease. J. Thorac.Cardiovasc. Surg., 60:491, 1970.Hoffman, S. N., TenBrook, J. A., Wolf, M. P. et al. A meta-analysisof randomized controlled trials comparing coronary arterybypass grafts with percutaneous transluminal coronary angioplasty:One- to eight-year outcomes. J. Am. Coll. Cardiol., 41:1293–1314,2003.Ivanov, J., Weisel, R. D., David, T. E. et al. 15-year trends in risk severityand operative mortality in elderly patients undergoing coronary arterybypass graft surgery. Circulation, 97:673, 1998.Khot, U. N., Friedman, D. T., and Pettersson, G., Radial artery bypassgrafts have an increased occurrence of angiographically severe stenosisand occlusion compared with left internal mammary arteries andsaphenous vein grafts. Circulation, 109:2086–2209, 2004.Kip, K. E., Alderman, E. L., Bourassa, M. G. et al. Differential influenceof diabetes mellitus on increased jeopardized myocardium after initialangioplasty or bypass surgery: Bypass angioplasty revascularizationinvestigation. Circulation, 105(16):1914–20, 2002.Kolessov, V. I. Mammary artery–coronary artery anastomosis as methodof treatment for angina pectoris. J. Thorac. Cardiovasc. Surg., 54: 535,1967.Marcel, J. B., van den Brand, B. J. W. M., Rensing, M.-A., Morel, M. et al.The effect of completeness of revascularization on event free survival atone year in the ARTS trial. J. Am. Coll. Cardiol., 59:559–64, 2002.Morrison, D. A., Sethi, G., Sacks, J. et al. Percutaneous coronaryintervention versus repeat bypass surgery for patients with medicallyrefractory myocardial ischemia; AWESOME randomized trial andRegistry experience with post CABG patients. J. Am. Coll. Cardiol.,40:1951–4, 2002.Peduzzi, P., Kamina, A., and Detre, K. 12- year follow up in the VACooperative study of coronary artery bypass surgery for stable angina.Am. J. Coll. Cardiol., 81:1393, 1998.Schaff, H. V., Gersh, B. J., Fisher, L. D. et al. Detrimental effect ofperioperative myocardial infarction and late survival after coronaryartery bypass. Report from the Coronary Artery Surgery Study(CASS). J. Thorac. Cardiovasc. Surg., 88:972, 1984.SOS Investigators. Coronary artery bypass versus percutaneous coronaryintervention with stent implantation in patients with multivesselcoronary disease (the stent or surgery trial), a randomized controlledtrial. Lancet, 360:965–70, 2002.

C-Reactive Protein and the HeartI. A Marker of RiskII. Clinical StudiesIII. Perspective and Research ImplicationsGLOSSARYallograft a graft between animals of the same species, but ofdifferent genotype.angina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.atheroma the same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallsof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).Atherothrombosis thrombosis complicating a ruptured orfissured plaque of atheromadyslipidemia the same as hyperlipidemia, elevated blood cholesterol,LDL cholesterol, triglycerides, or low HDL cholesterol.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.unstable angina severe angina usually occurring at rest.I. A MARKER OF RISKC-reactive protein (CRP) is an acute phase reactant producedby the liver in response to inflammatory cytokines(1L-1, 1L-6) and tumor necrosis factor- (TNF-).C-reactive protein has been identified as a marker of riskfor coronary events independent of other factors.Although CRP has been found in atheromatous plaquesand is suspected to enhance rupture of the plaque by bothactivating complement and impairing endothelial cellfunction, the exact source of elevated CRP levels amongpatients with acute coronary syndromes remains unclear.The suspicion is difficult to prove, and it is not wellestablished if CRP is a marker of risk, a risk factor, or both.In some studies CRP has been found to have prognosticvalue among patients without evidence of myocardialnecrosis. In patients with acute coronarysyndromes and negative troponin-T, elevated CRP appearsto be predictive of future adverse events. In addition it hasbeen observed that CRP is a strong independent predictorof short- and long-term mortality among patients treatedwith early revascularization.Many workers in the field agree high levels of CRP areassociated with an increased risk of cardiovascular diseases,but the predictive power of this association is markedlydiminished when adjusted for the risk factors. The clinicalsignificance of the added value of CRP over conventionalmarkers of coronary artery disease remains debatable.Some studies have shown elevated CRP levels in morethan two-thirds of patients diagnosed with unstableangina, and these levels declined somewhat within 6months. Such high levels occur in association with unstablecoronary plaque activation and increase in subsequentcoronary events including progression of unstable anginafor myocardial infarction. These findings, however, aremuch less common in patients who present with acutemyocardial infarction without preceding unstable angina.Current techniques are not sufficiently reliable andcoronary angiography has not been very useful inidentifying inflamed atheromatous plaques. In addition ithas been well established that serious cardiac events thatincluded acute coronary syndromes (unstable angina, anacute myocardial infarction) often occur in coronaryarteries in which the obstruction by plaque is less than60% reflecting mild-to-moderate degrees of coronaryartery stenosis. There is no doubt, however, that in bothchronic and acute coronary syndromes a high CRP is oftenpresent and is associated with adverse short- and long-termprognosis. These finding suggest some form of inflammatoryprocess that increases the size of the plaque and maypredispose the plaque to rupture (see Fig. 1). In studies of277

278C-REACTIVE PROTEIN AND THE HEARTFIGURE 1 Age-adjusted relative risk of future cardiovascular events, according to base-line C-reactive protein levels (solid bars) and LDL cholesterollevels (open bars). (From N. Engl. J. Med., 347(20), 1561, 2002.)patients undergoing coronary angiography, an intracardiacinflammatory response has been observed in patients withunstable angina that appears to be a result of low-grademyocardial necrosis. The ruptured plaque does not appearto contribute to the acute phase response.It must be emphasized, however, that an inflammatoryresponse may be mounted by the body in the absence ofinfection by bacteria or other microorganisms. A nonspecificinflammatory response may be caused by severalnatural mechanisms mounted by the body as a protectivemeasure. The mechanisms (pathogenesis) that underlie theformation and progression of atheromatous lesions andthe rupture that finally causes obstruction of bloodflow require considerable further research. The excellentresearch and investigative work on coronary artery diseasecarried out in many centers worldwide over the past30 years have not resulted in a major breakthrough.II. CLINICAL STUDIESA. Ridker et al.Study question: CRP and LDL cholesterol levels are bothelevated in individuals at risk for cardiovascular events.This study sought population-based data that directlycompared these two biological markers because such dataare not available.Methods: LDL cholesterol and CRP were measuredat baseline in 27,939 healthy American women. Theoccurrence of myocardial infarction, ischemic stroke, ordeath from cardiovascular causes at follow up of 8 yearswas analyzed.Results: Overall, 77% of all events occurred amongwomen with LDL cholesterol levels below 160 mg/dl(4.14 mmol/L) and 46% occurred among those with LDL

III. PERSPECTIVE AND RESEARCH IMPLICATIONS279FIGURE 2 Multivariable-adjusted relative risks of cardiovascular disease according to levels of C-reactive protein and the estimated 10-year risk based onthe Framingham Risk Score as currently defined by the National Cholesterol Education Program and according to levels of C-reactive protein and categoriesof LDL cholesterol. (From N. Engl. J. Med., 347(20), 1564, 2002.)cholesterol levels below 150 mg/dl (3.36 mmol/L). Thelevel of CRP showed an apparent superiority over LDLcholesterol in terms of the prediction of risk of thecomposite end point: coronary heart disease, stroke, anddeath from cardiovascular causes (see Fig. 1). Comparisonwith the Framingham risk score is given in Fig. 2.Conclusion: The authors of this study concluded:the data suggest that CRP is a stronger predictor ofcardiovascular events than LDL cholesterol levels, andthat it adds prognostic information over and above thatobtained with LDL cholesterol and other risk scoreassessments.B. Study by Labarrere et al.This study showed that heart transplant recipients withhigh concentrations of CRP have more severe and morerapid progression of coronary artery disease in thetransplant. In addition, this finding was associated witha high expression of endothelial intracellular adhesionmolecule-I (ICAM-I) and high concentrations of ICAM-Iin serum. Eisenberg et al. found that the rise in CRP levelsin nine consecutive cardiac transplant patients significantlypredicted graft failure. At 10-year follow up therewas a significant reduction of allograft survival in patientswith high CRP. Immune mechanisms have been postulatedbecause only the vessels of the allograft were involvedwith accelerated atherosclerosis sparing the host’s nativearteries.C. Study by Danesh et al.This large, well-conducted study concluded that elevatedlevels of C-reactive protein are associated withonly a moderate increase in the risk of coronary heartdisease.III. PERSPECTIVE AND RESEARCHIMPLICATIONSInvestigative methods for detecting vulnerable atheroscleroticplaques include intravascular ultrasonography,magnetic resonance imaging plaque thermography, andcirculating markers such as CRP and cytokines may havea role in the future. Evidence is insufficient to warrantwidespread screening with CRP. The measurement wouldbe of practical value in patients with coronary arterydisease and cardiovascular disease, with optimal levels ofLDL cholesterol greater than 95 mg/dl (2.5 mmol/L; toconvert values for LDL cholesterol to mmol per litermultiply by 0.02586).There is little doubt that the link between inflammationand clinical coronary artery disease is strong, butimportant gaps in our knowledge remain. The atheromatousplaque itself may initiate an inflammatory response.Although infection appears to accelerate the clinical courseof atheroma, the contribution of infection in areas of the

280C-REACTIVE PROTEIN AND THE HEARTbody outside the plaque to nonspecific inflammatoryactivity within the arterial wall remains obscure. Randomizedclinical trials using antibiotics in patients with acutecoronary syndrome have not been beneficial. Further largescaleclinical trials are unnecessary. Even if the inflammationhypothesis is correct, the cost effectiveness of alteringmanagement on the basis of the results of screening forCRP needs to be determined.Patients with heart disease or cardiovascular diseasewith LDL cholesterol levels greater than 2.5 mmol/L arerecommended to receive a statin to maintain a goal ofless than 2.5 mmol/L. The treatment with statins hasbeen shown to reduce CRP levels.Patients at high risk: acute coronary syndrome, shouldachieve LDL goal of less 80 mg/dl (2 mmol/l) and CRPlevels lowered to normal regardless of LDL levels. Ridkeret al. indicate that CRP monitoring should be usedin patients with acute coronary syndrome to assess risk;patients who have low CRP levels after statin therapyappear to have better clinical outcomes than those withhigher CRP levels regardless of the level of LDL achieved.BIBLIOGRAPHYBlake, G., and Ridker, P. M. C-reactive protein and other inflammatoryrisk markers in acute coronary syndromes. J. Am. Coll. Cardiol.,41:37S–42S, 2003.Buffon, A., Biasucci, L. M., Luzzo, G. et al. Widespread coronaryinflammation in unstable angina. N. Engl. J. Med., 347:5–12, 2002.Cusak, M. R., Marber, M. S., Lambiase, P. D. et al. Systemicinflammation in unstable angina is the result of myocardial necrosis.J. Am. Coll. Cardiol., 39:1917–23, 2002.Danesh, J., Wheler, J. G., Hirschfield, G. M. et al. C-reactive proteinand other circulating markers of inflammation in the predictionof coronary heart disease. N. Engl. J. Med., 350:1387–1397, 2004.Eisenberg, M. S., Chen, H. J., Warshofsky, M. K. et al. Elevated levelsof plasma C-reactive protein are associated with decreased graftsurvival in cardiac transplant recipients. Circulation, 102:2100–2104,2000.Feldman, M., Jialal, I., Devaraj, S. et al. Effects of low-dose aspirin onserum C-reactive protein and thromboxane B2 concentrations: Aplacebo-controlled study using a highly sensitive C-reactive proteinassay. J. Am. Coll. Cardiol., 37:26–41, 2001.Labarrere, C. A., Lee, J. B., Nelson, D. R. et al. C-reactive protein, arterialendothelial activiation, and development of transplant coronary arterydisease: A prospective study. Lancet, 360:1462–1467, 2002.Mosca, L. C-reactive protein — to screen or not to screen? N. Engl.J. Med., 347:1615–16, 2002.Nissen, S. E., Tuzcu, E. M., Schoenhagen, P. et al. For the reversal ofatherosclerosis with aggressive lipid lowering (REVERSAL) investigatorsstatin therapy, LDL cholesterol, C-reactive protein, and coronaryartery disease. N. Engl. J. Med., 352:29–38, 2005.Ridker, P. M., Rifal, N., Rose, L. et al. Comparison of C-reactive proteinand low-density lipoprotein cholesterol levels in the prediction of firstcardiovascular events. N. Engl. J. Med., 347:1557–65, 2002.Ridker, P. M., Cannon, C. P., Morrow, D. et al. For the Pravastatinor Atorvastatin Evaluation and Infection Therapy–Thrombolysisin Myocardial Infarction 22 (PROVE IT–TIMI 22) Investigator:C-reactive protein levels and outcomes after statin therapy. N. Eng. J.Med., 352:20–28, 2005.Rossi, E. C-reactive protein and progress of atherosclerosis. Lancet,360:1436, 2002.Tall, A. R. C-reactive protein reassessed. N. Engl. J. Med., 350:1450–1452, 2004.

Cytochrome P-450I. Definition and NomenclatureII. FunctionsIII. P-450s RegulationIV. P-450s and Cardiovascular Drug InteractionsGLOSSARYantiarrhythmic agents cardioactive drugs used to prevent andtreat arrhythmias.myopathy disease of muscle.rhabdomyolysis disintegration of striated muscle fibers withexcretion of myoglobin in the urine.xenobiotic compound that is foreign to the body, such as a drugor an environmental pollutant.THE CYTOCHROME P-450 (CYP450) METABOLICpathway is involved in the metabolism of many cardiovascularmedications. Many significant drug interactionsoften involve this pathway.I. DEFINITION AND NOMENCLATURECytochrome P-450 refers to a colored substance in the cellthat absorbs light at around 450 nm within the visiblespectrum. The word cyto means cell and chrome meanscolor. The P in P-450 refers to pigment and the 450 refersto its wavelength.Cytochrome is a cellular heme-containing protein. Itsprincipal function is electron transport. Hemoglobintransports oxygen whereas cytochrome P-450 is a monooxygenaseusing one atom from oxygen and two electronsto oxidize chemical substrates.In the early 1960s P-450 was thought to be one enzyme.Gonzales et al. isolated the first cDNA encoding acomplete cytochrome P-450 protein. Since then dozensof different enzymes have been isolated. The P-450 cytochromesare ubiquitous enzymes found in microorganismsand throughout the plant and animal kingdoms. Themustard plant contains 249 active CYP genes and therice plant has 324. The human cytochrome P-450 has57 genes.Cytochrome P-450 proteins are arranged into familiesand subfamilies on the basis of percentage of aminoacid sequence identity. Enzymes that share more than40% identity are assigned to a particular family designatedby an Arabic numeral, whereas those sharing morethan 55% identity make up a subfamily designated by aletter.II. FUNCTIONSThe human cytochrome P-450 superfamily is comprisedof 57 genes. Cytochrome P-450s use electrons fromnicotinamide adenine dinucleotide (NADH) and oxygento oxidize their substrates. These genes code for enzymesthat have a role in many metabolic processesincluding:Metabolism of drugs and foreign chemicals includingplant metabolites and environmental contaminantsMetabolism of arachidonic acid and eicosanoidsCholesterol metabolism and bile acid biosynthesisSteroid synthesis and metabolismVitamin D3 synthesis and metabolismRetinoic acid hydroxylationSaturated and unsaturated fatty acidsThe cytochrome P-450 acts on many endogenoussubstrates introducing oxidative, peroxidative, and reductivechanges into small molecules. Cytochrome P-450smetabolize various drugs and natural plant products;environmental chemicals and pollutants are successfullydetoxified. These important enzymes are the primaryinterface between humans and the chemical environment.The actions of these enzymes may produce toxic metabolites,however, that may increase risks of cancer, birthdefects, and other toxic effects.281

282CYTOCHROME P-450TABLE 1List of Human P-450s, Tissues in which they are Expressed, andSome of their SubstratesGene a Tissue b Substrates cCYPIA1 Liver Benzo(a)pyrene (C)Lung7,12-Dimethylbenz(a)anthracene (C)PlacentaOtherCYPIA2 Liver Acetaminophen (D)2-Acetylaminofluorene (C)Aflatoxin B 1 (C)Heterocyclic arylamines (C)Phenacetin (D)CYP1B1 Adrenal Similar to CYPIA1OvariesCYP2A6 Liver (P) CoumarinNasal epithelium N-Nitrosodiethylamine (C)OtherCYP2B6 Liver (P) 7-Ethoxy-4-trifluoromethylcoumarinAflatoxin B 1 (C)CYP2B7 LungCYP2C8 Liver Tolbutamide (D)R-Mephenytoin (D)CYP2C9 Liver Tolbutamide (D)R-Mephenytoin (D)Warfarin (D)CYP2C19 Liver S-MephenytoinCYP2D6 Liver (P) Bufuralol (D)KidneyDebrisoquine (D)Dextromethorphan (D)Nortriptyline (D)Propranolol (D)CYP2E1 Liver Acetoacetate (E)OtherAcetol (E)Acetaminophen (D)Ethanol (D)Halothane (D)N-Nitrosodiethylamine (C)CYP2F1 Lung 7-EthoxycoumarinLiverTestosterone (E)OtherCYP3A4 Liver Aflatoxin B 1 (C)GI tractCortisol (E)KidneyCyclosporine (D)OtherErythromycin (D)Midazolam (D)Nifedipine (D)Warfarin (D)Testosterone (E)(Continued )TABLE 1ContinuedGene a Tissue b Substrates cCYP3A5 Liver (P) Similar to CYP3A4OtherCYP3A7 Liver (fetal) Dehydroepiandrosterone-3-sulfate (E)CYP4A9 Liver Lauric acidOtherArachidonic acid (E)Other fatty acidsCYP4A11 Liver Similar to CYP4A9OtherCYP4B1 LungOtherCYP7A1 Liver Cholesterol (E)CYP11A1 Adrenal gland Cholesterol (E)OvaryTestisCYP11B1 Adrenal gland 17-Hydroxyprogesterone (E)OvaryTestisProgesterone (E)CYP17A1 Adrenal Dehydroepiandrosterone (E)Ovary17-Hydroxyprogesterone (E)Testis17-Hydroxypregnenolone (E)Progesterone (E)CYP19A1 Ovary Androstanedione (E)PlacentaCYP21A2 Adrenal gland Progesterone (E)Ovary17-Hydroxyprogesterone (E)TestisCYP26A1 d Liver Cholesterol (E)a The amino acid sequences of all P-450s listed have been determinedusing human cDNA libraries, except for CYP26A1, which encodes thecholesterol 26-hydroxylase. Because this enzyme is a member of a cascadeof enzymes involved in bile acid formation, it is presumed to exist inhumans.b The tissues listed are known to express P-450s, however, not everyhuman tissue has been carefully examined. On the basis of studies inrodents, some P-450s are believed to be expressed in other tissues. Somegenes are polymorphically expressed (P).c The substrates listed fall into the classes of carcinogens (C), drugs(D), and endogenous compounds (E). The unmarked substrates arechemicals that happen to be substrates but are not drugs or carcinogens.The carcinogenicity of these compounds in rodents varies considerablyfrom the potent aflatoxin B 1 to the weak heterocyclic arylamines. In mostcases, the carcinogenic potency in humans is unknown. This list is notinclusive. Several of these P-450s are known or presumed to metabolizemany other compounds. It should also be noted that a single substrate canbe metabolized by multiple P-450 forms (e.g., aflatoxin B 1 , 7-ethoxycoumarin).d Present in rodents and believed to be present in humans.(From Gonzalez, F.J. (1997). Cytochrome P-450. Encylopediaof Human Biology, 2nd ed., San Diego: Academic Press, p. 124. Withpermission.)

IV. P- 450s AND CARDIOVASCULAR DRUG INTERACTIONS283Several P-450s are involved in the metabolism of foreigncompounds (xenobiotics) such as drugs, plant-derived orfungal-derived secondary metabolites consumed with food,and thousands of environmental pollutants that includearylamines, halogenated hydrocarbons, herbicides, industrialcomplex mixtures, ingredients of combustion, pesticides,and polycylic aromatic hydrocarbons.Deficiencies in the xenobiotic-metabolizing P-450s areassociated with clinical drug oxidation polymorphismswhich result in toxic reactions to several prescription drugs.Table 1 gives a list of human P-450s, the tissues in whichthey are expressed, and some of their substrates. Figure 1gives the substrates for CYP2D6 which include thecommonly used beta-adrenergic blocking and antiarrhythmicagents.III. P-450s REGULATIONHuman P-450s that metabolize foreign chemicals arevirtually all in the CYP1, CYP2, CYP3, and CYP4families. P-450s are regulated by a number of xenobioticsand the cellular content of a P-450 is elevated by the samecompound that it metabolizes. This induction of P-450sby various compounds is known to advance via a receptormediatedmechanism.IV. P- 450s AND CARDIOVASCULAR DRUGINTERACTIONSThe induction of P-450s has implications for significantcardiovascular drug interactions including statins andbeta-adrenergic blocking agents.A. StatinsThe HMG-CoA reductase inhibitors, statins, are potentcholesterol-lowering agents used worldwide. Myopathy,rhabdomyolysis, and deaths have been reported in patientsreceiving therapy with statins. This adverse effect is causedby elevated blood levels of these agents. Patients at highrisk are those concurrently taking other medicationsknown to be metabolized by the P-450 metabolic pathway,thereby inhibiting clearance of the statin. A mainroute of atorvastatin, cerivastatin, lovastatin, and simvastatinmetabolism is via cytochrome P-450 3A4. Cases oflovastatin-induced rhabdomyolysis associated with medicationssuch as azithromycin, erythromycin, and clarithromycinhave been reported. Fluvastatin inhibits CYP2C9,and interactions between fluvastatin and other CYPC9substrates such as oral anticoagulants including warfarin,oral hypoglycemic agents, phenytoin, and nonsteroidalanti-inflammatory drugs (NSAIDs) may occur.Cerivastatin (Baycol) is metabolized by both 3A4 and2C8; the drug was withdrawn from the market in 2001because of the occurrence of rhabdomyolysis, kidneyfailure, and 52 deaths worldwide. Some of these deathsoccurred because of high-dose cerivastatin therapy, andseveral were caused by interactions with gemfibrozil, afibrate. A statin combined with a fibrate is not an approvedcombination. The fibrates are partly metabolized by the3A4 pathway. When cerivastatin was given together withother agents such as cyclosporine, erythromycin, anditraconazole, there was a potential for drug interactionsbecause its concentration increased by 40–300%.Caution: The statins, particularly lipophilic agents thatuse the P-450 pathway, should not be combined with thefollowing drugs that also use the pathway: Fibrates Antibiotics such as azithromycin, clarithromycin,erythromycin, and rifampicin Antifungal agents such as itraconazole Cyclosporine Niacin (the combination with a statin is being tested ina clinical trial)Other agents and substances known to be metabolizedby the P-450 pathway and are potential interactantsinclude fluoxetine and other antidepressant agents, nefazodone,grapefruit juice, amlodipine and other dihydropyridinecalcium antagonists, and Viagra. Fluvastatin caninhibit 2C9-mediated oxidation of diclofenac, an NSAID,resulting in increased peak plasma concentrations ofdiclofenac. A Fluvastatin and warfarin interaction hasbeen reported. Mibefradil (Posicor), a calcium antagonist,was removed from the market recently because it interactedsignificantly with other medications that are metabolizedby P-450 3A4. The interaction caused serious arrhythmiasincluding torsades de pointes. Prior to the recall of thisproduct, the pharmaceutical firm cautioned against thecombination with statins because of reported cases ofrhabdomyolysis in patients receiving simvastatin andPosicor.Recent experience with troglitazone is relevant. Despiteincreasing reports of acute liver failure and four successivewarning letters from the Food and Drug Administration,by the time of its withdrawal from the market the drug hadbeen linked to 43 cases of liver failure.Pravastatin and rosuvastatin are hydrophilic statins thatare eliminated by the kidney. They are not metabolizedby the P-450 pathway which may render them relativelysafer components of the statin armamentarium when

284CYTOCHROME P-450FIGURE 1 Substrates for CYP2D6. The hydroxylation positions of each substrate are indicated by arrows. The conversion of the analgesic codeine to itsactive derivative morphine is shown at the bottom of the figure. (From Gonzalez, F.J. (1997). Cytochrome P-450. Encyclopedia of Human Biology, 2 nd ed.,San Diego: Academic Press, p. 124. With permission.)

IV. P- 450s AND CARDIOVASCULAR DRUG INTERACTIONS285agents that are metabolized by P-450 are administeredsimultaneously.converts the inactive analgesic codeine to its activederivative morphine.B. Beta-Adrenergic Blocking AgentsBeta-blockers are cardioactive agents commonly used inthe management of angina, heart attacks, hypertension,arrhythmias, and heart failure. These agents have beenused worldwide since 1969. Interactions are, however, few.A single P-450 can oxidize a large number of drugs(see Fig. 1) and CYP2D6 can metabolize compounds witha wide range of structures such as beta-blockers, tricyclicantidepressants, antiarrhythmics, and dextromethorphan,a component of cough suppressants. This enzyme alsoBIBLIOGRAPHYFarmer, J. A. Learning from the cerivastatin experience. Lancet,358:1383–84, 2001.Fleming, I. Cytochrome P-450 under pressure: More evidence fora link between 20-hydroxyeicosatetraenoic acid and hypertension.Circulation, 111:5–7, 2005.Gonzalez, F. J. Cytochrome P450. Encyclopedia of Human Biologym,second edition. Academic Press, San Diego, 1997, p. 115.Nebert, D. W., and Russell, D. W. Clinical importance of thecytochromes P450. Lancet, 360:1155–62, 2002.

Deep Vein ThrombosisI. Incidence and LocationII. Pathogenesis of Deep Vein ThrombosisIII. Diagnostic FeaturesIV. ManagementGLOSSARYdistal further away from the heart and near to the feet or fingers.edema accumulation of fluid.embolus, embolism a blood clot that forms in an artery, a vein,or the heart that breaks off and is carried by the circulatingblood, finally lodging and blocking the artery that suppliesan organ with blood; for example, pulmonary embolism isan embolus blocking the artery in the lung.fibrin an insoluble protein that is essential to clotting of blood,formed from fibrinogen by action of thrombin.hypercoagulability increased clotting of blood.phlebitis inflammation of the wall of a vein.prophylaxis prevention of disease; preventive treatment.proximal near to a center point of the body such as the heart.thrombus (thrombi) blood clot(s).I. INCIDENCE AND LOCATIONA. IncidenceDeep vein thrombosis occurs in the veins of the legs, thigh,and pelvis. It can lead to a life-threatening condition calledpulmonary embolism and is a common problem worldwide.The incidence of venous thromboembolism in theUnited States is approximately 600,000 cases annually.Approximately 30% of patients undergoing major surgerydevelop deep vein thrombosis and some cases may goundetected. High-risk procedures such as implantation ofknee or hip prosthesis or other orthopedic surgery on thesejoints have an incidence of deep vein thrombosis ofapproximately 50–60% with more dangerous proximalversus below-the-knee distal deep vein thrombosis.B. LocationThrombosis of veins that lie deep in the calf or thighmuscle are more dangerous than clots occurring insuperficial veins just under the skin, because deep veinsare much larger and communicate more directly withthe lungs and the heart. A thrombus that is lodgedin the femoral or iliac veins may break off and travel intothe bloodstream, be carried to the right heart and pumpedinto the lungs. This traveling clot is called an embolus,thus the term pulmonary embolism. Because pulmonaryembolism occurs in patients with thrombosis of thefemoral and iliac veins, this condition is considered lifethreatening.Thrombi in veins below the knee close to theankle may not extend above the knee and this type of clotrarely embolizes. The incidence of postphlebitic syndrome,however, in these so-called benign clots is approximately35%. Postphlebitic syndrome causes swelling of the legsand aching that may persist for years. It is important tomake the diagnosis of thrombi above the knee. Althoughthrombi occurring in veins between the knee and the feetare not as dangerous as those above the knee, they do causebothersome swelling and pain. Unfortunately the diagnosisof below-the-knee thrombosis is often missed by ultrasonography.II. PATHOGENESIS OF DEEP VEINTHROMBOSISA. ImmobilizationThrombi form in veins of the lower limbs and pelvisbecause of certain factors that increase the tendency of freeflowingblood to clot. A sudden increase in the tendencyof the blood to clot commonly occurs soon after surgicaloperations or fractures that immobilize the lower limbs.Sudden immobilization for more than 48 h causes theblood to flow very slowly through the limb that is immobilized.This slow-flowing (stasis) blood through veins inthe extremities tends to form ‘‘sludge’’ and clots. This is287

288DEEP VEIN THROMBOSISsimilar to very slow-flowing or stagnant water in a streamthat forms moss on rocks. Immobilization, therefore,explains the high incidence of clots in veins after surgicaloperations that involve the lower limbs versus surgery ofthe chest and upper regions of the body where the lowerlimbs are free to move.B. Coagulation FactorsSoon after surgery or the birth of a baby small particlesin the blood called platelets become sticky and clumptogether. This together with other substances called coagulationfactors in the blood orchestrate the clot; oncea reaction is initiated there is a cascade of processes thatlead to the formation of a firm, fibrin clot.Damage to veins by traumatic injury and infections alsopredispose to clot formation.C. Predisposing Factors1. Surgery and ImmobilizationSituations that are associated with or predispose a patientto deep vein thrombosis and thromboembolism include: Surgery, injury, or fractures of the lower extremities orpelvis including soft tissue injury Orthopedic surgery of the hip or the knee Prolonged anesthesia associated with surgery Bed rest and sudden immobilization for more than 48 h Heart failure which causes slow circulation through thevenous system because the heart pumps inefficientlyand these patients are partially immobilized Cancer of different types may cause changes in thecoagulation factors and an increased tendency to clot Pregnancy and within 48 h of giving birth; plateletsand other coagulation factors are activated perhaps asnature’s way of preventing placental hemorrhage Use of oral contraceptives or estrogens Obesity Sitting for more than 8 h while on an airplaneA study by Scurr et al. concluded that asymptomaticdeep vein thrombosis might occur in up to 10% of longhaulairline travelers. The investigators recruited 89 maleand 142 female passengers over 50 years of age with nohistory of thrombotic problems. Passengers were randomlyallocated to one group who wore below-the-knee elasticcompression stockings while the other group did not.All passengers made journeys lasting longer than 8 h.Duplex ultrasonography was used to assess the deep veinsbefore and after travel. Twelve of 116 passengers developedasymptomatic deep vein thrombosis in the calf. Of thesepassengers, none wore elastic compression stockings. Noneof the passengers who wore class 1 compression stockingsdeveloped deep vein thrombosis. The authors concludedthat wearing elastic compression stockings during normalair travel is associated with a reduction in asymptomaticdeep vein thrombosis.2. Inherited DiseasesDiseases that cause hypercoagulability states include: Factor V Leiden (a mutation in coagulation factor Vthat results in resistance to activated protein C or aPC) Antithrombin 3 deficiency Protein C deficiency Protein S deficiency Antiphospholipid antibody syndrome (see the chapterAntiphospholipid Antibody Syndrome)III. DIAGNOSTIC FEATURESA. Symptoms and SignsDeep vein thrombosis occurring in the lower limbs isoften difficult to diagnose from the history and physicalexamination. Some individuals present with pain andswelling of the calf muscle, others are asymptomatic. Theobstruction to the vein causes chronic congestion of themuscle tissues which become edematous. The diagnosismay be confused with other conditions that cause achesand pains in the lower limbs such as a muscle tear, musclecramps, a ruptured Baker’s cyst, cellulitis, and postphlebiticsyndrome. The presence of associated precipitatingfactors for deep venous thrombosis listed above lendsstrong support to its diagnosis.1. D-DimerB. Diagnostic TestingThe measurement of the degradation products of crosslinkfibrin (D-dimer) circulating in the bloodstream is ahighly sensitive but nonspecific screening test for suspectedvenous thromboembolism. D-dimer is measured byenzyme-linked immunosorbent assay (ELISA). A negativetest result, however, provides reassurance in more than90% of cases that a serious event such as pulmonary

IV. MANAGEMENT289embolism is not present. Clinical studies indicate that deepvenous thrombosis can be ruled out in a patient who isjudged clinically unlikely to have deep vein thrombosis andwho has a negative D-dimer test.2. UltrasonographyCompression ultrasonography carried out by experiencedtechnicians is accurate in detecting above-the-knee thrombosisin patients who are symptomatic. An incompleteobstruction or small clots may not be detected. The testis sensitive and fairly specific in symptomatic patients,but in asymptomatic patients the sensitivity is only 59%.In addition, this highly touted test does not adequatelyvisualize the deep veins of the calf or pelvis.3. VenographyVenography is the investigation of choice for patients withindeterminate diagnosis from ultrasound, D-dimer, and theprobability from clinical assessment by a physician. Analgorithm for the diagnosis of the deep vein thrombosis isgiven in Fig. 1. Not all scenarios are covered by algorithms,however.IV. MANAGEMENTA. HeparinAll patients with proven deep vein thrombosis are treatedwith heparin for days and sometimes weeks followed byoral anticoagulants. The goals of therapy are to preventpulmonary embolism, restore venous patency and valvularfunction in veins, and to prevent postphlebitic syndrome.For the past 40 years or more intravenous heparin hasbeen the standard therapy used for several days beforecommencing oral anticoagulation with warfarin. Duringthe past few years, however, clinical trials have shown thatlow molecular weight heparin (LMWH) given subcutaneouslyprovides the same protection as intravenousheparin. Most important, these agents can be used in thehome avoiding expensive hospitalization.B. ProphylaxisThe prevention of deep vein thrombosis in patientsundergoing hip and knee surgery is vital. These patientsshould be treated with LMWH, such as enoxaparin administeredapproximately 6 h after surgery and continued for2–3 weeks. In Europe LMWH is often administeredSuspected DVTUltrasonographyNormalD-dimerAbnormalD-dimerNormal*AbnormalNormal*AbnormalNo DVT PCA PCALowHigh orintermediateLowHigh orintermediateUltrasonographyin 1 weekDVTVenographyFIGURE 1 Algorithm for the diagnosis of deep venous thrombosis (DVT). PCA ¼ probability from clinical assessment; * ¼ exclude myocardialinfarction, congestive heart failure, pneumonia, cancer, post surgery. (From Khan, M. Gabriel (2001). On Call Cardiology, 2 nd ed., Philadelphia:W. B. Saunders, p. 360.)

290DEEP VEIN THROMBOSISapproximately 12 h prior to surgery. This strategy hasrecently evolved. A study by Hull using LMWH approximately6h after surgery provided significant efficacy overoral anticoagulants without increased risk of bleeding.This strategy reduced the risk of all deep vein thrombosisby 50% and reduced the risk of proximal (above-theknee)deep vein thrombosis by 72% ( p < 0.001). Othertrials indicate that the best effects are achieved whendeep vein thrombosis prophylaxis is initiated close tosurgery.BIBLIOGRAPHYBengt, I., Eriksson, Bergqvist, D., Käleboet, P. et al. Ximelagatran andmelagatran compared with dalteparin for prevention of venousthromboembolism after total hip or knee replacement: theMETHRO II randomised trial. Lancet, 360:1441, 2002.Colwell, C. W., Collis, D. K., Paulson, R. et al. Comparison ofenoxaparin and warfarin for the prevention of venous thromboembolicdisease after total hip arthroplasty. Evaluation and humanhospitalization three months after discharge. J. Bone Joint Surg.,92:81–8, 1999.Goldhaber, S. Z., Turpie, A. G. G. et al. Prevention of venous thromboembolismamong hospitalized medical patients. Circulation,111:e1–e3, 2005.Hull R. D., Pineo, G. F., Francis, C. et al. Low-molecular-weight heparinprophylaxis using dalteparin in close proximity to surgery vs. warfarinin hip arthroplasty patients: A double-blind, randomized comparison.North American Fragmin Trial Investigators. Arch. Intern. Med.,160:2199–2207, 2000.Kelly, J., and Hunt, B. J. Role of D-dimers in diagnosis of venousthromboembolism. Lancet, 359:456–57, 2002.Khan, M. Gabriel. On Call Cardiology, 2nd edition, W. B. Saunders,Philadelphia, 2001, pp. 357–71.Kucher, N., Koo, S., Quiroz, R. et al. Electronic alerts to prevent venousthromboembolism among hospitalized patients. N. Engl. J. Med.,352:969–977, 2005.Scurr, J. H., Machin, S. J., Bailey-King, S. et al. Frequency and preventionof symptomless deep-vein thrombosis in long-haul flights: Arandomised trial. Lancet, 357:1485–89, 2001.Wells, P. S., Anderson, D. R., Rodger, M. et al. Evaluation of D-dimer inthe diagnosis of suspected deep vein thrombosis. N. Engl. J. Med.,349:1227–35, 2003.

Depression and the HeartI. Pathophysiologic MechanismsII. Drug ManagementDEPRESSION IS COMMON IN PATIENTS WITHcoronary artery disease and is believed to confer anincreased cardiac risk on healthy individuals and onpatients with known coronary artery disease. It is stated bysome that the degree of risk with major depression appearsto be comparable to that observed with other known riskfactors and is largely independent of them. Nonetheless,this association needs careful documentation to ascertainwhat is fact and what is fiction. A few studies indicate thatafter a heart attack significant depressive features are foundin approximately 33% of patients, and major depressionis observed in about 15% of these individuals. Otherstudies indicate symptoms of depression and anxiety aftermyocardial infarction with rates ranging from 17–37%.Symptoms often persist over the ensuing months andadversely affect the patient’s quality of life, but there is nodocumentation of increased cardiac mortality. The risk ofdepression is twice as high in women compared with men.Further studies are required because of the variablereports.1. Depressed mood was observed to be a significant predictorof subsequent fatal and nonfatal heart attacks in aprospective study of 2832 healthy adults.2. Over a 15-year observation in 2573 adults, however,depression was not associated with increased risk ofcoronary events.3. In a study by Lesperance et al., a total of 896 postmyocardial infarction (MI) patients were administeredthe Beck Depression Inventory during admission and atone year. The severity of depression symptoms duringadmission was directly linked to the five-year mortality.The greater the depression the higher the five-yearmortality. Even though the one-year scores were alsolinked to five-year cardiac mortality, most of theimpact was explained by baseline scores. The authorsconcluded that the severity of depression symptomsduring admission rather than the changes in depressionsymptoms at one year was more closely linked tolong-term survival.4. Lane et al. indicated that ‘‘the balance of evidence andargument suggests that it is right for one to be skepticalabout a causal link between mood, whether anxiety ordepression, after MI and subsequent cardiac events andmortality.’’5. In a study by Gottlieb et al., 48% of patients with heartfailure scored as depressed.I. PATHOPHYSIOLOGIC MECHANISMSAutonomic arousal with hyperactivity of the hypothalamic–adrenocorticaland sympathoadrenal axis is provokedby depression. This axis increases corticosteroids andresults from this hyperactivity are believed to stimulatethe atherosclerotic process that leads to obstruction ofcoronary arteries. This stimulates the process and increasesblood cholesterol and free fatty acids. Norepinephrinesecretion is increased and catecholamine surge may causean increase in blood pressure. Depressed cardiac patientshave been shown to have diminished heart rate variabilitycaused by a relative increase in sympathetic tone.This increases the risk for serious and sometimes lifethreateningabnormal heart rhythms. Small blood particlessuch as platelets and coagulation factors are activatedby serotonin and this may contribute to the increased riskof MI.II. DRUG MANAGEMENTRecent studies indicate that selective serotonin reuptakeinhibitors (SSRIs) constitute a major advance in themanagement of depressed patients with heart disease.Randomized controlled trials are required to documenttheir beneficial effects over a 5- to 7-year period. Theantidepressant heart attack randomized trial (SADHART)studied 370 patients with acute MI or unstable angina291

292DEPRESSION AND THE HEARTand major depressive disorder. After a two-week placeborun, patients were randomized to receive sertraline(Zoloft), 50 mg daily or placebo for 24 weeks. Approximately33% of these patients had previous episodes ofdepression. Results indicated that sertraline was effective intreating patients with more severe, recurrent episodes ofdepression. This drug did not cause adverse cardiac effects,for example, changes in left ventricular ejection fraction orother cardiac measurements. The incidence of the cardiovascularevents was less frequent in this group, and 22.4%versus 14.5% in the placebo group. This difference did notreach statistical significance, but it is reassuring that noadverse cardiac effects were observed and depression wassignificantly ameliorated. This was a short-term studyand trials to observe whether these agents reduce cardiacmortality long-term are necessary.The Canadian Cardiac Randomized Evaluation ofAntidepressant and Psychotherapy Efficacy (CREATE) isin progress with patients randomized to four arms.Patients either received citalopram (Celexa), and interpersonalpsychotherapy, placebo and interpersonal psychotherapy,routine clinical management, or routine clinicalmanagement and placebo. Other agents in this groupinclude fluoxetine (Prozac), the serotonin antagonistmirtazapine (Remeron), and the norepinephrine- anddopamine-reuptake inhibitor bupropion (Wellbutrin).These drugs may cause significant increase in bloodpressure and should be avoided in patients with hypertensionor ischemic heart disease manifested by angina orheart attack.Serotonin antagonists and reuptake inhibitors: nefazodone(Serzone), trazodone (Desyrel). These agents Thebicyclic venlafaxine (Effexor) may cause hypertension,Serotonin and norepinephrine reuptake inhibitors. Tricyclicantidepressants (amitriptyline, imipramine, doxepin,desipramine). These older antidepressants are well knownto have adverse cardiac side effects and are contraindicatedin patients with heart disease.BIBLIOGRAPHYBlumenthal, J. A., Lett, H. S., Babyak, M. A. et al. Depression as a riskfactor for mortality after coronary artery bypass surgery. Lancet,362: 604–09, 2003.Bonnet, F., Irving, K., Terra, J. L. et al. Anxiety and depression areassociated with unhealthy lifestyle in patients at risk of cardiovasculardisease. Atherosclerosis, 178:339–344, 2005.Ellis, J. J., Eagle, K. A., Kline-Rogers, E. M., Erickson, S. R. et al.Depressive symptoms and treatment after acute coronary syndrome.Int. J. Car., 99:443–447, 2005.Gottilieb, S. S., Khattta, M., Friedman, E. et al. The influence of age,gender, and race on the prevalence of depression in heart failurepatients. J. Am. Coll. Cardiol., 43:1542–1549, 2004.Lane, D., Carroll, D., and Lip, G. Y. H. Anxiety, depression, andprognosis after myocardial infarction: Is there a causal association?42:1808–1810, 2003.Lesperance, F., Frasure–Smith, N., Talajic, M. et al. 5-year risk of cardiacmortality in relation to initial severity and 1-year changes in depressionsymptoms after myocardial infarction. Circulation, 105:1049–1053,2002.Mallik, S., Krumholz, H. M., Lin, Z. Q. et al. Patients with depressivesymptoms have lower health status benefits after coronary artery bypasssurgery. Circulation, 111:271–277, 2005.Rumsfeld, J. S., Ho, P. M. et al. Depression and cardiovascular disease:A call for recognition. Circulation, 111:250–253, 2005.Whooley, M. A., and Simon, G. E. Managing depression in medicalpatients. N. Engl. J. Med., 343:1942–49, 2000.

Diabetes and Cardiovascular DiseaseI. Size of the ProblemII. Clinical Features and Complication of Type 2DiabetesIII. Pathogenesis of Type 2 Diabetes and ResearchImplicationsIV. Maturity Onset Diabetes of the YoungV. Management of Type 2 DiabetesVI. Hyperglycemic Hyperosmolar ComaVII. Dyslipidemia in Type 2 DiabetesVIII. Clinical Studies, Type 2 DiabetesIX. Coffee Consumption and Risk of Type 2 DiabetesX. Insulin ResistanceXI. Type 1 DiabetesGLOSSARYatheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).cardiomyopathy heart muscle disease.edema accumulation of fluid.endothelial dysfunction endothelium (lining of the arteries) isinfluenced by many substances some of which derange thefunction of the endothelial cells.hyperglycemia high blood glucose levels.hypoglycemia low blood glucose.macrovascular damage damage to arteries, arterioles (smallarteries), and small vessels.microvascular damage damage to capillaries.vasodilatory dilatation of the lumen of arteries or veins; thisincreases blood flow.visceral adiposity marked accumulation of fat that covers theabdominal organs, often termed abdominal obesity; the fataround the waistline also covers the internal organs withinthe abdomen.I. SIZE OF THE PROBLEMA. IncidencePresently there are more than 16 million type 2 diabeticsin the United States, and it is expected that this numberwill rise to approximately 22 million adults with diabetesin the year 2025. In addition, there are greater than40 million individuals who may not satisfy strict criteriafor the diagnosis of diabetes but have normal or minimallyelevated blood glucose levels with associated hyperinsulinemiaand peripheral insulin resistance. These‘‘prediabetic’’ individuals have a 10% annualized risk ofdeveloping type 2 diabetes. Importantly, most diabetics dieof cardiovascular disease, and atherosclerosis that causesobstruction to arteries in the heart and brain accountsfor greater than 80% of all diabetic mortality.Worldwide the incidence of diabetes differs greatly.Indians living in India have a much higher rate of diabetesthan those Indians observed in the United States. Thisincidence is increased after Indians immigrate from theircountry, and here they have been shown to have a higherrate of diabetes than other ethnic groups. This wellrecognizedobservation has been noted in Indians living inSingapore, South Africa, Malaysia, Fiji, and Trinidad. Theprevalence of diabetes is greater than 35% among PimaIndians versus approximately 4% in the non-Pima Indianpopulation in the United States. In randomized clinicaltrials conducted in the United States that involve patientswith heart disease, stroke, or cardiovascular diseases, greaterthan 20% are diabetics, however. The Chinese andEskimos have a much lower prevalence of diabetes.Type 1 diabetes (commonly known as insulindependentdiabetes and juvenile diabetes) occurs mainlyin younger individuals aged 10–14 years and compriseabout 10% of all cases of diabetes, that is, a prevalence ofapproximately 0.3%. Type 1 diabetes is not a disorderlimited to young people, however. Recent studies support adifferent model in which the disease can occur at any age.293

294DIABETES AND CARDIOVASCULAR DISEASEThese two types of type 1 diabetes have a differentcausation and symptoms, signs, and treatment aremarkedly different. It is interesting that type 1 diabetesis extremely rare in Pima Indians, Eskimos, and Micronesians,but it is more common in Caucasian populations(see Section III).B. Diabetic DistressThe distressing news is that greater than 25% of all newcases of severe renal failure occur in patients with diabetes,and this serious complication develops 25 years earlier thanin nondiabetics, most of whom will never have renal failure(see Fig. 1). More than 25,000 amputations mainly of toesfeet and legs are carried out in patients with diabetes,and diabetes is the leading cause of new cases of blindnesswith greater than 5000 cases occurring annually in theUnited States.Because the optimal treatment of diabetes by themedical profession does not prevent the occurrence offatal and nonfatal heart attacks and only mildly retardsthe onset of renal failure, stroke, and peripheral vasculardisease, diabetics have a poor prognosis. The problem isimmense and there is very little hope in sight. NewAll major causes of death + disabilityHeart Attack + Heart failureStrokeoccur 20 years earlier than average.Kidney failure 30 yearsbefore averageresearch avenues must be sought by those who are motivatedto do genuinely meaningful research.II. CLINICAL FEATURES ANDCOMPLICATION OF TYPE 2 DIABETESA. Symptoms of Type 2 DiabetesBelow is a list of symptoms of type 2 diabetes.1. Polyuria (elimination of excessive volumes of urine,two to four-times daily normal voiding amounts); thismay be present for several weeks or months beforenoted as an abnormality by an individual2. Polydipsia (excessive thirst)3. Polyphagia (excessive ingestion of food, particularlysweets and chocolates)4. Weakness, fatigue, and lethargy5. Weight loss occurs frequently, but in the Westernworld more than 80% of patients are overweight orobese at onset; minimal weight loss may occur in theseoverweight individuals followed by failure to loseweight6. Headache, dizziness, and blurred vision7. Urinary infections, carbuncles, boils, failure of smalllesions to heal normally, and fungal infections of thenails and groin8. Tingling and numbness in the feet due to neuropathy(nerve damage)9. Swelling of the ankle and lower legs caused by edema10. In many individuals no symptoms or only minorsymptoms that go unnoticed occurB. DiagnosisDISTRESSRESEARCHREQUIREDFIGURE 1Severe visual loss50 years earlierPoor response to coronaryballoon angioplastyCoronary bypass surgery not asbeneficial as fornon diabeticsOptimal therapy yetmacrovascular complementingabove not significantlyaltered.Polypharmacy 1: need to take manymedications for control ofDiabetes + complicationsDiabetics in distress.1. DefinitionThe definition of diabetes based on the glucose levels isgiven in Table 1. An algorithm for screening for diabetes isgiven in Fig. 2. Recommended diagnostic and screeningtests include a fasting glucose level. After an 8-h fast, afasting plasma glucose greater than 126 mg/dl (mmol/L)establishes the diagnosis of diabetes mellitus. A fastingglucose of less than 110 mg/dl is considered normal andlevels between 110 and 125 mg/dl refer to impaired fastingglucose. Two hours following an oral administrationof 75 g of glucose, a plasma glucose level greater than140 mg/dl is diagnostic and a level less than 200 mg/dl isconsidered impaired glucose tolerance (IGT).According to criteria developed by the NationalDiabetes Data Group, the presence of any of the classicsymptoms such as polyuria and polydipsia, ketonuria, and

III. PATHOGENESIS OF TYPE 2 DIABETES AND RESEARCH IMPLICATIONS295TABLE 1Definition of DiabetesFasting glucose [mg/dl (mmol/L)] Peak glucose [mg/dl (mmol/L)] 2 Hour glucose [mg/dl (mmol/L)]Normal

296DIABETES AND CARDIOVASCULAR DISEASETABLE 2Characteristic Features of the 2 Main Types of Diabetes MellitusType I: insulin-dependent diabetes mellitus(IDDM)Type II: noninsulin-dependent diabetes mellitus(NIDDM)Prevalence 10% 90%Age of onset Typically onset 40 yearsBody weight Usually thin >80% obesePresentationAcute onset, with polyuria, polydipsia, weight loss,lethargy, pruritus vulvae, balanitisInsidious onset, micro- and macrovascular complicationsmay be present at diagnosisEtiologyInadequate insulin secretion due to autoimmune destructionof the pancreatic b-cellsImpaired insulin secretion, increased hepatic glucoseproduction and peripheral insulin resistanceKetosis Prone Not proneGeneticsHLA-DR3 and DR4 common; 50% concordance in HLA unrelated; 100% concordance in identical twinsidentical twinsCirculating islet cell antibodies Yes NoTreatment with insulin Always necessary Usually not requiredInsulin secretion Severe deficiency Variable moderate deficiency to hyperinsulinemiaInsulin resistance Occasional with poor control on aggressive insulin Usual: caused by receptor and post receptor defectsantibodiesDYSLIPIDEMIA*HEART ATTACKFatalnon-fatalHEART FAILURESTROKEComplicationsEye DISEASES - - - blindnessPERIPHERAL VASCULAR DISEASEgangrene footHYPERTENSIONNEUROPATHYKIDNEY DAMAGEKidney failureProtein in urineFIGURE 3Complications of diabetes. *See chapter entitled Dyslipidemia.DialysisSwelling of feet+ legs[edema]

III. PATHOGENESIS OF TYPE 2 DIABETES AND RESEARCH IMPLICATIONS297AduposetissueProduction VDLS: accumulation of triglyceride richlipo proteins in circulating blood.LDL-cholesterol + qualitativelyHDL-cholesterol + qualitatively= Dyslipidemia? mechanismCardiovascular DiseaseeventsLiverglycogeneisglycogenolysis? mechanismFreefatty acidsglucagon +severalmechanismsPancreasIsletbeta cellsbeta cell distruction+ dysfunctionFreefattyacidsIncrease*glucose production[Receptor + postreceptor defect]InsulinResistanceMuscleglucoseupdakeglucose to bloodpoulImpairedinsulin secretionBlood glucose= PoolhyperglycemiaFIGURE 4Diabetes mellitus pathophysiology and metabolic abnormalities. Note increase production: how to halt this? New concepts.Blood glucoselevelsAmino acidsglucagonneuralfactors+ others2. Insulin resistance because of a deficiency of cell surfaceinsulin receptors (see Fig. 4)3. Increased hepatic glucose production (see Fig. 4)4. Glucagon secretion is increasedInsulin Secretion RegulatorsPancreas.Betaislet cellsFIGURE 5 Factors that influence glucose levels and insular secretionnormally and in type II diabetes. Mechanisms may dictate where to attackfor development of new therapies.amino acids are also important. Neural influences, gutinsulinogenic hormones, and other factors appear to be ofminor importance.B. Underlying MechanismsThe great majority of patients with type 2 diabetes havefour major defects (see Fig. 4):1. Insulin deficiency caused by a decline in pancreatic betacell functionThe major mechanism of hepatic glucose production isnot emphasized in medical textbooks and in the scientificliterature. Although it is crucial for diabetics to maintainstringent diets that lower blood glucose levels and drugsare used to increase insulin secretion from the pancreas(a host of old and new sulfonylureas), it appears thatinhibition of glucose release by the liver has escaped theattention of researchers. In addition, agents similar tometformin and new agents that may overcome insulinreceptor deficiency may have a role. Most of the glucose inthe plasma is produced by the liver. Thus, one approachfor the control of glucose levels in type 2 diabetes is tolimit hepatic production of glucose.Excess glucagon secretion contributes significantly toincreased glucose production. Decreased insulin secretionand resistance as well as increased glucagon secretion aremajor players in the pathogenesis of type 2 diabetes.Perhaps future glucagon receptor blockers can be developed(see Figs. 4 and 6).It appears that the medical profession has concentratedmainly on hepatic glucose production. Most

298DIABETES AND CARDIOVASCULAR DISEASEInhibits hepaticglucoseproduction*Actions of InsulinCarbohydrate Homeostasisdiabetologists agree that hyperglycemia contributes substantiallyto complications, but they concentrate onreducing blood glucose by diet and drugs that have amodest effect on increasing insulin secretion from dysfunctionalbeta islet cells. They also employ the use of theagent, metformin, which has minimal effects on peripheraluptake of insulin. Insulin action inhibits some of therelease of hepatic glucose but other agents must be sought.Agents that can overcome insulin resistance at receptorsites are important in future diabetes treatment.C. Effects of Insulinstimulates peripheraltissues, utilizationand disposalCellular upatakeFIGURE 6 Basic actions of insulin simplified. *Therefore type IIdiabetes best treated with insulin to inhibit glucose production:sulfonylureas are not effective.Insulin is a hormone that binds to specific cell surfaceinsulin receptors. It stimulates peripheral glucoseuptake and disposal by cells in all regions of the body.It further inhibits hepatic glucose production andplays a key role in carbohydrate homeostasis (see Figs. 4and 6).D. Mechanisms of Vascular Abnormalitiesin Diabetes MellitusImportant causes of vascular abnormalities in diabetesmellitus include hyperglycemia. This leads to an increasedconcentration in the cell of the metabolite diacylglycerolwhich is an activator of a family of enzymes called proteinkinase C (PKC). These enzymes perform key regulatoryfunctions by phosphorylating proteins and are nowbelieved to play a significant role in the pathophysiologyof cardiovascular complications. It is well known that nitricoxide synthase enhances arterial endothelial vasodilatoryfunction and activation of PKC can inhibit expression,although a nitric oxide synthase can inhibit beneficialvasodilatory function. Glucose-induced activation of PKChas been shown to increase the production of extracellularmatrix macromolecules that accumulate during atheromaformation.A selective inhibitor PKC-beta given to diabetic ratshas been shown to improve retinal blood flow. Theseenzymes appear to be implicated in muscle dysfunctionand cardiomyopathy in diabetes. Intensive research is beingpursued in this interesting direction. Hyperglycemia causesan overproduction of oxygen-derived free radicals thatpromotes endothelial cell dysfunction. It appears that theantioxidant effect of high doses of vitamin C improvesendothelial-dependent vasodilatation in diabetic individuals.Hyperglycemia impairs endothelial-dependent vasodilatation,and this deleterious effect is also caused bydyslipidemia. Treatment with fibrates or statins improvesendothelial function.Hyperglycemia also leads to the production of sorbitol,which can be converted to fructose. Accumulation ofsorbitol and fructose increases intracellular osmolarity withwater influx and swelling of nerve cells. This may explainwhy diabetics have damage to their peripheral nerves.E. DyslipidemiaDyslipidemia or hyperlipidemia is the most substantiatedmechanism involved in progressive atheroma formationin the process of obstructing atherosclerosis. The dyslipidemiathat is common in type 2 diabetes is generated byincreased hepatic production of very low density lipoproteins(VLDLs; see Fig. 4).1. Free Fatty AcidsIn type 2 diabetes there is increased delivery of fattyacids to the liver. Striated muscle takes up less free fattyacids because of insulin resistance and excess free fatty acidsare delivered to the liver. Insulin resistance plays animportant role in type 2 diabetes and this role should bequantified. Agents that decrease insulin resistance shouldbe developed.Central abdominal obesity or visceral adiposity drainsdirectly into the portal vein that leads to the liver. Visceraladiposity is therefore an important root of diabetic dyslipidemia,because it increases the delivery of free fattyacids to the liver.Free fatty acids are the substrate for liver synthesis ofVLDLs. These particles carry endogenously producedtriglycerides and have a particle diameter ranging from 300to 800 nm. An abundance of triglyceride-rich lipoproteinsaccumulate in the plasma. Additionally, in uncontrolledtype 2 diabetes lipoprotein lipase activity is decreasedresulting in the failure of clearing triglyceride-rich

V. MANAGEMENT OF TYPE 2 DIABETES299particles derived from food intake. The abundance ofVLDLs in the plasma provides an increase in substrate forcholesterol ester transfer protein which causes a flux ofcholesterol from HDL particles. This decreases the level ofHDL cholesterol in the blood.Fenofibrate, a thiazolidinedione, has been shown toimprove insulin sensitivity by activating peroxisomalproliferation-activating receptor gamma (PPAR-gamma).In the Veterans Affairs (VA) high-density lipoproteincholesterol intervention trial, patients who have a lipoproteinprofile of insulin resistance were treated with afibrate which showed a reduction in coronary heart diseaseevents and stroke. Also, the Diabetes Atherosclerosis InterventionStudy (DAIS), showed delayed angiographic progressionof coronary atherosclerosis in diabetic patientstreated with fenofibrate.2. High-Density LipoproteinsHigh-density lipoproteins (HDLs) mainly carry cholesterolester and are small particles with a diameter of 50–90 nm.HDL is believed to be protective in cardiovascular diseaseprobably because of a number of potential mechanismsincluding reverse cholesterol transport. The protectiveeffect of HDL is believed to result from its ability to reducethe oxidation of LDL cholesterol. Also, in diabetics theHDL particle appears to be qualitatively different andprovides less protection from oxidation (see Fig. 4).3. LDL CholesterolLDL cholesterol carries the bulk of circulating cholesterol,and its main component is cholesterol ester. The LDLparticle has a diameter of 180–280 nm and is highlyatherogenic. It is believed to be the main particle involvedin producing atheroma in uncontrolled diabetics. TheLDL particles have qualitative differences (see Fig. 4).They are smaller and denser particles in diabetics andshow greater susceptibility to oxidation compared withnondiabetics. LDL cholesterol is mild to moderatelyincreased in diabetics and treatment with statins hasshown a decrease in risk of coronary events.F. Defect in Fibrinolysis and ThrombosisAn increased level of fibrinogen and plasminogen activatorinhibitor type 1 (PAI-1) has been detected in plasmaand in arterial lesions in patients with diabetes. Plateletfunction is also abnormal. These defects in the coagulationsystem are believed to increase the incidence of thrombosisand perhaps, the atherosclerotic process.G. Genetic AbnormalitiesA specific mutation that causes insulin-resistant diabetesmellitus and hypertension has been defined in a smallnumber of individuals. PPAR-gamma mutations have beennoted in members of two young affected kindreds.IV. MATURITY ONSET DIABETESOF THE YOUNGMaturity onset diabetes of the young (MODY ) is aclinically heterogenous group of disorders characterized byan autosomal dominant mode of inheritance and onsetusually before age 25. It is a primary defect in the functionof the beta cells of the pancreas. Mutations in any one ofsix different genes may result in MODY.These genes are expressed in beta cells, and mutation ofany of them leads to beta cell dysfunction and diabetesmellitus. Fortunately individuals with MODY do notusually develop ketotic diabetes mellitus, which occursfrequently in type 1 diabetes.V. MANAGEMENT OF TYPE 2 DIABETESInitially, therapy for diabetes includes special diets to reducecarbohydrate intake and thus blood glucose and weightreduction. Anti-diabetic drugs are the next of course ofaction.A. Drugs1. Drugs to Increase Insulin Production by the PancreasIncluded in this group are the sulfonylureas such asglyburide, glipizide, gliclazide, and glibenclamide. Theseagents have been used for more than 50 years. The wellknownagents used in the 1950s, tolbutamide and chlorpropamide,have been replaced by the new agents listedabove. Several other agents are now available, but they arefar superior to the old agents. Additionally, sulfonylureasare relatively ineffective drugs because they are not able tosqueeze sufficient insulin from dysfunctional pancreaticbeta islet cells. There may also be some cardiotoxic effectwith prolonged use. The use of sulfonylureas over the past30 years has not altered the prognosis of diabetes and its

300DIABETES AND CARDIOVASCULAR DISEASEcomplications (see Fig. 1). Physicians should seek othermethods of treatment.2. Drugs that Appear to Increase Peripheral Uptakeof InsulinOne example is metformin. This biguanide is commonlyused at a dose of 500 mg twice or three times daily witha maximum dose of 2000 mg daily, but physicians oftenexceed this maximum dose. Metformin has interestingactions and there is potential for developmental researchin this area.This drug acts primarily on hepatic glucose production.The reduced hepatic glucose output is caused mainlyby inhibition of gluconeogenesis. The exact mechanismthrough which metformin reduces hepatic glucose productionas well as its effectiveness in the suppression ofgluconeogenesis remain unclear. The primary site ofaction appears to the hepatocyte mitochondria, where thedrug disrupts respiratory chain oxidation of complexsubstrates such as glutamate, lactate, pyruvate, glycerol,and amino acids. There is, however, minimal effect on thesplitting up of glycogen in the liver-yielding glucose(glycogenolysis).Metformin possesses some effects on peripheral insulinsensitivity. This would be an extremely useful action of thedrug, but its effect is minimal and mainly in insulinsensitivetissues. The drug’s effect on peripheral insulinsensitivetissues requires the presence of insulin for its fullaction. In insulin-sensitive tissues such as skeletal musclethe drug facilitates glucose transport by increasing tyrosinekinase activity in insulin receptors and enhances glucosetransporter trafficking to the cell membrane. It is claimedthat metformin improves insulin resistance, which is animportant mechanism in type 2 diabetes. But review of itsactions indicates only a minimal effect. Type 2 diabeticpatients are insulin resistant primarily because of decreasedinsulin receptors. Thus metformin has a modest effect onimproving insulin resistance.Other agents to treat diabetes must be investigated. Inthe UK Prospective Diabetes Study Group (UKPDS) therewas an increased mortality during combination therapywith metformin plus sulfonylureas despite improvement inthe control of blood glucose levels with combination versusmonotherapy. Was the mortality increase observed causedby sulfonylureas, metformin, or the natural course of type2 diabetes? More research is needed in this area.Metformin has only modest beneficial effects on lipidmetabolism, clotting factors, and platelet function. Thisdrug has been shown to improve diabetes-induced cardiacdiastolic dysfunction in laboratory animals. It also appearsto improve vascular relaxation and may cause a milddecrease in blood pressure in some individuals.Caution:This drug is contraindicated in patientswith renal dysfunction (mild-to-moderate renal failure),congestive heart failure, and in patients with lung diseaseassociated with hypoxia. In a review of prescriptions almostone-quarter of patients with a prescription for metforminhad one or more contraindications. Several recent studiesin Europe have documented similar rates of inappropriateprescriptions for metformin. Metformin has been associatedwith the development of lactic acidosis, and since itsmarketing in 1995, the FDA has required a black boxwarning in the package insert. In the first 40 months afterits release in the United States, the FDA received 47confirmed cases of lactic acidosis associated with the useof the drug with a 42% mortality. More than 90% ofthese patients had relative or absolute contraindicationsto metformin. This drug along with phenformin was usedsparingly in the 1970s when the incidence and dangers oflactic acidosis became widely known. In the 1990s andrecently, however, the drug has become the most widelyused oral hypoglycemic agent prescribed.Metformin is more beneficial when used along withsmall doses of insulin. A study of the pathogenesis andactions of hypoglycemic agents allows the conclusion thatwhen metformin is used with insulin, the sulfonylurea thatis commonly prescribed in triple therapy may not required.This is one more drug removed from the polypharmacythat is inflicted upon diabetics. These patients must alsotake drugs to protect their hearts, reduce blood pressure,and protect their kidneys as well as other medications.Metformin, however, has an important role in themanagement of type 2 diabetes until more effective agentsare available to overcome insulin resistance and decreasehepatic production of glucose. The Diabetes PreventionProgram in the United States and the Diabetes PreventionStudy in Finland have recently demonstrated that lifestylemodification programs and metformin can delay the onsetof diabetes in glucose-intolerant individuals.3. InsulinDuring the past five years, diabetologists have advocatedthe addition of insulin to the oral drugs to maintainoptimal glucose levels. This is the treatment advised indiabetic clinics and general practitioners have followedthese guidelines. It is unfortunate that this triple-drugregimen does not prevent the macrovascular complicationsof diabetes. This therapy has had no impact on the riskfor coronary heart disease and fatal and nonfatal heartattacks. The combination of insulin and metformin withoutsulfonylureas appears to be a more logical regimen.

VII. DYSLIPIDEMIA IN TYPE 2 DIABETES301Statins*to control dyslipidemiaC-Reactive proteininflammatory processHyperglycemia Osmotic Diuresis Loss ofElectrolytesand Waterimprove endothelialdysfunctionSomnolenceComaHyperosmolalityBeta blocker: cardioselectivemetoprolol or bisoprolol**-prevent cardiac eventsaspirin 80 to 325 mg daily-prevent thrombosisSerumOsmolalityAzotemiaGlucose RetentionFIGURE 8Decreased GFRPathogenesis of hyperosmolar state.Impaired SensoriumWater IntakeDehydrationinsulin - hepatic glucose production(Restrict use of not effective agents)Metforminimprove insulin resistance***usual Dietary + life style changesACE inhibitor or ARB # to proteinuria,renal damageand control for storage riskFIGURE 7 New concepts for the management of type II diabetesand research implications. *Fibrates in selected individuals triglycerids>500 mg/dL 5 mmol/L; ** ¼ See section on beta blockers for choiceof agent; *** ¼ Modest effect, need new agents to overcome resistance;# ¼ ARB ¼ angiotensin II receptor blocker.precipitating factor is usually present such as myocardialinfarction, stroke, infection, and overzealous use of diureticsand steroids. The pathogenesis of hyperosmolar coma isshown in Fig. 8.Hyperglycemia causes chronic osmotic diuresis whichresults in severe dehydration and loss of potassium andsodium. Ketosis is absent mainly because critical amountsof insulin are still present and capable of suppressinglipolysis. The blood glucose in these patients is oftengreater than 600 mg/dl (30 mmol/L).Management necessitates immediate rehydration andthis should be done more slowly than in patients withdiabetic ketoacidosis. Most patients are quite sensitive toinsulin and only small doses are required. The precipitatingfactors should be identified and treated.4. ThiazolidinedionesThese agents have a mild effect on the lowering of bloodglucose levels, but it is not as effective as sulfonylureas.Troglitazone has been voluntarily withdrawal from themarket because of severe hepatotoxicity. Pioglitazone androsiglitazone are available in United States, but their useis restricted in patients with congestive heart failure. Thisrestriction is in place because they increase retention ofsodium and water which worsens heart failure. They alsoproduce significant weight gain and they should not beprescribed to persons with familial polyposis.Figure 7 gives concepts for the management of type 2diabetes and research implications that may result in adecrease in cardiovascular complications.VI. HYPERGLYCEMICHYPEROSMOLAR COMAThis complication occurs in older patients with type 2diabetes who cannot recognize the need for water. AVII. DYSLIPIDEMIA IN TYPE 2 DIABETESA. CharacteristicsDyslipidemia is common in diabetics and is characterizedby borderline (200–400 mg/dl; 2.3–4.5 mmol/L) to moderateelevations of triglyceride levels greater than 400 mg/dl(see Fig. 4). There is also an increase in total cholesterollevels to greater than 240 mg/dl with increased levels ofsmall, dense LDL cholesterol (bad cholesterol) of greaterthan 160 mg/dl. Another characteristic of dyslipidemiais a low level of HDL cholesterol less than 35 mg/dl(0.9 mmol/L).B. Management of Dyslipidemia1. Statin DrugsThe management of this deleterious manifestation of diabetesis crucial, because cardiac events and deaths can beprevented. Patients with elevated LDL cholesterol (220–300 mg/dl), mild elevation of triglycerides (

302DIABETES AND CARDIOVASCULAR DISEASEand lowered HDL (500 mg/dl;5 mmol/L)and particularly when the HDL levels are verylow (>0.8 mmol/L). The combination of a statin andfibrate may cause muscle damage that is associated withmarked elevations of creatinine kinase in the blood.Damage to muscle or myositis may be reversible but canbe extensive enough to damage to the filtration system ofthe kidney and cause kidney failure. This drug combinationis recommended by diabetologists and used in diabeticand lipid clinics, but the author believes that this strategy isnot justifiable because the combination has caused kidneyfailure and deaths worldwide, albeit rarely, and the FDAhas not approved the combination.3. TorcetrapibIt is most important to increase levels of HDL cholesterolit is cardioprotective. Inhibition of cholesteryl ester transferprotein (CETP) appears to be a new and most usefulstrategy to raise HDL cholesterol levels. Brousseau et al.conducted a small study of 19 individuals with HDLcholesterol levels

XI. TYPE 1 DIABETES303output in the liver. Can coffee consumption decrease therisk of type 2 diabetes?Methods: Investigation of 17,111 Dutch men andwomen aged 30–60.Results: During 125,774 person-years of follow up, 386new cases of type 2 diabetes were reported. Individualswho drank at least seven cups of coffee daily were 0.50times as likely as those who drank two cups daily todevelop type 2 diabetes (P ¼ 0.0002).Conclusion: Coffee consumption was associated witha substantially lower risk of clinical type 2 diabetes.X. INSULIN RESISTANCEA. Abbasi et al.Study question: To define the relationship between bodymass index and insulin resistance in 314 nondiabetic,normotensive healthy volunteers.Methods: ‘‘Insulin resistance was quantified by determiningthe steady-state plasma glucose concentrationduring the last 30 min of a 180-min infusion of octreotide,glucose, and insulin.Results: The body mass index and steady-state plasmaglucose were significantly related.Conclusions: Insulin resistance at any given degree ofobesity appears to accentuate the risk of coronary heartdisease and type 2 diabetes.B. Other StudiesA research study of interest indicates that both abnormalpteridine metabolism and vascular oxidative stress arelinked to coronary endothelial dysfunction in the insulinresistance subject.In the Western Scotland Coronary Prevention Study of5974 men, 2.6% of these men aged 45–64 developed type2 diabetes. A 30% risk reduction for diabetes was observedamong pravastatin users.In the United Kingdom Prospective Diabetes GroupStudy the efficacy of intensive glucose control using acomplex protocol with either insulin or sulfonylureascompared with conventional treatment failed to demonstratedefinite clinical benefit in macrovascular complicationsin patients with type 2 diabetes.Van Belle et al. conducted the following study.Study question: What are the effects of coronarystenting on vessel patency and long-term clinical outcomeafter percutaneous coronary revascularization in diabeticpatients?Methods: There were 314 diabetic patients treatedwith either coronary stenting or standard balloon angioplasty(BA).Results: At six months the rate of stenosis (27% vs.62%; P < 0.0001) and occlusion (4% vs. 13%; P < 0.005)were lower in the stent group than in the BA group.At four years, the combined clinical end point of cardiacdeath and nonfatal infarction in the stent group was14.8% vs. 26% (P ¼ 0.02) and repeat revascularization was35.4% vs. 52.1% ( p ¼ 0.001).Conclusions: In diabetic patients, coronary stent implantationwas associated with a highly beneficial effect at sixmonths and at four years compared with BA.Perspective: In the Bypass Angioplasty RevascularizationInvestigation (BARI), all-cause mortality was 34.7%in diabetics who underwent BA versus 19.1% for bypasssurgery. In nondiabetics mortality was much lower, 9.5 and10.3% over five years, for angioplasty and bypass surgery.The BARI study indicated that bypass surgery was superiorto angioplasty in diabetics, but the study was done beforethe current experience with stents. In selected patients withdiabetes, PCI using stents gave results that are comparableto bypass surgery as indicated in this study. In addition,diabetics undergoing PCI show significant benefit with theuse of platelet glycoprotein IIb/IIIa receptor blockers.XI. TYPE 1 DIABETESA. Pathogenesis and EpidemiologyThe incidence of type 1 diabetes is extremely variableamong different ethnic populations. The rate of diabetesseems to be increasing in almost all populations, but theincrease is highest in nations with presently low incidence.In the Zunyi region of China the incidence is 0.1 per100,000 per year, but it is 40 per 100,000 in Finland andin Sardinia about 3000 km away. But the incidence inneighboring Estonia is about one-quarter that of Finland.These differences within ethnic groups, perhaps, lies indifferences in environment or in genes. Estimates suggestthat the incidence of type 1 diabetes may become 40 timeshigher in 2010.In an excellent review Atkinson et al. stated that thegenetics of type 1 diabetes cannot be classified accordingto a specific model of dominant, recessive, or intermediateinheritance of a specific set of genes. The disorderis heterogenous and polygenic with approximately 20 ofnon-HLA loci contributing to disease susceptibility thatis already identified.Results of considerable environmental research throwdoubt on the implication of Coxsackie and cytomegalo

304DIABETES AND CARDIOVASCULAR DISEASEviruses, breast-feeding versus early introduction of a cow’smilk, and vaccines. But the Finnish reports suggest thepotential for such associations. The current view is thatpenetrance and expression of heritable immune dysregulationin association with target organ defects interact withenvironmental factors, which include infectious agentstoxins, vaccines, sanitation, and others. Atkinson et al.emphasized that type 1 diabetes has increased dramaticallyover the past few decades, perhaps due to improved healthcare and sanitation.A great percentage of children develop anti-islet autoantibodiesbetween 1 to 3 years and those who progress tothe diabetic state express multiple anti-islet autoantibodiesby the time of diabetes onset. It appears that approximately15% of patients with type 2 diabetes have what is calledlatent autoimmune diabetes in adults (LADA), and theseindividuals express the islet autoantibodies that includeglutamic acid decarboxylase (GADA).B. Pathologic FeaturesThe islet cells are observed to be infiltrated with mononuclearcells with reduction in beta cell volume and somedegree of insulitis. There is suggestive evidence that aninteraction between Fas on beta cells and Fas ligand oninfiltrating cells might trigger selective apoptotic beta celldeath in inflamed islets which results in type 1 diabetes.This pathogenesis and pathophysiology lacks clarity, thus,preventive treatment remains obscure (see Fig. 9). TheFIGURE 9 The treatment for type 1 diabetes. Many studies from animal models of type 1 diabetes in combination with a much more limited series ofinvestigations in human beings suggest that early intervention not only is more effective in terms of disease prevention, but also often requires more benignforms of therapy. In contrast, the ability to identify an individual who will truly develop type 1 diabetes (among an at-risk population) increases as theindividual approaches onset of overt disease. Although this model does not restrict the ability to provide preventative intervention therapy for individualsat or near onset of disease, the degree of residual ß-cell mass must be considered when assigning individuals to various therapeutic protocols.IVGTT ¼ intravenous glucose tolerance test; IAA ¼ insulin autoantibodies; GADA ¼ glutamic acid decarboxylase. (From Atkinson, M.A., The Lancet, 358,230, 2001.)

XI. TYPE 1 DIABETES305Glucose uptakeINSULIN DEFICIENCYAbsolute or RelativeHyperglycemia Gluconeogenesis KetogenesisOsmotic DiuresisElectrolyte DepletionKetonemiaKetonuriaHypotonic Losses Dehydration AcidosisPathogenesis of diabetic ketoacidosis.FIGURE 10Protein CatabolismAminoAcidsNitrogenLossGlycerolLipolysisFreeFattyAcidsexact cause for the destruction of beta cells remains elusiveand intensive research is required.ketosis usually has a precipitating cause that should beidentified, corrected, and avoided in the future.2. Clinical Studiesa. The Diabetes Prevention Trial–Type 1(DPT–1)Study question and methods: The comparison of prophylacticinsulin therapy was assessed. In this study,84,000 relatives of affected children were screened forislet cell antibodies. Individuals were selected on the basisof very high risk — a greater than 50% chance of progressionto diabetes within five years. Approximately 30% ofindividuals had IGT on randomized addition. This wasan exceptional trial in that families had a choice to acceptinsulin treatment for relatives who did not have diabetesor to deny children a therapy likely to be beneficial.Conclusions: Insulin treatment did not delay the onsetof type 1 diabetes.C. Symptoms, Signs, and ComplicationsPolyuria, polydipsia, weight loss, tiredness, lethargy,fatigue, and infections of the skin and urogenital tractare often bothersome. The most life-threatening complicationof diabetes is diabetic ketoacidosis manifested byacceleration of both the abovementioned and the followingsymptoms: Hyperglycemia: Plasma glucose usually greater than300 mg/dl (17 mmol/L) Hyperketonemia: Ketones present in the blood andurine Acidosis: pH less than 7.2 and bicarbonate less than15 mEq (mmol/L) Anion gap greater than 16 mEq/L (mmol/L) Diabetic ketoacidosis is always caused by insulindeficiency, either absolute, i.e., a previously undiagnosedpatient or one who omitted insulin) or relative(i.e., too little insulin injected or antagonism by stresshormones); see Fig. 10D. Management1. EmergenciesThe initial goal of therapy is to treat life-threateningemergencies which include dehydration and deficienciesin insulin and potassium. The circulating blood volume islow because of dehydration and this must be restored tomaintain cerebral, coronary, and renal perfusion. Diabeticb. Cyclosporine TrialIt is believed that approximately 10% of beta cells areviable on the onset of symptoms of type 1 diabetes, andthere is the potential for recovery of some beta cell function.Trials with cyclosporine and immune interventionshowed modest benefits, but this dissipated when treatmentwas discontinued. There is need for newer agentswithout these adverse effects.CD3 complexes are located on the surface of lymphocytesin association with the T-cell receptor and they havebeen shown to play a significant part in the antigen-specificactivation of T cells. Anti-CD3 antibodies bind to thiscomplex. They have been tested but appear to be of limitedvalue.3. TransplantationAlthough some ‘‘cures’’ have been accomplished withboth pancreas and islet transplantation, limitations of bothforms of transplantation are obvious. A worldwide epidemiccannot be treated by transplantation; the relativelack of organ donors for allogeneic transplantation andthe need for continuous immunosuppression to block therecurrent autoimmune islet cell destruction renders thistreatment modality to only a few fortunate individuals.E. PerspectiveA considerable amount of research has been done, butscientists have not uncovered the exact pathogenesisof type 1 diabetes. Prevention of the disease and its

306DIABETES AND CARDIOVASCULAR DISEASEcomplications and prolongation of life appear to beunobtainable. If environmental determinants can bedefined as playing a definite role in the basis of thedisease, then there is hope for a cure. This statement fromAtkinson et al. appears appropriate:Prospective studies of infants developing antiisletautoantibodies and eventually diabetes couldimprove and refine our understanding of potentialenvironmental-like triggering factors in infancy,although the DAISY study from the United Statesand the BABYDIAB study from Germany did not showany adverse effects from early cow’s milk exposure,breast-feeding, enteroviral infection, or timing ofvaccination.Nonetheless, the Finnish reports suggested a strongpotential for such associations.BIBLIOGRAPHYAbbasi, F., Brown, B. W., Lamendola, C. et al. Relationship betweenobesity, insulin resistance, and coronary heart disease risk. J. Am. Coll.Cardiol., 40:97–143, 2002.Atkinson, M. A., and Eisenbarth, G. S. Type 1 diabetes: New perspectiveson disease pathogenesis and treatment. Lancet, 358:221–29,2001.Brousseau, M. E., Schafer, E. J., and Wolfe, M. L. Effects of an inhibitorof cholesteryl ester transfer protein on HDL cholesterol. N. Engl.J. Med., 350:1505–1515, 2004.Cho, E., Rimm, E. B., Srampfer, M. J. et al. The impact of diabetesmellitus and prior myocardial infarction on mortality from myocardialinfarction and from coronary heart disease in men. J. Am. Coll.Cardiol., 40:954–60, 2002.Fajans, S. S., Bell, G. I., and Polonsky, K. S. Molecular mechanisms andclinical pathophysiology of maturity onset diabetes of the young.N. Engl. J. Med., 345:971–78, 2001.Gale, E. A. M. Can we change the course of beta cell destruction intype 1 diabetes? N. Engl. J. Med., 346:1740–41, 2002.Marso, S. P. Optimizing in the diabetic formulary: Beyond aspirin andinsulin. J. Am. Coll. Cardiol., 40:652–61, 2002.Masoudi, F. A., Inzucchi, S. E., Wang, Y., Havranek, E. P., Foody, J. M.,Krumholz, H. M. et al. Thiazolidinediones, Metformin, and outcomesin older patients with diabetes and heart failure: An observationalstudy. Circulation, 111:583–590, 2005.Moreno, P. R., Fuster, V. et al. New aspects in the pathogenesisof diabetic atherothrombosis. J. Am. Coll. Cardiol., 44:2293–2300,2004.Nesto, R. W., and Libby, P. In Heart Disease. E. Braunwald, ed.W. B. Saunders, Philadelphia, 2001, pp. 2133–47.Shinozaki, K., Hirayama, A., Nishio, Y. et al. Coronary endothelialdysfunction in the insulin resistance state is linked to abnormalpteridine metabolism and vascular oxidative stress. J. Am. Coll.Cardiol., 38:1821–8, 2001.Tuomilehto, J. T., Lindstrom, J., Eriksson, J. G. et al. To prevention ofType II diabetes by changes in lifestyle among subjects with impairedglucose tolerance. N. Engl. J. Med., 344:1343–50, 2001.United Kingdom Prospective Diabetes Study Group. Tight blood pressurecontrol and risk of macrovascular and microvascular complicationsin type 2 diabetes. BMJ, 317:703, 1998.Van Belle, E., Perie, M., Braune, D. et al. Effects of coronary stenting onvessel patency and long-term clinical outcome after percutaneouscoronary revascularization in diabetic patients. J. Am. Coll. Cardiol.,40:410–7, 2002.Van Dam, R. M., and Feskens, E. J. M. Coffee consumption and risk oftype II diabetes. Lancet, 360:1477–80, 2002.Weinstein, A. R., Sesso, H. D., Lee, I. M. et al. Relationship of physicalactivity versus body mass index with type II diabetes in women. JAMA,292:1188–1194, 2004.

Diets and Heart DiseaseI. DietsII. Trans Fatty Acids and Coronary Artery DiseaseIII. Diet–Drug ValvulopathyIV. Fish OilsGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.coronary artery disease obstruction of the coronary arterieswith symptoms such as chest pain, angina, or heart attacks.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.CORONARY ARTERY DISEASE (CAD) IS A CAUSE OFserious cardiac events including angina and myocardialinfarction which may be fatal or nonfatal. Diets to preventCAD have been advocated for more than 40 years. Severalweight-reduction diets have been fashionable over the past50 years. The prevalence of obesity (body mass index orBMI > 30) and the population of overweight individuals(BMI > 25) has increased dramatically in North Americaduring the last 20 years(43% of the United States in1961 vs. 55% in 1994). This increase has occurreddespite attempts at dietary controls. In this population ofpatients the risk for diabetes and CAD is increased. Waistcircumference of greater than 35 inches in women andgreater than 40 inches in men is an easily measured markerof increased CAD risk.In patients where dyslipidemia is present, as defined byan elevated total cholesterol and low-density lipoprotein(bad) cholesterol, dietary restriction to reduce theseelevated levels has shown a definite but modest reductionin risk for CAD; see the chapters Dyslipidemia andCholesterol.I. DIETSA. Controversial DietsThese controversial diets include the Dean Ornishprogram and the Atkins diet.The Dean Ornish program advises a low-fat, vegetarianapproach coupled with exercise, stress reduction, andsmoking cessation. This diet appears to reduce the risk ofCAD, but again the reduction is modest and only formallytested by coronary angiograms in a few individuals. Thereis no randomized trial or large trial that has tested this diet.In addition, cessation of smoking is vitally important, butstress reduction and exercise are additive. Thus, the effectof the Ornish dietary program has not proven its valueand is particularly difficult to follow for the long periodof time necessary to significantly alter the risk for coronaryevents.The Atkins- type diet was tested in a small study conductedin only 45 adults. The 45 adults were randomizedand assigned to eat a high-fat, low-carbohydrate dietor a low calorie, high-carbohydrate, low fat [incorrectlycalled ‘‘conventional diet’’]. After a short period of onlythree months, the dangerous plasma LDL cholesterolincreased in the low-carbohydrate, high-fat group anddecreased slightly in the low-fat group. Thus the Atkinstypediet may substantially increase the risk for atheromadevelopment and progression in individuals who have apropensity to develop cardiovascular disease (see thechapters Obesity and Heart Disease and Atherosclerosis/Atherothrombosis).B. Recommended Diets1. The Mediterranean DietThere is good evidence to support the use of a Mediterraneanstyle diet for the reduction of CAD risk. The backgroundevidence gathered from the Seven Countries Studyin the 1960s suggested that the Cretan Mediterranean diet307

308DIETS AND HEART DISEASEwas associated with the lowest incidence of mortality fromCAD as compared to other countries in Europe and inNorth America. The cohort in Crete consumed less meatand saturated fats and had more fruit, nuts, legumes, fish,and unsaturated fats, with an abundance of olive oil andred wine. Two randomized studies have shown theeffectiveness of the Mediterranean diet.a. The Lyon Diet Heart StudyThis is a hallmark study.Methods: This study randomized 605 survivors of thefirst myocardial infarction to a Mediterranean type diet ora ‘‘prudent Western type diet.’’Results: After a median follow up of 46 months, therisk of fatal or nonfatal myocardial infarction was 65%lower for those on the Mediterranean diet.Mediterranean diet contents: High intake of bread,food, and margarine (canola oil base with added alphalinolenicacid), and canola and olive oil that has a highmonounsaturated fat, oleic acid content. In the abovestudy the total amount of oil consumed was similar forboth groups, but canola and olive oil was used in thetreated group and sunflower oil in the prudent diet group.The treated group intake consisted of 30% total fat, 8%saturated fat, 203 mg cholesterol daily, versus 34%, 12%,and 312 mg cholesterol, respectively, for the prudent diet.Alpha-linolenic and oleic acid intake was higher, andlinoleic acid intake was lower in the treated group.The mean serum cholesterol levels at the end of followup were 6.18 mmol/L in the control group and wassimilar, 6.20 mmol/L, in the treated group. Lipid-loweringmedications were used in 34 and 26.5%, respectively.Apart from the beneficial effect of alpha-linolenic andoleic acid, there may have been benefits in the experimentalgroup caused by higher consumption of antioxidantssuch as polyphenols that are present in fruits,vegetables, and red wine.b. Clinical Study by Singh et al., the Indo-MediterraneanDietMethods: There were 1000 patients in India, approximately59% with proven CAD (angina pectoris andmyocardial infarction), randomized to a diet rich inwhole grains, fruits, vegetables, walnuts, and almonds. Thecontrol group consumed a local diet similar to the step 1National Cholesterol Education Program prudent dietwhich includes a diet of fat intake reduced to 30% of foodenergy with approximately 15% from saturated fats and10% from polyunsaturated fats. It also included

II. TRANS FATTY ACIDS AND CORONARY ARTERY DISEASE309at room temperature. The process used to produce transfatty acids and solid fats is called partial hydrogenation.In addition, partial hydrogenation is frequently usedcommercially because it removes the beneficial linolenicacid that may cause the fat to become rancid when exposedto high temperatures used for commercial deep fatfrying and when stored. Trans fat usage increased overthe past two decades because of the concern over the use ofpalm and coconut oils that were used extensively inprocessed foods. These two oils contain a high amount ofsaturated fat.A. Clinical Study: Oomen et al.Study question: A Dutch population with a fairly hightrans fatty acid intake including trans fatty acids frompartly hydrogenated fish oils was investigated. The relationbetween trans fatty acid intake and CAD were studied.B. Zutphen Elderly StudyMethods: This investigation prospectively studied 667men aged 64–84 years and free of CAD. The dietary surveywas used to establish the participants food-consumptionpatterns. Information risk factors were obtained in 1985,1990, and 1995.Results: From 1985 to 1995 trans fatty acid intakedecreased from 4.3 to 1.9% of energy. Trans fatty acidintake at baseline was positively associated with a 10-yearrisk of CAD after adjustment for age, BMI, smoking, anddietary covariates.Perspective: From 1996 there has been a continuingdecrease in trans fatty acid intake in The Netherlands andin other European countries, where there has been a fall intrans fatty acid content of margarines, but no increase in itsuse in commercially baked products and fast foods. In theUnited States, however, there has been a fall in trans fattyacid content of margarines but an increase in trans fattyacid consumption from commercially baked products andfast foods. The decrease in trans fatty acid intake of 2.4%of energy reported in this study could have contributed toabout 22% less deaths from CAD, approximately 4600 of20,000 coronary deaths in The Netherlands annually.C. Effect on Blood LipidsBoth trans fatty acids and saturated fats increase LDLcholesterol levels to a similar degree, but trans fatty acidslower HDL (good) cholesterol levels. Intake of saturatedfatty acids does not decrease HDL cholesterol levels. Theratio of LDL to HDL cholesterol has been shown to besignificantly higher with the intake of trans fatty acids thanwith consumption of saturated fats. The net effect of transfatty acids on the LDL to HDL cholesterol ratio isapproximately double that of saturated fatty acids. Thus,trans fatty acid intake is expected to significantly increasethe risk of coronary artery events. Figure 1 indicates that anFIGURE 1 Results of randomized studies of the effects of a diet high in trans fatty acids (circles) or saturated fatty acids (squares) on the ratio of LDLcholesterol to HDL cholesterol. A diet with isocaloric amounts of cis fatty acids was used as the comparison group. The solid line indicates the best-fitregression for trans fatty acids. The dashed line indicates the best-fit regression for saturated fatty acids. (From Ascherio, A., Katan, M.B., Zock, P.L., et al.,Trans fatty acids and coronary heart disease, N. Engl. J. Med., 340, 1994–1997, 1999. With permission.)

310DIETS AND HEART DISEASEabsolute increase in 2% intake of trans fatty acid isexpected to raise the ratio of LDL to HDL cholesterol by0.1 unit; a 1-unit increase in this ratio is associated with a53% increase in the risk of CAD. The intake of 2% ofcalories from trans fatty acids would be predicted to causea substantial number of cardiac deaths in United States.Canadians are among the world’s biggest consumers oftrans fat, consuming an average of 10 g daily.Trans fatty acids also increase Lp(a)-protein levels thathave been associated with an increased risk of CAD. Inaddition, these acids raise triglyceride levels, so that theentire spectrum of lipid levels in the blood is high enoughto be considered a significant dyslipidemia (see the chapterDyslipidemia).D. Foods Containing Trans Fatty AcidsTrans fatty acids are present in:1. Solid fats produced by part hydrogenation of oils.2. Natural products originating from ruminant, cudchewinganimals. Importantly, milk contains virtuallyno trans fat.3. Commercially baked products and fast foods, forexample, a large order of french fries contains 3.68 gof trans fatty acids and one doughnut contains 3.2 g(see Table 1).A change in eating habits is necessary, particularly, inNorth America. Unfortunately manufacturers who producefoods high in trans fatty acids are not requested to includethe content in food labels. Even foods labeled cholesterolfreeand cooked in vegetable oil may have a high content oftrans fatty acids. Both stringent labeling and publiceducation should be required.III. DIET–DRUG VALVULOPATHYA. Anorectic AgentsObesity is a risk factor for CAD, diabetes, and hypertension.Weight-reduction diets assist less than 25% of obeseindividuals; a return of weight gain is common, oftenwithin months of ending the diet that is difficult to adhereto for several years. For the past 50 years drugs have beensought to decrease appetite and food intake that results insignificant weight loss. Most anorectic agents disappearfrom the market after 1–5 years because of adverse effectsand adverse publicity. The drug phentermine (phen-fen)was approved in United States in 1959. This noradrenergicagent was soon lost. Fenfluramine, a sympathomimeticamine that activates the serotonergic pathways in thebrain to induce its anorectic effects, and fenfluramine, theD-isomer of fenfluramine, were approved in 1973 and1996, respectively. The combination of fenfluramine andphentermine appeared more efficacious than monotherapy,and it was widely prescribed from 1995 to 1998 to about4.6 million individuals in the United States.TABLE 1Trans Fatty Acid Content of Some Popular Processed FoodsPrepared in Restaurants and Fast Food Outlets (any servingcontaining >0.5 g is considered excessive)ProductServing sizeTrans fattyacid (g/serving)Buttered popcorn 4 cups 5Chicken fingers One chicken finger 8Chicken wings 10 wings 10Cinnamon roll One roll 4Bran muffin One muffin 0.5Fried clams One clam 10Fried onion rings One serving with18dipping sauceFrench fries One 5Frozen fish (batter) One serving 2.5Hash browns One order 8Large hamburger One 4Waffles Two 21. Reasons for Withdrawal from the MarketReports in 1997 indicated that a few patients taking thedaily combination of fenfluramine and phentermine forseveral months developed pulmonary hypertension andvalvular defects such as aortic and mitral regurgitation.These valves were noted to be diffusely thickened andincompetent (regurgitant or leaky valves). Also, thehistologic findings appeared to be identical to valvulardamage observed in carcinoid syndrome where serotonin isresponsible for the valve damage. In carcinoid syndromethe valve lesions are usually on the right side of the heart,however, the lesions from the diet drugs included theaortic and mitral valves which are on the left side of theheart (see the chapter Carcinoid Heart Disease).Although only 24 patients were reported in 1997 byone group, a survey of five sites using echocardiographicevaluation found significant valve regurgitation in approximately1% of patients treated with a combination. Thesedrugs were withdrawn from the market in 1997.

IV. FISH OILS311Further studies indicated an incidence of this type ofvalvulopathy occurred in 7.1 of 10,000 patients treated forless than 4 months and 35 of 10,000 patients treated forgreater than 4 months. In one study of 1163 individualstreated with a combination a mild grade of aorticregurgitation was present in 8.8% of treated versus 2.6of control patients ( p < 0.01). Lesions of the valves wereworse in patients taking the combination for more than 6months. It appears, therefore, that there was about a 5.2%increase in prevalence of significant aortic regurgitation inthe drug-treated patients.Nearly all patients with valvular lesions who discontinuedthe drugs had no progression of lesions and someeven showed signs of regression. Only one of the originalpatients described required valve surgery.B. Perspective and Research ImplicationsThe problems that afflict overweight individuals will notdisappear. In fact the prevalence of obesity is increasingand becoming an insurmountable problem in NorthAmerica. There must be a continued search for anorecticdrugs that are as important for millions of individuals asthe elixir of life. Researchers should be able to find suitableagents that are devoid of cardiac or cardiovascular sideeffects. It is obvious that agents that involve the serotoninpathway would be expected to cause cardiac lesions. Thisis a fruitful area of research that can help millions ofindividuals worldwide.IV. FISH OILSThe low mortality from coronary heart disease in GreenlandInuit is attributed to their intake of more than 350 gper day of whale and seal meat. In Japan, the incidence ofcoronary heart disease is much lower in areas where fishconsumption is high, but the alpha-linolenic acid insoybeans and other products may be responsible for theirlow mortality from heart disease.Fatty fish contains omega n-3 fatty acids representedmainly by eicosapentaenoic and docosahexaenoic acids.These agents have an aspirin-like effect that prevents bloodplatelets from clumping together; this action prevents clotformation. They also have other beneficial effects on thewalls of the arteries.Nonetheless, studies of large populations in Norway andJapanese men in the Honolulu Heart Program showed nobeneficial effect of fish intake on cardiovascular disease.In contrast, however, a study in 872 men followed from1960–1980 showed a 40% reduction in the risk of deathfrom coronary heart disease in those who ate an average of70 g of fish a week compared with those who did not eatfish. The Western Electric Study of 1931 men followed for25 years showed some reduction in coronary heart diseasemortality in men eating approximately 60 g of fish perweek compared with those who ate no fish. Thesenonrandomized studies have many limitations, however,and may not answer questions adequately.In a small, randomized trial of diet in 2033 men whohad had a previous heart attack, it was found thatconsuming two servings of 200–400 g of fatty fish perweek for two years caused a significant reduction inmortality and nonfatal heart attacks. Because this clinicaltrial and other surveys show a positive trend for protectionfrom heart attacks, investigators concluded that it isadvisable for individuals over age 25 to eat two servings of175 g (6 oz) of fatty fish weekly. Individuals with a familyhistory of heart attacks before age 60 and those who havehad a heart attack should use this simple nondrugprotective regimen. Fatty fish include salmon, tuna,mackerel, cod, and herring. Any beneficial effect isobtained with one or two servings of fish per week andmore is not better.BIBLIOGRAPHYAppeldoorn, C. C. M., Bonnefoy, A., Lutters, B. C. H., Daenens, K.,van Berkel, T. J. C., Hoylaerts, M. F., Biessen, E. A. L. et al. Gallicacid antagonizes P-selectin – mediated platelet – leukocyte interactions:Implications for the French paradox. Circulation, 111:106–112, 2005.Ascherio, A., Katan, M., Zock, P. L. et al. Trans fatty acids and coronaryheart disease. N. Engl. J. Med., 340:1994–98, 1999.Ascherio, A., Rimm, E. N. B., Stampfer, M. J. et al. Dietary intake ofmarine n-3 fatty acids, fish intake, and the risk of coronary diseaseamong men. N. Engl. J. Med., 332:977, 1995.Dallongeville, J., Yarnell, J., Ducimetiere, P. et al. Fish consumption isassociated with lower heart rates.Circulation, 108:820–825, 2003.Dansinger, M. L., Gleason, J. A., Griffith, J. L. et al. Comparison of theAtkins, Ornish, Weight Watchers, and Zone Diets for weight loss andheart disease risk reduction: A randomized trial. JAMA, 293:43–53,2005.de Lorgeril, M., Renaud, S., Mamelle, N. et al. Mediterranean alphalinolenicacid-rich diet in secondary prevention of coronary heartdisease. Lancet, 343:1454, 1994.Eckel, R. H., York, D. A., Rössner, S. et al. Prevention conference VII:Obesity, a worldwide epidemic related to heart disease and stroke:Executive summary. Circulation, 110:2968–2975, 2004.Foster, G. D., Wyatt, H. R., Hill, J. O. et al. A randomized trial of a lowcarbohydrate diet for obesity. N. Engl. J. Med., 348:2082–90, 2003.Katz, D. L., Evans, M. A., Nawaz, H., Njike, V. Y., Chan, W.,Comerford, B. P., Hoxley, M. L. et al. Egg consumption andendothelial function: a randomized controlled crossover trial. Int. J.Car., 99:65–70, 2005.Klein, S., Burke, L. E., Bray, G. A. et al. Clinical implications of obesitywith specific focus on cardiovascular disease: A statement forprofessionals from the American Heart Association Council on

312DIETS AND HEART DISEASEnutrition, physical activity, and metabolism: Endorsed by theAmerican College of Cardiology Foundation. Circulation, 110:2952–296, 2004.Knoops, K. T. B., de Groot, L. C. P. G. M., Kromhout, D. et al.Mediterranean diet, lifestyle factors, and 10-year mortality inelderly European men and women: The HALE Project. JAMA,292:1433–1439, 2004.Mann, J. I. Diet and risk of coronary heart disease and type II diabetes.Lancet, 360:73–88, 2002.Mozaffarian, D., Ascherio, A., Hu, F. B., Stampfer, M. J., Willett, W. C.,Siscovick, D. S., Rimm, E. B. et al. Interplay between differentpolyunsaturated fatty acids and risk of coronary heart disease in men.Circulation, 111:157–164, 2005.Mullis, R. M., Blair, S. N., Aronne, L. J. et al. Prevention conference VII:Obesity, a worldwide epidemic related to heart disease and stroke:Group IV: Prevention/Treatment. Circulation, 110:e484–e488, 2004.Murthy, T. H., and Weissman, N. J. Diet-Drug Valvulopathy. ACC Curr.J. Rev. Mar/Apr, 17–20, 2002.Oomen, C. M., Ocke, M. C., Fesken, E. J. M. et al. Association betweentrans fatty acid intake and 10-year risk of coronary heart disease in theZutphen Elderly Study: A prospective population based study. Lancet,357:746–51, 2001.Samaha,, F. F., Iqubal, N., Seshadri, P. et al. A low carbohydrate ascompared with a low fat diet in severe obesity. N. Engl. J. Med.,348:2074–81, 2003.Singh, R. B., Dubnov, G., Niaz, M. A. et al. Effects of an endoMediterranean diet on the question of coronary artery disease in highriskpatients (endo Mediterranean diet heart study): A randomizeddouble-blind trial. Lancet, 360:1455–1461, 2002.Szmitko, P. E., Verma, S. et al. Red wine and your heart. Circulation,111:e10–e11, 2005.Trichopoulou, A., Cistacou, T., Barmia, C. et al. Adherence to aMediterranean diet and survival in a Greek population. N. Engl. J.Med., 348:2599–608, 2003.Zitron, E., Scholz, E., Owen, R. W., Lück, S., Kiesecker, C.,Thomas, D., Kathöfer, S., Niroomand, F., Kiehn, J., Kreye, V.A.W., Katus, H. A., Schoels, W., Karle, C. A. et al. QTc prolongationby grapefruit juice and its potential pharmacological basis:HERG channel blockade by flavonoids. Circulation, 111:835–838,2005.

DiureticsI. IndicationsII. Renal PhysiologyIII. Individual Diureticsand in patients who have not responded adequately to oneof the three antihypertensive agents, beta-blockers, ACEinhibitors, or calcium antagonists.GLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.electrolytes sodium, potassium, calcium, and magnesiumlevels in the blood.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.gynecomastia enlargement of the breast, usually seen in men.hypertension high blood pressure.I. INDICATIONSA. HypertensionDiuretics, so-called water pills, are the most valuable,yet inexpensive agents of proven benefit for the managementof hypertension. These agents have been usedworldwide for more than 40 years and are still consideredby experts to be the first choice for the initial treatmentof hypertension. The World Health Organization (WHO)and the Joint National Committee (JNC) advise that adiuretic or a beta-blocker should be chosen as initialtherapy for most patients, except those with bronchialasthma in whom a beta-blocker is contraindicated.A diuretic is the drug of choice for the initial treatmentin individuals of African origin over age 60, because theseagents have been shown to be more effective than the threeother agents available for the management of hypertension.Diuretics are not as effective in the younger individuals ofAfrican origin. A diuretic is necessary for the managementof hypertension in patients with heart failure or edemaB. Heart FailureDiuretics, particularly loop diuretics such as furosemideand torsemide, are the mainstay of therapy for the millionsof patients with moderate-to-severe heart failure. Severeshortness of breath due to congestion of blood withretention of salt and water in the lungs is relieved bydiuretics. There is little or no benefit from the three majordrugs used for the optimal therapy of heart failure.Patients with severe heart failure graded as New YorkHeart Association class IV, and those with pulmonaryedema that causes life-threatening and distressing shortnessof breath with the patient at rest, attain immediate andsometimes temporary relief from these distressing symptomswith the administration of intravenous loop diuretics.In states of severe heart failure (class IV ), beta-blockingdrugs that are very beneficial in the management of class I–III heart failure are contraindicated and ACE inhibitorsdo not provide symptomatic relief.C. Edema Caused by Kidney or Liver DiseaseSome forms of kidney disease caused by nephrotic syndromediseases such as glomerulonephritis and diabeticnephropathy may cause considerable salt and water retentionand both legs may become swollen with pittingedema. This can be observed with finger pressure appliedto the legs. Fluid retention may be excessive and involvethe abdominal cavity (ascites). Similar accumulation offluid in the lower limbs and cavities of the body may occurin patients with cirrhosis.A combination of loop diuretics such as furosemidecombined with an aldosterone antagonist is usuallynecessary to elicit relief. An aldosterone antagonistis necessary as outlined in Section III.C.313

314DIURETICSII. RENAL PHYSIOLOGYFigure 1 is a diagrammatic representation of the nephron.It is important for readers to have some knowledge of thefluid and electrolyte balance of the body which ismaintained in a constant state by the automatic electronicfiltration system provided by the kidney. Each humankidney contains approximately one million nephrons. Eachnephron is a mini filter that includes a glomerulus thatcontains a group of capillary blood vessels. The primaryduty of the glomerulus is excretion of water and solutes.A considerable amount of sodium and water passes fromthe glomerulus into the renal tubule and then a substantialamount of sodium and water and other electrolytes mustbe reabsorbed into the circulation in correct proportionsto maintain the constancy of the body fluids. The primaryduty of the renal tubules are the retention and conservationof water and essential electrolytes such as sodiumand potassium. The tubules have a secretory function thatremoves a vast quantity of water from the tubules andreturns the fluid, sodium, potassium, and other electrolytesin correct proportions to the circulating blood. Thisnormal physiologic activity is inhibited by diuretics.The nephrons filter more than 180 liters daily (125 mlper minute). This volume of water passes into the tubulesand approximately 179 liters are reabsorbed daily withonly about 1–2 liters eliminated as urine. Without theintervention of the tubules between the glomeruli and the43Na +H +NaK75638glomerulusCl −Na13910Na +K2Cl −1141112cortexRenalMedula1415216FIGURE 1 The nephron and the site of action of diuretics. 1 ¼ single nephron; 2 ¼ the kidney 1 million nephrons; 3 ¼ distal tubule site of action ofaldosterone spironolactone and eplerenone; 4 ¼ amiloride and triamterene; 5 ¼ efferent arteriole; 6 ¼ macula densa; 7 ¼ glomerular capillaries;8 ¼ afferent arteriole; 9 ¼ thiazides; 10 ¼ loop diuretics; distal tubule 11 ¼ ascending limb; 12 ¼ loop of Henle; 13 ¼ collecting tubule; 14 ¼ to renal pelvis;15 ¼ to ureter; 16 ¼ bladder; * ¼ distal tubule: H 2 O reabsorption under control of vasopressin.

III. INDIVIDUAL DIURETICS315renal pelvis, which joins the ureter and the bladder, thewhole water and soluble constituents of the body would belost in less than 24 h. This situation occurs in conditionsthat cause obstruction of the tubules or renal tubularnecrosis.III. INDIVIDUAL DIURETICSThe generic and trade names of available diuretics aregiven in Table 1.A. Thiazides1. Mechanism of ActionFigure 1 shows a glomerulus and the four main sites ofthe renal tubules at which diuretics inhibit the reabsorptionof sodium and chloride. As the distal convolutedtubule of the nephron approaches the vicinity of theglomerulus, it comes in close proximity to the vascular poleof the structure. At this site for a short distance the afferentarteriole and distal convoluted tubule maintain contact (seesites 8 and 6 in Fig. 1). In this region the cells of the tubuleTABLE 1Generic and Trade Names of DiureticsGeneric name Trade name Tablets (mg)Usual maintenance(mg daily)Group I: ThiazidesChlorothiazide Diuril, Saluric 250, 500 500–1000Hydrochlorothiazide HydroDiuril, Hydrosaluric, Esidrix, 25, 50, 100 12.5–25Esidrex, Oretic, Direma Aprinox,Bendrofluazide Aprinox, Berkozide, Centyl, Neo-NaClex 2.5, 5 2.5–5Bendroflumenthiazide Naturetin 2.5, 5, 10 2.5–10Benzthiazide Aquatag, Exna, Hydrex 50 50–100Cyclothiazide Ahydron 2 2Hydroflumenthiazide Diucardin, Hydrenox, Saluron 50 50Chlorthalidone Hygroton 25, 50, 100 25–50Methyloclothiazide Enduron, Aquatensen, Diutensen-R 2.5, 5 2.5–5Polythiazide Renese, Nephril 1, 2, 4 0.5–4Trichlormethiazide Naqua, Metahydrin 2, 4 2–4Cyclopenthiazide Navidrex, Navidrix 0.5 0.5–1Metolazone Zaroxolyn, Metenix 2.5, 5, 10 2.5–5Quinethazone Aquamox, Hydromox 50 50–100Indapamide Lozol, Natrilix, Lozide (C) 2.5 2.5Group II: Loop diureticsFurosemide, Lasix, Dryptal, 20, 40, 80, 500 40–120Frusemide (UK) Frusetic, FrusidEthacrynic acid Edecrin 25, 50 50–150Bumetanide Burinex, Bumex 0.5, 1, 5 1–2Piretanide Arlix 6 (capsule) 6–12Torsemide Demadex 5, 10, 20, 100 5–20Group III: K þ -sparing diureticsEplerenone Inspra 25 25–50Spironolactone Aldactone 25, 50 (UK), 100 25–100Triamterene Dyrenium, Dytac 50, 100 50–100Amiloride Midamor 5 5–10Group IVThiazide þ K þ -sparing Aldactazide, Dyazide, Moduretic, ModuretFrusemide þ K þ -sparing Frumil, Frusene LasorideGroup VAcetazolamide Diamox 250 —

316DIURETICSare more closely aggregated together than in other regionsand form a specialized structure, the macula densa. Herethe wall of the afferent arteriole is thickened and the cellscontain special granules that secrete renin. This region iscalled the juxtaglomerular complex.The macula densa appears to function as a peripheralreceptor in a feedback mechanism that influences bothrenin production in cells which are sensitive to sodiumiron concentration. These specialized cells respond toa local decrease in blood pressure to stimulate the release ofrenin. The rate of release of renin is inversely related tothe amount of sodium passing into the tubules and itsrate of transport into the tubular cells; thus, a decrease inblood pressure or decrease in sodium excretion caused bysalt depletion increases renin secretion. Renin release isalso increased by activity of renal sympathetic nerves andmediated by beta-adrenergic receptors. Catecholaminesreleased from the adrenal glands stimulates renin release.Renin release is inhibited mainly by high levels of aldosteroneand angiotensin. The electronic capacity of thekidney and its unique ability to maintain a constantsodium and potassium level in the circulating blood isa marvelous work of wonder.Thiazide diuretics inhibit the reabsorption ofsodium chloride in the early part of the distal tubulebeyond the ascending limb of the loop of Henle; this site isdistal to the active tubular site of loop diuretic action(Fig. 1). The loop diuretics have no action at the site atwhich thiazides inhibit sodium reabsorption. Thiazidesalso increase the active excretion of potassium in thedistal renal tubule, and this may cause hypokalemia. Thethiazides have a long duration of action, approximately12–24 h versus loop diuretics with a duration of 2–6 h.These diuretics, even at large doses, lose their beneficialeffects in patients who have renal failure with a serumcreatinine greater than 2 mg/dl (180 mol/L); fortunatelyloop diuretics are potent and retain their ability to blocksodium reabsorption in patients with severe renal failure.2. IndicationsThiazide diuretics are indicated mainly for the managementof hypertension. Their exact antihypertensivemechanism of action is unknown, but it is believed to berelated to a decrease in vascular volume, negative sodiumbalance, and arteriolar dilation that occurs on a chronicbasis which causes a decrease in total peripheral resistance.A decrease in total peripheral vascular resistance causesa fall in blood pressure. Thiazides are not used inthe management of heart failure, but they are oftencombined with a potassium-sparing diuretic to preventpotassium loss.3. Adverse EffectsContraindications include hypersensitivity to thiazides orsulfonamides, acute and severe renal failure, pregnancyand breast-feeding, or concomitant use of lithium. Othercontraindications include dehydration and electrolyteimbalance with hypokalemia and hyponatremia. Patientswith an increase in uric acid with the precipitation ofpainful joints and gout should not be administered thiazides.Latent diabetes may be increased. Cardiac arrhythmiasmay occur because of the possibility of serumpotassium and magnesium imbalance.B. Loop Diuretics — FurosemideFurosemide is a well-known loop diuretic used worldwidesince the 1960s. Other loop diuretics such as bumetanideand torsemide have similar actions, indications, andadverse effects.1. Mechanism of ActionLoop diuretics inhibit the sodium/potassium/chloridetransport system of the luminal membrane in thethick ascending limb of the loop of Henle (Fig. 1); thusthey block chloride reabsorption at the site whereapproximately 40% of filtered sodium is normallyreabsorbed. Loop diuretics also inhibit calcium, potassium,and magnesium reabsorption in the loop where approximately25% of filtered potassium, 25% of calcium, and65% of magnesium are normally reabsorbed.2. IndicationsIntravenous furosemide at doses of 40–120 mg dramaticallyimproves severe shortness of breath caused bypulmonary edema in which there is congestion of thelungs where blood and fluid accumulates in the normallydry air sacs. Pulmonary edema is caused by left ventricularfailure. There are several million individuals in NorthAmerica with heart failure who must take between 40 to80 mg of furosemide to prevent bothersome shortnessof breath and fluid accumulation in the lungs and legs.Loop diuretics are indicated to remove extra fluidfrom the body in patients with renal failure as thiazidediuretics become ineffective in with these patients.3. Adverse EffectsThese are similar to the adverse effects described forthiazides, but severe hypokalemia commonly occurs when

III. INDIVIDUAL DIURETICS317high doses of furosemide must be used. The interactionsmay occur with a concomitant use of cephalosporinor aminoglycoside antibiotics such as gentamicin. Thedecreased sodium reabsorption in the proximal tubulescauses increased reabsorption of lithium which maycontribute to lithium toxicity.C. Aldosterone Antagonists/Potassium-SparingDiureticsThese agents include spironolactone, eplerenone, amiloride,and triamterene. These weak diuretics are often usedin combination with thiazides strengthening their rolein the management of hypertension and assuming a newrole in the management of heart failure. They appearto decrease the incidence of serious ventricular arrhythmiasin patients with heart failure and hypertension. Spironolactonehas a positive inotropic effect that is independentand additive to that of digoxin, and the drug increasesstroke volume.1. Spironolactonea. Mechanism of ActionIncreased renin release from the juxtaglomerular cells iscaused by several conditions: reduction in renal blood flowfrom heart failure, blood loss, hypotension or ischemia ofthe kidneys, sodium diuresis (excessive sodium loss inurine), and beta-adrenergic stimulation. Renin convertsliver angiotensinogen to angiotensin I. Angiotensin IIstimulates adrenal aldosterone production. An increase inaldosterone secretion occurs mainly in heart failure.Aldosterone causes reabsorption of sodium and waterin the tubules distal to the region of the macula densa,which appear to sense and monitor sodium concentrationat that point in the tubules. Aldosterone antagonists orinhibitors retain potassium in exchange for eliminationof sodium. Because most of the sodium and waterreabsorption occurs in the proximal tubule and in theloop of Henle, the exchange of sodium and potassium thatoccurs beyond the macula densa is very small but crucialto the maintenance of normal levels of sodium andpotassium in the blood.Spironolactone 25 mg added to ACE inhibitors inpatients with heart failure causes a more complete blockof the aldosterone production than is achieved solely withACE inhibition. A randomized clinical trial (RALES) hasbeen shown to decrease mortality and morbidity inpatients with heart failure. The beneficial effects arerelated not only to sodium loss but also to a decreasein cardiac fibrosis and increased production of the dilatornitric oxide. It appears that aldosterone has deleteriousfibrinogen properties and spironolactone may adversesome of these.Another side effect is gynecomastia, which is sometimesbothersome. An analog of spironolactone, eplerenone,has been shown in a recent large randomized clinical trialin patients with acute myocardial infarction complicatedby heart failure or left ventricular dysfunction to significantlyreduce mortality and morbidity (see discussionbelow and in the chapter Heart Failure).2. Amiloride and TriamtereneThese agents inhibit the sodium proton exchanger,which causes sodium reabsorption in the distal tubules.They act with lumen membrane transporters to preventurinary sodium entry into the cytoplasm. They are directinhibitors of potassium secretion; thus, potassium loss isindirectly decreased. The loss of sodium is achievedwithout a loss of magnesium. These agents act beyondthe activity of aldosterone and are strictly not directaldosterone antagonists. Triamterene and amiloride areweak diuretics and are most often used in combinationwith a thiazide to enhance the effectiveness of thiazidesand also to prevent hypokalemia.a. Adverse EffectsThe most common side effect is a marked and dangerouselevation of serum potassium (hyperkalemia) with a serumpotassium of 5.5 or greater than 6.0 mEq/L. This occursin patients with renal failure, a condition in which thekidney fails to excrete potassium. It also occurs in patientson ACE inhibitors that retain potassium and saltsubstitutes, which contain potassium in place of sodium.These agents should not be used in patients with mildrenal failure and in patients with a serum creatinine greaterthan 1.3 mg/dl (115 mol/L), which may indicate thepresence of renal dysfunction. Some patients with type 2diabetes may have hyporeninemic hypoaldosteronism andhyperkalemia may ensue with these agents.Megaloblastic anemia has been rarely seen with triamtereneand with amiloride and it has been associated withthe occurrence of aplastic anemia, albeit rarely. Spironolactonedoes not have these serious adverse effects butcauses bothersome gynecomastia.3. EplerenoneThis selective aldosterone blocker has been shown toprovide the same clinical benefits as spironolactone, but

318DIURETICSwith a mild decrease in the incidence of two mainadverse effects: gynecomastia and hyperkalemia. In theeplerenone post myocardial infarction and heart failureefficacy and survival study (EPHESUS), 6632 patientswho were 3–14 days post acute myocardial infarctionwith an ejection fraction of less than 40% with heartfailure and diabetes were randomized. Patients with aserum creatinine greater than 2.5 mg/dl (220 mol/L) orserum potassium greater than 5 mmol/L were excluded. Atone-year follow up eplerenone-treated patients had an allcausemortality of 14.45% versus 16.7% for spironolactone-treatedpatients (one life saved for every 100 patientstreated). But eplerenone-treated patients had slightlyand significantly higher rates of worsening renalfunction (creatinine increased 0.06 mg/dl vs. 0.02 mg/dl)and of serious hyperkalemia (5. 5% vs. 3.9%). Becauseeplerenone was not shown to be significantly moreeffective than spironolactone, the drug may not replacethe well-known spironolactone, except in men whoshow early signs of gynecomastia. Eplerenone has beenshown to be as effective as losartan in reducing bloodpressure in patients with high plasma renin activity andmore effective than losartan in patients with low plasmarenin activity.BIBLIOGRAPHYBloomfield, D. M., Steinman, R. C., Namerow, P. B. et al. MicrovoltT-wave alternans distinguishes between patients likely and patientsnot likely to benefit from implanted cardiac defibrillator therapy:A solution to the Multicenter Automatic Defibrillator ImplantationTrial (MADIT) II Conundrum. Circulation, 110:1885–1889, 2004.Flack, J. M., Oparil, S., Pratt, H. et al. Efficacy and tolerability ofeplerenone and losartan in hypertensive black and white patients.J. Am Coll. Cardiol., 41:1148–55, 2003.Khan, M. Gabriel Cardiac Drug Therapy, 6th edition. W. B. Saunders,Philadelphia, 2003, p. 103.Pitt, B., Remme, W., Zannad, F. et al. Eplerenone, a selectivealdosterone blocker in patients with left ventricular dysfunctionafter myocardial infarction. N. Engl. J. Med., 348:1309–21,2003.Rousseau, M. F., Gurne, O., Duprez, D. et al. Beneficial neurohormonalprofile of spironolactone in severe congestive heart failure. J. Am. Coll.Cardiol., 40:1596, 2002.

Down SyndromeI. GeneticsII. Incidence of Congenital Heart Malformationsits postnatal frequency. The risk rises steeply after age 35reaching 4% for women older than 44.GLOSSARYatrial septal defect a hole in the wall of the heart (septum) thatdivides the left and right atrium.ventricular septal defect a hole in the septum, that divides theleft and right ventricles.I. GENETICSDown syndrome, trisomy 21 is the most common chromosomeabnormality and occurs in approximately 1 inevery 650 births. It alone accounts for 1 in 20 congenitalcardiac malformations. In virtually all individuals withDown syndrome 47 chromosomes are found with anextra copy of chromosome 21 (trisomy 21), although inapproximately 3% of individuals it may originate froman extra copy of all or part of the long arm of chromosome21 translocated to another chromosome. The recurrencerisk is approximately 1% after a child with trisomy 21,and the recurrence is higher if one of the parents carriesa translocation.Increasing maternal age increases the incidence of Downsyndrome and prenatal screening has led to a reduction inII. INCIDENCE OF CONGENITAL HEARTMALFORMATIONSCongenital heart disease occurs in more than 40% ofpatients with Down syndrome. Malformations includeatrioventricular septal defects and approximately 33%of all atrioventricular septal defects are associated withDown syndrome. This congenital defect is referred to asan endocardial cushion defect or atrioventricular canalmalformation which results from a defective closure ofthe endocardial cushions. These are a group of abnormalitiesunified because of a complete absence of normalatrioventricular septal structures. This is a much morecomplicated lesion than the more common atrial septaldefect and is much more difficult to repair surgically.For more information about atrial septal defects see thechapters Atrial Septal Defect and Embryology. To learnmore about ventricular septal defects see the chapterCongenital Heart Disease.BIBLIOGRAPHYPyeritz, R. E. Genetics and cardiovascular diseases. In Heart Disease, sixthedition. E. Braunwald, D. P. Zipes, and P. Libby, eds. W. B. Saunders,Philadelphia, 2001.319

DyslipidemiaI. LipoproteinsGLOSSARYcoronary artery disease same as coronary heart disease; obstructionof the coronary arteries with symptoms such as chest pain,angina, or heart attacks.hypercholesterolemia elevated cholesterol level.hypertriglyceridemia elevated triglyceride level.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.DYSLIPIDEMIA IS THE TERM MOST FREQUENTLY USEDto describe blood lipid abnormalities. Hyperlipidemia,hyperlipoproteinemia, or dyslipoproteinemia are all termsused worldwide to describe dyslipidemia. Hypercholesterolemiadescribes the elevation of total blood cholesteroland hyperlipidemia describes elevation of a total cholesteroland LDL cholesterol. In the past decade theimportance of the smaller HDL cholesterol particle hasreceived much attention, because a very low HDL cholesterolcarries a risk for coronary artery disease even whenthe total cholesterol and LDL cholesterol are relativelynormal.I. LIPOPROTEINSA. SizeThe relative size of plasma lipoproteins according to theirhydrated density is shown in Fig. 1. Hydrophobic lipids(cholesterol, cholesteryl esters, phospholipids, and triglycerides)are transported in the blood by lipoproteinparticles, which are complex water-soluble particles thatprovide water-soluble transport packages.B. FunctionLipoproteins provide a transport for lipids as describedbelow.1. Transport of cholesterol to organs and tissues; cholesterolis required for the formation of membranes of redblood cells and for the production of steroid hormones.In the liver it is converted to bile acids.2. Triglycerides absorbed from the intestine are carriedto the liver and other sites of utilization and storage.3. Dietary fatty acids are transported.4. Food fats are absorbed as fatty acids and packagedinto very large lipoproteins called the chylomicrons.These are released from the gut into the portal systemof veins that transport blood from the gut to the liver(see Fig. 2).C. TypesThe major circulating lipoproteins are1. Chylomicron remnants that have a diameter greaterthan 300 nm and are rapidly cleared from thecirculation.2. Very low density lipoproteins (VLDLs) that carrytriglycerides and have a particle diameter between 300and 800 nm.3. Low density lipoproteins (LDLs) that carry most of thecirculating cholesterol and cholesteryl ester and havea particle diameter of 180–280 nm and a density of1.019–1.063 (Fig. 1).4. High density lipoproteins (HDLs) that mainly carrycholesteryl ester; this small particle with diameter50–90 nm has a high density of 1.063–1.210 g/ml.5. Lipoprotein(a) is an LDL-like particle that is linkedby a disulfhydryl group to a large hydrophilic glycoproteintermed apo(a); recently this particle has beenlinked to the presence and severity of atherosclerosis,but at present it is not considered to be as important as321

322DYSLIPIDEMIAChylomicron0.95ChylomicronVLDL1.006IDLDensity (g/ml)1.02LDLChylomicronremnant1.061.101.20HDL 3HDL 25 10 20 40 60 80 1000Diameter (nm)FIGURE 1 Relative size of plasma lipoproteins according to their hydrated density. (From Ridker, P.M., Genest, J., and Libby, P. (2001). Risk Factors forAtherosclerotic Disease. Heart Disease, 6 th ed., Braunwald, E., Zipes, D.P., and Libby, P., Eds., Philadelphia: W.B. Saunders, p. 1012. With permission.)2FFA1LPLChylomicronChylomicronremnant3LiverApo A-I, A-IIApo C-I, C-II, C-IIIPhospholipidsFree cholesterol 8FreecholesterolHL, EL610PeripheralcellsSteroidogeniccells7IntestinalPathway5NascentHDLLCATApo A-I, A-IIApo C-I, C-II, C-IIIPhospholipidsFree cholesterolTriglyceridesCETPPLTPHDL 39HDL 2Liver7LDLHepaticPathway4VLDLLPL2IDLCholesteryl esters3HL6FFAFIGURE 2 Schematic diagram of the lipid transport system. Apo ¼ apolipoprotein; LPL ¼ lipoprotein lipase; HL ¼ hepatic lipase; CETP ¼ cholesterylester transfer protein; LCAT ¼ lecithin cholesterol acl transferase; FFA ¼ free fatty acids; numbers are keyed to explanations in the text. (From Ridker, P.M.,Genest, J., and Libby, P. (2001). Risk Factors for Atherosclerotic Disease. Heart Disease, 6 th ed., Braunwald, E., Zipes, D.P., and Libby, P., Eds., Philadelphia:W.B. Saunders, p. 1015. With permission.)

I. LIPOPROTEINS323LDL cholesterol in the genesis of atherosclerosis andcoronary risk.D. AbnormalitiesDyslipidemias are abnormalities of lipoprotein metabolism.These abnormalities may be caused by geneticdisturbances (primary dyslipidemias) or by certain welldefineddiseases that are termed secondary dyslipidemias.Figures 3 and 4 show causes of primary and secondarydyslipidemias.1. HypertriglyceridemiaNormal blood levels of triglyceride range from 40 to200 mg/dl (0.45–2.25 mmol/L). The role of elevated bloodtriglycerides as an independent risk factor for coronaryartery disease remains controversial. Chemical determinationof triglyceride levels lacks precision, and intervariabilityand intravariability in measurements are substantial.Most important, hypertriglyceridemia occurs after severalclinical conditions without a predictable impact on coronaryartery disease risk. Hypertriglyceridemia is often associatedwith a low HDL cholesterol, however, and a lowHDL cholesterol increases coronary risk. Not all epidemiologicstudies have described an association betweenhypertriglyceridemia and coronary risk. A meta-analysisdone of six studies of fasting triglycerides and subsequentcardiovascular events in 10,000 women and 46,000 menestimated 37 and 14% increases in risk of coronary arteryHypercholesterolemia–heterozygous familial–homozygous familial very rare–polygenicdisease in women and men, respectively, for everymmol/L increase in triglyceride level, after adjustmentfor the HDL concentration. Thus it appears that in womenolder than age 50 hypertriglyceridemia confers a riskfor coronary artery disease. Figure 4 indicates that hypertriglyceridemiais commonly associated with diabetes,obesity, and alcohol abuse, all of which are commonconditions in the population at large older than 50 years(see the chapter Diabetes and Cardiovascular Disease).Hypertriglyceridemia may rarely occur in families withFrederickson type III, IV, and V hyperlipoproteinemia.In these rare conditions triglyceride levels are markedlyelevated (500–2000 mg/dl) and may cause pancreatitis.Hypertriglyceridemia greater than 500 mg/dl causes nosymptoms; however, symptoms may be caused by theunderlying disease.The treatment and correction of hypertriglyceridemiais usually not difficult, except in severe elevations thatoccur in familial disease. Fortunately this is rare and thiscondition responds dramatically to weight loss and exerciseand may be completely reversed so that medications areusually not necessary. This is in contrast to hypercholesterolemia,which unfortunately is not reduced by exerciseand weight loss. Hypertriglyceridemia associated withdiabetes is often associated with a low HDL cholesteroland mild elevation of total cholesterol. In this situationmedications are usually necessary because diabetics are athigh risk for coronary artery disease events. In patientswhere the cause of increased triglyceride levels is due toalcohol abuse, cessation of alcohol consumption causesnearly complete correction of the problem.When medications are required fibrates such as fenofibrate(Lipidil Supra) produce about a 33% lowering oftriglyceride levels. With this agent combined with weightreduction and exercise the abnormality can be corrected.FIGURE 3Primary combined hyperlipidemia–familial combined hyperlipidemia–type III* hyperlipidemiaHypertriglyceridemia–familial hypertriglyceridemia(*type IV or V)–familial chylomicronemia–lipoprotein lipase deficiencyHDL-cholesterol disorders–familial hypoalpha lipoproteinemia–lecithin: cholesterol acl transferasedeficiency–familial apo A-1/C-III deficiency–Tangier disease [fish-eye disease]Primary dyslipidemias.2. HypercholesterolemiaHypercholesterolemia is common in the western worldand in the European population. A heterozygous familialentity occurs with markedly elevated cholesterol levels(400–1200 mg/dl) and HDL cholesterol levels with agene frequency of approximately 1 in 500 individuals. Thisdisorder is one of the more common genetic abnormalitiesin Caucasians in the United States. These patients havea reduction of 50% of the circulating LDL receptors,which results in an approximate doubling of LDL cholesterolblood levels. Men with this condition usually developsignificant and severe coronary artery disease by the thirdand fourth decade and in women about 7–10 years later.Obstruction by atheromatous plaques may occur in other

324DYSLIPIDEMIALevelsCholesterol LDL HDL TriglycerideDiabetesHypothyroidism±−Kidney disease–nephrotic syndrome–glomerulo nephritis–chronic renal failureLiver disease–biliary cirrhosis–cirrhosis–obstructive jaundice±±±±±−−−−−Alcohol abuseObesityDietary–High saturatedfat + trans fattyacid intake± ±±± ±FIGURE 4Secondary dyslipidemias.Medications–HIV protease inhibitors–thiazide diuretic–Beta blockers(variable)–Retinoids–Corticosteroids−±±−±±±±±±arteries including the abdominal aorta that supplies thelegs with blood. The homozygous form of this disorderfortunately is very rare, 1 per million persons, andmyocardial infarction has been noted in infants.In the general population elevations in the range of220–300 mg/dl are associated with heart attacks. The maincauses for this disorder are high intake of saturated fats andtrans fatty acids, obesity, and a mild decrease in LDLreceptors that mop up cholesterol from the blood. Othercauses of dyslipidemias (secondary) are given in Fig. 4.For further discussion of hypercholesterolemia and HDLcholesterol, see the chapter Cholesterol.E. Drug Management1. StatinsThe management of dyslipidemias has been revolutionizedsince 1987 with the advent of therapy with statins. Formore than 30 years prior to their use controversies ragedas to whether an elevated blood cholesterol was the causeof heart attacks and whether this elevation increased therisk for the development of significant coronary arterydisease manifested by angina or heart attacks.The statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA), thekey enzyme catabolizing the early rate-limiting step in thebiosynthesis of cholesterol within the hepatocyte. Loweringof intracellular cholesterol results in an increase in thenumber receptors on the hepatocyte through the process ofregulation, which results in increased levels of circulatingLDL cholesterol and a decrease in total serum cholesterollevels. The statins are currently the most potent, welltoleratedcholesterol agents available. They are capable ofcausing a 20–40% decrease in total and LDL cholesterollevels.a. Clinical StudiesThe hallmark Scandinavian Simvastatin Survival Study(4S) indicates that long-term treatment for simvastatin issafe and improves survival in patients with coronary arterydisease. A total of 4444 patients with angina or previousheart attacks and a total cholesterol 5.5–8 mmol/L were

I. LIPOPROTEINS325randomized to a double-blind treatment with simvastatinor placebo. All patients followed a lipid-lowering diet.Over the 5.4 years and median follow up there were 189cardiac deaths in the placebo group and 111 in thesimvastatin (relative risk ¼ 0.58). The number of noncardiovasculardeaths was similar in both groups. Thetreatment group had a 37% reduction in the risk ofundergoing revascularization. Long-term simvastatin therapywas associated with a 25% decrease in cholesterol,35% reduction in LDL cholesterol, and an 8% increasein HDL cholesterol. In this study 79% of patients had ahistory of previous heart attack.b. Individuals StatinsThe major differences between the five available statinsrelates to their metabolism in the liver and cytochromeP50 enzymes (atorvastatin, fluvastatin, lovastatin, andsimvastatin) and the hydrophilic agents (pravastatin androsuvastatin) that are eliminated virtually unchanged inthe kidney. The agents that use cytochrome P50 pathwaysmay exhibit interactions when used concomitantly withagents such as erythromycin, clarithromycin, azithromycin,cimetidine, and grapefruit juice.Rosuvastatin, released in 2003, appears to be morepowerful than the potent atorvastatin in reducing LDLcholesterol levels. Additionally, it causes a modest decreasein triglyceride levels and an increase in HDL levels.Further discussion of statins and a table giving thegeneric and trade names of these agents is given in thechapter Cholesterol.Patients at high risk: acute coronary syndrome, shouldachieve LDL goal of less than 80 mg/dl (2 mmol/l) andCRP levels lowered to normal regardless of LDL levels.Ridker et al. indicate that CRP monitoring should beused in patients with acute coronary syndrome to assessrisk; patients who have low CRP levels after statintherapy appear to have better clinical outcomes thanthose with higher CRP levels regardless of the level of LDLachieved.2. FibratesThe first fibrate introduced worldwide for clinical use inthe 1960s, clofibrate, was abandoned after about 10 yearsbecause of minor adverse effects and no appreciable effecton coronary artery disease mortality.a. GemfibrozilThis agent is a chemical homolog of clofibrate and differssomewhat in mechanism of action and therapeutic effect.Gemfibrozil decreases production of very low densitylipoprotein triglycerides and enhances its clearance.It causes about a 40% reduction in the level of triglycerides,and a 10% increase in HDL cholesterol concentration,but unfortunately as with newer fibrates, ithas a negligible effect on lowering total serum cholesteroland LDL blood levels.b. Bezafibrate and FenofibrateThese agents are more effective than gemfibrozil andhave less adverse effects. Long-acting, once-daily formulationsare also available. Micro-coated fenofibrate (LipidilSupra) 100 and 160 mg once daily are effective formulationsthat are useful in diabetics with dyslipidemiaaccompanied by elevations of triglycerides, low HDLcholesterol, and minimal elevations of LDL cholesterol(see the chapter Diabetes and Cardiovascular Disease).These agents have been shown to cause reduced progressionand some regression of obstructive atherosclerosisin coronary arteries as measured by angiographic studies.The reduction in mortality caused by these drugs appearsto be less than that observed with statins.3. Cholesterol Absorption Inhibitorsa. Ezetimibe (Zetia; Ezetrol)This agent is the first of a new class of cholesterolabsorptioninhibitors with demonstrated clinical benefitsin lipid lowering. This drug localizes to the brush borderof the small intestinal enterocyte and inhibits enterocytecholesterol uptake and absorption. It further inhibitsintestinal cholesterol uptake and absorption prior tocholesterol reaching acetyl-CoA-acyltransferase (ACAT)and therefore is not an ACAT inhibitor. A dose of 5–10 mgreduces LDL cholesterol by 16 and 18%, respectively.The major advantage of this new agent is that it canbe combined with a statin without the risk of severe muscledamage and kidney failure, whereas the combination offibrates with statins may cause serious adverse effects,albeit rarely. Coadministration of ezetimibe (10 mg) andsimvastatin (40 mg) causes a mean LDL cholesterollowering of approximately 50%. Although ezetimibe wasdeveloped as a single agent, it will find a role in thearmamentarium for the management of dyslipidemiaswhen combined with a statin or a fibrate. Most important,in all of the reported studies, the agent has been verywell tolerated, either alone or in combination. A usefulcombination of simvastatin and ezetimibe (Vytorin) isavailable.

326DYSLIPIDEMIA4. Bile Acid Sequestrant Resinsa. CholestyramineThis agent has been available since the early 1970s. It wasrarely used by doctors and patients because of poorcompliance. The gritty taste and gastrointestinal sideeffects with only an approximate 10% reduction in cholesteroland elevation of triglycerides render this agentunsuitable for control of dyslipidemias.b. ColesevalemThis agent is a new formulation of the bile acid bindingresins introduced for use in 2002. The 4.5-mg dose hasbeen shown to reduce LDL cholesterol by 18% and thecombination of 2.3 g of the agent with 20 mg ofsimvastatin reduced LDL cholesterol by 42%, but itincreased triglycerides approximately 10%. Thus the drugis not advisable in patients with mixed dyslipidemias.Colesevalem is better tolerated than cholestyramine, but ina study of 240 patients adverse events were similar betweeneach of the groups. It may find a role in patients with purehypercholesterolemia and LDL elevation. This drug doesnot have a significant interaction with digoxin, lovastatin,metoprolol, quinidine, or warfarin as is noted withcholestyramine.5. New Agenta. TorcetrapibTorcetrapib increases HDL cholesterol 30 to 50%. Clinicaltrials are awaited. See chapter entitled Cholesterol.BIBLIOGRAPHYBoekholdt, S. M., Kuivenhoven, J. A., Wareham, N. J. et al. Theprospective EPIC (European Prospective Investigation into Cancer andnutrition)–Norfolk population study: Plasma levels of cholesterylester transfer protein and the risk of future coronary artery diseasein apparently healthy men and women. Circulation, 110:1418–1423,2004.CARE: The Cholesterol and Recurrent Events Trial Investigators: Theeffect of pravastatin on coronary events after myocardial infarction inpatients with average cholesterol levels. N. Engl. J. Med., 335:1001–9,1996.Davidson, M. H., McGarry, T., Bettis, R. et al. Ezetimibe coadministeredwith simvastatin in patients with primary hypercholesterolemia.J. Am. Coll. Cardiol., 40:2125–34, 2002.Durrington, P. Dyslipidemia. Lancet, 362:717–31, 2003.Executive summary of the Third Report of the National CholesterolEducation Program (NCEP) expert panel on detection, evaluation,and treatment of high blood cholesterol in adults (Adult TreatmentPanel III). JAMA, 85:2486–96, 2001.Gotto, A. M., and Brinton, E. A. Assessing the lower levels of highdensitylipoprotein cholesterol as the risk factor in coronary heartdisease. In a working group report and update. J. Am. Coll. Cardiol.,43:717–724, 2004.Graham, D. J., Staffa, J. A., Shatin, D. et al. Incidence of hospitalizedrhabdomyolysis in patients treated with lipid-lowering drugs. JAMA,292:2585–2590, 2004.Grundy, S. M. et al. Atherosclerosis imaging and the future of lipidmanagement. Circulation, 110:3509–3511, 2004.Heart Protection Study Collaborative Group. Effects of cholesterollowering with simvastatin on stroke and other major vascular eventsin 20,536 people with cerebrovascular disease or other high riskconditions. Lancet, 363:757–767, 2004.Hokanson, J. F., and Austin, M. A. Plasma triglyceride level is a risk factorfor cardiovascular disease independent of high density lipoproteincholesterol level: A meta-analysis of population based on respectivestudies. J. Cardiovasc. Risk, 3:213–19, 1996.Khan, M. G. Management of hyperlipidemias. In Cardiac Drug Therapy,sixth edition, W. B. Saunders, Philadelphia, 2003.LIPID: The long term intervention with pravastatin in ischaemic disease(LIPID) Study Group. Prevention of cardiovascular events and deathwith pravastatin in patients with coronary heart disease and a broadrange of initial cholesterol levels. N. Engl. J. Med., 339:1349–57,1998.Nissen, S. E., Tsunoda, T., Tuzcu, E. M. et al. Effect of recombinantApoA-I Milano on coronary atherosclerosis in patients with acutecoronary syndromes: A randomized controlled trial. JAMA,290:2292–2300, 2003.Nissen, S. E., Tuzcu, E. M., Schoenhagen, P. et al. For the reversal ofatherosclerosis with aggressive lipid lowering (REVERSAL) investigatorsstatin therapy, LDL cholesterol, C-reactive protein, and coronaryartery disease. N. Engl. J. Med., 352:29–38, 2005.Pietinen, P., and Huttunen, J. K. The dietary determinants of plasmahigh density lipoprotein cholesterol. Am. Heart J., 113:620–25, 1987.Ridker, P. M., Cannon, C. P., Morrow, D. et al. For the Pravastatin orAtorvastatin Evaluation and Infection Therapy–Thrombolysis inMyocardial Infarction 22 (PROVE IT–TIMI 22) Investigator:C-reactive protein levels and outcomes after statin therapy. N. Eng.J. Med., 352:20–28, 2005.Scandinavian simvastatin survival Study group: Randomized trial ofcholesterol lowering in 4444 patients with coronary heart disease:The Scandinavian simvastatin survival study (4S). Lancet, 344:1383,1994.Shepherd, J., Cobbe, S. M., Ford, I. et al. Prevention of coronary heartdisease with pravastatin in men with hypercholesterolemia. N. Engl.J. Med., 333:1301, 1995.Toth, P. P. et al. The ‘‘good cholesterol’’: High-density lipoprotein.Circulation, 111:e89-e91, 2005.Yonemura, A., Momiyama, Y., Zahi, A., Fayad, Z. A. et al. Effect oflipid-lowering therapy with atorvastatin on atherosclerotic aorticplaques detected by noninvasive magnetic resonance imaging. J. Am.Coll. Cardiol., 45:733-74, 2005.

EchocardiographyI. HistoricalII. InstrumentationIII. Echocardiographic ExaminationV. Research ImplicationsVI. New FrontiersGLOSSARYheart failure failure of the heart muscle to pump sufficientblood from the chambers into the aorta; inadequate supply ofblood reaches organs and tissues.hypokinesis decreased myocardial contraction usually caused bydamage and weakness of the heart muscle due to coronaryartery disease and cardiomyopathies.ischemia temporary lack of blood and oxygen to an area ofcells, for example, the heart muscle, usually due to severeobstruction of the artery supplying blood to this area of cells.mitral regurgitation the mitral valve remains open when itshould be completely shut; blood rushes backwards from theleft ventricle into the left atrium.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.I. HISTORICALThe Titanic disaster of 1912 lead the impetus for detectingstructures under the sea. In 1940 during World War IIultrasonic floor detectors were developed for trackingenemy submarines. In 1945 with the end of the war,attention was turned to imaging of body parts insteadof tracking submarines and technologic developmentsadvanced.A. W. D. KeidelIn 1950 this German investigator attempted to study theheart using ultrasound. He used transmission ultrasoundand obtained an acoustic shadow of the heart that variedwith cardiac volume.B. Inge Edler and Helmut HertzBeginning in 1953 Helmut Hertz, a physicist, borroweda sonar device from a local shipyard, and this led to anelectronic firm developing an ultrasonic reflectoscope.Hertz collaborated with Inge Edler, a cardiologist, inSweden. Dr. Edler became fascinated with echoes thatarose from the mitral valve leaflets and in 1960 at theEuropean Congress of Cardiology he presented a moviedepicting the mitral valve findings. He showed for the firsttime that cardiac ultrasound was capable of showing otherparts of the heart including the aortic valve and aorta. Thecardiac ultrasound was particularly effective in showingfluid in the pericardial sac (pericardial effusions). Dr. Edlerand Hertz are the recognized developers of cardiac ultrasound,but neither Hertz or Edler, who died in 2001,pursued this work after 1960.C. Jack Reid, John Wild, and Claude JoynerReid, an engineer, worked with Wild and used cardiacultrasound to study the heart. While completing his doctorateat Pennsylvania, Reid collaborated with Dr. Joyner,a radiologist, and duplicated Dr Edler’s observations ofmitral stenosis using cardiac ultrasound. The publicationof this work in the journal Circulation and the hosting ofthe instrument at the American Heart Association meetingin 1963 stimulated a vast number of investigators, and onein particular, Dr. Harvey Feigenbaum.D. Harvey FeigenbaumDr. Harvey Feigenbaum stated in an article publishedin the American College of Cardiology journal review inOctober 2001 that he was very disappointed when heviewed the instrument at the American Heart Association327

328ECHOCARDIOGRAPHYmeeting in 1963. But fortunately he placed the transduceron his chest and observed an echo coming from the backof his heart. He asked the salesperson what would happenif there was fluid behind the heart. The technician repliedthat fluid should be echo-free. Dr. Feigenbaum askedwhether the instrument could detect pericardial effusions,but the salesperson did not know. This answer sparkedDr. Feigenbaum’s interest enough to continue studyingthis technology.Dr. Feigenbaum states that he borrowed an echographfrom his neurology colleagues. The echograph was usedfor detecting the midline structures of the brain. With thisequipment he was able to record the echo from the backof the heart. He then selected a patient with a pericardialeffusion and as predicted, he located the echo-free space.Dr. Feigenbaum confirmed the detection of pericardialeffusions in dogs. In the 2001 article ‘‘History of Echocardiography,’’Dr Feigenbaum stated that ‘‘the work waspublished in March 1965 in the Journal of the AmericanMedical Association.’’E. Recent EraFrom the initial M-mode echocardiography, the 2-D modeevolved in 1970. The development of Doppler technologyadvanced the method considerably. We now have2-D, spectral Doppler, color Doppler, transesophagealearly three-dimensional echocardiography, and intravascularultrasound.Doppler echocardiography is based on the Dopplereffect first described by Christian Johann Doppler in 1842.He demonstrated that the frequency of sound reflectedfrom an object is altered if that object is moving. TheDoppler effect is, in essence, a change or shift in frequencyin relation to the direction of movement of its source. Themovement of blood cells produce a Doppler shift of ultrasoundfrequencies. The extent and direction of shift of theultrasound and the frequency are related to the velocityand direction of blood flow.More recently, advances in electronics have enabledcontrast echocardiography, harmonic and strain imaging,and the production of an echocardiography machine thesize of a laptop computer. Handheld echocardiography isthe newest evolution.The information derived from echocardiographic examinationof the heart has revolutionized the clinical practiceof medicine. Presently there is one important diagnosis,however, that the echocardiogram is not able to make.The obstruction of coronary arteries by atheroma thatcauses angina and fatal and nonfatal heart attacks cannotbe visualized on echocardiography. Intravascular ultrasounddone at the time of interventional procedures isimproving our knowledge of the atherosclerotic processand its complications, but this technique cannot be appliedin clinical practice. Recent developments are concentratingon the visualization of the left anterior coronary arteryusing transthoracic echocardiography.II. INSTRUMENTATIONUltrasound is sonic energy with a frequency higher thanthe audible range of 20,000 Hz. The development ofpiezoelectric transducers made the application of ultrasoundpossible. A piezoelectric (pressure electric) elementis the primary component of an ultrasonic transducer. Theshape of a quartz crystal varies with its polarity when anelectric current is impressed through the crystal. Theexpansion and contraction of the crystal produces compressionsand rarefactions or sound waves. Most important,when the crystal is struck by reflected ultrasound waves,the crystal creates ultrasound energy and then producesan electric impulse or signal.Ultrasound, like light, can be focused into a beam thatobeys the laws of reflection and refraction. An ultrasoundbeam travels in a straight line when it traverses a mediumof homogeneous density. When the beam hits an interfaceof different acoustic impedance, part of the energyis reflected. This reflected energy is used to construct animage of the heart.Figure 1 shows a block diagram of the components ofan ultrasonic echograph. The instrument is used to createan image using ultrasound.III. ECHOCARDIOGRAPHICEXAMINATIONA. Echocardiographic WindowBecause sound travels poorly through a gaseous medium,it is impossible for ultrasound to traverse the voluminouslung tissue and still obtain adequate echoes from the heart.The transducer must also not be placed over the sternumor ribs or other bony points. Almost all ultrasonic energyis reflected if one tries to direct an ultrasonic beam throughbone. Because of the rib cage and breast bone, the bestechocardiographic window lies between the second andfifth intercostal spaces and 3–4 cm to the left of theleft sternal border.

IV. CLINICAL APPLICATIONS329with the formulation and timing of treatment strategies.The following are some of these clinical entities.TISSUETRANSDUCERCATHODE RAYTUBETRANSMITTERRECEIVERSIGNALAMPLIFIERFIGURE 1 Block diagram of the components of an ultrasonicechograph. (From Feigenbaum, H., Echocardiography, fourth edition,Philadelphia: Lea & Febiger, 8, 1986.)B. Transthoracic EchocardiogramThe standard transthoracic echocardiogram provides viewsof the heart with the transducer position on the left chestwall. It gives an adequate visualization of the structures ofthe heart and abnormalities in more than 95% of patientswith valvular heart disease, heart attacks, ischemic heartdisease, heart failure, cardiomyopathy, hypertensive heartdisease, and assessment of left ventricular hypertrophy.It is, however, not satisfactory for complicated problemsin which a transesophageal echocardiogram (TEE) isrequired.C. Transesophageal EchocardiogramTEE is superior to transthoracic echocardiography becausethe transducer is placed in the esophagus. The esophaguslies immediately behind and adjacent to the left atriumand the thoracic aorta. Specific indications for TEEinclude congenital heart disease, detection of thrombi inthe left atrium, vegetations on the heart valves that occur ininfective endocarditis, and for the evaluation of prostheticheart valves in these situations.Figure 2 shows the visualization of the heart’s basicimaging planes by previous transducer positions. Figure 3shows a two-dimensional image of the heart and theparasternal long axis view. The cardiac chambers correlatewith the diagram in Fig. 2. Figure 4 shows an apical, four-,and two-chamber view.IV. CLINICAL APPLICATIONSEchocardiographic evaluation of heart disease is usedextensively to verify many clinical diagnoses and assistsA. Valvular Heart Disease1. Mitral Valve Diseasea. Mitral StenosisThis disease involves a tight mitral valve that restrictsblood flow from the left atrium into the left ventricle.Echocardiographic examination can estimate the degreeand state of stenosis. If the stenosis is mild the valvearea ¼ 1.6–2.0 cm 2 , in moderate mitral stenosis thevalve area ¼ 1–1.5 cm 2 , and in severe stenosis the valvearea ¼ < 1cm 2 .b. Mitral RegurgitationMitral regurgitation (mitral valve incompetence) consistsof a leaking or incompetent valve that includes mitral valveprolapse. It is difficult to decide from the history andphysical examination whether surgery is necessary in somepatients. Echocardiographic evaluation is extremely useful,especially TEE, to evaluate severe degrees of regurgitation,disruption of the chordae (tendinous cords that holdthe mitral valve in place), and a flail mitral valve leaflet thatmight require urgent surgical correction (see chapterentitled Valve Diseases).c. Aortic Valve StenosisIn aortic stenosis, a severely tight valve with an area lessthan 0.75 cm 2 usually causes severe shortness of breath,syncope, chest pain, or heart failure, and implantation ofa new valve is frequent. Echocardiographic follow up ofpatients with moderate degrees of stenosis is most usefulto clinicians. Pulmonary and tricuspid valve defects andprosthetic heart valve dysfunction are disease entities thatcan also be visualized with use of TEE.B. ThrombiThrombi (clots in the heart) occur in the left atrium and arecommon in patients with atrial fibrillation. TEE visualizationof thrombi is superior to transthoracic visualization.A thrombus may form in the cavity of the left ventricleafter a heart attack and this can be visualized by the simpletransthoracic echo.

330ECHOCARDIOGRAPHYFIGURE 2 Visualization of the heart’s basic tomographic imaging planes by various transducer positions. The long-axis plane (A) can be imaged in theparasternal, suprasternal, and apical positions; the short-axis plane (B) in the parasternal and subcostal positions; and the four-chamber plane (C) in theapical and subcostal positions. (From Rosendorff, C., Essential Cardiology, Philadelphia: W. B. Saunders, 145, 2001.)C. Congenital Heart DiseaseCongenital heart defects have been a difficult diagnosticarea for cardiologists and echocardiography is a dream cometrue. Figure 5 depicts a ventricular septal defect (see thechapter Congenital Heart Disease). Most important, carefulechocardiographic assessment of the heart can give hemodynamicdata that are identical with right and left heartcatheterization thus avoiding invasive catheterization inmany cases.D. Coronary Artery DiseaseCoronary artery disease causes a heart attack and thedamage and weakness of the muscle can be detected byechocardiography. Severe narrowing of a coronary arterymay cause transient chest pain and angina caused bytransient but severe deprivation of blood supply to theheart muscle. In these patients an echocardiogram mayreveal regional abnormal left ventricular wall motionabnormalities.E. Heart FailureThe most common cause of heart failure is severe weaknessto the entire left ventricular muscular wall. Echocardiographicassessment reveals poor contraction of the muscle(global hypokinesis). The amount of blood ejected fromthe heart (ejection fraction) normally exceeds 55%. Thismay be observed to be less than 40% or less than 25% insevere cases of heart failure.

IV. CLINICAL APPLICATIONS331FIGURE 3 (A) Two-dimensional image of the heart in the parasternal long-axis view. (B) Short-axis plane through the heart at the level of the papillarymuscle. (C) Two-dimensional image of the apical four-chamber plane. (D) Two-dimensional image of the apical three-chamber plane. (From Rosendorff, C.,Essential Cardiology, Philadelphia: W. B. Saunders, 145, 2001.)FIGURE 4 Apical four- and two-chamber views of the left ventricle. Note the normal ‘‘bullet shape’’ geometry of the left ventricle and the moretriangular right ventricle. Note also the more apical insertion of the tricuspid valve compared with the mitral valve. (From Braunwald, E., Zipes, D.P.,and Libby, P., Heart Disease: A Textbook of Cardiovascular Medicine, Philadelphia: W. B. Saunders, 2001.)

332ECHOCARDIOGRAPHYFIGURE 5 Two-dimensional images from two patients with ventricular septal defect. (A) Two parasternal short axis frames. The lower frame is throughthe level of the papillary muscles and at this point the interventricular septum is intact. As the beam is scanned superiorly the ventricular septal defect (VSD)is visualized. (B) A large ventricular septal defect seen in the apical four-chamber view. (From Julian, D.G., Ed., Diseases of the Heart, London: W.B.Saunders, 325, 1996.)F. Other Clinical IndicationsWith pericardial effusion there is fluid in the pericardial sac.This is readily detected on echocardiography and followedduring treatment. Echocardiography has proved mostuseful in the diagnosis of cardiac tamponade, in which alarge pericardial effusion compresses the heart and preventsits filling. This results in cardiogenic shock or death.Another clinical indication for echocardiography is infectiveendocarditis. This is an infection of the heart valvesthat produces vegetations or clumps of bacteria. Thesevegetations may grow on the valve leaflets and can rangefrom millimeters to a centimeter. These vegetations canbe detected with TEE.Hypertensive heart disease causes enlargement orhypertrophy of the heart that can be detected with echocardiography.Hypertrophic cardiomyopathy can also bereadily assessed with this technology (see the chapters Cardiomyopathyand Athlete’s and Sudden Cardiac Death)along with dilated cardiomyopathy, and muscle damagecaused by cancer chemotherapeutic agents can be defined.Finally, dissecting aneurysms, myxomas, and other tumorscan be easily diagnosed using TEE technology.V. RESEARCH IMPLICATIONSThe very important role of echocardiography in the practiceof cardiology has been outlined above. There is oneimportant diagnosis, however, that the echocardiogramis not able to resolve adequately. The obstruction ofcoronary arteries by atheroma, which causes angina andfatal and nonfatal heart attacks and accounts for morethan 90% of deaths from coronary artery disease cannotbe visualized with this technology. Intravascular ultrasounddone at the time of interventional procedures is improvingour knowledge of the atherosclerotic process and itscomplications, but this technique cannot be applied inclinical practice.

VI. NEW FRONTIERS333VI. NEW FRONTIERSA. Transthoracic Visualization of theCoronary ArteryIn a pertinent review done in 2003, Drs. Gradus-Pizloand Feigenbaum outlined the potential use of highresolution,two-dimensional transthoracic echocardiography(HR-2DTTE) for visualization of the left anteriordescending coronary artery (LAD). They indicated thatthe difference in the LAD wall thickness between patientswith coronary artery disease and in patients with normalcoronary arteries can be detected. Measurements of theLAD wall thickness with this method are larger thanmeasurements obtained by intravascular ultrasound andhistology. This thickness increases significantly with thedevelopment of atherosclerosis. This technique, whencrystallized, could be recommended for the detection ofsubclinical atherosclerosis for which there are presently noadequate noninvasive applicable tests.A noninvasive, reliable method to identify subclinicalcoronary artery disease in asymptomatic individuals at riskwould be a dream come true and would add great dimensionsto our diagnostic armamentarium. HR-2DTEE andits refinements has this potential.B. Handheld InstrumentsPresently weighing about 5 pounds, these instrumentsare due to trim down to a one-pound weight and hopefullycan be reduced further to 1 g in the future. Miniaturizationusing 3-D and 4-D parametric imaging can show areas ofmyocardial infarction. Ultrasound-guided focused ablationtechnology for arrhythmias and other potentials arealso on the horizon.BIBLIOGRAPHYDeMaria, A. N., and Blanchard, D. G. The echocardiogram. In Hurst’sThe Heart, 9th edition. R. C. Schlant, R. W. Alexander, and V. Fuster,eds. McGraw-Hill, New York, 415–517, 1998.Feigenbaum, H. Evolution of echocardiography. Circulation, 93:1321–7,1996.Feigenbaum, H. History of echocardiography. J. Am. Coll. Cardiol. ACCCurr. Rev. Sept/Oct 42, 2001.Gradus-Pizlo, I., and Feigenbaum, H. Potential use of high-resolutiontwo-dimensional transthoracic echocardiography for visualization ofthe left anterior descending coronary artery. Am. Heart Hosp. J.,1:77–82, 2003.Mason, W. P. Piezoelectric Crystals and their Application to Ultrasonics.Van Nostrand, New York, 1950.Schiller, N. B. Handheld echocardiography: Revolution or hassle? J. Am.Coll. Cardiol., 37:2023–24, 2001.

Effects of Smoking and Heart DiseaseI. Effects of Components of Cigarette SmokeII. Cigarette Smoke and AtheroscelerosisIII. Recent Epidemiologic StudyIV. Anginal Chest Pain and ImpotenceV. Habituation and CessationGLOSSARYarrhythmia general term for irregularity or rapidity of theheartbeat.atherosclerosis a hardened plaque in the wall of an artery: theplaque is filled with cholesterol calcium and other substances.The plaque of atheroma hardens the artery hence the termatherosclerosis (sclerosis equals hardening).myocardial infarction death of an area of heart muscle due toblockage of the coronary artery by blood clot and atheroma(atherothrombosis), medical term for a heart attack.Epidemiologic Studies strongly support the hypothesis thatcigarette smoking increases the incidence of fataland nonfatal heart attacks. But, despite a world fullof researchers, the exact constituent which resides incigarette smoke and the pathophysiologic mechanismsresponsible for cardiac events remain unknown. Ambroseet al., in an informative review, emphasize the lack of clearanswers.Low-tar cigarettes and smokeless tobacco have beenshown to increase the risk of cardiovascular events incomparison to nonsmokers. Passive smoke is associatedwith about a 30% increase in risk of cardiac eventscompared with an 80% increase in active smokers. Asmoke free environment in several cities reportedly hasresulted in a decreased incidence of cardiac events. It isbelieved that if cigarette smoking were eliminated, about aquarter of a million lives now lost because of cardiovasculardisease could be saved yearly in North America. Each year,lung cancer causes about 80,000 deaths. Smoking causesmost cases of lung cancer, which is becoming the leadingcause of death from cancer in women.Nonsmoking men age 45–55 are 10 times less likely tohave a fatal or nonfatal heart attack than heavy smokers.The Multiple Risk Factor Intervention Trial showed thatmen at high risk who stopped smoking had a significantreduction in their mortality.The detrimental effects of cigarette smoking were widelyadvertised in the mid-1970s, and since then more than 20million North Americans have stopped smoking. Smokinghas increased in teenagers and women, however, resulting inlittle change in the overall number of smokers. Heartattacks are rare in women aged, 40–48, but in women ofthis age who use oral contraceptives and smoke, the heartattack rate is increased. Over the past two decades cigarettesmoking has increased considerably in Japan, China, India,Russia, its former territories, and the developing world.Cardiovascular events are on the increase in these countries.Low-nicotine, low-tar brands, or filter cigarettes do notdecrease the risk of coronary heart disease, although therisk of lung cancer may be decreased. Filter cigarettesdeliver more carbon monoxide and cause a higher incidenceof coronary heart disease than do plain cigarettes.I. EFFECTS OF COMPONENTS OFCIGARETTE SMOKETobacco smoke contains more than 4000 components.Some of these are nicotine, carbon monoxide, ammonia,benzene, nitrobenzene, phenol, 2,4,dimethylphenol, acetaldehyde,hydrogen cyanide, toluene and O-cresol. Moststudies have been done on nicotine and various gases, inparticular, carbon monoxide (CO).Although the effects of the many constituents ofsmoke are not understood, the effect of nicotine is welldocumented.Cigarette smoke is divided into two phases:A tar phase: defined as the material that is trapped whenthe smoke stream is passed through the Cambridgeglass-fiber filter that retains 99.9% of all particulatematerial with a size >0.1 mm.A gas phase: the material that passes through the filter.335

336EFFECTS OF SMOKING AND HEART DISEASEA. NicotineNicotine stimulates the adrenal glands to put out excessiveadrenaline and noradrenaline. The higher the nicotineconcentration inhaled, the greater the outpouring of adrenaline.If someone puts a gun to your head, you need all theadrenaline and noradrenaline that your adrenals and nervescan produce to enable you to fight or run. So adrenalineis great stuff, but it has many harmful effects. The heartrate and blood pressure increase, which means more workfor the heart. The heart muscle will also require a biggersupply of oxygen. The platelets become sticky and mayclump onto the surface of atheromatous plaques in one ofyour coronary arteries and a heart attack can occur.Nicotine, by increasing the heart rate and blood pressure,can increase the frequency and duration of chest painin those who have angina.Nicotine can and does increase the excitability of heartmuscle, causing premature beats that can lead to seriousdisturbance in heart rhythm (arrhythmias). Sudden cardiacdeath is more common in heavy cigarette smokers.In individuals with seizures, the brain cells have athreshold level at which seizures occur. If this threshold isnot reached, seizures do not occur. Drugs includingalcohol decrease this threshold and seizures are more easilyproduced; we can prevent seizures by elevating the threshold.Drugs used to treat epilepsy, for example phenytoin(Dilantin), increase the threshold, therefore preventingseizures. Two products of cigarette smoke, nicotine andcarbon monoxide, decrease the ventricular fibrillationthreshold of the heart muscle. The ventricular fibrillationthreshold is decreased if the heart muscle is suddenlydeprived of blood, or exposed to high concentrations ofadrenaline, noradrenaline, and other drugs. During a heartattack, high amounts of noradrenaline are found in andaround the damaged muscle and can cause ventricularfibrillation. During ventricular fibrillation the muscle nolonger contracts, but quivers. Therefore, the heart is ata standstill — no blood is being pumped. The heart stopsbeating, the brain dies; thus there is heart and brain death.The ventricular fibrillation threshold is slightly increasedby only one or two available heart drugs. Beta-blockerscounteract the effects of adrenaline and noradrenalineat the cell surface and increase the ventricular fibrillationthreshold.Nicotine causes a smoking-related increase in cardiacoutput, heart rate, and blood pressure, but these do notrelate to the development of atherosclerosis or its complications,including thrombosis. Nicotine exposure alonehad been reported to cause no change, a decrease, or anincrease in endothelium-dependent vasodilation or NOavailability.Nevertheless smokers are inhaling two dangerous compounds,carbon monoxide and nicotine, as well as othergases that decrease the ventricular fibrillation threshold andtherefore are capable of causing death. The habituation,‘‘addiction’’ effects of nicotine are overwhelming.B. Carbon MonoxideThe hemoglobin of red blood cells transports oxygen toall cells and tissues of the body. Hemoglobin clings tocarbon monoxide about 200 times more readily than theoxygen circulating in the blood. In this situation oxygenclings strongly to whatever hemoglobin it can find, and lessoxygen is released to the cells. Carbon monoxide combineswith hemoglobin to form a compound called carboxyhemoglobin.The tissues, therefore, including the heartmuscle cells, are deprived of oxygen. This is particularlyimportant if the cells are already undernourished and lackoxygen because of severe narrowing of the coronary arteriesby atheromatous plaques. These plaques are present inmore than 50% of North Americans age 35 and over. Onlyabout 30% of the adult population are spared fromthe dreadful atheromatous blockage in arteries that causecoronary heart disease.Carboxyhemoglobin likely causes the wall of the arteriesto be more permeable to fats including cholesterol, andthis can speed up atheroma formation. Individuals withcarboxyhemoglobin levels greater than 5% are 21 timesmore likely to develop heart attacks or poor circulation inthe arteries of the legs than individuals with levels less than3%. There is scientific evidence indicating that heavycigarette smokers are subjected to eight times the carbonmonoxide exposure allowed in industry.A sane individual would certainly not stay in a closedgarage with the engine running knowing the danger of carbonmonoxide is death.High-nicotine or nonnicotine cigarettes produce thesame amount of carbon monoxide. Stickiness of theplatelets is also increased by carbon monoxide, thus increasingthe chance of clotting in the coronary arteries. Theventricular fibrillation threshold of the heart muscle andits electrical tissues is reduced by carbon monoxide;thus sudden death may not be a mystery.The effect of carbon monoxide on the development ofatherosclerosis and its complications is reportedly equivocal.Recently, however, Hedblad et al. reported thatheterogeneity of cardiovascular risk among smokers isrelated to a degree of carbon monoxide exposure: theincidence of a new vascular disease events and deathsincreased progressively with the degree of CO exposure.Men with CO in the top quartile had significantly

IV. ANGINAL CHEST PAIN AND IMPOTENCE337increased risks of a new cardiovascular disease events (RR:2.2; 95% CI: 1.00–4.6) and cardiovascular deaths (RR:3.2, CI: 1.2–8.3), adjusted for daily tobacco consumptionand other potential confounders. Hedblad et al. pointout: In smokers, the prevalence of leg atherosclerosis andincidence of cardiovascular disease is related to the amountof carbon monoxide in blood or expired air.C. Tar fractionPolycyclic aromatic hydrocarbons found in the tar fractionof cigarette smoke, however, in experimental models,accelerate atherosclerosis.II. CIGARETTE SMOKE ANDATHEROSCLEROSISA. Nitric Oxide and Vasodilatory FunctionImpairment of vasodilatory function is one of the earliestmanifestations of atherosclerotic changes in arteries. Inboth animal and human models, studies by Celermajeret al. and other investigators have demonstrated thatboth active and passive cigarette smoke exposure wereassociated with a decrease in vasodilatory function. Inhumans, cigarette smoke exposure has been shown toimpair endothelium-dependent vasodilation in macrovascularbeds such as coronary and brachial arteries and inmicrovascular beds. Nitric oxide (NO), a free radical,is primarily responsible for the vasodilatory function ofthe endothelium. Using cigarette smoke extract or isolatedcomponents such as nicotine, multiple in vitro studieshave found that cigarette smoke was associated withdecreased NO availability.B. Oxidation of LDL CholesterolCigarette smoke experimentally increases vascular inflammation,thrombosis, oxidation of LDL cholesterol, andoxidative stress. Nishio et al. indicated that cigarette smokeextract exposure appears to decrease the plasma activity ofparaoxonase, an enzyme that protects against LDLoxidation. In a hyperlipidemic rabbit model, Yamaguchiet al. have shown injection of cigarette smoke acceleratedatherosclerosis through oxidative modification of LDL.Burke et al., in pathologic studies of sudden coronarydeath indicate that cigarette smoke increased the risk ofplaque rupture and acute thrombosis of a lipid-rich, thincappedatheroma in men; in female smokers, the prevailingmechanism was plaque erosion with superimposedthrombosis. In addition, smoking may also be a risk factorfor coronary vasoplasm.C. Genetic PredispositionGenetic predisposition influences the development ofatherosclerosis in individuals exposed to cigarette smoke.The intersubject variability in the atherosclerotic process insmokers may be partially mediated by genetic variants.Either CYP1A1 MSP polymorphism or certain endothelialNO synthase intron 4 polymorphisms increased thesusceptibility to cigarette smoke. In vivo, cigarette smoke isassociated with an increased level of multiple inflammatorymarkers including C-reactive protein, interleukin-6, andtumor necrosis factor alpha in both male and femalesmokers.D. Platelet Dysfunction and ThromboticFactorsRival et al. have shown that platelets isolated from smokersexhibited an increased stimulated as well as spontaneousaggregation. A higher fibrinogen blood level found insmokers correlates with the number of cigarettes smoked.Hirohiko et al. observed only 2-week smoking cessationimproves platelet aggregability and intraplatelet redoximbalance of long-term smokers.III. RECENT EPIDEMIOLOGIC STUDYIn the recently published INTERHEART study reportedby Yusuf et al.: ‘‘risk factors were significantly ( p < 0.0001)related to acute myocardial infarction, except alcohol,which had a weaker association ( p ¼ 0.03). After multivariateanalysis, current smoking and raised ApoB/ApoA1ratio (top vs. lowest quintile) were the two strongest riskfactors, followed by history of diabetes, hypertension, andpsychosocial factors. Body-mass index was related to riskof myocardial infarction, but this relation was weaker thanthat of abdominal obesity (waist/hip ratio).’’IV. ANGINAL CHEST PAIN ANDIMPOTENCEA. Anginal PainIn conditions such as angina, where oxygen supply to theheart muscle is low, the frequency and severity of chest painmay be increased by cigarettes. Nicotine causes a slightincrease in blood pressure and heart rate. Therefore, the

338EFFECTS OF SMOKING AND HEART DISEASEheart muscle demands more oxygen. Thus, the combinationof carbon monoxide and nicotine increases the badeffects. Patients with angina who are smokers develop chestpain at lower levels of exercise. See chapter entitled Angina.Other components of cigarette smoking include aglycoprotein that is highly allergenic and may causeshortness of breath, asthmatic attacks, or eye irritation.In addition, the glycoprotein is believed to cause damageto the lining of arteries and an increase in atherosclerosis.B. ImpotenceSmoking causes endothelial dysfunction and appears tocause a constriction of small penile arteries implicated asone of the many factors responsible for impotence in someindividuals. Endothelial dysfunction is common to thepathophysiology of both erectile dysfunction and coronaryartery disease events.V. HABITUATION AND CESSATIONA. HabituationHabituation is a major problem because nicotine is apotent chemical that has been conclusively shown toproduce ‘‘addiction’’ and dependence. The smoker willgo to extremes to purchase his or her cigarettes and ensurethat they are readily available.B. How to Stop1. MotivationMotivation is the key but this is difficult to sustain. Mostindividuals recognize that nicotine has addicting potentialbut this does not alter thinking of young individuals age10–18 of those under stress who require the effects ofsmoking a cigarette. More important, perhaps motivationmay be derived from the following thought:Carbon monoxide in cigarette smoke is potentially asdangerous as carbon monoxide in a home with adefective furnace or the fumes from a running motorcar engine in a closed garage.2. StrategiesCraving and hunger can be satisfied by smoking acigarette or by chewing nicotine-containing gum,wearing a nicotine patch, or use of a tablet.Participation in stop-smoking clinics and other groupsthat emphasize educational and behavioral modification;hypnosis for selected individuals.Help health programs: American Cancer Society ‘‘Iquit kit’’. National Cancer Institute: ‘‘Helping smokersquit’’.Note that some heavy smokers who stop cold turkey do notget symptoms of withdrawal.C. Effect of CessationRosenberg et al. indicated that cessation of smokingsignificantly reduces cardiovascular risk over a 1- to 3-yearperiod with an exponential decline approaching the riskin ex-smokers within 5 years of cessation. Reportedly,Seargent et al. indicate that a citywide smoking ban inpublic places over a 6-month period in Helena, Montana,reduced the incidence of acute MI by 60% during thattime period.There is no doubt that smoking causes chronic bronchitisand emphysema which leads to corpulmonale, heartfailure due to lung disease; this debilitating disease can bearrested by cessation of smoking.BIBLIOGRAPHYAdams, M. R., Jessup, W., and Celermajer, D. S. Cigarette smoking isassociated with increased human monocyte adhesion to endothelialcells: Reversibility with oral L-arginine but not vitamin C. J. Am. Coll.Cardiol., 29:491–497, 1997.Ambrose, J. A., and Barua R. S. The pathophysiology of cigarettesmoking and cardiovascular disease: An update. J. Am. Coll. Cardiol.,43:1731–37, 2004.Barua, R. S., Ambrose, J. A., Eales-Reynolds, L. J., DeVoe, M. C.,Zervas, J. G., and Saha, D. C. Dysfunctional endothelial nitric oxidebiosynthesis in healthy smokers with impaired endothelium-dependentvasodilatation. Circulation, 104:1905–1910, 2001.Barua, R. S., Ambrose, J. A., Srivastava, S., DeVoe, M. C., andEales-Reynolds, L. J. Reactive oxygen species are involved insmoking-induced dysfunction of nitric oxide biosynthesis andupregulation of endothelial nitric oxide synthase: An in vitrodemonstration in human coronary artery endothelial cells. Circulation,107:2342–2347, 2003.Burke, A. P., Farb, A., Malcom, G. T., Liang, Y. H., Smialek, J., andVirmani, R. Coronary risk factors and plaque morphology in menwith coronary disease who died suddenly. N. Engl. J. Med., 336:1276–1282, 1997.Burke, A. P., Farb, A., Malcom, G. T., Liang, Y., Smialek, J., andVirmani, R. Effect of risk factors on the mechanism of acutethrombosis and sudden coronary death in women. Circulation,97:2110–2116, 1998.Celermajer, D. S., Sorensen, K. E., and Georgakopoulos, D. et al.Cigarette smoking is associated with dose-related and potentiallyreversible impairment of endothelium-dependent dilation in healthyyoung adults. Circulation, 88:2149–2155, MEDLINE, .1993.

V. HABITUATION AND CESSATION339Celermajer, D. S., Adams, M. R., Clarkson, P. et al. Passive smoking andimpaired endothelium-dependent arterial dilatation in healthy youngadults. N. Engl. J. Med., 334:150–154, MEDLINE, 1996.Craig, W. Y., Palomaki, G. E., and Haddow, J. E. Cigarette smoking andserum lipid and lipoprotein concentrations: An analysis of publisheddata. BMJ, 298:784–788, 1989.Czernin, J., Sun, K., Brunken, R., Bottcher, M., Phelps, M., andSchelbert, H. Effect of acute and long-term smoking on myocardialblood flow and flow reserve. Circulation, 91:2891–2897, 1995.Frei, B., Forte, T. M., Ames, B. N., and Cross, C. E. Gas phase oxidantsof cigarette smoke induce lipid peroxidation and changes inlipoprotein properties in human blood plasma: Protective effects ofascorbic acid. Biochem. J., 277:133–138, 1991.Hedblad, B., Ögre, M., Engström, G. et al. Heterogeneity ofcardiovascular risk among smokers is related to degree of carbonmonoxide exposure. 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G., and Patel, K. P. Effect of nicotine on endotheliumdependentarteriolar dilatation in vivo. Am. J. Physiol., 272:H2337–H2342, 1997.McVeigh, G. E., Lemay, L., Morgan, D., and Cohn, J. N. Effects oflong-term cigarette smoking on endothelium-dependent responses inhumans. Am. J. Cardiol., 78:668–672, 1996.Morita, H., Ikeda, H., Haramaki, N. et al. Only two-week smokingcessation improves platelet aggregability and intraplatelet redox imbalanceof long-term smokers. J. Am. Coll. Cardiol., 45:589–594, 2005.Nishio, E., and Watanabe, Y. Cigarette smoke extract inhibits plasmaparaoxonase activity by modification of the enzyme’s free thiols.Biochem. Biophys. Res. Commun., 236:289–293, 1997.Napoli, C., and Ignarro, L. J. Nitric oxide and atherosclerosis. NitricOxide, 5:88–97, 2001.Ota, Y., Kugiyama, K., Sugiyama, S. et al. 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ElectrocardiographyI. HistoricalII. General ApplicationsIII. The Normal ElectrocardiogramIV. Diagnosis of Specific ConditionsV. Recent DiscoveriesGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.hypertrophy increase in thickness of muscle.ischemia temporary lack of blood and oxygen to an area ofcells, for example, the heart muscle, usually due to severeobstruction of the artery supplying blood to this area of cells.left ventricular dysfunction poor contractility of the ventricle,this leads to heart failure.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.myocardium the heart muscle.pericarditis inflammation of the pericardium or sac surroundingthe heart; this is not a heart attack.I. HISTORICALThe development of the modern electrocardiographicinstrument illustrates how medicine, a branch of the biologicsciences, took advantage of the concepts of physicalscience and its instrumentation. The invention of theelectrocardiographic instrument would not have beenpossible without the notable orchestrated work of engineers,physicists, physiologists, and researchers. Of particularimportance was the development of the stringgalvanometer by Ader, a French electrical engineer.Thus, it seems reasonable to give readers the followinghistorical details. The initial work of Galvani (1791),Muller (1856), Waller (1890–1900), and Ader (1897)initiated Einthoven’s discovery from 1901 to 1903. Therather heavy and cumbersome Einthoven machine was toocomplicated for routine diagnostic use as it occupiedtwo rooms and required five assistants to operate theinstrument. Advances that led to the modern electrocardiographrequired the perseverance of the CambridgeScientific Instrument Company and the diligent researchwork of Sir Thomas Lewis, Frank Wilson, Goldberger, andothers.A. Early TimelineIn about 1760 Luigi Galvani observed that an electricalstimulus applied to a motor nerve caused contraction ofthe associated muscle. In 1856, Muller, who was workingon the dissection of live frogs, observed that when a motornerve to a frog’s leg was laid over the isolated beatingheart, the frog’s leg kicked with each heartbeat. In 1887,Waller observed that the heart’s rhythmic electrical stimulicould be monitored from a person’s skin. Waller’s initialwork in electrocardiography was conducted at St. Mary’sHospital in London. He called the tracing obtained witha Lippmann capillary electrometer an electrogram. Theinstrument was too large to adopt for clinical use and hisrecordings prior to 1901 were difficult to understand.Einthoven had attended Waller’s first demonstration ofthe device at St Mary’s hospital and would go on to furtherthe technology.In 1897, Ader, a French engineer, invented the firstsingle-string galvanometer, which suspended a fine metalwire between the poles of a large magnet. This instrumentwas devised mainly for transmission of telegraphic data athigh speed, but without this invention today’s electrocardiographicrecordings would be impossible.B. EinthovenA year after receiving his medical degree, Einthovenwas appointed professor of physiology and histology at341

342ELECTROCARDIOGRAPHYLeyden University. Around 1895 Einthoven returnedfrom Waller’s lecture and laboratory full of enthusiasm.He became disenchanted with the capillary electrometer,however. He initially experimented with the d’Arsonvalgalvanometer and assessed the thesis of his tutor, Bosscha,who wrote ‘‘The Differential Galvanometer’’ in 1854.Einthoven finally considered the work of Ader and theimportance of the single-string galvanometer. He acknowledgedAder’s contribution when he published his landmarkpaper in 1901.Einthoven recognized that the heart possessed electricalactivity, and he recorded this activity using two sensorsattached to two forearms and connected to a silver wirethat ran between two poles of a large permanent magnet.He noted that the silver wire moved rhythmically withthe heartbeats, but to visualize the small movementsEinthoven shone a light beam across the wire and the wavymovements of the wire were recorded on moving photographicpaper. Einthoven recorded the waves and spikydeflection, and labeled the first smooth rounded wave,P, the spiky deflection QRS, and the last recordeddeflection he named T wave (Fig. 1). The choice of thisFIGURE 1 Demonstration of perfect agreement between the recordobtained with Einthoven’s modified galvanometer and the mathematicallycorrected curves obtained with the capillary electrometer. (Photo source:University of Central Florida. Literary source: Fleckenstein, K. (1984).The early ECG in medical practice. Medical Instrumentation. Vol. 18, no.3, May-June. With permission from Association for the Advancement ofMedical Instrumentation, 1901 N. Ft. Meyer Drive, Ste 602, Arlington,Virginia, 22209.)lettering obeyed the convention used by geometricians:curved lines were labeled beginning with P and points onstraight lines were labeled beginning with Q. Einthoven’spaper in German on the galvanometric registration of thehuman ‘‘elektrokardiogramm’’ (EKG) was published in1903. Because of the German publication, the abbreviationEKG was used until post World War II, when inAmerica the currently used ECG was adopted. It is relevantto note that Waller finally abandoned the capillaryelectrometer and used Einthoven’s string galvanometerfrom 1910 to 1917.In addition, Fig. 1 shows the tracing obtained withthe capillary electrometer and Einthoven’s corrected curve.The upper and middle records were shown in his paperon the galvanometric registration of the human elektrokardiogrammpublished in 1903.C. Sir Thomas LewisIn 1911 Sir Thomas Lewis, Einthoven, and others correlatedthe ECG waves with the contracting heart and notedthat the P wave was related to the contraction of the atriumand that the QRS spiky deflection was associated withventricular contraction.The Cambridge Scientific Instrument Company madeimprovements in the size and capabilities and brought outa table model in 1911, one of which was leased to Lewis atthe London Hospital. In 1917 Herrick reported the firstcase in which the electrocardiogram was diagnostic ofmyocardial infarction. In 1926 a fully portable instrumentwas marketed.From 1934 to 1946 improvements in the quality ofrecordings were due to the immense work and techniqueof Frank Wilson at the University of Michigan. He hadstudied with Lewis and had purchased one of theearly electrocardiograph machines manufactured by theCambridge Scientific Instrument Company in 1914.Wilson’s work led to the introduction of the centralterminal, the V leads applied to the chest wall, and theleads applied to the limbs which improved the qualityof recordings. Goldberger, in 1942, introduced a techniqueof obtaining augmented unipolar extremity leads,labeled aVR, aVL, and aVF. This allowed a large amplitudedeflection to be recorded.II. GENERAL APPLICATIONSDespite the advent of expensive and sophisticated cardiologictests, the electrocardiogram remains the most reliabletool for the confirmation of acute myocardial infarction.

IV. DIAGNOSIS OF SPECIFIC CONDITIONS343The electrocardiogram — not the cardiac enzymes, troponins,CK–MB, echocardiogram, or Sector PET scan —dictates the rapid administration of lifesaving thrombolytictherapy. There is no test to rival the electrocardiogram inthe diagnosis of arrhythmia, which is a common problemseen in clinical practice. Also, the diagnosis of acutepericarditis can only be confirmed by electrocardiographicfindings. The very common condition of myocardialischemia which causes chest pain in patients with anginacan be confirmed in some by electrocardiographic findingsat rest and particularly during exercise.III. THE NORMAL ELECTROCARDIOGRAMThe electrocardiogram picks up the heart’s electricalimpulses transmitted through the skin of the chest.Figure 2 gives a simplified concept of ion exchange —the polarized, depolarized, and repolarized state of themyocardial cell; and the action potential. An electricalcurrent arriving at the cell causes positively chargedirons to cross the cell membrane (depolarization),followed by repolarization which generates an actionpotential: phase 0, 1, 2, 3, and 4. This electrical eventtraverses the heart and initiates mechanical systole or aheartbeat.Figure 3 gives a diagrammatic representation of theelectrocardiogram and its relationship to the potassiumand sodium exchange across the cardiac cell membranewith the generation of an action potential. The heart isinitially activated by an infinitesimal current generated bythe sinoatrial (SA) node, a natural pacemaker. The currentof activation spreads radially from the SA node across theatria to the atrioventricular (AV) node and down thebundle branches to the ventricular muscle and Purkinjenetwork (see Fig. 4). The SA node tracing shows no steadyresting potential and is characterized by spontaneousdepolarization. Figure 5 shows a normal ECG tracing.IV. DIAGNOSIS OF SPECIFIC CONDITIONSA. Acute Myocardial InfarctionThe ECG diagnosis of acute myocardial infarctionis revealed by an elevation of the ST segment in theResting state= polarized+++++++++Depolarized state Repolarization Resting state+++++ ++++++++ +++++++++++++++K + K + K +Na +K + to Na + ions30:1K + K + K +K + K + K +Na + Na + Na +Cell membrane!!!!!!!!!!!!!!Na + pump: Na + out, K + inInward Na + currentK + efflux+0−12−45−90millivoltsPhase 0of the actionpotential3Phase 4FIGURE 2 A simplified concept of ionic exchange; the polarized, depolarized, and repolarized state of myocardial cell; and the action potential.An electrical current arriving at the cell causes positively charged ions to cross the cell membrane, which causes depolarization, followed by repolarization,which generates an action potential: phases 0, 1,2, 3, and 4. This electrical event traverses the heart and initiates mechanical systole, or the heart beat.(From Khan, M. Gabriel, Rapid ECG Interpretation, second edition, Philadelphia: Elsevier, 2003.)

344ELECTROCARDIOGRAPHYRPPRQRS1JST segment2T waveVulnerableperiodIsoelectric line: horizontallevel betweeen cardiac cyclesPPhase 0QT3Phase 4Cell cytoplasmK + K + K + Na +K + K + K + Na +− − − +++ + − − − − −+ + + − − − − + + + + Cell membrane(Sodium) Na +K +Na + Na + K + Na + influx EffluxFIGURE 3 Sodium influx, potassium efflux, the action potential, and electrocardiogram. (From Khan, M. Gabriel (2003). Rapid ECG Interpretation,2 nd ed., Philadelphia: W.B. Saunders.)0SA node actionpotential−90millivoltsSA nodeRight atriumSVCIVCSVC=Superior Vena CavaIVC=Inferior Vena CavaLV=Left VentricleRV=Right Ventricle=Radial spread of atrial acticationRVVentricular muscleaction potentialLVLeft atriumAV nodeLeftbundlebranchPurkinje networkFIGURE 4 Electrical activation of the heart by the sinoatrial (SA)node. The current of activation (arrows) spreads radially from the SAnode across the atria to the atrio-ventricular (AV) node and down thebundle branches to the ventricular muscle and Purkinje network. The SAnode tracing shows no steady resting potential and is characterized byspontaneous depolarization. (From Khan, M. Gabriel (2003). Rapid ECGInterpretation, 2 nd ed., Philadelphia: W.B. Saunders.)patient who has acute chest pain. Figure 6 shows theECG of a patient with infarction of the anterior wallof the heart. The typical diagnostic ECG finding isST-segment elevation in the leads taken over the chest,precordial leads V1 through V6 (ST-segment elevationmyocardial infarction). Figure 7 shows involvement ofthe inferior myocardium during inferior myocardialinfarction.Based on this simple ECG finding, physicians, nurses,or paramedics can commence two chewable aspirin, a betablockingdrug, and intravenous thrombolytic therapy thatcan save the life of greater than 33% of heart attackvictims if this therapy is given within the first hour ofonset of symptoms. If treatment is delayed for more than4 h approximately 15% of lives would be saved, and after6 h benefit is negligible. Most important, based on theresults of two ECGs done 15–30 minutes apart diagnosisis usually sufficiently conclusive to allow such patients toproceed to a catheter laboratory to have coronary angiogramto visualize the blockage of the coronary artery. Thisis followed by balloon angioplasty and stent implantationthat could be life-saving.In patients with chest pain only, ECG findingsdifferentiate patients into two large population groups:ST-segment elevation myocardial infarction and

IV. DIAGNOSIS OF SPECIFIC CONDITIONS345FIGURE 5Normal electrocardiogram.FIGURE 6ST segment elevation in V1 through V6: pathological Q-waves in leads V1 to V5: indicate acute anterior myocardial infarction.

346ELECTROCARDIOGRAPHYnon-ST-segment elevation myocardial infarction (non-Q-wave infarction; see Fig. 8). The treatment strategiesfor these two groups are very different (see the chapterHeart Attacks).IaVRB. Hypertrophy of the HeartEnlargement of the heart, particularly the left ventriclemuscle, is readily detected by ECG. Also patients withhypertrophied hearts caused by hypertrophic cardiomyopathyusually have abnormal ECGs.IIaVLIIIaVFFIGURE 7 Deep pathologic Q waves in II, III, and aVF with markedST segment elevation; acute inferior MI.C. Electrical Conduction DefectsThe electrical current that traverses the atrium and reachesthe ventricle via specialized electrical conducting cablesmay be delayed because of disease in the conductingcables. The branching of cables that supply the right andleft ventricle (Fig. 4) may show signs of an electricalconduction block called right or left bundle branch block.The spiky deflection in the QRS deflection is widenedbeyond 0.12 seconds. Figure 9A and Figure 9B show theelectrocardiographic manifestations of the right bundlebranch block. Figure 10A and Figure 10B, shows manifestationsof the left bundle branch block. Figure 10Breveals two abnormalities, a left bundle branch block anda large deformed P wave in lead I, which indicates leftatrial abnormality. This ECG finding is of importancebecause it is a clue to the presence of hypertrophy orenlargement of the left atrium and an increase in the leftatrial volume or pressure. These clues point to severalunderlying disease states such as left ventricular straincaused by hypertension, left ventricular dysfunction,congestive heart failure, cardiomyopathy, and valvularheart disease. This shows that a simple ECG tracing revealsa considerable amount of information about specific heartabnormalities.FIGURE 8Marked ST segment depression in leads V2 to V6: indicate non-ST segment elevation myocardial infarction (non-Q-wave MI).

IV. DIAGNOSIS OF SPECIFIC CONDITIONS347FIGURE 9 A. Genesis of the QRS complex in right bundle branch block. (From Khan, M. Gabriel (2003). Rapid ECG Interpretation, 2 nd ed.,Philadelphia: W.B. Saunders.) B. ECG shows an rs R pattern in V1 and V2 with a slurred S wave in V6: features of right bundle branch block.D. ArrhythmiaThe most common arrhythmia observed in clinicalpractice is atrial fibrillation. In this condition the atriumfibrillates but does not contract; thus, the P waves areabsent. The atria beat at approximately 300–500 beats perminute. Because of a block in the AV node that separatesthe atrial current from that in the ventricle, the ventriclesbeat slower at 100–200 beats per minute. This conditionis usually not life-threatening and is easily controlledwith drugs such as digoxin or a beta-blocking drug thatreduces the ventricular rate and thus the heart rate to lessthan 100 beats per minute.Figure 11 shows a tracing from a patient with atrialfibrillation in whom the ventricular rate is rapid at 210beats per minute. The rapid ventricular rate causes extrawork for the left ventricle which requires more oxygen.Heart failure may precipitate in patients with disorderssuch as mitral stenosis and many diseases that cause leftventricle dysfunction. In addition, with atrial fibrillationthe left atrium does not contract but quivers; this leads tothrombi formation that attaches to the left atrial wall.These clots may break off and are swept away (embolized)in the bloodstream and may block arteries in the braincausing stroke. Embolism may also occur in the kidneyand leg vessels causing gangrene. Atrial fibrillation can onlybe diagnosed by the ECG.Figure 12 shows the ECG tracing of a patient with atrialfibrillation in whom the fast ventricular rate has beenreduced to 105 beats per minute by a beta-adrenergicblocking drug. (For other arrhythmias, see the chapterArrhythmias/Palpitations).

348ELECTROCARDIOGRAPHYFIGURE 10 A. The contribution of vectors I, II, and III, labeled V(I), V(II), and V(III) to the genesis of left bundle branch block. (From Khan,M. Gabriel (2003). Rapid ECG Interpretation, 2 nd ed., Philadelphia: W.B. Saunders.)FIGURE 11ECG shows atrial fibrillation with an uncontrolled ventricular rate of 210 beats per minute.

V. RECENT DISCOVERIES349FIGURE 12ECG shows atrial fibrillation with a controlled ventricular rate of 105 beats per minute.Figure 15 shows features of WPW syndrome: Deltawave in leads 11, 111, a VF and V1 to V5. Note the shortPR interval

350ELECTROCARDIOGRAPHYFIGURE 13Features of WPW syndrome: Delta waves and a short PR interval.

V. RECENT DISCOVERIES351FIGURE 14 Holter monitor showing multifocal ventricular prematurebeats; couplet, salvos of three, nonsustained ventricular tachycardia.(From Khan, M.G. (2001). On Call Cardiology, 2 nd Ed., Philadelphia:W.B. Saunders.)FIGURE 15 Sustained alternans with onset

EmbryologyI. Development of the HeartGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.caudal pertaining to toward the tail or distal end of the body.cephalic pertaining to the head or to the head end of the body.blastula usually spherical body produced by cleavage of a fertilizedovum, consisting of a single layer of cells (blastoderm)surrounding a fluid-filled cavity (blastocele).embryo developing human from conception until the end of the8th week by which time all organ systems have been formed.ischemic heart disease atherosclerosis (atheromatous plaques)causes obstruction to coronary arteries depriving the myocardiumof blood containing oxygen and necessary nutrients.karyotype chromosomal characteristics of an individual or cellline.myocardium the heart muscle.IT IS NOT WIDELY KNOWN THAT IN THE HUMANembryo, the unique little heart begins to beat as early asday 22. Further research in cardiovascular embryology iscrucial to the understanding of different cardiac anomaliesand the development of therapeutic and preventivestrategies.I. DEVELOPMENT OF THE HEARTCommitment to the cardiogenic cell lineage occurs earlyin development soon after gastrulation (the embryonicstate following the blastula), approximately 48 h followingfertilization. The molecular basis for the formation ofcardiac myocytes from the presumptive mesoderm requiresfurther elucidation. The mesoderm consists of three germlayers that are incorporated in the building of the tissuesand organs of the embryo. Cells committed to the cardiaclineage are first seen to possess characteristics of cardiacmyocytes prior to the formation of the tubular heart.Within 10–14 days of gestation a pair of mainstemvessels are first differentiated; they are the primitive aortae.This pair of tubes comes to lie parallel and close to eachother in the cephalic region of developing body cavity(see Fig. 1). These vessels appear in the splanchnicPrimitive ventral aortaBulbus cordisAtriumPosition oforifice of atrioventricularcanalVentricleTruncus arteriosusBulbus cordisVentricleAtriumSinus venosusVitelline veinTruncus arteriosusBulbus cordisAtriumAtrio-ventricularcanalVentricleVitelline veinTruncus arteriosusVitelline veinAuricle of atriumPosition oforifice of atrioventricular canalRight ventricleIIIAIVAIIIBIVBIIIPrimitive ventral aortaTruncus arteriosusBulbus cordisAtriumAtrio-ventricularcanalSinus venousVentricleVitelline veinTruncus arteriosusVTruncus arteriosusBulbus cordisAuricle of atriumBulbus cordisLeft ventricleAtriumSinus venosusAtrio-ventricularcanalVentricleVitelline veinFIGURE 1 Primitive ventral aorta; formation of a tubular heart andsubsequent stages of development.353

354EMBRYOLOGYmesoderm of the pericardial region of the embryonic areaand extend to the caudal end of the embryo. At thecephalic end the primitive aortae are continuous withanother pair of stem vessels called the vitelline veins.Within a few days when the embryo is less than 2.5 mmlong, the heart is formed in the septum transversum andthe dorsal wall of the pericardium by fusion of the caudalparts of the ventral aortae. A section of main vasculartube specializes and possesses contractile elements withinits walls. These walls of the heart tubes consist of a twocelllayer of myocardial cells and an internal single layerof endothelial cells separated from each other by a thirdlayer called cardiac jelly.In the embryo between 14 to 18 days, precardiac cellsare present in a pair of crescent-shaped regions ofmesodermal tissue lateral to the primitive streak. Furtherdevelopment involves hyperplasia, proliferation of themyocyte cell pool, and growth in cell size (hypertrophy).Pacemaker activity begins at an early primitive stagebefore sinoatrial and atrial tissues have differentiated.By the 21st day, a small region in the left caudal part ofthe conoventricular tube acts as a pacemaker.Study of the biophysical differentiation of the heartin the embryo may reveal embryonic cardiac actioncurrents that indicate how sodium and other channelswork in the adult. Appreciation of the sodium channelsand potassium flux is essential to our understanding ofarrhythmias and the cardioactive agents that may showsalutary effects without causing harm. Conditions andproperties of the cardiac action potential in the embryoresemble those in patients with ischemic heart disease.In the second month the tubular heart doubles overonto itself to form two parallel pumping systems, eachwith two chambers and a great artery. The tubular heartnow speeds up its development. Figure 1 shows furtherstages in heart development. The tubular heart is separatedSeptum primumOstium primumLt. common cardinal veinSeptum secundumCrista terminalisPulmonary veinsACommon pulmonary veinOstium secundumAtriovent.septumSeptal cuspof tricuspidvalveVein ofmarshallAnt. cuspof mitralvalveOstium primumBInf. endocardialcushionLt. sinus valveRt. sinus valveAnt. papillarymuscleModerator bandPrimary int. vent.foramenPost papillarymuscleECDFIGURE 2 Sections through heart of embryos of different ages. Diagrammatic. (A) 6 mm, (B) 9 mm, (C) 12 mm, (D) 17 mm, and (E) 40 mm.(From Van Mierop LHS: Embryology of the atrioventricular canal region, in Feldt RH (ed.) Atrioventricular Canal Defects, W. B. Saunders, Philadelphia,1976, p. 6.)

I. DEVELOPMENT OF THE HEART355by constrictions into six parts named from the caudalto the cephalic end: (1) sinus venosus, (2) atrium, (3) atrioventricularcanal, (4) ventricle, (5) bulbus cordis, and(6) truncus arteriosus. Two ventral aortae and two dorsalaortae fuse in parts of their extent to form a mediandescending aorta.As the heart tube elongates by additional precardiacmesoderm at the caudal end and starts to take on a curvedshape, the pacemaker cells move progressively to thecaudal-most extremity that remains part of the ventricle.After a few days pacemaker function shifts to the rightside, as sinoatrial tissue begins to form. The pacemakeractivity, thus, commences at a primitive stage in thedevelopment of the embryo before the atrial or sinoatrialtissues have differentiated. The two atria develop from thesinoatrium.Figure 2 shows sections through the heart of an embryoat different stages of development. The AV canal is dividedby the endocardial cushions into tricuspid and mitralorifices, and the right and left ventricle are formed fromthe primitive ventricle and bulbus cordis. The atrioventricularcanal leads into the primitive left ventricle, andblood reaches the primitive right ventricle only throughthe primary interventricular foramen.Table 1 shows developmental stages in human embryos.From day 33 to 36 upper limbs are paddle shaped, lensand nasal pits are visible, optic cups are present, lowerlimb buds have appeared, and most important, the heartprominence is distinct (see Fig. 3).Several anomalies may result from defects in the basiccardiac developmental pattern. Table 2 gives teratogenicagents in humans. Lithium plays a role in Ebstein’sTABLE 1Developmental Stages in Human Embryos aAge (days) Stage No. of somites Length (mm) Main characteristics20–21 9 1–3 1.5–3.0 Deep neural groove and first somites present. Head fold evident.22–23 10 4–12 2.0–3.5 Embryo straight or slightly curved. Neural tube forming or formedopposite somites, but widely open at rostral and caudal neuropores.First and second pairs of branchial arches visible.24–25 11 13–20 2.5–4.5 Embryo curved due to head and tail folds. Rostral neuropore closing.Otic placodes present. Optic vesicles formed.26–27 12 21–29 3.0–5.0 Upper limb buds appear. Caudal neuropore closing or closed. Three pairsof branchial arches visible. Heart prominence distinct. Otic pits present.28–30 13 30–35 4.0–6.0 Embryo has C-shaped curve. Upper limb buds are flipper-like. Four pairsof branchial arches visible. Lower limb buds appear. Otic vesicles present.Lens placodes distinct. Attenuated tail present.31–32 14 b 5.0–7.0 Upper limbs are paddle-shaped. Lens pits and nasal pits visible.Optic cups present.33–36 15 7.0–9.0 Hand plates formed. Lens vesicles present. Nasal pits prominent.Lower limbs are paddle-shaped. Cervical sinus visible.37–40 16 8.0–11.0 Foot plates formed. Pigment visible in retina. Auricular hillocks developing.41–43 17 11.0–14.0 Digital, or finger, rays appear. Auricular hillocks outline future auricleof external ear. Trunk beginning to straighten. Cerebral vesicles prominent.44–46 18 13.0–17.0 Digital, or toe, rays appearing. Elbow region visible. Eyelids forming.Notches between finger rays. Nipples visible.47–48 19 16.0–18.0 Limbs extend ventrally. Trunk elongating and straightening.Midgut herniation prominent.49–51 20 18.0–22.0 Upper limbs longer and bent at elbows. Fingers distinct but webbed.Notches between toe rays. Scalp vascular plexus appears.52–53 21 22.0–24.0 Hands and feet approach each other. Fingers are free and longer.Toes distinct but wedded. Stubby tail present.54–55 22 23.0–28.0 Toes free and longer. Eyelids and auricles of external ears are more developed.56 23 27.0–31.0 Head more rounded and shows human characteristics. External genitalia stillhave sexless appearance. Distinct bulge caused by herniation of intestinesstill present in umbilical cord. Tail has disappeared.a Modified, with permission, from K. L. Moore (1982). Criteria for estimating developmental stages in human embryo. In ‘‘The Developing Human:Clinically Oriented Embryology,’’ 4th Ed. Saunders, Philadelphia.b At this and subsequent stages, the number of somites is difficult to determine and therefore is not a useful criterion.

356EMBRYOLOGYTABLE 2ContinuedAndrogenic hormonesBusulfanChlorobiphenylsCocaineCoumarin anticoagulantsCyclophosphamideDiethylstilbestrolDiphenylhydantoinEnalapril (and other ACE inhibitors)EtretinateIodides and goiterFIGURE 3 Well-developed embryo at stage 15, length 7 mm, showingdeveloping eye (arrow), mouth (arrow), heart (h), upper limb (U), andlower limb (L). The presence of tail (T) is a normal finding at this stage.Umblical cord (u) contains three vessels. (From Encyclopedia of HumanBiology, 1997.)TABLE 2Teratogenic Agents in HumansLithiumMercury, organicMethimazole and scalp defectsMethylene blue via intraamniotic injectionMisoprostolPenicillamienTetracyclinesThalidomideTrimethadioneValproic acidRadiationAtomic weaponsRadioiodineTherapeuticInfectionsCytomegalovirusHerpes virus hominis I and IIParvovirus B-19 (Erythema infectiosum)Rubella virusSyphilisToxoplasmosisVenezuelan equine encephalitis virusMaternal metabolic imbalanceAlcoholismDiabetesEndemic cretinismFolic acid deficiency (includingfollowing gastric bypass surgery)HyperthermiaPhenylketonuriaRheumatic disease and Sjögren’ssyndrome (congenital heart block)Virilizing tumorsChorionic villus sampling, early before the 60th dayDrugs and environmental chemicals13-cis Retinoic acid (isotretinoin and accutane)Aminopterin and methylaminopterin(continued)Possible teratogens?Binge drinking?Carbamazepine?Cigarette smoking?Disulfiram?Fluconazole, high dose?High vitamin A?Lead?Primidone?Streptomycin?Toluene abuse?Varicella virus?Zinc deficiencyUnlikelyAgent OrangeAnestheticsAspartameAspirin (but aspirin in the second half of pregnancy mayincrease cerebral hemorrhage during delivery)Bendectin (antinauseants)Birth control pillsIllicit drugs (marihuana, LSD)MetronidazoleProgesterone (hydroxyprogesterone and medroxyprogesterone)Rubella vaccineSpermicidesUltrasoundVideo display screens

I. DEVELOPMENT OF THE HEART357anomaly and tricuspid atresia. Dilantin is known to causepulmonary stenosis, aortic stenosis, coarctation, and patentductus arteriosus. Rubella is a known cause of patentductus arteriosus, atrial septal defects, and ventricularseptal defects as well as other anomalies.During the past decade workers have identified severalmyogenic determination genes and factors involved in theregulation of muscle gene expression. Gene regulation inthe heart is still poorly understood and fruitful research ison the horizon. A single gene mutation is causativein the familial forms of atrial septal defect, mitral valveprolapse, ventricular septal defect, situs inversus, Noonansyndrome, Holt-Oram syndrome, and Marfan syndromeas well as other anomalies.BIBLIOGRAPHYFriedman, W. F., and Silverman, N. Congenital heart disease ininfancy and childhood. In Heart Disease, sixth edition. E. Braunwald,D. P. Zipes, and P. Libby, eds. W. B. Saunders, Philadelphia, 2001.Kalousek, D. K., and Hendson, G. Embryofetopathology. In Encyclopediaof Human Biology, second edition, Academic Press, San Diego, 1997,p. 605.Shepard, T. H. Teratology. In Encyclopedia of Human Biology, secondedition, Academic Press, San Diego, p. 253, 1997.

EndocarditisI. Definition and Sites of InfectionII. DiagnosisIII. TherapyIV. PreventionGLOSSARYendocarditis infection of the endocardial lining of heart valves.endocardium the interior lining of the heart (see the chapter.Anatomy of the Heart and Circulation).nosocomial pertaining to or originating in a hospital.I. DEFINITION AND SITES OF INFECTIONValves previously affected by rheumatic fever and othervalve diseases are thick, rough, and swollen. Bacteria thatgain entry into the bloodstream on their way throughthe heart may attach to the roughened valve surface and setup an area of infection. This bacteria may grow to forman ‘‘abscess’’ on the valve. The abscess resembles a clumpof moss that swings and sways on the valve leaflet as itopens and closes.Infection of the heart valves is called infective orbacterial endocarditis. Usually the infection is by bacteria,thus the term bacterial endocarditis, but infections causedby fungi, Coxiella, or chlamydiae can occur, thus the terminfective endocarditis is used by many physicians. Infectionnay involve heart valves not previously known to beabnormal such as a bicuspid aortic valve, mitral valveprolapse, and rarely a septal defect or ventricular aneurysm.Coarctation of the aorta, patent ductus arteriosus,aneurysms, or arteriovenous shunts may be the sitesof infective endocarditis. Prosthetic heart valves maybe involved and infection at the site of implantation offoreign material may pose a particularly difficult problem.In susceptible individuals, bacterial endocarditis canbegin weeks or months after simple manipulations suchas scaling and cleaning of teeth, other dental work, andsurgery in areas of the body where infection may gainaccess. Patients who have mild heart valve lesions but cannormally live a normal life to beyond age 80 may havetheir lives suddenly shortened by this infection.Clinicians find it convenient to classify endocarditis infive categories:1. Endocarditis that involves predominantly left-sidednative valves (mitral and aortic) affected by disease,particularly of rheumatic, degenerative, or congenitalorigin.2. Prosthetic valve endocarditis.3. Endocarditis in intravenous drug users: the tricuspidvalve is infected in more than 50% of cases, and theaortic in about 25%. More than 75% of patients haveno known pre-existing valve lesions. The predominantorganism is Staphylococcus aureus, but Pseudomonasand fungi cause severe valve infections. HIV positivepatients may present with unusual organisms bartonella,salmonella, and listeria.4. Nosocomial endocarditis is most often caused Staphylococcusand enterococci; infections that are associatedwith indwelling catheters and medical-surgical proceduresincluding hemodialysis and bone marrowtransplant.5. Culture negative endocarditis exhibits the usualbacterial organisms but they are masked by previousantibiotic therapy. Slow-growing penicillin-sensitiveorganisms with fastidious nutritional tastes may notbe detected because special culture medium arerequired for their growth, isolation, and detection;also, Brucella, Chlamydia, and Coxiella may not bereadily detected.II. DIAGNOSISThe diagnosis of endocarditis requires a high index ofsuspicion. The condition must be considered and carefully359

360ENDOCARDITISexcluded in all patients with a heart murmur and feverof undetermined origin that persists for more than a fewdays. Diagnosis is made in the majority of patients by threeor four separate sets of blood cultures taken from a separatevein puncture site over 24 h.Transesophageal echocardiography (TEE) is superior totransthoracic assessment in the search for infected vegetationslocated on heart valves and is crucial for the diagnosisof endocarditis. Transthoracic two-dimensional Dopplerechocardiography gives poor detection of prosthetic heartvalves, especially in the mitral position, and of calcificsclerotic native valves. Vegetations that are less than 5 mm,6–10 mm, or greater than 10 mm are observed in 25, 65,and 70%, respectively, by transthoracic technique. This is100% for all lesions using TEE.Bacterial endocarditis is caused most often by infectionwith Streptococcus viridans (40%) followed by S. aureus(30%) enterococci in about 10–15% of cases.Other organisms include Staphylococcus mitis, S. bovis, S.anginosus, Haemophilus influenzae, Pseudomonas aeruginosa,P. cepacia, and Serratia marcescens.gentamicin (1–1.5 mg/kg every 8 h) and monitor levelsand adjustment for renal function. Gentamicin is givenfor 4 weeks.4. S. aureus: Methicillin-sensitive strains constitute themost cases of S. aureus endocarditis and these are treatedwith nafcillin or cloxacillin (at doses given above) orflucloxacillin (IV 2 g every 4 h) plus optional addition ofgentamicin (1 mg/kg every 8 h IV) for 4–7 days; thedose is to be monitored by levels. The dose is reduced inelderly patients and those with renal dysfunction,whereas the dosing interval is increased. Gentamicin isdiscontinued after 1 week, and nafcillin or flucloxacillinIV is continued for 5–6 weeks. The length of treatmentis usually from 4–6 weeks. In the UK, S. aureusendocarditis is usually treated with IV flucloxacillinfrom 4–6 weeks and gentamicin IV for 14 days.Antiplatelet agents including aspirin, ticlopidine, andclopidogrel are not recommended because they increase therisk of bleeding in patients with endocarditis complicatedby cerebral emboli; these agents may also decrease beneficialplatelet induced bactericidal activity.III. THERAPYIntravenous antibiotics are commenced soon after sufficientblood cultures are obtained; usually a combinationof nafcillin (oxacillin or flucloxacillin), ampicillin, andgentamicin is administered. Changes are made when theorganism and antibiotic sensitivities are established.Organisms that commonly cause endocarditis and appropriateantibiotic combinations include the following:1. S. viridans or S. bovis: If the MIC to penicillin is lessthan 0.1 mg/ml, give penicillin (IV 2–3 million U every4 h for 4 weeks) or 2 weeks IV then amoxicillin (orally500 mg every 6 h for 2 weeks) or ampicillin/sulbactam(2 g every 6 h for 2 weeks IV) and then amoxicillin(orally 500 mg every 6 h for 2 weeks) or penicillin andgentamicin IV for 2 weeks or ceftriaxone 2 g once dailyIV for 2 weeks. Then IV or IM therapy once daily givenas an outpatient or in the home is cost saving; but IMceftriaxone is painful.2. Partially sensitive S. viridans or S. bovis, MIC penicillingreater than 0.1 mg/ml: penicillin (3 million U every 4 hIV) plus gentamicin (1–1.5 mg/kg every 8 h IV for 2 to4 weeks) or, from the third week, amoxicillin (500 mgorally every 6 h for 2 weeks).3. S. fecalis, S. fecium, S. durans, or similar fecal streptococciare difficult to eradicate: If the length of illnessis less than 3 months, it is advisable to give ampicillin/sulbactam (IV 2–3 g every 6 h for 4 weeks) plusIV. PREVENTIONPrevention of some cases of bacterial endocarditis isachieved by intelligent use of appropriate antibiotics onthe day of dental or other surgery. Approximately 25% ofcases of endocarditis are believed to be of dental origin andin approximately 75% of cases the portal of entry cannot beidentified. In over 40% of cases infection occurs on valvesnot known to be abnormal, especially on bicuspid aorticvalves and in patients with mitral valve prolapse. Except forprosthetic valves in which a powerful antibiotic regime isadministered, prophylaxis is aimed at streptococci, whichaccounts for only about 65% of all cases of endocarditis.The American Heart Association has guidelines forpreventing bacterial endocarditis. Patients with valvularheart disease must be given antibiotics one hour prior to alldental or surgical procedures. The antibiotic is given orallyfor dental work done under local anesthetic. It is givenintravenously for patients with prosthetic valves, patientswith highest risk of developing endocarditis, or patientswho are having a general anesthetic. All dental proceduresthat are likely to result in gingival bleeding such as extractions,root canal, scaling and cleaning, surgery in the oralcavity, biopsies, and many surgical operations and testssuch as cystoscopy require antibiotic coverage to preventendocarditis.Another guideline includes oral antibiotic therapy tobe given when a local anesthetic is used such as amoxicillin

IV. PREVENTION3612 g one hour prior to the procedure. Patients allergic topenicillin usually receive clindamycin 600 mg one hourprior to the procedure. For surgery on the intestine orthe genitourinary systems, other antibiotics are requiredintravenously. Patients must warn the doctor in thehospital or dentist regarding the presence of heart valvedisease that require prophylactic antibiotics. Prophylacticregimens are given in Tables 1 and 2.A. Case History IMrs. S., age 69, had a fever of 100–104 F with chillsand weakness over a period of 14 months. She hadattended several clinics and physicians including oneperiod of hospitalization. She was previously quite welland was not known to have heart disease. She had sixchildren who were alive and healthy, and it was a surpriseto them that their previously healthy mother was nowbedridden. She was not short of breath and there wasno cough. The diagnosis was obvious. The woman hada soft systolic murmur at the apex of the heart and typicalswelling of the fingertips near the nailbed called fingerclubbing. Clubbing is a hallmark of bacterial endocarditis.On questioning, she admitted that 14 months previouslyshe had all her teeth removed. She was treated witha combination of penicillin and streptomycin for a periodof 6 weeks and she made an uneventful recovery. Ten yearslater she was alive and well.B. Case History IIOne unfortunate morning L. H., a 29-year-old femalewho was known to have a soft heart murmur, was walkingto the bathroom and fell to the floor. Her left arm feltweak and her speech was slurred. She was rushed to thehospital, and after three days she made a complete recoveryand was discharged.Three weeks later she had the typical features offinger clubbing, murmur, and fever and was admitted tothe hospital. She had a temperature of 100–102 F. Herblood was taken and cultured and grew a bacteria calledS. viridans. This is the most common cause of bacterialendocarditis. She was treated with penicillin and streptomycinfor 6 weeks and made a good recovery. Herpreviously mild mitral valve regurgitation became moderate.Twenty-five years later, she is able to do her usualwork, exercises, and enjoys life with minimal restrictions.Apart from infection of previously damaged heart valvesas well as prosthetic valves, normal valves can becomedamaged. Fortunately this is extremely rare and seenmainly in drug addicts. Contaminated syringes and needlesmay introduce germs into the bloodstream and can infectvalves on the right side of the heart (tricuspid and pulmonaryvalves). These germs are very active growing types;thus, they can damage normal valves. The bacteria foundin such cases are staphylococcus and pseudomonas.Preventive medicine has helped to eradicate streptococcusnot only by the use of antibiotics but also through therelief of overcrowding and the improvement of sanitationand ventilation in disadvantaged socioeconomic groups.Thus, rheumatic fever is now rare in North America but iscommon in India, Pakistan, Africa, the West Indies, andSouth America.BIBLIOGRAPHYCabell, C. H., Abrutyn, E., and Karchmer, A. W. Bacterial endocarditis.The disease, treatment, and prevention. Circulation, 107:e185,2003.Khan, M. Gabriel Cardiac Drug Therapy, sixth edition, W. B. Saunders,Philadelphia, 2003.Moreillon, P., and Que, Y.-A. Infective endocarditis. Lancet,363:139–149, 2004.Remadi, J. P., Najdi, G., Brahim, A., Coviaux, F., Tribouilloy, C. et al.Superiority of surgical versus medical treatment in patients withStaphylococcus aureus infective endocarditis, pages 195–199.

Endocrine Disorders and the HeartI. AcromegalyII. Thyroid DiseasesIII. Adrenal DisordersGLOSSARYangina chest pain caused by temporary lack of blood to anarea of heart muscle cells, usually caused by severe obstructionof the artery supplying blood to the segment of cells.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiomyopathy heart muscle disease.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.myocardium heart muscle.tachycardia increase in heart rate exceeding 100 beats perminute.I. ACROMEGALYThe anterior pituitary gland secretes at least sevenpolypeptide hormones. Two of these hormones are releasedby the hypothalamus: somatostatin-releasing hormonewhich stimulates growth hormone secretion and somatostatinwhich regulates the release of growth hormone fromthe anterior pituitary. Growth hormone regulates anindividual’s growth. It also increases the heart rate andmyocardial contractility. Specific receptors for growthhormone in the myocardium promote cardiac remodeling,increased contractility, and myocytic hypertrophy.Excess growth hormone secretion causes acromegaly. Withthis disease, the left ventricle mass, stroke volume, andcardiac output increase significantly. Virtually all cases ofacromegaly are caused by a chromophobic or eosinophilicadenoma of the pituitary. Rarely, it is caused by excessivesecretion of the somatostatin-releasing hormone from thehypothalamus.A. Clinical FeaturesThese features include enlargement of the heart, prematurecoronary artery disease, congestive heart failure, hypertension,intraventricular conduction defects, and cardiacarrhythmias. Mild hypertension occurs in more than50% of patients. Other manifestations include headache;visual field defects (bitemporal hemianopsia); the growthof the hands, feet, and head; coarsening facial featureswith elongation of the jaw giving a typical lanternjawappearance; enlargement of the liver; and glucoseintolerance.Acromegalic cardiomyopathy occurs, albeit rarely. Thereis myocyte hypertrophy and an increase in the collagencontent per gram of heart compared with normal myocardium.The defect in the myocardium causes arrhythmias,which weaken the myocardial force that leads tocongestive heart failure. Treatment of patients withsomatostatin analogs that inhibit secretion of growthhormone, octreotide and lanreotide, have shown beneficialeffects in small studies. In some patients congestive heartfailure has been completely controlled. The left ventriclemass index and mean wall thickness have also shownimprovement with this therapy. Still, in patients withlong-standing acromegaly there is nonreversible interstitialfibrosis with little recovery.B. ManagementHeavy particle, proton beam irradiation or surgery isusually curative. Hypertension can be controlled withdiuretics or other antihypertensive agents and acromegalic363

364ENDOCRINE DISORDERS AND THE HEARTcardiomyopathy may show some amelioration with theadministration of octreotide.shows sinus bradycardia, elongation of the QT interval,and low voltage.II. THYROID DISEASESA. ThyrotoxicosisHyperthyroidism (thyrotoxicosis) is caused by an excessivesecretion of thyroid hormone, L-thyroxine. This hormonehas direct cardiac effects manifesting in a marked increasein heart rate and myocardial contractility.1. Clinical FeaturesSymptoms of thyrotoxicosis include heat intolerance,excessive sweating, nervousness, irritability, anxiety,marked weight loss, increase in appetite, and palpitationswith fast heart rates. Palpitations may be caused by amarked increase in heart rate, but the heart rhythm maybecome irregular because of the occurrence of atrialfibrillation. Physical signs include tachycardia, agitation,enlargement of the thyroid gland, and typicaleye signs.Atrial fibrillation with a rapid heart rate of more than150 beats may force patients to seek attention. Increasingshortness of breath is usually caused by excessivecardiac work resulting in myocardial dysfunction and heartfailure.2. ManagementThe cardiovascular manifestations of thyrotoxicosis areoften resistant to therapy. Atrial fibrillation does notrespond to treatment with digoxin, and the beta-blockingagents are most useful in controlling the fast heart rateevidenced in sinus tachycardia or caused by atrialfibrillation until specific treatment of the thyroid disturbancebecomes effective. Irradiation with radioactiveiodine or surgical removal is usually successful.2. ManagementThese cardiac complications are rarely seen because ofmore efficient diagnosis and treatment. Administration ofL-thyroxine in adequate doses usually produces beneficialresults after 3–6 months of therapy.III. ADRENAL DISORDERSA. Cushing’s SyndromeThis disorder is caused by either an ACTH-dependentadenoma or an ACTH-independent adenoma. Cushing’sdisease in greater than 70% of the cases is caused byectopic ACTH syndrome, and 10% percent of the timeit is caused by an ectopic corticotropin-releasing hormone.An ACTH-independent adrenal adenoma causes Cushing’ssyndrome in 10% of cases, it is caused by adrenalcarcinoma in 10% of the cases, and rarely it is seen inmicronodular adrenal diseases and during iatrogenicexogenous glucocorticoid administration.1. Clinical ManifestationsThese manifestations include a characteristic form oftruncal obesity which involves the abdomen, chest, andthe upper back causing a buffalo hump. The upper andlower limbs are thin and some wasting and weakness of theupper thigh muscles (the quadriceps) occurs. Because ofthis, the patient has difficulty climbing stairs.Cardiovascular complications such as hypertension maybe severe. Diabetes may occur and along with hypertensionthis increases the risk for myocardial infarction. Acceleratedatherosclerosis is a common finding in patients nottreated early in the course of this disease.B. Hypothyroidism (Myxedema)1. Cardiovascular ManifestationsThe heart may become dilated and the heart rate is oftenreduced to less than 50 beats per minute. The heart muscleis partially replaced by interstitial fibrosis with weakeningof the cardiac muscles resulting in heart failure. There isa marked increase in serum cholesterol and angina or myocardialinfarction occurs prematurely. Electrocardiogram2. ManagementCushing’s disease requires transsphenoidal pituitarysurgery and adrenal tumors require adrenalectomy. EctopicACTH syndrome occurs and requires treatment of theunderlying tumor. Correction of hypokalemia withpotassium replacement and spironolactone and drugsthat block steroid synthesis may be also be required.

III. ADRENAL DISORDERS365B. HyperaldosteronismHyperaldosteronism is usually caused by an aldosteroneproducingadenoma and rarely by bilateral adrenocorticalhyperplasia.1. Clinical ManifestationsPotassium depletion occurs that may produce muscularweakness. Sodium retention causes an increase in bloodpressure, but hypertension is usually mild to moderate inintensity. It may be resistant to the usual antihypertensivemedications.Aldosterone has a direct effect on collagen metabolismin cardiac fibroblasts and reactive perivascular and interstitialcardiac fibrosis occurs. Aldosterone appears toincrease plasminogen activator inhibitor type 1 expressionand secretion and contributes to the inflammatoryresponse accompanying microvascular disease. The weakdiuretic, spironolactone, an aldosterone antagonist, hasbeen shown in a large randomized clinical trial in patientswith severe heart failure to reduce mortality and morbidity.A new agent, eplerenone, has the same actions as spironolactoneand has also been shown to reduce mortality andmorbidity in a large randomized trial of patients withsevere heart failure (see the chapter Diuretics).C. PheochromocytomaThis disorder is an extremely rare. The lesion is usually atumor of the adrenal medulla (10% are bilateral), 10%of the time it is malignant, and 10% of the time it is outsidethe adrenal medulla where 10% of those are familial.1. Cardiovascular ManifestationsCardiovascular manifestations of pheochromocytomainclude severe headaches and profuse sweating, palpitations,severe labile hypertension or sustained severehypertension, palpitations due to sinus tachycardia, andcardiac arrhythmias. A life-threatening myocarditis mayoccur, and in some cardiomyopathy and heart failuremay develop that may be reversed when the offendingtumor is removed.Diagnosis requires the finding of an elevated 24-h urinetotal of metanephrines and an increase in plasma catecholamines.Elevated dopamine serum levels are estimatedon the same blood samples taken for epinephrine, becausedopamine may be the only chemical produced by somemalignant pheochromocytomas. An MRI may reveal atumor.2. ManagementHypertensive crisis may require use of phentolaminebefore the administration of phenoxybenzamine. Nitroprussideshould be used to lower blood pressure during acrisis and nifedipine is also useful for emergency bloodpressure control. Surgery provides an expected cure in upto 80% of patients.BIBLIOGRAPHYMasoudi, F. A., Inzucchi, S. E., Wang, Y., Havranek, E. P., Foody, J. M.,Krumholz, H. M. et al. Thiazolidinediones, Metformin, and outcomesin older patients with diabetes and heart failure: An observationalstudy. Circulation, 111:583–590, 2005.Moreno, P. R., Fuster, V. et al. New aspects in the pathogenesis of diabeticatherothrombosis. J. Am. Coll. Cardiol., 44:2293–2300, 2004.Ripoli, A., Pingitore, A., Favilli, B., Bottoni, A., Turchi, S., Osman, N. F.,De Marchi, D., Lombardi, M., L’Abbate, A., Iervasi, G. et al. Doessubclinical hypothyroidism affect cardiac pump performance? JACC,45:439–445.Seely, E. W., and Williams, G. H. The heart and endocrine disorders.In Heart Disease, sixth edition. E. Braunwald, D. P. Zipes, and P. Libby,eds. W. B. Saunders, Philadelphia, 2001.Weinstein, A. R., Sesso, H. D., Lee, I. M. et al. Relationship of physicalactivity versus body mass index with type II diabetes in women. JAMA,292:1188–1194, 2004.

Erectile Dysfunction and the HeartI. Mechanism of Erectile DysfunctionII. Causes of Erectile DysfunctionIII. ManagementGLOSSARYdyslipidemia the same as hyperlipidemia, elevated blood cholesterol,LDL cholesterol, triglycerides, or low HDL cholesterol.endothelium the innermost part of the intima that comes incontact with circulating blood, a silky smooth layer of epithelialcells.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severe obstructionof the artery supplying blood to this area of cells.myocardial infarction death of an area of heart muscle due toblockage of the coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.ERECTILE DYSFUNCTION (ED) IS OBSERVED OFTENin men with cardiovascular disease. In a Boston surveyof 1790 free living men age 40–70, 50% reported somedegree of ED — 10% severe and 25% moderate. EDoccurs in men worldwide and has several causes, butcardiovascular disease and diabetes play a major role inmany individuals. Some investigators have suggested thatED may serve as a predictor for cardiovascular disease,because in both conditions endothelial dysfunction isderanged. Endothelial dysfunction is a well-defined entityand is a major player in the pathogenesis of atherosclerosis,its complications, and symptomatology. Endothelial dysfunctionshares many common risk factors with bothatherosclerotic vascular disease and ED.I. MECHANISM OF ERECTILEDYSFUNCTIONA. Physiology of Penile ErectionED is a disorder of the blood supply to the penis. Nitricoxide (NO) bioavailability is at the core of normal andabnormal erectile function. Nitric acid is synthesized fromthe amino acid L-arginine in response to sexual stimulation.Physical or emotional stimulation causes brain orneuronal NO synthase (bNOS) located in nonadrenergic,noncholinergic cavernous nerves of the penis to releaseNO. Nitric oxide is a powerful dilator of blood vesselsand is formed during the conversion of L-arginine toL-citrulline by the enzyme NO synthase. It is a small unstablemolecule that mediates many of the normal functionsof the endothelial lining of blood vessels.The endothelium is the inner lining of blood vesselsthat is in contact with circulating blood. NO is responsiblefor neurally induced vasomotor changes at the level of thecorpora cavernosa which generates penile erection. Also,cholinergic nerves release acetylcholine, which acts on thesurface receptors of endothelial cells leading to activationof endothelial NO synthase (eNOS) and in healthyendothelium it releases significant levels of NO. The bioactiveNO diffuses to the trabecular smooth muscle cellssurrounding the sinusoidal spaces and acts on guanylylcyclase, which generates cyclic guanosine monophosphate(cGMP). This has a vasodilatory effect and appears tocause relaxation of the cavernosal smooth muscle, allowinga marked inflow of blood into the sinusoidal spaces andengorgement of the penis. As the penis fills with blood, aveno-occlusive process comes into play blocking theoutflow of blood. This maintains the erection (see Fig. 1).There is arterial dilatation with increased inflow ofblood and cavernous filling followed by entrapment ofblood. It is believed that the essential relaxation of thecorpus cavernosal smooth muscle required for penile367

368ERECTILE DYSFUNCTION AND THE HEARTPhysical or emotional stimulationNA/NC NEURONSCholinergic nerves: acetylcholineEndothelial cells of penile blood vesselsNOIncrease blood flow4. Corpus cavernosum2Guanyiatecyclase*PDEscGMP12Cavernous engorgementVeno-occlusive processEntrapment**3. Relaxation ofsmooth muscleFIGURE 1Erection maintainedNormal physiology of penile erection.erection involves a nonadrenergic, noncholinergic mechanismmediated by NO and cGMP, but the exact mechanismneeds further elucidation (Fig. 1).A state of increased oxidative stress renders NO inactive.Release of norepinephrine from adrenergic nervesenhanced by many stimuli, coupled with the endothelialrelease of endothelin, induces smooth muscle cell contractionand hinders penile erection. Endothelin is a potentvasoconstrictor and endothelial dysfunction increases thesynthesis and release of endothelin. The same pathophysiologicprocesses generate a temporary decrease in bloodsupply through the coronary arteries to the heart muscleduring attacks of anginal chest pain. Endothelial dysfunctionplays a role, therefore, in both ED and ischemic heartdisease.Erectile dysfunction may be the presenting symptomin patients who have diseases characterized by endothelialdysfunction such as coronary artery disease, diabetesmellitus, hypertension, and dyslipidemias. Nobel LaureateR. F. Furchgott brought endothelial dysfunction to lightwhen he observed that arteries denuded of endotheliumcontracted in response to acetylcholine, while normalarteries dilated. There is little doubt that endothelialdysfunction is caused in many instances by a decrease inthe bioavailability of endothelial NO, and ED is oftencaused by decrease in NO of endothelial or neural origin.All the common risk factors for cardiovascular diseaseare associated with an enhanced oxidative stress andendothelial dysfunction. The production of superoxide isincreased in these conditions and causes inactivation ofNO. Cardiovascular risk factors increase the production ofsuperoxide in endothelial cells where NO is producedcausing immediate decrease in NO bioavailability, evenwhen normal amounts are produced. Thus, the amount ofbioactive NO is a function of the state of oxidative stressin the endothelium as much as of the total amount ofNO synthesized by eNOS and in the situation of penileerection, also by bNOS. Mechanisms are not complete,however, because NO is not only released from endothelialcells but also from neurons in smooth muscle andpossibly from the cavernous smooth muscle cells. So endothelialdysfunction, now proclaimed by many to be theroot of the problem, may be only a branch (see Fig. 1).In addition, the corpus cavernosum does not containmuch muscle. Virtually all of the corpus cavernosumconsists of a fine sponge-like framework whose interspacescommunicate freely with one another and are filled withblood (Fig. 1). These spaces lead directly into veins of

III. MANAGEMENT369the penis. The size of the penis varies with the amount ofblood in the erectile tissue, and there is more blood thanmuscle. Relaxation of muscle may not be as importanta feature as stated in most descriptions of ED, and theuse of phosphodiesterase inhibitors and the accumulationof cGMP causes a marked inflow of blood followed byentrapment of blood that maintains the erection.II. CAUSES OF ERECTILE DYSFUNCTIONPsychogenic factors including depression are commoncauses of ED. About 25–75% of patients with depressionexperience some degree of ED. Cigarette smoking andalcohol have a negative impact on penile blood flow aswell as on the nerve supply. Cigarette smoking appears tocause a constriction of small penile arteries.More than 30% of cases of ED are estimated to correlatewith a comorbid illness. Pathologic causes of ED includethe following: Vascular disease, 40% Diabetes mellitus, 20% Severe dyslipidemia, 10% Medications, >5% Endocrine, 5% Urologic, 5% Neurologic,

370ERECTILE DYSFUNCTION AND THE HEARTarteries, arterioles, and sinusoids of the corpus cavernosumof the penis. Phosphodiesterases are enzymes that hydrolyzecGMP, a prime mediator of vasodilation. Sildenafil, aphosphodiesterase inhibitor, has a high affinity for thephosphodiesterase-5 (PDE-5) isoform that is abundant inthe corpus cavernosum vascular smooth muscle, visceraland skeletal muscle, and in platelets. Figure 1 indicatesboth the normal physiology of penile erection and thatinhibition of PDE-5 causes accumulation of cGMP. Thisaccumulation produces arterial dilatation and increasedblood flow to the corpus cavernosal smooth muscle.The exact mechanism for penile smooth muscle relaxationfollowing NO-induced cGMP accumulation and theveno-occlusive phenomenon which causes entrapmentof blood that maintains engorgement and sustains theerection remain unclear (Fig. 1).2. Patients with uncontrolled hypertension with bloodpressure greater than 180 systolic or greater than105 mmHg diastolic3. Patients with heart failure or coronary artery diseasemanifested by unstable angina or with angina that hasshown even a minimal increase in severity and that mayprovoke the use of nitroglycerin4. In patients with retinitis pigmentosa5. Concomitant use of agents that use the cytochromeP450 3A4 pathway: erythromycin, azithromycin,cimetidine, ketoconazole, antifungal agents, proteaseinhibitors, and probably some statins (see Table 1)TABLE 1List of Representative Organic NitratesB. SildenafilSildenafil was originally developed as an antihypertensiveagent, but the fortunate observation of the interesting sideeffects for ED provided us with an excellent addition to ourarmamentarium that improves the quality of life of manyworldwide. More than one billion tablets of sildenafil havebeen used.Sildenafil is usually taken as a 50-mg tablet about onehour before sexual activity. The maximum dose is 100 mg.The drug requires sexual stimulation to be effective. The25-mg tablet is advisable in patients with blood pressure inthe low normal range of 110–120 mmHg, in individualsover age 70, and in those with renal dysfunction or liverdisease. The drug becomes effective from a half an hour to2 hours and lasts about 4 hours.1. Side EffectsAdverse effects of the three available drugs are headache,flushing, indigestion, and an erection lasting more than4 hours, which requires emergency treatment to preventdamage to the penis.2. ContraindicationsBelow is a list of contraindications for the use of sildenafil,vardenafil, and tadalafil.1. Individuals with low blood pressure of less than100 mmHg systolic should avoid these drugs; it isalso advisable, however, to avoid the drug if the systolicblood pressure is frequently less than 110 mmHgNitroglycerinDeponitMinitranNitrokNitro-BidNitrocineNitrodermNitro DiscNitro-DurNitrogardNitroglycerinNitroglycerin T/RNitroglynNitrol ointmentNitrolingual sprayNitrongNitro-ParNitropressNitro SANitrospanNitrostatNitro-trans systemNitro transdermalNitro-TimeTransiderm-NitroTridilIsosorbide mononitrateImdurISMOIsosorbide mononitrateMonoketIsosorbide nitrateDilatrate-SRIso-Bid(continued)

III. MANAGEMENT371TABLE 1ContinuedIsordilIsordil tembidsIsosorbide dinitrateIsosorbide dinitrate LASorbitrateSorbitrate SAPentaerythritol tetranitratePeritratePeritrate SAErythrityl tetranitrateCardilateIsosorbide dinitrate/PhenobarbitalIsordil w/PBIllicit substances containing organic nitratesAmyl nitrate or nitrite (It is known that amyl nitrate or nitrite issometimes abused. In abuse situations, amyl nitrate or nitrite may beknown by various names, including ‘‘poppers.’’)Drugs that are Metabolized by or that Inhibit CytochromeP450 3A4Antibiotic/antifungalBiaxin (clarithromycin)ClotrimazoleErythromycinDiflucanSporanoxKetoconazoleMiconazoleNoroxinTroleandomycinCardiovascularAmiodaroneNorvascDigitoxinDiltiazemDisopyramidePlendil (felodipine)DynaCirc (isradipine)Cozaar (losartan)Posicor (mibefradil)NifedipineQuinidineVerapamilHMGLipitor (atorvastatin)Mevacor (lovastatin)Zocor (simvastatin)Central nervous systemAlprazolam(continued)TABLE 1ContinuedCarbamazepineProzac (fluoxetine)Luvox (fluvoxamine)ImipramineSerzone (nefazodone)PhenobarbitalPhenytoinZoloftTriazolamOthersAcetaminophenHismanal (astemizole)Tagamet (cimetidine)Prepulsid (cisapride)CyclosporineDexamethasoneEthinyl estradiolNaringenin (grapefruit juice)Prilosec (omeprazole)RifampinTacrolimusSeldane (terfenadine)TheophyllineRezulin (troglitazone)Viagra (sildenafil)Protease inhibitors: Crixivan (indinavir), Norvir (ritonavir), Viracept(nelfinavir), Invirase (saquinavir)Biaxin is a registered trademark of Abbott Laboratoreis. Diflucan,Norvast and Zoloft are registered trademarks of Pfizer Inc. Sporanox,Hismanal and Propulsid are registered trademarks of JanssenPharmaceutica Inc. Noroxin, Cozaar, Mevacor and Zocor are registeredtrademarks of Merck & Co, Inc. Plendil and Prilosec are registeredtrademarks of Astra Merck Inc. DynaCirc is a registered trademark ofNoratis Pharmaceuticals Corporation. Posicor is a registered trademarkof Roche Pharmaceuticals. Lipitor and Rezulin are registered trademarksof Parke-Davis. Prozac is a registered trademark of Eli Lilly and Company.Luvox is a registered trademark of Solvay Pharmaceuticals, Inc. Serzone isa registered trademark of Bristol-Myers Squibb Company. Tagamet is aregistered trademark of SmithKline Beecham Pharmaceuticals. Seldane isa registered trademark of Hoechst Marion Roussel. Viagra is a trademarkof Pfizer Inc.6. Concurrent use of oral nitrates or sublingual nitroglycerin;oral, sublingual, or any form of nitratepreparation should not be taken up to 48 h prior;combination with nitrates causes severe reductions inblood pressure, which can cause a heart attack, death, orstroke. Nitric oxide (NO) donors, (Nitroglycerin andall nitrates including those listed in Table 1 stimulateguanylate cyclase, which increases the production of

372ERECTILE DYSFUNCTION AND THE HEARTcyclic GMP. When nitrates are given at the same timeas PDE5 inhibitors, there is both an increase inthe production of cyclic GMP (due to the NO donor)and an inhibitation of its breakdown (caused by thePDE5 inhibitor); this causes an accumulation of cyclicGMP with resulting intense vasodilation and severehypotension7. Sildenafil is well tolerated and safe in patients receivingmost concomitant antihypertensive agents except for-blockers. The label precaution advises that 50 or100 mg sildenafil should not be taken within 4-hoursof -blocker (such as terazosin) administrationIf angina occurs, a nitrate preparation should not beadministered within 24 h for sildenafil, and for newerlonger acting preparations 48 h may be required for thesafe use of nitrates. In any event a patient with coronaryartery disease who experiences angina during or followingsildenafil use for intercourse should take two or three babysize (80 mg) chewable aspirin and proceed immediatelyto an emergency medical facility. Fortunately nitrates arenot very useful in preventing myocardial infarction orserious cardiac events and more appropriate drugs areadvisable. These include the use of a beta-blocker andmorphine to abolish the chest pain until the patientis assessed further. The electrocardiogram and troponinlevels are helpful in making decisions; coronary angiogramsfollowed by revascularization remains the moresuitable and advisable therapy in a patient with coronarydisease who develops chest pain with use of PDE-5inhibitors.3. Cardiovascular AdviceIn all cardiovascular patients it is necessary to determinethe patient’s risk. Risk stratification is necessary and ifcarefully documented, these agents can be used safely inmore than 70% of patients with cardiovascular disease.PDE-5 inhibitors play a major role in improving qualityof life and can be used in virtually all of stable patientswith cardiovascular disease. This includes hypertensioncontrolled with one or at the maximum two drugs, stableangina, Canadian Cardiovascular Society grade I–II, andpatients with stable heart failure New York heartAssociation class I–II. Asymptomatic patients with priormyocardial infarction more than 1 year ago with no recurrentangina and a satisfactory exercise treadmill test maybe given a trial of 25 mg.Patients with stable coronary heart disease who cancomplete an adequate treadmill test without demonstratingischemia: >6 metabolic equivalent (METS), are at a lowrisk for ischemia during intercourse with a familiar partner.A heavy meal or excessive alcohol consumption should beavoided. Care should be taken to avoid concomitant useof the cardioactive agents listed in Table 1.In 53 clinical trials with sildenafil in more than 6000patients, no excess incidence of myocardial infarction ordeath was observed. Also, in a prescription eventmonitoring study in more than 5000 men in the UK,there was no increased incidence of myocardial infarction,death, or total mortality compared with the overall UKpopulation.4. Clinical study: Halcox et al.Sildenafil was studied in 24 patients and an additional24 patients with coronary artery disease and ischemiaduring exercise and 12 control subjects receiving either100 mg or 10 mg of isosorbide dinitrate or placebo.Patients were studied during exercise on three separate daysin a randomized, double-blind manner. Flow-mediateddilatation of the brachial artery was measured and coronaryartery disease patients underwent treadmill exercisetesting. Sildefanil was shown to dilate epicardial coronaryarteries, improve endothelial dysfunction, and inhibitplatelet activation in patients with coronary artery disease.The beneficial effects were modest and most important,not harmful. This agent has an intermediate effect onmyocardial ischemia compared with isosorbide dinitrateand placebo.It is of interest that sildenafil appears to be somewhatbeneficial in the treatment of lung fibrosis andpulmonary hypertension; it causes preferential pulmonaryvasodilatation and improves gas exchange in patientswith severe lung fibrosis and secondary pulmonaryhypertension.C. Valdenafil and TadalafilVardenafil (Levitra) is a potent and highly selective PDE-5inhibitor with a long half-life of about 5 h. The drug iseffective in about 30–60 minutes and lasts approximately4 hours.In a double-blind, crossover single-dose multicenterstudy, 41 men with reproducible stable exertional anginadue to coronary artery disease received vardenafil 10 mgor placebo followed by exercise tolerance testing(5–10 METS).Relative to placebo the drug did not alter exercisetreadmill time to first awareness of angina and significantlyprolonged time to ischemic threshold. Sildenafil

III. MANAGEMENT373significantly prolonged time to ST segment depression, agreater than 1 mm change from baseline.Tadalafil (Cialis) supplied; 10, 20 mg tablets. The drughas a long half-life of about 17 h and a duration of actionof about 36 h. The drug is effective in 30–60 minutes andlasts up to 36 h. A topical agent, alprostadil, is currentlybeing tested.Vardenafil, and tadalafil appear to be well tolerated andsafe in patients receiving most concomitant antihypertensiveagents except -blockers but caution is required.Vardenafil is contraindicated in patients taking -blockers assevere hypotension may be precipitated.Tadalafil is contraindicated in patients taking -blockersexcept for 0.4 mg tamsulosin but caution is required.Vardenafil has been shown to cause a small increase inQTc. The label warning says ‘‘should be avoided in patientswith congenital QT prolongation and patients takingclass IA antiarrhythmics,’’ (eg. quinidine, procainamide)or class III (eg, amiodarone, sotalol). Several agents knownto prolong the QT interval should be avoided.BIBLIOGRAPHYDeBusk, R., Dory, Y., Goldstein, I. et al. Management of sexualdysfunction in patients with cardiovascular disease and recommendationsof the Princeton consensus panel. Am. J. Cardiol., 86(2):175–81, 2000.DeBusk, R. F. et al. Sexual activity in patients with angina. JAMA,290:3129–3132, 2003.DeBusk, R. F., Pepine, C. J., Glasser, D. B. et al. Efficacy and safety ofsildenafil citrate in men with erectile dysfunction and stable coronaryartery disease. Am. J. Cardiol., 93:147–153, 2004.Furchgott, R. F., and Zawadzki, J. V. The obligatory role of endothelialcells in the relaxation of arterial smooth muscle by acetylcholine.Nature, 288(5789):373–76, 1980.Ghofrani, H. A., Wiedemann, R., Schermuly, R. T. et al. Sildenafil fortreatment of lung fibrosis and pulmonary hypertension: A randomizedcontrolled trial. Lancet, 360:895–900, 2002.Halcox, J. P J., Nour, K. R. A., Zalos, G. et al. The effect of sildenafil onhuman vascular function, platelet activation, and myocardial ischemia.J. Am. Coll. Cardiol., 40:1232–40, 2002.Hermann, H. C., Chang, G., Klugherz, B. D. et al. Hemodynamic effectsof sildenafil in men with severe coronary artery disease. N. Engl. J.Med., 342:1622–1626, 2000.Kloner, R. A., Hutter, A. M., Emmick, J. T. et al. Time course of theinteraction between tadalafil and nitrates. J. Am. Coll. Cardiol.,42:1855–1862, 2003.Kloner, R. A. et al. Cardiovascular effects of the 3 phosphodiesterase-5inhibitors approved for the treatment of erectile dysfunction. Circulation,110:3149-3155, 2004. doi:10.1161/01.CIR.0000146906.42375.D3.Kloner, R. A., Hutter, A. M., Emmick, J. T. et al. Time course of theinteraction between tadalafil and nitrates. J. Am. Coll. Cardiol.,42:1855–1860, 2003.Kloner, R. A., Mohan, P., Norenberg, C. et al. Cardiovascular safety ofvardenafil, a potent, highly selective PDE5 inhibitor in patients witherectile dysfunction: Analysis of five controlled clinical trials.Pharmacol. Ther., 22:1371, 2002.Prasad, S., Wilkinson, J., Gatzoulis, M. A. et al. Sildenafil in primarypulmonary hypertension. N. Engl. J. Med., 343:1342, 2000.Thadani, U., Smith, W., Nash, S. et al. The effect of vardenafil, a potentand highly selective phosphodiesterase-5 inhibitor for the treatmentof erectile dysfunction, on the cardiovascular response to exercisein patients with coronary artery disease. J. Am. Coll. Cardiol.,40:2006–12, 2002.Wilkens, H., Guth, A., Konig, J. et al. Effect of inhaled iloprost plusoral sildenafil in patients with primary pulmonary hypertension.Circulation, 104:1218–1222, 2001.Zhao, L., Mason, N. A., Morrell, N. et al. Sildenafil inhibits hypoxiainducedpulmonary hypertension. Circulation, 104:424–428, 2001.

Exercise and the HeartI. Benefits of ExerciseII. Aerobic ExerciseIII. Isometric, Static ExerciseIV. Weight Reduction and ExerciseV. Effects on Blood Pressure and AtheromaVI. Effects on BloodVII. Clinical Studies of Exercise and Heart DiseaseVIII. Injuries During JoggingIX. How to Start an Exercise ProgramX. Exercise Stress TestXI. ConclusionGLOSSARYafterload arterial impedance, restriction to blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of wall stress.angina pectoris short duration, recurrent chest pain or pressureoften accompanied by feelings of suffocation and impendingdoom; most frequently associated with lack of blood andoxygen to the heart muscle.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).fitness ability to undertake physical exercise without unduefatigue; the several types of fitness include aerobic, strength,coordination, and flexibility.maximal oxygen consumption the most oxygen that the bodycan use in aerobic exercise; synonymous with maximal aerobicfitness.mitochondria small spherical cytoplasmic organelles; mitochondriaare the principal sites of ATP synthesis and containenzymes of the citric acid cycle for fatty acid oxidation,oxidative phosphorylation, and other biochemical pathways.They contain their own DNA and ribosomes, replicateindependently, and synthesize some of their own proteins.myocardial infarction death of area of heart muscle due toblockage of a coronary artery by blood clot and atheroma,medical term for a heart attack or coronary thrombosis.ventricular fibrillation the heart muscle does not contract but‘‘quivers’’; therefore there is no heartbeat (cardiac arrest) andno blood is pumped out of the heart; death occurs withinminutes if the abnormal heart rhythm is not corrected.I. BENEFITS OF EXERCISEOne of the main reasons for practicing some form ofregular, moderate exercise is that it always makes you feeland look better. Exercise does not have to be vigorous orstrenuous to achieve important goals. Important psychologicalbenefits can be produced by moderate exercise suchas the combination of brisk walking for 20–30 minutes,performing stretching exercises for 10 minutes, and wherepossible, cycling or swimming for 10–15 minutes dailyor at least every second day. These simple exercises arepractical, inexpensive, and not time-consuming.Exercise is a necessary part of weight loss programs. It isimpossible to lose weight without the use of regularexercise. Long-term weight reduction requires regular exercise.In addition, such exercises pose no danger to individualsover the age of 40 and yet are sufficient to causerelaxation and produce a sense of well-being and a mentalattitude that can better deal with stress.If you do 30–40 minutes of moderate exercise a day andadd a favorite sport such as tennis, other racquet sports,or skiing, you will be considered relatively fit. By relativelyfit, you have the stamina and energy to do your daily workand favorite sport without shortness of breath, musclefatigue, or a pounding heart.Some people between the ages of 15 and 40, as well as15% of North Americans over the age of 40, seek to exceedthese achievements. Individuals who engage in regular vigorousexercise often reach a new ‘‘high,’’ and studies haveshown that high levels of endorphins are produced in thebodies of such individuals. Endorphins are opiate-likechemicals similar to morphine that increase pain threshold375

376EXERCISE AND THE HEARTand euphoria. With regular vigorous exercise, cardiovascularconditioning is quickly achieved. A minimumfrequency of three aerobic training bouts of exercise perweek repeated for many weeks is a necessary requirementto produce training adaptations. Exercise continued dailyfor several weeks improves the ability of the heart to pumpblood causing more blood to be ejected from the leftventricle into the aorta, which carries blood to all organsand tissues of the body. However, the heart muscle itself isnot strengthened and coronary arteries do not feed theheart indefinitely with more blood. Unfortunately, exercisedoes not prevent the formation of atheroma or atheromatousobstruction of coronary arteries and has little effecton the prevention of angina or heart attacks.II. AEROBIC EXERCISEAerobic literally means ‘‘with air’’; that is, oxygen isrequired. Aerobic exercise involves the rhythmic contractionand relaxation of large muscle groups and movementof joints, for example, brisk walking, swimming, cycling,jogging, and dancing.Oxygen is obtained in the lungs and transported bythe blood. Exercising muscles require an increasing supplyof oxygen, glucose, and other constituents. The body getsthe additional oxygen by increasing the rate of breathing,the heart rate, and the output of blood from the heart. Theamount of blood pumped each minute (cardiac output)increases from the average resting value of about 5 L toaround 20 L. A large part of this output goes to theexercising muscles.During aerobic exercise oxygen is used by the muscles.Oxygen converts energy in glucose and fatty acids to theenergy form, adenosine triphosphate (ATP). Muscle fibersrequire a direct source of energy such as ATP to contractand cause limbs to move during exercise. The quantity ofoxygen consumed during aerobic exercise tells us howmany calories of sugar and fats were used and quantifiesthe caloric cost of the exercise. . Walking uses much lessoxygen than a slow jog, which requires less oxygen thana fast run.Aerobic exercises cause an increase in heart rate andsystolic blood pressure. The diastolic blood pressure isunchanged or slightly increased and the blood flowthrough nonexercising muscles, the liver, intestine, andkidneys is reduced. If you exercise mainly your upperlimbs, this will cause a slightly higher increase in heart rateand blood pressure than exercise utilizing the legs.The oxygen consumption during maximal aerobicexercise is used to classify the work fitness of the heart.The more heart-fit an individual is, the greater number ofcalories are used per minute before fatigue sets in.A. Cardiopulmonary Physiology1. Oxygen ConsumptionThe oxygen consumption of the body is equal in thesteady-state to the uptake of oxygen in the lungs. In anormal subject the oxygen consumption is about 250 mlper minute. Moderate exercise, which increases the heartrate to about 125 beats per minute, increases oxygen consumptionfrom 250–300 ml per minute to 1200–1500 mlper minute.2. Cardiac OutputThe cardiac output is matched to the total metabolic needof the body. The mechanisms that regulate cardiac outputto achieve the these metabolic needs are heart rate (pulserate), myocardial contractility (contraction of the heartmuscle during systole), preload, and afterload.During preload the more the ventricles are distendedand filled with blood during diastole, the greater thevolume of blood ejected during the next systolic contractionof the ventricles. Conditions that decrease intravascularvolume reduce ventricular filling and result in asmaller end diastolic volume. This reduces stroke volume.Thus, in individuals who are severely dehydrated or havelost a large quantity of blood from bleeding, the heartis unable to fill properly, and there is a drastic fall incardiac output despite a marked increase in heart rate(see Fig. 1). Preload can be visualized as the amount ofmyocardial stretch at the end of ventricular relaxation(diastole) just before contraction of the ventricles (systole).Afterload is defined as the ventricular wall stress ortension that develops during systolic contraction andejection of blood into the aorta. It reflects the resistancethat the left ventricle must overcome in order to emptyits contents into the aorta and arterial tree (systemiccirculation). Another simple definition of afterload is awall of pressure against which the heart muscle mustpump blood. When the wall is high the heart muscle mustpump harder to overcome this resistance. This wall stress isexpressed as force per unit area.If there is no obstruction between the left ventricle andaorta, for example, at the aortic valve, the left ventricularsystolic pressure or the arterial systolic pressure gives anapproximation of the afterload. A higher pressure loadcaused by hypertension or an increased chamber size thatoccurs with heart failure or dilated cardiomyopathy can

II. AEROBIC EXERCISE377213Heart rate × stroke volume = Cardiac ouput * L/min.FIGURE 1 The cardiac output and exercise. 1 ¼ stroke volume ¼volume of blood ejected from the left ventricle into the aorta with eachventricular contraction; 2 ¼ preload: filling the heart chambers with bloodwhich is often expressed as end-diastolic volume or pressure; 3 ¼ aortaand arteries: resistance ¼ afterload. The force against which themyocardium contracts which is a major determinant of myocardial wallstress; 4 ¼ left ventricle, normal contractility; * ¼ normal, which is 6 litersper minute and varies from 3.5 to 7.5 liters per minute.cause an increase in left ventricular wall stress. An increasein the wall thickness of the left ventricle is a compensatoryplayer in reducing ventricular wall stress. Afterload is animportant parameter; it is the force against which themyocardium contracts in systole and is a major determinantof wall stress.Cardiac output ¼ heart rate stroke volume (Fig:1ÞThe normal resting cardiac output is approximately 6 Lper minute and varies from about 3.5 L per minute to7.5 L per minute. The normal blood volume of about 5 Lis composed of about 2.75 L of plasma and 2.25 L ofred blood cells. The total volume of blood in the heart isabout 600 ml, and the left ventricular volume at the endof diastole is about 150 ml. The stroke volume of the leftventricle (the amount of blood pumped from the ventricleinto the aorta) is about 100 ml, and the amount of bloodleft in the left ventricle at the end of systolic contraction(the end systolic volume) is 50 ml. The ejection fractionis the fraction of the end diastolic volume ejected witheach systolic contraction from the left ventricle into theaorta and this is [100 divided by 150] % ¼ 66%. Normalejection fraction is greater than 50%.4FIGURE 2 The time of work until the work cannot be continued anylonger (due to fatigue) is inversely related to the percentage of maximaloxygen consumption invoked by the work being done. When personA has one-half the absolute value of maximal oxygen consumption ofperson B, and when persons A and B work at the same intensity or oxygenconsumption, then person B will work a shorter time before fatigue,because person B is working at a higher percentage of his maximal oxygenconsumption. (Reprinted with permission from Strauss, R.H. (1984).Sports Medicine, Philadelphia: W.B. Saunders, p. 44.)B. Effect of ExerciseModerate exercise to increase the heart rate to approximately120 beats per minute causes an increase in strokevolume to 125 ml, cardiac output to 15 L, and oxygenconsumption to 1200–1500 ml per minute. Blood gastensions and pH do not change significantly. More severeexercise requires an oxygen consumption of 2500 ml perminute, which is achieved by the trained athlete. Anuntrained individual shows evidence of accumulation ofexcess lactate and other acids that produce excess acidity ofthe blood called metabolic acidosis and this is reflectedby a fall in pH. An individual with a high maximal oxygenconsumption can either do the same workload for a longerperiod or undertake higher quantities of physical aerobicwork for the same time than a person with a low maximaloxygen consumption.An important aspect of of the concept of maximaloxygen consumption in aerobic exercise is that its valuedetermines how long an individual can work beforebecoming fatigued. The reason for fatiguing sooner whenthe percentage of aerobic effort is higher is that the timeone can exercise aerobically at a given oxygen consumptionis inversely related to the percentage of maximal oxygenthat can be consumed per minute (see Fig. 2).C. Caloric Costs of WorkWork is defined as force times the distance. Duringrunning work is the weight of the body times the distancemoved. It is important to recognize that the effect ofspeed is small compared with distance; running one mile

378EXERCISE AND THE HEARTuses only about 10 kcal more than walking, and walkingfive miles uses almost five times as many kilocalories asrunning one mile.D. Cardiovascular Conditioning — TrainingEffectThe minimum amount of aerobic exercise required toimprove the pumping capacity of the heart, or the deliveryof more blood from the left ventricle into the aorta, isabout 20–30 minutes daily for three to four days per week.Repeated for many weeks, this type of activity is necessaryto produce training adaptations. During this level ofexercise the heart rate (þ pulse rate) should reach approximately70% of the calculated maximal rate for theindividual.70% of maximal heart rate¼ 0:7 maximal heart rateþ resting heart rateresting heart rate The maximal heart rate is obtained by subtractingthe individual’s age from 220. For a 70-year-old with aresting heart rate of 60, the maximal heart rate is 150 beatsper minute and 70% of maximal heart rate is0:7 ð150 60Þþ60 ¼ 123When a physically inactive individual suddenly decidesto walk up four or five flights of stairs or commencesunaccustomed aerobic exercise, he quickly gets winded orshort of breath and feels the heart thumping away at a fastrate. The lack of physical fitness is obvious to theindividual. If the same activity is repeated daily or everyother day, after two or three weeks the individual no longerexperiences the shortness of breath, the heart rate increasesonly slightly, and there is a faster return to normal restingheart rate after exercise. The training effect has beenachieved and the heart, lungs, blood vessels, and muscleshave started to adapt to the repeated exercise.During exercise, muscles require an increase in oxygensupply. The lungs must take in more oxygen, the heartmust pump faster and harder to get the oxygen to themuscles, and the muscles must extract more oxygen. Theheart is a powerful muscular pump but needs oxygen togenerate energy for its muscle contraction. The amountof oxygen the heart muscle requires at any time (myocardialoxygen consumption) can be determined by complicatedtechniques. A simple relationship, the product of theheart rate and systolic blood pressure, has been shown tobe a reliable indicator of the oxygen requirement for theheart muscle. Increased heart muscle efficiency is indicatedby a decreased oxygen requirement for a similar amount ofwork. Regular exercise increases the efficiency of the heartmuscle so that it requires less oxygen for the same amountof work. At rest, the heart muscle extracts about 65% ofthe oxygen reaching its muscle cells, and not much morecan be extracted on exercise. Therefore, if the heart musclerequires more oxygen, the coronary arteries must dilate tosupply more oxygenated blood. This situation can occuronly if the coronary arteries are normal and capable ofdilating.With frequent exercise, the heart becomes conditionedto do the same work at a lower heart rate. You no longerfeel your heart pumping away as if it wants to jump outof your chest or throat. If your exercise is then increasedboth in intensity and duration for at least 30 minutes daily,you will find that your resting heart rate may be reducedby 5–20 beats.The heart rate is controlled by the brain and nervesthat innervate the heart and the pacemaker (sinus node).The nerves that stimulate the heart to beat faster are calledsympathetic nerves and they are stimulated from the brain.For example, if someone is going to attack you and youwish to flee, the sympathetic nerves are stimulated by thefright, anxiety, and tension. Noradrenaline produced bythe nerve endings and adrenaline produced by the adrenalglands stimulate the heart to beat faster and stronger.An opposing nerve called the vagus nerve (parasympatheticnerve) causes the heart to slow down. The vagusnerve is like the reins of a horse that keep the horse fromrunning away out of control. Some individuals have aninborn, strong vagal nerve action and have a slow averageresting heart rate that is about 64 instead of 72 beatsper minute. Frequent exercise increases the effects of thevagal nerve (tightens the reins) and therefore leads to aslower heart rate. Many athletes have a resting heart rate of35–50 beats per minute so that on exercise the heart rategoes up much less. In an untrained 50-year-old, a quartermilejog may produce a heart rate of 150–170 beats perminute. With training, the same exercise may cause a heartrate of only 120–140 beats per minute, and the product ofheart rate and blood pressure will be reduced. It meansthat a conditioned heart will not have to work as hard topump the same amount of blood. The heart muscletherefore requires less oxygen during the exercise.The coronary arteries fill only when the heart muscleis relaxed (during diastole). A slower heart rate means thatthe heart is relaxed for a longer period of time and thus hasmore time to fill the normal or partially obstructedcoronary arteries. Therefore, a better supply of oxygen

II. AEROBIC EXERCISE379and other nutrients reaches the heart muscle. A fit heartidles at a lower speed and does not strain during maximalactivity. The difference between the unfit and fit heart issimilar to the performance of a poorly tuned 1934 caras opposed to a new 1996 model. Although frequentexercise may slightly lower your heart rate at rest and fora given exercise, there is lack of scientific evidence thatthis effect can prevent fatal or non fatal heart attacks.The slower heart rate does not prevent clot formation oratherosclerosis.During exercise the requirement for oxygen by exercisingmuscle causes a lack of oxygen. Therefore, the rateat which you breathe increases from about 12 breaths perminute to 24–30 per minute, so that more oxygen is takeninto the lungs and given up to the blood. Also duringexercise resting muscles extract only about 30% of theoxygen from the blood bathing the muscle cells.Vigorously exercising muscle can extract over 75% of thecirculating oxygen. The amount of oxygen extracted atpeak exercise is your maximal oxygen uptake and reflectsthe limit of your endurance or cardiopulmonary (cardiovascular)conditioning. An increase in your maximaloxygen uptake is the adaptation of the body to aerobicexercise. The body makes more efficient use of the oxygenavailable, and there is also less work for the heart. It isthis physiological adaptation that allows you to have morestamina and less fatigue at a given level of aerobic exercise(Fig. 2).Figure 3 illustrates the integrated control of multipleorgans during aerobic exercise. Both the nervous andhormonal systems communicate to all organs and tissuesduring exercise, and each organ system undertakes aspecific function. When all organ systems work together,sufficient oxygen and caloric fuel for the contraction oflarge masses of skeletal muscle during exercise is allowed.It also allows for elimination of metabolic by-productssuch as CO 2 from the lungs and hydrogen irons fromthe kidney, which prevent excessive acidity of the bloodcalled metabolic acidosis.The density of mitochondria and capillary networksincreases in response to aerobic training. Increased mitochondriaspare the body’s stores of glucose during aerobicexercise and the trained skeletal muscle uses less glucose.The process of muscle shortening requires the energysource ATP. The trained muscle uses fat as an energysource to make ATP. Glucose is stored as glycogen mainlyFIGURE 3 Integrative control of multiple organs during aerobic exercise. Both the nervous and hormonal systems communicate to all organs and tissuesin the body during exercise and cause each organ system to undertake a specific function, so that the summation of all organ systems allows sufficient oxygenand caloric fuel for the contraction of large masses of skeletal muscle during exercise and allows for the elimination of metabolic by-products, such as carbondioxide (from the lungs), and heat (from the skin), and hydrogen irons (from the kidneys). (From the Encyclopedia of Human Biology, second edition,Academic Press, San Diego, 1997.)

380EXERCISE AND THE HEARTin the liver, and the storage is limited as glucose is rapidlyused as fuel during exercise. When glucose concentrationfalls the body is unable to continue exercising at the samespeed mainly because nerves and red blood cells can onlyuse glucose to make ATP. A high-carbohydrate snack priorto intensive running delays exhaustion and fatigue. Thetraining adaptation of glycogen-sparing permits runningfor longer periods at the same speed before glycogendepletion causes fatigue.Aerobic exercise and hemorrhage initiate the samefight-or-flight reaction. During hemorrhage, blood pressurefalls and insufficient blood and oxygen reaches organsand tissues. This signals nature’s reflex survival mechanism.This mechanism includes stimulation of the sympatheticnervous system, which causes constriction and narrowingof arteries and arterioles. This increases total peripheralvascular resistance. Sympathetic stimulation increases theheart rate and myocardial contractility in an endeavor toincrease cardiac output.Blood pressure¼ cardiac output total peripheral resistancecardiac output ¼ cardiac stroke volume heart rate Epinephrine(adrenaline) and norepinephrine (noradrenaline)are fight-or-flight hormones that are immediatelyreleased from the adrenal glands. They cause increasedcardiac contractility, increased heart rate, and constrictionof arteries. This stimulates increased blood pressure tomaintain the circulation of blood and oxygen to organsand tissues, which is a vital need for survival.During aerobic exercise more blood and oxygen arerequired by exercising muscles so there is dilatation ofarteries, arterioles, and a large capillary network to supplyblood to these areas. These areas could be consideredas empty cisterns that must be filled immediately. This canonly be accomplished by an increase in cardiac outputand increased blood pressure, which allows more blood tobe delivered to fill the empty cisterns or vascular spaces.The heart beats faster and blood pressure increases as anormal physiologic response. The systolic blood pressureincreases from 20 to 60 mmHg depending on the levelof exercise. Thus a baseline systolic blood pressure ofapproximately 130 may reach 150–190 mmHg and inhypertensive individuals may exceed 220 mmHg.E. Physiologic HypertrophyThe left ventricular mass of trained athletes is approximately40% greater than that of age-matched controls.The athlete’s heart becomes enlarged mainly in enddiastolic cavity dimensions with lesser changes in endsystolic dimension and in posterior wall and septal wallthickness. The hypertrophied heart has a 30–60% increasein stroke volume at rest and during exercise. This typeof cardiac hypertrophy occurs within three to six monthsof vigorous training, and usually reverts back to baselinevalues within three to four weeks of detraining. Hypertrophyof heart muscle caused by exercise is an absoluteincrease in cardiac mass and does not result from hyperplasia(an increase in the number of cardiac muscle cells).Hypertrophy of the heart caused by exercise produceselectrocardiographic and echocardiographic abnormalities(see the chapter Athletes and Sudden Cardiac Death).III. ISOMETRIC, STATIC EXERCISEIsometric means ‘‘equal measure.’’ The muscle fiber lengthremains the same when muscular tension is exerted againsta fixed resistance; that is, static exercise involves thedevelopment of tension within muscle fibers and results inlittle or no movement of bones and joints. Weightliftingand pushing against a wall are both examples of isometricexercise. Such exercise is also called resistance exercise.Resistance exercise is generally not recommended forindividuals who have hypertension, heart failure, or knownheart disease, because it causes a marked increase in bloodpressure during the effort. The pressure of tensed musclessqueezes blood vessels, and therefore, less blood passesthrough these arteries. Also, the constriction of bloodvessels causes an increase in blood pressure. The heartworks harder to pump against the resistance in theconstricted arteries, but the amount of blood the heartpumps only increases slightly because the few muscles thatare used require less oxygen than would be required duringisotonic exercise. Despite this lower oxygen requirementof the exercising muscle during static exercise, the heartwork is increased and the heart muscle requires moreoxygen. During a double leg press in which a trained lifteris allowed to hold his breath, blood pressure can increaseto greater than 250 mmHg systolic and greater than130 mmHg diastolic. Pressures increase to overcome thehigh intramuscular pressures to maintain effusion ofmuscle tissue. The response to an acute resistance effortis a marked elevation of diastolic blood pressure, which isrelatively unchanged during aerobic exercise. If atheromatouscoronary artery disease is present, the heart musclemay suffer from a shortage of oxygen that can result inchest pain, angina, or precipitation of a heart attack (seethe chapter Angina). Hypertensive individuals should notengage in isometric exercises.

V. EFFECTS ON BLOOD PRESSURE AND ATHEROMA381During static exercise there is an increased heart rate andblood pressure, but only a mild increase in cardiac outputand rate of breathing. Therefore, physical conditioningmay be achieved, but the cardiopulmonary conditioningtraining effect cannot be obtained. Weightlifting producesincreased strength of those skeletal muscles that are usedbut does not improve the capacity of the heart to work anddoes not increase blood circulation to the heart. Weightliftingand power training do not maintain an increasedheart rate that is more than 70% of maximal heart ratefor 30 consecutive minutes. Only aerobic exercise in whichseveral strength exercises performed sequentially withoutrest periods in between produces some heart fitness.Anaerobic exercise is different from aerobic exercise.Anaerobic means ‘‘without oxygen,’’ and energy is derivedfrom the breakdown of glucose in the blood and musclewith the formation of lactic acid. Static exercise such asmoderate and heavy weightlifting or very high-intensityaerobic exercise such as a 100-yard sprints are examples ofanaerobic exercise. Heart patients cannot take part in suchexercises because they may precipitate heart failure.IV. WEIGHT REDUCTION AND EXERCISEA regular exercise program can cause mild weight reduction,which is greatly enhanced by a weight-reduction diet.Exercise is most helpful in long-term weight-reductionprograms. Physical activity requires energy, which ismeasured in calories. Think of the body as having severalfactories. If you shut down half of these factories and letthe other half work at half the speed, your output wouldbe diminished. This is equivalent to turning down yourmetabolic rate (metabolic thermostat). If you go on a crashdiet, your metabolic thermostat is turned down to get byon less food. Aerobic exercise 20–40 minutes doneregularly three to four times weekly can boost yourmetabolic rate by 20–30%, and this will accelerate thebreakdown of fat stores. The body of an obese individualis programmed to form fat and to store it away. Inaddition, your cells slow down and you burn fewer caloriesthan normal. Cells slow down even more if you are on asevere weight-reduction diet to conserve energy. The moreyou exercise, the more dependent you become on fatmetabolism. Many obese individuals do not overeat, buttheir metabolic rate is so low that they store fat. Therefore,start exercising first, then a few weeks later start your dietand continue on an exercise program for at least five yearsto keep the weight down.The caloric equivalent 10 pounds of body fat is 36,500kcal. Because only about 0.03 pounds of fat is used foreach additional mile done daily, reduction of body fatby aerobic exercise is a long-term process that can onlybe accomplished with exercise three or four times weeklyfor several years. Long-term body weight is a function ofcalories eaten minus calories burned.To burn 100 calories, a 170-pound individual needsto walk briskly one to two miles or jog one mile. Note thatbrisk walking is nearly as good as jogging because the speedat which you complete the distance makes little differenceto the total amount of calories you burn. Distance coveredis more important than speed. As stated above, runningone mile uses only 10 kcal more than walking; walkingfive miles uses almost five times as many kilocalories asrunning one mile.Therefore, a brisk mile in 15–20 minutes twice dailyor two miles once daily is of value until you can addother exercises. If you do this daily, you will lose onepound in less than 14 days. If your diet usually provides1200–1500 calories daily and you drop to a 1000-caloriediet during this exercise program, you will have anadditional one-pound loss in 14 days. This may seemsmall, but the good news is that in six months you will be24 pounds lighter and you will be able to hold on tothis reduction. Now that you are used to exercise, if youcontinue your program four days weekly, you will find itis easy to stay on a 1000- to 1200-calorie diet and maintainyour ideal weight.Exercise alone without restriction of calorie intakeresults in only mild weight reduction. Therefore, bothexercise and diet should be used to achieve the best results.A combination of a low-carbohydrate and a low-saturatedfat diet gives more sustained weight reduction of thanonly a low-saturated fat or only a low-carbohydrate diet.This allows a more balanced diet that can be toleratedby most individual over the long-term and has healthbenefits (see the chapter Diet and Heart Disease).V. EFFECTS ON BLOOD PRESSUREAND ATHEROMABlood pressure is not significantly lowered during vigorousexercise. During vigorous exercise such as five miles ofjogging or 20 minutes of continuous aerobic exercise, thesystolic blood pressure increases markedly in most individuals.In many, the rise in blood pressure is substantial andit is possible that damage can occur in arteries duringvigorous exercise. For example, a 40-year-old with anormal systolic blood pressure of 130 mmHg whilerunning one to two miles, will usually have an increase inblood pressure during the run to about 150–180 mmHg.

382EXERCISE AND THE HEARTThere is usually no increase in the diastolic blood pressureexcept in patients who have hypertension. Blood pressurerapidly falls on cessation of exercise and returns to thenormal resting level within a few minutes.Individuals with mild hypertension who engage in aregular exercise program may obtain a slight reductionin their resting blood pressure, and this is believed to bedue to a combination of factors including weight lossand relaxation. Therefore, indirectly, regular exercises areimportant to assist with weight reduction, thereby loweringblood pressure in individuals with mild hypertension.If you have moderate or severe hypertension, do notdepend on exercise; it will not reduce blood pressure andcan cause an increase in existing high blood pressureduring vigorous exercise.We cannot exclude the possibility that damage toarteries and dangerous atheroma formation and progressionmay be increased by vigorous exercise in someindividuals. Increase in turbulent blood flow at the site ofbranching of arteries may initiate or cause progression ofatheroma formation (see the chapter Atherosclerosis/Atherothrombosis). Atheromatous obstruction to thecoronaries and other arteries is responsible for more than14 million deaths annually worldwide, and this willincrease to approximately 25 million deaths by the year2020 and beyond in a population of approximately7.5 billion. Walking two to three miles daily, swimming,cycling, and one hour of low-intensity aerobic exercise issafe and beneficial for most individuals including thosewith mild forms of heart disease or hypertension.VI. EFFECTS ON BLOODA. Plasma Lipoprotein CholesterolRegular vigorous exercise increases high-density lipoprotein(good) cholesterol from 1 to 10%. It is debatablewhether this slight rise in HDL cholesterol decreasesrisk over a long period of time. Moderate exercise has avariable effect. The total blood cholesterol and low-densitylipoprotein (bad) cholesterol are not significantly reducedby exercise. Elevated triglycerides are reduced by exercise,but elevated triglycerides are not considered to be a definitiverisk factor for coronary heart disease. The evidencelinking elevated blood triglycerides with atheromatousdisease of the coronary arteries remains weak.1. Clinical StudyKraus et al. performed a prospective randomized study ofthe effects of the amount and intensity of exercise onlipoproteins.Methods: A total of 111 sedentary, overweight menand women with mild-to-moderate dyslipidemia wererandomly assigned to participate for 6 months in a controlgroup for approximately eight months in one of threeexercise groups: high amount high-intensity exerciseequivalent to jogging 20 miles per week; low amounthigh-intensity exercise equivalent to jogging 12 miles perweek; or low amount moderate-intensity exercise equivalentto walking 12 miles per week. Individuals wereencouraged to maintain their baseline body weight. In thisstudy, 84 subjects complied with these guidelines andlipoprotein analysis was assessed.Results: The highest amount of weekly exercise, withminimal weight change, had modest beneficial effects onblood lipoprotein profile. The improvements were relatedto the amount of activity and not to the intensity ofexercise or improvement in fitness. Both lower amountexercise groups always had better responses than thecontrol group.Exercise training had no significant effect on the totalcholesterol or LDL cholesterol concentrations. It did,however, exert effects on the concentrations of LDLcholesterol subfractions, but the clinical importance of thischange is unclear. HDL cholesterol increased a modest 9%in the high amount high-intensity group; a change frombaseline of 42.1 mg/dl to 45.9 mg/dl (9% change). Therewere no appreciable changes in HDL cholesterol in theother exercise groups.Blood triglyceride levels showed a reduction in all exercisegroups, as to be expected. Triglyceride concentrationsare sensitive to weight loss and exercise, but as emphasizedabove triglyceride levels bear a low relationship to atheromatouscoronary artery disease or vascular disease ingeneral.B. Other EffectsVigorous exercise causes a variable effect on blood-clottingfactors. A substance in the blood, factor VIII, is necessaryfor blood clotting and is absent in bleeders (hemophiliacs).Hemophiliacs who exercise get a mild and helpful increasein factor VIII. Vigorous exercise in healthy individualsincreases factor VIII, as well as the number and stickinessof platelets. This is offset in healthy young individualsby a mild increase in factors that tend to dissolve bloodclots. Individuals who have atherosclerosis of the arterypresent have an impaired ability to dissolve clots.Consequently, small clots (thrombi) may form on plaquesof atheroma, thus increasing their size. Slowly, over 5–10years, this may cause or promote existing coronary heartdisease. Rapid walking at a rate of four miles per hour,

VII. CLINICAL STUDIES OF EXERCISE AND HEART DISEASE383however, does not cause an increase in factor VIII orplatelets, and the stickiness of platelets is slightly reduced.Therefore, walking two to three miles daily remains thebest exercise.VII. CLINICAL STUDIES OF EXERCISE ANDHEART DISEASEMillions of North Americans participate in regular exerciseprograms. This is a major achievement motivated byvarious advertisements and literature and the desire to feelfit and well and to possibly to stay alive longer. A fewstudies have suggested that cardiac death is more commonin sedentary individuals than in the physically active, butfurther analysis of these studies revealed major defects inmethodology and interpretation. Published studies onexercise and the risk of coronary heart disease lackstandardization of the diagnosis of coronary heart disease,information on the effects of associated risk factors, andreliable evaluation of recreational or occupational physicalactivity.Below are a number of studies that address exercise andits relation to cardiac disease.A. San Francisco LongshoremenTo assess the role of physical exertion in relation to riskof fatal heart attack, the 1951–1972 work experience of6351 San Francisco longshoremen was studied. Amongmen age 35–54 there were 24 heart attack deaths in thoseengaged in heavy work, 37 deaths in men classified asdoing moderate work, and 28 deaths in those engaged inlight work. Thus, there was no difference in the death ratesin men age 35–54.Among men age 65–74 there were 8 deaths in menengaged in heavy work six months prior to death, 9 deathsin those engaged in moderate work, and 275 deaths inthose engaged in light work six months before death. Eachman who had a fatal heart attack was classified in the jobcategory that he held six months before death.This study is controversial because of errors inmethodology. Men 64–75 are usually engaged mainly inlight work activity and death is expected in this age group.We know that the 275 men over 64 who died wereengaged in light work six months prior to death, butthe study does not indicate how many engaged in lightwork and what their activity level was during age 35–64.There may be health reasons why these men engaged inlight work.B. London Bus DriversA study done in 1966 showed that London bus drivers hada slightly higher incidence of heart attacks than Londonbus conductors, but other risk factors confounded theanalysis. For example, from the outset, the bus drivers wereheavier with a higher blood pressure and blood cholesterolthan bus conductors and were, therefore, at higherrisk. These risk factors were probably more important thanjob activity classification.In a seven-country collaborative study, moderately activeFinns had a 2-1/2 times higher incidence of coronaryheart disease than the least active and the most activeFinns. Confounding factors in this study included a highincidence of elevated blood cholesterol, which may havemodified the effects of increased physical activity.It is worth noting that in Finland there is a high occupationallevel of physical exertion, yet coronary heartdisease mortality is very high. Individuals in Finland,consume a high-saturated fat diet, and although they haveremarkably high levels of HDL (good) blood cholesterol,the incidence of coronary artery disease is higher than inmost countries worldwide.C. University AlumniIn a study of 17,000 male university alumni, 2000 kcalof exercise per week slightly reduced the risk of coronaryheart disease. Vigorous sports, climbing stairs, and walkingto obtain a minimum of 500 kcal of exercise per weekappeared to be necessary to obtain a reduced coronaryartery disease risk. In the Harvard Alumni Health Study,the trend of reduced coronary artery disease risk withincreasing levels of walking was not significant.D. Australian StudyAn Australian group studied 370 men who took part in atwice-weekly exercise program with one hour of calisthenics,volleyball, and running who improved physical fitnessby 17%. This program was continued for five years, andeven though the men felt physically fit, there was noreduction in blood cholesterol, weight, or blood pressure.Morris et al. analyzed the exercise habits of 18,000sedentary male office workers. Those with vigorous leisuretime activity had about a 50% reduction in heart attacks.The 18,000 men were asked on a Monday morning tocomplete a record indicating their level of physical activityon the preceding Friday and Saturday. In this study,vigorous exercise included sports and recreation, i.e.,singles tennis, swimming, jogging, running, walking at a

384EXERCISE AND THE HEARTrate of four miles per hour and cycling fast uphill, and veryheavy work. At the end of 8-1/2 years, there were 24(1.1%) fatal and 42 (2%) nonfatal heart attacks in thevigorous-exercise group of 2200 men, but 411 (2.4%) fataland 570 (3.4%) nonfatal heart attacks in the nonvigorousexercisegroup of 16,800 men. Thus there was about a50% reduction in heart attacks attributed to the goodeffects of vigorous exercise. These results are statisticallysignificant. However, selection of individuals may havecreated a bias and the study can be criticized.Marathon running does not offer any guarantees, and itis not believed to be as protective as some enthusiastswould have us believe. In four of seven marathoners whohad completed a total of 64 marathons and died, autopsyshowed severe atherosclerosis of their coronary arteries.The bad news is that severe coronary atherosclerosis is themost common cause of death, even among marathoners.E. Tanasescu et al.Study question: This study is carried out to assess theamount, type, and intensity of physical activity in relationto risk of coronary artery disease among men.Methods: A cohort of 40,444 American men enrolledin the health professionals follow-up study and were followedfor 12 years. Incidence of myocardial infarctionduring this time was noted. Men aged 40–75 yearsanswered a detailed questionnaire. Follow-up questionnaireswere sent every two years to identify newlydiagnosed cases of coronary artery disease.Results: Men who ran for an hour or more per weekhad a 42% risk reduction compared with men who did notrun ( p ¼ 0.001 for trend). Men who trained with weightsfor 30 minutes or more per week had a 23% riskreduction, but this reduction claimed by the authors ofthe study was actually clinically nonsignificant ( p ¼ 0.03).In clinical medicine a value p < 0.02 is considered significantand meaningful in terms of lives saved. A half hourper day or more brisk walking was associated with an 18%risk reduction.The self-report of physical activity is a limitation of thestudy. The authors claim that walking pace was associatedwith reduced coronary artery disease risk independent ofthe number of walking hours is not valid.F. Albert et al.Study question: Does vigorous exercise increase ordecrease the risk of sudden cardiac death (SCD)?Methods: By means of a questionnaire, information onthe frequency of vigorous exercise was obtained from21,481 male physicians aged 40–84 participating in thePhysician’s Health Study. Strenuous exercise was defined asexercise vigorous enough to cause sweating. Each exercisesession was assumed to be associated with 30 minutesduring and 30 minutes after exercise exposure time tosudden death.Results: There were 122 sudden cardiac deaths during12 years of follow up with an incidence of 1 death per 19million person-hours. The majority of physicians reportedengaging in vigorous exertion two to four times per week.Among men who engaged in vigorous exercise less thanonce a week there was a 74-fold increase in the risk ofsudden death during vigorous exercise. Men who engagedin vigorous exercise at least five times a week had an11-fold increase in risk.Conclusion: The authors of this study concluded thatthere appears to be a 17-fold increase in risk of SCDduring strenuous exercise, and this risk is attenuated byhabitual vigorous exercise. This study was not able to showa net beneficial effect of vigorous exercise on SCD. Thestudy conclusion is limited, because the baseline data onthe frequency of exercise were not dated during 12 years offollow up; thus, the conclusions should not be considereddefinitive.G. Frolkis et al.Study question: Would the presence of ventricular ectopyafter exercise predict an increased risk of death better thanventricular ectopy during exercise?Methods: In this study, 29,244 patients were referredfor exercise testing aged 56 11 years without a historyof heart failure, valve disease, or arrhythmia. Ventricularectopy was defined as the presence of seven or more ventricularpremature beats per minute, ventricular couplets,triplets, or ventricular tachycardia.Results: There were 945 (3%) patients who had ventricularectopy only during exercise, 589 (2%) only duringrecovery, and 491 (2%) during both exercise and recovery.After propensity matching for confounding variables,frequent ventricular ectopy during recovery predicted anincreased risk of death ( p ¼ 0.003), but frequent ventricularectopy during exercise did not ( p ¼ 0.53).H. Vigorous Exercise and RiskThe relationship between vigorous exercise and the riskof a fatal or nonfatal heart attack has long been thesubject of controversy. Reportedly, vigorous exercise canprecipitate SCD in healthy individuals. The risk of suddendeath is higher in men with low levels of habitual

IX. HOW TO START AN EXERCISE PROGRAM385activity who engage in unusual vigorous exercise. Even inmen who were accustomed to vigorous activity, however,the risk of SCD was moderately increased during highintensityexercise.The authors only analyzed nine deaths. It would befoolhardy to make any generalizations from such a study.This study was done in King County, Washington, an areacontaining 1.25 million people. Only nine cardiac arrestsduring vigorous exercise occurred in 14 months — fivein men with low levels of habitual activity and four in menwith high levels of activity. This study should not influencethe medical profession or public except to emphasize thatjogging is relatively safe and cardiac arrest is very rare.However, sedentary individuals should not rush out anddo vigorous exercises without engaging in levels of gradualactivity. In addition, in Rhode Island during a six-yearperiod, only one jogging death occurred per year for every6720 joggers. This is a very low death rate, but it is higherthan expected. Despite our defense of jogging for thosewho love it, we must emphasize that all studies showa much higher incidence of heart attacks during exercisethan would be expected by chance. Heart attack is the mostcommon cause of death during exercise.I. PerspectiveThe death of exercise enthusiast James Fixx is a goodexample of nonprotection by exercise. In his early 30she recognized that he was at high risk because his familyhistory was strong for heart attacks before age 50. A dailyrun of 5–10 miles for more than 15 years did not protecthim from the silent killer. Note that during joggingand running the systolic blood pressure may be slightlyor moderately increased. The combined increase in bloodpressure and high-velocity blood flow may, over a periodof years, increase atherosclerosis.Strenuous exercise can precipitate death in individualswho have a very rare heart muscle problem called obstructivecardiomyopathy. The division (septum) between theright and left ventricle becomes extremely thick for reasonsunknown and obstructs the blood flow from the leftventricle into the aorta. This condition explains the raresudden death that occurs in some athletes under the ageof 30. This obstructive heart muscle problem is fortunatelyvery rare and is easy to exclude. This is done by a doctorlistening with a stethoscope and with added tests such asan ECG and an echocardiogram. (See chapter entitledCardiomyopathy.)All patients with known heart disease or with symptomsthat suggest heart disease — pain or discomfort in thechest, throat, jaw, or arms during activity; shortness ofbreath; palpitations (fast, pounding heartbeats or skippedheartbeats) — should have an assessment by a doctor anda stress test before engaging in moderate or vigorousexercise. Patients with previous heart failure or markedheart enlargement should engage only in moderate exercisesuch as walking or its equivalent. Exercise is well known toprecipitate heart failure in such individuals; therefore,further advice from your doctor is necessary if you want todo exercise other than the equivalent of walking one miledaily.VIII. INJURIES DURING JOGGINGThe up and down motion of jogging causes tendon,muscle, and joint injuries. In one survey, about 1800 injuriesoccurred in 1650 amateur runners. Injuries included:(1) Achilles’ tendonitis where the heel and the tendonbecome painful; (2) shin splints where the muscles at thefront of the leg (frontal compartment syndrome) becomepainful and swollen; (3) painful knees with inflammationof the fluid-filled sac (bursitis), strain on ligaments, orpainful knee caps (chondromalacia patellae); (4) painfulfeet with inflammation of the sole of the foot, plantarfasciitis, and trauma to the bones of the foot; and(5) exacerbation of arthritis of the hips, knees, and ankles.Patients with arthritis must not jog. Women are moresusceptible to knee injuries or stress fractures in the pelvis,and in some, osteoporosis (loss of bone) may develop.If you must jog, purchase good running shoes, exercisethe ankle joint, and warm up properly to prevent injuries.Despite such precautions, injuries are very common amongjoggers.IX. HOW TO START AN EXERCISEPROGRAMA. General AdviceIf you are under 40, do not have arthritis or moderate orsevere hypertension, and feel in good health, you canengage in all activities including vigorous exercise asfrequently as you desire. Regardless of age, it is wise to do5–10 minutes of warm-up exercises before going on tovigorous exercises. Warm-up exercises prevent the pulseand blood pressure from increasing abruptly, therebyputting sudden strain on the heart. You should engage forone to two weeks in moderate exercise such as walking oneto two miles or jogging one mile daily before consideringvigorous aerobic exercise such as running two to five miles

386EXERCISE AND THE HEARTthree or four times weekly. If you are under 35, there isvery little reason to check the pulse rate. If you feel yourheart pounding away very rapidly, then slow your pace. Forthose engaged in competitive sports: We are in agreementwith other experts that running is perhaps the best exercisefor those who require the stamina to perform well. Theswimmer, boxer, or cyclist should jog to develop staminaand medium weight training to strengthen other muscles.Similarly, the runner should engage in other exercises,especially swimming and cycling.For individuals over age 40 in good health, the followingadvice is given. Walking two miles in a half hour, swimming,and cycling are excellent exercises. They are efficientand safe as well as economical. Walking four miles in60–70 minutes and climbing six flights of stairs twice dailycan produce cardiovascular conditioning. You do notrequire special equipment and you do not have to travel toa gym, ski slope, or racquet club. Walking two milesquickly burns up as many calories as jogging one mile.Jogging exercises the legs but not the important quadricepsmuscles at the front of the thighs. Walking up three tosix flights of stairs twice daily or cycling will strengthenthe quadriceps and strong quadriceps strengthen andstabilize the knees.If you are physically inactive at work and at home formore than six months, you should start very slowly. Startwith daily or alternate-day 10-minute stretching exercises,moving all the joints and the muscles of the upper andlower limbs as well as the trunk. Follow with 20 minutesof brisk walking (a little more than a mile), and then cyclefor 5–10 minutes. A stationary bicycle or treadmill is agood investment.After about four weeks of this mild exercise, increase thewalk to 30 minutes and cycle for 10–15 minutes. After onemonth of this routine, if you feel well with no abnormalsymptoms such as chest, throat, or arm discomfort, veryfast heartbeats, or shortness of breath, you can freelyengage in your favorite racquet sport. Swimming is wellknown to be an excellent conditioner as well as pleasurableexercise. If you wish to move to vigorous exercise, youshould have a medical checkup. It is a pity that manyindividuals commence regular jogging or other exerciseat 18 and stop at 38. For some it is a pleasure and forothers an obsession that imposes stress. Those who lovejogging should obviously continue, especially through thevulnerable years between 35 and 55.B. Heart Rate Maximum and Training RangeLearn to take your heart rate and determine your maximaland submaximal heart rate. During your medical checkup,your doctor will show you how to feel the pulse at the wrist(radial artery) or the carotid artery in the neck. Countthe pulse beat for 10 seconds and multiply the number by6 to get the heart rate per minute.The heart rate increases to high levels with vigorousexercise, and these upper limits have been establishedby doctors engaged in exercise conditioning programs.Several charts have been designed by experts and used indifferent countries. At age 20 the highest heart rate that thenormal heart can achieve is between 200 and 220 beatsper minute, and this is called the maximum attainableheart rate (Table 1). To be safe, doctors advise that youshould not exceed 85% of this maximal value, that is,about 170 beats per minute if you are young and healthy.During the first few weeks of training, keep the heart rateat about 70% maximum, that is, about 140 beats perminute, and increase the exercise to 85% if you are underage 30. If you are in good health, it is safe to exercise sothat your heart rate reaches 70–85% of your maximal valueand to keep it at this rate for about 20 minutes. After six toeight weeks of strenuous exercise, you should achievephysical and cardiopulmonary conditioning. At age 40 yourmaximum heart rate should be approximately 220 40, or180, and your training range, your ‘‘target zone,’’ fromTABLE 1Age-Related Maximum Attainable Heart Rates and Training RangeAge 20 25 30 35 40 45 50 55 60 65MaximumHeart Rate 200 195 190 185 180 175 170 165 160 155(220-age)85% 170 165 161 157 153 148 144 140 136 131Training Zone70% 140 136 133 130 126 122 119 115 112 108

X. EXERCISE STRESS TEST387125 to 150. Your pulse counted for 10 seconds should bea minimum of 20 and a maximum of 25 beats. You do notnecessarily need to reach and maintain the target zone, assome have claimed, to obtain conditioning or the trainingeffect.Maximum rates and training ranges are given in Table 1.Individuals over age 40 who have not engaged in strenuousexercise in the last two years or who have a family historyof heart attacks before age 50, blood cholesterol greaterthan 220 mg, or mild hypertension are advised to havea stress test before starting vigorous exercise.X. EXERCISE STRESS TESTGraded exercise testing introduced by Robert Bruce fivedecades ago remains an important diagnostic test forcoronary artery disease. When coronary arteries becomeobstructed by atheromatous plaques, the supply of bloodto the heart muscle becomes deficient and the muscleshows signs of ischemia that can be detected by the ECG.Ischemia is defined as a temporary lack of blood andoxygen to an area of cells for example the heart muscle,usually due to severe obstruction of the artery supplyingblood to this area of muscle. Thus, the term ischemic heartdisease is often used by physicians as it is the manifestationof coronary artery disease.A stress test involves walking on the treadmill or cyclingwhile your ECG is continuously recorded. The ECGterminals are taped onto your chest. Walking on the treadmillis easier if you wear running shoes or other comfortableflat shoes. The treadmill speed and its inclination areprogrammed to increase every three minutes so that youwalk faster up a grade and are jogging by the 10th minute.Healthy individuals are exercised to 90% of their maximalheart rate. The test is discontinued if chest or leg pain,fatigue, or shortness of breath develops or if the ECGshows insufficient oxygen to the heart muscle. The bloodpressure is taken every three minutes, and the systolicblood pressure usually rises by 20–40 mmHg. A 40-yearoldwho is physically fit with good cardiopulmonarycondition can usually exercise for 10–12 minutes, reachinga heart rate of 160–180 beats per minute without havingundue shortness of breath. The test is completed by about2 minutes of slow walking to cool down before thetreadmill is turned off.A well-conditioned 35-year-old athlete’s heart rate mayincrease only to 140 beats per minute during 12 minutesof such exercise. On resting, the heart rate should fallquickly to under 100 per minute within one to fourminutes and to less than 70 beats within two to threeminutes. During the recovery phase the ECG continues tobe recorded because abnormalities caused by ischemiamay be detected at this stage such as ischemic changes,premature beats, and arrhythmias.The electrocardiographic hallmark of exercise-inducedmyocardial ischemia is depression of the ST segment.A horizontal or down-sloping ST segment depression equalto or greater than 1 mm in two or more leads is diagnostic.If this electrocardiographic change is noted at low levelsof exercise, for example, less than four minutes on thetreadmill, or at slow heart rates like less than 120 beatsper minute, severe obstructive coronary artery disease isusually present.Diagnostic and prognostic variables during exercise orrecovery include: ST segment depression >1 mm, horizontal or downsloping ST segment elevation in leads lacking Q waves Chest pain and angina, relieved immediately by cessationof the exercise (within one to two minutes or relief withnitroglycerin) Inadequate blood pressure response or inadequate heartrate response (chronotropic incompetence); bloodpressure and heart rate should increase Presence of ventricular arrhythmiasDuring the recovery phase important information maybe obtained to point to the diagnosis of ischemic heartdisease, and this could be most useful when testing if theexercise phase reveals no abnormalities. Diagnostic pointsinclude ST segment depression greater than 1 mm anddelayed slowing of the heart rate.Monitoring of the heart rate during the recovery periodadds substantially to the value of exercise stress testing.Studies indicate that a delay in the decrease in the heartrate after exercise may result from inadequate reactivationof vagal tone. This predicts a poor outcome witha quadrupling of the risk of death over the next six years.The rate at which the heart rate decreases after exercise isa reflection of the level of the individual’s level of physicalfitness.The appearance of high-grade ventricular arrhythmiasduring the recovery time appears to predict subsequentmortality better than the occurrence of ventricular arrhythmiasduring exercise. The appearance of ventriculararrhythmias during recovery appears to be due to inadequatevagal reactivation. Figure 4 shows the electrocardiographictracings from a patient before, during. and afterexercise with the presence of delayed slowing of the heartrate and a malignant ventricular arrhythmia.

388EXERCISE AND THE HEARTFIGURE 4 Series of electrocardiographic tracings (lead V s ) from apatient before, during, and after exercise. During the recover period therewas delayed slowing of the patient’s heart rate and the development offatal ventricular fibrillation. (Tracings courtesy of Dr. Michael S. Lauer.)(From Curfman, G.D., and Hillis, L.D. (2003). A new look at cardiacexercise testing, N. Engl. J. Med., 348(9), 776.)XI. CONCLUSIONWe strongly recommend regular, moderate exercise forhealthy individuals and those with coronary or mildvalvular heart disease. Fitness makes one feel like living andconfers a sense of well-being. If you are relatively fit,you can enjoy your favorite sport with better breathingcapabilities and without feeling your heart pounding.If you are fit, you are not likely to be overweight, yourclothes fit you better, and you feel and look better. Westrongly recommend regular, moderate exercise to achievea state of ‘‘relative fitness.’’We recommend vigorous exercise to those who arehealthy and already fit. A fit heart idles at a slower speed.A heart that beats slower allows better filling of normal orpartially obstructed coronary arteries. There is no scientificproof or adequate evidence, however, to suggest thatvigorous exercise will make you live longer. If you are overage 40, mainly sedentary, and engage in occasional mildexercise, do not start vigorous exercise without having amedical check or stress test. Start with walking one to twomiles daily, slowly adding cycling, swimming, or similarexercise. Avoid vigorous exercise until you have done morethan two months of daily moderate exercise.Vigorous exercise in previously inactive individuals overage 35 carries a high risk of fatal or nonfatal heart attacksor sudden death. Therefore, do not rush to get superfit.Get fit slowly over three to six months, remembering thatfitness is a relative term — fit to do what?In addition, we emphasize that simple exercises such aswalking two miles in a half hour or when possible fourmiles in an hour, climbing stairs, or peddling a stationarybicycle for 15 minutes are excellent, safe exercises.Walking is always helpful and ‘‘never’’ causes a heartattack. It does not increase blood pressure, instead itimproves circulation in the legs and may have a favorableinfluence on blood clotting. Therefore, if you walk, youmay win the race.Exercise has important benefits, but it cannot beexpected to halt the progression or complications ofcoronary artery disease, and attention to aggressive controlof known risk factors is necessary. Exercise prescriptions forpatients who have heart disease, especially coronary heartdisease, are discussed in the chapter Heart Attacks.BIBLIOGRAPHYAdams, V., Linke, A., Kränkel, N. et al. Impact of regular physical activityon the NAD(P)H oxidase and angiotensin receptor system in patientswith coronary artery disease, Circulation, 111:555–562, 2005.Albert, C. M., Mittleman, M. A., Chae, C. U. et al. Triggering of suddendeath from cardiac causes by vigorous exertion. N. Engl. J. Med.,343:1355–61, 2000.Booth, F. W., and Tseng, B. S. Exercise. Encyclopedia of Human Biology,Academic Press, San Diego, CA, 1997, p. 853.Cole, C. R., Blackstone, E. H., Pashkow, F. J. et al. Heart rate recoveryimmediately after exercise as a predictor of mortality. N. Engl. J. Med.,341:1351–7, 1999.Curfman, G. D., and Hillis, D. A new look at cardiac exercise testing.N. Engl. J. Med., 348:775–76, 2003.Frolkis, J. P., Pothier, C. E., Blackstone, E. H. et al. Frequent ventricularectopy after exercise as a predictor of death. N. Engl. J. Med.,348:781, 2003.

XI. CONCLUSION389Kraus, W. E., Houmard, J. A., and Duscha, B. D. Effects of the amountand intensity of exercise on plasma lipoproteins. N. Engl. J. Med.,347:1483–92, 2002.Lakka, T. A., Venalainen, J. M., Rauramaa, R. et al. Relation ofleisure time physical activity and cardiorespiratory fitness to the riskof acute myocardial infarction in men. N. Engl. J. Med., 330:1549,1994.Marsh, S. A., and Coombes, J. S. Exercise and the Endothelial Cell,165–169, 2005.Milvey, P., and Siegel, A. J. Physical activity levels and altered mortalityfrom coronary heart disease with an emphasis on marathon running; acritical review. Cardiovasc. Rev., 2:233, 1981.Morris, J. N., Hagan, A., Patterson, D. C. et al. Incidence and predictionof ischemic heart disease in London busmen. Lancet, 11:553,1966.Paffenbarger, R. S., Jr., Wing, A. L., and Hyde, R. T. Physical activity asan index of heart attack risk in college alumni. Am. J. Epidemiol.,108:161, 1978.Siscovick, D. S., Weiss, N. S., Fletcher, R. H. et al. The incidence ofprimary cardiac arrest during vigorous exercise. N. Engl. J. Med.,311:874, 1984.Taffet, G. E., Holtz, R. W., and Tate, C. A. Exercise and cardiovascularfunction. Encyclopedia of Human Biology, Academic Press, San Diego,CA, 1997, p. 865.Tanasescu, M., Leitzmann, M. F., Rimm, E. B. et al. Exercise time andintensity in relation to coronary heart disease in men. JAMA,288:1994–2000, 2002.Thompson, P. D., Funk, E. J., Carleton, R. A. et al. Incidence of deathduring jogging in Rhode Island from 1975 through 1980. JAMA,247:2535, 1982.

Gene TherapyI. StrategiesII. Clinical ApplicationIII. Clinical TrialsIV. Adverse OutcomesGLOSSARYangina pectoris short duration, recurrent chest pain or pressureoften accompanied by feelings of suffocation and impendingdoom; most frequently associated with lack of blood andoxygen to the heart muscle.arterioles small branches of arteries.atherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow of blood; theplaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).capillaries fine, thin-walled blood vessels that branch fromarterioles and feed the tissues and cells with blood and fluids.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severeobstruction of the artery supplying blood to this area of cells.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.myocardium the heart muscle.ANGINA PECTORIS IS A FRUSTRATING PROBLEMfor both the patient and the cardiologist. It is refractory tooptimal medical therapy and not amenable to revascularizationprocedures that include percutaneous coronaryinterventions (PCI) such as balloon angioplasty withintracoronary stents and coronary artery bypass graft(CABG) surgery. Alternative strategies for improvingblood flow to the myocardium include transmyocardiallaser revascularization, but it has not proved successful.Gene therapy including the use of angiogenic peptides isanother possible therapy.A major goal of gene therapy and the use of antigenicpeptides is the production of therapeutic angiogenesis, orfunctional new blood vessel growth in the myocardium. Itis hoped that this should improve myocardial oxygensupply. Gene therapy has yet to show convincing efficacyin humans and the therapy may even be harmful.Angiogenesis must be distinguished from arteriogenesis.Angiogenesis is the formation of new vessels that lack atunica media; arteriogenesis describes nature’s phenomenonof newly formed arterioles with fully developedtunica media. A prime example of arteriogenesis iscollateral vessels observed angiographically in patientswith severe obstructive coronary artery disease (ischemicheart disease) or long-standing peripheral vascular disease.An example of angiogenesis is the formation of thin-walledfragile capillaries along the borders of a myocardial infarct.The formation of strong arterioles with a normal media isan acceptable goal that may never materialize.I. STRATEGIESGene therapy involves either the delivery of whole activegenes (gene transfer) or the blockade of native gene expressionby transfection of cells with short chains of nucleicacids (oligonucleotides). These short, single-stranded DNAmolecules are used as drugs to target the inactivation ofmRNA- or DNA-binding proteins.Manipulation of gene activity or gene expression isachieved by introducing foreign DNA into target cellswhere subsequently it is expressed in a process known astransduction or transfection (see Fig. 1). Systems includerecombinant viral vectors that permit relatively competentinsertion of genetic information and oligonucleotides thatare used to modify native gene expression. Gene blockademay also be achieved by the use of ribozymes, segments ofrRNA that can act as enzymes to destroy certain sequencesof target mRNA. A third type of gene blockade involvesthe use of gene regulatory proteins known as transcriptionfactors, which regulate gene expression by binding tochromosomal DNA. This process activates an adjacent391

392GENE THERAPYFIGURE 1 Gene therapy strategies. (A) Gene transfer involves delivery of an entire gene, either by viral infection or by nonviral vectors, to the nucleus ofa target cell. Expression of the gene via transcription into mRNA and translation into a protein gene product yields a functional protein that either achieves atherapeutic effect within a transduced cell or is secreted to act on other cells. (B) Gene blockade involves the introduction into the cell of short sequencesof nucleic acids that block gene expression, such as antisense ODN that bind mRNA in a sequence-specific fashion and prevent translation into protein.(From Ehsan, A., Mann, M.T., and Dzan, (2001). Essential Cardiology: Principles and Practice (Rosendorff, C., Ed.), Philadelphia: W.B. Saunders, p. 781.With permission.)gene. Synthetic DNA decoys prevent binding of transcriptionfactors to the promoter site of many genes involved incell proliferation. This process inhibits cell cycle progression,potentially leading to inhibition of neointimal hyperplasiaand may cause reduction in stenosis of venous bypassgrafts.The recombinant virus particles used as gene transfervectors do not have the ability to replicate. Table 1 listsgene therapy vectors. Recombinant adenoviruses arecommonly used viral vectors and unfortunately achievegene expression for only a few weeks after infection. Theventricular myocardium appears to be receptive to theintroduction of foreign genes, and gene transfer has beenachieved using direct injection into the myocardium orintracoronary infusion of material that has been geneticallyengineered in cell culture.Small, circular DNA pieces called plasmids are simpletools of molecular biology. They lack viral elements thatsubstantially reduce the risk of toxicity and immunereactions. Plasmids are taken up by most cells, however,and promote low gene transfer effects. They are alsounprotected against cellular defense mechanisms. Neverthelessthey appear to be safe, although their effects appearto be transient.There is ongoing development of an artificial virus thatmay incorporate the plasmid necessary to confer effectivetranslocation into the cell at high efficiency. Third generationlentiviruses are also being tested.II. CLINICAL APPLICATIONGene therapy remains a daunting task. Table 2 lists thepertinent cardiac conditions. There has been no clinicaltrial for heart failure or transplantation. Presently improvedoxygen supply to a myocardium deprived of oxygenbecause of atheromatous coronary artery obstruction is thegoal. Success has thus far not been obtained. In addition

II. CLINICAL APPLICATION393TABLE 1Gene Therapy VectorsVector Advantages DisadvantagesViralAdenovirusAdeno-associatedvirus (AAV)RetrovirusLentivirusHybrid virusesNonviralNaked plasmid DNADNA-lipsomesProtein-DNA complexArtificial VirusSendai virus-liposomecomplexAdenovirus-lipsome complexEfficient transduction of both dividing andnondividing cells; high titersEfficient transduction of both dividing andnondividing cells; less pathogenic; sustainedtransgene expression; possible target-specificintegrationLong-term transgene expression if integrationinto host DNA occursLong-term transgene expression in dividingand nondividing cellsEfficiency of adenovirus transduction; lowimmunogenicity and sustained transgeneexpression of AAV or retrovirusSafe; no transgene size limitation; simplemethodology; low immunogenicitySafe; no transgene size limitation; flexiblecomposition; wide cell range of transfectionCell specificity determined by protein; notransgene size limitationEfficient transfer of both transgenes andoligonucleotides; low toxicity andimmunogenicityIncreased efficiency of liposome-mediatedtransferHost immune response limits longevity of geneexpression; 8-kb insert size limitation;complementing cell lines required; lack oftransduced cell specificity5-kb insert size limitation; moderate titersLow transduction efficiency in nondividing cells;insertional mutagenesis possible; packaging cellline requiredHIV reactivation risk; low titers; insertionalmutagenesis possibleComplexity of construction, packaging, and hightiter productionLow efficiency of transfer and gene expressionModerate efficiency of transfer; transientgene expressionIntermediate efficiency of transfer and geneexpression in vivo; may be immunogenicExtensive preparation requiredAdenoviral construct needed; lower efficiencythan adenovirus-mediated tansductionAAV, adeno-associated virus; HIV, human immunodeficiency virus.From Antman, E.M. Ed. (2002). Cardiovascular Therapeutics, 2nd ed., Philadelphia: W.B. Saunders, p. 1027TABLE 2Cardiac Gene TherapyClinical disease Pathobiology Gene augmentation Antigene targetMyocardial ischemia Preconditioning PKG, MAPK, iNOS,adenosine A(1) receptorMyocyte apoptosis1GT-1, Akt, PI 3-kinase,Bcl-2, FLIP, IAPs, gp 130AngiogenesisVEGF, FGF, angiopoietin,engineered angioblastsHeat failureImpaired contractilitySERCA2a, PKA IGF-1, Akt,Myocyte apoptosisPI 3-kinase, Bcl-2, FLIP, IAPs, gp 130Cardiac transplantrejectionHost immuneresponseFas ligand, IL-4, IL-10,soluble receptors to proinflammatorymediators (e.g., TNF, interferon-g)Fas ligand, p53, p38Endostatin, angiostatinPhospholamban,bARK1 Fas ligand, p53, p38NFkB, IL-8, ICAM, VCAMbARK1, b-adrenergic receptor kinase; FGF, fibroblast growth factor; FLIP, Fas-associated death domain-like IL-1b-converting enzyme-inhibitoryprotein; IAP, inhibitor of apoptosis; ICAM, intercellular adhension; IGF, insulin-like growth factor; IL, interleukin; iNOS, inducible nitric oxide synthase;MAPK, mitogen-activated protein kinase; PKA, protein kinase A; PKC, protein kinase C; SERCA, SR calcium ATPase pump; TNF, tumor necrosis factor;VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.From Rosendorff, C., Ed. (2002). Essential Cardiology, Philadelphia: W. B. Saunders, p. 1030.

394GENE THERAPYthis goal is fraught with danger, because angiogenesis mayincrease plaque growth and decrease the thickness of thefibrous plaque which is protective and fragile. New vesselswithin the plaque are prone to rupture causing ultimateplaque rupture and severe cardiac events, see Section IV.The most interesting future goal is that gene therapyinterventions may be capable of increasing HDL cholesterollevels and lowering blood triglycerides. This could bea most valuable addition to our therapeutic armamentarium,because the lifesaving statins that lower LDLcholesterol do not significantly increase HDL levels.The cholesterol ester transfer protein (CETP) mediatesthe exchange of cholesteryl ester in HDL for triglyceride invery low-density lipoprotein (VLDL). Thus, CETPappears to reduce HDL and cause progression of atheromaformation; a pharmacologic inhibitor supports thishypothesis and gives hope that an anti-gene approach tothis target may be possible.III. CLINICAL TRIALSA. The EuroinjectOne trial was presented at the American College ofCardiology scientific session in March of 2003. Thismultinational study, however, involved only 80 patients.Patients with end-stage refractory angina with severeischemic heart disease not amenable to all forms ofrevascularization therapy were randomized. Patients withrecent myocardial infarction or proliferative retinopathywere excluded.Direct myocardial injections of gene therapy withphVEGF-A165 (vascular growth factor) were tested. Tenmyocardial injections of a plasmid solution was thetherapy. After three months’ follow up using various teststhere was an increase in blood flow and new vesselsobserved. Angina symptoms showed a modest improvement.The improvement in myocardial perfusion observedneeds further studies for confirmation. The investigatorsagreed that there was a large placebo effect. No majoradverse effects were noted in the short-term study.such trial to date and follow up indicates no significantdifferences in treatment versus placebo.C. Adenovirus Gene Therapy Trial(AGENT)TrialSixty patients received direct injection of recombinantadenovirus 5 FGF-4 and 19 patients received placebo.Follow-up treadmill tests at 12 weeks showed a greaterthan 30% increase in exercise tolerance time as comparedwith placebo group. But the placebo group showed markedimprovement from baseline, indicating the need fordouble-blind placebo-controlled trials.D. Small TrialsA trial of 32 patients who received AdVEGF121 wasundertaken. Thirty myocardial injections were administeredduring mini thoracotomy. The 32 patients receivedoptimal medical therapy. At 26 weeks patients in thetreated group exercised on average 1 minute longer beforethe appearance of ST segment depression, and improvementfrom 4 minutes to 5 minutes. This one-minuteimprovement shown on electrocardiographic testing wasproclaimed significant by the investigators, despite the factthat there were two postoperative deaths in the treatedgroup and that this treatment was an absolute failure.E. Initial StudyThe first evidence of human vascular angiogenesis in apatient was reported by Isner et al. in 1996. Four weeksafter intra-arterial gene transfer of a plasmid encoding forvascular endothelial growth factor, improvement in theischemic leg was observed. An increase in collateral vesselsat the knee and lower leg was verified by angiography, butafter 5 months the patient’s leg was removed below theknee because of gangrene. To date none of the over 200well-designed, peer review human trials have demonstrateda significant and meaningful therapeutic effect.B. Study in Patients with Disabling IntermittentClaudicationRegional angiogenesis with vascular endothelial growthfactor in peripheral arterial disease (RAVE) is a phase torandomized double-blind controlled trial in patients withdisabling intermittent claudication. This well-conductedstudy showed no improvement in claudication and otherparameters after 26 weeks of therapy. This is the largestIV. ADVERSE OUTCOMESA. Progression of AtherosclerosisAn old pathology textbook, Muir’s Pathology , (1958)statesWinternitz (1938) has shown that atheromatouspatches may contain new capillaries, some of which

IV. ADVERSE OUTCOMES395take origin from the intimal lining, and these delicatevessels are exposed to the fluctuations in pressure withinthe parent arteries. It is not surprising, therefore, thathemorrhage into such patches should sometimes followexertion.Hemorrhage into an atheromatous plaque causesrupture of the plaque with subsequent thrombosis andocclusion of the vessel. Microvessels within plaques havefunctional significance. Administration of inhibitors ofangiogenesis to mice has been shown to inhibit experimentallyinduced atheroma formation and limit lesionexpansion. Thus, it is not surprising that attempts toaugment myocardial new vessel formation by genetherapy or other strategies might have adverse effectson plaque growth and plaque rupture. An inhibitoryeffect of angiostatin in a murine model of atherosclerosissuggests the potential proatherogenic role forangiogenesis.Gene transfer methods have been shown to reducesmooth muscle cell proliferation and neointimal formation.The smooth muscle cells play a protective role instrengthening constitutional plaque into in the formationof a fibrous cap. Any measure that decreases smoothmuscle cell proliferation is fraught with danger.Studies have shown that there is an inverse correlationbetween smooth muscle proliferation and cyclindependentkinase inhibitors (CKIs) such as P21 and P27.Gene transfer methods that result in overexpression ofCKIs reduce smooth muscle cell proliferation andneointimal formation. P1 and P27 knock-out mice givena Western diet undergo accelerated arterial cell proliferationand atherosclerosis.B. Other EffectsSignificant clinical trial-related deaths have occurred. Thepotential for vector-induced cytotoxicity remains. Proliferativeretinopathy and retinal hemorrhage occur andcaution is warranted.BIBLIOGRAPHYCappell, D. F. In Muir’s Textbook of Pathology, seventh ed. Edward ArnoldLtd., London, 1958.Grines, C. L., Watkins, M. W., Helmer, G. et al. Angiogenic gene therapy(AGENT) trial in patients with stable angina pectoris. Circulation,105:1291–7, 2002.Hughes, G. C., Biswas, S. S, Yin, B. et al. A comparison of mechanicaland laser transmyocardial revascularization for induction of angiogenesisand arteriogenesis in chronically ischemic myocardium. J. Am.Coll. Cardiol., 39:1220–8, 2002.Isner, J. M., Pieczek, A., Schainfeld, R. et al. Clinical evidence ofangiogenesis after arterial gene transfer of ph VEGF 165 in patientswith ischaemic limb. Lancet, 348:370–374, 1996.Kim, M. C., Kini, A., and Sharma, S. K. Refractory angina pectoris.Mechanisms and therapeutic options. J. Am. Coll. Cardiol., 39:933–34, 2002.Losordo, D. W., and Isner, J. M. Vascular endothelial growth factorinducedangiogenesis: Crouching tiger or hidden dragon? J. Am. Coll.Cardiol., 37:2131–55, 2001.Seppo lä-Herttuala, S., Markkanen, and J. E., Rissanen, T. T. Genetherapy for ischemic cardiovascular diseases: Some lessons learned fromthe first clinical trials, Trends in Cardiovascular Med., 14:(8)295–300,2004.

Heart AttacksI. PerspectiveII. Causes and PathophysiologyIII. Door-to-Needle TimeIV. SymptomsV. Physical SignsVI. Mimics of a Heart AttackVII. Ambulance TransportVIII. What to Expect in the HospitalIX. Diagnostic TestsX. Specific ManagementXI. Clinical TrialsXII. Non-ST Elevation Myocardial InfarctionXIII. Complications of Myocardial InfarctionXIV. Heart Attack and Emotional ImpactXV. Depression and AnxietyXVI. Diet After a Heart AttackXVII. Rehabilitation, Retirement, and TravelXVIII. Retirement and TravelXIX. Sexual ActivitiesXX. Beta-BlockersXXI. Eplerenone (Inspra)XXII. Case History of a Heart PatientXXIII. Risk Factors and PreventionXXIV. Heart Attack Prevention DietGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to this area.arrhythmia general term for an irregularity or rapidity of theheart beat, an abnormal heart rhythm.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery hence the term, atherosclerosis(sclerosis ¼ hardening).ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker ofventricular contractility.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.left ventricular dysfunction poor ventricular contractility, thisleads to heart failure.preload the degree of ventricular muscle stretch present at theonset of myocardial contraction; often expressed as enddiastolic volume or pressure.venodilatation dilation of veins, as may occur during hotweather, hot baths, and by some drugs such as ACE inhibitorsand nitroglycerin.WHEN A HEART ATTACK BEGINS, THEindividual is suddenly stricken by pain in the center ofthe chest. This pain is often unbearable and may be apressure-like discomfort accompanied by difficult breathing,profuse sweating, and a strange frightened feeling. Thecause of a heart attack in the majority of cases is a blockageof a coronary artery that feeds the heart muscle with bloodcontaining oxygen, glucose, sodium, potassium, calcium,and other nutrients. In more than 90% of patients, theblockage has been shown conclusively to be due to a bloodclot. This blood clot is often present on the surface of apartially obstructing plaque of atheroma that showsfissuring (rupture or ulceration). The blocked artery cutsoff blood to a segment of heart muscle (myocardium), thecells of which die because they are deprived of the nutrientsin the blood. This death of heart muscle cells is calleda myocardial infarction (see Fig. 1).A heart attack, medically called a myocardial infarctionor coronary thrombosis, is a common occurrence,particularly, in young men aged 35–55. It is called thewidow maker because death occurs during the attack inmore than 50%. A heart attack is the most common causeof death in women age 55–85.397

398HEART ATTACKSunits in the early seventies, thrombolytic agents in the lateeighties, coronary angioplasty in the eighties and nineties,and stents during the past decade have improved survivalbut this can be considered ‘‘a spit in the ocean expectingthe tide to rise.’’ The development of left ventricular assistdevices (that are clearly bridge to transplantation and notartificial hearts) requires considerable financial supportfor their development, but they will save less than 4000lives annually worldwide. [See the chapter, Artificial heart]II. CAUSES AND PATHOPHYSIOLOGYFIGURE 1 Coronary heart (artery) disease. (a) Normal coronaryartery; (b) obstruction of a coronary artery by atherosclerosis causing lessblood to reach the heart muscle, producing chest pain, called angina; (c)blood clot; (d) complete obstruction of a coronary artery byatherosclerosis and blood clot (coronary thrombosis); (e) damage anddeath of heart muscle cells, i.e., a heart attack (myocardial infarction).I. PERSPECTIVEMore than one million patients have an acute myocardialinfarction in the United States annually and more than40% of these patients die within the first hour. Of thoseadmitted to the hospital, approximately 15% die duringhospitalization. Additionally, more than one millionpatients with symptoms suggestive of acute myocardialinfarction are admitted annually to coronary care units. Inthe year 2000 more than 12 million people died because ofcardiovascular disorders mainly caused by atheroma andsubsequent thrombosis (atherothrombosis). It is estimatedthat in the year 2025 more than 24 million people will diefrom this disease in a world population of approximately7.4 billion. Intensive research is required to preventatherothrombosis rather than the management of itscomplications which include fatal and nonfatal heartattack, angina, heart failure, abdominal aortic aneurysm,stroke, kidney failure, and peripheral vascular diseasecausing intermittent claudication and gangrene of thelower limb.Most of the research done in major institutions in theUnited States and in developed countries is directed at themanagement of complications of atherosclerotic coronaryartery disease. The advent worldwide of coronary careThe cause of a heart attack in the majority of cases is ablockage of a coronary artery by a blood clot. This clotusually occurs on the surface of a partially obstructingplaque of atheroma (see the figures in the chapterAtherosclerosis/Atherothrombosis). The surface of a plaqueruptures and the plaque contains substances that increasethe clotting of blood. A clot therefore forms on the surfaceof the rupture and also inside the plaque. The rupturedplaque, by direct release of tissue factor and exposure of thesubintima, is highly thrombogenic. Exposed collagenfurther provokes platelet aggregation. Some plaques,particularly those that have a high lipid content and athin fibrous cap, are prone to rupture (see the chapterAtherosclerosis/Atherothrombosis). Considerable researchhas been done during the past decade on the complexityand the instability of vulnerable plaques.Coronary angiography performed during the early hoursof infarction confirms the presence of total occlusion ofthe infarct-related artery in over 90% of patients. It isnot surprising that aspirin, through inhibition of plateletaggregation, reduces the incidence of coronary thrombosisand prevents the progression of unstable angina tothrombosis and myocardial infarction. Aspirin is particularlyuseful when given at the onset of chest pain producedby an infarction. However, it does not block all pathwaysthat relate to platelet aggregation (see the chapterAntiplatelet Agents).The increased morning incidence of acute myocardialinfarction documented in several studies of the diurnalvariation of infarction is related to the early morningcatecholamine surges, which induce platelet aggregation.This morning incidence is also related to an increase inblood pressure and hydraulic stress, which may lead toplaque rupture (see Fig. 2). Beta-blockers have been shownin randomized clinical trials to decrease the early morningpeak incidence of acute myocardial infarction and suddendeath. Use of a beta-blocking agent may inhibit plaquerupture by its ability to decrease cardiac ejection velocity.

II. CAUSES AND PATHOPHYSIOLOGY399BETA-ADRENERGIC BLOCKERSBlock effects ofcatecholamine surgesVFthresholdHeart rateBPEarly a.m.plateletaggregabilityEjection velocityDoubleproductHydraulic stressImprovesdiastoliccoronaryperfusionMyocardialcontractilityIncidence ofplaque fissuring?Myocardial O 2requirementCoronarythrombosisISCHEMIACatecholaminereleaseNonfatal orFatalmyocardial infarctionEarly a.m.Sudden deathIncreaseDecreaseFIGURE 2 Salutary effects of beta-adrenergic blockade. (From Khan, M. Gabriel (2005). Heart Disease, Diagnosis and Therapy, second edition,New Jersey: Humana Press.)This action reduces hydraulic stress on the arterial wallwhich might be critical at the arterial site where theatheromatous plaque is predisposed to rupture.In approximately 10% of patients with acute myocardialinfarction, rupture of fragile capillaries within the plaqueoccurs causing a small hemorrhage into the plaque andsubsequent rupture and thrombosis. The reason forrupture of these capillaries within the plaque may berelated to a surge in blood pressure caused by increasedcatecholamine release.Occlusion of the coronary artery leads, in about 20minutes, to death of cells in areas of severely ischemictissue, which will usually become necrotic over three to sixhours. Because early and late mortality are directly relatedto the size of the infarct, limitation of infarct size orprevention of necrosis by means of thrombolytic therapyinitiated at the earliest possible moment is of the utmostimportance.The ischemic zone surrounding the necrotic tissueprovides electrophysiologic inhomogeneity which predisposesthe occurrence of lethal arrhythmias. Thesearrhythmias are most common during the first few hoursafter the onset and contribute to one of the majormechanisms of sudden death that commonly occurs withinthe first hour of onset. Extensive myocardial necrosis is themajor determinant of heart failure; papillary, septal, andfreewall rupture; and cardiogenic shock in which morethan 35% of the myocardium is usually infarcted andnecrotic. The most effective means of reducing the extentof myocardial necrosis is administration of thrombolytictherapy, aspirin, and a beta-blocking agent within threehours of onset. For large infarctions or in those withcontraindications to thrombolytic agents, the openingof the infarct-related artery with balloon angioplasty plusintracoronary stent is the most effective way to reducenecrosis. Newer intracoronary stents that have a lowincidence of in-stent restenosis will revolutionize themanagement of acute myocardial infarction (see thechapter Stents).In the majority of patients who have a heart attack, noprecipitating factor can be identified. The individualmay wonder, why today? What did I do wrong? Only

400HEART ATTACKSoccasionally is there some circumstantial evidence that maybe related to the incident; for example, excessiveunaccustomed exertion or severe stress. A large fattymeal, bed rest for several months, and overwork withoutundue distress do not appear to be precipitating factors.No one knows when a plaque of atheroma will rupture andcause a clot. If the blood is thicker and has a greatertendency to clot than normal, the individual is obviously atgreater risk of having a heart attack. Substances that causerapid and intense clotting are released when the plaqueruptures. These substances are exposed to the flowingblood and a clot quickly forms, thus blocking the artery.Possibly, new drugs could be produced to inhibit theclotting (thrombogenic) substances in the plaque. A pharmaceuticalfirm or scientists should explore this potentialavenue which may produce a product that can prevent afatal or nonfatal heart attack. The simple drug aspirincertainly helps to prevent some heart attacks and save lives,but it does not nullify the clotting properties of theruptured plaque contents.After a few months the area of dead heart muscle formsa well-healed scar. The size of the myocardial infarctiondepends on the coronary artery affected, i.e., a main vesselor a branch artery, and what part of the heart muscle itsupplies (see the illustrations in the chapter on Anatomy ofthe Heart and Circulation). If the anterior part of the heartis involved, this is more serious than involvement of theback (inferior) part of the heart. Inferior infarction hasa very good prognosis.receive therapy within four hours of the onset ofsymptoms.It is important for all individuals age 35 and over tolearn the symptoms and signs of a heart attack (see SectionIV). Someone experiencing a heart attack should take twoor three chewable aspirins [total dose 160 to 325 mg] andgo immediately to the nearest emergency room of ahospital. All hospitals have the facilities to give drugs thatdissolve clots in the coronary arteries. This life-savingtreatment should be given within minutes of your arrival.If you need to wait more than 20 minutes to receive thedrug, your spouse or person accompanying you to thehospital should complain. The choice of thrombolyticagent is not as important as the rapidity of administration.The real problem in the emergency room is the door-toneedletime. It is in excess of 30 minutes in more than60% of patients admitted in the United States and in manycountries worldwide. Fortunately in some countries facilitiesfor immediate angioplasty and stent deploymentare available to maintain patency of the infarct-relatedcoronary artery.IV. SYMPTOMSThe symptoms of a heart attack are often typical and easyto recognize. In some patients, however, symptoms can beso varied that both the patient and the doctor can bemisled.III. DOOR-TO-NEEDLE TIMEAs outlined above, in the majority of individuals the causeof a heart attack is a clot (thrombosis) in one of thecoronary arteries. This clot can be dissolved by specialdrugs (thrombolytic agents). For this thrombolytic treatmentto be most effective, it should be given within threehours from the onset of the symptoms of a heart attack,that is, three hours from the onset of chest pain, which isthe most common symptom. Beyond six hours, the chanceof success with this treatment is remote, because the heartmuscle cells become irreversibly damaged and die betweenfour and six hours after the blood supply has been cut off.Many patients are given treatment from 6 to 12 h after theonset of their symptoms with the hope of saving a fewlives. The number of lives saved by treating 1000 patientswith thrombolytic therapy given at less than 1, 3, 6, and 12h from the onset of symptoms are 65, 27, 25, and 8,respectively. Widespread advice to the population at risk iscrucial. Less than 33% of heart attack victims presentlyA. Type of PainPeople have unique feelings and sensations and usedifferent words to describe similar symptoms. Heartattacks vary a great deal in their severity, and patients arenot all alike. Thus, the characteristics of pain and theaccompanying symptoms can be very different from oneindividual to another.People experiencing a heart attack often have difficultydescribing the type of pain or peculiar discomfort ordistress. Some words used by various patients to describethe discomfort are in the following list.Crushing or compressing pain or a heaviness over the chest:The pain is most often described as ‘‘a crushing painacross my chest,’’ or the patient states that it feels like avery heavy weight or bar is resting on the center of thechest, especially over the breastbone (sternum). Anothercomplaint is ‘‘it feels as if someone is crushing orwalking on my chest.’’Viselike tightness, squeezing, constricting: It feels as if thechest is in a vise or as if a tight metal band is being

IV. SYMPTOMS401pulled around the chest. The constricting feeling isoften described as a tightness. The patient tries todescribe the tightness by clenching a fist.A disagreeable choking, strangling, sickening feeling in thecenter and across the chest: This type of sensation canoccur in patients with anxiety and may not be due to aheart attack. The strangling sensation is, however, veryimportant because it resembles the discomfort inpatients with angina pectoris. Patients with angina candevelop chest discomfort mainly on exertion due to alack of blood supply to the heart muscle. If thestrangling sensation comes on at rest and lasts for morethan 30 minutes, and especially if it is accompaniedby the associated symptoms of a heart attack, seekattention.Burning-like indigestion: A burning discomfort or painin the center of the chest, especially when accompaniedby sweating or sensations listed above, must be takenseriously as it can be caused by a heart attack. Painoriginating from the stomach is often burning inquality, but the associated symptoms differentiate heartfrom stomach pain. For example, heart pain is veryoften associated with profuse sweating, whereas stomachpain rarely ever causes sweating. There is a tearing,gripping pain as if the chest were being pulled apartfrom the breastbone.Fullness in the chest: As if it wanted to explode, may be asymptom of a heart attack, but it can be due to painoriginating from the stomach or gullet (esophagus), forexample, gas pains or reflux esophagitis.Just a discomfort: The patient may not perceive thesensation as pain but as a mild-to-moderate discomfort.Such a discomfort is a common feature and must not beignored, especially if associated signs and symptoms arepresent. Tingling, numbness, or heaviness over the left orright arm may occur at the same time as the pain in thechest but is rarely the only manifestation of a heartattack. However, there are many causes of such symptomsin the arms, especially pain from the nervessupplying the arms, muscular pain, or a small stroke, inwhich case the hand and the arm will be very weak. Aheart attack does not cause the arm or hand to becomeseverely weak and it never causes paralysis. A pointed,sharp, stabbing, sticking, knifelike pain is seldom amanifestation of a heart attack. Such chest pain is oftenproduced by other sources such as the chest wall or thelungs as in pleurisy and gas pains.Dizziness and/or severe weakness: This commonly occursalong with the chest pain of a heart attack, but is rarelythe only symptom.Nausea without vomiting or diarrhea: If associated withpain in the chest or discomfort or shortness of breath,weakness or dizziness, it can be a symptom of a heartattack. This rarely occurs without chest pain. In sucha situation, associated shortness of breath points to adisturbance of the heart rather than the stomach.Aching pain under the breastbone or arm: This isoccasionally described by patients.B. The Location of the PainIn the majority of individuals the pain of a heart attack isin the center of the chest under the breastbone (retrosternal).The pain is more often located under the lowertwo-thirds of the breastbone (see Fig. 3). Note that theheart projects to the left side of the breastbone and painunder or outside of the nipple line rarely comes from aheart attack.The next most common area for pain is the upper halfof the breastbone and the pit of the stomach. Heart painoccurs mainly in the center of the chest, and doctors oftenuse the term ‘‘central retrosternal chest pain’’ as beingtypical of a heart attack. Finally, pain from all three areascan move (radiate) up or down to involve the entire chest,neck, throat, and lower jaw (not higher than the upperjaw) and commonly extends to the arms, forearms, andhands. Both arms may feel painful, heavy, numb, or tingly.Left arm discomfort is more common than right, and asshown in Figs. 1 and 2, the inner aspect (ulnar side of thearm) is the most common site of arm pain. Most of thearm or a small part such as the wrist may be the site of painor discomfort without involvement of the chest. However,arm, jaw, or throat pain is usually accompanied by pain inthe chest. If pain is present only in the upper limb, theaccompanying symptoms and signs of a heart attack thenbecome very important in making the diagnosis. Forexample, if there is associated shortness of breath, nausea,and sudden generalized weakness, the arm pain can be amanifestation of a heart attack.Pain below the level of the belly button (umbilicus) isnot from the heart. In addition, the pain of a heart attackvery rarely goes through to the back. If it does, it is usuallythe zone between the left shoulder blade and the spine.Pain only in the area on both sides of a vertical line drawnthrough the nipple is most unlikely to be due to a heartattack (see Fig. 1). Centrally located breastbone pain canradiate across the entire chest, that is, to the left andoccasionally to the right of the nipple line and upward tothe neck and jaw. Thus, while in some cases, the size of thearea may be that of one to three clenched fists or the entirespan of the palm and outstretched fingers, pain can involvethe entire front of the chest. Presyncope or syncope may

402HEART ATTACKSFIGURE 3Common locations of heart pain.occur due to bradyarrhythmias that occur mainly inpatients with inferior myocardial infarction.C. Severity and Duration of the PainThe pain of a heart attack varies in intensity. In about 50%of patients it is described as severe pain. In about 10% ofpatients it is very severe and unbearable. In about 20% ofpatients, the pain is a moderate pain that is not in itselfdistressing and may well be a mild discomfort not reachingthe level of pain. In such patients the associated symptomsare important, especially the feeling of anguish or fear ofimpending doom, which is common in patients who arehaving a heart attack. In about 10% of cases, pain is notprominent but one or more of the following accompaniesthe vague discomfort: profound weakness, sweating,dizziness, nausea, or palpitations. In the remaining 10%of cases, particularly in diabetics and in the elderly, nosymptoms occur and a heart attack is discovered onlyon subsequent routine electrocardiographic or autopsyexaminations.The pain of heart attack usually lasts more than 30minutes and frequently one to four hours. A pain that lastsless than one minute and returns each time only to last acouple of minutes is usually not due to a heart attack,especially if there are no other associated symptoms. Painlasting less than 10 seconds, even when recurrent, is notdue to a heart attack. The pain of angina usually lasts from1–5 minutes and its maximum is 15 minutes. If the pain issimilar to the accustomed anginal pain but now lasts morethan 20 minutes, especially if you are at rest, you must

IV. SYMPTOMS403seriously consider the possibility of a heart attack and havethe situation assessed in a hospital emergency room.Diabetics and people over age 75 may have little or no painduring a heart attack. The elderly may get weakness orshortness of breath without chest pain.The pain of a heart attack can come on gradually over30 minutes to 1 h with increasing intensity that mayremain steady for a few hours. It is usually a steady pain,not an on-and-off pain such as occurs with crampystomach problems or abdominal pain that is usuallydescribed as colic (colicky or spasmodic pain). After one tofour hours, the pain of a heart attack may suddenlydisappear never to return and the individual may feel fairlywell. The patient may no longer be disturbed and canmake the mistake of not going to an emergency room or ofleaving the hospital. Pain ceases as the heart muscle cellsdie when they are deprived of blood and dead muscle cellsproduce no pain. On rare occasions, pain may persist for6–12 h in three or four bouts each lasting a few hours, andbetween times a dull pressure, tightness, heaviness or acheremains somewhere in the center of the chest or areasdescribed above.D. Warning AttacksAbout 20–30% of patients who have a heart attackexperience a ‘‘warning’’ some time during the two weeksprior to the attack. Patients who have chest pain (angina)suddenly notice a change in the duration and frequency ofthe pain. Instead of lasting 1–5 minutes, the pain may last5–20 minutes and is brought on with less activity and mayeven occur at rest. This usually indicates that the anginais progressing or unstable. If the pain lasts longer than30 minutes and is not relieved by two nitroglycerin tablets,it is likely due to a heart attack. If the pain lasts from 15 to30 minutes, it is likely due to unstable angina that can leadto a heart attack over the next few months. In such asituation, a heart attack is preventable if the properattention is sought. In patients who are not known to haveangina, pain may suddenly come on for the first timeduring a bout of unaccustomed exertion such as shovelingsnow, pushing a car, hauling a boat, or running. Chest painor discomfort may last only 2–10 minutes and may beignored only to return in full force within a few days. Ifpain occurs for only a few minutes, take special note if thepain is relieved within one to two minutes after stoppingthe precipitating activity. About 25% of such patientsare likely to have a heart attack within the next month,which may be prevented by the combination of a betablockingdrug and one aspirin daily. In addition, the ECGis usually normal in such patients when pain is absent.Thus, they are often sent away from the emergency room.This must not deter patients from seeking appropriateexpert medical care.E. Associated SymptomsAs discussed above, pain or discomfort of a heart attack isnearly always accompanied by one or more symptoms thatmay help the patient or the doctor clarify the diagnosis.Therefore, identifying these associated symptoms is of vitalimportance.1. Sweating is often profuse for at least a few minutes, inparticular, the forehead is usually covered with a coldsweat. Indigestion or stomach pains that can beconfused with a heart attack do not usually causeprofuse sweating. It is well known that sweating occursduring a fever as the temperature rises above 100 F(38 C). A heart attack, however, does not cause a rise inbody temperature until about the second day. Therefore,if you have sudden pain and definite fever, it isunlikely to be due to a heart attack.2. Difficulty breathing is very common and may last for afew minutes. Persistence of shortness of breath for morethan 10 minutes suggests that blood and fluid areaccumulating in the lungs due to heart failure andrequires prompt attention. Shortness of breath must bedistinguished from sighing respirations, which involvetaking one or two deep breaths and completelyexhaling. Sighing is a common occurrence in individualswho are under stress and can be due to tiredness,exhaustion, or anxiety. Difficulty breathing means apatient cannot take a deep breath because the chesthurts; for example, if a rib is fractured or there is aninfection on the outer surface of the lung membrane(pleurisy). Moving the chest wall produces lung pain;therefore, a deep breath cannot be taken because itcauses pain and the individual is forced to take shallowbreaths. Shortness of breath is a different sensation, andit means that you feel out of breath and are forced togasp and struggle for breath and breathe rapidly andshallowly. The feeling is similar to that of running upfour or five flights of stairs; afterward, you are out ofbreath and have to breathe harder and quicker. Duringheart failure the lungs have extra water and blood andbecome ‘‘stiff,’’ making a very deep breath impossible;therefore, breathing tends to be a little shallow. Whenshortness of breath is due to heart trouble, it is madeworse by lying flat and can improve a little if theindividual sits up and dangles the legs. Some nervousand anxious individuals hyperventilate, and this mustbe differentiated from true shortness of breath. The

404HEART ATTACKSpain of a heart attack is not increased by taking a verydeep breath, coughing, or sneezing.3. A feeling of impending doom is experienced byvirtually all patients who are having a heart attack.This fear and anxiety can provoke the secretion ofepinephrine (adrenaline)and noradrenaline, whichincreases heart damage and may disturb the heartrhythm. The increase in adrenaline causes irritability ofthe dying heart muscle and triggers the production ofextra beats. This may occasionally result in ventricularfibrillation during which the heart muscle does notcontract but quivers. It is imperative that pain, fear, andanxiety be quickly relieved with adequate pain-relievingdrugs such as morphine, oxygen, and with reassuranceby a doctor. A patient will be reassured by quicklyreaching a hospital where adequate facilities exist torelieve pain and combat the heart attack.4. Severe and sudden weakness may be associated withchest discomfort in about one-third of patients with aheart attack. The heart muscle is damaged and cannotpump with maximum force. Less blood is ejected fromthe heart at each beat; therefore, blood pressure fallsand less blood reaches the brain. Thus the patient mayfeel weak and feel like fainting. Transient loss ofconsciousness for a couple of minutes can occur but isuncommon. The blood pressure soon becomes restoredto near normal because of the body’s compensatoryresponses, and weakness improves. In a few patientswith a severe heart attack, the blood pressure remainsvery low and the weakness is profound (cardiogenicshock).5. Dizziness or light-headedness may occur in somepatients due to a drop in blood pressure. Ringing inthe ears (tinnitus) or severe rotational dizziness (vertigo)are not usually features of a heart attack.6. Nausea and occasionally vomiting accompany the painin a significant number of patients. Severe pain fromany cause may precipitate vomiting, and pain relieverssuch as morphine usually increase nausea and vomiting.However, unaccustomed sudden nausea may occurinstead of pain or chest discomfort. Thus, distressingnausea with sweating and shortness of breath should beconsidered due to a heart disturbance until provenotherwise.7. Restlessness may occur as the patient tries to find acomfortable position. However, the pain or discomfortof a heart attack is not relieved by any particular position.The pain is not made better or worse by sitting,standing, lying, or rolling from side to side.8. Shortness of breath may develop if the heart muscle isvery weak and heart failure occurs during the heartattack. The individual may even be gasping. In suchcases, some relief is obtained when the patient ispropped up in bed.9. A cough may suddenly develop with the productionof frothy pink or blood-stained sputum.10. A sharp drop in blood pressure may occur signaled byconfusion and loss of consciousness. If the heart attackis very severe this develops because of the lack ofoxygen to the brain. Loss of consciousness is rare and aloss for more than two minutes is not a feature ofheart attacks. When the heart muscle is suddenlyweakened by a heart attack, the blood pressure mayfall 10–40 mmHg and the pulse may become rapid.Thus in about half of patients with heart attacks,the systolic blood pressure may fall from an average of125 mmHg to less than 105 mmHg. However, duringthe next few hours, if the heart attack is not a verylarge one, the body’s compensatory responses may besufficient to increase the blood pressure to the normalsystolic range for the individual. The fall in bloodpressure caused by a heart attack often reduces theblood pressure of a hypertensive patient to normal sothat medications for high blood pressure may not berequired for several months and in some cases ever.Patients with known coronary heart disease andperhaps all males over 40 and females over 50would be wise to invest in a blood pressure instrument(sphygmomanometer). A blood pressure readingshould be taken every six months so that the averageblood pressure is known (see the chapter Hypertension).Thus, if chest discomfort or indigestion that isnot relieved by an antacid and your systolic bloodpressure falls more than 30 mmHg below the averagebaseline, visit an emergency room. If there is doubtbecause the discomfort seems to be in the stomach, anassociated fall in blood pressure may warn you andsave your life. On the other hand, because not allpatients have a fall in blood pressure and the rarepatient may have a mild increase in blood pressurebecause of pain and nervous reflexes, do not wait fora fall in blood pressure if chest pain with otherassociated symptoms is present; go directly to theemergency room.11. A change in heart rate accompanied by chestdiscomfort may indicate that a heart attack is underway. It is important for everyone over the age of 35 tolearn how to determine the heart rate by feeling thepulse at the wrist. Chest discomfort is experienced andthe pulse decreases by 20 or increases by 20 when atrest, this is likely to be a warning of a heart attack. Forexample, if the resting pulse rate is usually in the rangeof 70–80 beats per minute and it is suddenly at 50–60beats per minute while having chest discomfort, the

VI. MIMICS OF A HEART ATTACK405disturbance likely originates from the heart. This isespecially true if beta-blockers, which slow the pulserate, are not part of a patient’s drug therapy. Areduction in heart rate of 10 or less is too small to bediagnostic.If the back of the heart muscle is affected during theattack (inferior heart attack), the pulse usually slows. If thefront part of the heart muscle is affected (anterior heartattack), the pulse usually increases by 20–40 beats perminute and can reach 100–120 beats per minute at rest.If you have coronary heart disease or if you are over 45,your home should be equipped with a sphygmomanometer,nitroglycerin, and plain aspirin. These are asessential as having a smoke detector or a fire extinguisherin the home. It is far more important to learn thesymptoms and signs of a heart attack and the procedure formeasuring your blood pressure and taking your pulse thanit is to learn about cardiopulmonary resuscitation (CPR).F. Clinical ExampleA 48-year-old male had several typical symptoms duringhis heart attack. He suddenly experienced a disagreeablesensation in the chest, which increased to a heavy crushingsensation over and beneath the lower part of thebreastbone. During the next 10–15 minutes, the painfelt like a heavy bar across the chest and within a fewminutes spread to his left arm, which felt as heavy as lead.He was not known to have angina and therefore had nonitroglycerin available. He was overcome by a strange fearwith a feeling that life was going to be extinguished. At thispoint, his pain had lasted about 40 minutes and wasmoderately severe but could not be described as unbearable.He was sweating profusely and upon furtherquestioning, he admitted that it was his fear that promptedhim to call the ambulance. It is true that many people areafraid of a heart attack and may develop anxiety. Manyindividuals with pain in different parts of the body maybecome a little anxious, but few feel as if they arestrangling, and this sensation seems to produce great fearand anxiety.V. PHYSICAL SIGNSDuring the examination of a patient the following physicalsigns and abnormalities may be observed:The patient may appear anxious, apprehensive, andsweaty, and clammy. The location of chest pain may be indicated with aclenched fist held over the area of the chest wall. In patients with infarction of the inferior wall the heartrate is bradycardic at less than 60 beats per minute. Thisis found in more than 66% of patients. The bloodpressure may have fallen 20–40 mmHg lower than thenormal baseline for the given individual. In someindividuals it may be 110 mmHg systolic or as low as80 mmHg from cardiogenic shock. Some patients withanterior myocardial infarction may reveal tachycardiawith a rate greater than 110 beats per minute and anincrease in blood pressure. If the area of infarction isextensive the pressure usually falls, and in some patientscardiogenic shock or heart failure supervenes. In more than 25% of patients admitted to the hospitalshortness of breath is caused by heart failure andphysical abnormalities that include an increase injugular venous pressure and crepitations and rales areheard with the stethoscope over the lower lung fields. Extra heart sounds such as a third or fourth heart soundmaybe present. A soft mitral murmur of acute mitral regurgitationmay suddenly occur caused by dysfunction papillarymuscles. Often there are no abnormal physical signs observed.The finding of symptoms suggestive of a heart attackshould not decrease the level of suspicion that thepatient may have an acute infarction.VI. MIMICS OF A HEART ATTACKSeveral conditions cause symptoms that can mimic heartattacks. These are the most common: Indigestion and reflux esophagitis, hiatus hernia andesophageal spasm, acute gastritis Gallbladder disorders Lung infections such as pleurisy and pneumonia Pericarditis Chest wall pain originating from the muscles, ribs,intercostal nerves or costochondral joints, or due tocostochondritis Arm pain and tingling and numbness in the left or rightupper limb, not related to exertion such as a brisk walkRest assured that about half of all patients admitted tothe hospital because of chest pain are not having a heartattack. These patients usually have an unstable form ofangina pectoris, chest wall pain, stomach problems (inparticular, reflux esophagitis with esophageal spasm),gallstones, and very rarely pericarditis. Occasionally nocause can be found.

406HEART ATTACKSA. Indigestion and Stomach ProblemsIndigestion can be distinguished from the symptomsor discomfort caused by a heart attack. Pain of a heartattack can be present in the pit of the stomach (upperepigastrium) and the lower sternal area and may even beburning in type. Burning pain is more common withstomach and esophageal pain and is relieved by antacids,but the burning caused by a heart attack is not relievedby antacids. Associated profuse sweating or shortness ofbreath points to a heart attack rather than stomach oresophageal pain. Pain from ulcers in the stomach does notcause sweating, but it is related to meals and is oftenrelieved by antacids.B. Reflux Esophagitis and Hiatus HerniaThe cardiac sphincter is a muscle present at the junction ofthe esophagus and stomach (see Fig. 1). This sphinctercloses tightly when an individual is at rest, but relaxes andopens in response to swallowing to allow food to enter thestomach. When you are not swallowing, the loweresophageal sphincter is tightly closed and prevents stomachcontents such as hydrochloric acid and constituents of thebile from flowing backward into the lower esophagus(gastroesophageal reflux). In some individuals, either inresponse to a hernia of the stomach that protrudes into thechest along the lower esophagus (hiatus hernia), heredity,or aging, the sphincter becomes incompetent and opensduring rest. It opens further if intra-abdominal pressure isincreased during straining, stooping, or lifting heavyobjects or during pregnancy. Reflux is always worsewithin one hour of eating, especially if excess fluids weretaken. A high-fat meal delays emptying of the stomach,and reflux may last for hours rather than minutes. Thereflux of acid and stomach contents such as pepsin, bilesalts, and pancreatic enzymes causes severe irritation and attimes inflammation of the lower esophagus. This conditionis called esophagitis, which is similar to having anulcer in the stomach. Distressing symptoms persist formany years and may result in narrowing (stricture) of thelower esophagus which results in difficulty in swallowing.Reflux esophagitis often causes discomfort in the lowerchest (retrosternal) as does heart attack or angina. Theburning, pressure-like pain or discomfort can radiate alongthe entire breastbone to the back and sometimes the arm.Heartburn is common and regurgitation of bitter sourfluid or food, without vomiting, commonly occurs. Freeacid reflux in the esophagus when an individual is sleepingcan cause that person to be awakened by the discomfort.Spicy and acid foods, especially citrus juice, coffee, andfatty meals increase the discomfort, which at times may bedifficult to differentiate from a heart condition such asangina. As mentioned earlier, a heart attack can causeprofuse sweating and shortness of breath, whereas refluxesophagitis does not. The ECG remains normal when painoriginates from the esophagus or stomach.The diagnosis of esophagitis is made by x-ray. Usinga barium swallow or a meal, the radiologist documentsthe reflux of barium from the stomach into the esophagus.Tests are available to detect incompetence of the cardiacsphincter, and gastroscopy shows inflammation of thelower end of the esophagus with or without the presenceof a hiatal hernia. A hernia often increases reflux, butthe effect is variable. Reflux usually occurs without thepresence of hernia and may not occur when a hernia ispresent.Esophageal reflux is relieved by: Taking antacids Elevating the head of the bed and refraining from lyingdown for at least two hours after a meal or a drink ofliquid Avoiding spicy foods, fatty foods, and acid liquids suchas citrus juices Avoiding bending, stooping, and lifting, especiallywithin one hour after meals Reducing weight Using drugs such as metoclopramide, which increasesthe tone or competence of the lower esophageal sphincter(see Fig. 1) and inhibitors of hydrogen secretionsuch as omeprazoleC. Esophageal SpasmThis condition is not as common as gastroesophagealreflux, but can closely mimic a heart attack and frequentlyoccurs in patients who have esophageal reflux. Esophagealspasm can occur at any age but is more common after age40. The most common site of pain is behind the lower halfof the breastbone which can radiate upward along thebreastbone to the throat, jaw, back, or arms. Pain can besqueezing, dull, or sharp; moderate to severe; and lastminutes to hours. The pain can occur at night with theindividual awakened by moderately severe pain that can bemistaken for a heart attack. Pain may come on during orafter a meal, especially after a drink of cold liquid. Severeanxiety and stress can produce an attack, but there may beno precipitating factors.In many patients with esophageal spasm, there is somedifficulty in swallowing, and this can occur with orwithout the presence of pain. The diagnosis is usually

VII. AMBULANCE TRANSPORT407confirmed by x-ray fluoroscopy during which theindividual swallows liquid barium. Other confirmatorytests can be done by a gastroenterologist. Nitroglycerinmay relieve the pain of esophageal spasm, and a calciumantagonist, nifedipine, which relieves muscle spasm, cansometimes abolish the pain. Antacids or warm milk mayrelieve the pain of esophageal spasm, but not the pain ofheart attack. An ECG done when pain is present duringesophageal spasm is normal and excludes a heart attack.usually relieved by pain medications such as aspirin, butcan recur over several months. The doctor may inject thejoint with a combination of a local anesthetic and acortisone compound. This causes relief for several monthsduring which time nature heals the condition, but the painmay recur. This is a benign condition that never gets worseand does not lead to heart attacks or arthritis in other partsof the body. However, in a few patients costochondritiscoincided with heart pain.D. Lung InfectionsPneumonia may produce pain, and this is usually a sharppain that is made worse by taking a very deep breath orcoughing. The pain occurs because the outer membrane ofthe lung, the pleura, is involved in the inflammation.Usually there are fever, chills, and cough.E. PericarditisThis is an inflammation of the outer membrane of theheart, which can be caused by a virus or bacteria or mayoccur a few days after a heart attack. The pain is usuallysharp, located over the lower breastbone or a little to theleft of the breastbone, and is sometimes made worse bydeep breathing when the pericardium and pleura are bothinvolved. The pain is usually made worse by lying downand improves within seconds or minutes on sitting up andleaning forward. Three or four days after a heart attacka few patients may develop pericarditis. This resolves in afew days. There are many other causes of pericarditis suchas kidney failure, cancer, lupus, radiation, and as a sideeffect of some drugs.G. Arm Pain, Tingling, and NumbnessMany people experience tingling and numbness in the armif the arm is rested over the back of a chair for severalminutes or hours or by sleeping on the arm in an unusualposition. This pain is caused by pressure on the nerve andnormally subsides quickly once the unusual pressure hasbeen removed. Arm pain, tingling, and numbness mayoccur when the nerves supplying the upper limb becomeaffected by conditions such as arthritis of the spine in theneck region. Pressure is then exerted on the roots of thenerves as they emerge from the spine. Cervical disk diseaseis similar to sciatica, which produces low back and legpain. Pain arising from sciatica usually lasts several hoursand may occur over many days and may be related toposture. It is an aching pain that is only occasionallyassociated with chest pain. Nerve and muscle pain doesnot get worse during vigorous walking. This serves todifferentiate the pain from angina, which can cause pain inthe arm during brisk walking. Moderate to severe pain inthe wrist or the arm without trauma or other precipitatingcause, especially if there is no tenderness on pressure ormovement of the limb, warrants medical advice.F. Chest Wall PainPain occurring in the wall of the chest is extremelycommon and may be due to pain in the muscles, ribs, andcostochondral joints. A costochondral joint is formed at apoint where the hard bone of the rib joins the softer bone(cartilage) that attaches to the breastbone. The costochondraljoints frequently get irritated producing costochondritis.Pain can be localized to a small area the size of oneor two fingertips and the area is tender to pressure. Sittingin a draft or exercise such as raking a lawn may aggravatethe condition. Costochondritis is very common betweenthe ages of 30 and 60, and occasionally patients maybecome worried that it is the heart. This condition is morecommon in women and occurs more often on the left sideover the second and third costochondral joints. The pain isVII. AMBULANCE TRANSPORTA. What to do Before the Ambulance ArrivesIf you think you are experiencing the symptoms and signsof a heart attack (see Section IV) you should get to thehospital emergency room as quickly as possible. Denial orwishful thinking that the pain will disappear in the nexthour is about the worst thing you can do. Do not try toreach a physician for advice. Call the ambulance first, thenask someone to make a call to your doctor or cardiologist.If you cannot reach the doctor, leave a message; do notwait for a reply. If you are fortunate to live in an area wherea mobile heart ambulance exists, then please use thisservice. If this is not available, use 911 or ambulanceservice. If no ambulances are available, have someone drive

408HEART ATTACKSyou immediately to an emergency room. Do not driveyourself to the hospital if you have pain lasting longer than15 minutes, particularly if you have unusual profusesweating, shortness of breath, dizziness, or feel weak.While waiting for the ambulance, which should arrivewithin minutes of your call, try to keep calm. Fear andpanic cause further damage to the heart because theyprovoke the secretion of adrenaline, which increases thework of the heart and may increase the size of the heartattack or induce abnormal heart rhythms. While waiting,do the following:Chew and swallow one 325-mg plain aspirin immediatelyor preferably take two or 3 soft, chewable 80-mgaspirins. The chewable baby aspirins are more effectivethan coated aspirin or a hard regular aspirin inpreventing a heart attack because they are quicklyabsorbed in the stomach. Chewable baby aspirin shouldbe carried by all patients who have had a heart attack orthose at risk. The use of two chewable aspirins is moreimportant than use of nitroglycerin under the tongue.Nitroglycerin does not prevent a heart attack or death,but chewable aspirins have proved effective in randomizedclinical trials to prevent fatal or nonfatal heartattacks.Do not take a coated aspirin because it takes severalhours to be effective. Any form of regular aspirin maysuffice to prevent a heart attack, but coated aspirins arenot recommended for emergency prevention of heartattacks because they take too long to dissolve and to beabsorbed by the stomach.Sit or lie propped up on three or four pillows and take anitroglycerin tablet under the tongue. One tablet can dono harm. It will help calm your nerves as it will increasethe blood supply to the coronary arteries. It also poolsblood in the veins of the legs; therefore, less bloodreturns to the heart so there is less work for it to do.Nitroglycerin may decrease the size of a heart attack. Itis reassuring to take one tablet under the tongue andbelieve that it will help. The drug is not as effective ifyou are lying flat. It is most effective if you sit up withyour legs dangling over the edge of the bed or in acomfortable chair as this causes the blood to stay in thelegs longer. Nitroglycerin may cause a headache, butthis is to be expected because the drug dilates arteriesincluding those in the scalp as well as the coronaryarteries.There is no need to worry about the throbbing that youwill feel in the head. Nitroglycerin does not increase bloodpressure. Put on a pajama top, loose shirt, or blouse. Donot overdress. There is no reason to put on a vest, sweater,shirt, tie, jacket, or blouse that is difficult to remove. Thesegarments will only have to be pulled off when you are inpain and lying on a stretcher in the emergency room.Therefore, if it is not excessively cold, wear clothing thatcan be easily opened to allow the doctor to examine youquickly and facilitate placement of the leads of the ECGthat must go on the chest. In addition, blood pressureis best taken with no garment around the arm. Everyambulance should have blankets to keep you warm. It isa waste of precious time to try to remove clothing inthe emergency room.When the ambulance arrives, you will be given oxygen.Oxygen given at this stage will help allay anxiety and panic.Put the oxygen mask right over your nose and mouth andbreathe in the gas. There is nothing like believing thatsomething will help when you are scared to death. Westrongly recommend the use of oxygen and nitroglycerin asa technique to break the fear-anxiety-adrenaline reaction.The reassurance of a trusted physician or specialist andthe use of morphine can be lifesaving. Until these areavailable, use aspirin, nitroglycerin, and oxygen. They willhelp. Someone telling you to stay calm during the pain andfear of a heart attack is of no avail. Therefore, do the thingsthat carry some hope.Remember that morphine is used not only to relievepain but to relieve anxiety. Morphine is the best drug forthis purpose, and you should not be opposed to its use. If asecond injection is necessary, even if your pain is mild, donot object to its use.B. Mobile Coronary Care AmbulanceWhen a plaque of atheroma ruptures, a clot is formedwithin minutes. This causes centrally located chest painassociated with sweating and often shortness of breath. Ifyou believe you are having a heart attack, quickly go to theemergency room of the nearest hospital. Approximately500,000 individuals with heart attacks die each year in theUnited States and Canada before reaching the hospital.The only way to save some of these lives is by the use ofmobile heart squads. It is estimated that about 50,000 livescould be saved annually in North America by the use ofmobile heart squads.The first mobile coronary care ambulances wereoperated at the Royal Victoria Hospital in Belfast byDr. J. F. Pantridge and Dr. J. S. Geddes in 1965. Theobjective was to reach the patient quickly and stabilize theheart rhythm, relieve pain as well as to afford reassurance,and thus prevent death from abnormal heart rhythms.When the heart is found to be quivering and notcontracting (ventricular fibrillation), the heart is defibrillatedusing a portable defibrillator. The success of such

VIII. WHAT TO EXPECT IN THE HOSPITAL409units led to the establishment of coronary care ambulancesin Seattle and several other American cities.Properly equipped emergency care ambulances are stilllacking in Canada, in many areas of the United States, andin most countries worldwide. Perhaps with the advent ofthe new drugs that dissolve clots in the coronary arteriesand the emphasis on early administration of such treatment,special mobile units may become necessary if wewish to save the countless lives lost before reachinghospitals.In North America about half a million deaths occuroutside the hospital whereas about 60,000 die from a heartattack in the hospital. It is estimated that coronary careunits save about 30,000–40,000 lives annually in NorthAmerica, but at a very high but justifiable cost of runningsuch units. It is simple to equip and run mobile emergencycare units. The vital equipment consists of a lightweightportable defibrillator, an EGG recorder, intravenouspreparations, morphine, and oxygen. A system in a cityof one million people can be serviced by two units at a costof about $100,000. It is the manpower that escalates thecost of running such units. It is feasible to send out atrained physician, a nurse, and a driver trained in CPR insuch a unit. Perhaps doctors in training will see the needfor such services in a community and help to organizesystems with the help of their chiefs and with financialassistance from service clubs until government bodies aremade aware of the lifesaving potential that justifies the costof mobile emergency care units.Over the next decade drugs to dissolve clots in thecoronary artery will need to be given intravenously bytrained staff running mobile heart squads. This shouldavoid a further 30- to 40-minute delay on reaching anemergency room. The public can assist by lobbying theirelected representatives to achieve better mobile emergencycare services and treatment in ambulances or in the homeon the arrival by the ambulance staff.VIII. WHAT TO EXPECT IN THE HOSPITALIf you still have pain on arrival at the emergency room, youcan be reassured that the pain will be relieved within fiveminutes. Usually no time is wasted. The emergency roomstaff are primed to move quickly to deal with ambulancecases, particularly those suspected to be heart attackvictims. You are mainly expected to say to the nurse or thedoctor that you are having chest pain. Point to the areaof pain, indicating whether it is severe or very severe andthat you are scared and would like something as soon aspossible for the pain. You can then cooperate by answeringall the other questions that the doctor may wish to ask. Youwill usually have to state whether you are allergic tomedications. You will quickly receive an intravenousinjection of morphine, which relieves the pain in two tofive minutes. Because the injection is given intravenously,very small doses are used; for example, it may be given in2-mg increments every minute until the pain is completelyrelieved. Do not be embarrassed to say that you are scared.A heart attack makes everyone afraid, and the doctor maysometimes forget this. Also, relief of pain by morphine canprevent some complications of a heart attack.You will be quickly hooked up to continuous oxygen,and a blood pressure cuff will be placed around your arm.The doctor will examine you and ask you relevantquestions. There is very little reason for the doctor to askmore than 12 questions, because the diagnosis is usuallyeasily made from your description of the chest pain andfrom the ECG that is done within minutes of your arrival.The ECG writes the electrical rhythm and rate of eachheartbeat. You will be immediately hooked up to a cardiacmonitor and small electrodes similar to ECG electrodeswill be placed on your chest and connected to the monitor.The electrodes detect the electrical impulses from theheart, which are recorded continuously on a monitoredscreen. The nurses and doctors can see the visual display ofthe continuous ECG, showing each heartbeat as well as theimportant heart rate and rhythm of the heart. If the ECGconfirms the diagnosis of heart attack, streptokinase,tenectaplase, t-PA, or reteplase is given intravenously todissolve the clot. In some hospitals with equipment andspecial staff, a coronary angiogram is done and angioplastyis used instead of drugs to clear the obstruction in theartery. This technique is lifesaving but needs to be tested inlarge clinical trials.The area of damaged muscle during a heart attack maycause electrical discharges that interrupt the normal clocklikerhythm of the heart, which causes premature beats.These premature beats will show up on the monitor (seethe chapter Arrhythmias/Palpitations). If these extra beatsare frequent or of a special variety, they act as warningsignals and the doctor suppresses these beats by giving adrug called lidocaine intravenously and then through acontinuous intravenous drip. Lidocaine is effective instabilizing the heart rhythm and has no serious side effects,so you have no need to worry or be afraid.It is important for you to start seeing the brighter side ofthings. Once the morphine is given, the worst is over. Youare out of danger because you have made it to the hospitalwhere expert care is available. Most deaths occur before thepatient reaches the hospital. Those who die before reachingthe hospital have either a very large heart attack, experienceelectrical disturbances that cause the heart to quiver

410HEART ATTACKS(ventricular fibrillation) or stop beating, or have remainedtoo long outside of the hospital with extensive damage tothe heart muscle.Next, blood is taken and several blood tests are done.Cardiac enzymes are taken for diagnostic purposes. Theheart muscle cells that are deprived of blood undergo aseries of changes ranging from injury to death of the cellsand liberate cardiac enzymes, which can be detected in theblood. The most reliable of these enzymes are troponinand creatine kinase (CK). The special fraction of CK (CK–MB) that is derived solely from heart muscle is measuredto distinguish it from the release of ordinary skeletalmuscle enzymes. The ECG is taken hourly for six hoursthen daily for a few days. This is still the quickest, mostreliable, and least expensive test for detecting a heartattack.The damaged heart muscle will heal itself over the nextfew weeks. Although it will be difficult, you should try notto worry about the future at this time. You need rest andreassurance. Let others do the worrying.A. Coronary Care UnitsHospitals that provide efficient heart care strive to getpatients to the coronary care unit (CCU) within a halfhour of emergency room arrival and soon after commencingstreptokinase or t-PA. The CCU is a special area of thehospital, which usually consists of 6–12 beds with a staff ofspecially trained doctors and nurses along with sophisticatedelectronic equipment to deal with heart attackpatients. It will take some adjustment, over 6–24 h, for apatient to get used to all the gadgets. The patient will havealready had an ECG in the emergency room, and this isrepeated in the CCU and once daily for three days. Thepatient is attached to a cardiac monitor similar to the oneused in the emergency room.The ECG is the main diagnostic tool and can accuratelymake the diagnosis in the majority of patients. In morethan 90% of cases during a first heart attack, typicalfindings occur on the ECG and are easily recognized. If thefirst ECG is only suggestive of a heart attack, repeat ECGs6 and 24 h later usually give an accurate diagnosis. Inpatients who have had previous heart attack, the ECG isless diagnostic and is positive in about 75% of the cases.Less than 10% of patients having a first heart attack havean ECG that may be nondiagnostic, and it can be normalin about 5% of the cases. In these difficult cases, when theECG is repeated 6–24 h later, typical changes confirm orexclude the diagnosis of a heart attack.It is necessary in a difficult case for the doctor in theemergency room to pay special attention to the patient’sdescription of the chest discomfort. Therefore, in suchcases, the patient must put up with answering questionsposed by several doctors. Perhaps the fortunate patient isnot having a heart attack. In this case, the doctor may electto admit the individual for 24-h observation. The CKenzyme starts to increase about four to six hours after theheart attack and may be normal in some cases if taken veryearly during the attack. A careful physician often repeatsthe ECG and blood test for troponin or CK–MB everytwo hours. If both ECG and blood enzymes are normaland the description of chest pain does not suggest a heartattack, the doctor may elect to send the individual homeafter 24 h. The patient is advised to return to theemergency room if the pain recurs. A risk is therefore takenand the public must understand that the doctor may notbe able to admit every patient and that the pain may bedue to other causes. Policy varies depending on thephysician in charge. If doubt exists, the patient is admitted,and if three ECGs done over a 48-h period and a repeattest for cardiac enzymes is normal, then a heart attackcan be excluded with confidence. In rare instances, thediagnosis is firmly established only on the third day of theillness.A routine chest x-ray is taken in the hospital. It cannotdiagnose a heart attack, but it is useful in making thediagnosis of heart failure, which occurs for a few days inmore than 50% of heart attack patients.Occasionally the blood pressure is very low and drugcombinations are given intravenously to maintain thesystolic blood pressure between 90 and 100. Bloodpressure of 95–105 systolic is very common in patientshaving heart attacks, but it can be 110–140 in those whohad slightly higher blood pressure before the heart attack.In some units, other instruments are used to monitorthe amount of blood ejected from the left ventricle, that is,the cardiac output. Because of the many parameters thatare measured, several veins in the arm may be used for theintroduction of a venous tube, which is usually about oneto two inches long and is not harmful.An echocardiogram may be done to verify the strengthof the heart muscle. Nuclear scans can be helpful in the fewpatients who do not have classical diagnostic findings onECG or cardiac enzymes. It is not routine to have nuclearscans because the ECG and blood test for cardiac enzymesare sufficient in more than 90% of the cases for a firmdiagnosis. Nuclear scans and other tests increase the cost toboth patient and state and are not justifiable.In patients with a heart attack and complications such assevere heart failure, a monitoring catheter may be insertedinto the right side of the heart to monitor the pressurewithin the heart. This assists with evaluation of thetreatment in critically ill patients. If the patient is not

IX. DIAGNOSTIC TESTS411critically ill and complications have not occurred, thisexpensive and invasive test is not justifiable.The procedure for introducing the catheter is simple.The skin area over the vein is infiltrated with localanesthetic. The specially made fine tube (catheter) has atiny balloon and sensing devices at its tip. The catheter isinserted into the vein and threaded into the right ventricleand the pulmonary artery. Its position is verified by x-ray.Patients with severe heart failure and very low bloodpressure may require several drugs and fluid replacementgiven intravenously. The monitoring catheter that ispositioned in the pulmonary artery is useful for the infusionof intravenous preparations, but a simple intravenousline in the arm vein is preferable in the majority ofcases, because this method is inexpensive and devoid ofcomplications.On day one treatment is continued with oxygen, whichcan be discontinued after a few hours in the majority ofpatients. The amount of oxygen in the arterial blood istested by a simple measurement, and if this is normal, theoxygen is usually discontinued. Generally, no food or drinkis allowed for the first eight hours, since the process ofdigestion steals blood from the heart; also, if vomitingoccurs, vomitus may be aspirated into the lung. During thestay in the coronary care unit, the patient receives sufficientsedation to prevent anxiety and to ensure adequate rest.In the CCU on day two a light diet is usually given andincreased over a few days to a normal diet. On the secondday, patients are usually sitting at the bedside. Late on thesecond or on the third day, the patient is moved from theCCU to an intermediate care area or to a ward with otherpatients. In the standard room, the patient is allowed morefreedom each day starting with walks to the bathroom andprogressing then by day five to walks in the corridor of thehospital. If the individual is making a good recovery, theintravenous tubes are removed by the third or fourth day.The education process will now begin and both husbandand wife are usually given instructions together in aquestion-and-answer period each day. The individual isoften concerned that pain is no longer present and wonderswhy it is necessary to stay in the hospital. The pain ofa heart attack usually disappears between one and sixhours, and in most patients, there is usually no recurrenceof pain during the hospital stay, and in many there is nopain for several years.By the fourth day, the patient is very well and enjoysmeals and walks around alone. At this stage the doctor willwish to discuss the question of how much rest is necessary.The patient must understand that a blockage of a coronaryartery has taken place. This caused damage and death to asegment of heart muscle cells. Special cells in the body thatform bridges (scar tissue cells) move into the area and formscar tissue joining the two normal areas of heart muscle.The scar tissue is similar to that following the healing ofa surgical incision. It takes time for scar tissue to formand heal. The healing process usually takes three to sixweeks. During the 1950s, it was common practice to keeppatients in the hospital for four to eight weeks. In the1970s, it became apparent that after seven days, if therewere no complications, most patients could be allowedhome. In some countries discharge on the fourth or fifthday is not unusual. In most hospitals, patients are dischargedhome between the 6th and 10th day dependingon the size of infarction, complications, and their homesituation.By the fifth day the patient is walking approximately100 feet, two or three times daily. By the 7th to 10th day,the patient has been supervised while walking up one flightof stairs and should have had a stroll on the treadmill toreach a heart rate of 120 beats per minute. This modifiedstress test is repeated in 6–10 weeks and decisions arethen made regarding further medical treatment, angioplasty,or bypass surgery if the decision was not made priorto discharge. In many patients percutaneous intervention(PCI) involving angioplasty and intracoronary stent wouldhave been done during day one.Discharge from the hospital is usually on the fifth orsixth day, but in many hospitals worldwide discharge is onthe third or fourth day, particularly if PCI was successful.IX. DIAGNOSTIC TESTSA. ElectrocardiogramDespite the advent of expensive and sophisticatedcardiologic tests, the ECG remains the most reliable toolfor the confirmation of acute myocardial infarction. TheECG — not the blood cardiac enzymes (CK–MB andtroponin), echocardiogram, cardiac nuclear scans —dictates the rapid administration of lifesaving thrombolytictherapy or angioplasty with intracoronary stent.Two major types of acute infarctions are recognizedfrom the ECG tracing: ST segment elevation myocardialinfarction (see Figs. 4 and 5) and non-ST segmentelevation myocardial infarction (formerly called non-Qwavemyocardial infarction; see Fig. 6; also see the figuresin the chapter entitled Electrocardiography). Thesediagnoses have replaced the old terminology, transmuraland nontransmural myocardial infarction. Today a newterm, acute coronary syndrome, has been used to identifypatients with acute chest pain who may have ST segmentelevation infarction or non-ST segment elevation infarction.Patients without biochemical markers, CK-MB, or

412HEART ATTACKSV1V4V2V5V3V6FIGURE 4 (A) ST segment elevation in V 1 through V 5 ; poor R wave progression in V 2 through V 4 typical of recent anterior infarction. (B) Variation inshapes of ST elevation. (From Khan, M. Gabriel (2003). Rapid ECG Interpretation, second edition. Philadelphia: W.B. Saunders.)troponins are regarded as having unstable angina. Figure 5illustrates the current system using acute coronarysyndrome. This new terminology is somewhat redundant.It appears that physicians bask in the formulation of newsyndromes sometimes with unneeded terminology. Toretain the term ST elevation myocardial infarction (MI)would be simple. The diagnosis is easily made and therapyfor this condition has been well-defined since the 1980s. Itcould also be simple in patients with acute chest pain touse the term non-ST elevation if there is ST segmentdepression with positive cardiac enzymes MI. Both termsbecame ingrained during the late eighties. Patients withnegative troponins are labeled unstable angina. In Fig. 7the words acute coronary syndrome are synonymous with‘‘cardiac-like chest pain’’ and can be eliminated from thealgorithm. Nonetheless, the term acute coronary syndromeis here to stay and is likely to be used in many countries.There is no test to rival the ECG in the diagnosis ofarrhythmias, which are a common clinical cardiologicproblem and a common finding in patients with acutemyocardial infarction. Arrhythmias occurring during thefirst few hours of infarction may be life-threatening.B. Blood Tests/Cardiac EnzymesThe results of cardiac enzymes, CK–MB and troponins,are not relevant for the diagnosis of ST segment elevationMI. This diagnosis must be made within the hour by ECGand cannot await the results of cardiac enzymes thatbecome elevated only after 6–12 h from the onset of chestpain. An elevation of troponin levels indicates the presenceof micro-infarction, and if the ECG does not show ST

X. SPECIFIC MANAGEMENT413FIGURE 5 Deep pathologic Q waves in II, III, and aVF with marked ST segment elevation indicate acute inferior myocardial infarction. (From Khan,M. Gabriel (2003). Rapid ECG Interpretation, second edition. Philadelphia: W.B. Saunders.)elevation, then the diagnosis is clearly non-ST segmentelevation MI.infarctions, heart failure, valvular abnormalities, andpericardial effusion.C. EchocardiographyThis test is not indicated in all patients admitted to theemergency room. The area of infracted muscle isdetected as an area that moves very poorly during systoliccontraction and is described as the presence of leftventricular wall motion abnormalities. An ejection fractioncan be obtained and is useful for risk stratification.Echocardiography is useful in patients with complicatedX. SPECIFIC MANAGEMENTA. Pain1. MorphinePain precipitates and aggravates autonomic disturbanceswhich may cause arrhythmias, hypotension, or hypertension,thus increasing the size of infarction. Pain relief mustbe achieved immediately. Morphine is the drug of choice

414HEART ATTACKSV1V4V1V4V2V5V2V5V3V6V3V625 mm/sec 10.0 mm/mV ~ 0.50-10025 mm/sec 10.0 mm/mV ~ 0.50-100FIGURE 6 (A) Non-Q-wave infarction (acute subendocardial infarction) in a patient with a clinical picture of infarction and elevated CK-MB. Notewidespread ST-T depression in the limb and chest leads but no associated Q waves. (B) The same patient’s ECG tracing 18 hours earlier than depicted in(A). (From Khan, M. Gabriel (2001). On Call Cardiology. Philadelphia: W.B. Saunders, p. 105.)CARDIAC LIKE CHEST PAINAt rest or on minimal exertion =ACUTE CORONARY SYNDROMEECG FINDINGSST SEGMENT ELEVATION≥ 1 mm in 2 or morecontiguous leadsNO ST SEGMENT ELEVATIONTROPONIN elevatedYes*CK-MB +veor −veNoST ELEVATION MINON ST ELEVATIONMI**UNSTABLEANGINAFIGURE 7 Diagnosis of ST segment elevation myocardial infarction (MI) and non-ST segment elevation MI. *Excludes false-positive. If troponins areunavailable, being positive for the MB isoenzyme of creatine kinase (CK-MB) also confirms the diagnosis. Patients who are CK-MB negative and haveassociated ECG changes are at high risk of unstable angina. **According to the American College of Cardiology/American Hospital Association guideline,0.5 mm associated with ST depression; according to the European Society of Cardiology, 0.1 mV, 1 mm.for relief and should be given slowly intravenously: 4–8 mgIV at a rate of 1 mg per minute repeated if necessary at adose of 2–4 mg at intervals of 5–15 minutes until pain isrelieved. Morphine allays anxiety, relieves pain, and causesvenodilatation, therefore, reducing preload. This is of somebenefit in patients with left ventricular failure.2. Beta-BlockersBeta-blockers must be given a more important place in themanagement of chest pain resulting from myocardialinfarction. They can be considered as important secondlineagents for the control of ischemic pain. This is

X. SPECIFIC MANAGEMENT415important in patients with acute infarction accompaniedby sinus tachycardia and systolic blood pressure greaterthan 110 mmHg. Dramatic pain relief and reduction of STsegment elevation can be obtained by the administrationof a beta-blocking agent and the requirement for opiates isthus reduced. In some patients pain has been documentedto be relieved by the administration of beta-blockerswithout concomitant use of opiates. Metoprolol 5 mg ata rate of 1 mg per minute is repeated if necessary at5-minute intervals to 10 mg. A maximum dose of 50 mgfollowed by an oral dose of 50 mg every 12 h can begiven if no contraindication exists (asthma, heart block,bradycardia of less than 50 beats per minute, and bloodpressure less than 90 mmHg diastolic).3. Intravenous NitroglycerinIntravenous nitroglycerin is used if pain is not relieved bymorphine and to assist the management of left ventricularfailure if present.4. OxygenOxygen is given two to four liters per minute for the firsttwo to four hours then discontinued. Oxygen is usedfurther if left ventricular failure is present or if hypoxemiais observed on blood gas analysis.B. Strategies to Reduce Morbidity andMortalityTable 1 lists strategies that are important for the reductionof morbidity and mortality.1. ACE InhibitorsIn patients with anterior infarction an ACE inhibitor iscommenced provided the systolic blood pressure remainsgreater than 100–110 mmHg. These agents are used ifheart failure is present of if the ejection fraction is less thanTABLE 1Thrombolytic Therapy: Timing of Admission and SurvivalTime from onsetof symptomsLives savedper 1000 treatedWithin 1 hr 652–3 hr 274–6 hr 257–12 hr 840% (see the chapter Angiotensin-Converting EnzymeInhibitors/Angiotensin Receptor Blockers for their beneficialeffects in heart failure and in patients with lowejection fractions).2. Beta-BlockersThese agents have been shown in large randomized clinicaltrials to reduce morbidity and mortality in patientsfollowing myocardial infarction in the acute phase and toimprove survival over the long term. The CAPRICORNstudy caused a significant 23% reduction in all-causemortality in patients in whom the drug was commencedduring infarction and continued for 2.5-year studies. TheCOPERNICUS study showed that beta-blockers alsoimprove survival in patients with myocardial infarctionand mild-to-moderate degrees of heart failure. (See thechapter Beta-Blockers for other clinical trials.)3. Thrombolytic TherapyFive drugs have been shown to be successful in dissolvingclots in the coronary artery and released for general use:streptokinase, tissue-type plasminogen activator (t-PA),reteplase, anistreplase (APSAC), and tenecteplase (TNKase).Others thrombolytic drugs are investigational.Streptokinase has been shown to be useful when infuseddirectly through an arm vein, and it dissolves the clot inabout 60% of patients. It must be given within four hoursof the onset of symptoms to be successful, but some benefitis seen up to six hours. Streptokinase, t-PA, reteplase, orAPSAC given intravenously through an arm vein has a70% chance of dissolving a clot in the coronary artery. AnItalian clinical trial in 1986 and a UK trial in 1988 showedintravenous streptokinase to be useful in preventing deathsin patients given the drug within four hours of onset oftheir heart attack. This beneficial effect is markedlyTABLE 2Strategies to Reduce Morbidity and MortalityPrompt defibrillation is performed where required.Aspirin 320 mg, preferably 4 chewable 80 mg aspirin, chewed andswallowed rapidly achieves high blood levels; aspirin causes a decrease inmortality rate and enhances the efficacy of thrombolytic agents.Prompt administration of thrombolytic therapy is performed if nocontraindication exists. Therapy is commenced in a mobile emergencyunit or within 15 min of arrival in an emergency room.Pain is abolished by opiates.A beta-blocking drug is administered if there is no contradiction.ACE inhibitor therapy is given.

416HEART ATTACKSimproved when an aspirin is taken along with streptokinase.The drug t-PA (alteplase) does not cause allergicreactions as seen occasionally with streptokinase. Thesereactions are, however, very mild and occur in less than 2%of patients. t-PA is slightly more effective than streptokinase,but the cost is $2000 versus $200. Although thebenefits are mainly seen up to 6 h from onset of symptoms,the timing has been extended to up to 12 h after the onsetof symptoms. Table 1 gives the timing of administrationof thrombolytic agents and survival.There is great hope for patients who have suffered aheart attack provided they can get to the emergency roomof a hospital quickly and that thrombolytic therapy is givenwithin 15 minutes of arrival or within 3 h of onset ofsymptoms.bundle branch block, diabetics and in patients with heartfailure. In patients presenting within four hours from theonset of symptoms, the speed of reperfusion is of lessimportance and streptokinase has a role. Streptokinase isthe logical choice in the young patient with an inferiormyocardial infarction.It does not appear to be logical to administer t-PA ortenecteplase to all patients based on the net clinical benefitand cost-effectiveness. The choice of tenecteplase, t-PA,or streptokinase is of little consequence to public-healthworldwide, particularly when the real problem is theemergency room door-to-needle time. This is still inexcusablyhigh at an excess of 30 minutes in more than66% of patients admitted to the hospital in the UnitedStates.a. Streptokinase, 1986The Italian GISSI trial done in 1986 was the first largerandomized clinical trial of thrombolytic agents. Itindicated that streptokinase produces adequate reperfusionif it is given within the first three hours of onset ofthe ischemic event. The GISSI study and sis-2 indicatedthat an IV infusion of 1.5 million units of streptokinaseover one hour is not particularly expensive or troublesometo give routinely and most important, heparin is notrequired.b. Alteplase (t-PA), 1993The Global Utilization of Streptokinase and TissuePlasminogen Activator for Occluded Coronary Arteries(GUSTO) trial studied 41,021 patients with acute myocardialinfarction. It demonstrated a modest 14% reductionin mortality rate compared with streptokinase(p ¼ 0.001). In this trial treatment times for infusion ofthrombolytics averaged 68 minutes.c. Tenectaplase, 1999The ASSENT-2 trial compared single bolus tenecteplasewith front-loaded t-PA in 16,493 patients. After 30 daysmortality rates were almost identical, but in patientstreated after 4 h mortality rate was 7% for tenectaplase and9.2% with t-PA (p ¼ 0.018).In patients presenting within four always of seven toonset, speed of reperfusion is an organ, and connectivethey is a for accelerated t-PA administration is preferred,particularly in patients at high risk: anterior MI, left4. Unfractionated HeparinUnfractionated heparin has been used intravenously for themanagement of acute myocardial infarction for more than40 years (see the chapter Anticoagulants). When t-PA ortenectaplase are administered, heparin must be used for afew days to prevent re-occlusion of the artery. Heparin isnot required when streptokinase is used.5. Low-Molecular Weight HeparinRecent studies indicate that low molecular weight heparingiven subcutaneously is as effective as unfractionatedheparin given intravenously in the management of STelevation MI and non-ST elevation MI, and may replaceIV heparin. Several clinical trials have shown that theseagents are effective and a safe alternative to intravenousheparin. They have been shown to improve clinicaloutcomes and to provide a more predictable therapeuticresponse, longer and more stable anticoagulation, and alower incidence of an unfractionated-heparin-inducedthrombocytopenia. Enoxaparin, however, appears to bethe only low molecular weight heparin to have demonstratedsustained clinical and economic benefits incomparison with unfractionated heparin in the managementof non-ST segment elevation MI.6. Coronary Angioplasty/Intracoronary StentThe rapid reopening of an occluded coronary artery byadministration of thrombolytic therapy within three hoursof onset of chest pain or reopening the artery mechanically

XII. NON-ST ELEVATION MYOCARDIAL INFARCTION417with PCI (balloon angioplasty and intracoronary stent)both provide beneficial improvements in mortality andmorbidity in short- and long-term follow up. Severalstudies indicate that PCI may confer an improvement inoutcomes compared with thrombolytic therapy in patientswho present between 3 and 12 h after symptom onset.PCI with deployment of intracoronary stent has emergedas the treatment of choice for patients with ST segmentelevation MI. Thrombolytic agents are used when facilitiesfor PCI are not available or in selected patients.XI. CLINICAL TRIALSA. Meta-AnalysisA comprehensive meta-analysis involving 23 trials in 7739patients demonstrated some superiority of primary PCIover thrombolytic therapy in reducing the individualend points of death, nonfatal infarction, and stroke. Therisk of hemorrhagic stroke was significantly reduced byprimary PCI.The door-to-balloon time is the strongest predictorof outcome. A prospective registry of more than 27,000patients undergoing primary PCI for acute myocardialinfarction showed that in-hospital mortality significantlyincreased when the door-to-balloon time was delayedbeyond two hours.B. Danami-2, Andersen et al.One of the first large randomized trials in assessing thebenefits of primary PCI in patients with acute ST segmentelevation infarction was done in Denmark.Methods: Patients with acute myocardial infarction(1572) were randomized to treatment with angioplasty oraccelerated treatment with intravenous alteplase.Results: Among all patients the better outcome ofangioplasty was driven primarily by a reduction in the rateof reinfarction (1.6% in the angioplasty group vs. 6.3% inthe fibrinolysis group; p < 0.001). No significant differenceswere observed in the rate of death (6.6% vs. 7.8%;p ¼ 0.35). Also 96% of patients were transferred fromreferral hospitals to an invasive treatment center withintwo hours.This study showed a significant reduction in majoradverse cardiac events: primary PCI group 8% versus13.7%; ( p ¼ 0.003). This benefit was also observed in the1129 patients who were transferred for primary PCI(8.5% vs. 14.2%; p ¼ 0.002). The door-to-balloon timein patients randomized to transfer was 115 minutes, only10 minutes longer than in those who were brought directlyto a PCI facility.C. Prague-2In the Prague-2 trial 850 patients with ST segmentelevation infarction were randomized to immediate thrombolysisor transfer to a PCI facility. There was no significantreduction in 30-day mortality with transfer for primaryPCI (6.8% vs. 10.0%; p ¼ 0.12). Only the patients whopresented later, between 3 and 12 h from onset of symptoms,showed a significant mortality benefit derived fromthe transfer of primary PCI versus immediate thrombolytictherapy (6.0% vs. 15.3%; p ¼ 0.02). This study indicatesthat early thrombolytic therapy (less than 3 hours) fromonset of symptoms may cause reperfusion comparable tothose of primary PCI. This important observation requiresconfirmation from large randomized trials.D. CaptimIn this trial 840 patients were randomized to thrombolysiswith t-PA administered by staff of a mobile unit followedby transfer to a PCI facility versus primary PCI. The doorto-balloontime was approximately 80 minutes in patientsrandomized to primary PCI with a coronary stent used in75% of the patients. There was no significant difference inthe causes of death or reinfarction and stroke betweenthe prehospital thrombolysis and primary PCI (8.2%vs. 6.2%; p ¼ 0.29). Also 26% of thrombolytic-treatedpatients required rescue PCI. If these data hold true inother large trials, it may become standard for ambulancecrews to administer thrombolytics, and approximately25% of these patients will require rescue PCI.Conclusions: A strategy for reperfusion involvingthe transfer of patients to an invasive treatment centerfor primary angioplasty is superior to on-site fibrinolysis,provided that the transfer takes two hours or less.XII. NON-ST ELEVATION MYOCARDIALINFARCTIONA. DiagnosisNon-ST segment elevation MI (non-Q-wave MI) is treateddifferently from acute myocardial infarction in which theECG shows elevation of the ST segment (see Figs. 2 and 3).The diagnosis is made from the ECG pattern, and the

418HEART ATTACKSpresence of elevated cardiac enzymes, particularly elevatedtroponins, assessed in blood samples taken on admission tothe emergency room and 6 and 12 h later. The troponinsare a more sensitive marker of cardiac necrosis than theCK–MB enzymes. Troponin testing represents a majoradvance in detecting micro-infarctions that may be missedby CK–MB.The diagnostic ECG features include ST segmentdepression greater than 0.5 mm (in Europe it is greaterthan 0.1 mV, see Fig. 4).B. ManagementFigure 8 gives an algorithm depicting the managementof non-ST segment elevation MI.1. Beta-BlockersA beta-blocking drug and intravenous nitroglycerin areadministered to relieve pain and cause cardiac stabilization.2. Platelet IIb/IIIa Receptor BlockerBeta blockers are recommended for high-risk patients.Abciximab has proven beneficial after angiography inpatients selected for immediate PCI. This drug has no roleoutside this indication. It proved more beneficial thantirofiban in clinical trials. Eptifibatide and tirofiban areapproved for PCI and for use during the wait beforeangiography. High-risk patients are most vulnerable duringthe first 48 h after admission awaiting PCI. Diabeticpatients benefit the most from platelet receptor blockertherapy and benefit is maximal in diabetic patients whenabciximab is used for PCI.3. ClopidogrelClopidogrel combined with aspirin has been shown toprovide short- and long-term benefits in patients undergoingPCI, in particular when intracoronary stents areused. A loading dose of clopidogrel 6–24 h prior to PCI isadvisable (see the chapter Antiplatelet Agents). Clopidogrelis withheld in patients in whom bypass surgery is plannedto prevent excessive hemorrhage.XIII. COMPLICATIONS OF MYOCARDIALINFARCTIONA. Arrhythmias1. TachyarrhythmiasThe most malignant arrhythmia, ventricular fibrillation,is most common during the first four hours of infarctionCHEST PAIN and ECG ST SEGMENT DEPRESSIONTROPONIN POSITIVEYESNONON ST ELEVATION MIUNSTABLE ANGINA[see chapter, angina]*CORONARY ANGIOGRAMSCABGPCI[Clopidogrel** or platelet 11b/111a receptor blockers]FIGURE 8 Management of non-ST elevation myocardial infarction (MI). * ¼ Virtually all patients should receive coronary angiograms to directsuitability for PCI or coronary artery bypass graft (CABG). ** ¼ Loading 6–12 hours prior.

XIII. COMPLICATIONS OF MYOCARDIAL INFARCTION419occurring in about 5% of patients and in about 0.4% ofthose admitted later. Ventricular fibrillation may occurwithout a warning arrhythmia and in the absence of heartfailure or cardiogenic shock. This malignant arrhythmiamay occur despite an adequate suppression of ventricularpremature beats. Warning arrhythmias are seen frequentlyin those who have ventricular fibrillation as well as in thosethat who don’t. Thus, ventricular fibrillation cannot beaccurately predicted.It is possible that when ventricular fibrillation isprecipitated by early occurring ventricular prematurebeats, R-on-T phenomenon, the ventricular fibrillationthreshold at that time has been decreased by certain factors.These include myocardial ischemia, tachycardia, hypoxemia,alkalosis or acidosis, hypokalemia, or catecholaminerelease in the area of infarction that increases cyclicadenosine monophosphate activity, which is believed tofacilitate the development of ventricular fibrillation.The use of prophylactic lidocaine to suppress ventricularpremature beats has been abandoned. The early administrationof beta-adrenergic blockers should suffice for mostpatients with ventricular premature beats. This strategy hasbeen shown to reduce the incidence of ventricularfibrillation and death from acute infarction.Atrial fibrillation or supraventricular tachycardia with afast ventricular rate precipitating hemodynamic deteriorationis converted electrically using low energy shock. Ifthere is no hemodynamic disturbance, the short-actingbeta-blocking agent esmolol may be used to slow theventricular rate.2. BradyarrhythmiaBradycardia with heart rates of 48–60 beats per minute iscommon and occurs with acute inferior infarction and isusually not harmful. Severe bradycardia at less than 48beats per minute causing hemodynamic compromise suchas hypotension or ventricular ectopy is managed with smalldoses of atropine to increase the heart rate to a maximumof 60 beats per minute. Bradycardia associated withsecond-degree type II AV block and complete heartblock unresponsive to atropine usually requires temporarypacing.B. Heart Failure1. DiureticMild left ventricular failure occurs during the first 24 h ofacute myocardial infarction, particularly if the area ofinfarction is large. Mild heart failure usually responds toadministration of small doses of the diuretic, furosemide,given 20–40 mg daily for a few days. Serum potassiummust be maintained at a level greater than 4.5 mEq/L. Theadministration of morphine relieves symptoms of heartfailure and allays anxiety.2. NitratesMore severe degrees of heart failure are managed with theabove measures and the addition of intravenous nitroglycerinor isosorbide dinitrate. Nitrates are useful to reducepreload when pulmonary congestion is present with a highpulmonary wedge pressure.3. ACE InhibitorsACE inhibitors are administered to virtually all patientswith heart failure and those with left ventricular dysfunctionmanifested by an ejection fraction of less than 40%.These agents reduce morbidity and mortality in patientswith heart failure caused by myocardial infarction (see thechapter Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers).4. Beta-BlockersThe beta-blocking agent carvedilol gave excellent results inthe CAPRICORN study. Patients with acute infarctionand ejection fractions less than 40% treated with an ACEinhibitor were randomly assigned and the treatment armreceived carvedilol 6.25 mg increased progressively to25 mg twice daily. Carvedilol caused a significant 23%reduction in all-cause mortality in patients followed for 2.5years. The absolute reduction in risk was 23%. Thisreduction in mortality by carvedilol occurred in additionto reduction caused by ACE inhibitors alone.C. Right Ventricular InfarctionThis common acute inferior infarction is accompanied byright ventricular infarction in proximity 40% of patients.These patients are observed to have a high mortality rate:31% mortality and 64% in-hospital complication versus6% and 20%, respectively, for those with pure inferiorinfarctions. Management is difficult and includes plasmavolume expansion combined with inotropic agents such asdobutamine. The conventional treatment for heart failurewith diuretics and nitrates is harmful and contraindicatedin right ventricular infarction because these agents reducepreload and filling of the ventricle. Thrombolytic therapy

420HEART ATTACKSis strongly indicated but PCI is strongly advisable becausemortality can be reduced by this strategy.ventricular premature beats or occurrence of paired beats(couplets).D. Risk Assessment for Long-Term OutcomeEchocardiography and low-level exercise testing areperformed prior to discharge. The echocardiogram givesan approximate assessment of the ejection fraction whichmay indicate mild, moderate, or severe left ventriculardysfunction. Exercise testing after acute infarction isusually done between days five and six often using alow-level exercise protocol. The results of these tests allowthe physician to give guidance to the patient regardingactivities, rehabilitation, sexual activity, and approximatedate of return to employment.1. Left Ventricular DysfunctionThe mortality rate during the first year following amyocardial infarction is inversely related to left ventricularsystolic function. The risk for death increases dramaticallyin patients with ejection fractions less than 30% and islargely caused by a larger size of infarction and malignantventricular arrhythmias. The ventricular ejection fraction isthe single most powerful predictor of mortality and therisk for malignant, life-threatening ventricular arrhythmiasduring the first two years following myocardial infarction.Antiarrhythmic agents have been shown to increasemortality in this subset of patients and implantation of acardioverter defibrillator (ICD) in selected high-riskpatients with ejection fractions less than 30% with nonsustainedventricular tachycardia and inducible sustainedventricular tachycardia is undergoing trials. Currently, inthis high-risk subset of patients the combination of thebeta-blocking drug carvedilol and an ACE inhibitor alongwith spironolactone or eplerenone improves survival.2. Lethal ArrhythmiasLethal, malignant arrhythmias account for approximately50% of deaths during the first two years followinginfarction. The risk associated is related to the timing ofthe ventricular ectopy following infarction. Ventricularectopy occurring during the first 24 h is not predictive oflong-term outcome. The longer the period between theinfarction and the occurrence of ventricular arrhythmiaand the longer the duration of the arrhythmia, the greaterthe attributable risk. Patients with nonsustained ventriculartachycardia and three or more consecutive beats are at agreater risk than those with a similar frequency of isolated3. T Wave AlternansMicroscopic T wave alternans characterized by microvoltchanges in contour, amplitude, or polarity of the T waveunaccompanied by gross changes in cycle length, usuallyevery other beat, appears to be the result of cellular andmolecular alterations associated with repolarization heterogeneity.Small studies have indicated a relationshipbetween T wave alternans and serious arrhythmias. Thesestudies, however, have shown the specificity and positivepredictive value of the test to be lower than the finding of alow ejection fraction (

XVII. REHABILITATION, RETIREMENT, AND TRAVEL421communicate with the patient in an open and frankmanner so that the patient can air feelings and have allquestions answered during the time in the hospital. Asocial worker may have to be involved in some cases, andsupportive home visits, advice on job orientation, anddiscussions regarding financial matters may be necessary.Two weekly visits to an understanding family doctor mayhelp to dissipate depression with the recognition that all isnot lost. The doctor should reassure the patient thatdepression and anxiety with the associated weakness andtiredness are normal and will be alleviated with time. Ittakes six weeks for the damaged muscle to heal and form afirm scar. During the same six weeks, anxiety anddepression dissipate in the majority of patients. The firstfour weeks will be tough. Thereafter, the assistance of anexercise program, the ability to drive again, and the returnof sexual activity may help to lift the despair. Time heals allwounds, including the muscle damage and psychologicalinsults. A few (less than 1% of patients) require antidepressantdrugs. These are nonaddicting and can be veryuseful when given as a single bedtime dose for 3 to amaximum of 12 weeks. An exercise rehabilitation programis useful in many respects and is of definite assistance in themanagement of most heart attack patients (see the chapterDepression and the Heart).XVI. DIET AFTER A HEART ATTACKA low-salt diet is prescribed only for patients with heartfailure who require water pills (diuretics) or digoxin, aswell as for the previously hypertensive patient (see Table 3).Patients are advised on the use of a weight-reduction dietand a modified diet to reduce cholesterol and saturated fatintake. Lipid-lowering drugs are administered to patientswho have an LDL cholesterol greater than 100 mg/dl(2.5 mmol).The total cholesterol, LDL, and HDL cholesterol areestimated for the patient in the hospital and three monthslater. The goal is to maintain the LDL cholesterol at lessthan 100 mg/dl (2.5 mmol; see section XXIII). Alcoholshould be avoided for the first four weeks; thereafter one totwo ounces daily are allowed. Alcohol is restricted if heartfailure is present or if the heart is enlarged.XVII. REHABILITATION, RETIREMENT,AND TRAVELMost patients under age 65 can return to work between6 and 12 weeks after discharge. The return date takesinto account the patient’s age, financial resources, existingTABLE 3List of Foods with Comparative Sodium (Na) ContentFood Portion Sodium (mg)Bacon back 1 slice 500Bacon side (fried crisp) 1 slice 75Beef (lean, cooked) 3 oz (90 g) 60Bouillon 1 cube 900Garlic powder 1 tsp (5 ml) 2Garlic salt 1 tsp 2000Ham cured 3 oz (90 g) 1000Ham fresh, cooked 3 oz 100Ketchup 1 tbsp 150Meat tenderized regular 1 tsp 2000Meat tenderized low Na 1 tsp 2Milk pudding instant whole 1 cup (250 ml) 1000Olive green 1 100Peanuts, dry roasted 1 cup 1000Peanuts dry roasted, unsalted 1 cup 10Pickle dillLarge (10 4 1/2 cm) 19001 (50 g)Wieners 500CANNED FOODSCarrots 4 oz 400Carrots raw 4 oz 40Corn whole kernel 1 cup 400Corn frozen 1 cup 10Cor n beef cooked 4 oz 1000Crab 3 oz 900Peas cooked green 1 cup 5Salmon salt added 3 oz 500Salmon no salt added 3 oz 50Sauerkraut 1 cup (250 ml) 1800Shrimp 3 oz 2000Soups (majority) 1 cup (250 ml) 1000Salad dressingBlue cheese 15 ml 160French regular 15 ml 200Italian 15 ml 110Oil and vinegar 15 ml 1Thousand Island 15 ml 90FAST FOODChopped steak 1 portion 1000Fried chicken 3-piece dinner 2000Fish & chips 1 portion 1000Hamburger double 1000Roast beef sandwich 1 1000Pizza 1 medium 1000The normal diet contains 1000 to 3000 mg sodium. Dailyrequirement is less than 400 mg.

422HEART ATTACKSdiseases, and type of work. The physical and emotionalstress associated with the job should be thoroughlyexplored.Patients with uncomplicated myocardial infarctions areadvised to increase activity and return to about 90% of thepreinfarction level in three months. If at 6–10 weeks theexercise stress test and ejection fraction (the volume ofblood the heart pumps) are satisfactory, the patient’sprognosis should be excellent. Types of exercise arediscussed in the chapter Exercise and the Heart. Exerciseat home should be graduated. During the first three days athome, walk in the house and for the remainder of the firstweek, walk outside the home 50–100 yards daily. Duringthe second week walk 200 yards once or twice daily. In thethird week cover 300 yards once or twice daily. During thefourth week go a quarter mile or 440 yards once or twicedaily. In the fifth week, walk a half mile daily, and duringthe sixth week, walk one mile once or twice daily. This is arough estimate of what you should be doing during thefirst six weeks after a heart attack. Thereafter, if you feelwell and have no chest pain, you should be able to do moreexercise such as joining an exercise program. One- to threemilewalks are usual by the eighth week post myocardialinfarction. Doubles tennis, golf, and similar past times arereasonable at three months.Patients may join supervised exercise programs providedthere is no evidence of persistent heart failure, angina,abnormal heart rhythm such as frequent premature beats(see the chapter Arrhythmias/Palpitations), and moderateto severe problems with heart valves. A stress test is usefulat some point, especially if you want to do differentactivities. In patients under age 70, a stress test donebetween the 6th and 10th week should result in the patientbeing able to do more than seven minutes of walking onthe treadmill. Patients who can complete about nineminutes without undue shortness of breath, chest pain, orECG changes, which indicate oxygen lack to the heartmuscle, are usually allowed to engage in all exerciseactivities. Competitive sports and extreme exertion shouldbe avoided. Patients who can complete six minutes, butneed to stop because of fatigue, tiredness, or leg discomfortand who show a normal heart rate and blood pressurewithout an abnormal heart rhythm or ECG changes, areallowed to participate in a restricted and, if possible,supervised exercise program, but they should be retested inthree months. Exercise programs should be individualized.There are many useful rehabilitation programs attached tomajor hospitals. Provided that adequate supervision isobtained, exercise programs play a great role in assistingpatients to maintain good body tone and to return toparticipation in games, sexual activity, and the work theywere accustomed to before a heart attack.Exercise programs are strongly advised provided that thepatient is stress-tested and conditions that contraindicateexercise programs are reviewed by the physician for eachindividual. There is no evidence that moderate tostrenuous exercise prevents heart attacks or limits the sizeof a heart attack. The physician should recognize theminority of patients in whom a very gradual program oronly mild exercises are appropriate. Walking certainlyprovides safe and adequate exercise.Because you have had a heart attack, it does not meanthat you will be crippled for life. About 10 million NorthAmericans can testify that you can recover from a heartattack and go on to live a very active and normal life. Themajority return to the same job. Within three to sixmonths, the majority engage in the same activities they didprior to the heart attack. Tennis, golf, and skiing are only afew of the many activities that are enjoyed. Someindividuals lead a more active life and learn to handlestress better and often report that they feel better than 10years prior to their heart attack. If you like jogging, youshould know that six months after their heart attack, morethan 50% of patients are able to jog one to three milesdaily. We are not suggesting that you do this, but ifyou enjoy jogging, then one to two miles four times weeklywill improve your endurance. Similar exercises includinga one- to three-mile walk and stair climbing are suitableactivities.A. Don’tsDo not do static exercises such as weightlifting or pushups.Such exercise uses sustained muscular contractionthat squeezes the blood vessels, and thus increases bloodpressure and the work of the heart.Do not exercise immediately after a meal. Wait one totwo hours after a light snack or two to three hours aftera heavy meal. Do not exercise if you have a fever.Do not stop exercising suddenly; always warm up andcool down for 5–10 minutes.During the first six weeks at home, do not engage instrenuous exercise or housework such as heavy cleaningor repairs, gardening such as raking leaves or mowingthe lawn, or snow shoveling.Do not take a hot or cold shower immediately before orafter exercise. Do not take a sauna because the heatdilates the vessels in the skin and steals blood away fromthe heart and the brain.

XIX. SEXUAL ACTIVITIES423XVIII. RETIREMENT AND TRAVELA. RetirementRetirement may well be a problem for many individuals,especially those who do not have enough hobbies to keepthem sufficiently occupied. Often individuals becomebored and depressed, therefore, retirement must beselective. If possible, it is best to get back to work becausethis prevents the development of neurosis and depression.There is no doubt that returning to a job that waspreviously distressing can lead to further harm. Patientswho can afford to change jobs or retire and have enoughhobbies do extremely well. The good news is that thedisease may burn itself out. Individuals who have had largeheart attacks with complications such as severe heart failurethat restrict exercise programs are strongly advised to retire,especially if they are over 65. A change in lifestyle may belifesaving.B. TravelPatients should not drive for about six weeks. If a stress testis satisfactory at three weeks, necessary flying is allowed,otherwise elective flights should be postponed beyondthree months. Patients with stable angina are allowed to flyany time, but not if angina is unstable (see the chapterAngina). Patients should take along a current ECG tracing.This may save unnecessary admission to a hospital andprovide a physician with a prior ECG for comparison.Nitroglycerin should be carried, too, along with allmedications advised by the doctor. Oxygen is not necessaryduring the flight.XIX. SEXUAL ACTIVITIESSex is a part of living. For the majority, it is one of the mostenjoyable, satisfying, stress-relieving activities that lifeprovides. Most of what is said regarding heart attacksand sexual activity relates to men, because the heart attackrate is far more common in men than women at age35–65. Also, men have far more hang-ups about sex thanwomen, especially because a man cannot will an erection.Fear interferes with performance; thus some men, due to alack of proper discussion with their doctor before hospitaldischarge, develop fears that may cause problems withsexual function. In addition, the female partner developsfear and apprehension that intercourse could cause thedeath of her husband. The female partner may thereforeturn the whole thing off. This disturbance in a maritalrelationship can be quite traumatic and increase the anxietyand depression that is so common after a heart attack.It is important for males to understand that a heartattack does not cause impotence, and that if you do nothave intercourse for six weeks, it will not alter sexualperformance in the future. The good news is that 12 weeksafter a heart attack, more than 75% of patients are able toengage in sexual intercourse with the same frequency asbefore. A heart attack is not the end of your sex life. Somephysicians believe that sex can be resumed about two weeksafter discharge from the hospital, but the majority ofphysicians agree that it is reasonable and safe to resumeintercourse about six weeks after a heart attack. There is nohard and fast rule; you should do what comes naturally andwithout fear. If, about four weeks after discharge, you areable to walk one mile and climb two flights of stairswithout chest discomfort or undue shortness of breath andexperience the urge to have sex with your usual partner,then you should go ahead without fear of precipitatinganother heart attack.The amount of physical exertion required during sexualintercourse is equivalent to walking up about four flights ofstairs or a brisk one-mile walk. Most heart attack patientsshould be engaging in this type of exercise about six weeksafter a heart attack anyway. If during such activity there isno chest discomfort or undue shortness of breath, sexualactivities are considered safe. In a study of 6000 cases ofsudden death, only 34 were related to sexual intercourseand 27 of those deaths occurred during extramarital sexualrelations.Most deaths in males during intercourse occur whileengaging with partners other than their wives. Middle-agedmales who have been married for a number of years are atgreatest risk. Intercourse with a much younger extramaritalfemale partner may lead to more emotional reactions,causing a much higher increase of blood pressure and heartrate, thus putting the heart under severe strain. Furthermore,such a moment may also be accompanied by theingestion of a large meal and alcohol, which adds tocardiac work. Sudden death or heart attack is extremelyrare when the heart attack patient engages in intercoursewith the usual partner.It is advisable to use the sexual position to which you aremost accustomed. There is no reason to change to side-tosideor female on top if this was not the most oftenpracticed and most favorable position. If the patient ismale and erection is easily achieved, the female on top —superior crouched — is often recommended. In thisposition, the woman has both knees touching the bed for

424HEART ATTACKStraction; therefore, she is the active partner. What is mostfamiliar is always the best position as it increases confidencein the male and allays anxiety in the female, whois afraid that the husband may die or have a heart attackduring intercourse. There is no need to decrease thefrequency of sexual activity. After three months if there isno chest pain, undue shortness of breath, or palpitationson walking two to three miles or climbing four flights ofstairs or jogging one mile, the individual should be capableof enjoying the same sexual frequency as before the heartattack. Drugs such as sildenafil should be avoided forthe first 3 months and until stress tests indicate absenceof significant ischemia. Nitroglycerin or nitrates must beavoided if sildenafil or similar agents are used.A. Don’tsThese apply to the first three months after a heart attackand for patients with chest pain on effort (angina) or heartfailure: Do not take a hot shower immediately beforeintercourse. Hot showers or saunas dilate vessels ofthe skin, thus stealing blood from the heart and thebrain. Do not have intercourse immediately after a heavymeal; wait two to three hours. Do not have more than one drink of alcohol or beerand indulge in intercourse. More than three drinksconsumed in two hours will make it more difficult toachieve an erection and may also decrease heart musclecontraction. Smoking can also decrease sexual performance. Smokinghas been shown to cause constriction of small penilearteries and therefore impotence.B. SuggestionsA simple exercise program improves physical enduranceand nearly always increases sexual performance. Therefore,start your walking program one week after discharge andincrease it to a brisk one- to two-mile walk daily by thesixth week. Each week increase from one, then two, thenthree flights of stairs by the sixth week. If your hospital orcommunity offers a rehabilitation program, it is wise tojoin this with the advice of your cardiologist, or plan yourown program with some common sense. At this stage, youshould know how to take your pulse and try to keep theheart rate for about five minutes within the target zone,i.e., 60–70% of your maximal heart rate. After a fewmonths of exercise, if you feel well, you can keep the heartrate in the target zone for about 5–10 minutes during30 minutes of exercise. A stress test at this stage mayincrease your confidence, and your physician can advise onadditional exercises.Rest is more important before rather than after sexualactivity, although if you feel tired after the activity and feellike sleeping, certainly it is wise to have a 30- to 60-minuterest. Therefore, if possible, have intercourse in the morningafter a night of sleep or any other time after rest orrelaxation. If you are very short of breath or develop chestdiscomfort during intercourse, stop and take nitroglycerin.Discomfort during your first sexual experience does notmean the discomfort may occur again. It also does notindicate that you are likely to develop a heart attack duringintercourse. However, if pain does recur or if there is anydifficulty with sexual activity, be sure to discuss this withyour doctor at the next office visit. Medications given ondischarge may interfere with sexual performance, and thesemay be reduced at your next office visit. Diuretics (waterpills), beta-blockers, antihypertensive drugs, or antidepressantscan alter sexual performance (see the chapter ErectileDysfunction and the use of sildenafil).XX. BETA-BLOCKERSBeta-blocking drugs were discussed in the chapter Angina,and the present discussion explains the rationale for theiruse in patients after a heart attack. Beta-blockers block theaction of adrenaline and noradrenaline at receptor sites onthe surface of cells. They cause a reduction in heart rate;therefore, less oxygen is required by the weakened heartmuscle. They decrease the force of contraction of the heartmuscles, and this further decreases the work and theamount of oxygen required by the heart. Most of theeffects on the heart and arteries are related to this blockingof the actions of stress hormones. Beta-blockers stabilizethe heart rhythm and can prevent premature beats such asthose that are precipitated by mental and physical stress.They can prevent some episodes of ventricular fibrillation,which is the cause of sudden death.Beta-blockers, statins to lower cholesterol, and aspirinare the only oral drugs that are proven by studies toprevent death from heart attacks. When beta-blockers aregiven to patients from day one after a heart attack and forup to two years, they significantly reduce the incidence ofdeath from heart attack including sudden death. They alsoreduce the recurrent rate of subsequent heart attacks.About 70 of every 100 heart patients are eligible fortreatment with beta-blockers, and these include patientswho have angina after the heart attack.

XX. BETA-BLOCKERS425In the UK, a survey of actively practicing Britishconsulting cardiologists was carried out to determine theirpractices when prescribing beta-blockers after a heartattack. Half of the cardiologists reported that they use betablockersin all patients who can take the drug startingabout one week after the heart attack and continuing forabout two years. The other half reported that they gave thebeta-blockers to patients at high risk. It is stronglyrecommended to give a beta-blocker to all post heartattack patients from day seven if there is no contraindicationto their use.Despite the proven beneficial effects of beta-blockers inpreventing death and infarction, less than 33% of patientsreceived beta-blockers from their physicians from 1985 to1995. Currently about 66% of patients receive betablockertherapy. More than 50% of the physicians inNorth America are reluctant to prescribe the drugs forpatients after a heart attack. This reluctance stems from theteaching of a minority of experts and failure to update theirknowledge.The argument of the physicians who oppose the routineuse of beta-blockers is as follows: Although the betablockertimolol has been shown to cause a 33% reductionin cardiac deaths and a 67% reduction in sudden deaths ina well-run multicenter randomized clinical trial, a 33%reduction means that of every 100 patients with a heartattack treated with a beta-blocker, ‘‘only’’ 3 lives can besaved. That is, if you take 100 heart attack patientsdischarged from the hospital, studies have established that10 patients will die in the next year and 33% of the 10deaths can be saved (three patients). Thus these physiciansbelieve that it is not worthwhile to treat 100 patients with abeta-blocker to save only three.Some physicians use expensive, sophisticated tests todetermine high-risk patients who are likely to die in thenext year. Beta-blockers are then given to the few patientswho are considered high-risk. Prediction by tests, especiallystress tests, nuclear scans, and Holter monitoring, can bemisleading, however.To these opposing physicians, the following question isposed: The next 20 years of extensive and expensiveresearch may produce a medication capable of a 60%reduction in deaths in patients who have had a heart attackand then treated for one year. This result will be acceptedby all physicians as good news. If the majority ofphysicians will then agree to treat 100 to save 6, whynot treat 100 to save 4 at present? Is the difference betweensix and three patients that great? The new drugs fordissolving blood clots soon after a heart attack save 2 to 5lives in every 100 patients treated, and this is considereda major achievement. Logical therapeutic decision makingand application of common sense in prescribingproven remedies appear to be a worldwide weakness ofphysicians.The dose of a beta-blocker used for the prevention ofdeath and recurrent heart attacks is not high and sideeffects are infrequent. A fall in pulse rate from the usualaverage 70 beats per minute to 55 beats per minute isexpected if the drug is working. On mild to moderateexercise the heart rate stays under 120 beats per minute asopposed to racing to 140–150 beats with a moderateamount of exercise. The slowing of the pulse is a goodeffect; therefore, do not be afraid of a heart rate of 50–60beats per minute. Only a few patients, less than 10%, getsymptoms of dizziness if the pulse falls below 50 beats perminute. The dose of drug is then reduced by half and thepulse stabilizes between 54 and 64 beats per minute. In afew patients, the drug has to be discontinued because toomuch slowing may occur on a very small dose. Fortunatelythese sensitive patients are rare (less than 1%).The commonly used beta-blocking drugs are Propranolol: 40 mg twice daily for two weeks then80 mg twice daily for one month followed by 160–240mg long-acting once daily in nonsmokers Metoprolol: 50 mg twice daily for two weeks then100 mg twice daily or Toprol XL, 50–100 mg oncedaily, is a major advance; Toprol XL is unfortunatelynot available in Canada Carvedilol has proven effective after heart attacks and inpatients with left ventricular dysfunction at a dosage of12.5–25 mg twice daily Timolol: 5 mg twice daily for a few weeks then 10 mgtwice daily Atenolol: 50–75 mg daily; a 25-mg tablet is available inthe United States and is useful in the elderly; this agenthas not been proven to prevent fatal or non fatal infarctionsbut is widely used (see the chapter Beta-Blockers) Bisoprolol 5–10 mg dailyMany other beta-blockers are available, but the oneslisted above have been shown to be useful in post heartattack patients. Propranolol may not confer protection insmokers. It is important, therefore, to also discontinuesmoking.If you notice side effects, especially wheezing, increasedshortness of breath, dizziness, or impotence reduce thedaily dose of beta blocker by half and consult your doctor.Do not stop the drug suddenly. Impotence is very rare butdoes occur in about 4 in every 100 patients treated. Heartattacks do not cause impotence but can decrease sexualactivity; therefore it may not be the prescribed drug. Inany event, alteration in sexual activity should promptthe doctor to reduce the dose of beta-blocking drugs.If there is no improvement, the beta-blocker may be

426HEART ATTACKSdiscontinued and the effect on sexual function is quicklyreversed.The use of beta-blocking drugs can save between 40,000and 100,000 lives annually in the United States andCanada, and many nonfatal heart attacks can be prevented.This information has been available since 1981. We trustthat physicians would want to smarten up and use thislifesaving drug.XXI. EPLERENONE (INSPRA)In the EPHESUS study reported by Pitt et al., eplerenone,a selective aldosterone blocker, administered to patientswith left ventricular dysfunction after myocardial infarctionproved beneficial. In the study 3313 patients wererandomly assigned eplerenone, 25 mg daily to a maximumof 50 mg or placebo and 3319 patients were administeredoptimal medical therapy.Results: During a mean follow up of 16 months, therewere 478 deaths in the eplerenone group and 554 deaths inthe placebo group (P ¼ 0.008). There were 407 cardiovasculardeaths in the eplerenone group and 483 in the placebogroup (P ¼ 0.005). The rate of death from cardiovascularcauses or hospitalization for cardiovascular events wasreduced by eplerenone (P ¼ 0.002), as was death from anycause or any hospitalization (P ¼ 0.02). The rate of suddencardiac death was significantly reduced (P ¼ 0.03). The rateof serious hyperkalemia was 5.5% in the eplerenone groupand 3.9% in the placebo group (P ¼ 0.002). The rateof hypokalemia was 8.4% in the eplerenone group and13.1% in the placebo group (P < 0.001).Eplerenone possesses the beneficial actions of spironolactonewithout the drawback of gynecomastia. This drugis not advisable in patients with a serum creatinine of >1.1mg/dl because hyperkalemia may be precipitated.XXII. CASE HISTORY OF A HEARTPATIENTO.W., age 47, was sitting watching television when hesuddenly felt a pain in the center of his chest. The pain feltlike nothing he had ever experienced before. The entirelower two-thirds of his breastbone and part of his left chestfelt as if someone was crushing him in a vice. He started tofeel weak and afraid, and he loosened his collar to relievethe feeling of strangulation. He called his wife for someantacid for what he assumed must be terrible indigestiondue to the high-fat meal he had eaten 30 minutes earlier.Two antacid tablets did not relieve the pain and he startedto pace restlessly around the room. He soon became dizzy,felt faint and was forced to lie down. The pain was notrelieved by lying flat, so his wife propped him up andstarted rubbing his back. About 7–10 minutes went by andthe pain was becoming worse; he felt as if he was going todie. Though a sense of panic was beginning to set in, hedid not want to alarm his wife. His entire life seemed tofloat before him. He was determined to sit up and to walkto see if it would ease the pain. He moved across the room.The dizziness was less than before, but the pain was of thesame intensity. Both arms, from the shoulders to below theelbows, were now aching as if he carried a 50-poundweight in each hand. There was no pain in his back. Hetried to analyze what could be the reason for this pain. Hehad not done any physical work in the past month. Itcould easily be stomach upset because there was somediscomfort at the lower end of his breastbone and stomach(epigastric area). He had been under pressure at work forthe last month. His job was on the line and he wasdetermined to show his colleagues and boss that he couldcope. He had faced similar stressful situations before.Suddenly, as he was wondering about the past, the painbecame excruciating, constricting his chest. He could nolonger hide his fear. His wife noticed his face had becomepale. She dashed for the phone and called an ambulance,which came 20 minutes later. The wait was agonizing ashis breathing and the strangling sensation worsened. Hehad no nitroglycerin in the house because he was notknown to have coronary heart disease. As soon as theambulance arrived an oxygen mask was applied and he wasrushed to the emergency room of the nearest hospital. Adiagnosis of acute myocardial infarction was made and hewas admitted to the CCU of the hospital. He made areasonable recovery and was discharged on the 10thhospital day. He did have mild heart failure during the firsttwo days in the hospital but this cleared quickly. A fewdays after his attack, he was placed on a beta-blocker,propranolol, and a drug to try to prevent blood clotting,sulfinpyrazone. He discontinued his two-pack-a-daysmoking habit. His cholesterol was 1.3 mmol (280 mg),which is moderately elevated. He was not overweight buthe was placed on a diet with low cholesterol, low saturatedfat, and moderate salt restriction. He was placed on anexercise program. He had liked jogging in the past, andthree months after his heart attack he was able to jog one tothree miles daily.He did well for the next two years, during which time hetook his medications regularly. He continued his exerciseprogram doing 3–10 miles daily, 6 days weekly. About 18months later, while standing in line at the bank.He suddenly dropped to the floor. Fortunately, a trainednurse was in the line and CPR was commenced. He was

XXIII. RISK FACTORS AND PREVENTION427resuscitated and rushed to the hospital. He was found tohave complete heart block, and a permanent pacemakerwas inserted. He was discharged from the hospital a fewdays later and resumed his daily exercises.About one year later, while on vacation, he suddenlyexperienced central chest pain that was similar to his firstheart attack and he was rushed to the hospital. His attackwas complicated by heart failure. His heart failure wascleared by the use of digoxin, furosemide, and a vasodilatorcalled captopril. Investigations showed that he haddeveloped an aneurysm, a small swelling of part of theheart muscle.He wanted to get back on an exercise program. At thisstage he was not the best candidate for exercise, so hestarted slowly over the next few weeks by walking one tothree miles. He eased into jogging a quarter mile daily, butwhen he tried to do a half mile, he started getting shortnessof breath and pain in the chest. This pain was immediatelyrelieved by stopping the run. Angina was present and henow agreed to have a catheter study. Coronary arteriographywas done, and this showed a complete block in oneartery, more than 80% obstruction in two branches, and asmall aneurysm of the left ventricle. He underwentcoronary artery bypass surgery with three bypass graftsand repair of the aneurysm. Two weeks later he wasdischarged from the hospital. He slowly began an exerciseprogram, and 10 months later he was once again joggingone to two miles daily. He completed the Terry Fox 10 kmFun Run in September 1985 and 1990. In the late 1990she enjoyed a normal lifestyle but developed atrialfibrillation and sick sinus syndrome requiring a pacemaker.He remains active today.XXIII. RISK FACTORS AND PREVENTIONThe identification of factors that increase the risk of heartattack has been made possible by various population studiesincluding the well-known Framingham Study. Its statisticalcorrelation has been consistent enough to enable researchersto state with confidence that high blood cholesterol, highblood pressure (hypertension), and cigarette smoking aremajor risk factors and, if present, increase your probabilityof having a fatal or nonfatal heart attack or stroke. Theserisk factors can be subdivided into three groups.Group I: Uncontrollable Risk Factors1. Heredity: A strong family history of heart attackespecially before age 55 increases the risk.2. Age: Risk increases with age.3. Sex: Everyone recognizes that heart attacks are about 10times more common in men than in women in the35–50 age group. After menopause and beyond age 70women catch up.Group II: Controllable Risk Factors1. High blood cholesterol, LDL cholesterol2. Hypertension3. Cigarette smoking4. StressGroup III: Other Factors of Importance1. Diabetes (see the chapter Diabetes)2. Sedentary lifestyle, lack of exercise3. Strenuous unaccustomed exertion4. Obesity5. Type A personality6. Two or three fruits and vegetables dailyHigh blood pressure (hypertension) is a preventable riskfactor. It is extremely difficult to get the population at riskto discontinue smoking. Hypertension, however, can bedetected and does respond to nondrug treatment, andwhere this fails, safe and effective drugs are now available(see the chapter Hypertension).It is well established that hypertension increases the riskof heart attacks, especially if there is concomitant highblood cholesterol and/or cigarette smoking. Hypertensioncauses mechanical damage to the lining of the artery, andcholesterol is drawn into the injured tissues. There isconclusive scientific evidence that control of hypertensionmarkedly lowers the incidence of stroke, heart failure, andkidney damage, and it is believed to decrease the incidenceof fatal and nonfatal heart attacks. Hypertension acceleratesatherosclerosis, and blockage or rupture of an arteryoccurs from 10–20 years earlier than in individuals withnormal blood pressures.In recent years, heart attacks have been observed inmales age 27–34, but this occurrence is rare. Such malesusually have a very high blood cholesterol, hypertension orrare diseases of the coronary arteries, and a family historyof heart attack before age 50. Heart attacks before age 27are extremely rare and may occur in patients with familialhypercholesterolemia who have a cholesterol in the rangeof 600–1000 mg (15–25 mmol). Menstruating females areoften protected from heart attacks, except those whosmoke and simultaneously take birth control pills or thosewith diabetes, hypertension, and rare familial hypercholesterolemia.Family history is important. Individuals witha strong family history, that is, a parent and one or moreuncles or aunts dying of heart attacks before age 55, havean increased risk. These individuals should have a medicalcheckup, including total cholesterol, LDL (bad) cholesterol,and HDL (good) cholesterol measurements at about

428HEART ATTACKSage 25. The advice of a physician is required if the LDL isless than 4 mmol and HDL is less than 1 mmol. A stresstest at about age 40 is appropriate if the cholesterol isborderline.If you are a male over age 35 and have one of the fourmajor risk factors — high blood cholesterol, hypertension,cigarette smoking or stress — your chance of having aheart attack doubles. Two risk factors increases your risk tomore than three times that of a person with no risk factors.If you have all four and your mother or father had a heartattack prior to age 55, your risk increases to about seventimes. No one can predict with any degree of certainty whois going to have a heart attack. Some people are just plainlucky. They have the correct genes, they disobey all therules, they never exercise, and they lead a stressful life andyet never have a heart attack. People of this type are notoverweight, and fortunately have blood pressures that areon the low side of normal (110–120 systolic). If yourblood pressure is low (less than 120/80), and you areaverage or slightly underweight and your parents bothlived to beyond 75, you are on the right side of the track.Women are at risk after age 55 and need preventivemeasures from at least age 48 (see the chapter Women andHeart Disease).XXIV. HEART ATTACK PREVENTION DIETConsult the tables in the Cholesterol chapter and followthe advice given in Sections A, B, and C below. This willfulfill the recommendation of fat intake to be 30% of foodenergy. You will receive enough polyunsaturated fat andprotein without having to do complicated calculations.The American Heart Association Prudent Diet givessimilar recommendations.These recommendations do not strictly apply if yourblood cholesterol is less than 180 mg/dl, because youobviously deal with cholesterol by your own naturalprocess. Foods with a high salt (sodium) content should beavoided or used sparingly (see Table 3).A. Do Not Use the Following Foods Organ meats such as liver, kidney, sweetbreads, heart, orbrain Meat fat, heavily marbled steaks, mutton, salt pork, orduck Whole milk or whole milk products, cream, lard, andnon-vegetable margarine, or vegetable margarine thathas saturated fats or palm oilCoconut oil or products containing coconut oil such asnondairy coffee cream substitutes, palm oil and peanutoil, or peanut butterB. Use the Following Foods Sparingly and inSmall Amounts Roast beef, luncheon meats, bacon, sausages, hamburger,and spare ribs Butter, egg yolk, cheese made from whole milk orcream, pies, chocolate pudding, whole milk pudding,and ice cream Lobster, which has a high cholesterol content and isoften served with abundant butter Peanuts, cashews, and brazil nutsC. Use the Following Recommended FoodsAll root vegetables; lentils, and split peas, which are richin protein and fiber; fruits daily including avocadodespite its very small saturated fat content. Do not‘‘overindulge’’ in vegetables containing a high contentof vitamin K such as broccoli, alfalfa, turnip greens,squash, and lettuce, because an increase in vitamin Kintake may increase clot formation.Fish of all types, even when described as fatty fish,contain little saturated fat but have an abundance ofomega-3 fatty acids that protect the arteries. Shrimp arenot as bad as claimed, provided they are not fried inbatter and are used only occasionally. Remember, anyfood fried in batter increases the saturated fat content.Poultry, chicken breast, and turkey, which, whencooked with the skin off, contain little saturated fat orcholesterol. You must cut fat from meat, includingchicken, before cooking.Lean beef or veal.Fat and oils to be used include polyunsaturatedvegetable oils with alpha-linolenic acid such as canolaand soybean oil should be used for cooking, andpolyunsaturated or olive oil margarine to be used asmuch as possible in place of butter. A margarine withadded alpha-linolenic acid and without hydrogenationor added palm oil would be useful.Carbohydrates (sugars and starchy foods) such as breador other flour products, potato, and rice to maintainnormal body weight.Onions and garlic should be used, but use garlicpowder, not garlic salt, which has a high sodiumcontent (see Table 3).

XXIV. HEART ATTACK PREVENTION DIET429Alpha-linolenic acids found in walnuts and purslaneare rich in alpha-linolenic acid and are stronglyrecommended.Alpha-linolenic acid is a long-chain fatty acid, which is asignificant component of the Cretan Mediterranean diet.Alpha-linolenic acid has an aspirin-like effect and reducesthe stickiness of blood platelets and thus prevents clottingin arteries. A clinical study using an alpha-linolenic, acidrichMediterranean diet was reported in Lancet, June 1994.It is thought to be useful in decreasing recurrent heartattacks in patients following a first heart attack.The Mediterranean type diet consists of root and greenvegetables, more bread, fish, poultry, less beef, lamb, andpork and daily fruit, nuts, and olive oil. Butter wasreplaced by canola oil margarine with 5% alpha-linolenicacid added. 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XXIV. HEART ATTACK PREVENTION DIET431Takano, M., Inami, S., Ishibashi, F. et al. Angioscopic follow-up study ofcoronary ruptured plaques in nonculprit lesions. J. Am. Coll. Cardiol.,45:652–658, 2005.TAXUS: Stone, G. W., Ellis, S. G., Cox, D. A. et al. for TAXUS-IVInvestigators. A polymer-based, paclitaxel-eluting stent in patientswith coronary artery disease. N. Eng. J. Med., 350:221–231, 2004.Topol, E. J., and Kereiakes, D. J. Regionalization of care for acuteischemic heart disease: A call for specialized centers. Circulation,107:1463–1466, 2003.Valgimigli, M., Ceconi, C., Malagutti, P. et al. Tumor necrosis factor-receptor 1 is a major predictor of mortality and new-onset heart failurein patients with acute myocardial infarction: The cytokine-activationand long-term prognosis in myocardial infarction (C-ALPHA) study.Circulation, 111:863–870, 2005.van der Hoeven, B. L., Pires, N. M. M., Warda, H. M. et al. Drug-elutingstents: Results, promises and problems. Int. J. Cardiol., 99:9–17, 2005.Varnava, A. M., Mills, P. G., and Davies, M. J. Relationship betweencoronary artery remodeling and plaque vulnerability. Circulation,105:393–343, 2002.Vasan, R. S., D’Agostino, Sr., R. B. et al. Age and time need not andshould not be eliminated from the coronary risk prediction models.Circulation, 111:542–545, 2005.Vetrovec, G. W. et al. Optimizing percutaneous coronary interventionoutcomes: The next steps. Circulation, 111:125–126, 2005.Wang, K., Asinger, R. W., and Marriott, H. J. L. ST elevation inconditions other than acute myocardial infarction. N. Engl. J. Med.,349:2128–2135, 2003.Wong, G. C., Giugliano, R. P., and Antman, E. M. Use of low-molecularweightheparins in the management of acute coronary arterysyndromes and percutaneous coronary intervention. JAMA,289:331–342, 2003.Windecker, S., Remondino, A., Eberli, F. R., et al. Sirolimus-elutingand paclitaxel-eluting stents for coronary revascularization. N. Engl.J. Med., 353: 653–662, 2005.Yamaji, H, Iwsaki, K, Kusachi, S. et al. Prediction of acute left maincoronary artery obstruction by 12- lead electrocardiography;ST-segment elevation in AVR with less ST-segment elevation in leadV1. J. Am. Coll. Cardiol., 38:1348, 2001.Yusuf, S., Hawken, S., Ôunpuu, S., On behalf of the INTERHEARTStudy Investigators et al. Effect of potentially modifiable riskfactors associated with myocardial infarction in 52 countries (theINTERHEART study): Case-control study. Lancet, 364:937–52,2004.

Heart FailureI. Incidence and PathogenesisII. Basic Causes of Heart FailureIII. Precipitating FactorsIV. PathophysiologyV. Symptoms and SignsVI. DiagnosisVII. Drug TreatmentVIII. Nondrug TherapyIX. What to Expect in the Hospital and on DischargeGLOSSARYcardiomyopathy heart muscle disease.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 50 to 75%; a lowejection fraction is less than 45%; often used as a marker ofventricular contractility.inotropic an effect that affects the force of muscular contractions;negative inotropic refers to decreased myocardial contractilitythat may lead to poor pumping of blood, reducedejection fraction, and heart failure.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.THE WORLD FACES AN EPIDEMIC OF HEARTfailure. This condition, unlike coronary artery disease,has no territorial boundaries (see Tables 1 and 2 in thechapter Angina for worldwide statistics). Heart failure iscommon both in developed and developing countries. Inthe United States more Medicare dollars are spent on themanagement of heart failure than for any other diagnosis.The cost worldwide is astronomic.I. INCIDENCE AND PATHOGENESISHeart failure is present when the heart is unable to ejectenough blood from its chambers into the circulation tosatisfy the needs of the body. Heart failure is responsiblefor over one million admissions to hospitals in the UnitedStates.Heart failure is usually the result of a diseased heart. Themost common cause is a very weak heart muscle. The heartmuscle is the strongest muscle in the body. During anaverage life span, the heart beats about 2.5 billion times,pumping more than 227 million liters of blood. If thiswork could be accomplished in one moment, it would besufficient to lift a weight of about 400 million pounds offthe ground. If the heart muscle is severely weakened andunable to adequately expel the blood brought to the left orright ventricle, blood backs up in the veins that drain intothe left or right side of the heart.Oxygenated blood flows from the lungs through veins tothe left atrium and left ventricle (see Fig. 1). These veins inthe lungs can become overdistended with blood and leakfluid (sodium and water) into the lung tissue. This is calledlung edema due to left heart failure. If heart failure continuesfor several days, the fluid may also accumulate in thespace between the lungs and the chest wall. This is calledpleural effusion (water on the lungs).The lung is like a sponge and normally the spaces(air sacs or alveoli) are dry and full of air. In heart failure,the excess fluid is in the spaces as well as in the spongeworkof the lungs. This makes the lungs heavier and the fluidmakes them stiffer with less capacity to distend with eachbreath; therefore, the individual gets short of breath.With heart failure breathing is quicker and less deep thannormal breathing. The fluid in the air sacs and spongeworkof the lungs consists of water, sodium, and some redblood cells. The patient may cough up sputum, which issometimes blood-tinged. An individual with this typeof condition is said to be in left heart failure or simplyheart failure, because there is overdistension (congestion)of blood vessels and excess fluid in the spongework ofthe lungs. This condition is also called congestive heartfailure, but heart failure is the preferred term becauseheart failure may occur without significant congestion inthe lungs.In heart failure, blood and fluid overdistend orcongest the veins that bring blood into the failing muscular433

434HEART FAILUREFIGURE 1Structure of the heart and circulation of blood.chambers. This congestion or visible distension of veins isseen in the lung on a chest x-ray.In right heart failure, the distension and congestionoccur in the veins of the neck, arms, liver, and legs. Duringthe assessment for the presence of heart failure the examiningdoctor looks for these distended veins (jugular veins)at the side of the neck which take blood from the headand neck into the right side of the heart. When a normalindividual stands, sits, or is propped up with the back andhead elevated about 45 degrees, these neck veins are notvisibly distended. In normal individuals they becomedistended temporarily when there is a marked increasein intrathoracic pressure like during singing, trumpetplaying, and coughing spells. If these veins are distendedand associated with shortness of breath, the physician canbe fairly certain that heart failure is present.What about nonvisible veins in the body? Distensionbacks up in veins within the liver, which enlarges, and insome cases fluid may accumulate in the abdominal cavity(ascites). The veins of the legs may not be visibly distendedbut the blood is under backpressure and fluid leaksout into tissues, especially when the individual stands,walks, or sits for long periods. The swelling usuallyoccurs more frequently at the end of the day, improvesafter a few hours in bed, and is best in the morning.The fluid around the ankles and feet is called edema andis a hallmark of heart failure, although it can occur withobstruction of the veins from other causes. This fluidis similar to that described in the lungs, consisting of waterand sodium; therefore, the legs are brine-logged not justwaterlogged. The swelling usually occurs in both legswhereas in obstruction of veins it is one-sided. Theaccumulation of several gallons of fluid may result in veryextensive involvement of the entire legs, thighs, abdomen(ascites), and lungs (pleural effusion).II. BASIC CAUSES OF HEART FAILUREA. Coronary Artery DiseaseIn developed countries coronary artery disease causingmyocardial infarctions (heart attacks) is responsible formore than 40% of cases of heart failure. Left heart failure ismost often due to extensive damage to the muscle of theleft ventricle like the damage that occurs during one ormore heart attacks (see the chapter Heart Attacks). Patientsrecover within a few days as the muscle is able to functionwell enough in the majority of those with the disease. Inabout 30 in every 100 patients with acute myocardial

III. PRECIPITATING FACTORS435infarction, heart failure persists to a mild to moderatedegree and medications are necessary. With the occurrenceof a second heart attack further damage to the muscleoccurs, which leads to very poor heart function and heartfailure. Such patients should not feel that it is the end ofthe line; many can live for several years provided that thereis adequate medical treatment. Surgery is not usuallyindicated unless the muscle balloons to form what iscalled an aneurysm. Fortunately this is rare and onlyoccurs in about 1 in 10,000 patients. If the aneurysmcan be removed, a reasonable cure is possible with majorsurgery.B. HypertensionThe heart muscle is weakened over several years by highblood pressure. The left ventricle has more work to do topump millions of liters of blood against greater resistancethrough tight, constricted arteries. The additional workcauses the muscle of the left ventricle to increase in sizemuch like the increased biceps of a blacksmith or weightlifter.Heart enlargement (cardiomegaly) is easily seen on achest x-ray. After several years, the muscle is strained andthe patient may suddenly be stricken by an episode ofsevere shortness of breath due to failure of the muscle anda backup of fluid in the lungs. Incidentally, heart failureappears to be precipitated in blacks much more quicklythan in whites at lower levels of blood pressure.Hypertension and hypertensive heart disease are responsiblefor more than 40% of patients with heartfailure. More than 60% of individuals over age 65 inNorth America have hypertension and this increasesthe occurrence of heart failure. The incidence is higherin African-Americans. The prevalence of hypertension inthe developing countries in general is similar to that in thewhite population of the United States. (See chapterentitled Hypertension.)C. Valvular Heart DiseaseThe mitral and aortic valves are depicted in Fig. 1. Diseasesof the heart valves, for example, the aortic valve, canimpede the free flow of blood from the left ventricle intothe aorta — aortic stenosis. When the mitral valve betweenthe left atrium and left ventricle is tight and obstructingthe flow of blood (mitral stenosis), blood backs up inthe lungs and a cough with severe shortness of breath canoccur.Diseases of the mitral and aortic valves causing mitralstenosis, mitral regurgitation, aortic stenosis, and aorticregurgitation all lead to heart failure if they are notadequately managed medically and finally by surgicalcorrection (see the chapter Valve Diseases). Valvular heartdisease accounts for approximately 15% of all cases ofheart failure in developed countries and for more than30% of heart failure cases in developing countries.D. CardiomyopathyHeart muscle diseases (cardiomyopathy) not due to atherosclerosisof the coronary arteries or valvular disease arefortunately rare. In rare cases cardiomyopathy can becaused by alcohol abuse. Viruses that cause a very mildor moderate flu-like illness can cause microscopic scarsin the heart muscle (myocarditis) and weaken themuscle sufficiently to cause heart failure (see the chapterCardiomyopathy).E. Right Heart FailureHigh blood pressure may be limited to the arteries in thelungs (pulmonary arteries) where the blood from the rightventricle is ejected. This situation is called pulmonaryhypertension and it can occur in patients with severeemphysema. With emphysema many lung vessels are destroyed,thus increasing the resistance and blood pressure inthe lung circulation. This condition also occurs as idiopathicpulmonary hypertension. Disease of the pulmonaryvalves and pulmonary hypertension cause the rightventricle to enlarge and it finally fails causing rightheart failure. (See chapter entitled Pulmonary ArterialHypertension.)III. PRECIPITATING FACTORSIn addition to problems in the heart and with high bloodpressure, there are several factors that precipitate heartfailure when the muscle is weakened. These conditionsmust be avoided or treated. Problems that can precipitateheart failure in patients with a weak heart muscle ordiseased valve include the patient–physician problemslisted below.Reduction or discontinuation of digoxin or diuretics;the doctor may reduce or discontinue digoxin ordiuretics or the patient may stop taking the medicationsThe patient may increase the intake of foods containingexcess saltIncreased physical exertionObesity

436HEART FAILUREOther problems such as increased cardiac work imposedon the heart are precipitated by those listed below. A marked increase in blood pressure Abnormal heart rhythms; e.g., atrial fibrillation Pulmonary embolism (blood clot in the lung) Infection; e.g., pneumonia, chest, urinary, or others Thyrotoxicosis (overactive thyroid) or severe hypothyroidismProgression or complications of the basic underlyingheart disease include acute heart attack, several heart attacks,or aneurysm formation. Valvular heart disease causingincreased stenosis or regurgitation should also be included.Drugs that weaken heart muscle contraction and mayprecipitate heart failure are shown in the following list.Beta-blockers in large doses precipitate heart failurebut smaller doses of carvedilol, metoprolol, and bisoprololhave been shown to prevent heart failure andreduce mortality and hospitalizations for heart failureCorticosteroids (cortisone, prednisone)DisopyramideCalcium antagonists such as verapamil and diltiazemStimulant drugs that increase blood pressure, e.g.,adrenaline, amphetamine derivatives, and some coughand cold remediesAlcohol, acute excess (four to eight ounces of gin ina period of less than two hours causes depression ofcardiac contractility)Antiarthritic (nonsteroidal anti-inflammatory) agentsincluding indomethacin, ibuprofen, and piroxicam; thenewer selective nonsteroidal anti-inflammatory agents(COX-2 inhibitors) such as celecoxib, meloxicam, androfecoxib retain salt and water in the body and commonlyprecipitate heart failure in patients with poor heartmuscle function. (See chapter entitled Nonsteroidal Anti-Inflammatory Agents.)IV. PATHOPHYSIOLOGYA. Nature’s Defense MechanismsWhen heart failure is caused by any of the diseases orprecipitating factors outlined above, the body’s defensesare called upon to assist. Nature always has a way to compensate.Heart failure causes less blood to be ejected fromthe ventricles. Instead of about 5 liters per minute ejectedat rest, the cardiac output can fall to less than 2 liters andnot meet the needs of the body.One compensatory response involves the nervoussystem and adrenal glands. They are stimulated to produceadrenaline and noradrenaline. Adrenaline constricts arteriesand, therefore, increases the resistance in the arteries,which increases blood pressure to allow survival. Thisincrease in resistance is a great load that can be likened toa steep hill against which the left ventricle must pump.The muscle is already very weak, and the increasedworkload increases heart failure. Imagine a poorly tuned1934 car trying to climb a long, steep hill. Nature’s compensatoryresponses are usually useful to the body, butin this case, they are counterproductive. The only way theheart muscle can do the work is to increase the contractionof the muscle and to reduce the resistance in the arteries.Nature unfortunately does not have a built-in answerand increases the resistance in arteries in order to increaseblood pressure. The body is programmed to increase bloodpressure when the cardiac output and blood pressurefall for any reason. Fortunately, medical scientists, byunraveling these mechanisms, were able to produce a seriesof drugs in the early 1980s that reduce this resistance.These drugs are called vasodilators (see Section VII).Another compensatory mechanism involves neurohormonalactivation. This occurs when two enzymes, reninand angiotensin, are activated. Angiotensin causes severeconstriction of arteries and increases blood pressure. Reninstimulates the adrenal glands to secrete a hormone, aldosterone,which causes sodium and water to return to theblood vessels with the hope that blood supply and bloodpressure will increase. The increased sodium and waterreturned to the blood by the kidney further increases legand lung edema. Therefore, the body is once moredeceived.The kidneys react immediately and utilize specialdefense mechanisms that cause a considerable amount ofsodium and water to be returned to the blood vessels.The extra sodium and water again leak out of the bloodvessels into the lungs and legs, which cause congestion andshortness of breath increase. Diuretics, which cause thekidneys to excrete the excess salt and water, relieve shortnessof breath and leg swelling.As mentioned earlier, adrenaline is secreted duringheart failure and causes blood pressure to increase and theheart muscle to pump more forcefully. This compensatoryresponse is helpful and in some cases bed rest and oxygenwith this normal response may cause some relief. Drugs,such as adrenaline, which increase the force of contractionof the heart muscle, are called inotropic drugs but themajority of these inotropic agents, for example, dobutamine,amrinone, and others have serious adverse effectsand rarely used.The best known example of an inotropic drug isdigitalis, which has been used for the past 200 years for thetreatment of heart failure.

V. SYMPTOMS AND SIGNS437FIGURE 2Pathophysiology of heart failure. (From Khan, M. Gabriel (2003). Cardiac Drug Therapy, 6 th ed., Philadelphia: W.B. Saunders.)You will note that the central result of heart failure is alow cardiac output, which triggers the compensatoryresponses mentioned. Nature increases the blood pressureand heart rate but fails to increase the cardiac outputadequately. It is blood pressure that is vital for existence.No blood pressure means no circulation to the brain andcoronary arteries and, therefore, death. Researchers havefailed to produce drugs that could increase the cardiacoutput when given orally without producing seriousside effects.B. Relevant DefinitionsCardiac output ¼ stroke volume the heart rateStroke volume is a reflection of preload (filling pressure),myocardial contractility, and afterload (arterial impedance;see Fig. 1 in the chapter Exercise and the Heart).Left ventricular work and myocardial oxygen consumptiondepend on:heart rate blood pressure (rate pressure product)blood pressure ¼ cardiac output systemic vascularresistanceCompensatory adjustments are initiated by sympatheticstimulation that causes an increase the heart rate, forceof myocardial contraction, and systemic vascular resistance.The activation of the renin-angiotensin-aldosteronesystem causes intense constriction of arterioles and arteriesand, therefore, increases systemic vascular resistanceand blood pressure. An increase in aldosterone producessodium and water retention in the distal nephron (seeFig. 1 in the chapter Diuretics).V. SYMPTOMS AND SIGNSA. SymptomsShortness of breath (dyspnea) at rest and on minimalexertion, paroxysmal nocturnal dyspnea (awakened fromsleep because of shortness of breath), weakness, fatigue,edema of both legs, and an increase in abdominal girthare common complaints of heart failure. Minor physicalactivities are hindered because of bothersome shortnessof breath.

438HEART FAILURE1. New York Heart Association Functional ClassThis functional class is often used as a reference in publicationsand in medical reports.Class I: asymptomatic on ordinary physical activityassociated with maximal oxygen consumption (VO2)is greater than 20 ml/kg/minuteClass II: asymptomatic on ordinary physical activitywith maximum oxygen consumption of 16–20 ml/kg/minute Class III: asymptomatic on less than ordinaryphysical activity with maximum oxygen consumptionof 10–15 ml/kg/minuteClass IV: symptomatic at rest or on any activitywith maximum oxygen consumption of less than10 ml/kg/minuteB. Physical SignsPhysical signs of heart failure on examination of thepatient include the following list.There is an increase in jugular venous pressure greaterthan 2 cm above the sternal angle. This is a sign of rightand left ventricular failure. In some patients the venouspressure may be normal if the left ventricular failureis mild. The most common cause of right ventricularfailure is left-sided heart failure. On auscultation a thirdheart sound or a combination of the third and fourthsound summation gallop is heard. Crackles (crepitations)are heard on auscultation over the lower lungfields; if left ventricular failure is severe and pulmonaryedema is present crepitations may be heard over mostof the chest.Bilateral leg edema is characteristic of the left and rightheart failure. In patients with severe heart failure edemamay involve the legs and the lower back, sacral edemais seen in patients confined to bed.VI. DIAGNOSISA. Chest X-RayA simple chest x-ray is the most important confirmatorytest for the diagnosis of heart failure and reveals thefollowing patterns.Interstitial pulmonary edema (signs of accumulationof excessive blood and fluid components of the bloodin the spongework of the lung), pulmonary clouding,perihilar haze, and Kerley B or A lines caused by edemaand thickening of interlobular septaFrank pulmonary edema (fluid within the alveoli andair sacs), alveolar pulmonary edema which causes abutterfly pattern that is occasionally unilateralPleural effusions, the right usually greater than onthe leftConstriction of blood vessels in the lower lobe of thelung with dilatation of vessels in the upper lobes of thelung, a manifestation of pulmonary venous hypertensionthat is an early sign of left ventricular failureB. B-Type Natriuretic PeptideB-type natriuretic peptide is released from the cardiacventricles in response to the increased wall tension thatoccurs in heart failure. Used in conjunction with thehistory, physical findings on examination, and a chestx-ray, the rapid measurement of B-type natriuretic peptideis useful in establishing or excluding the diagnosis of heartfailure in patients with acute shortness of breath (see thechapter B-Type Natriuretic Peptide).C. EchocardiogramThe echocardiogram is the most useful test for the furtherevaluation of patients with heart failure proven by clinicalfindings, chest x-ray, and when needed, B-type natriureticfactor. Table 1 indicates the usefulness of echocardiography.VII. DRUG TREATMENTA. Digitalis (Digoxin)In 1775, William Withering, a Birmingham physician,learned of a midwife whose herbal brew had cured severalpeople suffering from severe swelling of the legs andshortness of breath. The condition at that time was calleddropsy. Withering studied the brew and concluded thatthe only active constituent of the 20 or more herbs wasderived from the foxglove plant (Digitalis purpurea). Heused the herb with a fair amount of success.Digitalis has since been used extensively across the worldto treat millions of people with heart failure. It causes theheart muscle to contract more forcefully which increasesthe flow of blood to the kidneys. Congestion, shortness ofbreath, and edema improve. This drug also slows the heartrate and causes the heart muscle to use oxygen moreefficiently. In some individuals, heart failure is precipitatedby a very irregular heart rhythm called atrial fibrillation,

VII. DRUG TREATMENT439TABLE 1Echocardiography, the Most Useful Test to Evaluate Patientswith Proven Heart Failiure1. Assess left ventricular (LV) function, provides a sufficientlyaccurate ejection fraction (EF) a for guidance of therapy2. Screen for regional or global hypokinesis3. Gives accurate cardiac dimensions; replaces radiology forcardiac chamber dilation4. Assess regional LV wall motion abnormalities that indicateischemia and significant coronary heart disease5. Assess hypertrophy: concentric or other6. Left atrial enlargement common with valvular heart diseaseand an early sign of left ventricular hypertrophy7. Assess valvular heart disease8. Congenital heart disease9. Diastolic dysfunction, assess after known normal systolicfunction and no valvular disease10. Pericardial disease, effusion, tamponade11. Myocardial disease12. Left atrial myxomaa Nuclear imaging is more accurate for EF in absence of atrialfibrillation but does not assess valves, hypertrophy, or items 3 to 11, costof two tests not justifiable.From Khan, M. Gabriel (2003). Cardiac Drug Therapy, sixth edition,Philadelphia; W. B. Saunders, p. 260.and heart rate may increase to 120–200 beats per minute.In such patients, digitalis is very successful in reducing theheart rate to 60–90 beats per minute and causes completeclearing of heart failure. Digitalis remains the only availableoral drug to treat heart failure caused by atrial fibrillation,and today this is its main indication.Digitalis is not used in all cases of heart failure wherethe heart rhythm is normal, because in some of these,a diuretic and an ACE inhibitor bring relief. Digitalis isavailable under various names. The most known andgenerally used preparation is digoxin. Digoxin is the purestpreparation of digitalis and gives reliable blood levels.Thus, we will confine most of the remarks to this preparation.Other preparations have very minor differencesin absorption from the gut, blood levels, and duration ofaction. Digoxin is marketed under different brand namesand Lanoxin is the most common.Supplied: Tablets: 0.125 mg, 0.25 mg.Dosage: For maintenance, 0.25 mg daily usually atbedtime. In patients over age 70, 0.125 mg daily isusually sufficient. A lower dose of digoxin is now usedcompared with the dose advised in the previous 50 years.A serum digoxin level 0.5–0.8 ng/ml is adequate forbeneficial effects in the management of heart failure.Patients on a low dose with the serum level indicated abovehave been shown to be less likely to experience worseningheart failure and both their ejection fractions and treadmillexercise times were significantly higher than patientstaking higher doses.As outlined earlier, digoxin causes an increase in theforce of contraction of the heart muscle and slows the heartrate, especially in patients who have atrial fibrillation. Itis excreted virtually unchanged by the kidney. Therefore,in kidney dysfunction or failure, the drug accumulatesand can reach toxic levels in the body. Patients with poorkidney function may therefore require 0.125 mg daily orevery other day.1. Advice and Adverse EffectsKidney dysfunction or failure is the most common causefor toxicity. Note that individuals over age 70 may havekidney blood tests (for creatinine) that are recorded asnormal when the kidney function is abnormal. The doctortherefore has to titrate the dose carefully in the elderly toavoid toxicity.Nausea and vomiting are common symptoms of excessdigoxin in the blood. Blue-green-yellow vision may occurbut reverts to normal as soon as the drug is stopped. A veryslow heart rate, less than 48 beats per minute, with extraheartbeats and the precipitation of abnormal heart rhythmsare also seen with toxic doses. If this occurs, the drug mustbe discontinued and levels in the blood measured. Lowblood potassium increases all adverse effects, and this mayoccur even with a small dose of digoxin. The potassiumlevel in the blood should be checked every four monthsor more frequently in some cases. Diuretics are well knownto cause potassium loss, and because they are virtuallyalways used along with digoxin to treat heart failure,digoxin toxicity may occur. This results in serious heartrhythm disturbances. Your physician will give advice onyour diet and tablets or if a liquid containing potassium isrequired. Digoxin toxicity was common during the 1970s.It must be emphasized that experts who have usedthis drug for over 20 years in patients with moderate tosevere heart failure due to poor left ventricular functionrecognize clearly that when the drug is discontinued or thedose reduced, heart failure often recurs. Toxicity does notoccur if the patient and a careful physician cooperate toprevent this.B. DigitoxinSupplied: Tablets: 0.1 mg, 0.15 mg, and 0.2 mg.Dosage: Initial and maintenance doses are the same:0.05–0.1 mg daily; maximum 0.15 mg daily.Digitoxin has a prolonged action and the effects canlast four to six days. It is broken down in the liver and

440HEART FAILUREexcreted in the gut. Omission of a dose or kidneyfailure has little effect on serum levels. Levels are notusually increased in patients with severe liver dysfunction.The main ‘‘disadvantage’’ is that when digitoxin toxicityoccurs, it can persist for several days.C. ACE Inhibitors and Angiotensin ReceptorBlockersThe angiotensin-converting enzyme (ACE) inhibitors andangiotensin receptor blockers (ARBs) are very useful in themanagement of all grades of heart failure and representa major medical breakthrough. They are considered vasodilatorsand have been shown to save lives and preventhospitalizations (see Table 2).TABLE 2ACE Inhibitors and angiotensin II Receptor Blockers (The DrugIndex gives the generic drug name in lowercase; the pharmaceuticaltrade names begin with a capital letter. C ¼ Canada whendifferent from US; F ¼ France, G ¼ Germany)USA UK EUROPE JAPANACE inhibitorsbenazepril benazepril benazeprilLotensinBriem (F)CibaceCibacinLotensinecaptopril captopril captopril captoprilCapoten Capoten Captolane (F) CaptoprilLopril (F)Lopirin (G)Tensobon (G)cilazapril cilazapril cilazapril cilazaprilInhibace Vascace Dynorm (G)enalapril enalapril enalapril enalaprilVasotec Innovace Pres (G) RenivaceRenitec (F)Xanef (G)fosinopril fosinopril fosinopril fosinoprilMonopril Staril Dynacil (G)Eliten (I)lisinopril lisinopril lisinopril lisinoprilPrinivil Carace LongesZestril Zestril Zestril (F)TABLE 2ContinuedUSA UK EUROPE JAPANmoexipril moexipril moexiprilUnivascPerdixperindopril perindopril perindopril perindoprilAceon Coversyl AcertilCoversumPexumquinapril quinapril quinapril quinaprilAccupril Accupro AccuprinAcuitelKorec (F)ramipril ramipril ramipril ramiprilAltace Tritace DelixRamaceTriatec (F)spirapril spiraprilRenpressSandopriltrandolapril trandolapril trandolapril trandolaprilMavik Gopten GoptenOdrikzefenoprilzefenoprilAngiotensin II receptor blockerscandesartan candesartan candesartanAtacand AmiaseprosartanTevetenirbesartanAvaproeprosartanirbesartanAprovellosartan losartan losartan losartanCozaar Cozaar Cozaarolmesarton olmesarton olmesartonBenicartelmisartan telmisartan telmisartan telmisartanMicardisvalsartan valsartan valsartan valsartanDiovan Diovan DiovanFrom Khan, M. Gabriel (2003). Cardiac Drug Therapy, sixth ed.,Philadelphia; W. B. Saunders, p. 517–518.(Continued )

VII. DRUG TREATMENT4411. Actions of Captopril, Enalapril, Lisinopril, and OtherACE InhibitorsAs outlined earlier, during heart failure the body tries tomaintain blood pressure at all costs in order to satisfy theneeds of the brain and organs. If the blood pressure falls orthe volume of blood reaching the kidneys falls, as occursduring bleeding or heart failure, the renin-angiotensinenzyme system is activated and angiotensin is produced.Angiotensin is a powerful constrictor of arteries andincreases blood pressure, but this increases the work of theheart and worsens heart failure. Captopril and enalaprilblock a ‘‘converting enzyme’’ that converts angiotensin toits active component. This new group of vasodilators aretherefore called angiotensin-converting enzyme (ACE)inhibitors. These drugs cause dilatation of the arteries,which reduces blood pressure and heart work. In addition,these drugs cause the kidneys to return less sodium andwater to the blood, further reducing the work of the heart.ACE inhibitors conserve potassium, and as mentioned, anormal potassium level is essential for the prevention ofdigitalis toxicity and the maintenance of the electricalstability of the heart. Available ACE inhibitors includecaptopril, enalapril, and lisinopril. (See chapter entitledAngiotensin-Converting Enzyme Inhibitors/AngiotensinReceptor Blockers.)a. Captopril (Capoten)Supplied: Tablets: 12.5 mg, 25 mg, 50 mg, and 100 mg.Dosage: Withdraw diuretics and other antihypertensivesfor 12 h, then give a test dose of 6.5 mg daily, increasingto 12.5 mg twice or three times daily, preferably one hourbefore meals. The maximum suggested daily dose forheart failure is 75–100 mg. This drug is excreted by thekidneys. If kidney failure is present, the dose interval isincreased; for example, 25 mg three times daily can bereduced to 25 mg twice daily or to 12.5 mg twice daily.With kidney failure less drug is needed at longer intervals.Advice and Adverse Effects: ACE inhibitors are notadvisable in patients with severe anemia or severe renalfailure. Do not combine with potassium in any form orwith water pills that retain potassium. Captopril may causea dry cough and severe itching of the skin. Increased proteinin the urine and reduction in white blood cells mayalso occur.b. Enalapril (Vasotec)Supplied: Tablets: 2.5 mg, 5 mg, 10 mg.Dosage: 5 mg once or twice daily up to 40 mg daily.Enalapril is an ACE inhibitor, and its effects are similarto those of captopril, as outlined above.Other vasodilators used in the management of heartfailure include hydralazine, but its effects are variableand only rarely helpful. Hydralazine is not an ACE inhibitorand it is used in heart failure only when ACEinhibitors or ARBs are contraindicated (see the chapterAngiotensin-Converting Enzyme Inhibitors/AngiotensinReceptor Blockers).c. Lisinopril (Zestril, Prinivil, Carace)Supplied: Tablets: 5 mg, 10 mg, 20 mg.Dosage: 2.5 mg once daily increasing as needed to maintenanceof 20–40 mg daily. Table 2 gives the names anddosage of ACE inhibitors and ARBs.D. Angiotensin receptor blockersARBs specifically block the angiotensin II receptor AT1,and this causes a blockade of the renin-angiotensinaldosteronesystem. Although, as with ACE inhibitors, theblockade is not compete. Because angiotensin can besynthesized outside of the renin-angiotensin system, ARBscould produce more effective control of angiotensin IIthan ACE inhibitors and have the potential to be moreeffective antihypertensive and heart failure agents. Inaddition they do not cause a dry cough or life-threateningangioedema like ACE inhibitors. The ARB, candesartan,demonstrates long-lasting blockade of the AT1 receptorand appears to have the most potent blood pressure loweringeffects in the ARB class.d. Candesartan (Atacand Amias)Supplied: 4 mg, 8 mg, 16 mg, 32 mg.Dosage: Initial 4–8 mg titrated to 16–32 mg once daily.e. Irbesartan (Avapro, Aprovel)Supplied: 75 mg, 150 mg, 300 mg.Dosage: 150–300 mg daily. Elderly: initial 75 mg.Only the 300-mg dose has been shown to be effectivein causing some degree of renal protection and reductionof microalbuminuria. See the chapter Angiotensin-Converting Enzyme Inhibitors/Angiotensin ReceptorBlockers for other agents of this class.Clinical Trial: CHARMThe Charm-Alternative trial (n ¼ 2028) examined theeffects of the ARB candesartan in patients with a reduced

442HEART FAILUREleft ventricular ejection fraction of less than 40% who wereACE inhibitor intolerant. Results of the study showedthat after 33.7 months of follow up patients administeredcandesartan were 23% less likely to experience the primaryend point: cardiovascular death or heart failure hospitalizationcompared with those who received standard heartfailure medications with the exception of ACE inhibitors( p ¼ 0.0004).CHARM examined the effect of candesartan on patientswho were already on an ACE inhibitor, the majority ofwhom were on a beta-blocker. After 41 months of followup patients receiving candesartan were 15% less likely toexperience the primary end point compared with thosegiven placebo (42% vs. 37.9; p ¼ 0.0011). This resultoccurred regardless of whether or not patients were ona beta-blocker and independent of the dose of ACEinhibitor used. When the combination of candesartan andan ACE inhibitor is administered, however, monitoring ofserum creatinine and for hyperkalemia is necessary,particularly if spironolactone or eplerenone are used inthe treatment regimen.E. DiureticsDiuretics are a very useful category of heart medication.They play a vital role in the treatment of patients withheart failure or hypertension. In heart failure, the legs andlungs become not just waterlogged, but brine-logged.Water in the legs, feet, and lungs can only be relieved byusing a diuretic, which forces salt and water from the bloodinto the urine. Severe shortness of breath and a feeling ofsuffocation is rapidly relieved by the diuretic furosemide.Diuretics used in conjunction with ACE inhibitors,beta blockers, and digoxin prolong life and cause reliefof symptoms.1. Furosemide (Lasix)Supplied: Tablets: 20 mg, 40 mg, and 80 mg.Dosage: 40–120 mg daily for patients with severecongestive heart failure. Long-term maintenance forpatients no longer in heart failure is 40–80 mg daily.F. NitratesThese preparations (see the chapter Angina) have a smallrole in patients who are not controlled with the use ofdigoxin and diuretics, plus an ACE inhibitor. Their mainaction is to dilate veins, pooling blood in the lower part ofthe body. This causes less blood to return to the heartand congestion in the lungs may be slightly reduced. Thiseffect is only mild, however, and the drugs lose effectivenessif used continuously over a few weeks. They areoften used in emergencies, in hospitals, or occasionally,at home to help patients with very severe heart failure getover a crisis.Preparations of oral isosorbide dinitrate and other oralnitrates may be added to digoxin and diuretics and evento the vasodilators mentioned above. Some patients mayfeel dizzy, however, with drug combination and closesupervision by a physician advisable to achieve the besteffects.G. Beta-BlockersBeta-adrenergic blocking agents play a key role in themanagement of patients with heart failure and are stronglyrecommended for the management of New York HeartAssociation class I–III heart failure. Transmyocardialmeasurements have documented that the failing humanheart is exposed to increased adrenergic activity. Chronicadrenergic activation has adverse effects on the naturalcourse of heart muscle disease. These cardioactive agentsblock the renin-angiotensin-aldosterone system and augmentatrial and brain natriuretic peptide. Cliniciansappear to have forgotten that beta-blockers decreaserenin secretion from the juxtaglomerular cells of thekidney, which causes a decrease in angiotensin levelsand reduces aldosterone production. Recent randomizedclinical trials have shown particular beta-blockers are asbeneficial as ACE inhibitors for the treatment of heartfailure. (See chapter entitled Beta-Blockers.)The COPERNICUS trial studied 2289 patients withsevere heart failure with ejection fractions of 16–24%but free from overt fluid retention or recent treatmentwith intravenous diuretics. The results showed a highlysignificant 35% reduction in all-cause mortality causedby the drug, carvedilol.The CAPRICORN study showed that in patients aftermyocardial infarction with an ejection fraction of 33%carvedilol caused a 23% relative reduction in mortalityidentical to that observed with ACE inhibitors. TheMERIT-HF trial involved patients with class II and IIIheart failure with a mean ejection fraction of 28%, whichresulted in risk reduction of 33% for total mortality orworsening heart failure. In this trial metoprolol was usedin combination with diuretics, digoxin, and an ACEinhibitor.In the CIBIS-II study of 2647 patients with classIII heart failure and an ejection fraction of 35%,bisoprolol administration reduced all-cause mortality by

VII. DRUG TREATMENT44332% ( p ¼ 0.00005) and sudden death by 45% ( p ¼0.001). A 30% reduction in hospitalization occurred inthe bisoprolol-treated group. Study patients receivedACE inhibitors, diuretics, and digoxin.COMET was a large randomized trial that comparedcarvedilol and metoprolol to clinical outcomes in patientswith chronic heart failure. The COMET investigatorsassigned 1511 patients with chronic heart failure New YorkHeart Association class II–IV to treatment with carvediloland 1518 to metoprolol. The all-cause mortality was 34%for carvedilol and 40% for metoprolol ( p ¼ 0.0017).Carvedilol showed superior beneficial effects comparedto metoprolol and is the beta-blocker of choice for themanagement of heart failure.Beta-blockers used judiciously are as effective as ACEinhibitors that are proven useful in the management ofheart failure. From the 1960s to the 1980s heart failurewas a recognized contraindication for the use of betablockers.The first documented use of beta-blockers totreat heart failure was carried out by Dr. Finn Waagsteinin Sweden in 1973, and he published a report of treatmentin seven patients in 1975. About 25 years later hiscolleague, Dr. Swedberg, made the comment: ‘‘in thelight of CIBIS-II, MERIT-HF, and COPERNICUS about25 years after our initial experience, it is gratifying torealize that beta-blocker therapy now is the best documentedand most effective treatment for chronic heartfailure.’’H. Aldosterone Antagonists1. Spironolactone (Aldactone)This drug blocks the effect of aldosterone in the distalrenal tubule (see Figure 1 in the chapter Diuretics). In theRales study the drug caused a 30% reduction in the risk ofdeath in patients with class III and IV heart failure treatedwith diuretics, ACE inhibitors, and digoxin. Hospitalizationfor recurrent heart failure was significantly reduced.This represents a major breakthrough in the managementof severe heart failure.Spironolactone causes potassium retention similarto ACE inhibitors, therefore, hyperkalemia may occur.This combination should be avoided in patients with renaldysfunction.With spironolactone the beneficial effect in themanagement of heart failure appears to the result of thefollowing.Distal nephron blockade of aldosterone causes sodiumand water excretion. This action is extremely importantin patients treated with furosemide; distal nephronblockade enhances the diuretic effect of loop diureticsand prevents recurrence of heart failure.Spironolactone appears to decrease cardiac fibrosis andendothelial dysfunction and increase nitric oxide bioactivity.Spironolactone has a mild positive inotropic effectindependent of and additive to that of digoxin; strokevolume is increased.2. Eplerenone (Inspra)The EPHESUS trial randomized 6000 patients andshowed that this selective aldosterone blocker added tooptimal medical therapy in patients with acute myocardialinfarction and heart failure with ejection fractions lessthan 35% significantly reduced mortality and morbidity.The dose of 25 mg can be titrated up to 50 mg daily.It does not cause gynecomastia like spironolactone so itmay replace spironolactone use in men. Both agents shouldnot be used in patients with a serum creatinine greater than1.3 mg/dl (115 mmol/L) or in type 2 diabetics with alteredglomerular filtration rates because hyperkalemia may beprecipitated. The serum creatinine does not reflect thecreatinine clearance, particularly in the elderly who aremost often treated for heart failure. In this randomizedtrial hyperkalemia occurred in 5.5 and 4% of patients inthe treated and placebo groups, respectively.I. ResynchronizationCardiac resynchronization therapy is an innovativepacemaker-based approach to the management of patientswith left bundle branch block, right bundle branchblock, and nonspecific intraventricular conduction delayas manifested electrocardiographically. It appears thatresynchronization provides electromechanical coordinationand improved ventricular synchrony in patients withintraventricular conduction defects and heart failure. Apacemaker lead is placed through the right atrium throughthe coronary sinus and into a cardiac vein on the lateralwall of the left ventricle. The left ventricular leadconstitutes the key difference between resynchronizationtherapy and the standard dual-chamber pacing that is usedfor other conditions requiring a pacemaker. One lead isin the left ventricle, one lead is placed in right atrium,and the third lead is placed in the right ventricle. Beneficialdocumented effects of resynchronization therapy includereverse remodeling which results in decreased heart size

444HEART FAILUREand ventricular volumes, an improvement in ejectionfraction, and a decrease in mitral regurgitation.Unfortunately in the MIRACLE clinical trial testingresynchronization therapy, 32% of patients had no changeor had a deterioration in the New York Heart Associationclass after resynchronization therapy. In addition, otherstudies have reported about a 30% nonresponse rate afterbiventricular pacing. Because of the cost of this modality,an important question to ask is how to determine inadvance of implantation which patients will respond toresynchronization therapy. Resynchronization therapy hasnot been shown to improve survival in patients with heartfailure and further trials are underway.J. Transplantation and the Artificial HeartCardiac transplantation is of proven benefit but onlyapproximately 4000 donor hearts are available worldwideannually (see the chapter Artificial Heart).VIII. NONDRUG THERAPYA. Advice on Drugs, Salt, Diet, Potassium,Alcohol, and ExerciseMedications must be continued as directed. Herbal remediesare not recommended for the management of heartfailure and these substances should be avoided. Do notstop any medications without consulting a physician.Digoxin is usually necessary for a lifetime and diureticsare continued in some in a small dose for a lifetime. Westrongly advise you to take your medications with you oneach visit to your doctor so that they can be rechecked oraltered.It is essential that the patient learn to live with alow-sodium diet. This does not mean that the individualmust go to extremes and follow a 0.5–1 gm sodium diet.To achieve a low salt intake, simply do the following: Do not add salt in cooking or at the table. If taste isa problem, use a salt substitute after testing severalpreparations on the market. Salt substitutes have potassiuminstead of sodium and are therefore better for you,but they should not be used if you are taking an ACEinhibitor. If you have kidney trouble, you retain enough potassium;therefore, extra potassium is not required. It issuch an important and confusing area that both patientand physician must be careful. If you are taking anACE inhibitor (captopril, enalapril), spironolactone,Aldactazide, Dyazide, triamterene, or Moduretic(Moduret) do not use excessive amounts of saltsubstitute, eat a potassium-rich diet, or take potassiumsupplements without the advice of your doctor.Appropriate advice from your doctor depends onblood tests to evaluate kidney function and electrolytes,which include blood potassium. Use foods containing small quantities of sodium.For further information on salt intake, see the chapterHypertension.Apart from a low-sodium intake and an increasedintake of potassium where necessary, your diet can benormal. There is no need to restrict cholesterol, fats, orsugars because this adds to the patient’s misery for littlereturn. Such strict diets may rob the patient of one beautyof life, that is, to be able to enjoy a meal. This can resultin a feeling of hopelessness and depression. Diabetics,however, still need to maintain their diets. Patients mustlose excess weight to decrease the work of a failing heart.Less weight always causes less shortness of breath. A lossof 10–25 pounds always causes considerable improvementin shortness of breath and less medications are required.The level of potassium in the blood must be kept withinthe upper normal range, 4–5 mEq/L. Except when kidneyfailure is present, extra potassium is often required inliquid or tablet form. The tablets or capsules may causesome gastrointestinal irritation. In addition, the pillsare large in size and often rejected by patients, and theycontain very little potassium. When a patient has a lowblood potassium and kidney failure is absent, we stronglyadvise a potassium-rich diet because the liquid medicationshave such an unpleasant taste. Foods containing a liberalamount of potassium are given in Table 3.TABLE 3Potassium-Rich FoodsPotassium-RichFoodsOrange juice Half cup 6 mEqMilk (skim, powdered) Half cup 27 mEqMilk (whole, powdered) Half cup 20 mEqMelon (honeydew) Quarter 13 mEqBanana One 10 mEqTomato One 6 mEqCelery One 5 mEqSpinach Half cup 8 mEqPotato (baked) Half 13 mEqBeans Half cup 10 mEqStrawberries Half cup 3 mEqAvocado, prunes and raisins, meats, and shellfish are rich in potassium.

IX. WHAT TO EXPECT IN THE HOSPITAL AND ON DISCHARGE445TABLE 4KCL-Liquids Ingredients mEq (mmol) mEq (mmol)Kay Ciel Kay-Cee-L KC120 20 1 mmol/LPotassium chloride 10% KCl 20 (or sugar free) K-Lord (piquet’s) KCl 20 K-Litchi KCl 25 Koehler 10%KCl 20 Klorvess 10% KCl 20 Cilium KCl 20 3* Kino Elixir K—*glaciate 20Kino-Cl 20% KCl 40 K-Lyte (effervescent) KH 2 CO 3 25 —*Potassium Triplex not KCl 15 —* Potassium Sandoz KCl 12 8*Rum K KCl 20 20Tablets/Capsules—Slow ReleaseK-Long KCl 6* 6 Cilium durules KCl 10* 10 Kaon K gluconate 5*—LeoK KCl 8 8* Micro K KCl 8* 8 Nu-K K 8 8*SandoK K 12 8*Slow-K KCl 8J 8**Note the low potassium and/or chloride content of some preparations.Dosage: Usual range 20–60 mEq (mmol) potassium daily. K þ ¼ potassium. Cl ¼ chloride.The intake of foods listed in Table 3 can prevent theuse of potassium pills or liquids. As an alternative, manydoctors advise a diuretic that retains potassium such asModuretic or Dyazide. In moderate to severe heart failure,a combination of furosemide, which causes a loss of potassium,and captopril or enalapril, which retains potassium,is advised. Various diuretics are discussed in the chapterDiuretics. Potassium chloride mixtures and tablets aregiven in Table 4. To be useful, these preparations mustcontain sufficient potassium with chloride.Alcohol causes the heart muscle to pump less forcefully.Eight ounces of gin given to normal healthy studentscaused a 33% reduction in the amount of blood ejectedfrom the heart. Can you imagine a sick heart with ahandicap? If you have had heart failure, either do notdrink alcohol at all or keep it under two ounces of alcohol,a pint of beer, or two ounces of wine daily. Patients whohave alcoholic heart muscle disease (alcoholic cardiomyopathy)should never drink alcohol.Exercise or unaccustomed activity imposes increasedwork on a weak heart muscle and often precipitates heartfailure. Walking is the safest and best exercise. Try to walka half to one mile and stop and rest if you get short ofbreath. It is not recommended to take longer walks of threeto five miles or jogging for patients with heart failure.Stooping and bending exercises may cause some dizziness,especially if you are on vasodilators, diuretics, and nitrates.Patients with class III or IV heart failure, especially ifrecurrent, are not advised to engage in exercise programseven if they are claimed to be rehabilitation programs.Walking a half to one mile daily and stretch exercisesshould suffice. You can only strain the heart muscle; youcan never improve it. The heart failure that occurs duringan acute heart attack is completely different and oftenclears within one week. Such patients can engage in variousexercise programs.IX. WHAT TO EXPECT IN THE HOSPITALAND ON DISCHARGEThe main symptom of heart failure is severe shortness ofbreath. Pain occurs only when heart failure is precipitatedby a heart attack. If nitroglycerin is available, put oneunder the tongue and remain propped up in bed or situntil the ambulance arrives.Oxygen is useful and is given immediately at onsetof heart failure. Morphine allays anxiety and pools bloodin the lower part of the body. Both of these actions bringrelief. Nitroglycerin paste, ointment, or patch is appliedto the skin, and a powerful diuretic, furosemide, is givenintravenously. Furosemide acts within minutes, poolingblood in the lower half of the body, and causes the kidneysto remove sodium and water from the blood and excretethem in the urine. If relief is not obtained, further injectionsof furosemide are given.The cause of heart failure and the precipitating factorsare then treated, if possible. Atrial fibrillation is successfullytreated with digoxin. Hypertension can cause heartfailure, and the blood pressure must be lowered. An ACEinhibitor is used to dilate arteries and lower blood pressure,and thus rest the heart. Patients with heart failure have ahospital stay of five to 7 days. Prognosis depends on thecause and precipitating factors outlined. Heart failure doesnot mean the end. Some patients do much less than before,

446HEART FAILUREbut they can live active lives for 5–15 years with goodmedical treatment. The reassuring news is that avoidanceof precipitating factors can help enormously and the recentuse of judicious doses of carvedilol or metoprolol alongwith spironolactone or eplerenone will have a majorimpact in improving morbidity and mortality from heartfailure.BIBLIOGRAPHYAbraham, W. T., Fisher, W. G., Smith, A. L. et al. Cardiacresynchronization in chronic heart failure. N. Engl. J. Med.,346:1845–53, 2002.Adams, K. F., Gheorghiade, M., Uretsky, B. F. et al. Clinical benefits oflow serum digoxin concentrations in heart failure. J. Am. Coll.Cardiol., 39:946–53, 2002.Bauersachs, J., Heck, M., Fraccarollo, D., Hildemann, S. K. et al.Additions of spironolactone to angiotensin-converting enzyme inhibitionin heart failure improves endothelial vasomotor dysfunction.J. Am. Coll. Cardiol., 39:351–8, 2002.Brad, G., Angeja, M. D. and Grossman, W., Evaluation and managementof diastolic heart failure. 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ACC/AHA 2005guideline update for the diagnosis and management of chronic heartfailure in the adult—Summary article: A report of the AmericanCollege of Cardiology/American Heart Association task force onpractice guidelines (writing committee to update the 2001 guidelinesfor the evaluation and management of heart failure). J. Am. Coll.Cardiol., 46: 1116–1143, 2005.Hunt, S. H., Baker, D. W., Chin, M. H. et al. ACC/AHA guidelines forthe evaluation and management of chronic heart failure in the adult:executive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J. Am.Coll. Cardiol., 38:2101, 2001.Jessup, M., and Brozena, S. Heart failure. N. Engl. J. Med., 348:2007–18,2003.Khan, M. Gabriel Heart Failure in Cardiac Drug Therapy, sixth edition.W. B. Saunders, Philadelphia, 2003.Khand, A. U., Rankin, A. C., Martin, W. et al. Carvedilol alone or incombination with digoxin for the management of atrial fibrillation inpatients with heart failure? 42: 1944–1951, 2003.Lokuta, A. J., Maertz, N. A., Meethal, S. V. et al. Increased nitration ofsarcoplasmic reticulum Ca2þ-ATPase in human heart failure.Circulation, 111:988–995, 2005.Maisel, A. S., Krishnaswamy, P., Nowak, R. M. et al. Rapid measurementof B-type natriuretic peptide in the emergency diagnosis of heartfailure. N. Engl. J. Med., 347:161–7, 2002.Masoudi, F. A., Inzucchi, S. E., Wang, Y. et al. Thiazolidinediones,Metformin, and outcomes in older patients with diabetes and heartfailure: An observational study. Circulation, 111:583–590, 2005.Maurer, M. S., Spevack, D., Burkhoff, D. et al. Diastolic dysfunction:Can it be diagnosed by Doppler echocardiography? J. Am. Coll.Cardiol., 44:1543–1549, 2004.McCullough, P. A., Philbin, E. W., Spertus, J. A. et al. 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IX. WHAT TO EXPECT IN THE HOSPITAL AND ON DISCHARGE447Ripoli, A., Pingitore, A., Favilli, B. et al. Does subclinical hypothyroidismaffect cardiac pump performance? J. Am. Coll. Cardiol., 45:439–445,2005.Shekelle, P. G., Rich, M. W., Morton, S. C. et al. Efficacy of angiotensinconverting enzyme inhibitors and beta-blockers in themanagement of the left ventricular systolic dysfunction according torace gender, and diabetic status. J. Am. Coll. Cardiol., 41:1529–38,2003.Strey, C. H., Young, J. M., Molyneux, S. L. et al. Endotheliumamelioratingeffects of statin therapy and coenzyme Q 10 reductionsin chronic heart failure. Atherosclerosis, 179: Issue 1, 201–206, 2005.Swedberg, K. Beta blockers in heart failure. How it all began. J. Am. Coll.Cardiol., ACC Curr. J. Rev. January/February, 61, 2001.Valgimigli, M., Ceconi, C., Malagutti, P. et al. Tumor necrosis factor-receptor 1 is a major predictor of mortality and new-onset heart failurein patients with acute myocardial infarction: The cytokine-activationand long-term prognosis in myocardial infarction (C-ALPHA) study.Circulation, 111:863–870, 2005.Weinstein, A. R., Sesso, H. D., Lee, I. M. et al. Relationship of physicalactivity versus body mass index with type II diabetes in women.JAMA, 292:1188–1194, 2004.Wiksrrand, J., Hjallmarson, A., Waagstein, F. et al. Dose of metoprololCR/ZL and clinical outcomes in patients with heart failure. J. Am.Coll. Cardiol., 40:491, 2002.Young, J. B., William, T., Abraham, M. D., Smith, A. L. et al forThe Multicenter InSync ICD Randomized Clinical Evaluation(MIRACLE ICD) Trial Investigators Combined Cardiac Resynchronizationand Implantable Cardioversion Defibrillation in AdvancedChronic Heart Failure. The MIRACLE ICD Trial. JAMA,289:2685–2694, 2003.

HemochromatosisI. IncidenceII. Genetics and Iron OverloadIII. Clinical ComplicationsIV. ManagementV. Research ImplicationsGLOSSARYarrhythmia general term for an irregularly or rapidity of theheartbeat, an abnormal heart rhythm.cardiomyopathy heart muscle disease.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60–75%; a lowejection fraction is less than 40%; often used as a marker ofleft ventricular contractility.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches the organs and tissues.myocardium the heart muscle.I. INCIDENCEHereditary hemochromatosis is not an uncommon condition.Approximately 10% of individuals of European andparticularly Celtic background are heterozygous carrierswho only develop iron overload if there is a second defectadded to environmental and nutritional factors.Homozygosity is about 1 in 400. Fortunately, the numberof individuals affected clinically is much less thanpredicted by the genetic frequency, perhaps, because ofvariable penetrance and other unknown factors. The frequencyof the clinical disease was estimated to be roughly1 in 5000 in the Pacific Northwest of the United Statesand 1 in 500 and 1 in 1000 in autopsy series in Scotlandand Sweden, respectively. The majority of affected homozygotesdo not exhibit signs or symptoms; the disease maytherefore go undetected. The development of clinicalhemochromatosis with damage to organs usually requiresa double dose of the mutant gene and affected parents arehomozygous. Individuals of Asian and African backgroundare rarely affected.HEMOCHROMATOSIS IS A CONDITION CAUSEDby a genetic defect in which excessive amounts ofiron are absorbed in the small intestine and deposited intissues and organs of the body. Iron overload has severalcauses one of which is repeated and excessive bloodtransfusions, as may occur in individuals with sicklecell anemia and beta-thalassemia major. Also, excessivealcohol consumption may increase the blood levels of ironbecause alcohol stimulates iron absorption. In addition,red wines contain increased amounts of iron. The containersin which alcoholic beverages are kept may alsocontain iron and increase the iron content of the beverage.The use of cooking utensils with an iron base from whichiron may leach can increase blood levels of iron anddeposition in the tissues. Such a condition was notedseveral years ago in the Bantus who used iron pots forpreparation of meals.II. GENETICS AND IRON OVERLOADThe gene responsible for hemochromatosis, HFE, wasdiscovered in 1996 and resides in chromosome 6 whichinvolves the mutation of a cysteine to tyrosine at position282 (C282Y). Iron is kept in a soluble state in the bloodbecause it binds to the protein transferrin. Cellular ironuptake takes place at transferrin receptors. Figure 1 showsthe transferrin shuttle pathway. Normally iron is separatedfrom transferrin in the endosome and is shuttled into theinterior of the cell.The genetic mutation C282Y produces a mutant HFEprotein that is not associated with the transferrin receptor anddoes not act as a brake on iron uptake into cells. The exactreason why iron absorption in the intestine is markedlyincreased has not been clarified and requires furtherinvestigation and research.449

450HEMOCHROMATOSISIII. CLINICAL COMPLICATIONSA. Myocardial Damage MechanismsIron-saturated transferrin attaches to cell transferrin receptorsand excess iron gains entry into the cell (see Fig. 1).Although much of the iron is stored as hemosiderin, forexample, within the Kuffer cells of the liver, and causes nodamage to tissues, some free iron is released into parenchymalcells. Free iron catalyzes the formation of reactiveoxygen species and the hydroxyl radical causes damageto cells. With damage and destruction of cells there isFIGURE 1 (A) The transferring shuttle pathway. Iron is released from its transferring-bound state in the circulation intracellularly in endosomes due toproton-pump-mediated acidic pH. The HFE protein, mutated in hemochromatosis, acts as a brake on iron internalization by binding to transferringreceptors. (From Andrew, N. C. Medical progress: Disorders of iron metabolism. N. Engl. J. Med., 341, 1985–1986, 1999.) (B) The transferring receptor(TFR)-HFE complex. Wild-type HFE protein is associated with beta 2 -microglobulin and binds to TFR, decreasing transferring binding (left). The C282mutant HFE protein does not associate with beta 2 -microglobulin, allowing TFR free to bind transferring (center). The H63D mutant HFE does associatewith beta 2 -microglobin but fails to decrease TFR affinity for transferring (right). (From Andrews, N. C., and Levy, J. E., Iron is hot: An update on thepathophysiology of hemochromatosis. Blood, 92, 1845–1851, 1998.)

IV. MANAGEMENT451Heart failureCardiomyopathyiron replacing the cartilage of the hip and destroying thehip or knee joint.CARDIACreplacement by collagen and fibrous tissue that weakensthe muscular wall of the heart. Severe damage and weaknessprimarily to heart muscle is called cardiomyopathy.Less blood is ejected from the left ventricle and heartfailure symptoms and signs occur. The weakened heartmuscle is stretched and the heart becomes dilated, resultingin a dilated cardiomyopathy, but some restriction to fillingof the heart occurs and there are also features of a restrictivecardiomyopathy (see the chapter Cardiomyopathy).Excessive iron is distributed throughout the myocardiumand in the electrical conducting tissues and arrhythmiasmay occur.B. Symptoms and SignsDamage to myocardiumElectrical conducting tissueArrhythmiasCirrhosisComplicationsLIVERCancerofPancreas DiabetesHemochromatosisHipsArthritisKneesTestes ImpotenceComplications of hemochromatosis.FIGURE 2The symptoms and signs of hemochromatosis depend onthe organ or organs involved. It usually takes 20–30 yearsof excessive absorption before the disease manifests. Inaffected women time onset is usually delayed because ofmenstruation.Figure 2 shows the clinical complications of hemochromatosis.Complications of heart failure such as shortnessof breath, fatigue, and edema of the ankles as well as othersymptoms and signs of heart failure occur. Palpitationscaused by arrhythmias may be bothersome and seriousarrhythmias can cause death. Signs and symptoms dueto other organ involvement include pigmentation of theskin, diabetes because of involvement of the pancreas,enlargement of the liver and cirrhosis may cause fluid toaccumulate in the abdomen, and ascites and cancer ofthe liver may be terminal. Arthritis may be severe withC. DiagnosisSerum ferritin, normally 16–320 mg/L is usually elevated tomore than 700 mg/L and may reach as high as 5000 mg/L.A liver biopsy usually confirms the type of damage causedby hemochromatosis and the genetic causation is confirmedby gene testing.Disturbance in the heart can be detected by echocardiographyor radionuclide ventriculography, bothof which show left ventricular dysfunction. The MRIis more specific; iron that is localized in the myocardiumand liver generates a characteristic signal dropout patternso that the liver and in part, the myocardium, becomeinvisible.IV. MANAGEMENTVenesection with removal of 500 ml of blood every 2 weeksfor several months followed by monthly venesectionfor a year usually results in a reduction of serum ferritinlevel to less than 50 mg/L. Venesections are continuedevery 3 months or more frequently to maintain a ferritinlevel 50 mg/L range. Alcohol increases absorption ofiron and should be curtailed, especially because cirrhosisis an outcome of the iron overload. If the serum ironis kept within the normal range before serious cardiacinvolvement has occurred, the prognosis is good. If cardiomyopathyresulting in heart failure has occurred, theprognosis is poor.Iron chelation may reverse some degree of cardiacdysfunction. Intravenous desferrioxamine on a 24-h perday regimen resulted in some improvement in left ventriculardysfunction and improvement in ejection fractionin some patients with severe cardiac dysfunction causedby transfusional iron overload.BIBLIOGRAPHYAndrews, N. C. Disorders of iron metabolism. N. Engl. J. Med.,341:1986–95, 1999.Andrews, N. C., and Levy, J. E. Iron is hot. An update on the pathophysiologyof hemochromatosis. Blood, 92:1845–51, 1998.

Herbal, Dietary Supplements, andCardiovascular DiseaseI. HistoricalII. Consumption and RegulationIII. Benefits, Adverse Effects, and Drug InteractionsIV. Substances Used by Athletessympathomimetic impulses from the sympathetic nervoussystem, adrenergic.vasoconstriction narrowing, decrease in the diameter of veins orarteries.GLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.arrhythmia general term for the irregularity or rapidity of theheartbeat, an abnormal heart rhythm.arterial dilatation enlargement or increase in the luminal diameterof the artery.dyslipidemia the same as hyperlipidemia, elevated blood cholesterol,LDL cholesterol, triglycerides, or low HDL cholesterol.flavonoid any of a large group of crystalline compounds foundin plants.free radical an atom or group of atoms that is highly chemicallyreactive, because it has at least one unpaid electron; freeradicals can attack cells.free radical scavenger a substance that removes or destroys freeradicals.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hypertension high blood pressure.hypotension marked decrease in blood pressure, usually lessthan 95 mmHg.inotropic an effect that affects the force of muscular contractions;negative inotropic refers to decreased myocardial contractilitythat may lead to poor pumping of the blood, reducedejection fraction, and heart failure.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.platelet aggregation clumping together of small particles in theblood; platelets increase clot formation.I. HISTORICALIn 350–377 BC, Hippocrates, the father of medicine,advised the use of diet and plant medicines. He tried torelieve the pain of his patients by asking them to chewwillow bark, which contains salicylic acid. Long beforeHippocrates, the ancient Sumerians (5000 BC), Egyptians,and the Chinese (1600–700 BC) were noted to useherbs such as onions, garlic, licorice, ginger, thyme, andAyurveda was commonly used in India.In 1640, Nicholas Culpeper published the EnglishPhysician People’s Herbal. In 1763 Reverend Stone ofChipping Norton, England, showed the benefit of willowbark (salicylic acid) for individuals with ague fever. In 1775William Withering, a Birmingham physician, learned ofa midwife whose herbal brew had cured several peoplesuffering from dropsy which caused severe swelling ofthe legs and shortness of breath. Withering studied thebrew and concluded that the only active constituent of the20 or more herbs was derived from the foxglove plant,Digitalis purpurea. He used the herb with a fair amount ofsuccess. For the past 210 years digitalis (digoxin) has beenused worldwide to treat millions of people with heartfailure.II. CONSUMPTION AND REGULATIONAlternative therapies with herbal, dietary, and vitaminsupplements have escalated considerably in the westernworld during the past 10 years. Alternative therapies wereused in more than 40% of adults in the United Statesduring 1997, and a consumer poll in 1998 indicated that453

454HERBAL, DIETARY SUPPLEMENTS, AND CARDIOVASCULAR DISEASEmore than 30% of respondents use herbal remedies. In theUnited States the use of herbal therapy in 1997 was 12%vs. 2.5 percent in 1990, at a consumer cost of greater than$5 billion. During 2001, more than $17 billion was spenton dietary supplements with greater than $4.2 billionspent for herbal remedies in the United States.It appears that of patients who take prescription medications,nearly 20% use herbal remedies, high-dose dietarysupplements, or both. More important, adverse druginteractions involving prescribed medications and herbalremedies are common. It is estimated that more than 20million adults in North America are at risk for theseadverse interactions, some of which are cardiovascular. In2001, the Food and Drug Administration (FDA) issuedwarnings about nephrotoxic and other toxic and carcinogeniceffects associated with products containing, kava,comfrey, and aristolochic acid. Reportedly approximately33% of Asian medicines contain toxic heavy metals such asarsenic, lead, and mercury that have deleterious cardiovasculareffects. Drugs such as ephedrine, chlorpheniramine,and testosterone are also contained in so-called herbalremedies.Because most herbal products are considered dietarysupplements rather than medicines, they are not requiredto meet standards specified in the Federal Food, Drug, andCosmetic Act. The manufacturer of an herbal or dietarysupplement can market the product as long as there isno claim of effectiveness for the prevention and treatmentof a specific disease. In Australia, France, Germany, andSweden strategies have been put in place for licensingherbal remedies.Reportedly, 75% of the world’s population uses herbalremedies. More than 25% of individuals in most countriesdevelop cardiovascular disease. Therefore, the potentialvalue of herbal medicines and dietary supplements to assistwith the management of cardiovascular disease, theiradverse effects, and interactions with prescribed cardiovascularmedicines must be carefully defined.noncoronary arteries. This substance has no inotropiceffect, and does not increase cardiac contractility. Thepossibility of coronary artery vasodilatation with Danshenrequires further investigation.1. Benefits and Adverse ReactionsTranshinone, in a double-blind study of 67 patientswith coronary artery disease, produced symptomatic andelectrocardiographic benefits. A decrease in the clearanceof warfarin and increased bioavailability may causebleeding in this substance.B. Ephedra sinica (Ma Huang)The active constituent in this herbal medicine is ephedrine,a known stimulant that possesses strong sympathomimeticactivity with properties similar to epinephrine. Figure 1AmphetamineEphedrineNorephedrineOHHCH 3HCH CH NHOH CH CH 33CH CH NHOHCH 3CH 3HCH CH NHOHHEpinephrineHOC C NHIII. BENEFITS, ADVERSE EFFECTS,AND DRUG INTERACTIONSA. Danshen (Salvia miltiorrhiza)Danshen is believed to possess vasoactive, free radicalscavenger, and demonstrable antiplatelet properties. It iswidely used in China for the management of anginaand acute myocardial infarction. The active substances ofDanshen are phenolics and tanshinones, which causegeneralized dilatation of arteries and thus decreases bloodpressure. But at high doses it causes vasoconstriction inHOOHH HFIGURE 1 Structure of epinephrine and non-epinephrine. Bothhormones and neurotransmitters are catecholamines and possess a ringstructure containing two –OH groups. They are synthesized fromtyrosine. They are cardiac stimulants; they are engaged in several actionsin the body including the fight or flight response. Note the stimulantsamphetamine and ephedrine.HHOHHC C NH 2

III. BENEFITS, ADVERSE EFFECTS, AND DRUG INTERACTIONS455shows that the molecular structure of ephedrine is similarto that of amphetamine and the related ephedra alkaloidand metabolite, phenylpropranolamine. The latter is foundcommonly in nasal sprays and in cough mixtures, and hasrecently (in 2000) been removed from products becauseof warnings from the FDA, Health Canada, and otherhealth authorities.Its effects on both alpha- and beta-adrenergic receptorsand its central actions resemble those of amphetamines.Unfortunately several dietary supplements and soft drinkscontain ephedra alkaloids and are widely used in theUnited States for increasing energy and to achieve weightloss. The FDA has proposed limits on the dose andduration of use of such supplements. Ephedrine is alsofound in unapproved herbal products that contain caffeine(herbal ecstasy) and aspirin; other products include Sidacordifolia and epitonin.1. BenefitsProducts containing ephedra or ephedrine are marketedonly as nasal decongestants and should be used for thispurpose only for two to a maximum of seven days. Highdosepreparations have been curtailed by the FDA andHealth Canada. The dose should be restricted to 8 mg ofephedrine per dose with a maximum 32 mg per day.2. Adverse Effects and InteractionsCardiovascular events ranging from hypertension, cerebralhemorrhage, arrhythmias, myocardial infarction, andcardiomyopathy have been observed. In a review of 140reports related to the use of ephedra alkaloids from 1997 to1999, 31% of cases were considered to probably be relatedand 47% involved cardiovascular symptoms. There werealso 17 reports of hypertension followed by palpitations,tachycardia, or both. Ten events resulted in death and13 events produced permanent disability.Interactions occur with caffeine and theophylline. Someof the adverse effects may be caused by concurrent useof excess caffeine; guarana is a source of caffeine andtheophylline. Herbal ecstasy contains caffeine, and othersources include green tea, cola nut, yerba mate, andyohimbe.C. Ginkgo1. BenefitsGinkgo biloba (maidenhair tree) leaf extracts, reportedly,have been used for more than 3000 years by the Chinese,and it is the best-selling remedy in the United States.Gingko is believed to be rich in flavonoids and terpenoids,which are believed to exert their salutary effects throughfree radical scavenging, antiplatelet activity, vasodilatation,.decreased blood viscosity, and anti-inflammatoryactions. Inhibition of monoamine oxidase-B and gammaaminobutyricacid receptor agonist have been reported.Mild antiplatelet activity has been observed, but a placebocontrolledtrial reported no effects on platelet aggregation,but an antiplatelet effect is the likely mechanism underlyingintracranial hemorrhage which has been observedwith the use of gingko, albeit rarely.In the new millennium ginkgo is commonly triedby patients who are not sufficiently benefited by currentmedical therapy for peripheral vascular and cerebrovasculardisease.Intermittent claudication is a peripheral vascular diseasein which pain occurs in the calf muscle after walkingfrom 50 to 100 yards. The pain eases off quickly withinminutes of stopping. Meta-analysis indicates that randomizedcontrolled trials (RCTs) in patients with intermittentclaudication have had mixed results. A modest improvementin pain-free walking distance increased by 45 and61 m, respectively, after 24 weeks of ginkgo treatment,compared with increases of 21 and 25 m, respectively, inthe placebo group. A meta-analysis of modestly beneficialprescribed medicines concluded that ginkgo improvespain-free walking distance by 32 m, but this effect wasmuch less than pentoxifylline (208 m) and naftidrofuryl(101 m). An RCT showed that a standardized extract ofginkgo significantly reduced the areas of limb ischemia, asmeasured by transcutaneous partial pressure of oxygenduring exercise.Alzheimer’s disease is a cerebrovascular disease for whichginkgo has been used. There has been conflicting evidencefor improved cognition and memory. In two long-termRCTs, modest but positive effects were identified in patientswith multi-infarct dementia or Alzheimer’s disease.These results were not corroborated by a further trial,although age-associated memory impairment has beencriticized as a broad and ambiguous concept.2. Adverse Cardiovascular EffectsCerebral hemorrhage, subarachnoid hemorrhage, subduralhematomas, and hemorrhage within the anterior chamberof the eye have been reported, but the exact incidenceappears rare and is difficult to appreciate from casereports. In patients where intracranial bleeding hasoccurred the prothrombin time (PT) and partial thromboplastintimes (PTT) were normal, but the bleeding time

456HERBAL, DIETARY SUPPLEMENTS, AND CARDIOVASCULAR DISEASEwas higher with a longer return to normal after discontinuationof the herbal medicine.Increased bleeding has been documented when ginkgois combined with aspirin, warfarin, or nonsteroidalinflammatory agents (e.g. ibuprofen) as well as the newselective agents such as rofecoxib (Vioxx). Because of anincreased risk of bleeding, ginkgo should be discontinuedone week prior to surgical procedures.D. Garlic (Allium sativum)Garlic is one of the most widely used dietary supplements.In 1998 market sales of garlic in the United states reachedapproximately $84 million. The active substance in garlicis allicin formed by the action of alliinase on alliin whengarlic is crushed. Other active substances in garlic includemethyl allyl trisulfide, other disulfides, and ajoene. Dosesof 300–900 mg daily of allicin content reportedly causemild reduction in total cholesterol, mild reduction inblood pressure, and appear to have favorable effects onatherosclerosis. Methyl allyl trisulfide reportedly dilatesblood vessels and causes mild reduction in blood pressure.Garlic is a component of the Mediterranean diet, whichhas been shown to reduce risk of cardiac events.1. BenefitsGarlic is beneficial in the treatment of dyslipidemia. Evidencefrom several meta-analyses, each using differentcriteria, arrived at consistent conclusions that garlic reducestotal cholesterol by approximately 10%. If this is indeedfactual, it is an impressive reduction in cholesterol judgingthat the best that a strict low-saturated fat, low-cholesteroldiet can do is only 10%. With the advent of powerfulcholesterol-reducing agents such as the statins, we are nowable to achieve 20–40% reductions. Thus, today a 10%reduction is a modest beneficial effect. Meta-analysis,however, of studies with poor methodological quality arefraught with danger.Dried garlic powder, 900 mg daily for 12 weeks,reduced blood cholesterol from 282 mg/dl to 210 mg/dl,whereas a fibrate, bezafibrate, caused a reduction from287 mg/dl to 208 mg/dl. The effect on LDL cholesteroland an increase in HDL cholesterol was similar for bothagents. Garlic also reduced elevated blood triglyceridelevels, but the effect was a little less than that observed withbezafibrate, 29% versus 42%. It appears that the constituentsof garlic can cause beneficial effects on dyslipidemiathat are similar to drugs which include fibrates.A well-designed RCT in England showed no beneficialeffects from garlic. A total of 115 men and women witha mean age of 53 years were treated with dried garlicpowder for 6 months. The pretreatment cholesterol valueswere 6–8.5 mmol/L; the trial was of sufficient size tohave 90% power to detect a difference of 0.6 mmol/L.No significant differences in lipid concentrations wereobserved between the groups in what is believed to be thebest well-run trial of garlic. A small but well-designedcrossover trial done in Australia also showed no beneficialeffects.Even standardized garlic products may contain differentquantities of allicin and therapeutic activity because ofdifferences in tablet formulation. A more standardized andtested product may have a role in cholesterol reduction,because the product does not appear to cause harm.Garlic can cause mild reduction in hypertension. Itinhibits platelet nitric oxide synthase, which is known tobe a powerful vasodilator. This results in a mild reductionin blood pressure that may be observed in individualstaking large doses (>2000 mg) of garlic powder. Theblood pressure lowering effect is so mild that it is not anadvisable strategy to use garlic. Several studies have shownno significant antihypertensive effect regardless of formulationor dose. A meta-analysis that only involved two trialswith hypertensive patients reports a systolic blood pressurereduction of 7.7 mmHg and a diastolic reduction of5 mmHg. This study had no comparison with antihypertensiveagents.Anticoagulant and antiplatelet activity are said tobe affected by garlic. The active trisulfides and disulfidesin garlic appear to inhibit thromboxane synthesis, whichconfers modest antiplatelet activity. Some constituents ofgarlic may inhibit binding of fibrinogen to platelet receptors.Dried garlic powder was shown to decrease plateletaggregation in three controlled trials, but no difference wasfollowed in 14 healthy men. Some trials indicate a modestfibrinolytic activity, but conclusive evidence is lacking.Although the effects on lipid lowering may cause beneficialeffects on the atherosclerotic process, there appears tobe a salutary effect independent of lipid lowering. Garlicprobably inhibits lipid peroxidation. The administrationof garlic for 4 years has been shown to reduce femoral andcarotid artery atheroma by 5–18%.Reportedly, a small study in India involved 432 patientswith myocardial infarction. In this study 216 patients weregiven 6–10 garlic cloves daily and the other group receiveda garlic-scented placebo. There were 45% fewer deaths anda 32% reduction in the recurrence of myocardial infarctionin patients administered garlic.

III. BENEFITS, ADVERSE EFFECTS, AND DRUG INTERACTIONS4572. Adverse Effects and InteractionsGarlic has mild antiplatelet activity and if used as a medicine(100–1000 mg), it should not be administered concomitantlywith antiplatelet agents which include aspirin,clopidogrel, and nonsteroidal anti-inflammatory agents.Garlic must be avoided in patients on anticoagulants. Theexcessive use of garlic has been observed to cause increasedpostoperative bleeding and occasionally spontaneous hemorrhagehas been reported. Garlic supplements should bediscontinued two weeks prior to surgical procedures.E. Ginger (Zingiber officinale)1. Benefits and Adverse EffectsDecreased platelet aggregation and inhibition of thromboxanesynthesis has been observed in in vitro studies, butclinical studies have not shown these effects and do notindicate beneficial or harmful effects on the cardiovascularsystem. Ginger has been advocated mainly to relievenausea and motion sickness. It is alleged to be a bloodthinner, but this claim has not been substantiated.F. Ginseng (Panax ginseng)This is a well-known herb that is used to enhance wellness.But in China, where it is believed to have been used formore than 3000 years, it is now used in the management ofheart failure, heart attack, angina, and left ventriculardiastolic dysfunction with promising results. Panax appearsto increase synthesis of nitric oxide, and this may be theexplanation for its mild antihypertensive effect. The activesubstances in P. ginseng are heterogenous triterpene saponinglycosides or ginsenosides. The species includes Asianginseng (P. ginseng), American ginseng (P. quinquefolius),and Japanese ginseng (P. japanicus). Another species isSiberian ginseng (Eleutherococcus senticosus), which is theroot of an unrelated species and does not contain the samesubstances as panax and technically is not ginseng buthas some similar effects. Ginseng, or ren shen in Mandarin,means root of man. It is so-called because the root ofthe plant has the shape of the human body. The wordginseng is derived from the Greek word for panacea.1. BenefitsGinseng is felt to be beneficial to patients suffering fromheart failure. Red ginseng, digoxin, and digoxin plus redginseng were evaluated in patients with heart failure inan open trial that showed hemodynamic improvementwith the combination. Although red ginseng was used inthe study, it is the same as white ginseng and refers toa different method of ginseng preparation. A mixture ofginseng and Chinese herbs was shown in a double-blind,placebo-controlled trial of coronary artery disease patientsto improve cardiac index and stroke volume index.A similar trial of panax plus captopril was comparedwith captopril in patients with left ventricular diastolicdysfunction. This is a condition which is extremely difficultto treat because there is no beneficial medical drugor surgical therapy available. The combination of panaxand captopril improved diastolic relaxation. Because of thisoutcome, further investigations are warranted.Red ginseng was observed to relieve hypertension bydecreasing systolic blood pressure significantly after 8 weeksof administration. Confusion has arisen because of thereported occurrence of an elevation in blood pressure insome individuals who use ginseng. This increased bloodpressure has occurred in individuals who abuse ginsengintake, and it also has been associated with the use ofSiberian ginseng, albeit rarely. As specified above, Siberianginseng is different and must not be confused with Panaxginseng.There are antioxidant effects with ginseng. It appearsto scavenge free radicals, but further studies are needed toconfirm this.2. Adverse Effects and InteractionsHypertension has been observed with overuse of ginsengand with the use of Siberian ginseng. Mild antihypertensiveeffects have been noted in small clinical trials. Maniahas been reported in a patient taking ginseng andphenelzine. Asian ginseng alone has also been associatedwith mania, albeit rarely.G. Feverfew (Tanacetum parthenium)The active substance in feverfew is parthenolide, a sesquiterpenelactone. Its other constituents include flavonoids.1. BenefitsThis herbal remedy inhibits the release of serotonin fromplatelets and leukocytes and is used mainly for migraineprophylaxis. The mild antiplatelet effect may increase

458HERBAL, DIETARY SUPPLEMENTS, AND CARDIOVASCULAR DISEASErisk of bleeding in patients administered aspirin, clopidogrel,and nonsteroidal anti-inflammatory agents. Also,interactions with anti-serotonin migraine prophylacticdrugs may occur, albeit rarely.H. Gugulipid (Commiphora mukul)Gugulipid is a naturally occurring resin produced by a treein India.1. BenefitsThe resin in gugulipid has lipid-lowering effects. In arandomized study, 125 patients were administered gugulipidand 108 were administered clofibrate. This resultedin an 11% decrease in blood cholesterol and a 17%decrease in blood triglyceride with gugulipid and 10 and22%, respectively, with clofibrate. In another study,gugulipid decreased LDL cholesterol by 15% and thetotal cholesterol ratio by 11% compared with no changein blood level in the placebo group.This resin appears to have a low adverse effect profileand is used in India. Further testing is required in RCTsto establish these modest beneficial effects that can beuseful in combination therapy with the powerful statins,which do not produce goal levels in more than 20% ofindividuals treated for dyslipidemia.I. Hawthorn (Crataegus Species)1. BenefitsHawthorn extracts from the leaves, berries, and flowersof this spiny shrub native to Europe and North Americaare one of the safer recognized herbal remedies. Europeanphysicians used the berries as a cardiotonic in the late19th century, and it is not surprising that it is a recognizedtreatment for heart failure in Western Europe. Germanstudies have confirmed that hawthorn improved shortnessof breath in patients with heart failure.Its active constituents are flavonoids and oligomericprocyanthins. These act as antioxidants with an inotropicaction which resembles that of digoxin, and are vasodilatory,anti-hyperlipidemic, and increase hepatic LDL receptoractivity. A moderate degree of angiotensin-convertingenzyme (ACE) inhibition has been reported (see thechapter Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers).Hawthorn is a cardiotonic agent used by patients mainlyfor heart failure. Clinical trials indicate that hawthorndecreases symptoms of heart failure and appears toimprove cardiac performance. In an open trial of morethan 1000 patients ejection fraction increased and arrhythmiasdecreased, but in a recent study arrhythmias wereaggravated. This herbal medicine appears to have somebeneficial effects in patients with mild heart failure(New York Heart Association class II). Improvement inexercise tolerance and decrease in shortness of breath havealso been noted. The RCTs, however, have been of shortduration; less than 8 weeks. A recent RCT compared atwice-daily regimen of 450 mg or 900 mg of standardizedhawthorn extracts with diuretic treatment in patients withstable class III heart failure. After 16 weeks the 1800-mghawthorn treated group showed a significant increase inmaximal workload tolerated and a statistically significantreduction in subjective symptoms. The effect of hawthornon cardiovascular mortality in patients with class II andIII heart failure is under investigation in the Survival andPrognosis Investigation of Crataegus Extract trial.2. Adverse Effects and InteractionsSide effects of hawthorn are rare, and in one RCT theyoccurred more often in the placebo group. Becausehawthorn has inotropic effects that increase myocardialcontractility, it should not be used concurrently withdigoxin, even though the claim that hawthorn potentiatesdigoxin has not been substantiated. No drug interactionshave been reported, and this is reassuring.J. Horse Chestnut Seed (Aesculushippocastanum)The active substance in horse chestnut seed is aescin.1. BenefitsIn Germany, horse chestnut seed extract has been approvedfor the management of chronic venous insufficiency ofthe lower limbs which causes swelling and fluid retentionin the legs. Placebo-controlled trials reported lower limbextremity volume and circumference as well as decreasedleg pain and itching.2. Adverse EffectsNausea and headache were the most common adverseeffects. One reported case of hepatitis was seen, and withmixed preparations a lupus-like syndrome has beenobserved.

III. BENEFITS, ADVERSE EFFECTS, AND DRUG INTERACTIONS459K. Hellebore (Veratrum)1. Benefits and Adverse EffectsThe veratrum alkaloids are known to be mild antihypertensivesubstances, but their use was discontinuedbecause of a high incidence of nausea and vomiting. Theseproducts may also cause arrhythmias and may interactwith digoxin. Bradycardia and hypotension have alsobeen reported in individuals who accidentally ingestedhellebore they mistook for gentian used to producegentian wine.L. Kava (Piper methysticum)Kava has been used extensively in the South Pacific sinceancient times and is incorporated in a beverage calledSakau. Kava, a member of the black pepper family, is apopular herb in the United States. Its active constituentsare kava pyrones, which appear to cause modest inhibitionof cyclooxygenase and thromboxane synthase.1. Benefits and Adverse EffectsThere are no cardiovascular claims, but in a small studyHDL cholesterol appeared to be higher in users of thisherb. Kava certainly causes some degree of relaxation andunlike tranquilizers, it does not affect mental alertness orcause the hangover produced by alcohol. It may, however,cause pulmonary hypertension and hepatitis. Interactionsoccur with tranquilizers including alprazolam, and comamay be induced in patients on other benzodiazepines.M. L-Arginine1. Benefits and Adverse EffectsL-Arginine is metabolized to nitric oxide, a known vasodilator.A Mayo Clinic trial indicated that L-arginine 9 gdaily improved coronary blood flow response to acetylcholineby 150% and caused a modest decrease in chest painand angina in patients with coronary artery disease.Further studies are required. There has been a rapid developmentin the use of L-arginine and the substance is nowavailable in nutritional bars. Foods high in arginine includealmonds, walnuts, peanuts, soybeans, gelatin, chocolate,dairy products, and green peas. Individuals with viralinfections such as herpes should not take supplementalarginine.N. Linoleic Acid1. Benefits and Adverse EffectsConjugated linoleic acid has been advertised as a compoundthat can cause weight loss, combat atherosclerosis,and assist with the control of type 2 diabetes. These claimsare not justified by clinical trials.O. Licorice1. Benefits and Adverse EffectsThis substance is used mainly as a sweetening agent. Noparticular cardiovascular benefits from licorice have beenadvocated. Cardiovascular adverse effects have been notedto include significant hypertension, hypertensive encephalopathy,edema, and heart failure. Damage to the heartmuscle causing dilated cardiomyopathy has also beenreported.P. St. John’s Wort1. Benefits and Adverse EffectsNo particular cardiovascular benefits have been claimed,but significant adverse effects have been documented andwell-recognized for St. John’s wort. Severe elevation ofblood pressure and hypertensive crisis have been noted. Anelevation of systolic blood pressure systolic to 210 anddiastolic blood pressure to 140 mmHg were reported inpatients who drank red wine and ate aged cheese the daybefore. St. John’s wort has monoamine oxidase inhibitingproperties and tyramine-rich foods should be avoided.Interactions with St. John’s wort are common. The herbinduces an increase in cytochrome P3A4, a hepatic enzymethat is active in drug metabolism, and increases the ratemetabolism of warfarin, cyclosporine, and a number ofanesthetic agents. The blood-thinning, anticoagulant effectof warfarin is decreased and interactions occur with statinsand cyclosporine. Acute rejection in two heart transplantpatients occurred because St. John’s wort reduces bloodlevels of cyclosporine and decreases digoxin blood levelsmore than 25%.Q. Yohimbine (Pausinystalia yohimbe)1. Benefits and Adverse EffectsNo cardiovascular benefits have been advocated, butcardiovascular adverse effects do occur. The active substanceof yohimbine is a competitive alpha-2-antagonistthat increases central sympathetic outflow and raises blood

460HERBAL, DIETARY SUPPLEMENTS, AND CARDIOVASCULAR DISEASEpressure, heart rate, and norepinephrine levels. Hypertensivepatients may observe seriously elevated blood pressureand arrhythmias. This compound antagonizes the effectsof centrally acting antihypertensive agents such as clonidine,guanabenz, and methyldopa.R. Other Natural ProductsBelladonna is a source of atropine and may cause tachycardia.Beta-carotene (provitamin A) has been shown tohave no significant beneficial cardiovascular effects in largestudies. The Physician’s Health Study randomized 22,071males in the United States to aspirin 325 mg daily or betacarotene50 mg every other day. After 12 years there were nocardiovascular benefits from beta-carotene administration.a. GrapefruitThe main constituent of grapefruit juice, naringeninis metabolized by the CYP450 metabolic pathway andinteracts with drugs that use the pathway. These agentsinclude calcium antagonists such as amlodipine, fluoxetine,sildenafil (Viagra), cyclosporine, statins (except pravastatinand rosuvastatin), metoprolol, and propranolol.Flavonoids are a class of natural polyphenolics found inplants, vegetables, fruits, and beverages of plant origin,such as tea and wine.Zitron et al. have found numerous different flavonoidcompounds in grapefruit juice that block cardiac HERGchannels. These investigators studied pink grapefruit whichhas a high concentration of naringenin. They showed thatnaringenin caused significant prolongation of the QTcinterval, and the effect is more potent than other flavonoidstested. The investigators claim that ‘‘we are the firstto show direct effects on the ECG by dietary compounds.Furthermore, we have demonstrated for the first time thatflavonoids act as specific antagonists of cardiac potassiumchannels.’’b. Purple Grape JuicePurple grape juice has been shown to decrease plateletaggregation, increase platelet-derived nitric oxide release,and decrease superoxide production. In a small study of 20healthy subjects whose average age was 30 years, a 14-dayconsumption of grape juice resulted in suppression ofplatelet-mediated clot formation (thrombosis). This effectis independent of alcohol consumption. The major polyphenoliccompounds isolated from purple grape juiceinclude cinnamic acids, anthrocyanins, flavonols, (quercetin),and polyflavan-3-ols.c. OthersBlack tea consumption has been shown to reverse endothelialor vasomotor dysfunction in patients with cardiacdisease. This modest beneficial effect is believed to be dueto the antioxidant effects of flavonoids.Several natural products increase digoxin blood levels orpotentiate its actions. These include hawthorn, oleander,black hellebore, adonis, black Indian hemp, lily of the valley,squill, strophantus, milkweed, kushen, and Siberian ginseng.IV. SUBSTANCES USED BY ATHLETESMany athletes may indicate that they are not takingmedications and fail to recognize that herbal preparationsand dietary supplements may contain prohibited substancesthat are cardiovascular stimulants. Substancescommonly used by athletes include ephedra alkaloids(e.g., Ma Hung or ephedrine) and guarana (caffeine).Adverse effects include arrhythmias and catecholaminecardiomyopathy.Anabolic steroids containing androstenedione or androstenediolmay cause left ventricular hypertrophy. Thesetwo compounds are precursors to testosterone andestrogen. Cases of sudden death have been reported inathletes using anabolic steroids. A catecholamine cardiomyopathymay be a dangerous complication. Dickermanet al. reported that 100% of athletes using anabolicsteroids had a left ventricle wall thickness greater than 11mm. These substances may cause hypertension anddyslipidemia.Creatine has been shown to enhance muscle growth andincrease strength without the side effects of the anabolicsteroids. This agent increases muscle mass in active athleteswho engage in intense isometric training, but not in thoseare who trained aerobically. No major side effects havebeen observed. Weight gain may occur during the first twoweeks of therapy.Gamma butyrolactone has been eliminated fromproducts in the United States because of an FDA warningin 1999 to manufacturers. This warning was made becausethere was a report of more than 55 cases of adversereactions including coma that required artificial ventilatorysupport. The coma occurred in a professional basketballplayer who ingested the substance to aid in sleep and helpmuscle growth. Gamma butyrolactone is metabolized into

IV. SUBSTANCES USED BY ATHLETES461gamma-hydroxybutyrate, which is known to cause seizuresand coma.BIBLIOGRAPHYAppeldoorn, C. C. M., Bonnefoy, A., Lutters, B. C. H. et al. Gallic acidantagonizes P-selectin–mediated platelet–leukocyte interactions:Implications for the French paradox. Circulation, 111:106–112, 2005.Bove, A. A. Dietary supplements in athletes. J. Am. Coll. Cardiol. ACCCurr. J. Rev., January/February, 18–20, 2002.DeSmet, P. A. G. M. Herbal remedies. Review article. N. Engl. J. Med.,347:2046–56, 2002.Dickerman, R. D., Schaller, F., and McConathy, W. J. Left ventricularwall thickening does occur in elite power athletes with or withoutanabolic steroid use. Cardiology, 90:145–148, 1998.Freedman, J. E., Parker, C., Li, L. et al. J. Am. Coll. Cardiol. Acc Curr. J.Rev., January/February, 28, 2002.Khan, M. Gabriel Drug interactions. In Cardiac Drug Therapy. 6ed,W.B. Saunders, 2003.Moss, A. J., Schwartz, P. J. et al. 25th Anniversary of the internationallong-QT syndrome registry: An ongoing quest to uncover the secrets oflong-QT syndrome. Circulation, 111:1199–1201, 2005.Sacks, F. M. et al. Dietary phytoestrogens to prevent cardiovasculardisease: Early promise unfulfilled. Circulation, 111:385–387, 2005.Szmitko, P. E., Verma, S. et al. Red wine and your heart. Circulation,111:e10–e11, 2005.Valli, G., and Giardina, E-G. V. Benefits, adverse effects and druginteractions of herbal therapies with cardiovascular effects. J. Am. Coll.Cardiol., 39:1083–95, 2002.Zitron, E., Scholz, E., Owen, R. W. et al .QTc prolongation by grapefruitjuice and its potential pharmacological basis: HERG channel blockadeby flavonoids. Circulation, 111:835–838, 2005.

HIV and the HeartI. IncidenceII. Cardiac Complications of AidsGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiomyopathy heart muscle disease.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60–75%; a lowejection fraction is less than 40%; often used as a marker ofleft ventricular contractility.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.infective endocarditis infection of the endocardial lining ofheart valves with microorganisms.myocarditis damage to the heart muscle caused by microorganismsor autoimmune and other undefined processes.pericardial effusion excess fluid within the pericardial sac.pericardium a membranous sac surrounding the heart consistingof an outer fibrous layer and an inner serosal layer whichare separated by a thin film of pericardial fluid in thepericardial sac.syncope transient loss of consciousness by lack of blood supplyto the brain; fainting describes a simple syncopal attack.ventricular dysfunction poor contractility of the ventricle usuallycausing a decrease in ejection fraction.SIGNIFICANT CARDIAC DISEASE OCCURS INpatients with the human immunodeficiency virus (HIV),and it is believed that in the next decade acquired immunodeficiencysyndrome (AIDS) will be one of the leadingcauses of acquired heart disease.I. INCIDENCESignificant heart disease occurs in approximately 5%of people with AIDS. In an autopsy series 18% of440 patients had cardiac involvement. In 1998, theJoint United Nations program on AIDS estimated thatapproximately 34 million people were living with HIVinfection worldwide. In the United States new infectionhas decreased significantly over the past four years anddeaths associated with HIV infection decreased approximately25% from 1997 to 1999 because of improvedantiretroviral therapies and the management of opportunisticinfections. Other workers estimate that approximately60 million adults and 10 million children arecurrently infected with the virus worldwide. These patientsare expected to live longer because of improved therapiesand control of opportunistic infections. This will resultin what may be an epidemic of HIV-related heart disease.The mean annual incidence is estimated at approximately16 cases of cardiac disease per 1000 HIV-infected patients.HIV infections were mainly observed in homosexual malesduring the early years of the HIV epidemic; new casescontinue to occur in IV drug users and heterosexualpartners of infected persons.II. CARDIAC COMPLICATIONS OF AIDSA. Pericardial EffusionPericardial disease is the most common cardiac complicationof HIV infection and it causes approximately 60%of all cardiac pathology. Figure 1 shows HIV cardiaccomplications. Approximately 5% of individuals infectedwith HIV show echocardiographic evidence of pericardialeffusions. In more than 75% of cases pericardial effusionsare small and usually asymptomatic, but they indicateadvanced disease and poor prognosis. Pericardial effusionsmay compress the heart, cause cardiac tamponade, andprevent adequate filling which results in a marked fall inblood pressure, cardiogenic shock, and death. In approximately30% of patients the effusion resolves spontaneously.The disease of the pericardium may be caused by thefollowing types of infections.1. Viruses: cytomegalovirus (CMV), HIV, herpes simplex2. Bacterial: Staphylococcus aureus, Streptococcus pneumoniae,Klebsiella pneumoniae, mycobacteria3. Fungi: Cryptococcus neoformans463

464HIV AND THE HEARTPericardial effusionCardiac tamponadeLeft ventricular dysfunctionEF < 45%HIVCARDIACCOMPLICATIONSHeart failureDilated cardiomyopathyMyocarditisInfective endocarditisPulmonary hypertensionFIGURE 1HIV cardiac complications.MalignancyMyocardial kaposis sarcomaB-cell immunoblasticlymphoma4. Neoplastic involvement: malignant lymphoma;Kaposi’s sarcoma may involve both the pericardiumand epicardial fatThe first case of cardiac involvement was reportedin 1983 in a 24-year-old Haitian woman with extensiveKaposi’s sarcoma that involved the entire anterior wall ofthe heart muscle.B. Myocarditis and Left ventricular SystolicDysfunctionWeakness of the muscle of the left ventricle with leftventricular systolic dysfunction is common and results indilated cardiomyopathy and heart failure (see the chapterCardiomyopathy). A five-year prospective clinical andechocardiographic study of asymptomatic HIV-positivepatients with CD4 counts greater than 400 defined theincidence of dilated cardiomyopathy as 16 cases perthousand patients. The incidence rate is higher in thosepatients with CD4 counts less than 100 cells/ml 4 .From 1998 to 2000, of the estimated 70 million peopleworldwide infected with HIV with an incidence of heartfailure of 10% over 2 years, there would be approximately7 million cases of heart failure during a 2-year interval dueto AIDS. Left ventricular dysfunction occurs in about 6%of infected children.The pathogenesis of myocarditis may be a result ofprimary infection with HIV or organisms such as CMV,Coxsackie virus, and a host of other microorganisms, orthe reactivation of latent infections.C. Other ComplicationsThese include infective endocarditis that is more commonin IV drug users with the infecting organisms S. aureusand salmonella. In the later stages of HIV malignancyoccurs. This takes the form of Kaposi’s sarcoma whichis linked with human herpesvirus 8 and mainly affectsHIV homosexuals (35%). Pulmonary hypertension andstroke may occur. Unexplained syncope or cardiac tamponadein younger individuals should alert the search forHIV infection.BIBLIOGRAPHYAutran, B. R., Gorin, I., Leibowitch, M. et al. AIDS in the Haitianwoman with cardiac Kaposi’s sarcoma and Whipple’s disease. Lancet,1:767–68, 1983.Barbaro, G., Di Lorenzo, B. G., Grisorio, B. et al. Incidence of dilatedcardiomyopathy and detection of HIV in myocardial cells of HIVpositive patients. N. Engl. J. Med., 339:1093, 1988.Barbaro, G. et al. Cardiovascular manifestations of HIV infection.Circulation, 106:1420–1425, 2002.Gisselwquist, D. et al. HIV transmission through health care in sub-Saharan Africa. Lancet, 364:2004.Heidenreich, P. A., Eisenberg, M. J., Kee, L. L. et al. Pericardialeffusion in AIDS: Incidence and survival. Circulation, 92:3229,1995.Lipshultz, S. E., Easley, K. A., Orav, E. J. et al. Cardiac dysfunction andmortality in HIV-infected children: The prospective P2C2 HIVMulticenter study. Circulation, 102:1542–1548, 2000.UNAIDS: Report on the Global HIV/AIDS Epidemic. Geneva,Switzerland. UNAIDS, June 1998.

Homocysteine and Cardiovascular DiseaseI. Homocysteine MetabolismII. Homocysteine and Vascular DiseaseIII. Clinical StudiesIV. Conditions Causing HyperhomocystinemiaV. ScreeningVI. Management of HyperhomocystinemiaVII. Benefits of Decreasing Homocysteine LevelsVIII. Clinical StudiesGLOSSARYatheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).endothelial pertaining to the innermost part of the intima thatcomes in contact with circulating blood.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.HYPERHOMOCYSTINEMIA HAS BEEN IDENTIFIED ASa possible risk factor in the development of cardiac,cerebral, and peripheral vascular disease as well as acutethrombotic events. Unfortunately this assumption is basedmainly on the results of case control studies andprospective studies have not been as compelling. Inaddition, there is growing belief that atheromatous diseaseof arteries itself may elevate homocysteine levels, and thatthis controversial risk factor is only a silent bystander andshould be considered a marker rather than a true riskfactor.I. HOMOCYSTEINE METABOLISMHomocysteine, a sulfa-containing amino acid, is an intermediateformed during the metabolism of the essentialamino acid methionine. In this metabolic pathway,methionine is demethylated to yield adenosine and homocysteine.In a reaction requiring the vitamin B6-dependentenzyme cystathionine, beta-synthase homocysteine becomesirreversibly transsulfurated to cysteine. In addition, homocysteinecan be remethylated back to methionine in apathway that utilizes vitamin B12-dependent methioninesynthase.II. HOMOCYSTEINE AND VASCULARDISEASEEpidemiologic studies suggest that hyperhomocystinemiamay be an independent risk factor for developing atherothromboticvascular disease. Although the mechanism foraccelerated atherosclerosis is unclear, proposed mechanismsfor increased risk of coronary artery disease includeendothelial dysfunction and toxicity, induction of vascularsmooth muscle cell proliferation, impairment of nitricoxide, increased LDL oxidation, and enhanced thrombosis.Hyperhomocystinemia has not been shown in animalsor in humans to cause atheroma formation, which leads toobstructive lesions in coronary arteries, cerebral arteries,the aorta, or vessels leading to the legs. Pathologic lesions inarteries of experimental animals indicate disease diffuselyinvolves the outer layer, the adventitia and the media withlittle involvement of the intima and without the formationof segmental atheromatous obstructive lesions. The lesionhas a more arteriosclerotic nature rather than atherosclerotic(see the chapters Arteriosclerosis and Atherosclerosis/Atherothrombosis).III. CLINICAL STUDIESA. Willems et al.Study question: The mechanism responsible for anincreased risk for coronary artery disease is unclear; itis generally assumed that hyperhomocystinemia causesendothelial dysfunction. It is unknown whether plasmahomocysteine levels improve coronary endothelial function465

466HOMOCYSTEINE AND CARDIOVASCULAR DISEASEin patients with hyperhomocystinemia and symptomaticcoronary heart disease. This study evaluated the effect ofthe administration of folic acid and vitamin B12 oncoronary endothelial function.Methods: There were 15 patients scheduled for ballooncoronary angioplasty with plasma homocysteine levelsgreater than 16 mmol/L who were randomized for sixmonths of treatment with folic acid 5 mg, cobalamin400 mg daily, or placebo. Coronary endothelial functionwas evaluated in a noncoronary vessel using acetylcholineinfusion.Results: In the folic-acid-treated group coronary bloodflow increased 96% after acetylcholine infusion whencompared with a decrease of 16% of the coronary bloodflow in the placebo-treated group( p ¼ 0.005).Conclusions: This study suggests that coronary endothelialfunction improves after treatment with folic acidand cobalamin. It is unclear, however if the salutary effectobserved bears any relation to atheroma formation and itsprogression to thrombotic events.B. Schnyder et al.Study question: This study was to evaluate a possiblerelationship between homocysteine levels and late outcomeafter successful percutaneous coronary intervention (PCI).Methods: Included were 549 patients after successfulPCI of at least one coronary stenosis with cardiac death,nonfatal myocardial infarction (MI), target lesion revascularization(TLR), and a composite of major adverse cardiacevents (MACE). Their homocysteine levels were assessed.Results: At 58 weeks’ follow up there were 6 cardiacdeaths, 14 with new MI; 71 required repeat TLR. Therewas a graded relationship between homocysteine levels andfreedom from MACE (p ¼ 0.01). Homocysteine levels wereassociated with cardiac death (14.9 1.7 mmol/L vs. 9.6 4.3 mmol/L; p < 0.005), TLR (10.7 4.4 mmol/L vs. 9.5 4.3 mmol/L; p < 0.05), and MACE (11.0 4.4 mmol/Lvs. 9.4 4.3 mmol/L; p < 0.005). These findings wereunchanged after adjustment for potential confounders.Conclusions: Homocysteine levels are an independentpredictor of mortality, nonfatal MRI, TLR, and overalladverse late outcome after successful PCI. The study resultsappear compelling, but there is growing belief that atheromatousdisease itself can cause elevated homocysteinelevels. In this prospective study, however, the associationbetween the homocysteine levels and outcome after PCIwas independent, although with traditional risk factors.Thus, elevated homocysteine levels appear to be just amarker rather than a risk factor for coronary artery disease.There is little doubt that this statement does not apply tothe problem of restenosis.IV. CONDITIONS CAUSINGHYPERHOMOCYSTINEMIAA. Medical ConditionsHomocysteine levels have been noted to increase soonafter an acute MI or stroke along with occurrence of theconditions listed below.Renal failureHypothyroidismSome forms of cancerInflammatory bowel diseaseRheumatoid diseasePsoriasisThe post-transplant stateVitamin B12 deficiencyFolate deficiencyMTHFR gene deficiency.A polymorphism in the MTHFR gene results in athermolabile enzyme associated with elevated homocysteinelevels. The prevalence of this mutation is low inAsian-Indians and Africans ranging from 0 to 2% vs. 10 to20% in other populations.B. MedicationsSeveral medications can cause elevation of homocysteinelevels. These include drugs that interfere with the:functional vitamin B6: niacin, theophylline, isoniazidfunctional vitamin B12: cholestyramine, colestipol,metforminfunction of folate: anticonvulsants, methotrexate.C. Lifestyle BehaviorsLifestyle behaviors that increase homocysteine levels areheavy alcohol consumption, excessive coffee consumption,cigarette smoking, and physical inactivity.V. SCREENINGScreening recommendations for hyperhomocystinemiaremain controversial and diverse. The lack of evidencesubstantiating clinical benefit of treatment of hyperhomocystinemiaas well as unnecessary laboratory costs arepotent arguments against recommending widespreadscreening.

VII1. CLINICAL STUDIES467A. American Heart AssociationRecommendationThe American Heart Association does not recommendpopulation screening. They do suggest, however, that screeningmay be useful in certain high-risk patients with conditionsknown to be associated with hyperhomocystinemia.0.5–5 mg taken daily, reduce homocysteine levels 25–30%.Multivitamins containing 400 mg of folic acid can causea similar reduction. The addition of vitamin B12 tofolic acid supplementation may reduce levels a further 7%.Also vitamin B6 intake can cause some reduction inhomocysteine levels.B. European International Task ForceRecommendationThe European International Task Force for the Preventionof Coronary Heart Disease recommends the measurementof homocysteine in patients with premature coronaryartery disease or stroke in the absence of the wellestablishedvascular risk factors. This appears to be areasonable approach in young individuals with stroke priorto age 45 caused by cerebral thrombosis (intracerebralhemorrhage and subarachnoid hemorrhage should beexcluded) and in patients with acute myocardial infarctionprior to age 35. These ages are selected by the author toclarify the above recommendations, because at this agethese conditions are rare as strokes usually occur after age55 in men and women and heart attacks commonly occurin men after age 40 and women after age 60.C. Canadian Task Force RecommendationThe Canadian Task Force on Preventive Health Careindicates that there is insufficient evidence to recommendscreening for homocysteine levels in any patientpopulation.D. Normal and Abnormal HomocysteineLevelsNormal homocysteine blood levels that range from 5 to15, 16 to 30, 30 to 100 and greater than 100 mmol/L aredescribed as mild, intermediate, and severe elevations,respectively. Women appear to have levels 1 mmol/L lessthan men; values increase with age in both sexes.VI. MANAGEMENT OFHYPERHOMOCYSTINEMIAA. Folic Acid IntakeA diet rich in folic acid and vitamins B12 and B6 mayreduce levels by approximately 10%. Folic acid tablets,VI1. BENEFITS OF DECREASINGHOMOCYSTEINE LEVELSUnfortunately no benefit to cardiovascular mortality ormorbidity has been observed in randomized clinical trials,except in patients who had successful coronary angioplasty.A modest decreased rate of coronary restenosis followingcoronary angioplasty has been noted after lowering ofplasma homocysteine levels, but this requires confirmationthat is unlikely to be forthcoming.In a sound crossover study, however, optimization ofdietary folate or low-dose folic acid supplements loweredhomocysteine levels, but they did not enhance endothelialfunction in healthy adults, irrespective of the MTHFR C677T genotype.VII1. CLINICAL STUDIESIn a meta-analysis of predominantly case control studies,14 of 17 papers supported the link between elevatedhomocysteine and an increase risk for vascular disease.Although these data appear impressive, there are severallimitations to case control studies and the data fromprospective studies are not convincing.Because homocysteine levels increase after acute myocardialinfarction and stroke, it makes case control studiesless useful. The overabundance of hypothesized clarificationsof homocysteine-induced cardiovascular diseasereflects the lack of a proven unified mechanism of vascularinjury.Although homocysteine levels can be successfullyreduced by folic acid administration, no benefit towardcardiovascular morbidity or mortality has been observedin randomized trials.A. The Recent FACIT Trial; Lange et al.A recent randomized clinical trial showed that folatetherapy increases restenosis rates in intracoronary stentrecipients. The folate therapy after coronary intervention

468HOMOCYSTEINE AND CARDIOVASCULAR DISEASE(FACIT) trial enrolled 636 patients who underwentsuccessful coronary stenting and were randomized toreceive supplemental treatment with folate and vitaminsB6 and B12. The trial investigated whether folate therapy,which is known to reduce high blood levels of homocysteine,can limit in-stent restenosis. After 6 months offollow up, folate therapy caused a significantly smallerminimum lumen diameter as well as higher restenosis andmajor adverse cardiac event rates; folate therapy shouldtherefore be avoided following coronary stent implantation.Contrary to previous findings, the administration offolate, vitamin B 6 , and vitamin B 12 after coronary stentingmay increase the risk of in-stent restenosis and the need fortarget-vessel revascularization.B. Toole et al.: The Vitamin Interventionfor Stroke Prevention (VISP) RandomizedControlled TrialObjecctive: To determine whether high doses of folic acid,pyridoxine, and vitamin B 12 administered to decreasehomocysteine levels reduce the risk of recurrent strokecompared with low doses of these vitamins.Methods: In this study 3680 adults with disablingcerebral infarctions were randomized to high- and lowdoseformulations of these vitamins.Results: At the end of two years a moderate reductionof total homocysteine had no effect on vascular outcomes.BIBLIOGRAPHYBrattström, L., Wilcken, D. E. L., Öhrvik, J. et al. Commonmethylenetetrahydrofolate reductase gene mutation leads tohyperhomocysteinemia but not to vascular disease: The result of ameta-analysis. Circulation, 98:2520–2526, Dec. 1998.Fruchart, J. C., Nierman, M. C., Stroes, E. S. G., Kastelein, J. J. P.,Duriez, P. et al. New risk factors for atherosclerosis and patient riskassessment. Circulation, 109:III-15–III-19, Jun. 2004.Hoogeveen, E. K., Kostense, P. J., Jakobs, C., Dekker, J. M., Nijpels, G.,Heine, R. J., Bouter, L. M., Stehouwer, C. D. A. et al.Hyperhomocysteinemia increases risk of death, especially in typeII Diabetes: 5-Year follow-up of the Hoorn study. Circulation,101:1506–1511, Apr. 2000.Lange, H., Suryapranata, H., De Luca, G. et al. Folate therapy andin-stent restenosis after coronary stenting. N. Engl. J. Med., 350:2673–2681, 2004.Pullin, C. H., Ashfield-Watt, P. A. L., Burr, M. L. et al. Optimization ofdietary folate or low-dose folic acid supplements lower homocysteinebut do not enhance endothelial function in healthy adults, irrespectiveof the methylenetetrahydrofolate reductase (C677T ) genotype. J. Am.Coll. Cardiol., 58:1799–805, 2001.Ridker, P. M., Brown, N. J., Vaughan, D. E., Harrison, D. G., Mehta, J. L.et al. Established and emerging plasma biomarkers in the predictionof first atherothrombotic events. Circulation, 109:IV-6–IV-19,Jun. 2004.Rodriguez, J., and Robinson, K. Homocysteine: Do we know how toscreen and treat? J. Am. Coll. Cardiol. ACC Curr. J. Rev., May/June,31–34, 2001.Schnyder, G., Flammer, Y., Roffi, M. et al. Plasma homocysteine levelsand late outcome after coronary angioplasty. J. Am. Coll. Cardiol.,40:1769–76, 2002.Schnyder, G., Roffi, M., Pin, R. et al. Decreased rate of coronaryrestenosis after lowering of plasma homocysteine levels. N. Engl. J.Med., 345:1593–600, 2001.Toole, J. F., Malinow, M. R., Lloyd, E. C. et al. Lowering homocysteinein patients with ischemic stroke to prevent recurrent stroke,myocardial infarction, and death. The vitamin intervention forstroke prevention (VISP) randomized controlled trial. JAMA, 291:565–575, 2004.Willems, F. F., Aengrvaeren, W. R. M., and Boers, G. H. J. Coronaryendothelial function in hyperhomocystinemia: Improvement aftertreatment with folic acid and cobalamin in patients with coronaryartery disease. J. Am. Coll. Cardiol., 40:766–72, 2002.

HypertensionI. Measurement of Blood PressureII. How High Is High?III. Causes of HypertensionIV. Pathogenesis of Primary Essential HypertensionV. ComplicationsVI. SymptomsVII. InvestigationsVIII. Nondrug TreatmentIX. Drug TreatmentGLOSSARYafterload arterial impedance, restriction to blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of ventricular wallstress.atherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence, the termatherosclerosis (sclerosis ¼ hardening).heart failure a failure of the heart to pump sufficient bloodfrom the chambers into the aorta, inadequate supply of bloodreaches organs and tissues.hypertrophy increase in thickness of muscle.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.renoprotection protection of the nephrons of the kidney fromdamage, destruction, and amelioration of albuminuria.generally very few symptoms associated with high bloodpressure. Dizziness and headaches may occur in somepatients but generally health complaints may not surfacefor 5–20 years, thus the term ‘‘the silent killer.’’Blood pressure is the pressure exerted by the bloodagainst the inner walls of the blood vessels, especially thearteries (see the chapter on Blood Pressure). The bloodpressure changes from minute to minute and is influencedby many factors such as activity, age, health, emotionaltension, and so on. With each heartbeat, about 70 ml ofblood is ejected from the heart and propelled throughapproximately 100,000 km of blood vessels. Constrictionof the blood vessels (arteries) causes high blood pressureand greatly increases the work of the heart. Arteries aretraumatized by high blood pressure and this increasesthe development of hardening of the arteries owing toplaques of atheroma (atherosclerosis). The heart mayenlarge, arteries may become gradually blocked, andcirculation to the heart muscle, the brain, and otherorgans may slowly become impaired until one day therewill be an emergency situation such as a sudden heartattack or stroke. It is true that hypertension maims andkills millions through preventable complications.Clinical trials during the past 20 years have revolutionizedthe treatment of hypertension with and withoutdrugs. Many familiar (old) drugs have been renderedobsolete because of newer, safer, and more effectivealternatives.Safe and effective treatment is available either withnondrug programs or with a suitably selected drug. Drugselection is important and is discussed in some detail in thefollowing sections.HYPERTENSION, COMMONLY KNOWN AS HIGHblood pressure, is a problem suffered by more than60 million people in the United States from the age of 65to 75.The incidence of hypertension is higher in African-Americans. There are approximately 1 billion individualswith hypertension worldwide.The complications of high blood pressure often leadto early death or serious physical handicaps. There areI. MEASUREMENT OF BLOOD PRESSUREThe instrument used to measure blood pressure is calleda sphygmomanometer. It measures the air pressure neededto raise a column of mercury (Hg). The instrument consistsof an inflatable cuff connected to a small bulb pump anda pressure gauge. By means of the inflatable cuff, whichencircles the limb (usually the upper arm), air pressure469

470HYPERTENSIONwithin the cuff is balanced against the pressure in the artery(usually the brachial artery at the elbow). The pressure isestimated by means of a mercury or aneroid manometer.The mercury manometer is the most accurate pressuregauge. The aneroid gauge is frequently used instead of themercury manometer because it is more compact and isconvenient as a portable instrument. Some electronicinstruments may give falsely high diastolic readings,but manufacturers will improve these to meet marketdemands.The cuff size of the sphygmomanometer is of greatimportance. If the cuff is too small for the patient’s arm,the blood pressure reading may be falsely high. In this casesome moderately obese patients may be falsely classifiedas hypertensives if a normal cuff is used. A regular cuffmay be used for arm circumference of less than 33 cm.A large cuff should be used whenever the mid-upper armcircumference exceeds 33 cm. The cuff must be appliedsnugly. To measure blood pressure, the cuff is wrappedaround the arm about one inch above the elbow crease.Ask your doctor or nurse to show you how to take yourown blood pressure. Occasionally both the radial pulseat the wrist and the brachial pulse at the elbow over whichthe stethoscope is placed are difficult to feel.The patient should be lying or sitting comfortably. Theforearm should rest on a comfortable support such as atable at near heart level. If the arm is not well supported,muscle contractions will falsely elevate the blood pressure.Apply the cuff so that the arrow or mark on the cuffis directly in line with the brachial artery (see Fig. 1). Thearrow on the edge of the cuff is then approximately oneinch above the point of application of the stethoscope.Feel the radial pulse at the wrist. Close the valve of theinstrument and hold the bulb in the right hand betweenthe palm and fingers. Squeeze the bulb rapidly and fully.Continue squeezing the bulb several times to pump airinto the cuff. The air pressure will at some point stop theblood flow through the brachial and radial arteries. Rapidinflation avoids trapping of blood in the veins of theforearm. As the cuff is inflated the radial pulse at the wristwill disappear. Keep on pumping so that the manometerpressure is increased by another 20–30 mmHg. Thengradually open the valve, decreasing the pressure slowlyat a rate of about 2 mm per second until you can just feel theradial pulse. Note the reading in millimeters of mercury(mmHg). This is the systolic blood pressure by palpation.To obtain the blood pressure using a stethoscope, if yoursystolic blood pressure is usually 140 mmHg, pump thecuff up to a pressure on the gauge of 170, then put thestethoscope on the brachial artery (position as indicatedin Fig. 1), then slowly release the air. Suddenly thuddingFIGURE 1Measurement of blood pressure.sounds are heard, which are impossible to miss if the roomis quiet and the stethoscope earpieces are fitting snugly.The sounds are produced by the blood being pushed byeach heartbeat through the artery previously blocked bythe air pressure. The air pressure recorded by the gauge inmmHg at which you first hear the sounds is the systolicblood pressure. These thudding sounds produced by bloodmovement and vessel vibrations are called Korotkoff’ssounds, as described by Dr. Nicolai Korotkoff in 1910 (seethe chapter Blood Pressure). Further decrease the airpressure until all sounds just disappear and take thereading from the gauge as the diastolic blood pressure.Record, for example, as follows: systolic 140, diastolic 80,or 140/80.It is important to center the arrow on the cuff andplace the stethoscope directly over the brachial artery.Your doctor can work out the line of the artery for you.The tendon of the biceps can be felt in the crook ofthe elbow and the artery is about 1 cm off-center, medialto the biceps tendon, that is, nearer the body. Place thestethoscope in the crook of the elbow just to the inside ofthe middle of your forearm. It can be helpful to tape thestethoscope’s diaphragm to the elbow if you are measuringyour own blood pressure. If you wish to repeat the bloodpressure reading, you must completely deflate the cuff

III. CAUSES OF HYPERTENSION471and wait 60 seconds; otherwise, congestion of blood inthe veins of the arm can cause subsequent diastolic readingsto be falsely high.Occasionally it may be necessary to take blood pressureboth while lying down and standing, especially if thepatient is on medication. Some antihypertensive drugscause the blood pressure to drop suddenly when thepatient stands, and this is called postural hypotension.In some patients over 65 years of age, markedly hardenedvessels may require higher cuff pressures to stop theblood flow through the artery. This results in falsely highsystolic pressure readings.II. HOW HIGH IS HIGH?The World Health Organization (WHO) and manyexperts agree that in individuals under age 65, a systolicblood pressure equal to or greater than 140 mmHg anda diastolic blood pressure of 90 mmHg or above is abnormal.Optimal systolic blood pressure is less than120 mmHg and optimal diastolic blood pressures are lessthan 80 mmHg. In patients age 65–80 a systolic pressuregreater than 165 on three or more readings weeks or monthsapart is considered hypertension. The Framingham Studyand other studies indicate a significant increase in cardiovascularrisk in individuals with a blood pressure in theborderline range. An individual is considered to have highblood pressure if several readings exceed 140/90, especiallyif three consecutive readings are elevated. The risk at anylevel of hypertension, including borderline hypertension, isgreatly increased by smoking or a high blood cholesterol.Mild hypertension is extremely common, and over a 10- to15-year period increases the risk of stroke, heart attack, andheart failure. Clinical studies have documented that blacksdevelop organ damage (stroke, heart failure, and damage tothe kidneys) much quicker than whites at the same level ofhypertension.Blood pressure changes from minute to minute and islowest during sleep, dropping as much as 10–30 mmHg. Itrises in the morning and usually becomes higher in theafternoon. This makes it necessary to measure the bloodpressure several times during the day and to record thetime of the measurement. An average of at least threereadings is often taken by the doctor. Blood pressureincreases to the adult level by age 16. The systolic bloodpressure tends to increase slightly after age 30. After age65, a greater increase often occurs, owing primarily tohardening of the arteries, and a falsely elevated pressuremay be recorded.A. Old convention, 1930–1996Levels used generally worldwide to indicate hypertensionin individuals under age 70, from 1930 to about 1996,were as follows: Mild hypertension: diastolic blood pressure is 91–100or systolic pressure is 140–160 Moderate hypertension: the diastolic is 100–110 orsystolic is greater than 180 Severe hypertension: the diastolic is 115–130, regardlessof the systolic pressure, and very severe if the diastolic isgreater than 130 mmHg.Prior to 1975, doctors believed that it was mainlythe high diastolic blood pressure that was dangerous. Anelevated systolic blood pressure, however, is as important asan elevated diastolic pressure. Such elevations in systolicblood pressure increase the risk of heart failure or stroke.The danger of heart failure is considerably increased ifthe patient has had a previous heart attack, heart failure,or has an enlarged heart.B. New Convention, 2003The Joint National Committee on Prevention, Detection,Evaluation, and Treatment of Hypertension, SeventhReport ( JNC 7), gives a classification and managementof blood pressure for adults (see Table 1). Individuals withan average blood pressure of more than 135/85 measuredat home are generally considered to be hypertensive.The heart rate multiplied by the systolic blood pressureis called the heart rate pressure product, and this productdetermines the oxygen requirement of the heart muscle.Elevation of the systolic blood pressure is just as badas elevation of the diastolic in the range of 95–110 mmHg.Elevation of either systolic or diastolic is important, butthe combined elevation is more common and furtherincreases the risks. Drugs that decrease both the bloodpressure and the heart rate are more effective in decreasingthe oxygen requirement of the heart muscle. Beta-blockingdrugs play a very important role in the drug treatment ofhypertension because of the aforementioned effects.III. CAUSES OF HYPERTENSIONA. Primary (Essential) HypertensionIn the majority of cases of hypertension, no detectableunderlying disease is present. There are several theoriesas to why the blood pressure may be increased. This type

472HYPERTENSIONTABLE 1Classification and Management of Blood Pressure for Adults Initial drug therapyBPClassificationSBP ammHgDBP bmmHgLifestylemodificationWithoutcompelling indicationWith compellingindicationsNormal

III. CAUSES OF HYPERTENSION473hyperaldosteronism (Conn’s syndrome), pheochromocytoma,and hyperthyroidism are all diseases of the adrenalglands and birth control pills can sometimes cause mildhypertension.Cushing’s syndrome is an excess amount of cortisoneand its derivatives that are secreted from the outer part(cortex) of the adrenal glands causing hypertension. Symptomsinclude a redistribution of fat and a typical moon facewith obesity of the trunk. The arms and legs are relativelythin and the thigh muscles often become weak. Fortunately,surgery can produce a cure.Hyperaldosteronism or Conn’s syndrome is due to asmall, benign tumor that secretes aldosterone. This hormonecauses a retention of salt and water in the body andan excretion of potassium in the urine. Thus the serumpotassium is low. The condition is rare and when diagnosedcan be cured surgically.Pheochromocytoma is a tumor in the center of the gland(medulla) that produces adrenaline (epinephrine) andnoradrenaline (norepinephrine). This tumor causes excessivesecretions and produces very severe hypertension.Fortunately, the condition is rare, only about 0.1% of allhypertensives have pheochromocytoma. This condition isimportant, however, because it is life-threatening, butwhen diagnosed, is surgically correctable. The features areoften typical. In about 50% of cases, the blood pressure isrelatively constant, and in the other 50%, the bloodpressure fluctuates with paroxysms of severe hypertensionoccurring daily, weekly, or monthly.The patient is quite well between episodes. Duringepisodes symptoms include very severe, intolerable throbbingheadaches; profuse sweating and palpitations; fear ofimpending doom; seizure-like activity or psychoneuroticspells; weight loss; and postural hypotension (theblood pressure is very high, but may fall on standing). Theblood pressure may be normal for several days or monthsand then suddenly rise to levels of 190–300 systolic and100–160 diastolic. Fortunately, this condition is easyto exclude by a urine test for adrenaline, noradrenaline,and breakdown products called vanillyl-mandelic acid(VMA) and metanephrines. A computerized tomographicscan (CT scan of the adrenals) will diagnose virtually allcases. Physicians and patient should be alerted by suchsymptoms and initiate screening tests when warranted.Another important clue to the diagnosis is a failure torespond to the usual antihypertensive drugs or a markedincrease in blood pressure that may be provoked by certaindrugs. For example, the patient’s blood pressure mayincrease with certain medications such as nasal decongestantscontaining adrenaline-like compounds, antihypertensiveagents such as methyldopa, and opiates such asmorphine and Demerol.Hyperthyroidism is increased activity of the thyroid(hyperthyroidism, thyrotoxicosis) which occasionally causesmild systolic hypertension. Estrogen-containing oral contraceptivepills are also a cause of mild hypertension. Inyoung women about 5% of users develop hypertension.The hypertension is usually mild, but rarely, severehypertension can occur, resulting in kidney damage. Ondiscontinuing the pill, the blood pressure returns tonormal in the majority of women within six months.The increase in blood pressure described may be lesswith the newer, low-dose estrogen contraceptive pills.The low-dose, 0.625 mg, of conjugated estrogen used totreat postmenopausal hot flashes very rarely causes a mildincrease in blood pressure.C. Malignant HypertensionThis is a very serious condition. With malignant hypertensionthe diastolic blood pressure is usually greater than130 for several hours or weeks. When such a diastolicblood pressure is associated with organ damage — notablyto the vessels in the eyes, kidneys, or brain — the diagnosisis confirmed. The blood pressure increases rapidly overdays or weeks to dangerous levels, and the systolic pressuremay be as high as 250–300 mmHg and the diastolicpressure as high as 130–160 mmHg. The retinas of theeyes often show hemorrhages and edema of the opticdisk. Small arteries are severely damaged; in particularthe kidney vessels are damaged and leak red blood cells.The urine therefore contains numerous red cells (microscopichematuria). The function of the kidney rapidlydeteriorates and a brain hemorrhage may also occur.This is a life-threatening condition with severe damage tothe kidney, brain, eyes, and heart.Fortunately, the condition is decreasing in incidencebecause of effective drug treatment of the moderate formsof hypertension. The reassuring news is that it is rare for apatient with the very common mild primary hypertensionto develop malignant hypertension. The patient usuallyhas moderate hypertension for a short period with bloodpressure ranging from 200 to 250/105 to120. In somecases the malignant phase is precipitated by kidney disease,such as nephritis, but rarely renal vascular hypertension(renal artery stenosis) or collagen disease such as sclerodermaor pheochromocytoma.Malignant hypertension can be quickly broughtunder control by a range of effective drugs given intravenously.This form of hypertension cannot be treatedwithout drugs. Blood pressure may be as high as 250/150,yet headaches can be absent. Other causes of hypertensioninclude brain tumors, bleeding around the surfaceof the brain from a ruptured artery (subarachnoid

474HYPERTENSIONhemorrhage), spinal cord injuries, and the well-knownpregnancy-induced hypertension.IV. PATHOGENESIS OF PRIMARYESSENTIAL HYPERTENSIONA. Salt HypothesisThe hypothesis accepted by the majority of researchers isthat an inherited defect causes the kidney to retain excesssodium (salt) in the body. If you have such an inheriteddefect and your diet contains a large amount of sodium,your kidneys will retain more sodium and water. A normalkidney that has no defect in handling sodium will expelin the urine any excess that you may add in the diet.The sodium and water retained by the kidney get intothe blood and also into the cells of the artery wall, therebyincreasing the tone of the artery wall. This means thatthe artery becomes constricted or tightened and increasesthe resistance against which the heart must pump, that is,there is an increase in total vascular resistance and anincrease in blood pressure (see Fig. 2).The relationship between salt and hypertension is easierto understand after looking at the following example. Ifan individual is bleeding severely from a large cut orfrom the stomach or other body site, the blood pressureFIGURE 2hypertension.Hypothesis for the causation of primary (essential)always falls, sometimes to very low levels such as 75/50.A transfusion of blood must be given quickly to increasethe blood pressure, because at such a low level, not enoughoxygen, glucose, and other nutrients will reach the brain,muscles of the heart, and other tissues of the body. However,blood is not usually available in emergency roomsfor up to two hours. During this time the doctor rapidlygives sodium chloride (salt) diluted in water into a vein(intravenous saline), and this nearly always increases theblood pressure to safe levels until blood is available. Duringthe bleeding described, the kidneys also immediately startto retain sodium and water and return it to the blood; thatis, the kidney gives us an immediate transfusion of saline.Nature always finds a way to compensate.Increased salt intake is believed to be the mostimportant factor causing hypertension in susceptibleindividuals. The evidence is strong enough to warrantgeneral education of the public. The U.S. Food and DrugAdministration, WHO, the American Heart Association,the American Medical Association, the National Heart,Lung, and Blood Institute, and two government-sponsoredbodies in the UK have advised the general population toreduce sodium consumption where possible (see Table 2).There is a considerable amount of scientific informationthat supports the view that increased salt intake causeshypertension in susceptible individuals: Population groups that consume very low amounts ofsodium, less than 2 g daily, have almost no primaryhypertension; for example, groups in South America,Africa, and the South Pacific. In contrast, in countriessuch as Japan and Korea, where sodium intake isexcessively high, i.e., greater than 6 g daily, hypertensionis very common. Twenty-seven studies in human populations haveshown a close correlation between sodium intake andblood pressure. There was a fall in the incidence of hypertension inJapan between 1971 and 1981, and this is believed tobe due to a fall in the daily sodium consumption fromabove 6 g to less than 4 g. In Belgium, between 1968 and 1981, a fall in dailysodium consumption from greater than 6 g to less than4 g was associated with a significant fall in mortalitydue to stroke. In children of hypertensive parents, increased sodiumintake causes an increase in blood pressure and a greaterrise in blood pressure after stress. Compounds that cause sodium and water retention bythe kidney (hydrocortisone, licorice) often increaseblood pressure. In patients with Addison’s disease, lowblood pressure is always present and is treated with

IV. PATHOGENESIS OF PRIMARY ESSENTIAL HYPERTENSION475TABLE 2Sodium Content of FoodsFood Portion Sodium (mg)Bacon back 1 slice 500Bacon side (fried crisp) 1 slice 75Beef (lean, cooked) 3 oz (90 g) 60Bouillon 1 cube 900Garlic powder 1 tsp (5 ml) 2Garlic salt 1 tsp (5 ml) 2000Ham, cured 3 oz (90 g) 1000Ham, fresh cooked 3 oz (90 g) 100Ketchup 1 tbsp (15 ml) 150Meat tenderizer, regular 1 tsp (5 ml) 2000Meat tenderizer,1 tsp (5 ml) 2low-sodium(Whole) milk1 cup (250 ml) 1000pudding, instantOlive, green 1 100Peanuts, dry-roasted 1 cup (250 ml) 1000Peanuts, dry-roasted, 1 cup (250 ml) 10unsaltedPickle, dill 1 lrg (10 4 1/2 cm) 1900Wieners 1(50 g) 500Canned foodsCarrots 4 oz (60 ml) 400Carrots, raw 4 oz (60 ml) 40Corn, whole kernel 1 cup (250 ml) 400Corn, frozen 1 cup (250 ml) 10Corned beef, cooked 4 oz (120 g) 1000Crab 3 oz (90 g) 900Peas, green 1 cup (250 ml) 5Shrimp 3 oz (90 g) 2000Salmon, salt added 3 oz (90 g) 500Salmon, no salt added 3 oz (90 g) 50Soups (majority) 1 cup (250 ml) 1000Sauerkraut 1 cup (250 ml) 1800Salad dressingBlue cheese 1 tbsp(15 ml) 160French, regular 1 tbsp(15 ml) 200Italian 1 tbsp(15 ml) 110Oil and vinegar 1 tbsp(15 ml) 1Thousand island 1 tbsp(15 ml) 90Fast foodChopped steak 1 portion 1000Fish and chips 1 portion 1000Fried chicken 3-piece dinner 2000Hamburger Double 1000Roast beef sandwich 1 1000Pizza 1 medium 1000Normal diet contains 1000 to 3000 mg of sodium. Daily requirementis less than 400 mg.cortisone. Cortisone retains sodium with water, and thiseffect always increases blood pressure. Diuretic drugscause the kidney to remove excess sodium from theblood and expel the sodium and water in the urine andthus cause a decrease in blood pressure.Patients with chronic kidney failure who lose excessivesodium in the urine tend to have a normal bloodpressure, but in those who retain excessive sodium,blood pressure is often elevated.Animal experiments show a close relationship betweensalt intake and hypertension.Despite the aforementioned points that incriminate anincreased salt intake with hypertension, the MedicalResearch Council blood pressure unit in Glasgow statesthat the evidence is unclear and unproven. Thus, they donot feel it justified to ask everyone to reduce sodiumintake. There are many individuals who handle saltadequately. In this situation, we cannot advise everyoneto reduce salt intake and we agree with the following:There is a consensus in North America and Europe that amoderate reduction in salt intake to less than 2 g has noadverse health effects, and whenever possible, it would beprudent for the general population to reduce sodiumintake, particularly, patients with primary hypertension intheir relatives. If you have kidney disease, you should notreduce salt intake unless advised by a physician (somekidney patients can reduce intake).The evidence suggesting an inherited kidney defectstems from the work of Dr. Lewis Dahl who bred twostrains of rats, one that consistently developed hypertensionwhen given an increased sodium diet, and the otherthat resisted the development of hypertension and neverbecame hypertensive while on the same diet. Further, whena kidney is taken from a hypertensive rat and transplantedinto a host rat with a blood pressure that is in the normalrange (normotensive rat), the blood pressure of the host ratrises. A kidney transplanted from a normotensive ratlowers the blood pressure of a hypertensive host rat. It isbelieved that both the genetic and environmental factors(salt, stress, etc.) act together to cause hypertension.B. Other HypothesesOther hypotheses for the causation of primary hypertensionare shown in Fig. 3. Hereditary factors andstress cause an increase in discharge from a center in thebrain (sympathetic center) which triggers the secretion ofadrenaline and noradrenaline. These compounds not onlycause an increase in heart rate and cardiac output, buta marked constriction of arteries and increased total vascularresistance too, thereby increasing blood pressure. This

476HYPERTENSIONFIGURE 3 Other hypotheses for the causation of primaryhypertension.sympathetic stimulation activates enzymes in the kidneyand adrenal glands (the renin-angiotensin-aldosteronesystem). Angiotensin is a powerful constrictor of arterieswhich elevates blood pressure. Aldosterone, a hormonesecreted by the adrenal glands, causes the kidney to retainsodium and water and this further increases blood pressure.The renin-angiotensin-aldosterone system appears, however,to have only a small role, and this is still undefined inthe causation of primary essential hypertension. A lowintake of calcium has been associated with an increasein blood pressure in two studies, but the evidence is notsufficient to implicate a low-calcium intake in the causationof hypertension. Further studies are necessary toclarify the aforementioned theories of causation.V. COMPLICATIONSA. Effects on Arteries and Heart1. Myocardial InfarctionHypertension damages the arteries in many vital organs,especially the brain, heart, kidneys, and eyes. Damage tothe walls of the arteries is due to the increase in bloodpressure, but important added factors are an increase inpulsatile force and velocity of the blood. The arterywall responds to this stress by thickening its walls, butthis leads to further narrowing of the arteries and a furtherincrease in blood pressure. The arteries must branch tosupply blood to various organs and tissues. Unfortunately,the branches to some areas take off at near right anglesand mechanical stress is greatest at these points. The highvelocity and pulsatile force of blood at a high pressureset up turbulence and mechanical stress that damage thesmooth lining of the arteries, occasionally causing smalltears (dissections) of the arteries. This mechanical injuryprovokes proliferation of smooth muscle cells of the arterywalls and accumulation of fatty material including cholesteroland small blood particles (platelets). This thickeningproduces a plaque (atheroma) that juts out into the lumenof the artery thus obstructing blood flow, which causes lowflow and turbulence in the artery.The term for hardening of the artery is sclerosis, hencethe combination ‘‘atherosclerosis,’’ meaning hardening ofthe arteries due to atheroma (see atherosclerosis in theglossary). This process is continuous over several years andproduces no symptoms. On these plaques or damagedpoints, a blood clot (thrombosis) may eventually occur invital organs such as the brain, heart, or kidney.In the heart, the coronary arteries feed the heart musclewith blood. A blockage of a coronary artery by atheromatousplaque or clot causes damage to the heart muscle,myocardial infarction that may be complicated by heartfailure, arrhythmia, angina, and death.2. Heart FailureHigh blood pressure causes enlargement and thickeningof the heart muscle. These changes may be observedoccasionally on examining the patient or detected on chestx-ray or ECG. At some point in time, the heart muscleweakens and thus fails to eject sufficient blood into thearteries to satisfy the needs of the tissues; this is called afailing heart or heart failure (see the chapter Heart Failure).Blood that cannot be ejected into the aorta backs up intothe lungs, which causes stiffness of the lung tissue andleakage of fluid into the air sacs (alveoli). These changes inthe lungs cause severe shortness of breath. Heart failure canbe precipitated by mild hypertension in patients whoalready have a damaged heart muscle due to an old heartattack (weakened scar). There are many other causes of aweakened heart muscle, however, hypertension of all gradesis detrimental in all types of heart disease. In African-Americans, heart failure is precipitated at a lesser degree ofhypertension than in whites.Studies indicate that approximately 66% of elderlypatients with heart failure had antecedent hypertension.

VII. INVESTIGATIONS477The bulk of heart failure is related to hypertension andmyocardial infarction. Effective hypertension control is thesingle greatest means to prevent diastolic and systolic heartfailure. Most important diastolic heart failure has noeffective therapy and prevention is the key.3. Abdominal Aortic AneurysmHypertension can weaken the wall of the aorta. The wallmay balloon and produce a weak spot, and this is referredto as an aneurysm of the aorta. The weak spot mayrupture and this is often catastrophic and the conditioncan be confused with a severe heart attack (see thechapter Aneurysm). The risk of narrowing or blockage ofthe arteries in the legs (peripheral vascular disease) isincreased by hypertension, especially when there is eitherassociated smoking, high cholesterol, or diabetes.4. ArrhythmiaThe most common arrhythmia caused by hypertensionis atrial fibrillation. It is the most common sustainedarrhythmia encountered in clinical practice (see the chapterAtrial Fibrillation). Figure 4 illustrates the commondetrimental effects of hypertension.B. StrokeIn the brain, a blockage (cerebral thrombosis) or rupture(hemorrhage) of an artery produces damage to a segmentof cells, which results in weakness or paralysis of limbs.This is referred to as stroke. Each year about 500,000North Americans suffer a stroke and more than 200,000die as a result.C. Kidney DamageIn the kidney, hardening of the arteries leads toreduced blood flow and chronic deterioration of theHYPERTENSIONRisk forFatal, non-fatal STROKEMI... systolic dysfunctionLVH... diastolic dysfunctionATRIAL FIBRILLATION*RENAL FAILUREHEART FAILURECHRONICPAROXYSMALRUPTURE AORTIC ANEURYSM orBERRY ANEURYSMFIGURE 4 Common detrimental effects of hypertension. * ¼ Not wellappreciated: epidemic of atrial fibrillation with its management problems.(From Khan, M. Gabriel (2003). Cardiac Drug Therapy, sixth edition.Philadelphia: W.B. Saunders.)kidney function, and this causes a further increase in bloodpressure. Fortunately, only in patients with severe hypertensionis kidney failure a final occurrence. The vessels inthe back of the eyes may be damaged by high bloodpressure, and the changes may be observed an examinationwith an ophthalmoscope.VI. SYMPTOMSThere is little doubt that hypertension either leads to earlydeath or inflicts serious physical handicaps to millions.Blood pressure may be mildly or moderately elevated forseveral years without symptoms until the occurrence ofstroke, heart attack, or heart failure.Symptoms may not occur for 5–20 years in the majorityof patients with mild and moderate primary hypertension.Headaches, dizziness, and nose bleeds occur withequal frequency in hypertensives as they do in individualswith normal blood pressure. Some individuals get headachesduring sudden elevations of blood pressure. Only ina few patients can symptoms be correlated with the heightof blood pressure. Because your blood pressure may bevery high and yet produce no symptoms, it is necessary tohave a blood pressure check once a year or more often ifyou were ever informed that your blood pressure was abovenormal.VII. INVESTIGATIONSBlood, urine, and other tests are performed to determineif hypertension is primary, that is, without a cause, orsecondary to diseases of organs, especially the kidney.These tests will also serve as a baseline for future comparisonand as a means for detecting side effects ofsome antihypertensive drugs. The tests and the reasons fortheir use are listed below.A complete blood count determines the number ofred and white blood cells in your blood. The red bloodcells contain hemoglobin; heme is the iron in yourblood, and this is combined with a protein calledglobin. The level of hemoglobin will indicate if youare low in blood (anemia). A very high hemoglobin(polycythemia) is a rare cause of hypertension.A test for electrolytes measures the amount of sodium,potassium, and chloride in the blood. The potassiumlevel in the blood is important as it may fall if you aretaking a water pill (diuretic), which is commonly usedto treat hypertension. The potassium level may increasewith the use of ACE inhibitors.

478HYPERTENSION Either the blood urea nitrogen (BUN) or serumcreatinine must be obtained. Urea and creatinine arewaste products excreted by the kidney into the urine.The level of these substances in the blood is fairlyconstant when the kidney is functioning normally, butrises in kidney dysfunction. The results of these testswill show if the kidney is the likely cause of yourhypertension. A urine test (urinalysis) may show excess proteins,bacteria, or fragments of cells (casts) in the urine, whichindicates kidney disease. A chest x-ray is necessary and will tell the doctor if theheart is normal in size or already enlarged due tohypertension. An ECG can more accurately tell if the heart is enlargedand under strain. A chest x-ray cannot indicate whetherthe left ventricle of the heart is strained by the highblood pressure. The ECG may also give other importantinformation. The reassuring news is that othertests are necessary in only a few hypertensive patients,perhaps 5 out of 100 patients. In a few hypertensive patients with suspected kidneydisease, an intravenous pyelogram (IVP) may be requestedby the doctor. A dye that can be seen easily onx-ray is injected into a vein in the arm and reachesthe kidney within a few minutes. X-rays of the kidneysare taken over a 20-minute period. If the kidney is functioningnormally, the dye is excreted into the urine andthe x-ray will show the kidney structure as well as givesome indication of kidney function. A renal nuclear scanmay be done instead of IVP and is a safer test. Special urine tests for the breakdown products ofadrenaline (nor metanephrines) as indicated earlier arerarely required to exclude a tumor (pheochromocytoma)of the inner part of the adrenal gland, whichsecretes adrenaline. A dye test showing the arteries of the kidney (arteriogram)may be required if your doctor suspects fromthe renal scan or IVP that the artery to the kidney isobstructed. This is a rare occurrence and is seen inabout 1 in 1500 patients.VIII. NONDRUG TREATMENTThe majority of patients with mild primary hypertensionare advised to persist with a one-year trial of nondrugtreatment. It is important to understand the essentialrequirements of the program. The hypertensive must beaware of the dangers of the so-called silent killer tobecome sufficiently motivated to comply with self-imposedtreatment. Individuals who persist with nondrug treatmenthave a 50% chance of lowering blood pressure to normal.The essential requirements are given in order of importance,and each will be discussed in detail below. Sodium in the diet should be reduced to less than 2 gdaily and at maximum 3 g (see Table 2). Weight reduction is absolutely necessary and is alwaysassociated with a fall in blood pressure. The loss of15–30 pounds always causes a considerable drop inblood pressure and medications may not be required. Removal of stress or learning to adjust to stress mayresult in reduction of high blood pressure, and a trial ofrelaxation techniques can be useful in some individuals. Regular exercise will assist with weight reduction andrelaxation. Alcohol intake should not exceed two ounces daily. The patient should reduce coffee intake and must stopsmoking.A. Sodium (Salt) RestrictionSodium added at the table is only a minor part of thedaily sodium consumption. A teaspoon, 5000 mg of salt(sodium chloride), contains 2000 mg of sodium (i.e.,40%). The body requires an intake of less than 400 mgdaily. The daily North American diet contains about4000–6000 mg of sodium (two to three teaspoons of salt).Clearly no one adds more than a teaspoon of salt dailyat the table or in cooking for a family. The remainingone to two teaspoons must come from the food we eat.The aim is to cut sodium intake by 50%, to 2 g daily.This can be accomplished only if the hypertensive orpotential hypertensive recognizes and reduces or discontinuesfoods that have a high-sodium content. The listis long and contains many surprises (see Table 2). Thephysician, the dietary adviser, and the patient must bealert and check the sodium content of foods consumedduring one-week periods. Foods that are not salty to tastemay have a very high sodium content. Note that somepuddings have more sodium than a helping of bacon. Alarge dill pickle has more than 1 g of sodium. Fast foodshave a high sodium content (hamburgers 1 g, three piecesof fried chicken, 2 g). Watch out for canned foods thathave excess sodium added as preservatives.Other high-sodium foods not listed in the table includesoy sauce, onion salt, celery salt, seasoned salt, saltedcrackers, pretzels, rye rolls, salted popcorn, most cannedvegetables, sausage, hot dogs, salt pork, sardines, smokedfish, TV dinners, buttermilk, waffles, and pies.It is obvious from Table 2 that the hypertensive individualmust look at food labels and determine if foods havea low- or high-sodium content. Anything that has more

VIII. NONDRUG TREATMENT479than 500 mg per can is high. Additives are listed on tinsin order of greatest quantity. Sodium benzoate, sodiumnitrate, or monosodium glutamate means sodium. Therefore,if any sodium compound is in the first five of theadditives and the milligram content is not given, it isbest to avoid the product. After a month or two of care,it will become second nature to purchase foods with alow-sodium content. If you cannot avoid canned foods,rinse the vegetables, tuna and the like under runningwater. Low sodium intake is possible if you use freshpoultry, fish, beef, fruits, and vegetables. Season foodswith spices and herbs instead of salt and use a low-sodiummeat tenderizer. Onions and raw tomatoes can be usedliberally in cooking. All hypertensives should have dietarycounseling at least once annually. The sodium contentof several over-the-counter antacids used for indigestionand stomach upsets is high. There are, however, severalbrands on the market that have a very low sodium content,so please read the labels or ask your doctor.Salt substitutes that contain potassium in placeof sodium are helpful and can be used in place of tablesalt, except in patients who have kidney disease or takemedications that retain potassium. You may need to tryout several salt substitutes to find one that has a reasonabletaste. Garlic powder but not garlic salt, onion powderbut not onion salt, and chili powder may be usefulto improve taste and yet remain low in sodium. Tomatojuice and all the tomato sauces are high in sodium, butmanufacturers are producing low-sodium tomato juicesand a wide range of canned products.B. Weight ReductionA loss of weight always produces a fall in blood pressureand is therefore strongly recommended. Weight reductionhas a greater blood pressure lowering effect thanexercise, relaxation techniques, and or sodium restriction.A weight-reducing, low-salt diet is often prescribed, butmany patients fail to stick to a diet. Thus the diet mustbe individualized. It is best to refer to a dietary adviser,who can at least review the patient twice annually.Hypertension carries a greater risk of heart attackand stroke in patients with an elevated cholesterol. Forpatients under age 55, the serum cholesterol should bemaintained at less than 200 mg/dl (5 mmol). The risksare considerably increased if the serum cholesterol isgreater than 240 mg/dl (6 mmol). It is important whenfollowing a weight-reduction diet not to increase intake offoods that are high in cholesterol. Low-cholesterol dietsand the optimal levels of total serum cholesterol andhigh-density lipoprotein (good) cholesterol are discussed inthe chapter Cholesterol. Weight-reduction diets must beindividualized; therefore, no specific recipes are given inthis book (see the chapter Obesity and Heart Disease).C. StressThe role of stress in high blood pressure is difficult todefine. What is important is the way we handle stress.Stress itself rarely produces sustained hypertension, butin a susceptible individual with an inherited predispositionto hypertension, stress may increase blood pressure (seeFig. 3). It is important to recognize that an individualwith an average blood pressure of 135/85, when understress, can increase blood pressure 20–40 mmHg systolicand 5–10 mmHg diastolic. These increases in bloodpressure may last minutes or several hours several timesdaily, and play an important role over several years. Thus,the patient with mild primary hypertension on nondrugtherapy will increase blood pressure significantlyduring the day under the influence of stress. The use ofrelaxation therapy has increased dramatically and manyclinics offer relaxation facilities, although scientific studieshave failed to show a sustained decrease in blood pressuredue to this therapy. On the other hand, some studies areemerging that lend support to the salutary effect ofrelaxation therapy. Biofeedback-aided relaxation therapyseems to benefit some patients. This mode plus deeprelaxation exercises are not harmful and can reduce bloodpressure in some patients. Because the blood pressure tendsto increase between periods of relaxation, do not rely solelyon relaxation therapy if your blood pressure is greaterthan 160/100. Occasionally patients may need to changejobs, reduce workload, or to engage in hobbies such astennis, golf, swimming, fishing, painting, listening tomusic, or other forms of recreation.D. ExerciseIsometric (static) exercise, such as weightlifting (pulling,pushing), increases muscular tension and constricts bloodvessels, thus increasing blood pressure. Such exercisesmust be avoided. Isotonic or aerobic exercises may causea variable increase in blood pressure during the exerciseand slight decrease immediately following the exercise.Walking, jogging, swimming, and other forms of exerciseshould be encouraged in mild hypertensives. A fall inblood pressure may be related to weight loss and relaxationproduced by exercise. If blood pressure remainselevated greater than 160/100 after six months of anexercise program, do not rely on exercise as a sole means tolower blood pressure (see the chapter Exercise and theHeart).

480HYPERTENSIONE. AlcoholThere is convincing evidence that any more thanthree ounces of liquor daily significantly increases bloodpressure. Alcohol should therefore be restricted in allhypertensives. It is often stated that alcohol may producerelaxation, and two to four ounces daily may relax thenerves as well as increase the levels of HDL, the so-calledgood cholesterol. The ideal choice is a drug that is effectivefor 24 h when given once daily that produces little orno adverse effects. Several drugs are effective only forsix to eight of hypertension is greater than the possiblebenefits of a modest and variable increase in HDLcholesterol. Alcohol should be avoided in patients whohave both hypertension and increased HDL cholesteroland heart failure. Four ounces of alcohol taken over a fewhours causes a decrease in contraction of the heart muscle,thereby reducing the amount of blood ejected from theheart at each beat (see the chapter Alcohol and the Heart).F. Coffee and SmokingCoffee is also known to stimulate the sympathetic nervoussystem and can cause mild elevation of blood pressurein susceptible individuals, especially if more than threecups per day are consumed. Tea has much less caffeinethan coffee and is not known to increase blood pressure.Smoking definitely increases the cardiovascular risk inpatients with hypertension. Also, many drugs do not workefficiently to lower blood pressure because smokinginterferes with their metabolism in the liver. The patientmust therefore be motivated to discontinue smokingcigarettes.IX. DRUG TREATMENTA. Number of Drugs AvailableHypertension affects more than 1 billion individualsworldwide and is the most common indication for bothvisits to physicians and for the use of prescription drugsin the United States, yet there are only five groups ofdrugs available to treat this condition. After more than50 years of research and proclamations on television andin popular magazines of new drugs, the hope of patientsdissipates when the new agents are tried without success.This situation is appalling when worldwide more than1 billion individuals require treatment.Only five antihypertensive drugs are available.1. Diuretics2. Beta-adrenergic blockers3. ACE inhibitors and angiotensin II receptor blockers4. Calcium antagonists (calcium channel blockers)5. Alpha blockers (use limited because of increased risk forheart failure)ACE inhibitors and the identical acting angiotensinII receptor blockers are a major advance but represent asingle class of agent. Although this class of agent isrepresented by more than 24 drug names in the marketplace,they have the same actions and represent a singledrugCalcium antagonists are not superior to the twoolder classes of agents, beta-blockers and diuretics. Alphablockersare not recommended agents and the recent ALLHATtrial indicates that they increase the incidence of heartfailure. These agents are therefore used only in selectedindividuals, particularly with renal dysfunction, whenan ACE inhibitor may be contraindicated and bloodpressure remains uncontrolled with other agents. The oldercentrally acting agents clonidine and methyldopa causeddepression and other adverse effects and have been renderedobsolete, although methyldopa still holds a place in themanagement of hypertension in pregnancy.In reality they are only four groups of antihypertensiveagents available. In clinical practice patients who cannottolerate one or two of the four types of agents are frequentlyencountered and many patients require two agentsto maintain adequate blood pressure control.The following statement is modified from the sixthedition of Cardiac Drug Therapy:This situation will change only if pharmaceuticalcompanies and experts who formulate hypertensiontherapeutic guidelines will admit that after morethan 50 years of research and numerous randomizedclinical trials we only have four antihypertensive agents.Recognition of the truth should promote more intensiveresearch to discover new groups of agents to add to ourarmamentarium.The organizers of randomized trials must provide soundmethodology, which has been lacking in many trials. Forexample, the well-known beta-blocker, atenolol, has beencompared with other agents in several trials. However,the nonlipid-soluble atenolol is not as cardioprotectiveas carvedilol, metoprolol, bisoprolol, or propranolol,which are the only beta-blockers proven in clinical trialsto be cardioprotective. Beta-blockers have subtle andimportant differences that appear to be unrecognized byexperts who organize clinical trials of hypertension.The physician should explain the problems associatedwith drug therapy so that the patient will accept

IX. DRUG TREATMENT481and comply with drug changes, which are oftennecessary.The standard approach to antihypertensive treatmentis to use a beta-blocker or a diuretic as the initial drug. Inrecent years beta-blockers have partially replaced diureticsas the first-line drug, but both drugs are advocated bynational consensus committees as the recommended agentsto commence treatment, except in special cases.Experts vacillate between drugs as to their choice ofa first-line drug. Other drugs can be used as first-line inselected individuals. Another important group of drugsthat have proved beneficial in the treatment of moderateand severe hypertension are called angiotensin-convertingenzyme (ACE) inhibitors. They are called this becausethey block the action of a series of enzymes (angiotensin,renin). (See chapter entitled Angiotensin-ConvertingEnzyme Inhibitors/Angiotensin Receptor Blockers.) Angiotensincauses powerful constriction of arteries and thereforeincreases blood pressure when the body requires a boost inblood pressure. By blocking angiotensin, these drugs causedilation of the arteries and a fall in blood pressure. Inaddition they do not stimulate the heart to beat faster as dosome drugs. They also retain potassium whereas diureticscause a loss of potassium. This group of drugs (ACEinhibitors) includes captopril and enalapril. Another groupof drugs recommended by the consensus panel are thecalcium blockers (antagonists).The drug treatment of hypertension must be individualized.In order to assist doctors to accomplish this goal, apast history of illnesses and response or bad reaction todrugs must be given. Previous response or adverse effect to antihypertensivedrugs should be a factor in determining furtherdrug treatment. A beta-blocker (for example, metoprolol, propranolol,or bisoprolol) is the drug of choice if the patienthas angina or palpitations or has had a heart attackor a strong family history of heart disease. Patientsfrom 25 to 75 years of age usually respond to betablockers.Your doctor must respect the contraindicationsto the use of beta-blockers. Beta-blockers mustnot be used if a patient has bronchial asthma oremphysema. Patients with stroke or poor circulation to the brainassociated with postural hypotension (a big fall in bloodpressure on standing) should avoid the use of methyldopa,prazosin, or hydralazine and other drugs thatcause considerable dilatation of the arteries on standing.Such drugs cause more blood to go down to the legson standing and therefore steal blood from the brain,which causes dizziness. It is important to note thatbeta-blockers do not cause postural hypotension andare therefore useful in this group.Four main groups of drugs are in use:1. Beta-blockers2. Diuretics3. Vasodilators (including ACE inhibitors and calciumantagonists)4. Drugs that act centrally in the brainBefore outlining the drugs used in hypertension andsome of their side effects and doses, it is wise to reflecton the following important question: Is the choice of drugor dosage really important in reducing blood pressure?The answer to this question is yes. The choice of drugand dosage is important. The available evidence suggeststhat beta-blockers have a definite advantage over diureticsand other agents as first-line therapy. When utilized,diuretics should be given in the smallest dosage necessaryto control blood pressure, for example, hydrochlorothiazide,25 mg daily. Hypokalemia (low serum potassium)must be avoided. A diuretic that conserves potassium suchas Moduretic (Moduret) or Dyazide has a definite place intherapy if kidney function is normal (see contraindicationsto Moduret or Dyazide use in Section IX.D.2.c and d).The following points must be considered when giving apatient an antihypertensive drug. It is not only the severityof hypertension that damages the arteries, but (1) theadded pulsatile force of the blood; (2) the heart rate multipliedby the systolic blood pressure, which determines theworkload of the heart and the amount of oxygen the heartmuscle requires (thus an enlarged heart muscle workingunder strain will require more oxygen); and (3) the peakvelocity of the blood multiplied by the heart rate, whichreflects the turbulence of blood (turbulence causes damageto the inner lining of arteries). These three parameters canbe favorably influenced by beta-blockers, made worse bydiuretics or vasodilators such as prazosin, and not alteredby drugs that act centrally in the brain.Beta-blockers are effective in preventing death inpatients who have sustained a heart attack and are treatedwith these drugs for an additional two years. Four betablockingdrugs have been studied in large clinical trials:acebutolol, 400 mg daily; metoprolol, 120–200 mg daily;propranolol, 160–240 mg daily; and timolol at a dose of10–20 mg daily were effective in preventing fatal andnonfatal heart attacks. Interest should be centered on thepotential complications and not just the blood pressure.The patient is not only worried about his blood pressurebut is afraid of stroke or heart attack. Doctors sometimeslose sight of this goal. They give drugs to reduce the bloodpressure and forget that some drugs do prolong life longer

482HYPERTENSIONthan others (see the section Beta-Blockers in the chapterHeart Attacks).B. Choice of Antihypertensive Agent forPatients Without Coexisting DiseasePatients with primary essential hypertension who have nocomplications of hypertensive disease and no coexistingissues such as diabetes or pulmonary disease are selectedfor a particular drug depending on age and whether theindividuals is white or of African descent.1. Recommendations for White Patients Less thanAge 65Initial choice begins with either a beta-blocking drug ora diuretic. Several randomized clinical trials (RCTs) haveemphasized the efficacy and safety of these agents and thecost-savings to patients when these old agents are used.Newer agents including ACE inhibitors, angiotensin IIreceptor blockers (ARBs), and calcium antagonists are notsuperior.The clinician should strive for the use of one agent inthe treatment of hypertension whenever possible. Thecombination of two agents at a low dose, however, mayachieve the therapeutic goal with less potential for adverseeffects and often combination therapy is required to attainthe therapeutic goal blood pressure.2. Recommendations for Younger Black PatientsCalcium antagonists are the most effective agents of thefour groups followed by beta-blockers. The combination ofa small dose of a beta-blocking drug such as bisoprolol,10 mg daily, plus a calcium antagonist such as amlodipine,5 mg daily, should attain goal blood pressure.3. Recommendations for White Patients Olderthan Age 65A beta-blocking drug or ACE inhibitor is a reasonable firstchoice of agents, but a small dose of diuretic may be triedand then a small dose combination (see Table 3).4. Recommendations for Elderly Black PatientsA diuretic is the treatment of choice. Calcium antagonistsare also effective, but in patients with an ejection fractionof less than 40% the risk of heart failure may be increased.TABLE 3Choice of Drug for the Treatment of Isolated SystolicHypertensionWhite patients younger than age 651. Beta-blocker: bisoprolol carvedilol or metoprolol (Toprol XL)preferredover other beta-blockers.2. ACE inhibitor: often requires combination with diuretic toachieve goal BP3. Diuretic4. Choice one or two þ3Black patients younger than age 651. Beta-blocker2. Calcium antagonist3. Choice 1 þ 2White patients older than age 651. Beta-blocker2. ACE inhibitor3. Diuretic4. Choice 1 þ 2 (not complementary but both cardioprotective,>65 at risk)5. Calcium antagonistBlack patients older than age 651. Diuretic2. Calcium antagonist3. Choice 1 þ 2From Khan, M. Gabriel (2003). Cardiac Drug Therapy, sixth edition.Philadelphia: W.B. Saunders, p. 140.C. Therapy for Patients with CoexistingDiseases or Target Organ DamageCoexisting diseases of importance include diabetes, coronaryartery disease (angina), myocardial infarction, previouscoronary artery bypass surgery, left ventricular dysfunction,dyslipidemia, stroke or transient ischemic attack, kidneydisease (nephropathy), and peripheral vascular disease.Target organ damage includes heart failure, left ventriculardysfunction, left ventricular hypertrophy retinopathy, andrenal insufficiency.Patients with coronary artery disease manifested byangina or myocardial infarction should be treated witha beta-blocking drug such as propranolol, carvedilol, orbisoprolol. If beta-blockers are contraindicated a calciumantagonist such as diltiazem sustained-release preparationmay be tried. Dihydropyridine calcium antagonistsincrease heart rate and may precipitate heart failureand should not be used without a beta-blocking drug.A diuretic is always useful in this group of patientsand combination with a beta blocker or ACE inhibitorprovides benefits.

IX. DRUG TREATMENT483An ACE inhibitor is particularly useful if left ventricledysfunction is present and the combination of a betablockerand an ACE inhibitor is advisable, because thesetwo agents have been shown to be cardioprotective.In patients with diabetes a combination of two ormore drugs is usually needed to achieve the target goalof less than 130/80 mmHg. ACE inhibitors and angiotensinreceptor blockers favorably affect the progressionof diabetic nephropathy and reduce albuminuria.Angiotensin receptor blockers have been shown toreduce progression to microalbuminuria. A beta-blockeris strongly recommended in addition to other agentsbecause beta-blocking drugs have been shown to reducecardiac death in patients at risk.Patients with heart failure and hypertension are besttreated with a combination of a loop diuretic, ACE inhibitor,and a small dose of a beta-blocker. In the absenceof renal artery stenosis in patients with kidney disease,an ACE inhibitor or angiotensin receptor blocker incombination with a diuretic, a beta-blocker, and calciumantagonist may be required to attain goal a blood pressureless than 130/80. Patients with renal artery stenosismay have an accelerated hypertension that is difficult tocontrol. Goal blood pressures in these patients should be ata high level of 140–150 mmHg systolic and diastolic750–90 mmHg to allow adequate renal perfusion. Lowblood pressures may cause deterioration of kidney functionD. Individual Antihypertensive AgentsSee Tables 7 and 8 for dosage and generic and trade namesfor the individual agents.1. Beta-Blockers (Tables 4 to 6)Beta-blockers are excellent antihypertensive agents for thefollowing reasons.They do not cause a fall in blood pressure on standing,unlike most other antihypertensive agents. Labetalol,GenericAcebutololAtenololMetoprololNadololPindololPropranololTimololTABLE 4Generic and Trade Names of Beta-BlockersPharmaceutical trade namesMonitan, SectralTenorminLopressor, Betaloc, Seloken, Toprol XLCorgard, SolgolViskenInderal, Angilol, Apsolol, BerkololBlocadren, Betim, TemserinBeta-blockerTABLE 5Dosage of Commonly Used Beta-BlockersDaily startingdose (mg)Maintenancedose (mg)which is really an alpha- and beta-blocker, does causepostural hypotension. This drug is useful in hypertensiveemergencies, but it is not recommended forthe long-term treatment of hypertension because ofpotential adverse effects.Beta-blocker drugs produce no major side effects onheart, liver, kidney, blood, or bone marrow.The one-a-day schedule necessary for these drugs makesit less likely for the patient to forget to take the drug.They can be used alone as first-line therapy and areeffective in more than 60% of hypertensive patientsaged 25–75, and used successfully in the majorityof patients in combination with a small dose of adiuretic or with an ACE inhibitor or calcium antagonist.They curb some adverse effects of vasodilatordrugs including calcium antagonists.They prevent hypertrophy of the heart muscle. Theyreduce the incidence of stroke, heart failure, heartattacks, and deaths from heart attacks.Beta blockers reduce blood pressure by:Maximumsuggested dose (mg)Acebutolol 100–400 200–600 1000Atenolol 50 50–100 100Bisoprolol 5 10–15 20Carvedilol 6.25 12.5–25 50Metoprolol 50–100 100–300 400Nadolol 40–80 80–160 160Propranolol 60–120 80–240 240Timolol 5–10 20–30 301. Decreasing cardiac output2. Inhibiting the release of the renin thus decreasingangiotensin and aldosterone effects3. Decreasing the central vasomotor activity4. Decreasing norepinephrine from sympathetic neurons(see the chapter Beta-Blockers)5. These agents reduce cardiac ejection velocity and hydrodynamicstress at arterial branching points and this mayprevent arterial injury that leads to atherosclerosisCommonly used beta-blockers are included in thefollowing sections.a. Propranolol (Inderal)This beta-blocker has been used since 1964 and is wellknown to most physicians. The drug is metabolized in

484HYPERTENSIONTABLE 6Generic and Trade Names of DiureticsGeneric name Trade name Tablets (mg)Usual maintenance(mg daily)Group 1: ThiazidesHydrochlorothiazide HydroDiuril, Hydrosaluric,25, 50, 100 25–50Esidrix, Esidrex oretic, DiremaBendrofluazide Aprinox, Berkozide, Centyl, Neo-Naclex 2.5, 5 2.5–5Bendoflumethiazide Naturetin 2.5, 5, 10 2.5–10Benzthiazide Aquatag, Exna, Hydrex 50 50–100Cyclothiazide Anhydron 2 2Hydroflumethiazide Diucardin, Hydrenox, Saluron 50 50Chlorthalidone Hygroton 25, 50, 100 50Methylclothiazide Enduron, aquatensin, Diutensen 5 2.5–5Polythiazide Renese, Nephril 1, 2, 4 2–4Trichlormethiazide Naqua, Metahydrin 2, 4 2–4Cyclopenthiazide Navidrex, Navidrix 0.5 0.5–1Metolazone Zaroxolyn, Metenix 2.5, 5, 10 2.5–5Quinethazone Aquamox, Hydromox 50 50–100Indapamide Lozide, Lozol 2.5 2.5Group II: loop diureticsFurosemide Lasix, Dryptal 20, 40, 80 40–80Frusemide Frusetic, Frusid 500Ethacrynic acid Edecrin 25, 50 50–150Bumetanide Burinex, Bumex 0.5, 1, 5 1–2Group III: Potassium-sparing diureticsSpironolactone Aldactone 25, 50 (UK), 100 50–100Triamterene Dyrenium, Dytac 50, 100 50–100Amiloride Midamor 5 5–10Group IV: Combination I and IIIThiazide andpotassium-sparingAldactazide, Dyazide,Moduretic (Moduret)the liver. It is strongly fat-soluble and therefore has ahigh concentration in the brain. This may be the reasonfor occasional weakness and fatigue, the very rare occurrenceof depression, and vivid dreams. A dosage of 40-mgtablets is used twice daily and can be increased to 80 mgtwice daily. Long-acting 80- or 160-mg capsules are availablefor once-daily use. Propranolol is the prototype of allthe newer beta-blockers, and there are really only subtledifferences; however, smoking decreases the effectiveness ofthe drug.b. Acebutolol (Sectral, Monitan)This beta-blocker has few side effects. It does not decreaseHDL cholesterol levels or slow the pulse rate. A dosageof 200–400 mg once or twice daily is effective and isnot altered by smoking.c. Atenolol (Tenormin)Atenolol is totally excreted by the kidney and, because of along half-life, it is given as a once-daily tablet, 25–100 mg.It is different from propranolol and nadolol in that it is‘‘cardioselective,’’ i.e., it works mainly on the heart withonly minimal effect on the lungs. Atenolol is thereforesafer for patients with bronchitis provided that the doseis kept at a moderate level. If you have bronchitis, however,it is best to avoid beta-blockers. Atenolol and long-actingpropranolol and nadolol have been shown to effectivelyreduce ambulatory blood pressure for up to 28 h afterthe last dose. The effectiveness of atenolol, acebutolol,and timolol are not modified by smoking.Atenolol has not been shown to cause a decrease incardiac mortality in RCTs. The drug does not providecardioprotection as observed with bisoprolol, carvedilol,metoprolol, propranolol and timolol. Beta blockers have

IX. DRUG TREATMENT485subtle and important differences which have not beenrecognized by senior researchers. Atenolol should not be usedin hypertensive drug trials that compare it with otherantihypertensive agents. The author’s opinion has beensupported by a recent review. Carlberg et al. systematicallyreviewed the effect of atenolol on cardiovascularmorbidity and mortality in hypertensive patients. Onlyrandomized controlled trials that assessed the effect ofatenolol on cardiovascular morbidity or mortality inpatients with primary hypertension were included. Thesuperiority of atenolol over placebo or no treatment inreducing blood pressure did not result in a beneficial effecton mortality or myocardial infarction. The analysis castsdoubts on atenolol as a suitable first-line drug for hypertensivepatients. Moreover, it challenges the use of atenololas a reference drug in outcome trials in hypertension.much less frequently with nadolol and atenolol comparedwith propranolol and metoprolol. The drug’s effectivenessis not affected by smoking.h. PindololPindolol does not cause adverse changes in blood lipidslike some beta-blockers. This drug may not decreaseblood pressure in hypertensives during sleep, however.The drug causes significant insomnia, disordered sleeppatterns, and in a few patients, nervousness, musclecramps, and joint pains. Pindolol has a stimulant effectbecause it contains beta-agonist activity, which destroysthe cardioprotective properties of beta blockade. Becauseof this, pindolol is no longer recommended.d. Bisoprolol (Zebeta; Monocor)This is a cardioselective beta-blocker that is excretedpartially by the kidney and the liver. It has a low sideeffect profile and a long duration of action and can begiven 5–10 to 15 mg once daily.e. Carvedilol (Coreg)Dosage: 12.5–25 mg twice daily.This beta-1 beta-2 agent has added vasodilator propertieswhich have shown to improve survival in patientswith heart failure and in patients following a myocardialinfarction.f. Metoprolol (Toprol XL)Dosage: 50–200 mg daily.Metoprolol is similar to atenolol in that it is alsocardioselective at low doses. It is a very popular betablockerand is used worldwide. This drug is given twicedaily. Other features of the drug are similar to propranolol,but there are fewer side effects. A long-acting tablet,Toprol XL, can be taken once daily and constitutes a majoradvance.g. Nadolol (Corgard)Dosage: 20–120 mg daily.Nadolol is similar to propranolol except that it isnot metabolized in the liver and is excreted by the kidney.Because of its long half-life in the body, it is given as aone-a-day tablet. Insomnia and vivid dreams occuri. TimololThis drug is six times more potent than propranolol,so for a given dose, a better blood level is achievedwith less variation. The drug must be taken as 5- or 10-mgtablets twice daily. Because of its potency and lack ofanesthetic property, timolol is used as eye drops for thetreatment of glaucoma. Smoking does not appear todecrease the drug’s effectiveness.Advice and Adverse Effects of Beta-Blockers: Betablockersshould not be given to patients with bronchialasthma, severe allergic rhinitis, Raynaud’s phenomenon,and second or complete heart block. These drugs produceslowing of the heart rate, but this is a desired effectand a reduction to 50 beats per minute is acceptable.Rarely the pulse may drop to less than 48 beats per minute,and if accompanied by dizziness and low blood pressure,the dose must be reduced or the drug discontinued.Fortunately, the latter effect is uncommon, judging fromthe millions of individuals who are taking beta-blockers.Slowing of the pulse occurs to a lesser degree withacebutolol. It may cause fatigue, and rarely mild depression.Reduction of libido and impotence are also fortunatelyrare. Do not stop the drug suddenly. Thiswithdrawal phenomenon is important only if the patienthas angina or severe heart disease and is not significant inpatients with hypertension alone.Beta-blockers reduce blood pressure and slow theheart rate. They reduce the work of the heart, therefore,preventing heart failure in virtually all hypertensivesexcept the very few in whom the heart muscle is alreadyseverely weakened. A weak heart muscle may exist inpatients who have had several heart attacks or who havesevere heart valve problems. Such patients usually havelow blood pressure because of the severity of heart disease.

486HYPERTENSIONThe patient’s past history makes it easy for the doctor toconclude that the heart muscle is weak, and this canbe confirmed by the examination of the heart, the chestx-ray, and the ECG. It is important to emphasize thatlarge clinical trials of hypertensives utilizing beta-blockersdo not show an increased incidence of heart failure.Clinical trials with timolol, propranolol, and other betablockersin patients who have had heart attacks andwere followed for two years showed that these drugs do notcause an increased incidence of heart failure. If patientsare carefully selected by physicians, heart failure is notusually precipitated by beta-blockers. Beta-blockers havebeen shown recently to benefit patients who have a mildor moderate degree of heart failure. This group of drugsis relatively safe and extremely important in the treatmentof hypertension, angina, heart attacks, and arrhythmias.They have recently been shown to improve survival andprevent hospitalizations in patients with heart failure.2. DiureticsThere is no question about the efficacy of diuretics inmild-to-moderate hypertension, and when combined withother antihypertensive agents they can be used in all typesand degrees of hypertension. The generic and trade namesand maintenance dosage of diuretics are given in thechapter Diuretics.a. HydrochlorothiazideHydrochlorothiazide is an example of a large group ofwidely used diuretics called ‘‘thiazides.’’Supplied: Tablets: 25 mg, 50 mg.Dosage: Commence with 25 mg each morning andkeep this dose as maintenance; maximum dose is 50 mgdaily. The blood pressure-lowering effect is related to:Decreased blood volume; patients who have an expansionof their blood volume especially due to sodiumand water retention have the maximum benefitIncreased excretion of sodium and water by the kidneyMild dilatation of arteries, thereby causing a decrease intotal vascular resistanceContraindications include hypersensitivity to thiazidesor sulfonamides (sulfurs), severe kidney failure, pregnantwomen and nursing mothers, and patients taking lithium.A decrease in blood potassium does occur in a significantnumber of patients receiving thiazides, and this isa potential danger. Diuretics also cause attacks of gout.These drugs cause an increase in blood levels of uricacid, and urate crystals precipitate in joints, which causessudden severe pain in the joint of the big toe or ankle.The joint becomes very hot, red, and swollen. Someindividuals are very susceptible to small doses of diureticsand frequent attacks of gouty arthritis occur. A course ofcolchicine or indomethacin relieves the painful gout intwo to three days and the patient is advised to switch toanother antihypertensive drug.Some doctors add a drug called allopurinol to thediuretics to reduce the levels of uric acid, and this isgiven for several years. It makes more sense to stop thediuretics. The addition of allopurinol is a prime exampleof ‘‘polypharmacy,’’ which adds to the handful of pillsthat patients are expected to take. It also adds to sideeffects and cost.b. Furosemide (Lasix)Furosemide is a powerful diuretic and is not recommendedfor hypertension except when associated withkidney failure. In this situation it is much more effectivethan thiazides.c. DyazideDyazide is a combination of 25 mg of hydrochlorothiazideand 50 mg of triamterene. The latter causes retentionof potassium so there is no need to take extra orange juiceor foods with a high-potassium content.d. Moduretic (Moduret in Canada)Moduretic is a potassium-retaining drug and contains50 mg of hydrochlorothiazide and 5 mg of the potassiumretainer amiloride. A half tablet is to be taken once daily.Dyazide and Moduretic are relatively safe when kidneyfunction is normal; if kidney function is impairedsuch that the serum creatinine is greater than 1.3 mg/dl(115 mmol/L), these drugs may retain too much potassium.High potassium in the blood may also occur ifpotassium-sparing diuretics are used concomitantly withACE inhibitors or angiotensin receptor blockers. Thesedrugs are widely used in the management of hypertensionand heart failure, and prevent the patient from havingto take unpleasant tasting potassium chloride mixtures.Diuretics such as Dyazide that contain triamterene shouldbe avoided in patients who are being treated for arthritiswith indomethacin, and should not be given to patientswho have had a renal stone. Moduretic and Dyazideshould be avoided in elderly diabetics and in patientstaking an ACE inhibitor.

IX. DRUG TREATMENT487Eplerenone (Inspra)Eplerenone is an aldosterone antagonist similar to spironolactonebut considerably more selective with a verylow affinity for progesterone and androgen receptors;thus, gynecomastia and sexual dysfunction which occurcommonly with aldosterone is rarely seen with eplerenoneadministration.In the EPHESUS study reported by Pitt et al., eplerenone,a selective aldosterone blocker, in patients with leftventricular dysfunction after myocardial infarction provedbeneficial. Patients were randomly assigned: 3313 to eplerenone,25 mg daily to a maximum of 50 mg or placeboand 3319 patients in addition to optimal medical therapy.Results: During a mean follow up of 16 months,there were 478 deaths in the eplerenone group and 554deaths in the placebo group ( P ¼ 0.008). Cardiovasculardeaths were 407 in the eplerenone group and 483 inthe placebo group ( P ¼ 0.005). The rate of death fromcardiovascular causes or hospitalization for cardiovascularevents, was reduced by eplerenone ( P ¼ 0.002), as wasdeath from any cause or any hospitalization ( P ¼ 0.02).The rate of sudden cardiac death was significantly reduced( P ¼ 0.03). This drug is not advisable in patients witha serum creatinine of >1.1 mg/dl because hyperkalemiamay be precipitated.Carr et al. assessed eplerenone using ambulatory andclinical blood pressure in patients with systemic hypertension.Ambulatory and clinical blood pressures werereduced significantly. The top effective dose in stage1–3 hypertension is 50–100 mg daily. The blood pressurelowering effect is similar to that obtained with thiazidediuretics, ACE inhibitors, calcium antagonists, andbeta-blockers. Eplerenone is a welcome addition to ourantihypertensive armamentarium.increased to 25 mg three times daily to a maximum of50 mg three times daily. A daily dose of 75 mg appearsto be as effective as higher doses. It is advisable not toexceed 50 mg three times daily. If mild kidney failureis present, the drug is given only once or twice dailybecause it is excreted by the kidney and can be retainedin excess in the body. These agents must not be used inpatients with severe kidney failure, because too muchpotassium may be retained.Captopril blocks the formation of an enzyme,angiotensin-converting enzyme (ACE), which normallyconverts angiotensin I to angiotensin II. Angiotensin IIcauses powerful constriction of arteries and increasesblood pressure; when the enzyme (ACE) is blocked,blood pressure falls.Advice and Adverse Effects: ACE inhibitors carry therare risk of life-threatening angioedema that can produceswelling of the tongue and difficulty with breathing.Although this occurrence is rare, 0.2% of patients treated,the physician must warn the patient to seek assistance inthe emergency room if there is swelling of the lips, eyelids,or tongue. This reaction can occur within days and evenup to two years from commencement of the medication.Deaths have occurred, albeit rarely. Mild hypertension isnot a serious disease and many patients tolerate the effectsfor more than 30 years before developing complications.Thus, agents that are potentially harmful must be usedonly when other drugs are ineffective or not tolerated.Captopril and other ACE inhibitors must not be takenalong with potassium supplements or potassium-sparingdiuretics such as Moduretic or Dyazide, because they allcause a retention of potassium by the kidney. Cough is acommon side effect of all ACE inhibitors. The drug rarelycauses a reduction in white blood cells, loss of taste, anditching.3. ACE InhibitorsACE inhibitors are useful antihypertensive agents, butcareful patient selection is necessary prior to commencementof therapy. They prevent left ventricular enlargement,hypertrophy, and heart failure and do not causefatigue. Impotence is rare.a. Captopril (Capoten)This is the first ACE inhibitor introduced into medicalpractice for the management of hypertension during theearly 1980s.Supplied: Tablets: 12.5 mg, 25 mg, 50 mg, and 100 mg.Dosage: 12.5 mg twice daily one hour before meals.If there is no major fall in blood pressure, the drug isb. Enalapril (Vasotec)Dosage: 5–30 mg once daily. Adverse effects are similar tocaptopril and other ACE inhibitors.c. Ramipril (Altace)Dosage: This long-acting agent is given once daily. 5 mgonce daily increasing to 10 mg to maximum 15 mg oncedaily.The effect of ramipril is similar to captopril.See the chapter Angiotensin-Converting EnzymeInhibitors/Angiotensin Receptor Blockers for other ACEinhibitors and for the angiotensin II receptor blockers:candesartan, eprosartan, irbesartan, losartan, telmisartan,and valsartan.

488HYPERTENSION4. Calcium Antagonists/Calcium BlockersThese agents decrease the inflow of calcium into the musclewall of arteries. A decrease in calcium within the musclecell causes the muscle to relax, thereby producing dilatationof the artery and decrease in blood pressure. Thelevel of calcium in the blood is not affected because thecalcium is blocked only in the wall of the artery. Becausethese agents block channels in the cell wall that takecalcium into the cell, they are also called calcium channelblockers.Unlike other antihypertensive agents, calcium antagonistsare effective in individuals at all ages and are evenmore effective in patients over age 65. Calcium antagonistsdo not cause the life-threatening angioedema that is rarelyobserved with ACE inhibitors.The calcium antagonist nifedipine (Adalat) has beenwidely used since 1982. Other calcium antagonistsinclude amlodipine, diltiazem (Cardizem), and verapamil(Isoptin). Verapamil slows the pulse rate and shouldnot be combined with a beta-blocker, except in specialsituations.a. Nifedipine (Adalat XL, Procardia XL)Supplied: Tablets: 30 mg, 60 mg, 90 mg.Dosage: One tablet taken once daily is sufficient tolower blood pressure over a 24-h period. the usual dosageis 30 mg once daily, if needed 60 mg, rarely 90 mg daily.Adalat XL and Procardia are slow-release preparationsthat have proven superior to the older formulation, nifedipinecapsules, which are used only in emergencies torapidly reduce very high blood pressure.This drug is very effective when combined with a betablocker.Thus a small dose of both drugs is often highlyeffective and has less adverse effects. Often physiciansincrease the dosage of a drug to levels that are advisedby the manufacturer and adverse effects may occur. Thecombination of a small dose of two drugs is often betterthat a large dose of one.Advice and Adverse Effects: Side effects include headaches,flushing, palpitations, dizziness, and swelling of thefeet in 5–10 percent of patients.b. Amlodipine (Norvasc)Dosage: 5–10 mg once daily.The actions and effects of amlodipine are similar tothat of nifedipine and other dihydropyridine calciumantagonists. This drug has a long duration of action.Edema occurs in approximately 10% of patients.c. Diltiazem (Cardizem, Tiazac)Supplied: Tablets: 30 mg, 60 mg, or Cardizem CD120 mg, 240 mg, and 300 mg.Dosage: Cardizem CD 120 mg once daily increasingif needed to 240 mg, maximum 300 mg.Advice and Adverse Effects: Adverse effects includemild flushing, rarely swelling of the feet, constipation,and slowing of the pulse rate.d. Verapamil (Isoptin)Supplied: Tablets: Isoptin SR 120 mg, 180 mg, and240 mg.Dosage: 120 mg daily increasing to 240 mg if needed.Advice and Adverse Effects: Constipation occurs inapproximately 15% of patients and is worse in the elderly.A slow pulse rate can occur.5. New Calcium AntagonistsLercanidipine, lacidipine, and manidipine are the newestcategory of long-acting dihydropyridines. These agentshave strong membrane binding and slow release to calciumchannels. The slow onset of action has important consequencesregarding the relative freedom from typicaldihydropyridine side effects which include tachycardia,palpitations, flushing, and edema that are significantlyreduced with these new agents. Because these newer agentsdilate both afferent and efferent arterioles, the highincidence of peripheral edema caused by older calciumantagonists is reduced more than 50%. The balancedeffect of lercanidipine and manidipine on efferent andafferent arterioles is important in renal protection. Theolder calcium antagonists listed above dilate only afferentarterioles. The COHORT study in elderly, hypertensivepatients concluded that lercanidipine and lacidipine aremuch better tolerated than amlodipine.Recent investigations indicate that lercanidipine administeredto hypertensive diabetic patients is more effectivethan the angiotensin receptor blocker, losartan, inreducing left ventricular hypertrophy and left ventricularmass.These third generation dihydropyridines represent animportant addition to the therapeutic armamentarium.Their place in clinical practice will increase furtherif they are shown to be devoid of the major adverseeffect of all calcium antagonists — the precipitation ofheart failure in patients with significant left ventriculardysfunction.

IX. DRUG TREATMENT4896. Other Vasodilatorsa. HydralazineSupplied: Tablets: 10 mg, 25 mg, and 50 mg.Dosage: 25–50 mg three times daily.Advice and Adverse Effects: This drug was used extensivelyfrom 1960 to 1966. It fell from popularity in 1968mainly because it produced significant side effects suchas an arthritis-like illness (systemic lupus erythematosus),dizziness, postural fall in blood pressure, and palpitations(tachycardia) and precipitation of angina in patientswith coronary heart disease.This drug is relatively ineffective when used alone,although it is effective when combined with a diureticand is even more effective when a beta-blocker is addedin a triple combination. Hydralazine is contraindicated inpatients with angina and aneurysms. Oral therapy isrecommended only when other regimens fail. This drug isuseful for controlling excessively high blood pressurein pregnancy just prior to delivery. It is contraindicatedin the first six months of pregnancy.7. Alpha-Blockersa. PrazosinSupplied: Capsules: 0.5 mg, 1 mg, 2 mg, and 5 mg (U.S.).Tablets: 1 mg, 2 mg, and 5 mg (UK and Canada).Dosage: For mild hypertension, start with 0.5 mg testdose at bedtime. If there is no weak spell (syncope)or other adverse effects 12 h later, then it is safe to take0.5–1 mg twice daily for a week then progress to threetimes daily.The average suggested maintenance dose is 2 mg threetimes daily for mild hypertension and 5 mg three timesdaily for moderate hypertension.A dose greater than 6 mg daily often causes an increasein heart rate and at this point the physician veryoften combines the drug with a beta-blocker, whichdecreases heart rate and further improves blood pressurecontrol.Prazosin blocks alpha receptors in the walls of thearteries. Alpha receptors in the artery wall, whenstimulated, cause constriction of the artery. By blockingthese receptors, prazosin causes the artery to dilate.The drug is thus a vasodilator.Advice and Adverse Effects: An unadvisable increasein heart rate is common. In this respect, the vasodilatordrugs, by expanding the arteries, cause a fall in bloodpressure similar to that of bleeding the patient. Thisproduces a reflex stimulation of the heart and an increasein heart rate. With hydralazine, palpitations may occurin 25% of patients and with prazosin, 5%. However,more than 20% of patients with either drug will have anincrease in heart rate.b. TerazosinThis alpha-blocker has actions similar to prazosin andis best used in combination with a beta-blocking agent.This reduces the tachycardia and increased cardiac ejectionvelocity caused by the alpha-blockers. These agents arenot recommended for treatment of hypertension exceptwhen other agents cannot be used because of adverseeffects. Alpha-blockers have been shown to increase theincidence of heart failure in patients with hypertension andin patients with left ventricle dysfunction and their useshould be curtailed.8. Drugs that Act Centrally in the Braina. ClonidineSupplied: Tablets: 0.1 mg and 0.2 mg.Dosage: 0.1 mg at bedtime and then increased to twicedaily, with the larger dose at night. Maintenance doseis 0.2–0.8 mg per day. Impulses or discharges originatein the brain (sympathetic impulses) and reach the arteriesand cause them to constrict, therefore elevating bloodpressure. Clonidine prevents these discharges or impulsesfrom leaving the brain.Advice and Adverse Effects: Clonidine is contraindicatedin patients with depression. Drowsiness isincreased by alcohol and tranquilizers. Dryness of themouth is common, and dry eyes may also occur. A severeincrease in blood pressure (rebound hypertension) canoccur if the drug is discontinued suddenly. This drugis rarely recommended.b. MethyldopaSupplied: Tablets: 125 mg, 250 mg, and 500 mg.Dosage: 250 mg twice daily increasing over days orweeks to 250 mg three times daily; 500 mg twice or threetimes daily.It is postulated that the action of tachycardia causedby alpha-blockers such as methyldopa is central in thebrain, decreasing sympathetic impulse outflow.Advice and Adverse Effects: Methyldopa shouldrarely, if ever, be used without diuretics, because it causessignificant sodium and water retention. This drug is aneffective antihypertensive agent when combined with adiuretic. Because of the potential side effects, methyldopa

490HYPERTENSIONis now reserved for treatment of moderate and severehypertension in combination with other agents that fail toachieve control. It is contraindicated with active liverdisease or depression. This has been known to cause a mildhemolytic anemia, so blood counts are necessary fromtime to time. If the drug is stopped suddenly, the bloodpressure often increases over the next 12 h to very highlevels (rebound hypertension); therefore, discontinue thedrug gradually. If the dose is increased too rapidly, asudden drop in blood pressure resulting in dizziness ora fainting spell may occur. Other adverse effects includedizziness, sedation, and sexual dysfunction. Methyldopahas been used successfully for more than 25 years to treatpregnancy-induced hypertension. It has an important rolein this setting because other agents except beta-blockersare contraindicated.9. New Agenta. Aliskiren [renin inhibitor]Gradman, et al. clinical trial; The antihypertensive effectof aliskiren, the first in a new class of orally effective,nonpeptide, low-molecular-weight renin inhibitors for thetreatment of hypertension was compared with the ARBirbesartan.Methods: The study was a randomized, multicenter,double-blind, placebo-controlled, active-comparator8-week trial in patients with mean sitting diastolic bloodpressure [DBP] 95 and

IX. DRUG TREATMENT491Hartman, R. P., Kawashima, A., King, F. et al. Evaluation of renal causesof hypertension. Radiol Clinic North America, 41:909, 2003.Heagerty, A. M. et al. Influence of changes of blood pressure on vascularangiotensin II receptor subtype expression. Circulation, 111:956–957,2005.Hermida, R. C., Ayala, D. E., Calvo, C., et al. Aspirin administeredat bedtime, but not on awakening, has an effect on ambulatoryblood pressure in hypertensive patients. J. Am. Coll. Cardiol.,46: 975–983, 2005.Kario, K., Pickering, T. G., Umeda, Y. et al. Morning surge in bloodpressure as a predictor of silent and clinical cerebrovasculardisease in elderly hypertensives: A prospective study. Circulation,107:1401–1406, 2003.Khan, M. Gabriel Hypertension. Cardiac Drug Therapy, sixth edition.W. B. Saunders, Philadelphia, 2003.Lakshman, M. R., Reda, D. J., Materson, B. J. for the Department ofVeterans Affairs Cooperative Study Group on Antihypertensive Agentset al. Diuretics and beta-blockers do not have adverse effects at 1 yearon plasma lipid and lipoprotein profiles in men with hypertension.Arch. Intern. Med., 159:551–558, 1999.Lenders, J. W. M., Eisenhofer, G., Mannelli, M., et al. Phaeochrocytoma.Lancet, 366: 665–675, 2005.Lucas, M. J., Leveno, K. J., Cunningham, F. G. et al. A comparison ofmagnesium sulfate with phenytoin: For the prevention of eclampsia.N. Engl. J. Med., 333:201, 1995.Lunde, H., Hedner, T., Samuelsson, O. et al. Dyspnoea, asthma, andbronchospasm in relation to treatment with angiotensin convertingenzyme inhibitors. BMJ, 308:18, 1994.Materson, B. J., Reda, D. J., Cushman, W. C. et al Single drug therapy forhypertension in men: A comparison of six antihypertensive agents withplacebo. N. Engl. J. Med., 328:914, 1993.Mattioli, A. V., Zennaro, M., Bonatti, S. et al. Regression of leftventricular hypertrophy and improvement of diastolic function inhypertensive patients treated with telmisartan. Int. J. Cardiol., 97:Issue 3, 383–388, 2004.Messerli, F. Evolution of the calcium antagonists: Past, present, andfuture. Clin. Cardiol., 26: (Suppl. 11), 1112-11-16, 2003.Nissen, S. E., Tuzcu, E. M., Libby, P. for the CAMELOT Investigatorset al. Effect of antihypertensive agents on cardiovascular events inpatients with coronary disease and normal blood pressure: TheCAMELOT Study: A randomized controlled trial. JAMA, 292:2217–2225, 2004.Panacek, E. A., Bednarxzyk, E. M., Dunbar, L. M. et al. Randomizedprospective trial of fenoldopam versus sodium nitroprusside in thetreatment of acute severe hypertension. Acad. Emergency Medicine,2:959, 1995.Pearson, A. C., Pasierski, T., Labovitz, A. J. et al. Left ventricularhypertrophy: Diagnosis, prognosis and management. Am. Heart J.,121:148, 1991.Pitt, B., Reichek, N., Willenbrock, R. et al. Effects of eplerenone,enalapril, and eplerenone/enalapril in patients with essential hypertensionand left ventricular hypertrophy: The 4E-left ventricularhypertrophy study. Circulation, 108:1831–1838, 2003.Pitt, B., Remme, W., Zannad, F. et al. Eplerenone post-acute myocardialinfarction heart failure efficacy and survival study investigators:Eplerenone, a selective aldosterone blocker, in patients with leftventricular dysfunction after myocardial infarction. N. Engl. J. Med.,348:1309–1321, 2003.Pitt, B., Reichek, N., Willenbrock, R. et al. Effects of eplerenone,enalapril, and eplerenone/enalapril in patients with essential hypertensionand left ventricular hypertrophy (EPHESUS): The 4E-LeftVentricular Hypertrophy Study. Circulation, 108:1831, 2003.Salathe, M., Weiss, P., Ritz, R. et al. Rapid reversal of heart failure in apatient with pheochromocytoma and catecholamine-induced cardiomyopathywho was treated with captopril. Br. Heart J., 68:527, 1992.SHEP Cooperative Study Group et al. Prevention of stroke byantihypertensive drug treatment in older persons with isolated systolichypertension: Final results of the Systolic Hypertension in the ElderlyPrograms (SHEP). JAMA, 265:3255, 1991.Slater, E. E., Merrill, D. D., Guess, H. A. et al. Clinical profile ofangioedema associated with angiotensin converting enzyme inhibition.JAMA, 260:967, 1988.UK Prospective Diabetes Study Group et al. Efficacy of atenolol andcaptopril in reducing risk of microvascular and macrovascularcomplications in type II diabetes: UKPDS. BMJ, 317:713, 1998.Verberk, W. J., Kroon, A. A., Kessels, A. G. H., et al. Home bloodpressure measurement: A systematic review. J. Am. Coll. Cardiol.,46: 743–751, 2005.Verdecchia, P., Angeli, F. et al. Natural history of hypertension subtypes.Circulation, 111:1094–1096, 2005.Wassertheil-Smoller, S., Blaufox, D., Oberman, A. et al. Effect of antihypertensiveson sexual function and quality of life: The TAIM Study.Ann. Intern. Med., 114:613, 1991.Wilkstrand, J., Warnold, I., Tuomilhto, J. et al. Metoprolol versus thiazidediuretics in hypertension. Morbidity results from the MAPHY Study.Hypertension, 17:579, 1991.Wood, S. M., Mann, R. D., Rawlins, M. D. et al. Angioedema andurticaria associated with angiotensin converting enzyme inhibitors.BMJ, 294:91, 1987.Yusuf, S., Gerstein, H., Hoogwerf, B. for the HOPE Study Investigatorset al. Ramipril and the development of diabetes. JAMA, 286:1882–1885, 2001.

Hypertrophy of the HeartI. PathophysiologyII. Causes and Complications of Heart HypertrophyIII. DiagnosisIV. Prevention and ManagementSuch an increase may depend upon enlargement of theindividual cells — hypertrophy proper — or they may beat the proliferation of the cells (hyperplasia) at the sametime; the two conditions are often present together.GLOSSARYafterload arterial impedance, restriction to blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of wall stress.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.cardiomyopathy heart muscle disease.concentric hypertrophy diffuse generalized thickening of themyocardium with little or no change in dimensions of the leftventricular cavity as seen in pressure overload of the leftventricle.eccentric hypertrophy hypertrophy with concomitant enlargementor dilatation of the ventricular cavity, as seen in volumeoverload of the left ventricle.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood and atheroma; medicalterm for a heart attack or coronary thrombosis.sarcomere the contractile unit of a myofibril; sarcomeres arerepeating units, delimited by the Z bands, along the length ofa myofibril that make up the myocardium of the heart.sudden cardiac death death from cardiac causes that occursinstantaneously or within the hour of the onset of symptoms;the hallmark features are an instantaneous and unexpectedtime and mode of cardiac death.NUMEROUS STUDIES HAVE DOCUMENTED Astrong relationship between hypertrophy of the heartand the risk of serious cardiac events. Hypertrophy is anincrease of the essential tissue of an organ, for example, themuscle cells of the heart or of the biceps in a bodybuilder.I. PATHOPHYSIOLOGYPhysiologic, naturally occurring hypertrophy usually representsas an adaptation to increased functional demands,and a similar principle dominates pathologic hypertrophy.Hypertrophy of the heart affects the left ventricle andleft ventricular hypertrophy is a feature of many forms ofheart disease. The left atrium may, however, hypertrophyto assist a left ventricle that is under stress and strainimposed by pressure or volume overload. The right ventriclemay hypertrophy in patients with pulmonary arteryhypertension or pulmonary valve stenosis. The rightatrium may hypertrophy to assist the right ventricle andalso be hypertrophied in patients with chronic obstructivepulmonary disease.A. Compensatory HypertrophyCompensatory hypertrophy occurs in response to abnormalfunctional demands imposed on the heart andthe processes are similar to the physiologic adaptationdescribed above. The heart muscle is capable of greathypertrophy when its workload is increased — such aswhen it has to pump against a pressure overload (systolicoverload) – as may occur with obstruction to the aorticvalve, aortic stenosis, or with chronic sustained hypertension.Hypertension is the most common cause of leftventricular hypertrophy.In hypertrophy of the heart the muscular wall becomesgreatly thickened, and the weight of the heart may be twicenormal or even more. The muscle fibers are increased inthickness and length, and enlargement of the individualfibers causes an increase in muscle mass. There is evidencethat division of muscle cells occurs, but this hyperplasia issubsidiary.493

494HYPERTROPHY OF THE HEARTReactive hypertrophy of the heart muscle may occurwhen myocardial muscle is lost. This is seen followinga myocardial infarction. This situation also occurs withdamage to the muscle caused by various cardiomyopathies.As muscle hypertrophy increases, the tension in the ventricularwall is amplified. This enhances hypertrophy ofsurviving myocytes and the following biochemical andpathophysiologic adaptations occur.1. The rate of contraction of the myocardium decreases,the time to achieve peak tension is delayed and relaxationis slowed.2. A slower myosin isoenzyme is synthesized to replace thenormal faster isoenzyme.3. The reaction of the myocardium to increased pressureoverload or afterload is to contract more forcefully butmore slowly.4. Volume overload of the ventricles occurs typically withsignificant mitral regurgitation, aortic regurgitation,and large ventricular septal defects.The biochemical and pathophysiologic processes thatengage in hypertrophy can be observed within hourswhen the heart is subjected to acute pressure overload. Itappears that the increased afterload stimulates myocardialhypertrophy by replication of sarcomeres in parallel. Thesarcomere structure looks like that of an electrostaticlinear motor (see Fig. 2 in the chapter Athlete and SuddenCardiac Death).The increase in myocardial mass occurs to compensatefor the decreased contractility of the heart muscle thatis subjected to pressure overload. The exact biochemical,neural, hormonal, or other pathophysiologic signal isunknown, but it is related to the chronic increase insystolic ventricular wall tension. Severe obstruction to theaortic valve or, aortic stenosis, is a typical pressure overloadsituation. Over time the hypertrophy of the ventricle takesplace in a concentric fashion; there is thickening of theentire left ventricle wall which includes the interventricularseptum. There is no increase in size of the left ventriclecavity, however. Concentric hypertrophy improves systolicwall tension and a strong heart muscle may pump forlonger than expected.In volume overload conditions there is an increase inpreload, defined as the degree of ventricular muscle stretchpresent at the onset of myocardial contraction. This isoften expressed as end diastolic volume or pressure.Volume overload causes the left ventricular wall and theventricular chamber to increase in size proportionately, andthis type of hypertrophy is termed eccentric hypertrophy.There is both hypertrophy and dilatation of the ventricularcavity as opposed to concentric hypertrophy inwhich the muscle mass increases but the ventricular cavityis not dilated or enlarged. The chronic increase in diastolicwall stress causes the production of additional sarcomerespredominantly in series. Preload, however, also increasessystolic wall stress and replication of sarcomeres in paralleltakes place and provides some normalization of systolicstress.The ventricular cavity expands to accommodate thelarge volume of regurgitant blood flow and this protectsthe ventricle from marked elevation of diastolic pressure.The heart is able to sustain this type of workload for severalyears before heart failure occurs. The molecular mechanismof hypertrophy, however, remains unclear. Myocardialstretch is recognized as playing an important role.B. Angiotensin IIMyocardial wall stretch stimulates the renin angiotensinaldosterone system (RAAS). Angiotensin II has beenshown to stimulate growth factors, cytokines, fibroblastactivity, myocyte hypertrophy, and myocardial fibrosis.The relative prevention of activation of the heart RAASby angiotensin-converting enzyme (ACE) inhibitors andmore recently by angiotensin receptor blockers has providedimportant additions to the armamentarium availableto prevent hypertrophy and/or cause regression. Otheragents that favorably influence the RAAS include the weakdiuretic spironolactone and a similar agent, eplerenone,which has less adverse effects. Beta-adrenergic blockingdrugs also decrease renin activity and complement theblockade of RAAS achieved with ACE inhibitors pluseplerenone.Although it is recognized that angiotensin II provides animportant mechanism for left ventricular hypertrophy,it appears that it is not the most important mechanism.Harada et al., in angiotensin II type Ia receptor knock–outmice were not able to prevent development of hypertrophy.The signaling processes that underlie the causes of myocardialhypertrophy require clarification which may providenew therapeutic strategies to prevent or amelioratehypertrophy.C. RNAAn important factor accounting for growth of the heartwhen it has to work against an increased pressure load isan increased concentration of RNA within the heart. Thelevels of RNA in the heart are elevated within 1–3 daysfollowing the burden of a high workload. Increasedcapacity for synthesis is a major determinant for the provisionof increased cardiac mass. After a rapid growthphase is over, RNA concentrations return to normal levels.

III. DIAGNOSIS495It is unclear whether the increase in RNA concentrationis due to faster synthesis or to reduce RNA degradation.Stretch of the ventricular wall seems to be the mechanicaldeterminant for the maintenance of the efficiency ofsynthesis and accelerated formation of new ribosomes.D. Mitochondria Mass and FunctionA decrease in the mass of mitochondria relative to the massof myofibrils occurs in experimental hypertrophy. Theremay be defects in mitochondrial oxidative phosphorylationand in mitochondrial calcium metabolism that couldlater lead to myocardial muscle failure.2. Volume overload due to clinical conditions such asmitral valve regurgitation, aortic valve regurgitation,large ventricular septal defects, and patent ductusarteriosus3. Reactive processes that may occur following obstructionto myocardial cells such as with myocardial infarction,myocarditis, dilated cardiomyopathy, and other causesof myocardial cell loss4. Diseases that primarily affect the myocardial musclesuch as hypertrophic cardiomyopathy (see Figure 1 inthe chapter entitled cardiomyopathy)5. Physiologic hypertrophy as seen in athletes (see thechapter Athletes and Sudden Cardiac Death).E. Other Factors1. Myosin and Myofibrillar ATPaseDuring hypertrophic processes there is decreased activity ofmyofibrillar and myosin adenosine triphosphatase whichmay explain alterations in contractile velocity.2. Connective TissueThe loss of cardiac myocytes stimulates hypertrophy ofexisting myocytes, but it is always accompanied by avariable replacement with collagen and other connectivetissue elements. Connective tissue is good supportingtissue, but its tensile strength is poor compared to that ofmyocardial muscle. It also has no contractile properties.Marked replacement with collagen is seen in hypertrophicas well as in other cardiomyopathies. Patchy and extensivereplacement of contractile myocardium with collagencauses weakening of the ventricular muscle. Ventricularsystolic and diastolic dysfunction results in and leadsto heart failure, which is a common feature of dilated cardiomyopathies(see the chapter Cardiomyopathy). Followinga myocardial infarction or myocarditis some patchyreplacement of necrotic myocytes by collagen and fibroustissue occurs.II. CAUSES AND COMPLICATIONSOF HEART HYPERTROPHYA. CausesCardiac hypertrophy can be caused by the followingprocesses.1. Pressure overload due to clinical conditions such asaortic stenosis, hypertension, pulmonary stenosis,coarctation of aortaB. ComplicationsLeft ventricular hypertrophy is associated with a significantincrease in the incidence of heart failure, myocardialinfarction, arrhythmias, and sudden death. In the presenceof left ventricular hypertrophy, the left atrium tries to pickup some of the stretch to aid the ventricle. The thin-walledweak chamber has very little to offer except that fibrosisoccurs during the course of left atrial hypertrophy andwith alterations the conducting tissue which culminatesin atrial fibrillation. Chronic hypertension that persistswithout adequate treatment for more than 10 years is acommon cause of mild left atrial hypertrophy and atrialfibrillation, which slowly predispose a patient to cardiacembolization to the brain causing stroke. Massive hypertrophy(>30 mm) in patients with cardiomyopathy isassociated with sudden death.III. DIAGNOSISThe diagnosis of left ventricular hypertrophy and leftatrial hypertrophy are readily made from electrocardiographicfindings. Figure 1 shows a normal ECG Figs. 2and 3 show features of left ventricular hypertrophy.The sum of the S wave in V1 (or V2 ) þ the R wave inV5 ( or V6) is 40 mm (normal is less than 35 mm; inthe normal tracing, Fig. 1, the sum is less than 30 mm).ST segment depression and T-wave inversion in leadsV5 and V6 (left ventricular strain pattern).Left atrial hypertrophy.The electrocardiogram, however, may not detect mildhypertrophy. Echocardiography is much more expensivebut more specific and sensitive for ventricular hypertrophythan the electrocardiogram. An expensive MRI test israrely required, but is extremely useful in differentiating

496HYPERTROPHY OF THE HEARTFIGURE 1 A normal ECG. Note the sum of the S wave in V1 (or V2), þ the S wave in V5 (or V6) is 30 mm, normal is less than 35 mm. There is nodeformity of the ST-T segment.FIGURE 2 Note the deep S waves in V1 and V2 and tall R waves in V5 and V6. Also note the deformity of the ST-T wave in V5 to V6 (left ventricularstrain pattern).

IV. PREVENTION AND MANAGEMENT497V1V4V2V5V3V6FIGURE 3 Note the standardization is at half voltage in V1 through V6 (thus the S waves are twice as deep and the R waves in V5 and V6 are twice astall, the sum being greater than 40 mm). ST-T abnormality in V5-V6 (strain pattern), lead V1 shows left atrial hypertrophy, which occurs early in thedevelopment of left ventricular hypertrophy. (From Khan, M. Gabriel Rapid ECG Interpretation, second edition, W. B. Saunders, Philadelphia, 2003).physiologic hypertrophy found in well-trained athletes asopposed to pathologic hypertrophy found in hypertrophiccardiomyopathy (see Figure 1 in the chapter Athletes andSudden Cardiac Death).A. Clinical study: Verdecchia et al.Study question: A prospective observational multicenterinvestigation was done because only a few single-centeredstudies support the prognostic value of elevated leftventricular mass in uncomplicated hypertension. Theprespecified aim was to explore the prognostic value ofleft ventricular mass in hypertension.Methods: Admission criteria included essential hypertension,and no previous cardiovascular events revealed onechocardiographic tracings. Then 1033 individuals (396men) were followed for a median of 3 years. Their meanblood pressure was 154/92, and left ventricular massgreater than 125 g per body surface area.Results: Left ventricular hypertrophy was associated withincreased risk of cardiac events. For each 39 g/m 2 increasein left ventricular mass there was an independent 40% risein the risk of major cardiovascular events ( p ¼ 0.0013).Conclusions: The findings showed a strong continuousand independent relationship of left ventricular mass tosubsequent cardiovascular morbidity.IV. PREVENTION AND MANAGEMENTHypertension is the main cause of left ventricularhypertrophy and aggressive treatment of hypertension

498HYPERTROPHY OF THE HEARTcan prevent it. Some antihypertensive agents are, however,not effective in preventing hypertrophy. With some agentsthe blood pressure may be lowered but hypertrophy maynot be arrested and may not show regression.A. Alpha-BlockersAlpha-1 receptor adrenergic blockers include prazosin,terazosin, and doxazosin. Several clinical studies haveshown that these agents do not prevent hypertrophy, and insome instances they have shown an insignificant increasein left ventricular mass. The reason for their lack ofeffectiveness is probably related to the fact they stimulatethe heart and increase ejection velocity as well as heart rate.This calls for more effort because the heart has to workharder. In addition, these agents increase norepinephrinelevels that stimulate the sympathetic nervous system. Theyalso cause sodium and water retention as well as increasedincidence of heart failure. The ALLHAT study indicatedthat these agents increase morbidity and mortality due toheart failure in hypertensive patients and they are nolonger recommended. These agents were widely used forthe management of hypertension from 1970 to 2001because they do cause a lowering of blood pressure and donot have deleterious effects on blood lipid levels. They arestill prescribed by specialists who give them to diabeticpatients because they do not raise blood lipid levels.B. ACE InhibitorsThese agents have been shown to be effective in preventinghypertrophy and cause regression. Similar agents suchas angiotensin II receptor blockers are just as effective.Blockade of angiotensin II by inhibition of its formationby an ACE inhibitor or by blockade of the effects ofangiotensin I at the AT1 receptor has favorable effects onleft ventricular hypertrophy. But these agents also inhibitthe formation of aldosterone, which increases hypertrophy.C. Beta-Adrenergic BlockersThese agents have been shown to decrease left ventricularhypertrophy but effects appear to be modest whencompared with ACE inhibitors. Nonetheless, these drugsare cardioprotective and strongly advisable for use in acombination of a beta-blockers to prevent hypertrophy,produce regression, and prevent cardiac events. Both betablockersand ACE inhibitors have been proven independentlyto reduce the risk of serious cardiac events. Anappropriate beta-blocker should be chosen, however,because subtle and important differences exist amongthe available beta-blockers. Bisoprolol, carvedilol, andmetoprolol (Toprol) are more effective agents than otherbeta-blockers and have proven cardioprotective effectsdocumented by randomized controlled trials.D. Calcium AntagonistsCalcium antagonists and calcium channel blockers includeamlodipine, felodipine, and nifedipine. These agents causeexcellent lowering of blood pressure but have notconsistently shown beneficial effects regarding preventionof left ventricular or its regression.An excellent study by Gottdiener et al. on 587 patientstreated with single agents and left ventricular hypertrophystudied by echocardiography showed that ACE inhibitorswere most effective followed by hydrochlorothiaziderather than atenolol. Atenolol is not a good beta-blockerfor a trial, however, because it has never been shown to becardioprotective in randomized clinical trials. Clonidine,prazosin, and diltiazem (a calcium antagonist) showed nochange or insignificant increases in left ventricle mass.E. DiureticsDiuretics commonly used include hydrochlorothiazideand chlorthalidone. These agents have been shown tocause modest reduction in left ventricular hypertrophyand regression in some studies, but other studies haveshown negative effects.F. Aldosterone Receptor Blocking Agentsa. SpironolactoneAldosterone is produced by the adrenal cortex under theinfluence of renin and angiotensin and has been shownto cause ventricular hypertrophy and myocardial fibrosis.Fibrosis causes weakness of the muscle and also producesabnormal relaxation of the left ventricle and left ventriculardiastolic dysfunction. This hormone appears toblock extraneuronal uptake of norepinephrine from themyocardium and may augment cardiac failure andincreased risk of sudden cardiac death that is associatedwith activation of the RAAS and left and hypertrophy.ACE inhibitors and angiotensin II blockers inhibitangiotensin production and actions that finally suppressaldosterone, but the suppression is far from complete.Even a combination of ACE inhibitors and angiotensin IIreceptor blockers has failed to completely suppressaldosterone production.

IV. PREVENTION AND MANAGEMENT499b. Eplerenone (Inspra)Because spironolactone causes gynecomastia and othermild adverse effects, new aldosterone receptor blockersare being sought. A new compound, eplerenone, does nothave the same side effects as spironolactone. Eplerenonewas developed by replacing the 17 alpha-thiacetyl group ofspironolactone with a carbomethoxy group. The drug isdevoid of sex hormonal effects of spironolactone because ithas a greater selectivity for the mineralo-corticoid receptorthan for steroid receptors.Pitt et al. have shown that 200 mg of eplerenone dailywas as effective as enalapril in controlling BP and inobtaining LVH regression. The combination of eplerenoneand enalapril was more effective in reducing LV mass andSBP than eplerenone alone.Dosage. 50–200 mg once daily. Hyperkalemia mayoccur when used concomitantly with ACE inhibitors,ARBS, or potassium-retaining agents.BIBLIOGRAPHYCarlberg, B., Samuelsson, O., Lindholm, L. H. et al. In hypertension: Is ita wise choice? Lancet, 364:1684–89, 2004.Devereux, R. B. Do antihypertensive drugs differ in their ability toregress left ventricular hypertrophy? Circulation, 95:1983–85, 1997.Gottdiener, J. S., Reda, D. J., Massie, B. M. et al. For the VA CorporativeStudy group on antihypertensive agents. Effects of single drug therapyon reduction of left ventricular mass in mild to moderate hypertension:Comparison of six antihypertensive agents. Circulation,95:2007–14, 1997.Harda, K., Komuro, I., Shiojima, I. et al. Pressure overload inducescardiac hypertrophy in angiotensin II type Ia receptor knock–out mice.Circulation, 97:1952–1959, 1998.Mattioli, A. V., Zennaro, M., Bonatti, S. et al. Regression of leftventricular hypertrophy and improvement of diastolic function inhypertensive patients treated with telmisartan. Int. J. Cardiol., 97:Issue 3, 383–388, 2004.Pitt, B. Regression of left ventricular hypertrophy in patients withhypertension. Blockade of the renin angiotensin aldosterone system.Circulation, 98:1987–89, 1998.Pitt, B., Reichek, N., Willenbrock, R. et al. Effects of eplerenone,enalapril, and eplerenone/enalapril in patients with essential hypertensionand left ventricular hypertrophy: The 4E-left ventricularhypertrophy study. Circulation, 108:1831–1838, 2003.Pitt, B., Remme, W., Zannad, F. et al. Eplerenone post-acute myocardialinfarction heart failure efficacy and survival study investigators:Eplerenone, a selective aldosterone blocker, in patients with leftventricular dysfunction after myocardial infarction. N. Engl. J. Med.,348:1309–1321, 2003.Verdecchia, P., Carini, G., Circo, A. et al. Left ventricular mass andcardiovascular morbidity in essential hypertension: The MAVI study.J. Am. Coll. Cardiol., 38:1829–35, 2001.

Kawasaki Heart DiseaseI. Clinical FeaturesII. DiagnosisIII. CausationIV. ManagementGLOSSARYarterial dilatation enlargement or increase in luminal diameterof the artery.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.vasculitis inflammation of the walls of a blood vessel.KAWASAKI DESCRIBED THIS ILLNESS INJapanese children in 1967. The major cardiac lesion isan inflammatory reaction of the walls of arteries orvasculitis of the coronary arteries. A similar disease ispolyarteritis nodosa. The exact cause of the disease isunknown. It is seen worldwide, however; in Japan childrenwith a mean age of 12 months are affected and in theUnited States the mean age is closer to 3 years. Kawasakiheart disease is rare in children over the age of 8 with morethan 85% being younger than 5 years. Children youngerthan 6 months or older than 8 years are rarely affected; butthe older group is at increased risk of coronary-arteryaneurysms. The reported annual incidence rate in Japanis approximately 140 per 100,000 children under 5 yearsof age versus 17 and 8 in the US and UK, respectively.Rheumatic fever caused by streptococcal sore throats wasa common occurrence in children in developed countriesprior to 1970. The disease is still common in nonindustrializedcountries. In Japan and the western world Kawasakidisease is now a more common cause of acquired heartdisease in young children than acute rheumatic fever.I. CLINICAL FEATURESThis disorder is virtually always accompanied by fever formore than 5 days. The fever has no identifiable cause(fever of unknown origin) and occurs without the commonmanifestation of an upper respiratory tract viral infectionor flu-like illness. The diagnosis is entertained if feverof unknown origin is accompanied by at least four of thefollowing:1. Bilateral conjunctival redness, injection2. Inflamed throat, redness of the tongue (strawberrytongue), fissuring of the lips3. Redness of the palms and soles of the feet, swelling,edema of the hands and feet4. Body rash5. Enlargement of lymph nodes around neck (cervicallymphadenopathy).Because these features are much more common inthe Far East, the condition is recognized as part of amucocutaneous lymph node syndrome. The cardiac partof this syndrome is now widely referred to as Kawasakidisease.Other symptoms are not necessary for the diagnosticconclusions including joint pains, diarrhea, vomiting,bowel pain, and aseptic meningitis. The disease maybe confused with and must be distinguished from thefollowing:1. Streptococcal sore throat and streptococcal infections2. Staphylococcal toxin-mediated illness3. Viral infections such as adenovirus, enterovirus, andmeasles4. Allergic reactions to various medications and householdproducts5. Myocarditis.II. DIAGNOSISDiagnosis is difficult and infants with three or moreof the above symptoms with unexplained fever for morethan 2 weeks should have an echocardiographic evaluationto exclude coronary artery aneurysms. Damage to thecoronary arteries by vasculitis occurs in more than 25%of infants and in about 10% of children age 2–5. Coronary501

502KAWASAKI HEART DISEASEartery aneurysm and thrombosis may cause myocardialinfarction and sudden death. Similar aneurysms may befound in the worst affected cases in the renal, cerebral, andabdominal arteries. Children frequently died duringthe acute phase of Kawasaki disease, but if they recoverthey may present with symptoms of aneurysms duringadolescence and rupture of an aneurysm may causesudden death. Coronary-artery aneurysms occur as asequela of the vasculitis in 20–25% of untreated children.The syndrome may remain silent until the third orfourth decade of life, when patients are present with anacute myocardial infarction. Cardiac complications includemyocarditis, pericarditis with effusion; mitral valvularlesions occur in about 1% of patients.Nonspecific findings include anemia, increasing whiteblood cell count, sediment rate and C-reactive protein, andmild elevation of liver enzymes. The electrocardiogrammay show nonspecific ST-T wave changes caused bymyocarditis.III. CAUSATIONThe cause of Kawasaki syndrome remains unknown;an infectious agent is suspected because of the following Seasonal peak in the winter and spring months in mostgeographic areas. Geographic focal epidemics occurred in the 1970s and1980s.Burns et al., point out that ‘‘peak incidence in thetoddler age-group with only rare cases in infants under 3months of age and in adults suggests a role for transplacentalantibodies conferring protection and developmentof protective immunity as a result of asymptomaticinfection in most individuals.’’ Burns et al., suggest that‘‘Research should focus on unique features of the vasculitisthat might serve as a diagnostic test, even if the underlyingcause remains unknown.’’Kawasaki syndrome and polyarteritis nodosa possesssimilarities and essential differences: Coronary artery aneurysms occur in about 20%of children with kawasaki and in less than 1% withpolyarteritis nodosa. The pattern of inflammation in Kawasaki revealsinfiltration of CD8-positive T cells and macrophage andfew polymorphonuclear cells with prominent edemawithout fibrinoid necrosis versus prominent fibronoidnecrosis, a hallmark of polyarteritis nodosa.IV. MANAGEMENTA. Intravenous Gamma Globulin TherapyCoronary artery abnormalities such as aneurysm andthrombosis are reduced by treatment with intravenousgamma globulin 2 g/kg in a single infusion over 10–22hours given within the first 10 days of illness. But morethan 5% of children treated develop dilatation of thecoronary arteries and in 1% giant aneurysms develop.Intravenous therapy is repeated if there is occurrence offever for more than 48 h.B. AspirinThe anti-inflammatory actions of moderate doses ofaspirin are useful in controlling fever, then the dose isreduced to approximately 5 mg/kg/day for 8 weeks.This small dose inhibits platelet aggregation and mayprevent thrombosis. Treatment with aspirin does notprevent formation of aneurysms. During the assumedrecovery phase, coronary artery vasculitis may precipitatemyocardial infarction.C. CorticosteroidsSome studies indicate that the use of steroids prevents theoccurrence of coronary artery aneurysms. As with otherconditions that cause vasculitis, corticosteroids appear toquench the fiery stage but they are not curative.Antithrombotic agents and occasionally coronary arterybypass graft is required to treat Kawasaki disease. Furtherresearch is required to uncover the etiologic process of thisdisease and its pathogenesis in order to develop logicaltherapeutic strategies.BIBLIOGRAPHYBurns, J. C. et al. Translation of Dr. Tomisaku Kawasaki’s original reportof fifty patients in 1967. Pediatr. Infect. Dis. J., 21:993–95, 2002.Burns, J. C., Glodé, M.P. et al. Kawasaki syndrome: Seminar. Lancet,364:533–44, 2004.Burns, J. C., Shike, H., Gordon, J. B., Malhotra, A., Schoenwetter, M.,Kawasaki, T. et al. Sequelae of Kawasaki disease in adolescents andyoung adults. J. Am. Coll. Cardiol., 28:253–57, 1996.Dajani, A. S., Taubert, K. A., Gerber, M. A. et al. Diagnosis and therapyof contrast at the disease in children. Circulation, 87:1776, 1993.Kato, H., Inoue, O., Kawasaki, T., Fujiwara, H., Watanabe, T., Toshima, H.et al. Adult coronary artery disease probably due to childhoodKawasaki disease. Lancet, 340:1127–29, 1992.

IV. MANAGEMENT503Kawasaki, T., Kosaki, F., Okawa, S. et al. A new infantile acute febrilemucocutaneous lymph node syndrome (MCLS) prevailing in Japan.Pediatrics, 54:271–76, 1974.Kawasaki, T. et al. Pediatric acute mucocutaneous lymph node syndrome:Clinical observation of 50 cases. Arerugi (Jpn. J. Allergy), 16:178–222,1967.Kushner, H. I., Bastian, J. F., Turner, C. L., Burns, J. C. et al. Rethinking theboundaries of Kawasaki disease. Perspect. Biol. Med., 46:216–33, 2003.Landing, B. H., Larson, E. J. et al. Are infantile periarteritis nodosa withcoronary artery involvement and fatal mucocutaneous lymph nodesyndrome the same? Comparison of 20 patients from North Americawith patients from Hawaii and Japan. Pediatrics, 59:651–62, 1976.Mitani, Y., Sawada, H., Hayakawa, H., Auki, K. et al. Elevated levels ofhigh-sensitivity C-reactive protein and serum amyloid-A late afterKawasaki disease: Association between inflammation and late coronarysequelae in Kawasaki Disease. Circulation, 111:38–43, 2005.Moran, A. M., Newburger, J. W., Saunders, S. P. et al. Abnormalmyocardial mechanics in Kawasaki syndrome. Rapid response togamma globulin. Am. Heart J., 139:217–23, 2000.Newburger, J. W., Takahashi, M., Burns, J. C. et al. Treatment ofKawasaki syndrome with intravenous gamma globulin. N. Engl. J.Med., 315:341–47, 1986.Newburger, J. W., Takahashi, M., Gerber, M. A. et al. Diagnosis,treatment, and long-term management of Kawasaki disease: Astatement for health professionals from the Committee on RheumaticFever, Endocarditis and Kawasaki Disease, Council on CardiovascularDisease in the Young, American Heart Association. Circulation, 110:2747–2771, 2004.Wu, M. T., Hsieh, K.S., Lin, C. C. et al. Evaluation of coronaryartery aneurysms in Kawasaki disease by multislice computedtomographic coronary angiography. Circulation, 110:e339, d,2004.

Miscellaneous DisordersI. Marfan SyndromeII. Cor PulmonaleIII. Ehlers-Danlos SyndromeIV. Noonan SyndromeV. Ebstein’s AnomalyVI. Turner SyndromeVII. Fetal Alcohol SyndromeVIII. Holt-Oram SyndromeIX. Paget’s DiseaseX. Ankylosing SpondylitisXI. Rubella SyndromeXII. Pseudoxanthoma ElasticumXIII. Myotonic Muscular DystrophyXIV. TakayasuXV. Lupus ErythematosusXVI. SarcoidosisXVII. SyphilisXVIII. Atrial Myxoma1. Heart and AortaMitral valve prolapse, dilatation of the sinuses of Valsalva,and aortic regurgitation are common findings in Marfansyndrome patients. Dilatation of the aortic root and ascendingaorta leads to aneurysm formation and dissectionwhich accounts for early mortality. The average age ofdeath is in the fourth and fifth decades of life.2. EyesThe eyes show a tremulous iris typical of dislocation ofthe lens (ectopia lentis), myopia, and retinal detachment.Sometimes there is a blue sclera.3. SkeletonThe skeleton shows joint hypermobility, long extremitiesand fingers, typical arachnodactyly (spider finger; thethumb protrudes beyond the little finger when the fistis clenched), tall stature, pectus excavatum or pectuscarinatum, a high-arched palate, and scoliosis.I. MARFAN SYNDROMEMarfan syndrome is an autosomal dominant disorderthat occurs in all races and ethnic groups. Marfansyndrome is caused by mutations in the gene thatencodes fibrillin-1, the major constituent of microfibrilsthat forms elastic fibers in tissues of the middle wall ofthe aorta and arteries.A. Diagnostic Symptoms and Physical SignsThe heart, aorta, the eye, and the skeleton show typicalfeatures that are diagnostic, but marked clinical variabilityand a high rate of new mutation make detectionof mildly affected young sporadic patients difficult todiagnose. Thus, failure to diagnose Marfan syndrome iscommon.B. ManagementEndocarditis prophylaxis is necessary as well as restrictionof severe exertional activity including weightlifting andcontact sports. The use of beta-adrenergic blocking drugssuch as metoprolol have been shown to delay the rate ofaortic dilatation and the risk of aortic dissection. Pregnancyshould be avoided in individuals with an aortic diameterthat exceeds 3.5 mm, because pregnancy enhances dissectionin the third trimester or during parturition and thefirst month postpartum.II. COR PULMONALECor pulmonale describes heart disease secondary to lungdiseases (pulmonary heart disease). These conditions causesevere chronic hypoxemia, which increases pulmonary505

506MISCELLANEOUS DISORDERSartery pressures and right ventricular workload resultingin right heart failure. Hypoxemia is a potent stimulus forvasoconstriction and pulmonary hypertension. Right heartfailure is manifested by shortness of breath and easyfatigability at rest or mild activity. Heart failure causesretention of salt and water by the kidneys which leads toswelling of the legs; the legs are brine-logged and notsimply waterlogged.A. Causes1. Chronic Bronchitis and EmphysemaThe most common causes of cor pulmonale are long-severechronic bronchitis and emphysema.2. Chronic and Restrictive Lung DiseasesChronic obstructive lung disease (COPD) is the mostcommon cause of cor pulmonale. Long-standing severechronic bronchitis and emphysema are the main causes ofchronic obstructive lung disease, which leads to severehypoxemia.Restrictive lung diseases also are a common cause of corpulmonale. They encompass a large group of diffuse lungdiseases that show a typical filling of the alveoli and/orinfiltration of the pulmonary interstitium, which results ina characteristic pattern of restrictive lung impairment withreduction in lung volumes and decrease in the complianceof the lung (see chapter entitled Pulmonary ArterialHypertension).These diseases include disorders of unknown cause(idiopathic pulmonary fibrosis, sarcoidosis, collagenvascular disease), infections (viral, bacterial, fungal, andparasitic), and environmental lung disease (pneumoconiosis,asbestosis, silicosis, berylliosis, silo-fillers disease).Restrictive lung disease causes severe hypoxemia whichresults from mismatching of ventilation and perfusion.Gas exchange is typically disturbed during exercise sorestrictive lung disease limits lifestyle considerably.Notable findings include:B. DiagnosisIncreased shortness of breath on minimal exertionEasy fatigability at restTachypneaPursed lips expirationParadoxical abdominal breathing and constant use ofaccessory muscles of respirationAsterixis and chemosisCentral cyanosis with warm extremities are observed,but the occurrence of peripheral cyanosis with coldextremities indicates that right heart failure hassupervenedFindings of diffuse crackles (crepitations) heard onauscultation over the lung fields. The PaO 2 is usually lessthan 55 mmHg when patients are free from an exacerbationof COPD. There is a reduced diffusion capacity forcarbon monoxide (Dlco) in patients with restrictive lungdisease and emphysema but not in those with pure chronicbronchitis. The chest x-ray may narrow the differentialdiagnosis when combined with a history and physicalexamination. High-resolution CT is often necessary toconfirm radiologic findings with further confirmationby thoracoscopic lung biopsy.C. ManagementManagement of patients with corpulmonale consistsof treatment of the underlying disease and correctionof hypoxemia with continuous oxygen administration. Aminimum of 15 h of oxygen daily to keep the PaO 2 greaterthan 60 mmHg may provide a modest improvementin survival and activity levels. Digoxin is indicated only ifatrial fibrillation is present. Furosemide is given to relievebothersome bilateral pitting edema at doses of 20–40 mgdaily.III. EHLERS-DANLOS SYNDROMEVarious defects of type III collagen are the cause of thephenotype in all patients with Ehlers-Danlos syndrome.Both skin and joint manifestations are associated withspontaneous rupture of medium and large caliber arteries.The skin is fragile leading to skin abnormalities and theeyes may show a blue coloring of the sclerae, which is alsoseen with osteogenesis imperfecta.A rupture of an artery without aneurysm formation ordissection may occur. The abdominal aorta or mediumsizedbranches of aorta; for example, the subclavian or largearteries of the limbs may rupture, but true aneurysmsrarely form. Mitral valve prolapse occurs, but aortic rootdilatation is rare.IV. NOONAN SYNDROMEThis it is an autosomal dominant disorder that leads toshort stature, cubitus valgus, neck webbing, congenitallymphedema, and congenital heart defects similar to that

XII. PSEUDOXANTHOMA ELASTICUM507of Turner syndrome. Both males and females are affectedand manifest deformity of the sternum, mental dullness,typical hypertelorism, and drooping of the eyelid (ptosis).Cardiac manifestations include valvular pulmonarystenosis; the valve cusps are thickened and dysplastic anda right-sided flow may be impeded by obstruction becauseof pulmonary artery hypoplasia. In more than one-third ofpatients an atrial septal defect occurs often in associationwith pulmonary valve stenosis.V. EBSTEIN’S ANOMALYThis disorder is characterized by downward displacementof the tricuspid valve into the right ventricle caused byanomalous attachment of the tricuspid valve leaflets. If thetricuspid valve is severely deformed, heart failure occursand death may result in utero or soon after birth. Withmild deformity individuals may remain symptom-free intoadulthood or beyond middle age. Associated malformationsinclude a patent foramen ovale, an atrial septaldefect, and pulmonary stenosis or atresia. An ostiumprimum atrial septal defect alone or combined with otherdefects indicates a bad prognosis. This abnormality may beassociated with congenital corrected transposition of thegreat vessels. Adult patients present with shortness of breathand fatigue, palpitations, associated Wolff-Parkinson-White syndrome, cyanosis from a right-to-left shunt, andoccasionally paradoxical embolus causing a cerebrovascularaccident. Diagnosis is usually made from echocardiographicexamination.VI. TURNER SYNDROMEThis anomaly is manifested in females who lack an Xchromosome (45, X karyotype). Coarctation of the aortamay be seen. A bicuspid aortic valve, aortic stenosis, anddilatation of the ascending aorta with the risk of aorticdissection may occur, even in the absence of a coarctation;thus, endocarditis prophylaxis is necessary.The body habitus includes low hairline, low-set ears,deafness, small jaw, short webbed neck, short stature,broad chest with widely spaced nipples, hypertelorism,epicanthal folds, ptosis, and a shortened fifth finger.VII. FETAL ALCOHOL SYNDROMEChildren born to alcoholic mothers may be affected withfetal alcohol syndrome. Because of maxillary hypoplasiathese individuals have an undeveloped appearing centralface along with a small upturned nose (micrognathia) andthin upper lip. Common associated cardiac lesions includeatrial and ventricular septal defects.VIII. HOLT-ORAM SYNDROMEIn this autosomal dominant disorder the common cardiacabnormalities are an atrial or ventricular septal defect thatis associated with a characteristic fingerized thumb. Thethumb resembles a finger that has been displaced intothe same plane as the other digits; the thumb may betriphalangeal, hypoplastic, absent, or unusually long.IX. PAGET’S DISEASEPaget’s disease of bone characteristically causes a large headsize. Cardiovascular lesions include large arteriovenous(AV) fistulas that may cause congestive heart failure.Calcification of the aortic valve may cause a loud murmurproduced by aortic sclerosis without stenosis. Calcificationof the electrical conduction system may result in a slowheart rate (bradycardia), and occasionally complete heartblock that may require an electronic pacemaker.X. ANKYLOSING SPONDYLITISThis disease of the skeleton often cause sacroilitis with apainful low back caused by a fused inflexible spine. Thepatient is hunched over because of an immobile curvedspine with forward jutting of the head. The associatedcardiac lesion is aortic regurgitation and sometimes atrioventricularblock.XI. RUBELLA SYNDROMEA history of maternal rubella is usually obtained.Manifestations include cataracts, nystagmus, and deafness.XII. PSEUDOXANTHOMA ELASTICUMIn this condition the skin around the armpit (axilla),the antecubital fossa, behind the knee (popliteal fossa),the neck, and other areas becomes lax with characteristicyellowish papules. Examination of the retina with

508MISCELLANEOUS DISORDERSthe ophthalmoscope may reveal angioid streaks. Lifethreateninggastrointestinal hemorrhage is common.The most important cardiac lesion involves the coronaryarteries, which develop a form of arteriosclerosis that maycause coronary artery occlusion resulting in myocardialinfarction. Other associated cardiovascular disordersinclude thickened aortic and mitral valves, mitral valveprolapse, and hypertension.The recessive and dominant forms of this disorder havebeen mapped to the same region of chromosome 16.Management includes control of hypertension and riskfactors for atherosclerosis. Dietary calcium intake shouldbe restricted including consumption of dairy products andavoidance of calcium supplements because of a positiveassociation between severity of the disease and dietarycalcium intake.XIII. MYOTONIC MUSCULAR DYSTROPHYIn adults diagnostic features of myotonic musculardystrophy include reflex, percussion, and grip myotonia.This is a characteristic inability to release after exerting agrip on an object. There is also weakness and atrophyof the skeletal muscles, premature baldness, cataracts,and mental retardation. Cardiologic involvement includesarrhythmia, intraventricular conduction defects, and completeheart block that may require electronic pacing. Thereis fibrosis and fatty infiltration with degeneration of thespecialized electrical conduction tissue, particularly thesinus node, AV node, and Purkinje system.XIV. TAKAYASUThis larger vessel vasculitis of unknown etiology occurs inyoung individuals in Asia and Mexico. In these areasTakayasu arteritis is one of the most common causes ofhypertension in young adults. Women are affected about10 times more often than men.A. Cardiovascular LesionsAneurysm formation of the aortic root leads to aorticregurgitation and arterial occlusions (stenosis) of the majorbranches of the aorta such as the subclavian, carotid,brachiocephalic, and renal arteries. Stenosis of the renalartery causes hypertension. Occlusion of one subclavianartery results in a low blood pressure recording in thatarm, and the high blood pressure that exists may not bedetected if the blood pressure is not checked in botharms. The characteristic histologic lesion is intense mononuclearleukocyte infiltration in the presence of giant cells.This pronounced intimal thickening leads to minimalresidual lumen of arteries and organ ischemia (lack ofblood perfusion) because of the stenotic lesions.The mortality rate is high because of the aggressivevascular disease caused by hypertension or primary cardiacrenal and central nervous system involvement. Mortality isas high as 35% at 5 years.Symptoms are caused by lack of blood supply toorgans and fatigue, night sweats, and fever may occur.Involvement of the aortic root may cause severe aorticregurgitation, angina, and congestive heart failure. Thesedimentation rate is assessed, but it may be normal in upto 50% of individuals with progressive lesions.B. ManagementCorticosteroid therapy, such as prednisone 1 mg/kg dailyproduces beneficial results in up to 60% of patients.Prednisone combined with cyclophosphamide or methotrexateproduces up to 40% remission, but relapse iscommon. Stenotic lesions throughout the vascular arterialsystem should be identified and corrected surgically ifpossible.XV. LUPUS ERYTHEMATOSUSThis well-known disorder may cause rare cardiac lesions.Pericardial lesions occur in more than 30% of patients,but significant pericarditis is manifested in less than 20%.The initial manifestation of lupus erythematosus (LE)may be pericarditis, but pericardial involvement mayoccur at any stage of the disease. Cardiac tamponade maybe caused by pericardial effusion.Acute myocarditis is a rare complication. Arteritis ofcoronary arteries may cause chest pain of acute coronarysyndrome and rarely results in acute myocardialinfarction. Conduction abnormalities rarely cause heartblock requiring a pacemaker. Arrhythmias may requireantiarrhythmic therapy.Valvular disease may occur as thickening of valve structuresand vegetations (Libman-Sacks noninfective endocarditis)are rare but characteristic lesions. Vegetationsare generally located on the atrial side of the mitral valveand the arterial side of the aortic valve. They are usuallyimmobile and thus rarely embolize to cause a mini stroke.Cardiovascular complications and renal disease are themost common cause of mortality (see the chapterBlood Clots).

XVIII. ATRIAL MYXOMA509XVI. SARCOIDOSISSarcoidosis is a well-recognized granulomatous diseasethat causes enlarged lymph nodes (lymphadenopathy) inthe hilar region of the lung. In some individuals the diseaseaffects the spongework of the lung (parenchyma) andcauses restrictive lung disease (see Section II and thechapter Cardiomyopathy). Sarcoidosis involvement of thelung may be confused with tuberculosis, lymphoma orcancer.The granulomatous involvement of the myocardiumand conducting tissue may cause atrioventricular block andcomplete heart block which requires an electronic pacemaker.Sarcoidosis may cause dilated cardiomyopathy thatmay be difficult to distinguish from idiopathic dilatedcardiomyopathy. Prednisone produces beneficial effectsin some patients.XVII. SYPHILISThe main cardiovascular lesion caused by syphilis is anaortitis that causes aortic aneurysms, aortic regurgitation,and coronary ostial lesions. Spirochetal infection was oncea common cause of aneurysm of the ascending thoracicaorta. These aneurysms cause complications includingcompression of the recurrent laryngeal nerve which resultsin hoarseness and pressure on the bronchi causes a brassycough.A characteristic radiologic finding is linear calcificationof the ascending aorta. Syphilitic aneurysms are nowa rare finding in the western world as a result of aggressiveantibiotic treatment of syphilis in its early stages.The latent period from the initial syphilitic infectionto significant aortic aneurysm formation is about 10–30years. The aortic valve ring is typically severely dilatedresulting in severe aortic regurgitation.Microscopically, the vasa vasorum of the aorta areinvolved in an endarteritis obliterans that causes weakeningof the arterial wall and aneurysm formation. Rupture ofaneurysms may rarely occur.XVIII. ATRIAL MYXOMABenign primary cardiac tumors are uncommon andmalignant tumors are rare. Metastatic tumors occur moreoften than primary tumors of the heart, but rarely causefunctional disturbances. A left atrial myxoma is the mostcommon cardiac tumor and is usually symptomatic.Symptoms include fever, weakness, malaise, Raynaud’sphenomenon, and finger clubbing. The diagnosis may bemissed because of nonspecific findings. Cardiac symptomsinclude shortness of breath on exertion, paroxysmalnocturnal dyspnea, syncope, and palpitations. Embolizationof tumor fragments may cause transient cerebralischemia attacks or small strokes. Embolization may occurto the limbs causing limb ischemia. Multiple embolizationmay mimic vasculitis or infective endocarditis.Mobile pedunculated left atrial myxomas may prolapseinto the mitral valve orifice causing obstruction toblood flow that results in syncope or cardiogenic shock.Symptoms and signs may mimic mitral stenosis (see thechapter Valve Diseases). Arrhythmias such as supraventriculartachycardia, ventricular premature beats, and occasionallyventricular tachycardia may occur. The patient’ssedimentation rate is usually markedly elevated andtransesophageal echocardiography should be diagnostic.MRI is also helpful in confirming the diagnosis. Surgicalremoval of the lesion usually produces a complete cure.BIBLIOGRAPHYBraunwald, E., Zipes, D. P., and Libby, P. eds. Heart Disease, sixth edition.W. B. Saunders, Philadelphia, 2001.Sutherland, E. R., and Cherniack, R. M. Management of chronicobstructive pulmonary disease. N. Engl. J. Med., 350:2689–2697,2004.

Murmurs and Heart DiseaseI. Clinical CasesII. Clinical Diagnosis of Heart MurmursIII. Investigative Testsmuscle and cause it to enlarge. The muscle finally becomesweak and heart failure occurs (see the chapter HeartFailure). Some murmurs such as that caused by mitralstenosis prevent the chambers of the heart from filling.GLOSSARYcardiac output the volume of blood pumped by the ventricleper unit time expressed in liters per minute; it is the functionof the stroke volume multiplied by the heart rate.heart failure failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.S1 the first heart sound caused by closure of the mitral andtricuspid valves.S2 the second heart sound caused by closure of the aortic andpulmonary valves.A HEART MURMUR IS A SOUND (BRUIT) HEARDon auscultation with a stethoscope placed at variouslocations over the chest or neck vessels and over dilatedarteries. Typically these sounds are periodic and of shortduration. They coincide with the short systolic or diastolictiming of the heart’s contraction and relaxation duringwhich blood is ejected or the chambers are filled duringsystole and diastole, respectively. Heart murmurs resultfrom disturbances of normal blood flow patterns in theheart. They are classified on the basis of their timing assystolic, diastolic, or continuous (systolic and diastolic).The most common murmur is systolic. Systolic murmursoccur during the contraction of the ventricles. Manysystolic murmurs are nonsignificant in that they mayoccur in individuals where no evidence of heart diseasecan be found and do not disturb the function of the heart.Murmurs that occur when the ventricles are relaxed, thatis, during diastole, are termed diastolic murmurs and arealways of significance. Murmurs are usually caused bydisease of the heart valves (see the chapter Valve Diseases).Over of a period of 5–50 years, significant murmursindicate valve disease that increase the work of the heartI. CLINICAL CASESA. Questions PosedA female, age 30, posed the following questions: My familydoctor says that I have a systolic murmur at the apex ofthe heart and referred me to a cardiologist. I would liketo know:1. What is my prognosis?2. Is there any contraindication to using birth controlpills?3. Will the murmur affect future pregnancy and thenumber of children I can have?4. When will an operation be necessary?5. Can I prevent it from becoming worse?B. AnswersBelow are the answers to the previous questions asked.1. A soft systolic murmur over the apex of the heart isusually of no significance. It is important, however,to identify any mild area of roughness or deformity ofthe valve, which can later develop an infection calledendocarditis. When a doctor states that a murmur is ofno significance, it means that the murmur will notaffect the person’s life span or activities. If you have nothad rheumatic fever and there are no other murmursand no shortness of breath, the murmur is likely dueto an increased blood flow across the valve, a commonfinding in normal young adults and also duringpregnancy. The cardiologist’s findings with the stethoscope,followed by a chest x-ray and electrocardiogram,usually exclude most serious problems. If some doubtexists, an echocardiogram is helpful. Echocardiography511

512MURMURS AND HEART DISEASEwill document a degree of stenosis or regurgitation.Diastolic murmurs are always significant, whereas softsystolic murmurs are often not.2. The murmur does not contraindicate the use of birthcontrol pills.3. The murmur will not affect your pregnancy, the fetus,or subsequent pregnancies and should not limit thenumber of children. If the murmur is loud and thedoctor hears it over a wide area of the chest, this isa different matter and further assessment includingan echocardiogram may be necessary to exclude severemitral regurgitation.4. An operation is never required in patients with a softsystolic murmur or mild mitral regurgitation. Surgeryfor mitral regurgitation is utilized only when thereare symptoms of severe shortness of breath or heartenlargement and when an echocardiogram shows severeregurgitation.5. If you have no symptoms and if the murmur isdescribed as soft and heard over an area of less than fivefingertips held together, it is most unlikely that yourcondition will get worse. Only infection of the valvecan shorten your life. Fortunately, the risk of gettingan infection on the valve is remote; when germs getinto the blood, they need to stick on the valve andgrow. There is a 1 in 1000 chance of this occurring,and prevention through antibiotics is the rule if themurmur is caused by a valve disease process. Antibioticsare not required for many ‘‘functional,’’ nonsignificantmurmurs (see the chapter Valve Diseases).stethoscope down from the base to the apex fixing thecardiac cycle with S2 as a reference point (see Figs. 1and 2).The point of maximal intensity of the murmur: Thisshould be identified, although this does not alwaysprovide information that is accurate; for example,the systolic murmur of aortic valve sclerosis andaortic stenosis may be heard best at the apex of theheart rather than at the second right interspace, theaortic area.The character or quality of the murmur: Assess if themurmur is high-pitched, low-pitched, rumbling, onlycrescendo, only decrescendo, or crescendo decrescendo(see Fig. 1). These features are typically distinctive to thetrained clinician’s ear. The difference between the highpitchedblowing diastolic murmur of aortic regurgita-S 1 S 2 S 11.“Draw..w..”Early diastolicOS2.Mid- and late diastolicII. CLINICAL DIAGNOSISOF HEART MURMURSA. Diagnostic CluesUsually the diagnosis is obvious from the patient’s efforttolerance and the finding of a murmur with the stethoscopeas well as other symptoms. A cardiologist makes thediagnosis in the office with 95% confidence in more than90% of cases.1. Diagnostic PointsThe timing of the murmur relative to the first heartsound, S1, and to the second heart sound, S2: Thisprovides the most meaningful piece of information thatfixes the timing of the murmur as systolic or diastolic.If the murmur is difficult to time, the examiner shouldidentify S2 of the base of the heart and move the3.4.Late diastolic(presystolic)Systolic and diastolicFIGURE 1 Patterns of diastolic and continuous murmurs. (1) Earlydiastolic murmur, high-pitched, decrescendo, maximal at the left sternaledge at the third or fourth intercostals space; typical of aorticregurgitation. Mimic by saying ‘‘Daw..w;’’ the ‘‘D’’ replaces the S 2 .(2) Mid- to late diastolic, low-pitched rumble with presystolic accentuationending in a loud S 1 ; typical of mitral stenosis. OS ¼ openingsnap. (3) Late diastolic murmur, i.e., presystolic murmur ending in a loudS 1 ; indicates mitral stenosis. This murmur usually disappears if atrialfibrillation is present. (4) Systolic and diastolic continuous ‘‘machinery’’murmur of patent ductus arteriosus; it is loudest at the time of S 2 . (FromKhan, M. Gabriel (2001). On Call Cardiology, 2 nd ed., Philadelphia: W.B. Saunders, p. 39.)

II. CLINICAL DIAGNOSIS OF HEART MURMURS513tion and the rumbling very low pitched diastolicmurmur of mitral stenosis is like night and day. Someaspects of murmur quality are not as distinctive, forexample, harshness, rough, creaky, musical, or blowing.Intensity.The intensity of a murmur is judged by six different gradelevels. Murmurs are graded, for example, as 2 over 6.Grade 1: A very soft murmur that is faintly heard; themurmur may be missed at the initial or on subsequentexaminationGrade 2: A soft murmur that is readily heardGrade 3: A loud murmur with no thrill (vibrations) felton palpation with the palm or finger pads placed overthe point of maximal intensity of the murmurGrade 4: A loud murmur with a thrill presentGrade 5: A very loud murmur with a thrill present thatcan be heard when the edge of the stethoscope isapplied to the area of maximal intensityGrade 6: The loudest murmur heard with the stethoscoperemoved a centimeter off the chest wallThe intensity of systolic murmurs does not always relateto the severity of the valvular lesion. A murmur caused bysevere obstruction to the aortic valve may be a soft grade2 in patients with low cardiac output and heart failure.The intensity therefore may prove useful if the examinerconsiders the volume and velocity of blood flow anddilatation of the aortic root in the given individual.B. ClassificationMurmurs are classified as follows: Systolic: beginning after S1 and ending at all or beforethe aortic or pulmonary sound, S2 (see Fig. 2) Diastolic: beginning with S2 and ending just before S1. Continuous: beginning in systole and continuingthrough S2 into part or all of diastole; continuousmurmurs are rare1. Systolic MurmursNonsignificant systolic murmurs can be heard in morethan 60% of children. The systolic murmur of aorticvalve sclerosis without stenosis is heard in more than50% of individuals older than 50 years. Systolic murmurscan be classified as early systolic, midsystolic, late systolic,or holosystolic (occurring all through the systolic timeinterval; Fig. 2).Midsystolic murmurs represent an important groupcaused by organic disease. These movements begin after1.2a.2b.34S 1 S 2 S 1Early systolicECMidsystolicClick and midsystolicCLate systolicHolosystolicFIGURE 2 Patterns of systolic murmurs. Timing of the murmur canbe diagnostic. (1) Early systolic murmur at apex and left lower sternalborder caused by acute mitral or tricuspid regurgitation; by regurgitationinto a normal-sized atrium; or by a very small ventricular septal defectwith late shunting abolished. (2a) Midsystolic murmur at left sternalborder and aortic area; is not always aortic stenosis — consider increasedflow, high-output states, some forms of mitral regurgitation, and innocentmurmurs. (2b) Midsystolic murmur preceded by an ejection click (EC) istypical of congenital aortic stenosis. The click is absent in rheumaticcalcific stenosis or nonpliable valves. (3) Late systolic murmur typicalof mitral valve prolapse (C ¼ click); one or more clicks may be heard.(4) Holosystolic murmur typical of chronic mitral or tricuspid regurgitationor ventricular septal defect. (From Khan, M. Gabriel (2001). On CallCardiology, 2 nd ed., Philadelphia: W. B. Saunders, p. 44.)S1 and end well before S2, that is, a clear gap betweenthe end of the murmur and S2 (see Fig. 2). Midsystolicmurmurs occur when there is obstruction to ventricularflow as observed with aortic or pulmonary valve stenosis.Mid to late systolic murmurs (Fig. 2) are usually causedby mitral valve prolapse. Holosystolic murmurs beginwith S1 and continue through the entire systolic interval.This murmur is caused by blood flow from a chamberor a vessel with a higher pressure and resistance

514MURMURS AND HEART DISEASEthan the receiving chamber or vessel. Holosystolicmurmurs are often regurgitant; a common cause is mitralregurgitation.degenerate systolic murmurs emerge. Musical murmurs inthis setting suggest a tear of a leaflet.2. Diastolic MurmursThese are classified as early mid or late diastolic. The mostcommon early diastolic blood is that caused by aortic valveregurgitation. This murmur is best heard with the diaphragmof the stethoscope firmly pressed against themid-left sternal edge with the patient sitting up at theside of the bed with the breath held after a full exhalation.The high-pitched blowing decrescendo murmur has typicalcharacteristics.3. Prosthetic Valve MurmursAortic mechanical valves cause turbulence that producesa grade 1 to 2 ejection systolic murmur that is of nosignificance. Sudden increase in the systolic murmurmay reflect obstruction by thrombus. A diastolic murmuris usually abnormal and suggests a perivalvular leak.Bioprosthetic valves produce no sounds, but when theyIII. INVESTIGATIVE TESTSChest x-ray, ECG, and echocardiogram are helpful toconfirm the clinical opinion obtained from the patient’shistory and relevant examination. In a few individuals withserious heart murmurs causing symptoms such as severeshortness of breath with or without heart failure, cardiaccatheterization tests are invaluable to corroborate thefindings on echocardiography. This is often done if surgicalcorrection is planned. The technique of catheterizationis outlined in the chapter Tests for Heart Diseases,and echocardiographic diagnostic points are given in thechapter Valve Diseases.BIBLIOGRAPHYKhan, M. Gabriel. On Call Cardiology, second edition. W. B. Saunders,Philadelphia, 2001.

Nonsteroidal Anti-Inflammatory DrugsI. Adverse Cardiovascular EffectsGLOSSARYacute coronary syndrome this syndrome defines patients withacute chest pain caused by myocardial infarction or unstableangina.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).cardioprotection protection of the heart from serious eventsthat include coronary artery disease and it complications,angina, myocardial infarction, and heart failure.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.CYCLOOXYGENASE (COX) OR PROSTAGLANDINendoperoxidase H synthase inhibitors, is a major componentof the rheumatologist’s armamentarium. Twoisoenzymes, COX-1 and COX-2, are encoded by separategenes located on different chromosomes. These isoenzymesare targets of nonselective nonsteroidal anti-inflammatorydrugs (NSAIDs).These agents are widely used for the control of pain inpatients with arthritis. Because the widely use steroidalanti-inflammatory agents of the sixties and seventies(cortisone, prednisone) caused relief but long-term useproduced serious adverse effects, nonsteroidal agents wereheralded as the answer for a variety of arthritic disorders.NSAIDs, however, cause the kidneys to retain sodiumand water. This action may cause an increase in bloodpressure. Also, an increase in sodium and water in thebody increases the work of the heart and can precipitateheart failure in patients with a weak heart muscle (leftventricular dysfunction). Patients may experience increasedshortness of breath and swelling of the ankles. These agentsare well known to cause bleeding from the stomach.Available NSAIDs used from the seventies includecarprofen, diclofenac, fenoprofen, flurbiprofen, ibuprofen,indomethacin, ketoprofen, naproxen, piroxicam, sulindac,and tolmetin. Newer agents discovered in 1989 andintroduced into medical practice in the early nineties blockCOX-2 and are called COX-2 inhibitors. These includecelecoxib, meloxicam, rofecoxib parecoxib, and valdecoxib.It was speculated that these specific COX-2 inhibitors(selective NSAIDs) would be safer and cause less gastricbleeding than the old NSAIDs, and this is the mainreason that COX-2 inhibitors are publicized as havingadvantages over NSAIDs.The older agents (NSAIDs) inhibit COX-1, but theinhibition is not permanent and they partially blockCOX-2. In contrast, aspirin permanently and irreversiblyacetylates and blocks cyclooxygenase, therefore preventingthe production of platelet thromboxane A2. The latter is apowerful platelet-aggregating agent that forms clots(thrombi). Aspirin, thus prevents platelet-derived thrombosisthat is involved in the causation of myocardialinfarction and stroke.NSAIDs clearly do not have this cardioprotective benefitof the wonder drug, aspirin; (see Figure 1). Aspirin,(acetylsalicylic acid) irreversibly acetylates the enzymecycolooxygenase, an enzyme necessary for the conversionof platelet arachidonic acid to thromboxane A2, a powerfulplatelet aggregating agent and vasoconstrictor. Thisbeneficial effect is not provided by NSAIDs or COX-2inhibitors (see the chapter entitled Aspirin for HeartDisease) and the newer agents, unfortunately, appear toincrease the risk of cardiovascular thrombotic events.I. ADVERSE CARDIOVASCULAR EFFECTSAll NSAIDs significantly inhibit the beneficial effects ofseveral drugs, including furosemide, hydrochlorothiazide,515

516NONSTEROIDAL ANTI-INFLAMMATORY DRUGSother thiazide diuretics, ACE inhibitors, and angiotensinreceptor blockers. Aspirin is a weak NSAID that doesnot cause sodium and water retention, increased bloodpressure, or heart failure, but it can interfere with theeffectiveness of ACE inhibitors.Recent studies have suggested that ibuprofen mayinterfere with the cardioprotective effects of aspirin onthe cardiovascular system. Thus, patients with cardiovasculardisease who require aspirin therapy should not beusing NSAIDs concomitantly.A. Effects on ProstacyclinNormal formation of prostacyclin (PGI 2), a vasodilatorand potent platelet inhibitor, is increased mainlythrough COX-2. NSAIDs and COX-2 inhibitors (selectiveNSAIDs) block prostacyclin production in vessel walls.Prostacyclin prevents platelet aggregation and cardiacarrhythmias. It keeps the arteries dilated and the arterialwalls ‘‘clean.’’ PGI 2 may limit the extent of plateletadhesion and activation at sites of atherothromboticdisease. COX-2 inhibitors are potent prostacyclin inhibitorsand increase cardiovascular atherothrombotic events.To reemphasize, selective inhibitors of cycolooxgenase,COX-2 inhibitors depress prostacylin but not COX-1–derived thromboxane A 2 . Thus, the harmful effects ofthromboxane A 2 are exaggerated by COX-2 inhibitors; thisaction predisposes cardiovascular patients to stroke andmyocardial infarction. See Figure 1. It is not surprising,therefore, that in 2004, warnings as to dangers of COX-2inhibitors were publicized.Aspirin in large doses inhibits prostacyclin, but smallbeneficial doses of aspirin less than 160 mg daily inhibitthromboxane A2 synthesis and platelet aggregation and donot significantly inhibit prostacyclin production. (see thechapter Aspirin for Heart Disease). Both selective andnonselective NSAIDs reduce prostacyclin formation in theinfarcted myocardium. They accomplish this by tippingthe balance of prostacyclin/thromboxane in favor of thromboxane,a prothrombotic eicosanoid. Acute myocardialischemia increases prostacyclin and thromboxane concentrationsin coronary vein blood. Thromboxane promotesplatelet aggregation, causes vasoconstriction, and initiatesventricular arrhythmias.COX-2 inhibitors have been shown to reduce prostacyclinformation in normal volunteers by up to 80%.Bing et al. have obtained evidence of changes in theprostacyclin/thromboxane ratioafter celecoxib,which lowersmyocardial prostacyclin production in the infarcted heartmuscle but fails to inhibit thromboxane. Thus, COX-2inhibitors tip the balance of prostacyclin/thromboxane infavor of thromboxane; this may be responsible for increasedvascular and thrombotic events.This deleterious process may explain the unfavorableresults of the Vioxx gastrointestinal outcomes research(VIGOR). In this trial of patients with rheumatoidarthritis, none of whom were allowed to be on low-doseaspirin, there was an excess of myocardial infarctionsin patients on rofecoxib compared with Naprosyn.Patients who took rofecoxib at 50 mg daily had a fivefoldincreased risk of myocardial infarction. There was noevidence of raised risk of coronary artery disease amongusers of rofecoxib 25 mg or less or among users of otherNSAIDs.Investigators have postulated that the higher infarctionrates probably occurred not because rofecoxib may haveincreased these rates, but because Naprosyn was cardioprotective.This is, however, wishful thinking. An epidemiologicstudy comparing high-dose rofecoxib with lowerdoses of rofecoxib and nonspecific NSAIDs suggested anincreased risk for myocardial infarction with high dosesof rofecoxib. Naprosyn and other NSAIDs have not beenshown to be cardioprotective; they do not have the permanentantiplatelet effects of aspirin. In addition, basicresearch indicates that COX-2 inhibitors and the wellknown nonselective NSAIDs limit infarct healing.B. Effect on AtherothrombosisCOX-2 is expressed in the monocytes and smooth musclecells that migrate from the media into the intima whichcharacterize atheromatous plaques (see chapter Atherosclerosis).Individuals with extensive atherothromboticdisease have enhanced formation of thromboxane A2.COX-2 inhibitors, by preferentially suppressing prostacyclingeneration and sparing thromboxane, may increaseatherothrombosis. There are some data, however, thatindicate that COX-2 expressed in monocytes/macrophagescontributes to development of atherosclerosis in animalmodels. In this setting COX-2 inhibitors may be expectedto prevent atheroma formation. A 30% reduction inatherosclerosis by the COX-2 inhibitor nimesulide wasobserved by Pratico et al. The nonselective COXinhibitors, aspirin and indomethacin, have been shownto retard the development of atherosclerosis in apoE miceto a greater extent than a selective COX-2 inhibitor.C. Increased Viral LoadThere is evidence suggesting a casual role of cytomegalovirus(CMV) in atherogenesis. CMV infection has beenshown to cause progression of atherosclerosis in a murine

I. ADVERSE CARDIOVASCULAR EFFECTS517model of atherosclerosis. Rott et al. demonstrated thatselective inhibition of COX-2 increases viral load inapoE-deficient mice. This increase in viral load was paralleledby increased anti-CMV antibody titers. Inhibition ofCOX-2 significantly increased early atherosclerotic lesionareas independent of viral infection.D. Hypertension and Heart FailureNSAIDs increase blood pressure and increase the incidenceof heart failure because they cause the kidneys to retainsodium and water. COX-2 inhibitors may cause a greaterelevation in the blood pressure and the incidence of heartfailure. They also interact with antihypertensive agents anddrugs used for the management of heart failure.E. CautionCaution is required with the use of selective NSAIDs inpatients with coronary artery disease. These agents shouldbe avoided in patients at risk for the development ofheart failure, hypertension, or acute coronary syndromes.Antiarthritic (nonsteroidal anti-inflammatory) agentsincluding indomethacin, ibuprofen, and pirogxicam andthe newer, selective nonsteroidal anti-inflammatory agents(COX-2 inhibitors) such as celecoxib, meloxicam, androfecoxib retain salt and water in the body and commonlyprecipitate heart failure in patients with poor heart musclefunction.BIBLIOGRAPHYBelton, O., and Fitzgerald, D. Cyclooxygenase-2 inhibitors andatherosclerosis. J. Am. Coll. Cardiol., 41:1820–2, 2003.Bing, R. J., and Lomnicka, M. Why do cyclo-oxygenase-2 inhibitors causecardiovascular events? J. Am. Coll. Cardiol., 39:521–522, 2002.Bresalier, MD, R. S., Sandler, MD, R. S., Quan, PhD, H. et al.Cardiovascular events associated with rofecoxib in a colorectaladenoma chemoprevention trial. N. Engl. J. Med., 352:1092–1102,Number 11, March 17, 2005.Burleigh, M. E., Babaev, V. R., Oates, J. A. et al. Cyclooxygenase-2promotes early atherosclerotic lesion formation in LDL receptordeficientmice. Circulation, 105:18 16–23, 2002.Burnett, M. S., Gaydos, C. A., Madico, G. E. et al. Atherosclerosis inApoE knockout mice infected with multiple pathogens. J. Infect. Dis.,183;226–31, 2001.Drazen, MD., J. M. et al. COX-2 inhibitors — A lesson in unexpectedproblems. N. Engl. J. Med., 352:1131–1132, Number 11, March 17,2005.Furberg, C. D., Psaty, B. M., FitzGerald, G. A. et al. Parecoxib,valdecoxib, and cardiovascular risk. Circulation, 111:249, 2005.Hsich, E., Zhou, Y. F., Paigen, B. et al. Cytomegalovirus infectionincreases development of atherosclerosis in apolipoprotein-E knockoutmice. Atherosclerosis, 156:23–8, 2001.Luis, A. G. R., Varas-Lorenzo, C., Maguire, A. et al. Nonsteroidalantiinflammatory drugs and the risk of myocardial infarction in thegeneral population. Circulation, 109:3000–3006, 2004.Mukherjee, D., Nissen, S. E., and Topol, E. J. Risk of cardiovascularevents associated with selective Cox-2 inhibitors. JAMA, 286:954–9,2001.Paul, A., Calleja, L., Camps, J. et al. The continuous administration ofaspirin attenuates atherosclerosis in apolipoprotein E-deficient mice.Life Sci., 68:457–65, 2000.Pratico, D., Tillmann, C., Zhang, Z. B. et al. Acceleration ofatherogenesis by COX-I dependent prostanoid formation in lowdensitylipoprotein receptor knockout mice. Proc. Natl. Acad. Sci.,U.S.A., 98:3358–63, 2001.Ray, W. A., Stein, C. M., and Daugherty, J. R. Cox-2 selectivenonsteroidal anti-inflammatory drugs and risk of serious coronaryheart disease. Lancet, 360:1071–3, 2002.Rott, D., Jianhui, Z., Burnett, S. et al. Effects off MF-tricyclic, aselective cyclooxygenase-2 inhibitor on atherosclerosis progression andsusceptibility to cytomegalovirus replication in apolipoprotein-Eknockout mice. J. Am. Coll. Cardiol., 41:1812–9, 2003.Solomon, MD, S. D., McMurray, MD, J. J. V., Pfeffer, M. A. et al.Cardiovascular risk associated with celecoxib in a clinical trial forcolorectal adenoma prevention. N. Engl. J. Med., 352:1071–1080,Number 11, March 17, 2005.Topol, E. J. et al. Arthritis medicines and cardiovascular events — ‘‘Houseof Coxibs’’. JAMA, 293:366–368, 2005.

Obesity and Heart DiseaseI. Incidence and DefinitionsII. Effects on the Cardiovascular SystemIII. ManagementIV. Clinical Studies of Dietsadults are overweight and have a BMI greater than 25.More than 30% are frankly obese, having a BMI greaterthan 30; approximately 9% are diabetic, many are prediabetics,and more than 25% have metabolic syndrome.GLOSSARYatherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood; theplaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).dyslipidemia the same as hyperlipidemia, elevated blood cholesterol,LDL cholesterol, triglycerides, or low HDL cholesterol.heart failure failure of the heart to pump sufficient bloodfrom the chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.A. Metabolic syndromeIndividuals with this syndrome possess more than 3 of thefollowing:Increased abdominal girth with a waist measurementgreater than 46 inches in men, 40 inches in women(visceral obesity) or BMI greater than 30kg/m 2Dyslipidemia indicated by low serum levels of highdensitylipoprotein (HDL) cholesterol and elevatedtriglyceridesHypertensionGlucose intolerance that contributes to insulin resistanceand an increased risk of diabetes and cardiovasculardisease (see the chapter Diabetes andCardiovascular Disease)I. INCIDENCE AND DEFINITIONSYou are considered obese if you are more than 25% abovethe average weight and have a high percentage of bodyfat. You are moderately obese if you are 25–50% abovethe average weight and have marked increase in body fat.A body weight exceeding the ideal weight by 75% isconsidered severe obesity. Measurement of body massindex (BMI), determined from your weight in kilogramsdivided by the square of your height in meters, is a usefulmeasure of relative obesity: Normal range for BMI ¼ 18.5 to 24.9 kg/m 2 Overweight range ¼ 25.0 to 29.9 Obesity ¼ >30.0 kg/m 2Statistics from the Centers for Disease Control andPrevention indicate that more then 66% of AmericanB. Metropolitan Height and Weight TablesThe Metropolitan height and weight tables are given inTables 1 and 2. These tables are still relevant. If you areslightly overweight, you would be happy to learn that theearlier Metropolitan Life tables of ideal or average weightswere derived from insurance applicants age 20–30 and donot represent the average weights of individuals age 40–60.If your weight is 10% more than that indicated in Tables 1or 2, you can consider yourself slightly overweight, butthere appears to be no health hazard unless you have otherrisk factors. The average weight of North Americans age30–50 is about 10–15% above those indicated in Tables 1and 2. Many North Americans age 35–70 are overweight,even by the conservative definition given above. If you arein this group and have other risk factors, you need toreduce your weight.519

520OBESITY AND HEART DISEASETABLE 11983 Metropolitan Life Height and Weight Tables for Men and WomenAccording to frame, ages 25–59: MenWeight in pounds (in indoor clothing)*Height (in shoes)Feet inches Small frame Medium frame Large frame5 2 128–134 131–141 138–1505 3 130–136 133–143 140–1535 4 132–138 135–145 142–1565 5 134–140 137–148 144–1605 6 136–142 139–151 146–1645 7 138–145 142–154 149–1685 8 140–148 145–157 152–1725 9 142–151 148–160 155–1765 10 144–154 151–163 158–1805 11 146–157 154–166 161–1846 0 149–160 157–170 164–1886 1 152–164 160–174 168–1926 2 155–168 164–178 172–1976 3 158–172 167–182 176–2026 4 162–176 171–187 181–207* Indoor clothing weighing 5 pounds for men and 3 pounds for women.TABLE 21983 Metropolitan Life Height and Weight Tables for Men and WomenAccording to frame, ages 25–59: WomenWeight in pounds (in indoor clothing)*Height (in shoes)Feet inches Small frame Medium frame Large frame4 10 102–111 109–121 118–1314 11 103–113 111–123 120–1345 0 104–115 113–126 122–1375 1 106–118 115–129 125–1405 2 108–121 118–132 128–1435 3 111–124 121–135 131–1475 4 114–127 124–138 134–1515 5 117–130 127–141 137–1555 6 120–133 130–144 140–1595 7 123–136 133–147 143–1635 8 126–139 136–150 146–1675 9 129–142 139–153 149–1705 10 132–145 142–156 152–1735 11 135–148 145–159 155–1766 0 138–151 148–162 158–179*Shoes with 1-inch heels.Source of basic data: Build Study, 7979, Society of Actuaries and Association of Life Insurance Medical Directorsof America, 1980.Copyright 1983 MetropolitanLife Insurance Company.

III. MANAGEMENT521II. EFFECTS ON THE CARDIOVASCULARSYSTEMIf you are slightly overweight, this alone does not significantlyincrease your risk of having a heart attack, hypertension,or diabetes provided that you do not already havethe risk factors — a family history of heart attacksoccurring at an early age (before age 55), hypertension,high blood cholesterol, diabetes, smoking, and a stressfullifestyle. Obesity is different from being mildly overweight.A. Coronary Heart DiseaseThe Framingham Study showed that in the 5000 peoplestudied, being overweight appeared to increase the risk ofsudden death and angina, but it did not increase thefrequency of heart attacks. When adjustments were madefor the prevalence of hypertension and hypercholesterolemia,then being overweight or obesity appeared to playa much less significant role.If a patient with coronary heart disease manifested byrecurrent chest pain on exertion (angina) or a myocardialinfarction is overweight, chest pains are likely to be morefrequent, as the heart has to work harder. Therefore,weight reduction helps in relieving pain in patients withangina pectoris, and less medication is then required.B. Heart FailureIn patients with heart failure, weight reduction is necessarybecause increased weight means more work for the heart.In heart failure patients the heart muscle is weak and themuscle is unable to pump sufficient blood from the heartinto the circulation; blood remains in the lungs causingfluid to accumulate causing shortness of breath and edemaof the legs occur (see the chapters Heart Failure and HeartAttacks).Kenchaiah et al. investigated the relation between theBMI and incidence of heart failure among 5881 individualsin the Framingham heart study. In this large,community-based sample increased BMI was associatedwith an increased risk of heart failure. As comparedwith individuals with normal BMI, obese subjects hada doubling of the risk of heart failure.C. HypertensionObesity is not a major cause of hypertension, but someobese patients do have increased blood pressure. A largersized cuff is required for measuring blood pressure if theindividual’s arm is large. If you are obese and lose weight,the blood pressure always falls. A significant number ofobese patients have diabetes and elevated blood cholesterol,and if hypertension or cigarette smoking is added, the riskis considerably increased.III. MANAGEMENTA. Weight Reduction DietWeight loss depends on calories you do not eat and caloriesyou burn up during exercise. A low-calorie diet must becombined with exercise that increases calorie expenditure;otherwise you will not be able to prevent weight gain,which often occurs three to six months after stoppinga low-calorie diet. It is best to lose slowly and plan yourstrategy over a one-year period. Therefore, try to losetwo to four pounds per month, that is, 24–48 pounds overone year.The body of an obese individual is programmed toform fat and store it. In addition, cells slow down and youburn fewer calories than normal. Your metabolic rate isslower than normal. When you go on a crash diet, yourmetabolic thermostat is turned down to get by on lessfood. Start your exercise program first, and after a monthof walking one to two miles daily and climbing two tothree flights of stairs four times daily, increase the exerciseand then start your diet. Remember that a brisk two-milewalk in 30 minutes burns about 200 calories. All dietsthat are proven to cause sustained weight loss over a periodof years depend on a reduced intake of calories combinedwith an exercise program that burns up calories.Cells and muscles need energy to carry out their work.Energy is measured in calories. The body cells are like lightbulbs. A bulb lights up when it receives enough electricalenergy. The cells derive energy from chemical reactionsinvolving glucose, oxygen, hydrogen, and high-energyphosphate bonds. The body needs glucose because it isone of the chief sources of energy — calories.The following example should help you understandweight loss and calories. Young diabetics lose a considerableamount of weight. Why? Insulin is required to transportglucose from the blood across the cell membrane toreach inside the cell to interact with other chemicals andthus produce energy. When insulin is absent, glucosecannot get into the cells. Therefore, glucose reaches highlevels in the blood and is passed out in the urine. The cellsrequire energy to function. When glucose is not present,the cells use fat as a source of energy. Thus, fat throughoutthe body is mobilized and broken down, resulting in

522OBESITY AND HEART DISEASEmarked a weight loss of about 20–30 pounds in 2–3months.1. CarbohydratesAll weight reduction diets entail a major reduction incarbohydrates and saturated fats. Simple carbohydratefoods (sugar and starchy foods) break down in the bodyto form glucose (sugar). Most calories are derived fromcarbohydrates: flour products, potatoes, ground vegetables,rice, custard, and ice cream. Therefore, you need to makea list of all such foods and reduce them by 50–75% (onehalfto three-quarters) of your usual intake. We have notprinted such a list because they are readily available in mostdiet books.2. Saturated FatsA decrease in saturated fat as advised in the Cholesterolchapter is advisable. Total fat intake should be reducedfrom the average 40% of total caloric intake to 30%. Onegram of fat is equal to 9 calories, thus reducing fat intakeby 120 calories derived from fat is not a difficultundertaking. A filet mignon is not fattening. Thus youcan eat filet mignon and chicken three times a week andstill lose weight.A smaller amount of calories are derived from leanmeats. To lose weight, therefore, eat only vegetables andlean meats such as chicken and fish with fruit for dessert.An abundance of fresh vegetables, legumes, and nuts thatinclude almonds and walnuts and a multivitamin supplementare required.Weight loss will be achieved if you reduce your calorieintake to 1000 calories daily and burn up some caloriesby exercise. It is possible to eat attractive, appetizingmeals and lose weight. Consider the following points inpreparing your meals:1. A high-protein, low-fat meal as detailed under theHeart Attack Prevention Diet is advisable.2. Reduce intake of high-calorie foods such as carbohydrateconsisting of refined sugars and refined starches.Remember that alcohol, mixes, beer, and soft drinkscontain an abundance of calories.3. Carbohydrate foods that have calories and can still betaken liberally include those containing high fiber.Foods with high fiber content allow you to eat a largemeal; therefore, you feel satisfied. Most of the materialstays longer in the stomach but is not digested and thusnot absorbed into the blood. Your meal may have morecalories, but you absorb only about half the amount ofcalories. We agree that high-fiber diets have a definiterole in weight reduction plans. High-fiber foods includewheat bran, green peas, chick peas, split peas, beans,corn and all vegetables and fruits such as apples, cherries,pears, plums, nectarines, because the skin containinghigh amounts of fiber is eaten.A word of caution: Every intervention, be it type of dietor treatment, must be done in moderation. Note the highvitamin K content of certain high-fiber foods oftenrecommended such as broccoli, turnip greens, spinach,and alfalfa. A high vitamin K intake may increase clottingfactors in the blood. In addition, the occasional individualfollowing a high-fiber diet may have an increase instools from once to three times daily, but this oftennormalizes. Very rarely anemia and bone loss (osteomalaciaor osteoporosis) as well as a decreased absorption ofminerals such as calcium, zinc, or magnesium, may occurwith a prolonged high-fiber reduction diet.For those of you who have difficulty counting calories,simply try the following:1. Reduce your usual intake of the following foods by onehalf(50%) to three-quarters (75%). For example, fourslices of bread daily becomes a maximum of two, orpreferably one slice daily. All white flour productsinclude bread, pasta, spaghetti, macaroni, and roti.Do not eat cakes, cookies, pastries, rice, or friedpotatoes. One medium baked potato with skin can beeaten twice weekly. Avoid fast foods and canned foodsbecause of their high calorie and salt content (seeTable 3).2. Increase your intake of all vegetables, including avocado,which is high in potassium and polyunsaturated fat.Avocado is not fattening as some would have us believe.Eat more of all fruits. Food with high fiber contentexcept broccoli, turnip greens, and alfalfa, which arerich in vitamin K, should be increased. Small helpingsof spinach or cabbage have less vitamin K and can beused. Fish, chicken, veal, turkey, and fatty fish containgood fats and should be eaten more frequently. Inaddition, if your blood cholesterol is greater than240 mg (6 mmol/L), use only lean cuts of beef or steaktwice weekly and only two eggs weekly.This combination of foods will afford pleasant tastingmeals that you can tolerate for a long period of timewithout depletion of protein, vitamins, or minerals. Youwill lose weight if you combine this diet with one hourof exercise at least five days weekly.Obesity has been known to be a difficult problem tocontrol. Motivation, willpower, and sacrifice are required.You may have greater success if you join a weight loss

IV. CLINICAL STUDIES OF DIETS523program or consult with a nutritionist regularly. Thougha behavior modification program may help some, to bereally successful you need to find a weight loss programthat will fit your particular lifestyle and weight loss goals.You should not use diet plans that recommend lowcarbohydrates and advise a moderate-to-high fat intake.Some diet recipes reduce carbohydrates, but increase eggs,cheese, and meat products. Therefore, an increase in bloodcholesterol may occur. Also, these very restrictive diets aredifficult to follow for more than 9 months.Studies have shown that liquid protein diets havecertainly caused deaths and must not be used. Fifty deathswere reported in individuals who were using liquid proteindiets. Seventeen of these individuals were known to behealthy, but developed abnormal heart rhythms while onthe liquid protein diet. No deaths occurred in a wellsupervisedstudy, however, in which about 4000 individualswere given an adequate amount (70 g) of first-classprotein daily, along with a very low calorie diet.IV. CLINICAL STUDIES OF DIETSA. The Atkins-Type DietAn Atkins-type diet that prescribes a low-carbohydrate,high-protein, high-fat intake has been popular in theUnited States during the past decade. Despite the knowledgethat high fat intake increases plasma LDL cholesterollevels and that this carries a high risk for the developmentof plaques of atheroma in vital arteries, this diet hasbeen allowed to be promoted for more than 20 years. Inaddition, the efficacy of this type of diet had not beentested, in randomized controlled trials until recently andthe trial was short-term not more than 12 months.1. Foster et al.This group conducted a randomized clinical trial comparingan Atkins-type diet versus what they deemed aconventional weight reduction diet: ‘‘a low calorie, highcarbohydrate, low fat diet.’’ Unfortunately, the authorsof the study state that ‘‘the conventional dietary approachto weight management recommended by leading researchand medical societies is a high-carbohydrate, low-fat,energy deficit diet.’’ Leading researchers and medicalsocieties have not advocated a high-carbohydrate intake asbeing part of a conventional weight-reduction program.Thus, the authors’ comparative diet flaws the study.Nonetheless, the small study provides some messages.Methods: A one-year controlled trial involving only63 obese men and women randomly assigned to either alow-carbohydrate, high-protein, high-fat diet (Atkins-type)or a low-calorie, high-carbohydrate, low-fat diet (referredto by the investigators as a conventional diet). Characteristicsof the individuals were age 44 9, BMI 34 3,and weight 98 19 kg. These individuals could beclassified as overweight individuals and not necessarilyobese. There were no diabetics and no patients withmetabolic syndrome, and there was no evidence ofsignificant dyslipidemia. The HDL cholesterol wasapproximately 47 mg/dl in both groups.Results: At six months individuals on the lowcarbohydratediet not surprisingly lost more weight thansubjects on the high-carbohydrate, low-fat diet ( 7.0 6.5 vs. 2.5 6.3% of the body weight; P ¼ 0.02), butthere was no significant difference at 12 months.Conclusions: Adherence was poor and attrition washigh in both groups. Only 42 and 37 individuals remainedin the study at 6 and 12 months, respectively. Longer andlarger studies are required to determine the long-termsafety and beneficial effects of low-carbohydrate, highprotein,high-fat diets.Perspective: Less than 60% of subjects adhered tothe diets at 12 months indicating that any approach tocaloric restriction that is not compatible with normal dailylifestyle patterns is unlikely to produce beneficial weightreduction sustained over a long-term period of severalyears. Caution is necessary because the dangerous LDLcholesterol increased in the low-carbohydrate, high-fatgroup and decreased slightly in the low-fat group. TheHDL cholesterol showed a mild increase in the subjectsfollowing the low-carbohydrate, high-fat diet, but thismay reflect a change in HDL subfractions which occurswith increased intake of saturated fat. This change has notbeen shown to be beneficial, thus, caution is required inthe interpretation of this data. A diet high in saturatedfat is known to be atherogenic and harmful to health andcannot be recommended under any circumstances. Inaddition the Atkins-type diet is unproven over the longterm. This type of diet has not been adequately tested inpatients with cardiovascular disease, diabetics, patientswith dyslipidemia, or in subjects with metabolic syndrome.Subjects in the study by Foster et al. had an averageweight of 220 lbs and BMI of approximately 34, featuresof mild obesity. The long-term effects in patients with amoderate degree of obesity (BMI 35–40), diabetes, ormetabolic syndrome have not been tested. Fortunatelyindividuals who weigh less than 400 pounds with a BMI>50 are a small percentage of the population and havesome form of as yet undefined underlying pathologicdefect probably related to hypothalamic-endocrine adiposetissue dysfunction.Adverse effects of an Atkins-type diet include atherogenicity,which potentially leads to atherosclerosis and an

524OBESITY AND HEART DISEASEincreased incidence of coronary events. This is of concernfor a diet that has not been tested in patients at risk forcardiovascular events. Calciuria, which causes renal stonesand decreased bone mass, is another adverse effect. A highproteindiet must be avoided in patients with renal andhepatic disease.B. A Low-Carbohydrate Diet Compared witha Low-Fat Diet1. Samaha et al.Methods: The investigators randomly assigned 132severely obese individuals (including 77 blacks and 23women) with a mean BMI of 43 and a high prevalence ofdiabetes (39%) or metabolic syndrome (43%) to a carbohydrate-restricted(low carbohydrate) diet or a calorie- andfat-restricted (low fat) diet. It is important to recognizethat the low-carbohydrate diet used did not have theadditional high-protein, high-fat component of the Atkinstypediet. The individuals assigned to the low-carbohydratediet were instructed to restrict carbohydrate intake to 30 gper day or less; no instruction on restricting total fat intakewas provided. The low-fat diet group was advised to createa deficit of 500 calories per day with 30% or less of totalcalories derived from fat.Results: A 6-month program was completed by 79individuals. Individuals on the low-carbohydrate diet lostmore weight than those on the low-fat diet ( 5.8 8.6 kg,vs. 1.9 4.2 kg; P ¼ 0.002) and had greater decrease intriglyceride levels ( 20 vs. 4%).Conclusions: This was a study of severely obeseindividuals with diabetes or metabolic syndrome, andthese individuals lost more weight at six months on acarbohydrate-restricted diet than on a calorie- and fatrestricteddiet. The authors warn that this finding should beinterpreted with caution given the small magnitude (9–18pounds) of overall loss and group differences in thesemarkedly obese subjects and the short duration of thestudy. The plasma cholesterol, LDL cholesterol, and HDLcholesterol did not change significantly during the6-month study within or between groups.In both the Foster and the Samaha studies, significantlygreater weight reduction with the low-carbohydrate dietthan with the reduced fat diet during the first six months(average reduction of 6–7 kg vs. 2–3 kg) was observed.The magnitude of the weight loss difference (4 kg inboth studies) was, however, relatively small and adherencein the two diet groups was low. Further studies evaluatinglong-term outcomes are needed before a carbohydraterestricted,relatively normal fat diet can be endorsedfor long-term use. A low-carbohydrate, high-fat, highproteindiet affords no advantages and may havedeleterious consequences in the long-term. It is notrecommended.C. RecommendationsThe combination of a low saturated fat, reduced carbohydrateintake, increased vegetables and fruits with abalanced food content and liberal exercise is recommendeduntil further long-term studies are available.BIBLIOGRAPHYBonow, R. O., and Eckel, R. Diet, obesity and cardiovascular risk. N.Engl. J. Med., 348:2057–58, 2003.Dansinger, M. L., Gleason, J. A., Griffith, J. L. et al. Comparison of theAtkins, Ornish, Weight Watchers, and Zone Diets for weight loss andheart disease risk reduction: A randomized trial. JAMA, 293:43–53,2005.Eckel, R. H., York, D. A., Rössner, S. et al. Prevention conference VII:Obesity, a worldwide epidemic related to heart disease and stroke:Executive summary. Circulation, 110:2968–2975, 2004.Foster, G. D., Wyatt, H. R., Hill, J. O. et al. A randomized trial of a lowcarbohydrate diet for obesity. N. Engl. J. Med., 348:2082–90, 2003.Kenchaiah, S., Evans, J. C., Levy, D. et al. Obesity and the risk of heartfailure. N. Engl. J. Med., 347:305, 13, 2002.Klein, S., Burke, L. E., Bray, G. A. et al. Clinical implications of obesitywith specific focus on cardiovascular disease: A statement forprofessionals from the American Heart Association Council onNutrition, Physical Activity, and Metabolism: Endorsed by theAmerican College of Cardiology Foundation. Circulation, 110:2952–296, 2004.Mullis, R. M., Blair, S. N., Aronne, L. J. et al. Prevention conferenceVII: Obesity, a worldwide epidemic related to heart disease and stroke:Group IV: Prevention/Treatment. Circulation, 110:e484–e488, 2004.Samaha, F. F., Iqubal, N., Seshadri, P. et al. A low carbohydrate ascompared with a low fat diet in severe obesity. N. Engl. J. Med.,348:2074–81, 2003.

PacemakersI. HistoricalII. Complete Heart BlockIII. Second Degree AV BlockIV. Sinus Node DysfunctionV. Permanent PacemakersVI. What a Pacemaker will not doVII. ActivitiesGLOSSARYAOO a pacemaker that stimulates the atrium as a fixed rate,independent of atrial activity.capture effective depolarization of the heart by the artificialpacemaker.demand or inhibited pacemaker any pacemaker that inhibitsits output upon sensing a natural or paced event and fires atthe preset rate when the sinus rate falls below the pacemaker’sprogrammed escape rate.transvenous anything that passes through a vein (catheter orpacemaker lead)WHEN THE HEART TEMPORARILY STOPS BEATINGfor 10–30 seconds, or the heart beat suddenly becomesremarkably slow (< 30 beats per minute) transient loss ofconsciousness occurs. This may be accompanied byconvulsive seizures that resemble an epileptic attack, orthe patient may fall without sufficient warning and injuriesor death may occur. The invention of the cardiacpacemaker is one of the greatest cardiologic developmentsof modern medicine. Countless lives have been saved andaccidents prevented by this innovative technologic solution.I. HISTORICALIn 1719 Gerbezius described a patient with a very slowpulse. The patient often had dizzy spells and from time totime was subjected to slight epileptic attacks. He did notconnect the slow pulse as the reason for the seizures.In 1761 Morgani reported two cases with recurrentfainting spells associated with slow pulse rate, but listedthe disturbance as neurological, perhaps, because it wasassociated with convulsive seizures. In 1826 Robert Adamswas the first to realize that the loss of consciousness(apoplectic attack or seizures) was related to a very slowpulse rate and that the disorder had a cardiac origin. Lateran autopsy revealed fatty degeneration of the myocardiumand Adams assigned a cardiac cause for the seizure-likedisorder.In 1846 Stokes was a firm believer in the use of thestethoscope, which had been developed by Laennec in1820. Stokes first observed two cases. He further analyzedand correlated seven cases from other physicians and wasthe first to describe the cardiac condition accurately indetailed writings and publications. He stated that theapoplectic seizures were caused by episodic deficits in thearterial blood supply to the brain, and through hispublications and textbooks the syndrome became knownto physicians. The syndrome was first labeled Stokes-Adams syndrome or Stokes-Adams attacks.In 1895 His discovered the underlying cardiac conditionwhich was delineated when he experimentally producedheart block. He suggested that a lesion of the atrioventricular(AV) bundle was responsible for blocking theconduction of electrical impulses from the atrium tothe ventricles (see Fig. 1). His further documented thecondition in a patient with heart block associated withsyncope and a recording was made with Sir JamesMackenzie’s polygraph.In 1913, Sir Thomas Lewis recorded the electrocardiogramof a patient with complete heart block.The world of cardiac pacing had to wait until SeymourFurman, in 1958, illustrated that transvenous endocardialcardiac pacing with a pacemaker electrode placed in theright ventricle corrected the electrical problem and wasa safe technique. The first small clinical trials described thesuccessful use of transvenous temporary cardiac pacing.This technique could not have evolved without cardiaccatheterization skills and techniques that began in Germany525

526PACEMAKERSHIS bundleFIGURE 1p. 230.)Electrical system of the heart. (From Khan, M. Gabriel, and Marriott, H.J.L. (1996). Heart Trouble Encyclopedia, Toronto: Stoddart Books,in the late twenties by Forssmann, who advanced a ureteralcatheter from a vein in his arm into the right atrium. Thenin the late forties the established role of catheterizationwas taken further by Cournand and others.The first electrode used on preliminary dog studies wasa diagnostic Cournand cardiac catheter with a steel wire asa conductor soldered distally to a bit of tinfoil wrappedaround the tip of the catheter. A Swedish physician, AkeSenning, performed a permanent implant that year usinga Siemens pacemaker.II. COMPLETE HEART BLOCKA. PathophysiologyNormally an electrical current originates in the sinus node(the natural pacemaker) and is conducted through theAV node (Fig. 1). It then traverses the right and left bundlebranches to reach the ventricular muscle and endocardium.The electrical current stimulates cardiac contraction thatcauses ejection of blood from the left ventricle into theaorta which results in an adequate supply of blood, oxygen,and other nutrients to the brain and vital organs. Theelectrical current may be halted by diseases that destroy thespecialized conducting tissue in the AV node or lowerin the bundle of His; the current fails to reach the ventricleand no cardiac contraction occurs (asystole). The brainis deprived of blood and the individual loses consciousness.The block in the electrical conduction may be temporaryand last several seconds to a minute. With return of electricalconduction, blood supply to the brain is restored andthe patient recovers. If blood fails to reach the brain andhead, the facial skin becomes blanched and when the heartbegins to contract again blood is pushed quickly andrapidly into the facial arteries causing intense flushingof the face. Loss of consciousness accompanied by facialpallor and during recovery followed flushed facies is acharacteristic of complete heart block (Stokes-Adamsattacks).If blood supply to the brain is cut off for moreprolonged periods convulsive seizures may occur and withmore prolonged asystole death may result. Transient lossof consciousness occurring in a patient who is lying downsuggests Stokes-Adams syndrome or epilepsy. Epilepsy,however, is often associated with premonitory symptoms,urinary incontinence, and convulsions, but the pulse rateis not slowed. With complete heart block the heart rateis usually less than 30 beats per minute followed by severalseconds of no heartbeats and possible loss of consciousness.This condition is called complete heart block becausethere is a block of the conduction of electrical impulsesfrom the atrium through the main electrical tunnel (AVnode) that transmits the impulses to the ventricle (seeFig. 1). The atrium normally contracts at 60–80 beats perminute and in heart block continues to beat at 72 beats

II. COMPLETE HEART BLOCK527per minute, but the ventricles fail to receive the message todo the same. Pacemaker cells in the ventricle may create anelectrical impulse but beat at a rate less than 36 beatsper minute. Occasionally, in this condition, the ventriclesfail to contract, as there is no electrical stimulus (asystole)or the ventricle quivers (ventricular fibrillation) and loss ofconsciousness occurs. The most dramatic manifestationof asystole is severe cerebral ischemia, varying from milddizziness to classical Stokes-Adams seizures. In suchpatients a pacemaker site in the ventricle may suddenlyrestart the heart and the patient recovers in a few seconds.B. Causes of Complete Heart Block — ThirdDegree AV block1. Coronary Artery Disease: Myocardial InfarctionIn 2 of every 100 patients with a heart attack, the electricalpathway connecting the atrium and the ventricle (AV nodeand bundle of His) become damaged and the heart ratebecomes very slow (see Fig. 1). The heart rate may fallto less than 30 beats per minute and asystole maysupervene. If the condition does not respond to drugs suchas atropine, a temporary pacemaker, which is required foronly 2–5 days, is inserted through a vein in the neck.If further damage occurs to the conducting tissue completeheart block may occur.These degenerative diseases may cause right bundlebranch block and left anterior hemiblock in persons overthe age of 50 with slow progression to complete heartblock a decade or more later (see Chapter Bundle BranchBlock).3. InfectionsChagas disease is an important cause of conductionblocks and is prevalent in South America (see chapterentitled Chagas Disease). Other infections that cause conductionblocks include Lyme disease, viral myocarditis,infective endocarditis, toxoplasmosis, tuberculosis,diphtheria, and syphilis.4. Collagen Vascular DiseaseComplete heart block may rarely occur as a complicationof rheumatoid arthritis, scleroderma, dermatomyositis,ankylosing spondylitis, polyarteritis nodosa, lupus erythematosus,and Marfan syndrome.5. Infiltrative DiseasesThese disease include hemochromatosis, amyloidosis,sarcoidosis, and rarely lymphomas and other forms ofcancer.2. Idiopathic Degenerative DiseaseLenegre’s disease and Lev’s disease are two lesions thatinvolve the electrical conduction bundles and producecomplete heart block in the absence of associated damagedue to coronary artery disease (myocardial infarction) andmyocardial diseases. Lev’s disease is caused by an invasionof the conduction bundles by fibrosis or calcificationspreading from any of the fibrous structures adjacent tothe conducting system. Severe calcification of the aorticvalve may cause complete AV block. Fibrosis or calcificationof the central fibrous bloody of the mitral valve ring isa cause of complete heart block in the elderly. Lenegre’sdisease is a sclerodegenerative process involving only theelectrical conducting system. In this rare degenerativedisease of the conduction system the electrical wires ofthe heart are bad, but the heart muscle, coronary arteries,and valves are relatively normal. In patients with degenerativedisease of the conduction system and with congenitalheart block, the remainder of the heart is completelynormal and the insertion of a permanent pacemaker allowsfor normal activity and life span.6. Neuromuscular DiseaseMyotonic muscular dystrophy, peroneal muscular dystrophy(Charcot-Marie tooth disease), and other dystrophiesare included in this classification.7. CongenitalCases of heart block may occur in childhood because ofa congenital defect in the conduction system. The AV nodemay have been the vulnerable target of anti-Ro antibodies.The block may be associated with other complicatedcongenital malformations including corrected transpositionand ventricular septal defect. Fortunately this conditionis rare and occurs as an isolated finding.8. Drug effectsDigoxin, amiodarone, and verapamil (a calcium antagonist)may rarely cause complete heart block.

528PACEMAKERS9. IatrogenicTherapeutic AV node ablation, inadvertent damage duringprocedures, postoperative or traumatic causes, and occasionallytherapeutic irradiation of the chest may causecomplete heart block.C. DiagnosisFindings of heart block on the ECG are diagnostic (seethe chapter Electrocardiography). Figure 2 shows completeabsence of AV conduction manifested by P waves andQRS complexes that are entirely independent. There aremore P waves than QRS complexes, and the ventricles beatregularly. This is indicated by regularly occurring QRScomplexes. The ventricular rate (heartbeat) is less than40 beats per minute, but with congenital heart block itmay be as high as 50 beats per minute or more. Plenty ofP waves are visible and the P to P intervals are equal andconstant.III. SECOND DEGREE AV BLOCKType II second degree AV block (Mobitz type II block)associated with a bundle branch block pattern is due toconduction defects usually below the bundle of His. Otherdropped beats are caused by intermittent block in thebundle branch. This type of block often progressesinsidiously to complete heart block with Stokes-Adamsattacks. This diagnosis is made from the ECG when atleast two regular and consecutive atrial impulses areconducted with the same PR interval before the droppedbeat and the P to P intervals are equal. Permanent pacingis usually required.IV. SINUS NODE DYSFUNCTIONIn this condition, because of coronary heart disease,degenerative disease, or unknown cause the normal sinusnode pacemaker may have been destroyed because oflack of blood supply or replaced by fibrous tissue. Theheartbeat then becomes erratic and the heart may beatvery slowly (28–42 beats per minute) and at other timesmay beat very quickly (100–150 per minute). Thus thecondition is sometimes called bradytachycardia or sicksinus syndrome.With sick sinus syndrome the patient may complain ofdizziness or transient loss of consciousness (syncope) thatoccurs without warning. This condition is common and ismost often seen in individuals over age 65. It is importantto document that these symptoms are due to a sicksinus, because they can also be caused by several otherconditions including cerebral arterial disease whichcauses lack of blood circulation to the brain for which aIIIIII1104 75MFIGURE 2 Complete atrioventricular block with idioventricular rhythm. The QRS complexes are abnormally wide and are different from those seenduring sinus rhythm. The ventricular rate is 36 bpm. (From Chou, T.C. (1996). Electrocardiography in Clinical Practice, 4 th ed., Philadelphia: W.B.Saunders.)

V. PERMANENT PACEMAKERS529pacemaker will not help. If the diagnosis is established assick sinus syndrome, a permanent pacemaker is insertedand the patient gets complete relief of symptoms.IV. PERMANENT PACEMAKERSA. Types of PacemakersA cardiac pacemaker is an electronic device that sensescardiac electrical activity and delivers electrical stimuli tothe heart when needed. If the natural pacemaker (AV sinusnode) is no longer working well or the electric current isblocked by disease of the conducting bundles, a pacemakercan be implanted. A pacemaker lead (electrode) is insertedinto the right ventricle and the pacemaker (pulse generator)is inserted just under the skin (see Fig. 3). The leadis then attached to the pacemaker. A small electricalcurrent is passed through the lead at the rate set by thecardiologist. When the impulse reaches the heart musclethe muscle contracts in the same way it would as ifthe electrical impulse occurred naturally.The pacemaker generator can be visualized as an eyethat stands guard over ventricular and in some cases atrialactivity. If the eye sees ventricular activity it inhibits its ownoutput electrical pulse, but if it sees no activity it deliversan electrical stimulus to the ventricle to keep it beating ata programmed rate. (see Fig. 4).FIGURE 3 Artificial pacemaker. (From Khan, M.G., and Marriott,H.J.L. (1996). Heart Trouble Encyclopedia, Toronto: Stoddart Publishing,p. 224.)V4FIGURE 4 Electronic pacemaker, demand mode; ventricular capturerate ¼ 75 bpm. The spontaneous beat in V 4 is followed by sensing andpacemaker capture at the appropriate interval, which is equal to thatshown in lead I. The pacemaker output is inhibited appropriately inresponse to the intrinsic QRS complex (the first beat in lead V 4 ).Permanent pacemakers can be classified on the basis offive characteristics:1. The cardiac chamber paced by the device, ventricle(V),or atrium (A)2. The chamber sensed by the device (V or A)3. Device response to sensing4. Device programmability5. Additional functions.A five-position North American Society of Pacingand Electrophysiology/British Pacing and ElectrophysiologyGroup generic pacemaker code is used to describepacemakers on the basis of the above features. VVI pacinghas a ventricular lead placed in the ventricle which pacesand senses only the ventricle. It looks for ventricularelectrical activity and delivers its stimuli when necessary;so that it paces only the ventricle, senses only the ventricle,and responds to sensing by inhibition of its stimulus. Thusthe output of the pacemaker is inhibited by the sensednormal ventricular signal as shown in Fig. 4. Generally thefirst three or four positions are used; for example, a VVIRpacemaker implies a pacemaker that paces and senses theventricle, is inhibited by a sensed event, and has rateresponse function. Figure 5 shows AOO, VDD, and DDDpacing modes.There are numerous pacemaker systems on the market.A cardiologist or cardiac surgeon will choose the one

530PACEMAKERSAAO 9 80 LEAD I 9.25mm/secAPRESENTING ECGBLEAD9.25mm/secPRESENTING ECGCLEAD II9.25mm/secFIGURE 5 Different modes of pacemaker function are shown. (A) AOO, fixed rate atrial pacing. Note narrow, paced QRS complexes in response topaced atrial beats. (B) VDD, the pacemaker senses the atrium and the ventricle and paces the ventricle. Each spontaneous P wave is followed by a pacedventricular complex. (C) DDD, the pacemaker senses and paces in the atrium and the ventricle. The sixth complex of this striprepresents a spontaneous Pwave that conducts to the ventricle, resulting in a narrow QRS complex with the pacing spike occurring in the ventricular refractory period. Arrows indicatepacing stimulus artifacts. (From Saksena, S. (1996). Nonpharmacologic therapy for cardiac arrhythmias: cardiac pacing, implantable cardioverterdefibrillators,catheter and surgical ablation. (Khan, M. Gabriel, Ed.). Baltimore: Williams & Wilkins.)appropriate pacemaker for each patient. Usually, the individualrequiring a pacemaker is admitted to the hospital.The pacemaker is inserted by a cardiac surgeon andoccasionally by a cardiologist during a simple operation.A pacemaker consists of a heart generator that weighsabout 30 g and is implanted under the skin of the lowerabdomen or near the collarbone. The tips (leads) of thepacing wire that emerge from the pacemaker generator areinserted into the vein and threaded through to reacha position inside the right ventricle (see Fig. 3). Anothermethod that is occasionally used attaches the tips of thepacing wire to the outside surface of the right ventricle.This type of pacemaker is called a ventricular pacemaker.Another type of pacemaker, dual-chamber, has certainadvantages for some patients. It utilizes two pacing wiresand one is positioned in the right ventricle and the otherin the right atrium. This DVI (AV sequential) pacemakerpaces both chambers but senses only the ventricles. It isinhibited upon sensing normal electrical ventricularactivity (a QRS complex).Prior to 1972, the power source for pacemakers wasderived from batteries that were chiefly mercury-zinc.These were heavy and only lasted 2–4 years. Now, mostmodern pacemakers are programmable, that is, by placinga device on the skin over the generator radio signals aredelivered to the pacer circuitry. This simple procedure isdone in a clinic. The patients are usually followed for 6–12weeks after the pacemaker is inserted, then twice annually.If signs of power-source depletion are observed, the patientis then seen monthly. Power-source depletion is easilydetected as a decrease in rate when the system is monitoredby passing a magnet over the generator. Batteries arechanged every 10 years depending on the make of thepacemaker. Changing the pacemaker batteries requiresminor surgery. The flap of skin is lifted and the pacemakergenerator is replaced. Pacemakers are often programmedso that they work only when the patient’s heart beatsbelow the set rate.B. Electrical SafetyCurrent pacemakers are electrically shielded so that it is nolonger necessary to avoid electrical equipment, as was thecase with older pacemaker systems. However, some cautionis required. Use only grounded (three-prong plug)electrical tools such as saws and drills.Use microwave ovens with caution. The newer modelsare well protected and little radiation occurs. If you usethe microwave often and become dizzy, step away fromthe ovenUse a rechargeable electric razor or hand razor ratherthan one that plugs into the wall.Check whether a person with a pacemaker can passthrough the electronic device safely at airports.When using an electrical device for the first time, if youbecome dizzy turn the equipment off and refrain fromusing the device.C. Complications1. General ComplicationsGeneral complications are uncommon but numerous andinclude vein damage causing extensive bleeding, embolus

V. PERMANENT PACEMAKERS531or thrombosis, pneumothorax, thromboembolism, leadplacement dislodgment or perforation of the right ventricleor coronary sinus, and infection or local hematoma of thegenerator.Seek immediate attention for the following:Increased shortness of breathMarked tiredness and fatigueSwelling of the extremities, fingers, hands, and anklesFever from 100–104 FDrainage from of the incision or swelling and increasedtenderness or redness of the incisionProlonged periods of dizziness or momentary dizzinesswhen changing positions such as getting out of bedFainting spells, syncope must be dealt with immediatelyProlonged hiccoughing.2. Pacemaker SyndromeSome patients with or without normal ventricular functionmay experience symptoms with ventricular pacing. Thesesymptoms include exercise intolerance, dyspnea, cough,chest discomfort, abdominal distention, nausea, fatigueand tiredness, dizziness, syncope or presyncope, andhypotension. This constellation of symptoms is referredto as ‘‘pacemaker syndrome’’ and is a result of loss ofAV synchrony. The diagnosis of pacemaker syndromeshould always be considered when persistent or new symptomssuggestive of low cardiac output or heart failure occurafter satisfactory implantation of a permanent ventricularpacemaker. Symptoms may be directly induced orexacerbated by pacing.A dual-chamber pacemaker is the treatment of choicein patients with pacemaker syndrome. Maintenance ofAV synchrony is important in these patients as VAconductioncauses hemodynamic derangements that raise atrialpressures and decrease cardiac output with associatedsymptoms.3. Pacemaker MalfunctionMalfunctions include: Sensing malfunction (see Fig. 6) Oversensing Pacing malfunction Lead fracture Pulse generator malfunction Pacemaker infection.D. Temporary PacingIt may be necessary to insert a temporary pacemaker inpatients where a heart attack has disturbed the electricalconducting system of the heart and spontaneous recoveryis expected within a few days. This procedure is a simpleone. The temporary pacemaker consists of a pacing wirethat is inserted through a vein in the neck, usually thesubclavian vein. The skin over the vein is infiltrated witha local anesthetic so that the procedure is not painful.A pacing catheter is threaded through the vein to reachthe inside of the right ventricle. The passage of thepacing catheter is usually done under fluoroscopic (x-ray)control because the wire is radio-opaque and can beseen on x-ray. Occasionally this procedure is done withthe assistance of an ECG and the final position of thecatheter is verified by x-ray. The external end of the wirecatheter is connected to a battery-operated pulse generator(see Fig. 3). The pulse generator is set, for example,at 65 beats per minute and commences pacing if theheartbeat falls below this set rate. The pacemaker works(fires) only when it is required. Complications are veryIIIIIIV 1V 3V 6570909 64FFIGURE 6 Ventricular demand pacemaker (VVI) with sensing malfunction. The pacemaker operates like a fixed-rate pacemaker. The spontaneousventricular beats are not sensed. The spontaneous rhythm is atrial fibrillation. (From Chou, T.C. (1996). Electrocardiography in Clinical Practice, 4 th ed.,Philadelphia: W.B. Saunders.)

532PACEMAKERSfew for the insertion and maintenance of a temporarypacemaker.VI. WHAT A PACEMAKER WILL NOT DOA pacemaker does not cause the heart muscle to contractmore forcefully; therefore, it does not help heart failure,except in some cases where a very slow heart rate wascontributing to the heart failure. In a special group ofpatients with heart failure and intraventricular conductiondelay pacing the heart may decrease the recurrence ofheart failure (see the chapters Heart Failure and BundleBranch Block).A pacemaker does not increase the blood supplythrough the coronary arteries; therefore, it does not helpchest pain or angina or prevent a heart attack. It does notreplace the usual cardiac medications prescribed for variousheart conditions. Prescribed medications must be continuedfor heart failure, angina, or other conditions that mayexist. A pacemaker is a great device but it does only whatit is designed to do. It stimulates the electrical system of theheart so that the heart beats at the correct time and atan appropriate rate. A pacemaker can prolong life providedthe problem is a slow a heart rate or no heartbeat becauseof heart block.VII. ACTIVITIESPatients are allowed to exercise freely to the extent ofmajor advances in electronics, and now virtually allpacemakers are powered by a variety of lithium batteries.The life of the lithium pacemaker varies from 7–10years. Each patient is given a card that documentsthe type, model, serial number, date of installation, andapproximate life of the pacemaker and should carrythe card at all times and wear a pacemaker awarenessbracelet.Pacemaker patients are strongly advised to attend apacemaker clinic for follow up in order to detect the rareoccurrence of intolerance. Many are able to jog one to fivemiles daily and do similar exercises if angina or heartfailure are not present. A patient with a pacemaker can leada normal life.BIBLIOGRAPHYAcierno, L. J. Electrophysiologic disturbances. In The History ofCardiology. Parthenon Publishing, New York, 1994.Cooper, J. Cardiac pacing. Heart talk/Tampa tracings, Florida, 1988.Saksena, S. Cardiac pacing. In Heart Disease Diagnosis andTherapy. M. Gabriel Khan, ed. Williams &Wilkins, Baltimore,MD, 1996.

Patent Foramen OvaleI. Developmental FeaturesII. Clinical Features and InvestigationsIII. Proof of PFO Involvement in StrokeIV. Perspective and Research ImplicationsGLOSSARYcryptogenic of obscure or doubtful origin.embolism, embolus a blood clot that forms in an artery, a vein,or the heart and breaks off and is carried by the circulatingblood, finally lodging and blocking the artery that suppliesan organ with blood; for example, pulmonary embolism isan embolus blocking an artery in the lung.TIA transient ischemic attack; transient lack of blood supply(ischemia) to the brain causing symptoms of mild stroke thatrecover within 24 h.oxygenated blood. A right-to-left shunt in individuals withcongenital heart disease (CHD) causes cyanotic congenitalheart disease which is life-threatening (see chapter entitledCongenital Heart Disease).The foramen is formed by overlapping flaps of the septumprimum and septum secundum (See Figure 1). These septafinally fuse to form the atrial septum in the newborn (seethe figures in the chapter Embryology and the figuresprovided in the chapter Anatomy of the Heart and Circulation).The foramen usually closes at the time of birthbecause of the acute decrease in pulmonary vascularresistance and increased pressures on the left side of theheart. It normally fuses completely within 2 years. A PFOhas been noted in up to 25% of structurally normal heartsDURING THE PAST 15 YEARS, BECAUSE OFechocardiographic visualization of the left atrium and theseptum, it became apparent that a patent foramen ovale(PFO) is present in approximately 25% percent of arandomly selected population. Because the transesophagealechocardiogram (TEE) gives excellent clarity of this regionof the heart, it is the preferred method of study fordiagnosis. There has been increasing interest in PFO andits role in systemic embolization especially to the brainwhich causes stroke of undetermined etiology (cryptogenicstroke).I. DEVELOPMENTAL FEATURESDuring fetal development PFO allows the necessaryshunting of oxygenated blood from the right atrium tothe left atrium; thus, oxygenated blood flows into the systemiccirculation to organs and tissues. This right-to-leftshunting of blood is crucial for fetal development, butit is also vital that no shunt should occur after birth,because the right side of the heart is no longer filled withFIGURE 1 Longitudinal imaging transesophageal echocardiographyin the mid-upper esophagus. A large patent foramen ovale (PFO) isevident. The arrow illustrates how to measure the PFO width. LA ¼ leftatrium; RA ¼ right atrium. (From Kerut, E. K. et al. (2001). J. Am.College Cardiol., 38(3), 614.)533

534PATENT FORAMEN OVALEFIGURE 2 Longitudinal transesophageal echocardiography (TEE) imaging in the mid-upper esophagus. A 32-year-old male presented with an embolicstroke. He was found to have occult thrombi in both calf veins. Transthoracic echocardiography with peripheral saline contrast during normal respirationand Valsalva were negative for a right-to-left shunt. (A) TEE revealed a small restrictive secundum atrial septal defect (ASD) (arrow). Note how thisappearance is different from that of a patent foramen ovale. (B) Color Doppler demonstrates a left-to-right shunt with a color mosaic pattern from the shuntin the right atrium (RA). The ASD was subsequently surgically repaired. LA ¼ left atrium; SVC ¼ superior vena cava. (From Kerut, E. K. et al. (2001).J. Am. College Cardiol., 38(3), 618.)at autopsy, and TEE studies report similar figures. A PFOis not similar to an atrial septal defect (ASD), where thereis a failure of part of the atrial septum to form rather thanfuse, which results in a hole in the septum that separatesthe right and left atrium (see Figure 2 and the chapterAtrial Septal Defect). A PFO is not a hole in the heart.Instead, it is a failure of fusion of the two flaps describedabove which causes a less than 5-mm, slit-like valvular

III. PROOF OF PFO INVOLVEMENT IN STROKE535opening in the interatrial septum (Figure 1). Mechanismsthat lead to a marked increase in pressures in the rightatrium, such as occur during a Valsalva maneuver or inpatients with pulmonary hypertension, can increase thedegree of shunting of blood from the right atrium throughthe slit-like opening of the PFO into the left atrium. Thisspurt of blood from the right side of the heart throughthe PFO gains access to the left ventricle, the aorta, andarterial supply to organs of the body. Thus, thrombi thatform in the right side of the circulation, from veins in thelegs and other areas that drain into the venous circulationto the heart (see the chapter Anatomy of the Heart andCirculation, Figs. 5 and 10), may gain access to the vitalorgans.II. CLINICAL FEATURESAND INVESTIGATIONSCryptogenic stroke is a nonhemorrhagic stroke (cerebralinfarcts) that occurs in younger individuals withoutidentifiable risk factors such as hypertension, diabetes,paroxysmal atrial fibrillation, atheroma of the ascendingaorta, hyperlipidemia, and lacunar strokes from smallvessel disease.No cause for cryptogenic strokes can be defined afterintensive investigation which includes a careful cardiovascularand neurologic examination, carotid Doppler,cerebral imaging (CT and MRI), tests for thrombophyllicdisorders, and Holter monitoring to uncover paroxysmalatrial fibrillation.Paroxysmal atrial fibrillation can be easily missed, andit is a more common cause of cerebral embolization thanthat caused by PFOs.III. PROOF OF PFO INVOLVEMENTIN STROKEIllustrations depicting PFOs are Figs. 1, 4, and 5 and atrialseptal defects, are given in Fig. 2. It is extremely difficult tobe certain if a PFO observed by TEE is the cause of strokein a given individual. There are very few credible reportson this subject. Findings of a thrombus in transit through aPFO have been reported in a few autopsy and echocardiographicreports (see Fig. 4).FIGURE 3 Apical four-chamber view recorded in a patient with an atrial septal aneurysm. Note the marked bulging of the atrial septum into the cavityof the left atrium (arrow). The right-hand panel is recorded after injection of saline contrast medium. Note the contrast medium has filled the rightventricular cavity, and there are numerous individual microbubbles seen in the cavity of both the left atrium and left ventricle, consistent with a right-to-leftshunt through fenestrations in the atrial septal aneurysm.

536PATENT FORAMEN OVALEFIGURE 4 Longitudinal transesophageal echocardiographic imaging in the mid-upper esophagus. Arrows point to a thrombus wedged through a patentforamen ovale and lodged in both the right atrium (RA) and left atrium (LA). SVC ¼ superior vena cava. (From Kerut, E. K. et al. (2001). J. Am. CollegeCardiol., 38(3), 619.)FIGURE 5 Original patent foramen oval-Star occluder is demonstrated with the center post, the expanded nitinol wires and the two Ivalon sails (left).After implantation the device is shown by transesophageal echocardiography in the vertical biatrial view (middle) and by magnetic resonance imaging in thefour-chamber view (right). Ao ¼ aorta; LA ¼ left atrium; RA ¼ right atrium. (Braun, M. U. et al. (2002). J. Am. College of Cardiol., 39(12), 2020.The finding of a clot in veins of the lower limbs (deepvein thrombosis, DVT), increases the probability of embolizationthrough the PFO. A DVT has been observed inapproximately 33% of individuals with cryptogenic strokeand PFO. It is extremely difficult to be certain of thediagnosis in individuals without DVTs or where predisposingfactors for DVT are absent. These predisposingfactors include postsurgical immobilization, fractures ofthe lower limbs, plaster casts applied to the lower limbs,immobilization for several days, and the postpartum state.A PFO may play a role in other situations such asvenous-to-arterial gas embolism in serious forms of severedecompression sickness in underwater divers and highaltitude aviators and astronauts. It may also occur in theplatypnea-orthodeoxia syndrome. In this syndrome significantright-to-left shunting of venous blood through aPFO occurs precipitated by postural and other undeterminedmechanisms.Atrial septal aneurysms (ASA; Fig. 3) are associatedwith PFO. ASA incidence is approximately 1% by autopsyand 2% by TEE. PFO was diagnosed in 70% of strokepatients with an ASA and 75% of controls with anASA. An ASA is common in patients with unexplainedstroke and is more frequently detected by TEE than by

IV. PERSPECTIVE AND RESEARCH IMPLICATIONS537transthoracic echocardiography. An ASA in theabsence of a PFO appears to be benign and interventionalrepair is usually not warranted.A. Clinical Study: Martin Braun et al.Study question: This study investigates the safety oftranscatheter closure in PFO patients with cryptogeniccerebral ischemia and mid-term follow up of thromboembolicevents after closure.Methods: In this study, 276 consecutive patientswith TIA and a history of at least one thromboembolicevent had percutaneous PFO closure with the PFO-StarOccluder (see Fig. 5). The mean age of patients was 45 13.7 years, 201 with stroke, and 273 with TIA.Results: Implantation was successful in all 276 patients.During a 15-month follow up the annual recurrence rateof thromboembolic events was 1.7% for TIA, 0% forstroke, and 0% for peripheral emboli.Conclusion: The authors of the study concludedthat interventional PFO closure with the PFO-StarOccluder device appears to be a promising technique,which results in a low recurrence rate of thromboembolicevents in patients with cryptogenic ischemia presumablydue to paradoxical embolization. Note that the authorsused the word presumably. In a study by Hung et al., a56-year-old patient had a stroke 6 months followingdevice placement that was well seated without residualshunting.IV. PERSPECTIVE AND RESEARCHIMPLICATIONSPFOs are very common, but not all PFOs are identicalor carry the same risk. Individuals who have PFOs can begrouped according to many PFO characteristics such aslarge PFOs 0.6–1 cm, versus small PFOs less than 0.6 cmand associated anatomic structures.The diagnosis of a stroke caused by the presence of aPFO is fraught with danger in the absence of definedthrombi in the veins of the lower limbs and the vena cavathat return blood to the right atrium. The investigativetechniques for detecting important PFO characteristics andassessing risk of embolic stroke are not clear and requireintensive research. Kerut et al. appropriately stated ‘‘thechallenge that remains is to determine which PFO andclinical contexts confer an increased risk of significantdisease.’’The diagnosis of PFO as a cause for cryptogenic strokecreates a dilemma for neurologists and patients. It is certainthat errors in diagnosis are made based on the presumedassociation of PFO and stroke.In addition some neurologists often advise aspirin forthe prevention of stroke in patients with PFOs. This advicelacks logic because clots that embolize through a PFOmust originate in the venous system and such clots arenot prevented significantly by the use of aspirin. Anticoagulantssuch as warfarin are advisable and superior toaspirin in patients who have sustained a TIA or strokeproven to be caused by paradoxical emboli via a large PFO.Warfarin is also advised in patients with a large PFOwith well-defined characteristics that is accompanied byproven thrombi in the venous system seen negotiating theforamen, a rare scenario (see Fig. 4).In this subset of patients transcatheter closure has a roleas outlined above, but cases have been described in whichsurgical closure has not prevented stroke in patientswith PFOs. Anticoagulation with warfarin is advisablefor PFO cryptogenic stroke when there is a high probabilitythat the PFO is indicated in paradoxical embolism.Transcatheter device closure should be reserved forthe management of PFOs and stroke caused by highprobabilityparadoxical emboli in individuals with thrombidemonstrated in veins of lower limbs or other veins thatdrain into the right atrium. If no clots are observed in theseveins, PFO as the cause of cryptogenic stroke should berelegated to low probability.BIBLIOGRAPHYBraun, M. U., Fassbender, D., Schoen, S. P. et al. Transcatheter closure orpatent foramen ovale in patients with cerebral ischemia. J. Am. Coll.Cardiol., 39:2019–25, 2002.Hung, J., Landzberg, M. J., Jenkins, K. J. et al. Closure of patent foramenovale for paradoxical emboli: Intermediate-term risk of recurrentneurological events following transcatheter device placement. J. Am.Coll. Cardiol., 35:1311–6, 2000.Keunt, E. K., Norfleet, W. T., Plotnick, G. D. et al. Patent foraminaovale: A review of associated conditions and impact of physiologicalsize. J. Am. Coll. Cardiol., 38:613, 2001.

Pericarditis and MyocarditisI. PericarditisII. Myocarditisrheumatic fever, rheumatoid arthritis, lupus erythematosus,and scleroderma; and trauma that is iatrogenic, postsurgical,or caused by a catheter or pacemaker.GLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.arrhythmia general term for irregularity or rapidity of theheartbeat, an abnormal heart rhythm.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hypotension marked decrease in blood pressure, usually lessthan 95 mmHg.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.pericarditis inflammation of the pericardium or sac surroundingthe heart; this is not a heart attack.I. PERICARDITISThe pericardium is a double membrane that covers theheart and can be involved in infective and noninfectivedisorders (see Figure 2 in the chapter entitled Anatomy ofthe Heart and Circulation).A. Causes1. Easily Recognizable Underlying DiseasesThese include post myocardial infarction pericarditis,which occurs within the first four days of infarction andlater after several months; renal failure; neoplastic diseases;tuberculosis; septicemia causing purulent pericarditis;endocarditis; myxedema; collagen vascular diseases such as2. Drugs and RadiationPericarditis can be caused by cancer chemotherapeuticagents (daunorubicin), dantrolene, hydralazine, isoniazid,minoxidil, procainamide, phenytoin, and anticoagulants.Radiation to the chest may rarely cause pericarditis.3. Viral InfectionsCoxsackie B2, B6 echo virus, HIV, Epstein-Barr, influenza,mumps, varicella, and rubella as well as other viruses,and the mycoplasma organism are all contributing factorsto pericarditis. When none of these underlying disordersare present, pericarditis is labeled idiopathic, andin many of these cases an undetected virus may beimplicated.B. Diagnosis1. Symptoms and SignsPericarditis may cause severe chest pain that is located inthe retrosternal or left precordial area. Occasionally painradiates to the trapezius ridge, a radiation that does notoccur with angina, but pain may radiate to the neck or leftarm and may stimulate angina or myocardial infarction.At times pain is localized to the upper epigastrium andleft upper quadrant. Typical features of pain include asharp, pleuritic pain that increases with deep inspiration,coughing, sneezing, or worsening of pain when lying down.The sharp pain that occurs in bed typically is relievedimmediately by sitting and leaning forward or on standing;pain recurs with recumbency.A pericardial friction rub is heard when a stethoscopeis placed between the left sternal edge and the apex539

540PERICARDITIS AND MYOCARDITISbeat, but the rub may be localized to any area of theprecordium. The rub is best heard with the diaphragm ofthe stethoscope pressed firmly against the chest wall withthe patient leaning forward holding his breath. The rubmay disappear if a pericardial effusion develops.2. Electrocardiographic FindingsThe ECG often shows typical findings that are diagnostic,for example, sinus tachycardia is usually present withwidespread ST segment elevation in leads II, III, and aVFand most of V3 to V6. The ST segment is concave upwardwith no T-wave inversion. Reciprocal ST segment depressionis observed in aVR and V1. After a few days the STsegment becomes isoelectric and the T waves flattened.After several days when the ST segment normalizes, diffuseT-wave inversion occurs. After several weeks the T wavesnormalize and rarely remain inverted.C. Viral PericarditisThe viruses implicated include: Coxsackie, echo, Epsstein–Barr, influenza, HIV, mumps, rubella and varicella. Themajority of cases of so-called idiopathic pericarditis arecaused by viral infections. Patients with these infections areusually hospitalized and monitored for the developmentof pericardial effusion. Pericardiocentesis is rarely necessary,but effusion may lead to cardiac tamponade.D. Cardiac TamponadeCardiac tamponade is manifested by hemodynamic compromise,elevation of the jugular venous pressure, andpulsus paradoxus that may be masked by severe hypotension.Presenting symptoms include severe shortness ofbreath, chest tightness, dysphagia, and a shock-like state.Hemodynamic compromise may be life-threatening.Echocardiography usually confirms the diagnosis withan early finding of diastolic right atrial collapse, whichoccurs in most cases except in regional tamponade whereright or left atrial collapse may be observed. Also seenon echocardiography is diastolic right ventricular collapse.A swinging heart may also be observed associated withelectrical alternans.Management of cardiac tamponade involves the maintenanceof an adequate preload to generate stroke volume.Thus, diuretics and preload reducing agents such asnitrates and ACE inhibitors must be avoided. Volumeexpansion with saline and even transfusion of packedred cells may provide hemodynamic stability untillifesaving pericardiocentesis is achieved. Reaccumulationof fluid and tamponade are indications for a subxiphoidpericardial window drainage carried out by a cardiothoracicsurgeon.E. Constrictive PericarditisConstrictive pericarditis causes a restriction to cardiacfilling and is the most common cause of a restrictivesyndrome.1. Symptoms and SignsShortness of breath, tiredness, and swelling of the abdomendue to ascites as well as other symptoms of underlyingdisease cause pericardial constriction. The presence ofmoderate ascites occurring weeks or months before thepresence of significant leg edema points strongly toconstrictive peritonitis and serves to distinguish the conditionfrom heart failure in which prominent leg edemaoccurs followed months later by mild ascites.Examination of the neck veins reveals a markedly elevatedjugular venous pressure with paradoxical inspiratoryincrease in jugular vein distension (Kussmaul’s sign).The venous pulse has a prominent y-descent (a majornegative wave), coincident with the rapid diastolic fillingof the ventricle. A prominent x-descent, coincident withfilling of the atrium is often observed in patients with sinusrhythm. The exaggerated x- and y-descents give the venouspressure wave a characteristic M- or W-shaped pattern.A characteristic high-frequency, early occurring third heartsound (a pericardial knock) should alert the physician tothe diagnosis of pericarditis. The pericardial knock soundis caused by cessation of diastolic filling. The knock occursearlier than the conventional third heart sound of heartfailure and has a sharp, high-pitched quality that is easilyheard with the diaphragm of the stethoscope. The knocksound may mimic an opening snap characteristic of mitralstenosis or an early filling sound heard in endomyocardialfibrosis.The presentation and investigational findings ofconstrictive pericarditis and restrictive cardiomyopathyresemble each other and differentiation is often challenging.Atrial fibrillation occurs in approximately 33% ofcases of constrictive pericarditis.2. ManagementWhen symptoms are persistent and bothersome andmedical therapy with the judicious use of diuretics and

II. MYOCARDITIS541digitalis to control the ventricular response in patients fails,then surgical pericardiectomy becomes necessary.II. MYOCARDITISAcute myocarditis is a disorder that can cause a fulminantillness resulting in severe functional impairment ordeath. Myocarditis appears to be a precursor to dilatedcardiomyopathy in some patients.A. CausesAcute myocarditis has been associated with infection byCoxsackie B3 and B5, mumps, Epstein-Barr, and influenzaas well as other viruses. In approximately 50% of patientswith HIV who developed dilated cardiomyopathy, associatedmyocarditis was observed on biopsy. In more than50% of HIV patients myocarditis was observed at autopsy.HIV or cytomegalovirus appears to be the cause of myocarditisin patients with AIDS.Chagas disease is the most common cause of myocarditisin Latin America and is caused by toxoplasmosis anddiphtheria. Acute myocarditis is associated with lupuserythematosus and Kawasaki syndrome. Forms of giant cellinfiltration of the myocardium may occur with Sjogren’ssyndrome, giant cell arteritis, thymoma, myasthenia gravis,chronic active hepatitis, and ulcerative colitis. Patientswith giant cell myocarditis appear to have a prognosisworse than that of lymphocytic myocarditis. Hypersensitivityto drugs and other exogenous agents may also causemyocarditis.heart failure and signs and symptoms of heart failure mayoccur.An easily heard third heart sound gallop (S3) is oftenpresent and is an unexpected finding in patients withsignificant myocardial involvement. The loud thirdheart sound may persist for several weeks. Very minimalsymptoms may be present and the commencement of thedisease may go unnoticed until severe damage to the heartmuscle causes signs of heart failure.ECG shows nonspecific ST-T wave changes, often withlow-voltage QRS complexes. Atrial and ventricularpremature beats with supraventricular tachycardia are acommon occurrence. Ventricular tachycardia may cause alife-threatening situation. Q waves simulating acute myocardialinfarction but without much ST segment elevationmay be seen on ECG, but serial ECGs from several hoursto a few days do not show the evolutionary changes that arehallmarks of acute myocardial infarction. Cardiac enzymes,CK–MB, and troponins may simulate acute myocardialinfarction, but with a different time course.C. ManagementMore than 85% of patients completely recover over severalmonths. In a few cases heart failure is manifested and clearsover several weeks with conventional medical therapy.If heart failure becomes progressively worse, it may beameliorated with administration of corticosteroids andcyclosporine. In the presence of lethal or potentially lethalarrhythmias the administration of amiodarone may belifesaving.B. Symptoms and SignsMajor manifestations include chest pain in more than 20%of patients associated with peritonitis. Chest pain mayoccur suddenly and last for several hours without featuresof pericarditis and mimic acute myocardial infarction.Patients may have recurrent or intractable chest pain overseveral days. Abnormal heart rhythms may cause palpitationsin approximately 33%. The disease may precipitateBIBLIOGRAPHYGarcia, M. J. Constriction vs. Restriction: How to evaluate? J. Am. Coll.Cardiol., ACC J. Rev., July/August, 49–53, 2003.Khan, M. Gabriel Pericarditis/cardiac tamponade. On Call Cardiology.W. B. Saunders, Philadelphia, 2001.Khan, M. G. In Heart Disease Diagnosis and Therapy: Pericarditis, secondedition. Humana Press, New Jersey, 2005.Lange, R. A., Hillis, L. D. et al. Acute pericarditis. N. Engl. J. Med.,351:2195–2202, 2004.

Pulmonary Arterial HypertensionI. Pulmonary HypertensionII. Primary Pulmonary HypertensionGLOSSARYascites accumulation of serous fluid in the abdominal cavity.dyspnea shortness of breath, usually on exertion.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply blood reachesorgans and tissues.syncope temporary loss of consciousness caused by lack of bloodsupply to the brain; fainting describes a simple syncopal attack.tachypnea increased respiratory rate.I. PULMONARY HYPERTENSIONIn 1998, the World Health Organization (WHO) classifiedprimary pulmonary hypertension (PPH) as one of thecauses of pulmonary arterial hypertension (PAH). PPHwas defined in the U.S. National Institutes of HealthRegistry as a mean pulmonary artery pressure of more than25 mmHg at rest or 30 mmHg with exertion, in theabsence of heart disease, chronic thromboembolic disease,underlying pulmonary disorder, or other secondary causes.as emphysema and collagen vascular diseases likescleroderma, sarcoidosis, and schistosomiasis Pulmonary venous hypertension in which the pulmonarycapillary wedge pressure is increased, chronic severeleft ventricular failure, severe mitral stenosis, severemitral regurgitation, left atrial myxoma, and pulmonaryveno-occlusive disease Diseases that cause a marked increase in resistancein the pulmonary arteries and large arterioles such aspulmonary embolism, in situ thrombosis of pulmonaryarteries, congenital heart disease caused by shunts, sicklecell disease, schistosomiasis, and sarcoidosis Drugs such as appetite suppressants [fenfluramine,dexfenfluramine, aminorex] and toxins including toxicrapeseed oil PPH is considered when all secondary causes areexcludedA most publicized risk factor for PAH is appetitesuppressant drugs. Aminorex fumarate was linked to anepidemic of PAH in Switzerland, Germany, and Austria inthe sixties, and withdrawal of this agent was followed bya fall in incidence of the disorder. The use of fenfluramineand its derivatives in Europe caused an increase in PAHcases. The combination of fenfluramine and phenterminein the United States has been implicated, and toxicrapeseed oil caused several cases in Spain.A. Causes and Risk FactorsAn approach to the elucidation of the many secondarycauses of PAH is given in Fig. 1. PAH may be caused byseveral disorders that include:Pathophysiologic causes of severe chronic hypoxemiaincluding alveolar hypoventilation disorders such aschronic obstructive pulmonary disease (COPD), numerousrestrictive lung diseases, chronic exposure to highaltitude, and sleep apneaDiseases primarily of the lung parenchyma that alsoaffect the abundant pulmonary vascular network suchB. Symptoms and Physical SignsMild pulmonary hypertension with a mean pulmonaryartery pressure less than 25 mmHg is usually asymptomatic.A moderate degree of pulmonary hypertension witha pulmonary artery pressure of 50–60 systolic with a meangreater than 40 mmHg may cause dyspnea on exertionand easy fatigability. Severe pulmonary hypertension witha pulmonary artery pressure greater than 80 and a meangreater than 55 mmHg may cause severe and bothersomedyspnea and is nearly always present. In the U.S. NationalInstitutes of Health Registry, 98% of patients with PPHhad dyspnea at enrollment. Less common symptoms543

544PULMONARY ARTERIAL HYPERTENSIONResistance to pulmonary venous drainage;pulmonary venous hypertension?NOYESPulmonarywedgeResistance in thepulmonary vascular bed?NOYESL V failure: all causesMitral stenosisMitral regurgitationMyxomaConstrictive pericarditisPulmonary veno-occlusive diseaseResistancemainly in thepulmonary arteriesand arteriolesYESCOPDRestrictive lung diseasePneumoconiosesCollagen-Vascular:sclerodermalupusrheumatoidARDSSchistosomiasisPulmonary embolismHypoxic pulmonary hypertension: ARDS, high altitudeHypoventilation: COPD, obesityCongenital heart disease (shunts)Primary pulmonary hypertensionFIGURE 1IncreaseDecreaseCommon causes of pulmonary hypertension.include tachypnea, chest pain, presyncope, syncope,palpitations, peripheral edema, and rarely sudden death.Abnormal physical signs or examination include a giantA wave in the jugular venous pulse. A left parasternal liftis seen and felt along the left sternal border caused byright ventricular hypertrophy. There is accentuation ofthe pulmonary component of the second heart sound, anejection click caused by dilation of the main pulmonaryartery, and right-sided third and fourth heart sounds.A murmur of pulmonary regurgitation and tricuspidregurgitation with prominent V waves is observed if thetricuspid valve annulus is dilated. Finally, signs of rightheart failure occur with jugular venous pressure elevation,ascites, and edema.C. Laboratory Studies1. Chest X-ray and CT ScanChest x-ray may show evidence of diseases that causessecondary PAH. With significant PPH the lung fields areclear with evidence of dilation of the main right and leftpulmonary arteries and attenuation of peripheral branches,but the chest x-ray is nonspecific. A CT may be helpful inresolving restrictive lung disease, other parenchymal lungdiseases, or mediastinal fibrosis.2. Electrocardiogram and EchocardiographyThe ECG is nearly always abnormal in patients withsignificant PAH from any cause and may reveal evidenceof right atrial hypertrophy, right axis deviation, andsometimes right ventricular hypertrophy or ST-segmentdepression with T-wave inversion in leads V1 to V3.Echocardiographic assessment is most valuable in detectingcauses of left heart failure, left atrial enlargement, mitralstenosis, left atrial myxoma, elevation of the pulmonaryartery pressure, right ventricular hypertrophy, tricuspidregurgitation, enlargement of cardiac chambers, shunts,and right ventricular dimensions and function.3. Other StudiesThe lung scan is nondiagnostic and must be analyzed inconjunction with the clinical assessment and chest x-ray.

II. PRIMARY PULMONARY HYPERTENSION545In the absence of chronic obstructive lung disease, the lungscan may help in differentiating chronic pulmonaryembolism from PPH. A complete blood count shouldinclude HIV antibody, liver function tests, thyrotropin,and an antinuclear antibody. To exclude other secondarycauses of pulmonary hypertension, a sleep study and pulmonaryangiography should be performed.II. PRIMARY PULMONARY HYPERTENSIONThe frequency of PPH is estimated as one to two cases permillion people. This rare disease is often fatal and frequentlyoccurs in young women who are affected twiceas often as male individuals. There appears to be amarked frequency observed in the Indian subcontinent.The disease presents in the third decade of life in womenand the fourth decade in men with a mean age at diagnosisof 36 years with a prevalence close to 10%. PPH accountsfor less than 0.5% of all cases of PAH.A. DiagnosisA thorough history and physical examination and assessmentof the laboratory tests outlined above should excludesecondary causes of PAH. Right heart catheterization inpatients with PPH gives accurate hemodynamic measurementsand appraisal of disease severity and prognosis.Increasing mean pulmonary artery pressure, right atrialpressure, and decreased cardiac index are associated withdecreased survival rates. A mean pulmonary artery pressureless than 55 or greater than 85 mmHg indicates a fair andpoor prognosis, respectively. A mean right atrial pressureless than 10 mmHg or greater than 20 mmHg indicatesa good and bad prognosis, respectively. A mean cardiacindex greater than 4 L/minute/m 2 (4 L/min/m 2 ) or lessthan 2 L/minute/m 2 indicates good and poor prognosis,respectively.B. Risk Factors and PathogenesisA proposed pathogenesis for the development of PPH isgiven in Fig. 2. Key factors include genetics and endothelialinjury and dysfunction. Studies indicate an autosomaldominant inheritance, estimated penetrance of10–20% and the onset of the disorder occurs at an earlierage in successive generations. A study of families affectedby PPH revealed BMPR2 as a primary gene for familialPPH on chromosome 2q33. Mutations in BMPR2 haveFIGURE 2 Proposed pathogenesis for the development of PPH. Genes implicated in the pathogenesis of PPH are prostacyclin synthase, serotonintransporters, nitric oxide synthase, serine elastases, and matrix metalloproteinases (MMPs), voltage-gated potassium (K V ) channels, angiotensin-convertingenzyme (ACE), vascular endothelial growth factor (VEGF), carbamoyl phosphate synthase, and plasminogen activator inhibitor type 1 (PAI-1). Endothelin-1 production adds to the vasoconstriction in PPH, but whether this is secondary to changes in the above genes, a result of endothelial dysfunction,or a primary pathogenetic event is not clear. Pulmonary vascular remodeling results from the effects of genetics, modifying genes, and environment.(From The Lancet, 361, 1536, 2003.)

546PULMONARY ARTERIAL HYPERTENSIONbeen noted in approximately 50% of familial PPH casesand 26% of sporadic cases.Endothelial injury and dysfunction also appear to be keypathogenic factors. There is strong evidence that points toan abnormality in the pulmonary vascular endothelium.Increased pulmonary vascular reactivity and vasoconstrictionobserved in individuals with PPH indicate that amarked vasoconstrictor tendency is an important pathogenicfactor in predisposed individuals.Hypovasodilatation appears to be the result of loss ofendothelial cell integrity. A defect in the nitric oxide synthasesystem appears to be implicated. Vascular endothelialcells synthesize nitric oxide from L-arginine. Patients withPPH appear to be deficient in the endothelial-derivedvasodilator prostacyclin and nitric oxide. Nitric oxide ismade by vascular endothelium and catalyzed by nitricoxide synthase which inhibits smooth muscle cell growth.Endothelium from patients with PPH showed negligiblechemical staining for nitric oxide synthase comparedwith healthy controls. An increase in the production ofthromboxane, a powerful vasoconstrictor, and decrease information of the powerful vasodilator prostacyclin havebeen documented.Increased expression of endothelin-1, a potent vasoconstrictor,and mitogen for smooth muscle cells in thepulmonary artery of patients appears to be related todisease severity and survival.Serotonin plasma levels are higher than normal in PPHprobably as a result of normal platelet processing andstorage. Appetite suppressant drugs serve as substrates forserotonin transporters and gain access into pulmonaryartery smooth muscle cells. The toxic action on smoothmuscle cells is perhaps the link between anorectic agentsand development of PPH.Voltage-gated potassium channels in pulmonary arterysmooth muscle cells appear to be blocked by anorecticagents, thus, causing enhanced smooth muscle cell proliferationand vasoconstriction.C. Therapy1. Calcium AntagonistsLess than 25% of patients with a mild-to-moderate degreeof PPH treated with calcium antagonists obtain sustainedhemodynamic improvement and survival. A trial of calciumantagonists is indicated in patients who respond toacute vasodilator testing with nitric oxide, adenosine,or prostacyclin. Vasodilator testing is done with shortactingagents because serious complications includinghypotension and death have occurred.2. ProstacyclinSeveral studies have demonstrated improvement in exercisetolerance, hemodynamic measurements, and survival inpatients treated with intravenous epoprostenol. Althoughthis agent is considered effective, its short half-life requirescontinuous long-term intravenous treatment via an indwellingcatheter. Complications are common and include localand systemic infection, hemorrhage, paradoxical embolism,and rarely fatalities because of delivery malfunction.Most important, patients without response to vasodilatortesting may obtain benefit from this therapy because ofdecreased platelet aggregation, factor VIII, von Willebrandantigen, and production of endothelin-1.Oral analogues of epoprostenol are being tested.Beraprost, administered orally and tested in a randomizedclinical trial of 12 of weeks in patients with PAH functionalclass II–III, showed improved exercise tolerance anddyspnea in patients with PPH. Iloprost administered byinhalation surprisingly caused more potent pulmonaryarterial vasodilatation than inhaled nitric oxide.3. Endothelin-1 Receptor AntagonistsEndothelin-1 is a potent endogenous vasoconstrictor andsmooth muscle mitogen that is overexpressed in the plasmaand lung tissue of patients with PPH. Two multicenter,randomized clinical trials have shown proven benefits ofan oral endothelin-1 receptor antagonist, bosentan. Thisagent is indicated for stable functional class III or IVpatients with PAH.a. Clinical Study: Rubin et al.Methods: This study randomly assigned 213 patients withPPH (all associated with connective tissue disease) toreceive 6.25 mg then 125 or 250 mg of bosentan orplacebo for a minimum of 12 weeks. The primary endpoint was the degree of change in exercise capacity.Results: At 16 weeks patients treated with this agentshowed an improved six-minute walking distance; themean difference between the placebo group and the combinedbosentan group was 44 m ( p ¼ 0.0001).The drug modestly improved the dyspnea index, WHOfunctional class, and increased the time to clinical worsening.At 16 weeks 38 and 34% of patients, respectively,had improved from class III to II. A significant numberof placebo patients improved their class because of theexercise program and encouragement to walk. The drugwas discontinued in 2% of patients because of liverdysfunction. Increasing the dose to 250 mg twice daily lead

II. PRIMARY PULMONARY HYPERTENSION547to a greater frequency of increased aminotransferase levelsCaution is necessary because the drug can precipitatehepatocellular injury, particularly at high doses. Selectiveantagonists of the endothelin (Eta) receptor are beinginvestigated, but sitaxsentan administration at high doseshas been associated with fatal hepatitis.4. Phosphodiesterase InhibitorsAcutely, oral sildenafil causes a reduction in mean pulmonaryartery pressure in patients with PPH. Sildenafil is aselective inhibitor of cyclic GMP-specific phosphodiesterasetype V; the main phosphodiesterase in the pulmonaryvascular bed. Urinary excretion of cyclic GMP has beennoted to be high in patients with PPH which correlateswith the severity of disease. Sildenafil combination therapywith prostacyclin analogues and endothelin-1 receptorantagonists is being tested in clinical trials.5. StatinsThe cholesterol-lowering agent, 3-hydroxy-3-methylglutarylcoenzyme A (statins), prevents hypoxia-mediateddownregulation of endothelial nitric oxide synthase. It doesthis by stabilizing its mRNA and repressing vascularsmooth muscle cell proliferation in response to plateletderivedgrowth factor and vascular injury. Statins havebeen shown to attenuate hypoxic pulmonary hypertensionin rats.6. L-ArginineL-arginine is necessary for the production of the potentvasodilator nitric oxide, and L-arginine supplementation isbeing investigated in combination with other agents inpatients with PAH. In a small placebo-controlled trial inpatients with PAH, L-arginine administration for one weekimproved maximum oxygen consumption during exercise.7. Lung TransplantationIndications for lung transplantation include disabledpatients, functional class IV despite optimal medicaltherapy, a cardiac index of less than 2 L/minute/m 2 ,right atrial pressure greater than 15 mmHg, and meanpulmonary artery pressure greater than 55 mmHg. Recentadvances in medical therapy will limit the need for lungtransplantation.BIBLIOGRAPHYAbenhaim, L., Moride, Y., Brenot, F. et al. For the international primarypulmonary hypertension study group. Appetite suppressant drugsand the risk of primary pulmonary hypertension. N. Engl. J. Med.,335:609–16, 1996.Badesch, D. B., McLaughlin, V. V., Delcroix, M. et al. Postanoidtherapy for pulmonary arterial hypertension. J. Am. Coll. Cardiol.,43:56S–61S, 2004.Barst, R. J., Rubin, L. J., Long, W. A. et al. A comparison of continuousintravenous epoprostenol (prostacyclin) with conventional therapy forprimary pulmonary hypertension. N Engl. J. Med., 334:296–301,1996.Barst, R. J., Rubin, L. J., McGoon, M. D. et al. Survival in primarypulmonary hypertension with long-term continuous intravenousprostacyclin. Ann. Intern. Med., 121:409–15, 1994.Channick, R. N., Sitbon, O., and Barst, R. J. Endothelin receptorantagonists in pulmonary arterial hypertension. J. Am. Coll. Cardiol.,43:62S–67S, 2004.Chockalingam, A., Gnanavelu, G., Venkatesan, S. et al. Efficacy andoptimal dose of sildenafil in primary pulmonary hypertension. Int. J.Cardiol., 99:91–95, 2005.Eddahibi, S., Humbert, M., Fadel, E. et al. Serotonin transporteroverexpression is responsible for pulmonary artery muscle hyperplasiain primary pulmonary hypertension. J. Clin. Invest., 108:1141–50,2001.Gaine, S. et al. Pulmonary hypertension: Grand rounds. JAMA,284:3160–3168, Dec 2000.Garcia-Dorado, D., Miller, D. D., Garcia, E. J. et al. An epidemic ofpulmonary hypertension after toxic rapeseed oil ingestion in Spain.J. Am. Coll. Cardiol., 1:1216–22, 1983.Ghofrani, H. A., Pepke, J., Barbera, J. A. et al. Nitric oxide pathway andphosphodiesterase inhibitors in pulmonary arterial hypertension.J. Am. Coll. Cardiol., 43S:68S–72S, 2004.Ghofrani, H. A., Wiedemann, R., Rose, R. et al. Combination therapywith oral sildenafil and inhaled iloprost for severe pulmonaryhypertension. Ann. Intern. Med., 136:512–22, 2002.Ghofrani, H. A., Wiedemann, R., Rose, F., Schermuly, R. T. et al.Sildenafil for treatment of lung fibrosis and pulmonary hypertension:A randomised controlled trial. Lancet, 360:9337, 895–900,2002.Hoeper, M. M., Olschewski, H., Ghofrani, H. A. et al. A comparison ofthe acute hemodynamic effects of inhaled nitric oxide and aerosolizediloprost in primary pulmonary hypertension. J. Am. Coll. Cardiol.,35:176–82, 1999.Hinderliter, A. L., Willis, IV, P.W., Barst, R. J. et al. Effects of long-terminfusion of prostacyclin (epoprostenol) on echocardiographic measuresof right ventricular structure and function in primary pulmonaryhypertension. Circulation, 95:1479–1486, Mar 1997.Humbert, M., Morrell, N. W., Archer, S. L. et al. Cellular and molecularpathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol.,43:13S–24S, 2004.Ichinose, F., Roberts, Jr., J. D., Zapol, W. M. et al. Inhaled nitric oxide:A selective pulmonary vasodilator: Current uses and therapeuticpotential. Circulation, 109:3106–3111, Jun 2004.Indolfi, C., Cioppa, A., Stabile, E. et al. Effects of hydroxy methylglutarylcoenzyme A reductase inhibitor simvastatin on smooth muscle cellproliferation in vitro and neointimal formation in vivo after vascularinjury. J. Am. Coll. Cardiol., 35:214–21, 2000.Mark, E. J., Patalas, E. D., Chang, H. T. et al. Fatal pulmonaryhypertension associated with short-term use of fenfluramine andphentermine. N. Engl. J. Med., 337:602–06, 1997.

548PULMONARY ARTERIAL HYPERTENSIONNewman, J. H. Treatment of primary pulmonary hypertension — thenext generation. N. Engl. J. Med., 346:933–35, 2002.Pietra, G. G., Capron, F., Stewart, S. et al. Pathologic assessment ofvasculopathy used in pulmonary hypertension. J. Am. Coll. Cardiol.,43:25S–32S, 2004.Preston, I. R., Tang, G., Tilan, J. U. et al. Retinoids and pulmonaryhypertension. Circulation, 111:782–790, 2005.Rich, S., McLaughlin, V. V. et al. Review: Cardiovascular drugs:Endothelin receptor blockers in cardiovascular disease. Circulation,108:2184–2190, Nov 2003.Royhman, R. B., Ayestas, M. A., Dersch, C. M. et al. Aminorex,fenfluramine, and chlorphentermine are serotonin transportersubstrates; implications for primary pulmonary hypertension. Circulation,100:869–75, 1999.Rubin, L. J., Badesch, D. B., Barst, R. J. et al. Bosentan therapy forpulmonary arterial hypertension. N. Engl. J. Med., 346:8 96–903,2002.Runo, J. R., and Lloyd, J. E. Primary pulmonary hypertension. Lancet,361:1533–44, 2003.Simmoneau, G., Galie, N., Rubin, L. J. et al. Clinical calcificationof pulmonary hypertension. J. Am. Coll. Cardiol., 43:5S–12S,2004.Williamson, D. J., Wallman, L. L., Jones, R. et al. Hemodynamic effectsof bosentan, an endothelin receptor antagonist, in patients withpulmonary hypertension. Circulation, 102:411–418, Jul 2000.Yuan, J. X. J., Rubin, L. J. et al. Pathogenesis of pulmonary arterialhypertension: The need for multiple hits. Circulation, 111:534–538,2005.

Pulmonary EmbolismI. IncidenceII. PathogenesisIII. PathophysiologyIV. DiagnosisV. InvestigationsVI. ManagementGLOSSARYhypocapnia deficiency of carbon dioxide in the blood.hypoxia low levels of oxygen in the blood (hypoxemia).tachypnea increased respiratory rate.thrombocythemia increased levels of circulating blood platelets.I. INCIDENCEIn the United States the incidence of pulmonary embolismhas been estimated to exceed 650,000 cases per year.A common and difficult problem, pulmonary embolismis the third most common cause of death in United States. Pulmonary embolism accounts for up to 100,000deaths annually and approximately 33% of the deathsoccur within one hour of the onset of symptoms. The diagnosis is not suspected in more than 50% ofpatients who die and symptoms may mimic a heartattack. Approximately 10% of patients with pulmonary embolismdie in the first hour and another 20% will die laterin the course of the illness. When a timely diagnosis is made more than 80% ofpatients will survive. When pulmonary embolism is overlooked, more than30% of cases will result in death. Prevention, earlydiagnosis, and treatment of this serious disease are vital.II. PATHOGENESISPulmonary emboli arise from a number of sites, but theprimary sources are the deep iliofemoral and thigh veins.Other sites include the pelvic veins and less commonly theright atrium and ventricle. The calf veins do not usuallygive rise to significant emboli but may extend upward intothe thigh in more than 20% percent of cases (see chapterentitled Deep Vein Thrombosis).Risk factors include any processes that increase venousstasis damage the intima of the venous system, and causea hypercoagulable state. High-risk clinical conditions andunderlying factors include: History of thromboembolic disease Prolonged anesthesia associated with surgery Surgery or injury to the lower extremities or hip Surgical treatment triggers an increase in factor VIIIand a decrease in protein C activity and an increase inplace adhesiveness Immobilization after a fracture or surgery, myocardialinfarction, heart failure, or stroke Pregnancy, particularly in the early postpartum phaseand also the use of estrogen-containing compounds Malignancy, tumor cells appear to interact with thrombinand plasmin-generating systems; some cancer causesa decrease in platelet antithrombin and antithrombinIII activities and cause an increase in fibrinogen Street drugs that increase platelet count and adhesiveness Hypercoagulable diathesis, protein C, S, or antithrombinIII deficiency, polycythemia vera, and thrombocythemiaare implicated in less than 15% of cases ofdeep vein thrombosis; rarely high levels of factor V orfactor VII may be underlying factors Patients with primary or secondary antiphospholipidsyndromeIII. PATHOPHYSIOLOGYThe effects of pulmonary emboli on gas exchange aremultifold:During increase in alveolar dead space there is ventilationof the dead space that receives no blood flowBronchoconstriction and loss of alveolar surfactant inthe area of embolusHyperventilationHypoxemia549

550PULMONARY EMBOLISMHemodynamic effects of pulmonary emboli dependnot only on the size of embolus but also on the patient’sbaseline cardiopulmonary status. Normal individualscan tolerate an embolic event of substantial size withoutsignificant changes in pulmonary artery pressures. Pulmonaryhypertension may occur when 30% or more of thepulmonary vascular bed is obstructed. In patients withsignificant underlying cardiopulmonary disease, however,smaller emboli can result in cor pulmonale if acute elevationsof the mean pulmonary arterial pressure exceed40 mmHg. In the patient with no pre-existing cardiopulmonarydisease, shock is usually precipitated by obstructionof more than 50% of the pulmonary circulation.Suspected pulmonary embolismLung scanHigh probability Nondiagnostic NormalD-dimer D-dimer D-dimer*Abnormal Normal *Abnormal Normal *AbnormalUSUSNormalIV. DIAGNOSISThe diagnosis of pulmonary embolism should be stronglyconsidered in patients who manifest one or more of thefollowing clinical patterns. Central chest pain: This can be accompanied byacute shortness of breath, tachypnea, and syncope orpresyncope. Symptoms may mimic a heart attack Acute unexplained dyspnea: Patients present withacute shortness of breath, tachypnea, and tachycardiabut these three findings may be transient. Tachypneaand tachycardia are sustained in patients with massiveembolism. Unexplained dyspnea accompanied by syncopemay occur. Pulmonary infarction: Patients usually have sustaineda submassive embolus. Most of these patients havepleuritic chest pain, dyspnea, and hemoptysis. Chestx-ray reveals an infiltrate, pleural-based consolidation.A small pleural effusion blunting the costophrenicangle is a suspicious sign in a patient with an acuteshortness of breath. Acute cor pulmonale and cardiogenic shock: Acute rightventricular dilatation and right heart failure supervene. Findings on examination of the patient are usuallynonspecific and are often nondiagnostic.The combination of the probability from clinical assessment(PCA), the result of D-dimer and lung scan mayindicate a diagnosis of embolism and should suggest theneed for venography of the thigh veins and for pulmonaryangiograms to confirm the diagnosis (see Fig. 1).V. INVESTIGATIONSA. Arterial Blood Gas AnalysisAcute respiratory alkalosis is the most common finding.Carbon dioxide retention only occurs with massivePCAHighPEUSAbnormalAbnormalPEIndeterminateNormalNormalAbnormalembolism. Because tachypnea and hyperventilation commonlyoccur, carbon dioxide is washed out from alveoli;thus, hypocapnia and hypoxemia may occur and these twofindings in association with a normal chest x-ray increasesthe likelihood of embolism. The absence of acute respiratoryalkalosis should not be taken as evidence againstthe diagnosis of pulmonary embolism. A normal bloodgas result does not exclude embolism. In general, bloodgas analysis is most often unhelpful.B. ElisaHighConsider venography orpulmonary angiogramNormalPCAIndeterminateNo PENo PEFIGURE 1 Algorithm for the diagnosis of suspected pulmonaryembolism (PE). PCA ¼ probability from clinical assessment;US ¼ ultrasonography of the veins of the lower limbs; * ¼ excludemyocardial infarction, congestive heart failure, pneumonia, cancer,post-surgery. (From Khan, M. Gabriel (2001). On Call Cardiology, 2 nded., Philadelphia: W. B. Saunders, p. 247.)Degradation products of the pulmonary clot containD-dimers that are released and can be detected in theplasma by monoclonal antibodies. A D-dimer enzyme–linked immunosorbent assay (ELISA) greater than 500 ng/ml 500 mg/L) is abnormal and is present in more than90% of patients with pulmonary embolism. The sensitivityis about 96% and the negative predictive value is about99%. The test is highly sensitive but not specific for

VI. MANAGEMENT551the diagnosis. Other conditions that give a positive resultshould be excluded, particularly myocardial infarction,congestive heart failure, pneumonia, cancer, and postsurgery. A normal test result gives reassurance in more than97% of cases that embolism is not present.C. ElectrocardiogramThis shows a sinus tachycardia and sometimes transientabnormal T-wave inversion in leads V1 to V4 (right ventricularstrain pattern) or transient right bundle branchblock; these are nonspecific findings.D. Lung ScanThe lung scan is interpreted as one of the following:Normal: A normal scan in the patient with a normalD-dimer indicates an absence of pulmonary embolismin more than 99% of casesNondiagnostic (intermediate and low-probability scans)High probability: This is indicated by multiple segmentalperfusion defects without corresponding ventilationabnormalities. A high-probability scan is about97% specific for embolism but lacks sensitivity.E. Venous UltrasonographyA normal result does not exclude deep vein thrombosis orembolism. More than 20% of patients with a normal studyhave proven pulmonary embolism.F. Pulmonary AngiogramThis test is necessary in patients with a nondiagnostic lungscan and a negative femoral venogram if the PCA is highand strongly indicative that embolism is present. The testis useful in patients with a high-probability scan and a highrisk of bleeding with use of anticoagulants.VI. MANAGEMENTHeparin is administered intravenously in a bolus of5000–10,000 U followed by a continuous infusion toachieve a partial thromboplastin time (PTT) of 60–80seconds, 1.5 to 2 times the patient control level. Thrombolytictherapy is of value to restore circulation in patientswith hemodynamic compromise in the setting of massiveemboli or cardiogenic shock. Caution is required, however,because patients with pulmonary embolism have a veryhigh risk of intracranial hemorrhage following thrombolytictherapy. Embolectomy is reserved for patients withmassive embolism and hypotension who have not respondedto conventional therapy.BIBLIOGRAPHYGoldhaber, S. Z. Pulmonary embolism. Lancet, 363:1295–1305,2004.Goldhaber, S. Z., Fanikos, J. et al. Prevention of deep vein thrombosisand pulmonary embolism. Circulation, 110:e445–e447, 2004.Nakamura, M., Nakanishi, N., Yamada, N. et al. Effectiveness and safetyof the thrombolytic therapy for acute pulmonary thromboembolism:Results of a multicenter registry in the Japanese Society of PulmonaryEmbolism Research. Int. J. Cardiol., 99:91–95, 2005.PIOPED Investigators: Value of the ventilation perfusion scan in acutepulmonary embolism. JAMA, 263:2753, 1990.Punukollu, H., Khan, I. A., Punukollu, G. et al. Acute pulmonaryembolism in elderly: Clinical characteristics and outcome. Int. J.Cardiol., 99:213–216, 2005.Punukollu, G., Khan, I. A., Gowda, R. M. et al. Cardiac troponin Irelease in acute pulmonary embolism in relation to the duration ofsymptoms. Int. J. Cardiol., 99:207–211, 2005.

Race and Cardiovascular DiseaseI. HypertensionII. Heart FailureIII. Coronary Artery Disease and StrokeGLOSSARYejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker ofleft ventricular contractility.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.left ventricular dysfunction poor contractility of the left ventricle,this leads to heart failure.men and women, respectively, compared with gendermatchedwhites.An important issue that remains unclear is the findingthat hypertension and its adverse clinical sequelae — heartfailure, stroke, and renal damage — are more commonamong African-American residents of the 13 southeasternstates than among African-Americans residing in otherareas of the United States. This appears to be the resultof a higher level of psychological stress related to racism,deprivation, and despair that occurs in those southeasternstates. Also, there is a higher number of obese African-Americans in these states compared to elsewhere, and theirlevels of physical activity are considerably lower. African-Americans who have realized financial stability engage inmore physical activity than those who live in an environmentof poverty.IT IS WELL-ESTABLISHED THAT CARDIOVASCULARmorbidity and mortality caused by hypertension, heartfailure, and coronary artery disease are substantially higherin African-Americans than in Caucasian Americans, anda plethora of explanations have been put forth. African-Americans are three times as likely to die from cardiovasculardiseases than Caucasians, and the Association ofBlack Cardiologists was formed in 1974 to bring specialattention to this issue.I. HYPERTENSIONA. EpidemiologyNearly one in three African-Americans suffer fromhypertension. In 1995 the death rate was 355% higherin African-American males and 352% higher in African-American females than in white males and females,respectively. The prevalence of stage 3 hypertension(>180/110 mmHg) is approximately 8% in African-Americans versus less than 1% in whites. The prevalence ofhypertension is 33 and 50% greater in African-AmericanB. Target Organ DamageMany investigators have noted a greater susceptibilityto target organ damage (heart, kidney, brain) at a givenblood pressure level in African-Americans compared withwhites. The pathogenesis of the premature blood pressureelevations and early target organ damage in African-Americans has not been clarified.Hypertension-related left ventricular hypertrophy, leftventricular strain, and heart failure are more commonin African-Americans than in whites, at lower levels ofblood pressure and at a timing that often appears to beof surprisingly short duration. There is no doubt thatrenal damage is a prominent feature of early hypertensivedisease in these individuals. There is an excess prevalenceand incidence of proteinuria, renal insufficiency, and renalfailure in African-Americans. The kidney in African-Americans appears to have increased sensitivity to elevatedblood pressure as reflected by the excess prevalence ofkidney damage and renal failure across a broad bloodpressure range in African-Americans compared to whiteswith similar blood pressure levels. Among African-Americans stroke mortality rates are 30–50% higherin the southeastern United States than elsewhere, and553

554RACE AND CARDIOVASCULAR DISEASEcoronary artery disease death rates for African-Americansare among the highest in the world.ACE inhibitor may be required in diabetics and in patientswith left ventricular dysfunction.C. Role of ObesityObesity is disproportionately prevalent among femaleAfrican-Americans, and this is prominent in the southeasternUnited States. Obesity causes hypertension thatis driven by activation of the sympathetic nervous andrenin-angiotensin-aldosterone systems and additionalplasma volume expansion. Flack and Staffileno postulateda linkage of obesity in African-American women withnormal to high normal blood pressure to both salt sensitivityand a reversible attenuation of normal nocturnaldecline in blood pressure. This causes a higher nighttimeblood pressure and thus a greater 24-h blood pressureburden that probably contributes to obesity-related targetorgan damage. In Jamaicans obesity has been associatedwith increased circulating angiotensinogen and serumangiotensin-converting enzyme activity. Circulating reninlevels in obese hypertensives are not usually suppressed,and there is increased renal sodium reabsorption in thedistal tubule.D. Management of HypertensionSalt sensitivity is more common among the African-American population than in others races, and it caninfluence the effect of some antihypertensive agents. Thereis little doubt that salt sensitivity, obesity, and stressare important inducers of sustained hypertension in theAfrican-American population, and management mustaddress these issues.1. Elderly African-American PatientsHypertension in the elderly patient of African origin overage 60 responds best to diuretic therapy. These low-costdrugs have been well tested and proven effective in severalrandomized, controlled trials and are highly recommend asfirst-line therapy for hypertension by the Joint NationalCommittee and the World Health Organization Society.Several randomized clinical trials have shown calciumantagonists to also be very effective antihypertensive agentsin this population. They are used as monotherapy inpatients intolerant to diuretics and in selected individualsthey are combined with a diuretic. Caution is required,however, in patients with an ejection fraction less than40%, because the risk of heart failure may increase withlong-term calcium antagonist therapy. The addition of an2. Younger African-American PatientsYounger individuals of African origin less than age 60 gainthe best antihypertensive effects with calcium antagonistsor beta-adrenergic blocking agents. The latter may betried first because these agents are safe, inexpensive, anduseful in patients with diabetes and those at high riskfor coronary artery disease events. In many patients thecombination of a calcium antagonist and a beta-blockingdrug (both at low doses) is usually effective in controllinghypertension.II. HEART FAILUREAfrican-Americans are 1.5 times more likely to die ofheart failure than Caucasians, and men younger than age60 are twice as likely as Caucasian men of that age tobe hospitalized for failure. African-American women arethree times as likely as Caucasian women of similar ageto be hospitalized because of heart failure.Small et al. showed that the alpha-2c Del322–325 andbeta-1 Arg389 receptors act synergistically to increase therisk of heart failure in blacks. They identified geneticvariants of the beta-1 adrenergic receptor and the alpha-2cadrenergic receptor which jointly represent a major riskfactor for the development of heart failure in blackssubjects. Norepinephrine released from cardiac sympatheticnerves activates myocyte beta-1 adrenergic receptors,which couple to stimulate the G protein Gs, activateadenyl cyclase, and increase intracellular cAMP therebyenhancing beta-1 adrenergic receptor activity and increasingthe risk for the development of heart failure.A. ManagementThe management of heart failure in African-Americansdoes not differ significantly from the therapeutic strategiesused for treating other population groups. Weight reduction,a graduated exercise program, and a restricted saltdiet are essential. In addition, the avoidance of precipitatingfactors such as the use of selective and nonselectivenonsteroidal anti-inflammatory agents and other drugsthat depress left ventricular contractility is crucial.Class III and IV heart failure should be treated with thecombination of a diuretic (furosemide 40–80 mg daily),an ACE inhibitor, a small titrated dose of a beta-blocker

II. HEART FAILURE555(carvedilol is strongly recommended), spironolactone oreplerenone, and digoxin. Class II heart failure should bemanaged with a diuretic, an ACE inhibitor, and carvedilolor metoprolol. Class I heart failure requires cardioprotectionwith an ACE inhibitor, a beta-blocker, and a variablesmall dose of a diuretic for the prevention of shortness ofbreath.1. DiureticA diuretic is very effective for the relief of shortnessof breath. Furosemide, 40–120 mg daily, is frequentlyrequired. Salt sensitivity is a common feature of hypertensionand heart failure in this population group. Ifhypertension is not controlled with an ACE inhibitor andbeta-blocker, then hydrochlorothiazide 25 g once daily canbe added to furosemide 40 mg daily. Serum potassiumshould be carefully watched so that it does not fall to lessthan 4 mEq/L. Magnesium depletion should be correctedand the dose of diuretics should be reduced if uric acidlevels are increased.2. ACE InhibitorThe effectiveness of ACE inhibitors in the managementof heart failure in this population group remains controversial.An underrepresentation of patients of Africanorigin in trials of therapy for heart failure is a majorimpediment to the analysis of racial differences in therapeuticresponse.a. Clinical TrialsThe only reference trial is a retrospective analysis of thestudies of left ventricular dysfunction (SOLVD). This wellrun,large placebo-controlled randomized clinical trialinvolved 5719 white patients with only 800 black patients.The trial, published in 1991, yielded conclusive evidencethat in white patients enalapril caused a 35% reduction inmortality rate in patients with heart failure and an ejectionfraction less than 35%. Enalapril significantly reduced thenumber of hospitalizations for heart failure. Becausegreater than 65% of patients in this trial were more than4 weeks post myocardial infarction, the study cannot begeneralized to all patients with heart failure. It appearedthat the few black patients enrolled in the trial did notobtain significant benefit, but their representation wassmall and the stigma that blacks do not benefit from ACEinhibitor therapy was propagated.Recently a pooled analysis of the SOLVD study wasmade by Exner et al. to address this controversy.Study question: Black patients with heart failure havea poorer prognosis than white patients, and the differencehas not been adequately explained. To addressthis issue Exner et al. pooled and analyzed data fromthe SOLVD prevention and treatment trials — twolarge, randomized trials comparing the ACE inhibitorenalapril with placebo in patients with left ventriculardysfunction.Methods: A mixed cohort design was used where up tofour white patients were matched with each black patientaccording to trial treatment assignment. A total of 1196white patients (580 from the prevention trial and 616from the treatment trial) were matched with 800 blackpatients (404 from the prevention trial and 396 fromthe treatment trial). Follow up was 35 months in theprevention trial and 33 months in the treatment trial.Results: Black patients had higher rates of hospitalizationfor heart failure (13.2 vs. 7.7 per 100 person-years).Enalapril, as compared with placebo, was associated witha 44% reduction in the risk of hospitalization for heartfailure among the white patients ( p < 0.001) but with nosignificant reduction among black patients ( p ¼ 0.14).Exner et al. concluded that this finding underscores theneed for additional research on the efficacy of therapiesfor heart failure in black patients.The methodology of this trial analysis leaves much tobe desired and the results should be disregarded.Dries et al. reanalyzed the effect of enalapril in the blackpatients assigned to the treatment arm of the SOLVDtrial (a post hoc analysis of the 3651 white and 403black patients). In this trial enalapril was administeredto 195 black patients and placebo to 208 and followed for33 months.Randomization to enalapril was associated with acomparable reduction in the relative risk of the developmentof symptomatic heart failure in black and whitepatients. Treatment with enalapril was associated witha comparable reduction in the risk of developing heartfailure in both black and white patients. Enalapril wasequally efficacious in reducing the risk of progression ofasymptomatic left ventricular dysfunction in these twoethnic groups. This study has several important limitations:it was retrospective and the number of blackpatients in the study was small. The results of this adhoc analysis, however, support the recommendation thattherapies demonstrated to improve survival in large,randomized trials should continue to be prescribed atappropriate doses for patients with heart failure irrespectiveof their ethnicity until results of large trials areavailable.

556RACE AND CARDIOVASCULAR DISEASEOmapatrilat is a vasopeptidase inhibitor that has actionssimilar to ACE inhibitors. A large, randomized clinicalstudy has shown beneficial effects, but the occurrence ofangioedema (life-threatening swelling of lips and tongue)was excessively high in black patients.3. Beta-BlockersBeta-blockers used in heart failure (carvedilol and metoprolol)are efficacious in both black and white patients.Yancy et al. analyzed the effects of carvedilol in 217 blackand 877 non-black patients assigned to the U. S. CarvedilolHeart Failure trial. Patients had heart failure classII, III, or IV and an ejection fraction less than 35%.Results: As compared with placebo, carvedilol reducedthe risk of death from any cause or hospitalization by48% in black patients and by 30% in non-black patients.The drug reduced the risk of worsening heart failureby 54% in black patients and 51% in non-black patients.Conclusions: Benefit of carvedilol was of similar magnitudein both black and non-black patients with heartfailure.Racial and ethnic differences in drug responses relatedto hepatic cytochrome P-450, which is responsible forthe metabolism of several drugs including carvedilol, havebeen described and reflect genetic differences in drugactivity.4. DigoxinThe therapeutic benefits of digoxin are of similarmagnitude in both black and non-black patients withheart failure. Lower doses than previously used are nowrecommended in all population groups, with digoxinblood levels of 0.6–1.2 ng/ml being considered adequate;women should be titrated to the lowest serum levelsbecause mortality may be increased at levels greater than1.0 ng/ml.5. Spironolactone or EplerenoneThe well-known mild diuretic spironolactone blocks theeffects of aldosterone in the distal renal tubules andenhances the effectiveness of diuretics. This drug also hasbeneficial cardiac effects that have been shown to preventrecurrence of heart failure. Eplerenone has the same effectivenessas spironolactone, but it does not cause bothersomegynecomastia which limits the use of spironolactone(see the chapter Diuretics).III. CORONARY ARTERY DISEASEAND STROKEA. African-AmericansIn 1995, death from coronary artery disease was 40%higher in African-Americans than in Caucasians. Fromages 35 to 74, the age-adjusted death rate from coronaryartery disease in African-American women is more than71% higher than that of Caucasian women. Coronaryartery disease death rates for African-Americans are amongthe highest in the world. High rates of smoking, unnoticedincreased LDL cholesterol, and the high prevalence ofobesity, diabetes, and stress all play a role in increasingcoronary-related mortality in African-Americans. YoungAfrican-Americans have a 2- to 3-fold greater risk ofsuffering a stroke and a 1.8-fold greater mortality rate forstroke than Caucasians.B. Heart Disease in Asian IndiansHigh prevalence rates of premature coronary artery diseasehave been reported in migrant Asian Indians. A comparisonof migrant Indians living in West London withnative Indians living in Punjab indicated that the migrantIndians had a higher body mass index, higher systolicblood pressure, and significantly higher lipid levels. Boththe migrant and native Indians, however, had elevatedlipoprotein(a) levels, suggesting that genetic influencesmay predispose Indians to premature coronary disease.The prevalence of coronary artery disease is risingrapidly in urban India. The overall figure of an 11% rateof coronary artery disease in the population representsapproximately a tenfold increase in the prevalence ofcoronary artery disease in urban India during the last40 years. This is expected to increase substantially overthe next 20 years.1. Clinical Study: Mohan et al.In a population-based study in Chennai (formerly Madras)involving 1262 individuals older than 20 years, theprevalence rates for coronary artery disease were 9.1,14.9, and 21.4% in those with normal glucose tolerance,impaired glucose tolerance, or diabetes, respectively. Theprevalence of coronary artery disease increased with anincrease in total cholesterol with an increased level of lowdensity lipoprotein cholesterol (3.49 0.86 vs. 2.81 0.88 mmol/L). LDL cholesterol was defined as the majorrisk factor. Although HDL cholesterol levels in this studypopulation were relatively low (1.03 mmol/L; 40 mg/dl),

III. CORONARY ARTERY DISEASE AND STROKE557there was no difference in mean HDL cholesterol levelsbetween the group with coronary artery disease and thegroup without coronary artery disease. In this smallpopulation survey cigarette smoking was low at less than15% in both groups.Perspective: It is important to emphasize that theportion of calories derived from fat, much of whichcomes from dairy products, is significantly higher in Indiathan in other parts of the developing world. Also, the useof ghee and cooking oils derived from coconut, palm,and peanut oil, and other atherogenic oils needs furtherassessment.C. Other Ethnic GroupsDeath rates from coronary artery disease in men andwomen are remarkably high in the following countries: Finland — 631 and 587 per 100,000 men and women,respectively Ukraine — 749 and 342 per 100,000 men and women,respectively, with a cardiovascular disease mortality of1490 for men and 830 for women Russian Federation — 767 and 288 per 100,000 menand women, respectively, with a cardiovascular diseasemortality rate of 1343 for men and 657 for women Scotland and Northern Ireland — 655 and 273 per100,000 men and women, respectively, with a cardiovasculardisease rate of 886 in men and 441 inwomenDeath rates are low in France with 142 men and 36women in 100,000; Spain with 181 men and 52 womenin 100,000; and Portugal 207 men and 73 women in100,000. Cardiovascular disease mortality is surprisinglylow in Slovenia and yet very high in the Ukraine. BothChina and Japan have low coronary artery disease deathrates but extraordinarily high hemorrhagic stroke rates.The low rates of coronary artery disease and high rates ofstroke may be caused by genetic factors, but it has beenpostulated that the overall low serum cholesterol levels maycontribute to high rates of hemorrhagic stroke.BIBLIOGRAPHYBudoff, M. J., Yang, T. P., Shavelle, R. M. et al. Ethnic differences incoronary atherosclerosis. J. Am. Coll. Cardiol., 39:408–12, 2002.Dries, D. L., Strong, M. H., Cooper, R. S. et al. Efficacy of angiotensinconverting enzyme inhibition in reducing progression fromasymptomatic left ventricular dysfunction to symptomatic heartfailure in black and white patients. J. Am. Coll. Cardiol., 40:311–7,2002.Exner, D. V., Dries, D. L., Domanski, M. J., and Cohn, J. N. Lesserresponse to angiotensin converting enzyme inhibitor therapy in blackas compared with white patients with left ventricular dysfunction.N. Engl. J. Med., 344:1351–7, 2001.Flack, J. M., and Staffileno, B. A. Hypertension in blacks. In Hypertension,A Companion to Brenner and Rector’s The Kidney. S. Oparil andM. A. Weber, eds. W. B. Saunders, Philadelphia, 558, 2000.Mohan, V., Deepa, R., Rani, S. S. et al. Prevalence of coronary arterydisease and its relationship to lipids in a selected population insouth India. J. Am. Coll. Cardiol., 38:682–7, 2001.Parmley, W. W. African American patients and heart disease. J. Am. Coll.Cardiol., 38:Editor’s page, 2001.Small, K. M., Wagoner, L. E., Levin, A. M. et al. Synergisticpolymorphism of beta-1- and alpha 2c-adrenergic receptors andthe risk of congestive heart failure. N. Engl. J. Med., 347:1135–42,2002.Wood, A. J. J. Racial differences in the response to drugs — pointers togenetic differences. N. Engl. J. Med., 344:1393–95, 2001.Yancy, C. W., Fowler, M. B., Colluccci, W. S. et al. Grace and theresponse to adrenergic blockade with carvedilol in patients withchronic heart failure. N. Engl. J. Med., 344:1358–65, 2001.

Sleep and the HeartI. Effects of Normal Sleep on theCardiovascular SystemII. Sleep ApneasIII. Sleep Apnea and Heart FailureIV. Sleep Apnea and HypertensionV. Sleep Apnea and ArrhythmiasGLOSSARYapnea cessation of airflow for at least 10 seconds.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is a marker of left ventricular contractility.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hypopnea abnormal decrease in depth and rate of respiration.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.IT IS WELL ESTABLISHED THAT SUDDEN CARDIACdeath occurs most often within a few hours of wakeningfrom sleep. Arousal from sleep causes circulatory, neural,and hormonal alterations that affect the heart and entirecirculatory system; the body is instantaneously preparedfor the fight or flight reaction. There is increasedsympathetic activation, increased secretion of epinephrine(adrenaline), and other processes that result in an increasein heart rate and blood pressure. In addition, catecholaminesecretion induces platelet particles in the circulatingblood to become sticky resulting in increased plateletaggregation and clot formation. The blockage of theflow of blood by thrombi precipitates acute myocardialinfarction and sudden cardiac death. Beta-adrenergicblockers have been shown to reduce the early morningsudden cardiac death rate by more than 35%. Arousalfrom sleep, therefore, has profound influences on thecardiovascular system. Recently sleep apnea and thearousal reaction have been shown to play a role inincreasing morbidity in patients with heart failure.It must be emphasized, however, that sleep apneas donot cause heart failure in individuals with normal heartsand normal ventricular function. Sleep apneas are notassociated with the epidemic of atherothrombosis, whichis the main cause for heart attack and stroke. Also its linkwith causation of hypertension in the population at largeremains controversial and is overexaggerated. Recentstudies suggest that sleep apneas are associated withincreased cardiovascular morbidity.I. EFFECTS OF NORMAL SLEEP ON THECARDIOVASCULAR SYSTEMNonrapid eye movement (NREM) sleep comprises morethan 85% of total sleep time and is associated with a stateof cardiovascular relaxation. There is a reduction in sympatheticnervous system activity, systemic arterial vascularresistance, heart rate, and cardiac stroke volume.Cardiac output ¼ cardiac stroke volume heart rate:Blood pressure (BP) falls because of the decrease in cardiacoutput (CO) and reduction in total peripheral resistance(TPR).BP ¼ CO TPR:Vagal activity increases thus the heart rate falls further to40–60 beats per minute.Rapid eye movement sleep (REM) constitutes approximately15% of total sleep time and intermittent surges insympathetic discharge, heart rate, and blood pressure mayoccur, but the average blood pressure and heart rategenerally remain below waking levels.II. SLEEP APNEASObstructive sleep apnea (OSA) and central sleep apnea(CSA) are the two major recognized forms of sleep apnea.559

560SLEEP AND THE HEARTObstructive sleep apneas and hypopneas are caused bycomplete or partial collapse of an abnormally narrowedpharynx. In these individuals the effort required toenhance airflow increases causing the rib cage andabdomen to distort and move out of phase; thus, there isprominent respiratory effort. Central sleep apnea is causedby reductions in the central respiratory drive manifested byan absence of respiratory effort.A. Obstructive Sleep ApneaSleep apnea is defined as repetitive episodes of decreasedor total cessation of repiratory airflow during sleep, leadingto a fall in oxygen saturation of 4% and sleepfragmentation.The severity of OSA is measured as the apnea-hypopneaindex (AHI). Approximately 20% of men and 10% ofwomen in the North American population have an AHIgreater than five events per hour of sleep. By definitionexcessive daytime sleepiness must be present to bediagnostic for significant sleep apnea. Using this definitiononly 4% of middle-aged men and 2% of women in NorthAmerica manifest symptoms of OSA and an AHI ofgreater than five events per hour of sleep. The diagnosis ofsleep apnea is generally based on the demonstration of atleast 10–15 apneas and hypopneas per hour of sleep. Thisdiagnosis is confirmed by the presence of excessive daytimesleepiness. Using this diagnostic claim less then 2% of thepopulation is expected to have significant sleep apnea.Other symptoms include excessive snoring, restless sleep,morning headaches, and fatigue, but these symptoms arenonspecific.More than 96% of individuals that comprise the NorthAmerican population have normal pharyngeal anatomyand sufficient partial withdrawal of pharyngeal dilatormuscle tone. This associated with pharyngeal collapseduring sleep. It is not surprising, therefore, that less than2% of individuals without heart failure have significantOSA, a condition that is greatly exaggerated and exploited.Approximately 2% of North Americans have ananatomically narrowed pharynx and superimposition ofthe normal withdrawal of pharyngeal dilator muscletone during sleep, which causes the pharynx to constrictmarkedly restricting airflow and precipitating apnea.1. Mechanisms underlying the hypertensive effectsof OSAThese are multifactorial: Nocturnal chemoreflex activation by hypoxia and hypercapnia,with consequent sympathetic activation causestransient increase in blood pressure (see Figure 1). It has been postulated that the above effect might carryover into excessive sympathetic activity and higherblood pressure during daytime. Chemoreceptor resetting and tonic chemoreceptoractivation may probably contribute to daytime increasesin sympathetic activity and blood pressure.2. Risk Factors for OSAObesity is a major risk factor of OSA. Obesity is presentin approximately 70% of patients. It is the only majorreversible risk factor. The underlying mechanisms areunclear, however. Pharyngeal airway size is probablydiminished with increased weight thus increasing thepropensity for obstructive apnea. It has been suggested thatlayering of fat adjacent to the pharynx narrows its lumenin obese patients.Alcohol consumption suppresses pharyngeal dilatormuscle activation and may predispose individuals toobstructive apnea, but these effects need further clarificationand observation.B. Central Sleep ApneaCentral sleep apnea that arises as a consequence ofheart failure is known by physicians as Cheyne-Stokesrespiration. It is a manifestation of severe heart failure,New York Heart Association class IV. It is well recognizedthat patients who manifest Cheyne-Stokes respiration havea poor prognosis and require aggressive medical therapy.Cheyne-Stokes respiration is a form of periodic breathingduring which CSAs and hypopneas alternate with periodsof hyperventilation that have a waxing and waving patternof tidal volume. In CSA, arousals are not required for theinitiation of airflow, but arousalsfrequently follow theresumption of breathing.Sleep is fragmented by frequent arousals but only a fewpatients complain of habitual snoring or excessive daytimesleepiness. The administration of supplemental oxygen atnight has been shown to abolish apnea-related hypoxia, butoxygen has not been shown to cause improvement incardiac function or quality of life over a one-month period.III. SLEEP APNEA AND HEART FAILUREObstructive sleep apnea has been observed in 11% ofpatients with heart failure. The incidence of OSA inpatients with heart failure ranges from 11 to 37% as shownin data from small studies. Most important, Javaheri et al.

III. SLEEP APNEA AND HEART FAILURE561FIGURE 1 Sympathetic nerve activity increases through the obstructive apnea, resulting in marked vasoconstriction followed by increased systolic anddiastolic blood pressure. Continuous positive airway pressure (CPAP) stabilizes both sympathetic activity and blood pressure surges. BP ¼ blood pressure(mm Hg); OSA ¼ obstructive sleep apnea; REM ¼ rapid eye movement; RESP ¼ respiration; SNA ¼ sympathetic nerve activation. (Adapted fromV.K., Dyken, M.E. et al., J. Clin. Invest., 96, 1897–1904, 1995. With permission.)noted that only a minority of patients in these studiescomplained of excessive daytime sleepiness, which suggeststhat many patients with heart failure have relativelyasymptomatic OSA. The mechanism by which heartfailure increases the propensity to precipitate OSA remainsunclear, and its effects on morbidity and mortality inpatients with heart failure require further studies.A randomized trial was done of patients with relativelysevere OSA with an AHI of greater than 30 events perhour of sleep that resulted in symptoms of excessive daytimesleepiness. This study showed that although patientsrandomized to CPAP (continuous positive airway pressure)were compliant, they did not derive any symptomaticor neurocognitive benefit. These findings do not support

562SLEEP AND THE HEARTthe use of CPAP for patients with OSA who have no complaintof excessive or inappropriate daytime sleepiness.1. Clinical Study: Kaneko et al.Methods: In this study 24 patients with a reduced leftventricular ejection fraction (EF) of less than 45% andobstructive sleep apnea on optimal medical therapy forfailure underwent sleep study. On the following morningBP and heart rate were measured and left ventriculardimensions and left ventricular EF were assessed by echocardiography.Individuals were then randomly assigned toreceive medical therapy either with (12 patients) or withoutthe addition of CPAP (12 patients) for one month.Results: In patients receiving medical therapy alonethere were no significant changes in daytime BP, heart rate,left ventricular systolic dimension, or EF. In the treatedgroup CPAP markedly reduced OSA, reduced daytimeBP and heart rate and, most important, reduced leftventricular and systolic dimension from 54.5 1.8 to 51.7 1.2 mm, and protein foam 25.0 2.8 to 33.8 2.4%( p ¼ 0.001).Conclusions: OSA appears to have an adverse effect onheart failure that can be ameliorated by CPAP.Patients in the study were obese, with a body mass indexof 31. Only 67 and approximately 50% of patients werereceiving digoxin and a beta-blocker, respectively. Patientshad New York heart Association class II or III heart failureand did not have bothersome daytime sleepiness.The mechanisms contributing to the improvement inleft ventricular ejection fraction were probably abolition ofpsychic surges in left ventricular wall tension during sleepand chronic downward resetting of sympathetic outflowand peripheral resistance secondary to the completecorrection of obstructive apnea. The observation thatCPAP used only at night causes improvement in EF thatpersisted in the daytime is an important observation.Nocturnal CPAP does not induce beneficial results inpatients with heart failure without sleep apnea. Theseobservations suggest that obstructive apnea has specificdetrimental effects on left ventricular function that ispartially reversible.Perspective: Large, randomized clinical trials in patientswith heart failure on optimal therapy (>90%) should beon quadruple therapy: ACE inhibitor, diuretic, digoxin,beta-blocker, and spironolactone are required to evaluatethe impact of treating OSA and to assess cardiovascularoutcomes. It is known that the abolition of hypoxia causedby OSA reduces nocturnal blood pressure and heart rate.Correction of OSA in patients with class IV heart failureawaiting transplantation may be an important therapeuticstrategy.CPAP maintains a patent airway during sleep by splintingthe airway with positive pressure applied through anasal mask. It also significantly corrects obstructive apneaand sleep fragmentation with amelioration of unwantedhemodynamic changes. Although it is successful, complianceremains a major problem and it is expensive.Nasal congestion, dryness, abrasion, and mask leak maybe bothersome and intensive education programs arerequired.In a randomized trials of three months’ duration,application of CPAP increased left ventricular EF. Sin et al.conducted a randomized trial of 29 patients with CSAand heart failure managed with CPAP. This showed asignificant reduction in the combined rate of mortalityand cardiac transplantation during a five-year period. TheCanadian CPAP trial for patients with congestive heartfailure and CSA (CANPAP) is in progress.A. Atrial Pacing in Sleep Apnea1. Study: Garrigue et al.Methods: Fifteen patients with central or obstructive sleepapnea who had received a permanent atrial synchronousventricular pacemaker for bradycardia were studied.All patients underwent a sleep study on consecutivenights: the first night for baseline, one night in spontaneousrhythm, and one in dual-chamber pacing mode withatrial overdrive with a basic rate 15 beats per minute fasterthan the mean nocturnal sinus rate.Results: The hypopnea index was reduced from 9 inpatients with spontaneous rhythm to 3 with atrialoverdrive pacing ( p ¼ 0.001). For both apnea and hypopneathe value for the index was 28 in spontaneous rhythmversus 11 with atrial overdrive pacing ( p ¼ 0.001).Conclusions: In patients with sleep apnea, atrialoverdrive pacing significantly reduced the number ofepisodes of central or obstructive sleep apnea. Reducingthe variations in heart rate markedly reduced the numberof episodes of sleep apnea.Perspective: Whether similar benefits could be achievedwith atrial pacing in patients who have no indicationfor pacemaker implantation remains to be determined.Central and obstructive apnea showed similar improvementwith atrial pacing. It is surprising that of the15 patients in the study with no evidence of heart failureand EFs ranging from 40–56%, 8 showed manifestationsof central apnea. This condition is usually seen with severeheart failure, New York Heart Association class IV, with anEF of less than 30%.

V. SLEEP APNEA AND ARRHYTHMIAS563IV. SLEEP APNEA AND HYPERTENSIONSince the mid-1980s there has been considerable controversyregarding the relationship between OSA andhypertension. Small studies and some population surveyssupport the notion that either condition may cause theother, but obesity may cause both hypertension and sleepapnea. More important, more than 80% of symptomaticpatients with sleep apnea appear to be at least 20%overweight. Some population surveys have shown minimalor no effect of sleep apnea on blood pressure. Althoughblood pressure decreases with CPAP administration,the blood pressure reductions observed are modest andinconsistent. There is a suggestion that obstructive sleepapnea can increase daytime hypertension, but a clearassociation has not yet been established.After the commencement of apnea, blood pressuredeclines transiently. After arousal and the resumption ofventilation blood pressure increases significantly for 10–15seconds and returns to baseline levels in about 45 seconds.An increase of systolic pressure from 20–50 mmHgabove awake pressures has been observed in small studies.There is evidence that patients with OSA have increasedsympathetic activity but despite a great deal of research,the mechanism of sympathetic activation has not beenclarified. Sympathetic activation causes peripheral arteriolarvasoconstriction that increases blood pressure (seeFigure 1). Some studies indicate that the brief arousals atthe end of apneic episodes stimulate sympathetic activation.Also, stimulation of carotid and aortic chemoreceptorsby hypoxemia activates mainstem cardiovascularcenters and increases sympathetic traffic. Hypoxemiacauses pulmonary arterial hypertension which may causeright ventricular strain.V. SLEEP APNEA AND ARRHYTHMIASA variety of minor, benign arrhythmias may occur duringsleep such as atrial and ventricular premature beats, andasymptomatic sinus bradycardia with heart rates of 32–42.Patients may be awakened by short runs of supraventriculartachycardia or paroxysmal atrial fibrillation with afast heart rate exceeding 150 beats per minute. Heartpauses of 3–6 seconds are often observed during Holtermonitoring, but if there is no sinus node dysfunctiona normal rhythm is rapidly restored.A rare, serious disorder, Brugada syndrome, is a congenitaldisorder of sodium cardiac channel functioncharacterized by typical ECG changes associated witha high incidence of sudden cardiac death. Some of theseepisodes of sudden cardiac death occur during sleep.A similar pattern of antiarrhythmic deaths during sleephave been observed in southeastern Asian communitiesand some regions in Italy. These arrhythmic syndromesmay culminate in sudden arrhythmic death often occurringat times of concomitant autonomic arousal and oftenduring sleep. This syndrome has a variety of names: Lai Tai(death during sleep) in Thailand, Bangungut (screamfollowed by sudden death) in the Philippines, and Pokkuri(unexpected death at night) in Japan (see the chapterBrugada Syndrome).BIBLIOGRAPHYBradley, T. D., and Floras, J. S. Sleep apnea and heart failure. Part I.Obstructive sleep apnea. Circulation, 107:1671–78, 2003.Bradley, T. D., and Floras, J. S. Sleep apnea and heart failure. Part II.Central sleep apnea. Circulation, 107:1822–26, 2003.Garrigue, S., Bordier, P., Jais, P., et al. Benefit of atrial pacing in sleepapnea syndrome. N. Engl. J. Med., 346:404–12, 2002.Javaheri, S., Parker, T. J., Liming, J. D. et al. Sleep apnea in 81 ambulatorymale patients with stable heart failure: Types and their prevalence,consequences, and presentations. Circulation, 97:2154–59, 1998.Kaneko, Y., Floras, J. S., Usui, K. et al. Cardiovascular effects ofcontinuous positive airway pressure in patients with heart failure andobstructive sleep apnea. N. Engl. J. Med., 348:1233–41, 2003.Lattimore, J.-D. L., Celermajer, D. S., and Wilcox, I. Obstructive sleepapnea and cardiovascular disease. J. Am. Coll. Cardiol., 41:1429–37,2003.Malhotra, A., and White, D. P. Obstructive sleep apnea. Lancet,360:237–45, 2002.Marin, J. M., Carrizo, S. J., Vicente, E. et al. Long-term cardiovascularoutcomes in men with obstructive sleep apnoea-hypopnoea with orwithout treatment with continuous positive airway pressure: Anobservational study. Lancet, 365:1046–53, 2005.Sin, D. D., Logan, A. G., Fitzgerald, F. S. et al. Effects of continuouspositive airway pressure on cardiovascular outcomes in heart failurepatients with and without Cheyne-Stokes respiration. Circulation, 102:61–6, 2000.Somers, V. K., Dyken, M. E., Clary, M. P., Abboud, F. M. et al.Sympathetic neural mechanisms in obstructive sleep apnea. J. Clin.Invest., 96:1897–1904, 1995.Wolk, R., Kara, T., Somers, V. K. et al. Sleep-disordered breathing andcardiovascular disease. Circulation, 108:9, 2003.

StentsI. A Major AdvanceII. RestenosisIII. Drug-Eluting StentsIV. Problems to be ResolvedGLOSSARYatheroma same as atherosclerosis, raised plaque filled withcholesterol, calcium, and other substances on the inner wallthat obstruct the lumen and the flow of blood; the plaque ofatheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).intima the innermost lining of the vessel that is in contact withflowing blood.smooth muscle cells cells that are predominant in the middlewall of arteries, the media; these cells migrate into the intimato strengthen the wall that is injured during the developmentof atheroma or following trauma from balloon angioplastyor intracoronary stenting. The strong smooth muscle cells arenature’s effective band-aid that help to fortify the damagedwall of arteries.I. A MAJOR ADVANCECoronary stenting is the most important advance ininterventional cardiology since the introduction of PTCAby Gruentzig in 1977. Currently the main method ofcoronary artery revascularization is PTCA, which accountsfor more than 1.5 million procedures worldwide annually.Restenosis, however, has remained a perplexing problem,and antiplatelet agents, antioxidants, anticoagulants,calcium antagonists, ACE inhibitors, prednisone, andcholesterol-lowering agents have not reduced its occurrence.The use of intracoronary stents has been shown inseveral studies to reduce the incidence of angiographicrestenosis in patients with discrete, de novo lesions in largetarget vessels.Stents provide favorable and predictable acute angiographicresults and improve the safety of PTCA bysuccessfully treating acute and threatened occlusions.Stents have been shown to improve long-term clinicaloutcomes by reducing restenosis, and they decrease thetotal procedure time for percutaneous coronary intervention(PCI). Stents also provide beneficial results incomplex lesion morphologies that have a poor outcomeusing PTCA; this is particularly observed with totalocclusions, ostial stenosis, and eccentric lesions.The wide acceptance of coronary stenting was based onthe results of the landmark Belgian-Netherlands stent(BENESTENT) study and the stent restenosis study(STRESS) trials demonstrating that the elective placementof intracoronary stents significantly reduced the incidenceof restenosis in patients with discrete lesions in large targetvessels. The exuberant use of stents and their provenbeneficial effects have stimulated the introduction ofnumerous stent designs.Stents can be classified according to: Their mechanism of expansion: self-expanding orballoon expandable Their composition: stainless steel, cobalt-based alloy,tantalum, nitinol, inert coating, active coating, orbiodegradable Their design: mesh structure coil slotted tube, ring,multi-design, or custom designAll stents are available premounted on a delivery system.Colombo et al. emphasized that with the advent of drugelutingstents many previous recommendations may bealtered. Although the technique of stenting may changesomewhat, one goal that will not change and will becomeeven more important is the reliable delivery of the stent tothe lesion.II. RESTENOSISIntracoronary stenting is still limited, however, by in-stentrestenosis. The angiographic restenosis rate in stented565

566STENTSarteries is 20–30% in short lesions and large arteries.Unfortunately, restenosis occurs in 30–50% of patientswith diabetes, lengthy lesions, diffuse lesions, and withlesions located at bifurcations. PTCA with stent implantationis associated with restenosis in approximately 20–50%of cases.The widespread use of stents was initiated in orderto reduce the high rate of PTCA restenosis (33%) at6 months. In the recent hallmark RAVEL study whichcompared a drug-eluting stent with a standard uncoatedstent, the angiographic rate of restenosis at 6 monthswas 26.6% in the standard stent group in patients withnoncomplex coronary lesions. This high rate of in-stentrestenosis in noncomplex lesions is clearly unacceptablefor standard stenting, and it should not be considered amajor advance compared with PTCA for which a secondPTCA often confers sustained long-term benefits. Preventionof restenosis following PTCA by some means requiresmore intensive investigative research and clinical trialtesting. The newly developed drug-eluting that have beenshown to be superior to standard stents in preventingin-stent restenosis need to be tested in long-term clinicaltrials in large numbers of patients; they are gainingworldwide acceptance.Restenosis after stent implantation is caused mainly byneointimal proliferation through the stent struts. At thesite of the stent struts a marked activation of inflammatorycells appear to play an important role in the process ofneointimal proliferation and restenosis. Prevention oramelioration of this inflammatory response is the targetof considerable research. A high plasma level of C-reactiveprotein (CRP) has been observed following successful stentimplantation and appears to predict the risk of restenosis.The bulk of in-stent restenosis consists of extracellularmatrix, proteoglycans, and collagen with less than 12%cells. Deeper penetration of stent struts causes greaterneointimal proliferation; this may explain why a largerluminal diameter achieved by PTCA does not necessarilyreduce the rate of restenosis. The mechanisms that dictaterestenosis following PTCA are different from in-stentrestenosis. Overstretching by the balloon catheter causeselastic recoil. Endothelial denudation and exposure ofsubintimal components cause platelet adherence andaggregation, fibrinogen binding, and thrombus formationinto which smooth muscle cells migrate. These cellssynthesize matrix and collagen and trigger neointimalhyperplasia. Inflammatory mediators and cells stimulatematrix production and further cellular proliferation isfollowed by remodeling mediated by adventitial myofibroblasts,and these intricate processes lead to restenosis.Stenting diminishes elastic recoil and negative remodeling,the important mechanical components of restenosis.III. DRUG-ELUTING STENTSA drug-eluting stents is a device that releases single ormultiple bioactive agents into the circulating blood, whichaffect tissues adjacent to the stent. The bioactive agentsmay be simply linked to the stent surface, embedded, andreleased from within polymer materials or surrounded byand released through a carrier. The carrier may coat orspan the stent struts.A. Sirolimus-Eluting StentsSirolimus (rapamycin) is a natural macrocyclic lactonewith potent immunosuppressive and antimitotic actionwhich was approved as an antirejection drug in renaltransplant recipients. Sirolimus blocks cell cycle progressionand expression of inflammatory cytokines, thus,inhibiting cellular proliferation. For this reason, theimmunosuppressive properties of sirolimus might inhibitneointimal hyperplasia, so a stent was made and coatedwith a mixture of synthetic polymers blended withsirolimus. A second layer of drug-free polymers wasadded to promote gradual release of the drug in acontrolled concentration over 30 days.1. The RAVEL StudyThe RAVEL study is a randomized study with thesirolimus-eluting Bx Velocity balloon expandable stent inthe treatment of patients with de novo native coronaryarteries. The trial randomized 238 patients with singlecoronary lesions. Patients with complex coronary lesionswere excluded. The angiographic rate of restenosis at6 months was 0% in the drug stent group and 26.6% inthe standard stent group. There were no reported casesof subacute thrombosis. Long-term beneficial or adverseeffects beyond 2 years are not available and caution isrequired.2. The SIRIUS TrialThis trial randomized 1100 patients to treatment withrapamycin-coated stent versus standard stent. Its purposewas to investigate long-term safety in complex coronarylesions. Short-term results indicate a reduction of in-stent(3.2% drug stent vs. 35.4% standard stent) and in-segmentrestenosis (8.9% vs. 36.3%) with no difference in adverseeffects. The high rate of restenosis with standard stents isalarmingly high. Drug-eluting stents will play a major roleif their beneficial effects are proven beyond 5 years.

IV. PROBLEMS TO BE RESOLVED567FIGURE 1 The Sirolimus-eluting stent, shown with the chemical structure of the molecule. (From Perspective. (2002). N. Engl. J. Med., 346(23),p. 1770.)B. Paclitaxel-Eluting StentPaclitaxel inhibits cell processes that are dependent on amicrotubule turnover, which include mitosis, cell proliferation,and cell migration, but the cells remain viable andin a cytostatic state. Therapeutic concentrations of paclitaxelcause cytostatic inhibition of smooth muscle cells.The Asian paclitaxel-eluting stent clinical trial(ASPECT) tested the safety and effectiveness of thisdrug-eluting stent system with the safety and effectivenessof uncoated stents of the same type. This small study of177 patients followed for 6 months effectively inhibitedrestenosis and neointimal hyperplasia with the safetyprofile similar to that of the standard stent. The longtermeffects of drug-eluting stents remain unanswered andtheir role in more complex lesions requires further largeclinical studies. Stone et al. studied 1314 patients. The rateof angiographic restenosis at nine months was reducedfrom 26.6% to 7.9% with the paclitaxel eluting stent.C. New AgentsAngiopeptin and everolimus are two new agents testedin drug-eluting stents. Angiopeptin, a synthetic cyclicoctapeptide analogue of somatostatin, inhibits productionof growth hormones including platelet-derived growthfactor and epithelial growth factor. This agent inhibitssmooth muscle cell proliferation, but because it is cytostaticit does not appear to cause local toxicity. A phosphorylcholine‘‘sponge’’ coating loads the drug on to thestent. Tests are being carried out with stents coated with asomatostatin analogue that is human vascular specific.Everolimus is a new antiproliferative agent that binds tocytosolic immunophyllin and inhibits growth factor drivencell hyperplasia. A bioabsorbable polymer matrix stayson the stent after the drug is gone. This minimizes theinflammatory response but must be degraded and mayenhance an unwanted inflammatory response.IV. PROBLEMS TO BE RESOLVEDA. Long-Term StudiesPolymer coatings have been shown to induce inflammatoryresponses and fibrinoid deposits. In addition, the stabilityof polymeric material may degrade over time and delayedintimal hyperplasia may ensue. The perfect carrier for thebioactive material requires substantial search. Biodegradablepolymers may prove useful, but the length of drugdelivery is a concern. Multilayered polymers for multipledrug release, antigen antibody coating to capture endothelialcells, and other modalities are under investigation.

568STENTSLong-term drug toxicity must be addressed, becausesome drug-eluting stent systems including dactinomycin,taxane, and batimatast showed delayed thrombosis,delayed restenosis, and aneurysm formation. In case oftwo stents placed together or overlapping there may belocal toxic effects that have not been studied. Beneficialeffects in complex coronary lesions must be shown andlong-term effects beyond 5 years must be observed andcarefully reported.Some pathologists see trouble ahead for drug-elutingstents. Animal studies indicate that they may merely delayrather than prevent neointimal hyperplasia and restenosis.Six months after stent implantation in animals after mostof the drug has been released and the artery has had achance to heal, neointimal growth has been shown to surgeahead. Late in-stent restenosis is of major concern.In addition, because drug-eluting stents are not fullycovered by smooth muscle cells and collagen for the firstseveral months, the likelihood of change position andmalposition for drug-eluting stents is approximately fivetimes that of bare metal stents. This movement enhancesthrombus formation. Also, biodegradable polymers mustbe absorbed by the body and may incite a more intenselate neointimal inflammatory reaction.B. Other Drugs to Prevent Restenosis1. Prednisone: Impress StudyThis remarkable study in a small group of 83 patientsundergoing successful stenting with CRP levels greaterthan 0.5 mg/dl 72 h after the procedure were randomizedto receive oral prednisone or placebo for 45 days.Results: The 12-month event-free survival rates were 93and 65% in patients treated with prednisone and placebo,respectively. The 6-month restenosis rate was lower in theprednisone-treated patients than in the placebo-treatedpatients (7% vs. 33%; p ¼ 0.001).Conclusions: In patients with persistently high CRPlevels after successful coronary artery stent implantation,oral immunosuppressive therapy with prednisoneproduced a striking reduction of events and angiographicrestenosis rate.Perspective: Although adverse effects were low, corticosteroidshave undesirable adverse effects and long-termrandomized studies are required to clarify the role ofprednisone, other corticosteroids, and immunosuppressiveagents in the management of in-stent restenosis.2. Folate for RestenosisA study by Lange et al. concluded that contrary to previousfindings, the administration of folate, vitamin B 6 , andvitamin B 12 , after coronary stenting, may increase the riskof in-stent restenosis and the need for target-vesselrevascularization.BIBLIOGRAPHYColombo, A., Stankovic, G., and Moses, J. W. Selection of coronarystents. J. Am. Coll. Cardiol., 40:1021–33, 2002.Fajadet, J., Morice, M. C., Bode, C. et al. Maintenance of long-termclinical benefit with sirolimus-eluting coronary stents: Three-yearresults of the RAVEL trial. Circulation, 111:1040–1044, 2005.Fattori, R., and Piva, T. Drug eluting stents in vascular interventionLancet, 361:247–49, 2003.Goy, J. J., Stauffer, J. C., Siegenthaler, M. et al. A prospective randomizedcomparison between paclitaxel and sirolimus stents in the real worldof interventional cardiology: The TAXi trial. J. Am. Coll. Cardiol.,45:308–311, 2004.Lange, H., Suryapranata, H., and De Luca, G. Folate therapy and in-stentrestenosis after coronary stenting. 350:2673–2681, 2004.Leopold, J. A., Antman, E. M. et al. Dual antiplatelet therapy forcoronary stenting: A clear path for a research agenda. Circulation,111:1097–1099, 2005.Moliterno, D. J., Healing achilles—sirolimus versus paclitaxel. N. Engl.J. Med., 353:724–727, 2005.Morice, M. C., Serruys, P. W., Sousa, J. E. et al. For the RAVEL studygroup. A randomized comparison of a sirolimus eluting stent witha standard stent for coronary revascularization. N. Engl. J. Med.,346:1773–80, 2002.Muni, N. I., Gross, T. P. et al. Problems with drug-eluting coronarystents-The FDA perspective. N. Engl. J. Med., 351:1593–1595,2004.Park, S.-J., Shim, W. H., Ho, D. S. et al. A paclitaxel-eluting stentfor the prevention of coronary’s restenosis. N. Engl. J. Med.,348:1557–45, 2003.Serruys, P. W., Ormiston, J. A., Sianos, G. et al. Actinomycin-elutingstent for coronary revascularization: A randomized feasibility andsafety study: The ACTION trial. J. Am. Coll. Cardiol., 44:1363–1367,2004.Stone, G. W., Ellis, S. G., Cox, D. A. et al. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease. N. Engl. J. Med.,350:221–231, 2004.van der Hoeven, B. L., Pires, N. M. M., Warda, H. M. et al. Drugelutingstents: Results, promises and problems. Int. J. Cardiol.,99:9–17, 2005.Versaci, F., Gaspardone, A., Tomai, F. et al. Immunosuppressive therapyfor the prevention of restenosis after coronary artery stent implantation(IMPRESS study). J. Am. Coll. Cardiol., 40:1935–42, 2002.Windecker, S., Remondino, A., Eberli, F. R., et al. Sirolimus-elutingand paclitaxel-eluting stents for coronary revascularization. N. Engl.J. Med., 353: 653–662, 2005.

Stress and Heart DiseaseI. Effects on the Cardiovascular SystemII. Type A BehaviorGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.atherosclerosis same as atheroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow of blood; theplaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for heart attack or coronary thrombosis.platelets very small disk-like particles that circulate in the bloodalongside red and white blood cells initiating the formation ofblood clots; platelets clump and form little plugs called plateletaggregation, thus causing minor bleeding to stop.STRESS IS NOT REALLY NERVOUS TENSION, SO WEwill not dwell on the subject of nervousness and chronicanxiety, the cause of which must be determined andremoved. Damaging or unpleasant stress, as Hans Selyestates, is ‘‘stress with distress and this is always disagreeable.’’Although stress can be associated with pleasantsituations, it is more often produced by unpleasant stimuli.The word ‘‘stress’’ is derived from the Old French andMiddle English words for ‘‘distress’’; the first syllable waslost over the years.I. EFFECTS ON THE CARDIOVASCULARSYSTEMThere is no doubt that stress is awful. With the exceptionof severe pain and death, severe stress with distress is one ofthe most difficult situations we have to face. Stress produceswell-known reactions in the body such as an increasein blood pressure which causes small blood particles(platelets) to become sticky. The platelet particles sticktogether to form clumps or sludge, which can lead toformation of a blood clot in the coronary artery.Trauma to arteries wreaks havoc like a silent killer.During the stress reaction, the arteries constrict under theinfluence of adrenaline and noradrenaline (epinephrineand norepinephrine). Consequently both systolic anddiastolic blood pressure increase. If the baseline bloodpressure is usually 120/80, it can go up to 160/90 or from145/95 to as high as 210/110. These elevated pressures,lasting only minutes, are injurious to the arteries, andwhen combined with the effects of excess adrenalinecausing platelet sludging in the arteries, the death toll fromheart attacks increases.How does stress cause heart pain (angina) and damageto the heart and arteries? When the coronary arteries arenarrowed by plaques of atheroma, chest pain may occur(see the chapter Angina). Chest pain is made worse byexertion such as walking up a hill. Pain at rest may occur,however, if the patient faces sudden emotional upset.Stress causes adrenaline and noradrenaline release. Thesestress hormones cause the heart rate and blood pressureto increase, giving the heart more work to do (see Fig. 1).In some patients, adrenaline may cause platelets to clumponto plaques of atheroma, thus causing oxygen lack to thatsegment of heart muscle. This oxygen lack may or may notproduce chest pain.Moderate stress associated with simple daily activitiescan decrease the blood supply to the heart muscle inpatients with coronary heart disease. In a study of 16patients who had angina, the moderate stress of mentalarithmetic caused oxygen lack to the heart muscle(myocardial ischemia) similar to that produced by exercise(see Fig. 2). In these patients a radioisotope material(rubidium-82) was injected into a vein, and when itreached the heart muscle photographs were taken. Thedark areas in Fig. 2 represent the uptake of blood supplyto the heart muscle. When the supply of blood isdecreased, the area of muscle is poorly supplied with569

570STRESS AND HEART DISEASEFIGURE 1 Stress and the heart. (From Khan, M. Gabriel andMarriott, H.J.L. (1996). Heart Trouble Encyclopedia, Toronto: StoddartPublishing, p. 248.)blood, the presence of the rubidium-82 is reduced, and thearea of darkness is diminished.In a similar experiment, a patient who was havingcatheterization of his heart (coronary arteriogram) wasasked to do mental arithmetic, asked to think of a paststressful situation, and saw the result of his catheter studies.His heart muscle function was determined during the testand showed no significant change with thinking of paststress, but showed a mild defect during mental arithmeticand severe defects in muscle function during theexplanation and viewing of the findings of his heartcatheter test.A stressful situation causes the ‘‘emotional center’’ in thebrain to trigger certain reactions (Fig. 1). The hypothalamussends signals to the pituitary gland and sympatheticnervous system, which lead to secretion of the ‘‘stresshormones’’ cortisone, adrenaline, and noradrenaline.Cortisone causes an increase in blood glucose and anincrease in blood pressure.As a result of a stressful situation (stressor), the innercompartment of the adrenal glands pours out adrenalineand noradrenaline and these compounds are involvedin the ‘‘fight or flight’’ reaction. The external stimulus(stressor) is usually a condition that produces anger, fear,anxiety, and deprivation. Common stressors include theFIGURE 2 The heart under stress. Changes in the uptake of rubidium-82 and the electrocardiogram in relation to chest pain before and after mentalarithmetic or exercise. Control scans, dark areas, show normal rubidium-82 uptake by the heart muscle in three patients, indicating normal blood flow.There are defects in uptake (arrows) with mental arithmetic and exercise, and these changes can be accompanied by ECG changes of oxygen lack to themuscle ¼ ischemia ¼ angina. N ¼ normal; AB ¼ abnormal. (Modified from The Lancet, 2, 1003, 1984. With permission.)

I. EFFECTS ON THE CARDIOVASCULAR SYSTEM571death of a spouse, conflicts with others, and projectsrequiring a deadline. Very often the stressor consistsof words that are interpreted by the individual as harshor hurtful, resulting in anger, hostility, humiliation, orresentment.The body reacts in the same way regardless of the typeor source of stress or unexpressed anger. Stress from anargument with the boss, fellow workers, a spouse, or othersis the same as stress from being chased by an assailant. Thefight for so-called prestige, recognition, and survival atwork or at home goes on daily, and for many years youmay bear the brunt of the stress.When an individual is riled to the point of bursting,adrenaline in excess has been poured into the circulatingblood. Visualize the adrenaline as little death potions thatone may drink at work and for some, unfortunately, athome. Adrenaline is helpful in some situations; forexample, when you want to flee from a charging bull oran assailant. These compounds increase the heart rate andblood pressure and increase the supply of blood containingglucose and oxygen to exercising muscles so that you areable to run. An excess of adrenaline and noradrenalinecan be dangerous because these chemicals can overstimulatethe heart, disturb its electrical stability and, onrare occasions, lead to ventricular fibrillation.Adrenaline causes a decrease in the ventricular fibrillationthreshold and can precipitate ventricular fibrillationand cardiac arrest. Adrenaline causes platelets to clump,and if this occurs on a plaque of atheroma, pain can occuror a clot can develop. These compounds can also causespasm of the coronary arteries, which in turn can producechest pain and sometimes death, especially if the spasmoccurs where the plaque partially blocks the artery.Heart deaths are due to two major problems: (1) formationof a blood clot at the site of partial blockage byatherosclerosis in a coronary artery and (2) electricaldisturbances that cause the heart to quiver and not contract(ventricular fibrillation). Sudden death is common, andthe possibility cannot be excluded that severe acute stressmay cause death by initiating a brain-adrenaline-heartinteraction (see Fig. 1). The clumping of platelets canenlarge the plaque, and over a period of years the buildupof clot on a plaque can cause complete obstruction of theartery. Animal experiments lend support to this hypothesis.Rats exposed to sudden trauma develop blockageof the coronary arteries, which results in damage to thesegments of the heart muscle (myocardial infarction).When rats were not physically traumatized but werestressed with nonphysical traumatic electric shocks, theydeveloped clots in the coronary arteries and died. Whenrats were pretreated with drugs that prevented plateletclumping, such as aspirin or dipyridamole, and thensubjected to similar electric shocks, clots were prevented inthe majority. If rats are pretreated with a beta-blocker,which blocks the dangerous effects of adrenaline, ventricularfibrillation is prevented and rats survive.Experimentally, adrenaline or noradrenaline given intravenouslycan cause severe electrical disturbances andventricular fibrillation. During a heart attack, there is anincrease in noradrenaline in the heart muscle. When bloodflow to the heart is reduced by atherosclerosis of thecoronary artery, severe stress can more easily precipitateventricular fibrillation.When a coronary artery is suddenly blocked in dogs,severe quivering of the heart occurs in some. When thehypothalamus (in the brain) and sympathetic nervoussystems are stimulated to produce noradrenaline at thesame time that the coronary artery is blocked, quiveringof the heart frequently occurs. Beta-blocking drugs blockthe actions of adrenaline and noradrenaline, and if dogs arepretreated with these drugs and the coronary artery isthen blocked, the dangerous quivering of the heart can beprevented.In a study involving 117 patients who were resuscitatedfrom cardiac arrest, 25 reported that they had severe stresssuch as job and family conflicts within the 24 h prior tothe cardiac arrest. Acute or prolonged (chronic) stress mayproduce severe damage to the coronary arteries. It mustbe remembered that atheroma of the arteries commonlyproduces no symptoms; it is a silent killer and after manyyears, a clot can develop on a ruptured atheromatousplaque. There is considerable evidence linking increasedstickiness of platelets to the production of atheroma andblockage of arteries.A. Stress and SportsDo not push yourself excessively during a run if you arenot a trained athlete. Do it if you feel great and enjoy it,and do not have to clench your jaws or tighten yourfacial muscles. If you have to push yourself to do anadditional mile, then you may secrete excess adrenalineand noradrenaline and this takes its toll on your cardiovascularsystem throughout the years. Similarly, be carefulnot to be overly competitive when playing racquet sports.B. The Symptoms and Signs of StressSweatiness, especially on the forehead and skull, andunder the armpits and on the palms owing to thepresence of excess adrenaline.Heart races and may easily pound.

572STRESS AND HEART DISEASE Achiness in the head and neck, especially in the templesor eyes. A feeling of turmoil or tightness in the chest or stomachas if there were butterflies in your stomach or there isa feeling of anguish, terror, fright, restlessness, agitationor tremulousness; feeling shaky, jittery, or weak all over. Slurred speech with feelings of being unable to screamor talk for a few seconds. Hostile, violent, full of rage and anger, and ready tofight back. Difficulty sleeping with frequency of urination, indigestion,or sometimes diarrhea.C. How to Handle StressStress is a part of living and cannot be completely avoided.When you understand how traumatic stress can be toyour heart and arteries, you may be motivated to developtechniques to deal with stress. Stress management is acomplex subject, beyond the scope of this book. Some ofthe ways that are indicated to cope with stress includemental diversion, techniques to develop a healthy selfconcept,time management, progressive deep relaxationtechniques, meditation, biofeedback, and exercise.D. ConclusionStress is as important as the major ‘‘risk factors’’ (cholesterol,hypertension, diabetes, dyslipidemia, cigarettesmoking), but it is difficult to prove this hypothesisscientifically. Stress, high blood cholesterol, hypertension,smoking, and blood-clotting factors work in concert in thegenetically susceptible individual to produce atherosclerosisand, finally, a fatal or nonfatal heart attack. A stressorcauses the sympathetic nervous system and adrenal glandsto secrete stress hormones, which increase the work of theheart and cause platelet clumping that can sometimes causea blood clot in the coronary artery. This chapter has outlinedhow excess adrenaline and noradrenaline alter theelectrical stability of the heart, predisposing it to a high riskof a curious quivering (ventricular fibrillation) duringwhich it fails to contract and sudden death may occur.Humans are fortunate that the working of the bodyis such that the reaction caused by one chemical is oftencounterbalanced by other chemicals that are producedin the body. Nature does not always win, but it can, witha little help from you. It is important to develop strategiesthat may enable you to deal with various stressfulsituations. Thus you will be able to handle stress andsubdue the brain-adrenaline-heart-artery reaction describedabove.II. TYPE A BEHAVIORType A individuals have an impatient, time-conscious,achievement-striving personality, and they often seek outa hectic environment that provokes undue stress. Leisurebrings a feeling of guilt, because their lives are an everlastingstruggle against time toward achievement andrecognition. The Type A individual takes on a project,including simple reading, with a certain violence. Speechis often harsh, explosive, or aggressive. When stressed, TypeA individuals have been shown to release more adrenalineand noradrenaline and to have a greater rise in bloodpressure than Type Bs. Type B people are easygoing, ableto relax, and rarely carry work home or set deadlines.Most of us are mixtures of Type A and B. It is difficult fora Type A person to change, but with expert assistance,modification of lifestyle is possible.Friedman and Rosenman have defined and establishedthe concept of the Type A behavior pattern. Theyemphasized that if you have Type A behavior, you havean increased risk of coronary heart disease. Several studieshave confirmed that a relationship exists between TypeA behavior and risk of coronary heart disease. This occursin both men and women independent of high bloodcholesterol, hypertension, and smoking. The NationalHeart Lung Blood Institute has accepted the evidenceregarding Type A behavior and increased risk of coronaryheart disease.The question of Type A behavior and increased riskof coronary heart disease remains controversial, however.The large Multiple Risk Factor Intervention Study anda small British study did not show any relationshipbetween Type A behavior and coronary heart disease.A study reported in the New England Journal of Medicinefound no relationship between Type A behavior andmortality from coronary heart disease in patients who hadhad a heart attack and were followed for three years.Commencing two weeks after their heart attack, 510patients were followed. At the end of three years, deathrate was not related to behavior, whether Type A orType B. The mean Type A score did not differ significantlyfrom the score of those who survived. The conclusionis: ‘‘Thus, we found no relation between type Abehavior and the long-term outcome of acute myocardialinfarction.’’

II. TYPE A BEHAVIOR573BIBLIOGRAPHYCase, R. B., Heller, S. S., Case, N. B., and Moss, A. J. Type Abehavior and survival after acute myocardial infarction. 312:737–741,1985.Friedman, M., and Rosenman, R. H. Type A Behavior and your Heart.Alfred A. Knopf, New York. 1974.Multiple Risk Factor Intervention Trial Research Group. Multiple riskfactor intervention trial: Risk factor changes and mortality results.JAMA, 248:1465, 1982.Yusuf, S., Hawken, S., Ôunpuu, S. on behalf of the INTERHEARTStudy Investigators et al. Effect of potentially modifiable risk factorsassociated with myocardial infarction in 52 countries (the INTER-HEART study): Case-control study. Lancet, 364:937–52, 2004.

Stroke/Cerebrovascular AccidentI. IncidenceII. Types of Cerebrovascular AccidentsIII. Cerebral Infarction/Ischemic StrokeIV. Transient Ischemic AttackV. Intracranial HemorrhageVI. Subarachnoid HemorrhageGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis ¼ hardening).atherothrombosis atheroma complicated by rupture or erosionof the plaque with subsequent thrombosis causing completeocclusion of an artery.embolism, embolus a blood clot that forms in an artery, a vein,or the heart that breaks off and is carried by the circulatingblood, finally lodging and blocking the artery that suppliesan organ with blood; for example, a pulmonary embolism isan embolus blocking an artery in the lung.infarction death of cells (necrosis) caused by a marked deficit inblood supply to the area of cells.ischemia temporary lack of blood and oxygen to an area of cells,for example, the heart muscle, usually due to severe obstructionof the artery supplying blood to this area of cells.I. INCIDENCECerebrovascular accident, the final outcome of cerebrovasculardisease, is the third most common cause of deathworldwide after coronary artery disease and cancer combined.It is the most common cause of disability in theworld. Annually more than half a million individualsin the United States have a first cerebrovascular accident.In 1990 cardiovascular disease accounted for more than14 million deaths in a population of 5.3 billion or 29% ofthe world’s 50 million deaths. Of these, 6.3 million deathswere due to coronary artery disease and 4.4 million werecaused by cerebrovascular accident. By 2025 cardiovasculardisease will be responsible for an estimated 25 milliondeaths annually or 36% of all deaths.The disease causing more than 60% of these cardiovasculardeaths is atherothrombosis. The words atheroma andatherothrombosis are hardly known to 99% of the populationand they are not a popular research topic for morethan 99% of physicians or scientific researchers. Thissituation is unfortunate and will not change much unlessthese statistics are publicized and the old word atherosclerosisthat connotes hardening of arteries is understoodand probably abandoned.Cardiovascular researchers are interested in left ventricularassist devices (purported to be artificial hearts) thatmay save the lives of about 4000 individuals worldwideannually at the cost of nearly $1 million per person. Thereis also much hype concerning the role of cardiovascularelectron beam computeri-zed tomography (EBTC) todetect the calcium content of coronary and other arteries.EBTC is a very expensive test that probably would save nomore than one life worldwide annually (see the chapterTests for Heart Diseases). Emphasis must be placed onextensive funding for research that would uncover the exactcause for atheroma format-ion which leads to atherothromboticocclusion of arteries in the heart, brain,and other areas of the body and the prevention ofthis malignant atheromatous process (see the chapterAtherosclerosis/Atheroma).II. TYPES OF CEREBROVASCULARACCIDENTSThe generic term stroke has become synonymous withcerebrovascular accident and has come to signify the575

576STROKE/CEREBROVASCULAR ACCIDENTabrupt impairment of brain function caused by pathologicchanges involving intra- or extracranial blood vessels.The cerebral deficit lasts more then 24 hours. If the neurologicimpairment lasts less than 24 hours, the condition isthen referred to as a transient ischemic attack (TIA).There are four pathological types of stroke:1. Cerebral infarction (nonembolic stroke): 40% of allstrokes are caused by atherothrombotic disease ofthe extracranial or less commonly large intracranialarteries; approximately 20% are caused by occlusion ofone of the deep perforating cerebral arteries (lacunarinfarct).2. Cerebral infarction caused by emboli mainly from theheart (embolic stroke), 20%.3. Intracranial cerebral hemorrhage: hemorrhagic stroke,10%.4. Subarachnoid hemorrhage, 5%.III. CEREBRAL INFARCTION/ISCHEMIC STROKEA. CausationThis most common form of stroke is caused by braindamage (cerebral infarction) that results from obstructionof an artery supplying that area of the brain. Obstructionof the artery is caused by blood clot formation in theartery, often at a point where the artery is narrowed byatheroma/atherosclerosis (see the chapter Atherosclerosis/Atherothrombosis). The term atherothrombosis is nowpreferred because it brings together the two essential componentsof the offending obstruction of the artery. Thisprocess is identical to that which causes a myocardialinfarction and is defined as death of an area of heartmuscle due to blockage of a coronary artery by bloodclot and atheroma (atherothrombosis). Atherothromboticischemic stroke accounts for approximately 55% of allstrokes. One risk factor for the development of atherothrombosisand occlusion of arteries is high LDL cholesterollevels of greater than 100 mg/dl (2.5 mmol/L). Morethan 40% of individuals in the western world, Europe,the UK, Ireland, Russia, and the former Soviet republiccountries have an LDL cholesterol greater than 100 mg/dland are at risk for coronary thrombosis and cerebralthrombosis. Baseline LDL cholesterol levels are on the risein individuals in developing countries. Diabetes has amajor impact on the development of atherothrombosis,and the incidence of diabetes ranges from 6 to 12% invarious parts of the world (see the chapter Diabetes).Hypertension occurs in more than one billion individualsworldwide and increases the risk for the developmentof atherothrombosis. Cigarette smoking also increasesatheroma formation.Embolic ischemic stroke represents approximately 15%of all strokes. Thrombi originating in the left atrium inpatients with atrial fibrillation or located on the left ofthe ventricular endocardium in patients following acutemyocardial infarction may dislodge and be propelled intothe circulation (embolize) and end up in a cerebral artery.The occluded artery deprives the brain cells of bloodcausing an ischemic stroke. In these patients anticoagulationwith warfarin is necessary. It has been shown thatin these anticoagulated patients, an INR of 1.5–1.9 onhospital admission is associated with a mortality rate similarto that for an INR of less than 1.5. Anticoagulation thatresults in an INR of 2 or greater reduces not only thefrequency of ischemic stroke but also its severity andthe risk of death from stroke (see the chapter AtrialFibrillation).Other conditions that increase the propensity of theblood to clot or cause damage to arteries and increasethe risk of stroke include: antiphospholipid syndrome,thrombocytosis (high platelet levels in circulating blood),protein C and protein S deficiency, factor V Leiden, streetdrugs, oral contraceptives used in smokers, estrogenichormone replacement therapy, lupus erythematosus,vasculitis, and hyperhomocystinemia. Fortunately theseconditions are rare and are responsible for approximately5% of all strokes.B. Symptoms and SignsIf the part of the brain that controls movement of thehand or leg is involved, then loss of strength or completeparalysis of the arm and/or leg occurs. If the speech areaof the brain is involved, speech difficulties (dysphasia)become apparent and in some patients, a complete loss ofspeech (aphasia) occurs.Clinical manifestations of ischemic stroke include thefollowing:Contralateral arm and leg weakness, paralysis (hemiparesis),lower facial weakness on same side as the braininfarctAphasia or dysphasiaGait ataxiaMemory impairmentVariable degrees of blindness depending on the arteryoccluded

IV. TRANSIENT ISCHEMIC ATTACK577IV. TRANSIENT ISCHEMIC ATTACKA. Symptoms and SignsThe symptoms and signs of a TIA depend on the cerebralartery being partially occluded restricting the supply ofblood to that part of the brain. There are more than 15possible arterial sites on each side of the brain and TIAsat each site have their own pattern of symptoms and signs.Some patients have warning attacks of stroke and thevarious patterns are listed below. Numbness with or without weakness of the face, hand,or leg; paralysis speech defects (dysphasia or transient aphasia) orslurred speech (dysarthria) Transient monocular blindness, double vision, orhemianopia Imbalance or incoordination Dizziness Confusion and headacheMimics of TIA include a drastic fall in blood pressureon sudden standing from a reclining position (posturalhypotension), vasovagal syncope, migraine attack, inner eardisease, transient global amnesia, subdural hematoma,parietal lobe epilepsy, hypoglycemia, polycythemia andother causes of hyperviscosity of blood, cervical diskdisease, hypoglycemia, and anxiety.These symptoms and signs may persist for only minutes,but can last up to 24 h with full recovery and withoutstroke occurring. Most TIAs resolve within 30 minutes, althoughsome last an hour. Thus if symptoms andabnormal signs last longer than an hour, then severe ischemiais likely to result in death of brain cells calledan infarction. The relevant clinical distinction between aTIA and stroke is whether the ischemia has caused braindamage (cerebral infarction) or temporary reversible ischemiathat has caused no significant damage to brain cells.The 24-h time frame for disappearance of symptoms is anold concept established in 1965. In the 1975 revision ofthe National Institutes of Health (NIH) classificationdocument a 24-h limit for TIAs was adopted.If symptoms and signs last more than an hour,infarction (stroke) often results. Levy has shown thatif symptoms last more than 1 hour the likelihood thatsymptoms will resolve completely within 24 hours is lessthan 15%. A TIA Working Group in 2002 proposed thefollowing new definition for TIA: It is a brief episode ofneurologic dysfunction caused by focal brain or retinalischemia with clinical symptoms typically lasting less thanone hour and without evidence of acute infarction.B. Outcome Following TIAA study conducted in northern California included 1707patients with TIA. During a 90-day period after the eventabout 1 in 9 patients had a stroke, and half of all strokesoccurred in the first 2 days. In another study of 198patients with TIA the risk of stroke was 10%. In patientswith atrial fibrillation and embolization of clots to thebrain causing TIA the 90-day risk of stroke is approximately10%.C. ManagementManagement involves isolating the cause of the TIA andcorrecting it. TIAs are commonly due to atheromatousdisease of the carotid arteries in the neck as the arterycontinues deep to the jawbone and enters the brain.Surgery to clean this artery, endarterectomy, is useful inpatients with more than 70% obstruction of the carotidartery. A simple test called a carotid Doppler examinesthe velocity of flow of blood through the carotid arteryand gives a reasonable estimate of obstruction: less than33% percent, nonsignificant; 50–69%, significant; orgreater than 75%, severe obstruction. The test is donewithin minutes as an outpatient and does not requirean injection. Before surgery is advised, the result of theDoppler may be confirmed by a dye test called a carotidangiogram.Doppler ultrasonography has a sensitivity of 83–86%for a stenosis of 70% or greater and should be performedwithin hours to define the problem.1. Carotid EndarterectomyCarotid endarterectomy is beneficial in patients withcarotid artery stenosis of 70–99%. MRC asymptomaticcarotid surgery trial (ACST) collaborative group carriedout the following study.Method: A total of 3120 asymptomatic patients withsubstantial carotid narrowing were randomized equallybetween carotid endarterectomy and in definite thesural of any endarterectomy. Patients were followed forfive years.Results: In patients younger than 75 years of age withcarotid stenosis, in >70% immediate carotid endarterectomyhalved the net five-year stroke risk from about 12%to about 6% (including the 3% perioperative hazard).Caution is made regarding a skilled surgical team.In selected patients with carotid lesions amenable forstent placement, beneficial results have been observed by

578STROKE/CEREBROVASCULAR ACCIDENTskilled investigators. The results of the large multicenterrandomized CREST trial should answer important questionsregarding carotid stenting versus endarterectomy.Prevention of stroke following a TIA can be partiallyachieved by slightly thinning the blood with aspirin75–325 mg daily. Success in patients has been achievedwith the use of 325–650 mg aspirin daily, but a dose aslow as 75 mg is usually effective. Aspirin prevents bloodparticles from sticking together to form small friableclots on the artery at the site of atheroma formation. Thesesmall friable platelet clots may break off and temporarilyblock small arteries in the brain causing TIAs, warningattacks, or a small stroke.Aspirin reduces the long-term risk of stroke followingTIA with an overall relative reduction in risk of 22%.Patients who cannot take aspirin because of bleeding fromthe stomach or gut benefit from the use of clopidogrel orticlopidine, but the latter agent may cause damage to whiteblood cells.Clopidogrel has been shown to be marginally betterthan aspirin in preventing stroke following stroke or TIA.Ticlopidine has the same beneficial effects but carries thehazard of blood dyscrasias (see the chapter AntiplateletAgents). The combination of extended-release dipyridamoleand aspirin has been shown to be superior to aspirinalone in reducing the risk of stroke among patients followinga stroke or TIA and is underused by neurologists andgeneral practitioners.Aggressive lowering of LDL cholesterol is mandatory forthe prevention of fatal and nonfatal strokes. The use ofeffective cholesterol-lowering drugs such as the statinsreduces LDL cholesterol 30–50% and has been shown todecrease atheroma progression. Randomized clinical trialshave shown reduction in fatal and nonfatal myocardialinfarctions and stroke.Excellent control of blood pressure helps to preventstrokes but does not eliminate the atheromatous obstructionin the carotid or other arteries and cannot be reliedupon to adequately prevent strokes. Hypertension increasesatheroma formation but is only one of the many players inthe formation and progression of atheromatous obstructionto arteries, which is the root of the problem causingstrokes and heart attacks.V. INTRACRANIAL HEMORRHAGEFocal cerebral hemorrhages occur spontaneously; some ofthese are caused by hypertension. Bleeding is believedto result from rupture of a microaneurysm in a smallintracerebral artery. Rarely hemorrhage occurs from rupturedatrioventricular malformations and as a complicationof anticoagulant therapy with warfarin or the use ofthrombolytic agents for the management of myocardialinfarction and stroke.VI. SUBARACHNOID HEMORRHAGEStroke caused by rupture of a small aneurysm of an arteryat the base of the brain may rupture and bleed intothe subarachnoid space around the brain. These smallaneurysms are called berry aneurysms and may be due toa developmental defect on the wall of the artery thatstretches, balloons, and forms a small aneurysmal dilatationof the artery. The blood from the ruptured aneurysmmay damage the brain substance, and the pressure of theblood clot pressing against the brain leads to a rapid lossof consciousness. This condition is called a subarachnoidhemorrhage (see the chapter Aneurysm).Considerable brain damage may occur, but urgent surgeryto remove the clotted blood that is compressing thebrain and to clip the aneurysm is often successful in 75%of the cases. Unfortunately, this type of hemorrhage occurssuddenly in young individuals aged 25–50. A sudden, verysevere headache becoming unbearable over minutes to anhour, especially associated with drowsiness or mild confusion,may herald the onset of this type of hemorrhage.Urgent investigation by surgery may prevent disaster. In afew patients, because of recurrent episodes of intenseheadaches, the diagnosis is made by an angiogram doneprior to the rupture of the aneurysm. Clipping the aneurysmis a simple operation because the artery lies outside thebrain substance, and it is highly successful. Patients withpolycystic kidney disease may have associated berryaneurysms.BIBLIOGRAPHYHans-Christoph, Bogousslavsky, J., Brass, L. M. on behalf of theMATCH Investigators et al. Aspirin and clopidogrel compared withclopidogrel alone after recent ischaemic stroke or transient ischaemicattack in high-risk patients (MATCH): Randomised, double-blind,placebo-controlled trial. Lancet, 364:331–37, 2004.Heuschmann, P. U., Kolominsky-Rabas, P. L., Roether, J. for the GermanStroke Registers Study Group et al. Predictors of in-hospital mortalityin patients with acute ischemic stroke treated with thrombolytictherapy. JAMA, 292:1831–1838, 2004.Hylek, E. M., Go, A. S., Chang, Y. et al. Effect of intensity of oralanticoagulation on stroke severity and mortality in atrial fibrillation.N. Engl. J. Med., 349:1019–26, 2003.

VI. SUBARACHNOID HEMORRHAGE579Johnston, S. C. Transient ischemic attack. N. Engl. J. Med., 347:1687–1692, 2002.Johnston, S. C., Gress, D. R., Browner, W. S. et al. Short term prognosisafter emergency department diagnosis of TIA. JAMA, 284:2901–6,2000.Levy, D. E. How transient are transient ischemic attacks? N. Engl. J. Med.,38:674–677, 1988.Milionis, H. J., Liberopoulos, E., Goudevenos, J. et al. Risk factorsfor first-ever acute ischemic non-embolic stroke in elderly individuals.Int. J. Cardiol., 269–275, 2005.MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group.Lancet, 363:1491–1502, 2004.Murray, C. J. L., and Lopez, A. D. The Global Burden of Disease. HarvardSchool of Public Health, Cambridge, MA, 1996.The NINDS rt-PA Stroke Study Group. Tissue plasminogen activatorfor acute ischemic stroke. The National Institute of NeurologicalDisorders and Stroke rt-PA stroke study group. N. Engl. J. Med.,333:1581–7, 1995.The TIA working group. Transient ischemic attack-proposal for a newdefinition. N. Engl. J. Med., 347:1715–16, 2002.Warlow, C., Sudlow, C., Dennis, M. et al. Stroke. Lancet, 362:1211–1124, 2003.White, C. J. Another nail in the coffin of carotid endarterectomy.J. Am. Coll. Cardiol., 58:1596–97, 2001.

SyncopeI. Definition and IncidenceII. CausesIII. Diagnostic EvaluationIV. ManagementGLOSSARYarrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).bradycardia heart rate less than 60 beats a minute.cardiomyopathy heart muscle disease.hypotension marked decrease in blood pressure usually less than95 mmHg.preload the degree of ventricular muscle stretch present at theonset of myocardial contraction; often expressed as end diastolicvolume or pressure.supraventricular tachycardia tachycardia arising in the atrium,that is above the ventricle.valvular heart disease pertaining to diseases of the heart and theheart valves.I. DEFINITION AND INCIDENCESyncope is a sudden transient loss of consciousness andpostural tone with spontaneous recovery. It is a commonmedical problem that is often disabling and causes injury;most important, albeit rarely, it may be the only warningsign of sudden cardiac death.Loss of consciousness during syncope occurs becauseof a reduction of blood flow to the reticular activatingsystem in the brain stem. Cessation of cerebral blood flowcauses loss of consciousness within approximately 10seconds because the metabolism of the brain is exquisitelydependent on adequate perfusion. A simple faint and otherforms of loss of consciousness lasting a few seconds causedby lack of blood to the brain are medically termed syncope.There are several causes of syncope, which is often difficultto evaluate and investigations to uncover them is expensive.The approximate cost of evaluating and treatingpatients with syncope in the United States is approximately$1 billion. Elderly individuals have a 6% annual incidenceof syncope and patients with syncope account for approximately1% of hospital admissions and 3% of emergencyroom visits.II. CAUSESCauses of syncope may be divided into five main groups:1. Reflex mediated syncope, the simple faint2. Orthostatic hypotension3. Cardiovascular disorders (see Table 1)4. Neurologic disorders5. Metabolic and miscellaneous disordersA. Reflex-Mediated SyncopeThis is the first and largest category and it consists of awide variety of disorders associated with sudden transienthypotension and/or bradycardia.1. Vasovagal SyncopeThis is referred to as the simple faint or by some asneurally mediated syncope or neurocardiogenic syncope.The term vaso is indicated by vasodilation and vagalinvokes a marked slowing of heart rate. Vasovagal syncopeis a common occurrence. Recovery is rapid if the headis kept lower than the legs so that blood can be deliveredmore efficiently to the brain. Placing the individual flaton the ground with the legs elevated is the quickest methodof getting blood to the brain, and afterwards the personrapidly regains consciousness.581

582SYNCOPETachyarrhythmiasBradyarrhythmiasCarotid sinus syncopeObstruction to stroke volumeOthersTABLE 1Cardiac Causes of SyncopeSustained and nonsustainedventricular tachycardiaTorsades de pointesAtrial fibrillationSupraventricular tachycardiaLong QT syndromeWolff-Parkinson-White syndromePacemaker mediatedSinus node dysfunction[sick sinus syndrome]Aortic stenosisHypertrophic cardiomyopathyTight mitral stenosisAtrial myxoma or thrombusCardiac tamponadeProsthetic valve dysfunctionPulmonary embolismPulmonary hypertensionPulmonary stenosisMitral valve prolapseInferior myocardial infarctionCoronary artery spasmAortic dissectionA good history taken by a physician who is willing tolisten and ask probing questions identifies a vasovagalepisode and can prevent expensive and time-consuminginvestigations. A vasovagal episode never occurs with theindividual in a recumbent position. A faint is heraldedby one or more of the following: a feeling of weakness,lightheadedness, nausea, abdominal discomfort, diaphoresis,dizziness, and blurring of vision. One or more of thesesymptoms may be present for a few seconds or for a coupleof minutes prior to the individual falling to the ground.Often there is sufficient warning to allow the individualto get to a sitting position and to put the head between theknees. Fainting usually occurs in certain settings when theindividual may have been standing for too long and bloodpools in the legs; less blood then reaches the brain andweakness with transient loss of consciousness may occur.Some individuals have a propensity to fainting spells.Fainting may be precipitated by drugs that excessivelylower blood pressure. Mitral valve prolapse, blood loss,severe vomiting and diarrhea causing dehydration, andhigh fevers may precipitate attacks. Vasovagal syncope isnot associated with abnormal movements of the limbs;such seizure activity may be accompanied by incontinenceor tongue biting, which is not observed with a faint.Vertigo (a rotational sensation) is not a symptom associatedwith a vasovagal attack.a. MechanismsThe combination of vasodepressor and vasovagal (bradycardic)features results in a faint. The vasodepressivecomponent with sudden reduction in blood pressure playsan important role in loss of consciousness. Bradycardiaplays a secondary role. Marked vasodilatation (dilationof arteries and arterioles) causes a temporary but profoundfall in blood pressure (hypotension). Marked vasodilatationis caused by the inhibition of sympathetic vasoconstrictoractivity at the very moment when arteriolar vasoconstriction is necessary to combat the marked fall inblood pressure. The exact reason for this paradoxicreaction of vasodilation instead of vasoconstriction is notwell clarified. An increase in cardiac myocardial contractilitytriggered by mechanoreceptors in the ventricularmuscle occurs 2–4 minutes before the onset of syncopeoccurs in some instances.b. TriggersTriggers associated with the development of the simplefaint include a decrease in preload causing reduced ventricularfilling similar to dehydration; prolonged, motionlessstanding during hot weather; hot baths or hot showers, orin hot environments, for example, saunas; and feverscausing vasodilation. In these and similar situationspooling of blood occurs in the legs and there is reducedreturn of blood to the heart. This leads to a reduction incardiac output and blood pressure in individuals who arealready extremely vasodilated because of heat or vasodilatordrugs. It is believed that vigorous contraction of thevolume-depleted ventricle leads to activation of mechanoreceptorsor C fibers that project centrally to the dorsalvagal nucleus in the medulla oblongata of the brainstem. It is believed that this leads to a paradoxic effectthat produces a withdrawal of peripheral sympathetictone causing further vasodilatation instead of beneficialvasoconstriction with bradycardia occurring in someindividuals.Another trigger is sudden increased catecholaminesecretion and reflexes mediated by the brain similar tosevere pain, fright, sight of blood, stressful situations, andextreme anxiety. The exact mechanisms are not clearlydefined. It is clear that not all reflex-mediated syncoperesults from activation of cardiac mechanoreceptors. Highercenters in the brain participate in the pathophysiology of

II. CAUSES583this form of simple faint, the vasovagal syncope. It isunclear how a sudden increase in catecholamine secretionprecipitates a vasovagal episode.Individuals with reflex-mediated syncope do not usuallyhurt themselves during a fall, because there is virtuallyalways a minimal warning that lasts several seconds. Whenthere is virtually no warning and serious injuries occur, thissituation is described as malignant vasovagal syndrome.Syncope occurring during micturition is believed to becaused by activation of mechanoreceptors in the bladder.Syncope that may occur during defecation or swallowingappears to be triggered by gut wall tension receptorsand afferent neural impulses arising in the esophagus orstomach, respectively.2. Carotid Sinus HypersensitivityAlthough carotid sinus hypersensitivity is uncommon inelderly individuals, the precipitation of syncope does occur,though rarely. Thus the diagnosis of syncope due to thisdisorder should be made only after exclusion of othercauses.B. OrthostaticOrthostatic hypotension is defined as equal to or greaterthan a 20 mmHg fall in systolic blood pressure within3 minutes of standing. On standing, 500–800 ml of bloodis displaced to the abdomen and lower extremities, lessblood reaches the heart, and cardiac output is reduced.This stimulates baroreceptors in the aortic arch and thecarotid artery which cause a reflex increase in sympatheticoutflow that increases heart rate, cardiac contractility, andtotal vascular resistance so blood pressure stabilizes onstanding. Table 2 lists causes of orthostatic hypotensionand noncardiac causes of syncope.Drugs are the most common cause of orthostatichypotension. Several drugs including diuretics that causevolume depletion, decrease preload, and others that causearterial vasodilatation may precipitate postural hypotension.C. CardiovascularSeveral cardiac disorders cause syncope or a faint-likefeeling (presyncope). Occasionally this is caused by anabnormally slow heart rate of less than 40 beats perminute. This form of disturbance in the electrical conductionof the heart may require the implantation of a pacemaker(see the chapter Pacemakers). Individuals whoTABLE 2NONCARDIAC a Causes of Syncope1. Vasodepressor [vasovagal] or neurocardiogenic causes [>30%]2. Orthostatic hypotension [10%]A. Decreased preload[1] Venous pooling, caused by extensive varicose veins, postexercisevasodilation, venous angioma in the leg[2] Drugs: nitrates, diuretics, and angiotensin-converting enzymeinhibitors[3] Decreased blood volume: blood loss[4] Dehydration: vomiting, diarrhea, excessive sweating, andAddison’s diseaseB. Drugs[1] Alpha blockers[2] Ganglion blockers[3] Bromocriptine[4] L-Dopa[5] NifedipineC. Neurogenic decrease of autonomic activity[1] Bedrest[2] Neuropathies and diabetes[3] Shy-Drager syndrome[4] Idiopathic causes3. Cerebrovascular diseaseA. Transient ischemic attackB. Subclavian stealC. Basilar artery migraineD. Cervical arthritis, atlanto-occipital dislocation, compression of thevertebral artery4. Situational causesA. Cough, sneeze, micturition, and defecation5. Other causesA. Drugs or alcoholB. HypoglycemiaC. HypoxemiaD. HypoventilationE. Hysterical reaction6. Unexplaineda No electrical or structural heart disease.experience loss of consciousness for a period of seconds orminutes without residual weakness in the limbs andwithout the precipitating factors mentioned above shouldconsult a physician to check for the possibility of abnormalheart rhythms.1. BradyarrhythmiasThere are several causes for bradyarrhythmias (slow heartrate). Sinus node dysfunction is one of them. This is a

584SYNCOPEdisease where there is failure of the sinus node pacemaker.Sick sinus syndrome is a common cause of syncope orpresyncope, and attacks of syncope may occur withminimal warning, a couple of seconds, or without warningresulting in injuries. A Holter monitor and ambulatoryrecord of the ECG for 24–48 h may reveal heart rates ofless than 36 beats per minute or sinus pauses with noheartbeat for 5–10 seconds. A pacemaker is required tomanage this problem.Bradyarrhythmia also occurs with disease of theatrioventricular conducting bundles that carry the electricalcurrent from the AV node to the ventricular muscle. Thismay be caused by degenerative disease or other disorders,and failure of conduction may result in complete heartblock and heart rates of less than 36 beats per minute orno beats for several seconds, which results in loss ofconsciousness (Stokes-Adams attacks).The long QT syndrome is an important cause ofsyncope to be recognized in patients between the age of5 and 20. Children and young adults with mysteriousfainting episodes are often misdiagnosed as having epilepsyor simple fainting that may culminate in sudden death.These syncopal episodes are usually caused by a tachyarrhythmiasuch as torsades de pointes (form of ventriculartachycardia), which is transient and reverts back to normalrhythm. A family history positive for fainting spells orunexplained sudden death is often present. Episodes maybe precipitated by stress, anger, fright, thunder, a siren,a telephone ringing, a clock alarm, and vigorous exertion.This condition is diagnosable only by an ECG, which isa simple inexpensive test that shows prolongation of theQT interval. The use of a continuous loop event recordermay be required.2. TachyarrhythmiasVery rapid heart rates (160–230 beats per minute) may becaused by ventricular or supraventricular tachycardiaresulting in syncope.3. Valve DisordersTight mitral valve stenosis or a left atrial myxoma (tumorclose to the mitral valve orifice) that obstructs the passageof blood from the left atrium to the left ventricle fillingmay cause syncope, albeit rarely. Patients with mitral valveprolapse occasionally present with syncope.Obstruction of blood flow from the left ventricle intoaorta may be caused by tight aortic valve stenosis orhypertrophic cardiomyopathy. When syncope occurs dueto aortic valve stenosis failure to correct the condition byvalve replacement results in a survival of approximatelythree years from onset of syncope. Syncope occurs in morethan 25% of patients with hypertrophic cardiomyopathy(see the chapters Cardiomyopathy and Valve Disease).4. Other DisordersBrugada syndrome is characterized by a typical ECGpattern of right bundle branch block with typical features(see the chapters Bundle Branch Blockand BrugadaSyndrome). Arrhythmogenic right ventricular dysplasia isa rare condition that causes syncope and may cause suddendeath. The electrocardiographic manifestation is T waveinversion in leads V1 through V3.Subclavian steal syndrome is an occlusive atheromatousdisease of the subclavian artery proximal to the origin ofthe vertebral artery. It may cause dizziness and syncope.Upper extremity exercise causes blood to be shunted fromthe brain through the vertebral artery to the distal subclavianartery beyond the blockage. The loss of blood fromthe cerebral circulation induces symptoms of cerebralischemia. This syndrome is suggested by the finding ofdiminished blood pressure in the affected arm, and theinduction of symptoms by exercise of the affected arm andforearm also produces symptoms.III. DIAGNOSTIC EVALUATIONA. Detailed History and Physical ExaminationA detailed relevant history of the event taken by an astutephysician and a thorough cardiovascular and neurologicexamination (if needed) is absolutely necessary. This mayreveal the diagnosis of reflex-mediated syncope in morethan 95%, orthostatic hypotension in 99%, detection ofcardiac abnormalities in more than 90%; and a neurologicdisorder in more than 90% of patients. The occasional caseof sinus node dysfunction may remain undetected andwill require further investigation. With accurate diagnosis,costly investigations may be avoided in more than 85%of patients. An algorithm for the assessment of syncope isgiven in Fig. 1. Table 3 gives clinical features suggestive ofspecific causes of syncope.B. Electrocardiography and Holter MonitoringIn individuals where a cardiac problem is suspected theECG with a rhythm strip may reveal the diagnosis in 5%and give a presumptive diagnosis in a further 5%. This testis inexpensive and is a necessary initial step. A 24- to 48-h

III. DIAGNOSTIC EVALUATION585NoObvious cardiac cause?YesTABLE 3Clinical Features Suggestive of Specific CausesPostural hypotension?No80%Vasodepressor 35%(vasovagal)Cerebrovascular 2%Situational 1%Others 7%DrugAlcoholHypoglycemiaHypoventilationHypoxemiaUnexplained35%*NoDrug?Yes10%Holter monitoring may help to exclude arrhythmias, butthe arrhythmia detected may not be the cause of syncope.Because episodes may only occur once a week or oncea month, the recording may be done when the patient isasymptomatic. This test is helpful in patients with sinusnode dysfunction, but when the test is negative furtherinvestigations are required.C. Event Recorders10%*See Table 1Decreased preload?Event recorders are small portable ECG recording devicesthat can be worn continuously and activated by the patientto record a rhythm strip immediately following an episode.The loop recorder can be activated immediately afterthe syncopal episode and the ECG recording of the events2–5 minutes earlier and 30–60 seconds after the episodeis taped for interpretation. Approximately 15% of patientswith frequent recurrent syncope have arrhythmia detectedthrough loop monitoring.A continuous loop event recorder carried for extendedperiods allows both retrospective and prospective ECGrecording. It is preferred because other types of eventrecorders records only when activated by the patient.Patients with unexplained syncope with injuries thatoccur only once or twice a year and negative ECG andelectrophysiologic (EP) testing present diagnostic problemsthat may be resolved by an implantable event recorder. Thisrecorder incorporates two electrodes within its containerYesNo Yes No YesNeurogenic Alpha blockersGanglion blockersL-dopaVenous pooling?Dehydrationor blood lossPreloadreducingagentsNitratesDiureticsACE inhibitorsAlgorithm for the assessment of syncope. *ApproximateFIGURE 1incidence. ACE ¼ angiotensin-converting enzymes. (Redrawn from Khan,M. Gabriel, Heart Disease Diagnosis and Therapy: A Practical Approach,second edition, New Jersey: Humana Press, 2005).Symptom or findingAfter suddenunexpected pain,unpleasant sight,sound, or smellDuring or immediatelyafter micturition, cough,swallow, or defectionWith neuralgia(glossopharyngeal or trigeminal)On standingProlonged standingat attentionWell-trained athleteafter exertionChanging position(from sitting to lying,bending,turning over in bed)Syncope with exertionWith head rotation, pressureon carotid sinus(as in tumors, shaving,tight collars)Associated with vertigo, dysarthria,diplopia, and other motor andsensory symptoms of brainstem ischemiaWith arm exerciseConfusion after episodeimplanted in the subcutaneous tissue of the chest that canbe used for approximately one year.D. EchocardiographyDiagnostic considerationVasovagal syncopeSituational syncopeBradycardia orvasodepressor reactionOrthostatic hypotensionVasovagal syncopeNeurally mediatedAtrial myxoma, thrombusAortic stenosis,pulmonary hypertension,pulmonary embolus,mitral stenosis,idiopathic hypertrophicsubaortic stenosis,coronary artery disease,neurally mediatedCarotid sinus syncopeTransient ischemic attack,subclavian steal,basilar artery migraineSubclavian stealSeizureFrom Kapoor WN: Syncope and hypotension (1997). In Braunwald E(ed): Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed.Philadelphia: W.B, Saunders, p. 868.Echocardiography is a common test, but the yield ispoor. It is used to verify severe aortic stenosis, severe mitralstenosis, hypertrophic cardiomyopathy, and left atrialmyxoma that cannot be diagnosed by other methods.Careful echocardiographic examination of the right ventriclemay reveal features of arrhythmogenic right ventriculardysplasia.

586SYNCOPEE. Electrophysiologic TestingEP testing is invasive, expensive, and rarely required. Thistest is reserved for patients with structural heart disease andsyncope that is unexplained after a careful history andphysical examination, ECG, echocardiography, Holtermonitoring, and continuous loop event recording. EPtesting is used mainly to verify the diagnosis of ventriculartachycardia. It may also be helpful in diagnosing sinusnode dysfunction in which doubt still exists after otherinvestigations. But it can miss this diagnosis. This test isrecommended also for the diagnosis of supraventriculartachycardia, but this disorder is benign and rarely leads tosudden death or injuries and the diagnosis may beestablished by less expensive investigations. More than21% of patients with negative EP studies are subsequentlydiagnosed as having intermittent, high-degree AV block orsinus node dysfunction. An EP study is not a sensitive testmeant to expose symptomatic bradycardia.F. Stress TestExercise and echocardiographic stress testing are not usefulin patients with ischemic heart disease in the absence ofsevere angina, because these individuals rarely present withsyncope.G. Tilt-Table TestingThis is a much abused test. It gives diagnostic evidence thatindicates susceptibility to neurally mediated syncope, forexample, vasovagal syncope (the simple faint). Astutephysicians using a carefully taken medical history andphysical examination should be able to make the correctdiagnosis in more than 95% of cases of vasovagal syncope.Tilt-table testing may help establish the diagnosisof neurally mediated syncope, but false-negative andfalse-positive results are common. This test may be ofsome value in patients with unexplained syncope in theabsence of structural heart disease and in patients who havesustained injuries.Tilt-table testing is expensive and nonspecific. This testcan also cause harm and its complications includehypotension and minor degrees of cardiac asystole, whichcan be occasionally prolonged resulting in cerebraldamage. Several deaths have also been reported. It is notlogical to perform this test to verify the diagnosis ofa benign condition that can be diagnosed with a carefulhistory and physical examination. There is a case report ofa surgeon who had a syncopal episode while performingsurgery and during the tilt test had a stroke.IV. MANAGEMENTA. Neurally Mediated SyncopePrecipitating factors for neurally mediated syncope shouldbe identified and eliminated. A moderate increase in saltintake causes improvement. Reconditioning is the cornerstoneof therapy in this benign condition. Exercises suchas the proper use of the muscle of the legs done dailyor standing upright against a wall for 30 minutes daily for3–4 weeks then 15 minutes 3 days weekly strengthen theautonomic system.If the condition recurs and the diagnosis is confirmed,drug therapy may be warranted. Beta-blocking agents suchas propranolol, metoprolol, or timolol may be triedjudiciously at small doses. There is no definitive, wellcontrolledanalysis of the efficacy of beta-blocking agentsin patients with recurrent vasovagal syncope.Two randomized controlled trials studied 50 patientsand 30 patients, respectively, and showed that propranolol,metoprolol, and atenolol were no more effective thanplacebo. Follow up was one year in one study and threemonths serially for propranolol, nadolol, and placebo inthe second study. There are many anecdotal reports andshort, nonrandomized trials that claim some benefit.Fludrocortisone, 0.1–0.2 mg daily, in combinationwith increased salt intake of greater than 3 g daily incombination with a beta-blocking drug is often effective.Serotonin reuptake inhibitors or midodrine are last resorts.Treatment with drugs is usually targeted to patients wheresyncope is recurrent without a protective warning andassociated with physical injury. A double-blind studyshowed that pacemaker therapy was no better than placebofor preventing recurrent vasovagal syncope.B. Orthostatic SyncopeDiscontinuation of drugs that cause orthostatic hypotensionor volume depletion such as diuretics andvasodilators is necessary. Autonomic neuropathies and autonomicfailure may respond to increased sodium intakeand fludrocortisone. Autonomic failure causing orthostatichypotension can be managed in properly selected patientswith midodrine, a selective postsynaptic alpha-1 adrenergicagonist. Salutary effects are caused by an increase in arterialand venous tone because venous pooling is prevented.C. Transient Ischemic AttackSyncope occurs in approximately 7% of individuals withtransient ischemic attacks (TIA). An attack that involves

IV. MANAGEMENT587Sensation of fainting?Is structural heart disease present?YesNoYesNoDecreasedcerebralperfusionSee Figure 1Spinning?YesNoVertigo? Imbalance?Injuries and no prodrome?EP studies Yes NoYesYesNoPositiveNegativeNa intakeVestibular+ConnectionsInjuries and no prodrome?Trial beta blocker,fludrocortisone, ordisopyramideVisionProprioceptionGait ataxiasNeuropathies“Dizzy feet”Vague lightheadednessFIGURE 2 Algorithm for evaluating patients with dizziness. (Redrawnfrom Khan, M.G. (1996). Heart Disease Diagnosis and Therapy: APractical Approach, Baltimore: Williams & Wilkins, p. 533.)YesConsider digitalelectrocardiaogramor “loop recorder”NoConsider beta blockerControlNothe vertebral -basilar artery causes characteristic symptoms— vertigo, diplopia, ataxia, and the loss of postural tonein the legs — that may mimic syncope.YesEitherNoControlYesD. Cardiac Causes1. TachyarrhythmiasSustained ventricular tachycardia with a duration of greaterthan 3 seconds or symptomatic nonsustained ventriculartachycardia commonly causes presyncope or syncope.Amiodarone can be used in patients with structural heartdisease, but an implantable cardioverter defibrillatormay be necessary. Supraventricular tachycardia with fastventricular rates (150–230 beats per minute) like in Wolff-Parkinson-White syndrome may cause syncope, andablation therapy usually produces salutary effects.2. BradycardiaBradycardia caused by sick sinus syndrome requiresremoval of drugs such as beta-blockers and digoxin asthey slow sinus node activity. A pacemaker is probablynecessary. Obstruction to intracardiac blood flow causedConsiderhead-up tilttesting*FIGURE 3 Algorithm for the management of unexplained syncope.*Use is abused; may not assist further with therapeutic strategies and is notwithout dangers of cortical damage. EP ¼electrophysiologic. (Redrawnfrom Khan, M. Gabriel, Heart Disease Diagnosis and Therapy: A PracticalApproach, second edition, New Jersey, Humana Press, 2005.)by severe aortic stenosis, mitral stenosis, or left atrialmyxoma requires surgical correction.E. Unexplained SyncopeFigure 2 gives an algorithm for the management ofunexplained syncope. Patients who have unexplainedsyncope without a few seconds of prodrome may sustaininjuries and require intensive investigations, as indicatedin Fig. 2.

588SYNCOPEBIBLIOGRAPHYCalkins, H., and Zipes, D. P. Hypotension and syncope. In Heart Disease,sixth edition. E. Braunwald, ed. W. B. Saunders, Philadelphia, 2001.Connolly, S. J., Robert Sheldon, Kevin, E. Thorpe. et al. For the VPS IIInvestigators. Pacemaker therapy for prevention of syncope in patientswith recurrent severe vasovagal syncope. Second vasovagal pacemakerstudy. JAMA, 289:2224–9, 2003.Flevari, P., Efthimios, G., Livanis, M. D. et al. Vasovagal syncope:A prospective randomized crossover evaluation of the effect ofpropranolol, nadolol and placebo on syncope recurrence and patientswell being. J. Am. Coll. Cardiol., 40:499–504, 2002.Kapoor, W. N. Is there an effective treatment for neurally mediatedsyncope? JAMA, 289:2272–2275, 2003.Kapoor, W. N. Syncope. N. Engl. J. Med., 343:1856–62, 2000.Khan, M. G. On Call Cardiology. Second edition. W. B. Saunders,Philadelphia, 2001.Madrid, A. H., Ortega, J., Rebollo, J. G. et al. The efficacy of atenololfor the prevention of neurally mediated syncope in a highlysymptomatic population: A prospective double-blind randomizedplacebo-controlled study. J. Am. Coll. Cardiol., 37:544–9, 2001.Maisel, W. H., and Stevenson, W. G. Syncope — getting to the heart ofthe matter. N. Engl. J. Med., 347:931–33, 2002.Moss, A. J., Schwartz, P. J. et al. 25th Anniversary of the internationallong-QT syndrome registry: An ongoing quest to uncover the secrets oflong-QT syndrome. Circulation, 111:1199–1201, 2005.Salim, M. A., Di Sessa, T. G. et al. Effectiveness of fludrocortisoneand salt in preventing syncope recurrence in children: A double-blind,placebo-controlled, randomized trial. J. Am. Coll. Cardiol., 45:484–488, 2005.

Tests for Heart DiseasesI. ElectrocardiogramII. Exercise Treadmill Stress TestIII. Chest X-RayIV. EchocardiogramV. Holter MonitorVI. Nuclear ScansVII. Coronary Arteriography/Cardiac CatheterizationVIII. Coronary Calcium EvaluationIX. Cardiovascular Magnetic Resonance Imaging/Magnetic Resonance AngiographyGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma:medical term for a heart attack or coronary thrombosis.I. ELECTROCARDIOGRAMAn electrocardiogram (ECG) at rest in patients with anginais often normal but can show signs of chronic oxygen lack(ischemia) or an old scar of a healed heart attack (myocardialinfarct). It may also show disturbances of the heartrhythm, that is, premature beats and electrical disturbancesas well as heart enlargement. An ECG is a valuable test forpatients with heart disease, but a normal ECG does notmean that the individual does not have angina coronaryartery disease (CAD).A resting ECG may show the following abnormalities:An acute heart attack in patients with chest pain; anECG is still the most important test used for thediagnosis of a heart attack An old heart attack, which has caused a residual scar inthe heart muscle Acute oxygen lack in patients with unstable angina Chronic ischemic changes due to oxygen lack orchanges that indicate that the left ventricle is workingunder strain (see chapter entitled Angina) Electrical disturbances such as blocks in the electricalbundles, called right or left bundle branch block orheart block (see chapter entitled Bundle Branch Block) Ventricular premature beats and a variety of abnormalheart rhythms that cause palpitations (see the chapterArrhythmias). Enlargement of the left or right ventricle and the leftatrium (see chapter entitled Hypertension) A very weak area or bulge of the heart muscle(aneurysm) A very slow heart rate, which may indicate disease of thesinus node generator (pacemaker)If a prior ECG is available, a comparison in pattern ismost useful. Therefore, it is wise for heart patients who aretraveling outside the country or state to carry a copy oftheir ECG while they travel. This may prevent any delayin emergency rooms and hasten discharge from thehospital. Several other disturbances are appreciated by aresting ECG such as potassium and calcium lack or excess,digoxin toxicity, pericarditis, athlete’s heart, and muscleproblems. Despite the advent of sophisticated and veryexpensive cardiologic tests, the inexpensive ECG retains itsusefulness as the only reliable test used for the diagnosis ofacute myocardial infarction, arrhythmias, and pericarditis,and it is a rapid screening test for myocardial ischemia.This test can also indicate the presence of a new or oldheart attack (see the chapter Electrocardiography).II. EXERCISE TREADMILL STRESS TESTAn ECG done during exercise (stress test) usually helpsto confirm the diagnosis of angina and can be used forfuture reference to detect the progression of coronaryartery disease. Treadmill test using the Bruce protocol is589

590TESTS FOR HEART DISEASESvery helpful in selecting patients for percutaneous coronaryintervention (PCI; coronary angioplasty/intracoronarystent) or bypass surgery. A negative test in an individualwho has completed 9 minutes or more of the Bruceprotocol and achieved more than 85% maximal heart rateusually indicates the absence of significant obstructivecoronary artery disease. Other aspects of the stress test arediscussed in the chapters Exercise and the Heart andWomen and Heart Disease.III. CHEST X-RAYA chest x-ray is usually normal in patients with angina butalways abnormal in patients with heart failure. It is oftenabnormal in those with significant valvular disease, heartmuscle disease, and congenital heart disease. It is themost important confirmatory test for the diagnosis ofheart failure and indicates the extent of acute heart failureor pulmonary edema.IV. ECHOCARDIOGRAMThe echocardiogram is a painless, noninvasive diagnostictechnique that utilizes ultrasound. It gives the cardiologista superb, simple, no-risk evaluation of the valves of theheart, the heart muscle, the force contraction of the heartmuscle, and the determination of the ejection fraction.The size of each chamber can be measured and enlargementof the heart muscle can be easily defined.Because the muscle contraction can be visualized,echocardiography is used in some patients after an acuteheart attack to detect special complications. In patientswith angina, an echocardiogram may show areas of abnormalleft ventricular wall motion abnormalities. This test ismost useful in patients with pericarditis because it detectswater accumulation around the heart (pericardial effusion).Transesophageal echocardiography (TEE) is crucial for thediagnosis and management of infective endocarditis (seethe chapter Echocardiography).V. HOLTER MONITORThe Holter monitor is utilized to detect abnormal heartrhythms in patients with coronary heart disease and othertypes of heart disease.[ See Electrocardiography ]Themonitor, about the size of a paperback book, records acontinuous electrocardiogram for 24 h. The instrument isstrapped to the waist, and the patient returns home andcarries out all normal activities, as well as sleep. After 24 h,the machine is returned to the doctor’s office or hospital.The tape is played and a recording is made. The tracings isassessed for the number of premature beats (extra beats)that occurred during this period and whether the abnormalbeats require treatment. This test is requested whenpatients complain of palpitations with or without fainting,when the doctor detects premature beats with thestethoscope, or sees such disturbances of rhythm onthe ECG. Important diagnoses obtained from assessmentof ambulatory electrocardiographic recordings include theextent of ventricular premature beats, atrial prematurebeats, supraventricular tachycardia, the presence of atrialfibrillation and ventricular tachycardia, and bradycardiacaused by sinus node dysfunction that may indicatethe requirement of a pacemaker (see chapter entitledHrrhythmias/Palpitations and the chapter entitledPacemakers).VI. NUCLEAR SCANSThe thallium or other radioisotope scan is useful inselected patients with angina to show the areas of the heartmuscle that are poorly perfused with blood. This techniqueis simple and painless. During an exercise stress test,usually on the treadmill, a known minute amount ofradioisotope, thallium-201, is injected into a vein. Theisotope reaches the heart and is distributed through thecoronary arteries. The areas of the heart muscle that are notreceiving adequate blood flow because of blockage of thecoronary arteries will receive less thallium, and these areasare assessed by special scanners.Errors in method and interpretation limit the usefulnessof this test. It is not sufficiently sensitive or specific forcoronary heart disease. Nuclear scans are expensive andtime-consuming, and the information gained is often notsufficiently accurate. Health-care costs can be contained ifsuch tests are limited. These tests should be done onlywhen treatment decisions can be appropriately altered bytheir results.Single photon emission computerized tomography(SPECT) uses a scanner plus tomography. Other radioisotopes(e.g., Tc-99 m sestamibi) have replaced thalliumin several laboratories, and SPECT complements exercisetreadmill stress testing.Positron emission tomography (PET) is an extremelyexpensive test. The advantages over SPECT need to bedetermined by studies to justify the high cost. ThePersantine rubidium stress test is appropriate in patientswho are unable to perform an exercise treadmill test andwalk sufficiently to achieve more than 85% maximalheart rate.

VII. CORONARY ARTERIOGRAPHY/CARDIAC CATHETERIZATION591Nuclear scans give only clues to the presence of cardiacdisease and have limited value in making decisions thatrelate to the choice of treatment for the patient. Falsepositivetests are common. In most instances the cost ofthese tests is not justifiable. If the ECG is normal in apatient with unstable angina a nuclear scan would behelpful. If a patient can do 9 minutes on an ECG treadmilltest using the Bruce protocol, or can achieve more than85% maximal heart rate without manifesting signs ofischemia, then a nuclear scan is not expected to addvaluable information that will alter treatment strategies.Nuclear cardiac imaging is widely performed, but the testis limited by a variable sensitivity and specificity andunfortunately exposes the patient to a very high radiationexposure. Additionally, the test is a time-consumingprotocol.Another relatively noninvasive test that gives a goodestimation of how much blood the heart ejects with eachbeat (ejection fraction) is the gated cardiac scan. With eachbeat the normal heart expels at least 50% of the bloodcontained in each ventricle. The percentage ejected iscalled the ejection fraction (EF) and it is one of the bestindicators of the efficiency and strength of heart contraction.Normal EF is between 50 and 75%.The EF is one of the most important measurementsused by the cardiologist to judge the strength or functionalcapacity of the heart. It is accurately measured duringcoronary arteriography, and with a similar degree of accuracy,it can be determined with the gated cardiac poolstudy. In this test a radioisotope, technetium, is injectedinto an arm vein. The isotope then binds to red blood cellsand reaches the chambers of the heart. The left ventricle iswell seen with sophisticated scintillation cameras and thedata is processed by computer. The force of contractionand the motion of the heart muscle wall is visualized ona video screen. If the muscle is contracting poorly orcontracting abnormally, as might be expected with ananeurysm, this can be detected in many cases. This testdoes not show structure inside the heart. Visualization ofstructures such as valves inside the heart and an ejectionfraction can be obtained with an echocardiogram. Theechocardiogram is used more often, but a gated scan ismore accurate for EF measurement.VII. CORONARY ARTERIOGRAPHY/CARDIAC CATHETERIZATIONA. HistoricalCardiac catheterization is probably the greatest technologicinnovation provided to cardiologists. It is often the finaldiagnostic test used to establish the diagnosis prior tocardiac surgical operations. Caude Bernard was the first toperform the procedure in 1844, and he is responsible fornaming it cardiac catheterization.Very little was made of the procedure until 1929 whenForssmann, a surgical resident in Germany, exposed avein in his left arm and threaded a ureteral catheter into theright atrium. He recorded this insertion with a chest x-ray.The physiologic use of the procedure had clinical applicationsbut was not actively pursued until Cournandarrived at Bellevue Hospital in New York in 1936 andbegan intensive studies and experimentation with the procedure.His work with others through 1945 improved thetechnical aspects and developed a double-lumen catheter.The late Sir John McMichael, motivated by Cournand’sgroup, introduced cardiac catheterization into the UK.Left heart catheterization was accomplished in 1950 byZimmerman who inserted a 6F catheter devised byCournand into the exposed ulnar artery in the forearm.Mason Sones deserves the credit for developing thetechnique of selective coronary arteriography in 1958.The Sones technique utilizes an antecubital incision overthe brachial artery that is exposed, and the catheter isthen inserted and passed to the aortic root and up to thecoronary orifices. This technique avoids aortoiliac diseasebut requires an arteriotomy and, finally, arterial closure.Seldinger accomplished a percutaneous insertion techniquethat avoids exposure of an artery. This techniquewas mastered and propagated by Judkins in 1967. Thistechnique introduced the catheter into the unexposedfemoral artery in the groin. This procedure is used todayfor coronary arteriography. It is interesting that Judkinswas a family physician assigned to a military post thatneeded urologists. Judkins was fascinated with ureteralcatheters. He spent a year in Sweden with one of theleading vascular radiologists and subsequently developedthe Judkins technique of coronary arteriography.B. Technique for Cardiac CatheterizationCoronary ArteriographyPrior to undergoing this technique, the patient is usuallyadvised not to eat solid food after midnight on the dayof the examination. Fluids are allowed up to one hourprior to the procedure. The patient is sedated with 5 mg ofdiazepam (Valium) given orally. The procedure is carriedout in a cardiac catheterization laboratory under sterileconditions. The most common sites for inserting the wireor hollow plastic catheter are in the femoral artery locatedin the groin or the artery in the arm at the elbow. Thesesites are preferred because the blood vessels are large andclose to the skin surface.

592TESTS FOR HEART DISEASESThe pulsation of the artery is easily felt and the skin isinjection with anesthetic. When the skin is frozen andpainless, a needle followed by thin wires is used to introducethe catheter into the artery ( Judkins technique)without exposing or incising the artery as is done with theSones technique (the Sones technique was used mainlyfrom 1966 to 1975). The catheter is then guided into theaorta and then into the cavity of the left ventricle. Thecatheter position is visualized at all times with the aid of anx-ray fluoroscope, which shows the catheter on a screen.The same technique is utilized for performing coronaryarteriography (angiograms) or for studying the heart valvesand pressures inside the heart chambers.The catheter is introduced and passed under x-rayguidance to the aorta and finally to the area where theaorta leaves the heart (aortic root). At this point, thecoronary arteries usually branch from the aorta, andthe catheter is directed into the left and then the rightcoronary artery. A dye is injected and can be visualizedby means of several x-rays taken in different planes. Thex-rays will show the heart and arteries including the normalones or ones with blockage by plaques of atheroma (see thechapter Atherosclerosis/Atherothrombosis). Any blockagein the coronary artery is clearly visualized. Coronaryarteriography is a relatively safe procedure in experiencedhands when done in well-equipped laboratories. Mortalityis less than 0.05% and minor complications are rare.Because the procedure is not without complications, thetest must be justifiable and the patient must be aware ofthe associated risks. Patients are usually very keen to havethe procedure because they understand it is the only wayto know, without a doubt, the extent and severity of theircoronary obstruction. Angioplasty or surgery cannot bedone without first visually examining the vessels, which isdone with cardiac catheterization(an x-ray movie is madeand can be replayed during surgery to show the blockages).For coronary angioplasty, a specialized catheter is used.It has a double lumen and a small inflatable balloon atthe tip. The length of the balloon is about 2.5 cm andthe inflated diameter is 2–4 mm. The catheter is guidedinto the appropriate coronary artery to the obstructionpreviously visualized by coronary arteriography. Duringcoronary arteriography, dye that looks white on x-rayfilm (radio-opaque) is injected into a catheter positionedselectively in the right and the left coronary arteries.All patients undergoing coronary angioplasty or coronaryartery bypass surgery must have coronary arteriographyto show the cardiologist or surgeon the exact site ofblockage by a plaque of atheroma (see Fig. 1 in thechapter Coronary Artery Bypass Surgery). Arteriographycan be done several hours or days prior to PCI, surgery, orother procedures.C. IndicationsThe most important reason to have this test is the presenceof angina (see the chapter Angina) that interferes withlifestyle to such an extent that it is deemed unacceptable bythe patient and the physician. The majority of patientswith stable angina are able to live with the occasionaloccurrence of the fleeting chest discomfort that they knowwill be precipitated by a particular exertion or emotion.They realize that the pain does not damage the heartmuscle and that on stopping the precipitating activity,pain or discomfort disappears immediately or is quicklyrelieved by a nitroglycerin tablet. Such patients may learnto live with angina for 20 years and nothing else is done.Symptoms can be further improved in many by the use ofbeta-blockers and in some with the addition of an oralnitrate or calcium blocker. The combination of drugsgreatly reduces the occurrence of chest pain. In a fewpatients with stable angina, pain may occur daily and caninterfere with work or lifestyle. Despite the fleeting natureof the pain, the patient may not be satisfied to live withthis annoyance and may ask, ‘‘What else can be done?’’The doctor in many cases may suggest that a coronaryarteriogram be performed.Patients with unstable angina will need coronaryangiograms within a few weeks or months after theirpain has subsided. The majority of these patients will needto undergo coronary angioplasty or bypass surgery. Ifsurgery is contraindicated because of other medicalproblems or age, then there is little point to submit thepatient to the test.There are a few patients in whom the diagnosis ofangina is confusing, especially when symptoms of refluxesophagitis make the diagnosis difficult. Coronary arteriogramsmay be necessary to unravel the mystery and preventpatients from becoming cardiac cripples.Again, the main reason for having a coronaryarteriogram is to show what part of the coronary arteryis blocked and to what extent, so it can be determinedwhether the individual is a candidate for PCI or coronaryartery bypass surgery (see the figures in the chapterCoronary Artery Bypass Surgery).Coronary arteriography remains the most importantmethod of defining the presence and severity of atherosclerosisof the coronary artery and it gives an assessmentfor valvular stenosis or regurgitation (see chapter entitledValve Diseases). This test also reveals the size and shape ofthe left ventricle, its ability to contract evenly and forcibly,and any problems with valves in the heart. More than onemillion coronary arteriograms are performed in the UnitedStates annually. The procedure is not painful, anddepending on the center, the patient is usually admitted

IX. CARDIOVASCULAR MAGNETIC RESONANCE IMAGING/MAGNETIC RESONANCE ANGIOGRAPHY593the night before, the tests are done the next day, and thepatient is discharged later that afternoon. In many institutions,facilities exist for a substantial number of patients tohave the test done during the day with discharge severalhours later if the condition is satisfactory.VIII. CORONARY CALCIUM EVALUATIONA. Electron Beam TomographyCoronary calcium scanning is available by electron beamtomography (EBT) multidetector scanners (MDCT) andmagnetic resonance imaging (MRI). Coronary CT scanscan detect and quantitate the presence of coronary arterycalcium deposits with ECG-gated images obtained witheither electron beam computed tomography (EBTC)or helical CT scanners. The entire test takes less than15 minutes to complete, but unfortunately exposes thepatient to a moderate amount of ionizing radiationequal to approximately 10–15 standard chest radiographs.EBTC is faster and more accurate for calcium scores thanspiral CT. Cardiac motion during imaging distorts CTimage density and calcium scores by spiral CT are generallyhigher than those from EBTC, thus potentially corruptingthe validity of a zero score. The EBTC uses an electronsweep of stationary tungsten target rings to generate x-rayimages that can detect small amounts of calcium withconsiderable accuracy, whereas helical CT uses a continuouslyrotating x-ray source.At the present time calcium scoring by spiral CT shouldnot be considered comparable to EBTC, especially becauseof the clinical connotation of a zero score. A total calciumscore of zero from EBTC should be highly predictive ofthe absence of obstructive coronary artery disease, butapproximately 90% of men and 70% of women age 60–75have coronary calcification that is nonspecific. Thus in thisage group the search for zero scores is an expensive one.The amount of calcium in the coronary arteriescorrelates to some degree with the amount of atheroscleroticplaque. The absence of calcium does not excludeplaque formation, however, because less than 50% ofplaques are calcified. The specificity of this test is poorwith less than 23% in men and less than 40% in women.In the age group where the tests could be most valuable(age 50–70), approximately 90% of men and 70% ofwomen have coronary artery calcification and it is impossibleto say if this means anything. EBTC is unlikely to beof value in young, asymptomatic individuals age 30–50who have no risk factors or in those with multiple riskfactors such as dyslipidemia, diabetes, hypertension,smoking, or strong family history of coronary arterydisease. Most important this test is not required in patientsat high risk for coronary events or those with multiple riskfactors, because these individuals require cardiac investigationsbeyond the estimation of calcium scores.EBTC adds little to the results of a clearly normal orclearly abnormal treadmill exercise test. If the treadmill testis equivocal, EBCT may have a role; in such individualsless than age 60 a negative EBCT (zero calcium score)probably indicates a noncardiac cause for symptoms or lowprobability risk for coronary events. If the test shows highcalcium scores then 20% of men and 40% of womenare expected to have significant coronary lesions. This lowspecificity presents a major obstacle for the developmentof a strategic algorithm.EBCT should be used in selected individuals only if theinitial stress test (treadmill stress test or stress plus nuclearimaging, pharmacologic stress test with nuclear imaging,echocardiographic stress test) results are equivocal or nondiagnostic.This test has been much abused and willcontinue to be misused at a high cost to patients, especiallyif it is used in the battery of (batter-selection, batch oftests) initial test in asymptomatic individuals or in low-tointermediaterisk patients. Additionally, this test is notindicated in patients with angina and in high-risk patientsor in those with multiple risk factors. An AmericanHeart Association Prevention V conference indicated thatindividuals of intermediate cardiovascular risk may beappropriate candidates for coronary calcium screening. Acalcium score of > 400 or above the 75th percentile for ageand gender generally represents a clinically significant positivetest, and it is suggested that these individuals should befurther investigated by exercise or nuclear stress tests.A recent task Force (#4, Wilson et al.) report states:Despite the lack of consistent recommendations, thecurrent practice by numerous physicians is to consider asignificant calcium score to warrant atherosclerosis thatmust be treated aggressively, as in the case a person withknown coronary artery disease. It will be several yearsbefore the results of the NIH-sponsored MESA arepublished. The study investigates the incremental valueof CT coronary calcium scores for prediction ofcardiovascular events over both standard and novelcoronary risk factors.IX. CARDIOVASCULAR MAGNETICRESONANCE IMAGING/MAGNETICRESONANCE ANGIOGRAPHYHigh-resolution cardiovascular magnetic resonance imaging(CMR) is providing major advances for atherosclerotic

594TESTS FOR HEART DISEASESplaque imaging and characterization. Various plaquecomponents such as the thickness of the fibrous cap,necrotic core, lipid composition, calcium, and otherparameters can be differentiated with CMR. The detectionof total coronary plaque burden is being evaluated instudies. CMR has the unique, but unproven, potentialto morphologically characterize the vulnerability ofatheromatous plaques. Use of CMR is likely the greatestpotential for future developments in the field.In a small study CMR was shown to accurately diagnose21 of 25 patients (84%) determined to have acutecoronary syndrome — a slightly higher level of sensitivitythan ECG criteria and blood enzyme levels. This testappeared to be more specific than an abnormal ECG inpatients with unstable angina and non-ST segmentelevation myocardial infarction. When available, CMRmay have a role in selected intermediate-risk patientsadmitted to the emergency room with acute coronarysyndrome not diagnosed by ECG and enzyme bloodlevels. The use of this expensive test, if it becomesavailable, should not be abused. Many patients presentingwith so-called acute coronary syndrome who turnout not to have significant unstable coronary arterydisease are discharged appropriately from emergencyrooms based on the history, clinical findings, ECG, andtroponin levels done on admission and 6 h later. Lessthan 1% of the large number of patients presentingwith chest pain with acute coronary syndrome who aresubsequently shown to have acute myocardial infarctionare discharged from emergency rooms without the eventdetected.A. Clinical Study: Kim et al.Study question: An accurate noninvasive technique forthe diagnosis of coronary artery disease would be animportant advance. The study’s authors investigated theaccuracy of magnetic resonance angiography (MRA)among patients with suspected coronary artery disease ina prospective multicenter study.Methods: MRA was performed during free breathing in109 patients before coronary angiography and the twodiagnostic procedures were compared.Results: A total of 636 of 759 proximal and middlesegments of coronary arteries (84%) were interpretedon MRA. In these segments 78 (83%) of 94 clinicallysignificant lesions (those with a greater than 50% reductionin diameter on angiography) were also detected byMRA. Coronary MRA had an accuracy of 72% indiagnosing coronary artery disease. The sensitivity andspecificity and accuracy for patients with disease of the leftmain coronary artery or three-vessel disease were 100%percent and 87%, respectively. The negative predictivevalues for any coronary artery disease, left main, or threevesseldisease were 81 and 100%, respectively. Themajority of individuals had a history of chest pain,hypercholesterolemia, and smoking, and 59% had angiographicevidence of coronary artery disease. The mean totalscanning time was 70 minutes.Conclusions: This noninvasive approach reliablyidentifies or rules out left main coronary artery orthree-vessel disease. MRA was unable to assess 16% ofcoronary segments and 6% of the study patients could notbe assessed for the presence of left main or three-vesseldisease.BIBLIOGRAPHYBudoff, M. J., Achenbach, S., and Duerinckx,A. Clinical utility of computedtomography and magnetic resonance techniques for noninvasivecoronary angiography. J. Am. Coll. Cardiol., 42:1867–1878, 2003.Fayad, Z. A., and Fuster V. The human high-risk plaque and itsdetection by magnetic resonance imaging. Am. J. Cardiol., 88:42E–5E,2001.Greeland, P., and Gaziano, M. C. Selecting asymptomatic patients forcoronary computed tomography or electrocardiographic exercisetesting. N. Engl. J. Med., 349:465–73, 2003.Haberl, R., Becker, A., Leber, A. et al. Correlation of coronarycalcification and angiographically documented stenoses in patientswith suspected coronary artery disease: Results of 1764 patients. J. Am.Coll. Cardiol., 37:451–7, 2001.Kim, W. Y., Danias, P. G., Stuber, M. et al. Coronary magnetic resonanceangiography for the detection of coronary stenoses. N. Engl. J. Med.,345:1863–9, 2001.Klocke, F. J., Baird, M. G., Lorell, B. H. et al. ACC/AHA/ASNCguidelines for the clinical use of cardiac radionuclide imaging–Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines forthe Clinical Use of Cardiac Radionuclide Imaging). Circulation,108:1404–1418, Sep 2003.Loscalzo, J., Bonow, R. O., Jacobs, A. K. et al. Coronary calciumscreening and the American Heart Association news embargo.Circulation, 110:3504–3505, 2004.Maceira, A. M., Joshi, J., Prasad, S. K. et al. Cardiovascular magneticresonance in cardiac amyloidosis. Circulation, 111:186–193, 2005.Maintz, D., Botnar, R. M., Manning, W. J. et al. Pitfalls in coronarymagnetic resonance angiography: Right coronary artery occlusion.Circulation, 111:e94-e96, 2005.Morin, R. L., Gerber, T. C., McCollough, C. H. et al. Radiation dosein computed tomography of the heart. Circulation, 107:917–922,Feb 2003.Redberg, R. F., Vogel, R. A., Criqui, M. H. et al. Task Force #3 — Whatis the spectrum of current and imaging techniques for the noninvasive

IX. CARDIOVASCULAR MAGNETIC RESONANCE IMAGING/MAGNETIC RESONANCE ANGIOGRAPHY595measurement of atherosclerosis? J. Am. Coll. Cardiol., 41:1855–917,2003.Rumberger, J. A. Electron beam tomography quantitation of coronarycalcium and assessment for ischemic coronary disease: A complementto stress testing. J. Am. Coll. Cardiol. ACC Curr. J. Rev., Nov/Dec,32–58, 2001.Wilson, P. W. F., Smith, S. C., Blumenthal, R. S. et al. Task Force #4 —How do we select patients for atherosclerosis imaging? J. Am. Coll.Cardiol., 41:1898–917, 2003.Wong, N. D. Detection of subclinical atherosclerosis: Implicationsfor evaluating cardiovascular risk. ACC Curr. J. Rev., March2004.

Thyroid Heart DiseaseI. High Thyroid (Hyperthyroidism)II. Low Thyroid (Hypothyroidism)III. Amiodarone-Induced Thyroid DysfunctionGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.heart failure failure of the heart to pump suction blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.I. HIGH THYROID (HYPERTHYROIDISM)A. SymptomsThe thyroid gland in the neck may suddenly becomeoveractive and secrete excessive amounts of the hormonethyroxine. This situation is common between age 20 and50; it can also occur later in life. Excessive thyroxinecauses increased metabolism of all tissues, therefore, weightloss can occur, despite a good appetite and food intake.Individuals feel nervous, anxious, irritable, and haveintolerance to heat. Shortness of breath, palpitations,tachycardia, and systolic hypertension are often observed.Other symptoms include the heart beating faster andcontracting more vigorously, and the pulse rate may be110–130 beats per minute at rest. Sinus tachycardia ispresent in more than 40% of patients and approximately15% develop transient atrial fibrillation followed bypersistent atrial fibrillation. In patients with heart diseaseand underlying left ventricular dysfunction, the extra workimposed on the heart by hyperthyroidism may precipitateheart failure. In patients with coronary artery disease, mildangina may be precipitated.B. Physical SignsThe thyroid gland may become slightly enlarged and abruit may be heard when the stethoscope is placed overthe gland. Protrusion of the eyeballs (exophthalmos) maybe pronounced and lid lag may be observed. The handsbecome warm and sweaty also. Sinus tachycardia, a hyperkineticcardiac apex, and a loud first heart sound may beaccompanied by soft flow murmurs.C. TreatmentTachycardia may require control with a beta-blocker untiltreatment with radioactive iodine causes destruction of thegland. Surgery is now rarely used.II. LOW THYROID (HYPOTHYROIDISM)A. Symptoms and SignsThis problem is common in the elderly but can occasionallyaffect individuals age 20 to 60. Lack of the hormonethyroxine causes weight gain; constipation; lethargy; sleepiness;a hoarse voice; dry, puffy skin; and intolerance tocold. Hypothyroidism or myxedema, causes bradycardia.The pathologic heart in severe myxedema appears pale,flabby, and grossly dilated. A pericardial effusion may bepresent and microscopic examination shows myofibrillarswelling and interstitial fibrosis. Cardiac enlargement, lowelectrocardiographic voltage, nonpitting facial and peripheraledema, and signs of congestive heart failure are nowrarely seen because of early diagnosis and treatment, butexertional dyspnea and easy fatigability are commonsymptoms.Patients who have hyperthyroidism treated with radioactiveiodine or surgery become hypothyroid after 10–20years and require treatment. Thus, hypothyroidism is a597

598THYROID HEART DISEASEcommon condition in the elderly. The disease can exist formany years before it is recognized by patients or detectedby physicians. A simple blood test, sensitive TSH, rapidlyand accurately identifies patients who have hypo- andhyperthyroidism.Hypercholesterolemia and hypertriglyceridemia areoften found in patients with hyperthyroidism and is associatedwith development of premature coronary arterydisease. Treatment of the hypothyroid condition correctsthe lipid abnormalities.B. TreatmentPatients with hypothyroidism require replacement therapywith thyroxine, usually a dosage of 0.05–0.2 mg daily(50–200 mg).iodine. Abnormal thyroid function tests (low TSH andelevated T4) may be observed with the chronic use ofamiodarone, but they are often not associated with clinicalmanifestations of thyroid dysfunction.Hypothyroidism is precipitated in approximately 15%of patients on chronic amiodarone therapy as observedin the United States, the UK, and Europe. Hyperthyroidismis less common in these countries and is observedmore often in developing countries due to iodinedeficiency. The finding of weight loss, heat intolerance,and tremor should alert suspicion, but the first symptommay be a cardiac arrhythmia with rapid heartrate. The finding of a low TSH, an elevated T4, andan increased T3 is diagnostic of amiodarone-inducedhyperthyroidism.III. AMIODARONE-INDUCED THYROIDDYSFUNCTIONThe widespread use of amiodarone for the managementof cardiac arrhythmias is a common cause of thyroidabnormalities in patients with heart disease. Amiodaronehas structural similarities to T4 and T3 and is also rich inBIBLIOGRAPHYRipoli, A., Pingitore, A., Favilli, B. et al. Does subclinical hypothyroidismaffect cardiac pump performance? J. Am. Coll. Cardiol., 45:439–445,2005.Sleely, E. W., and Williams, G. H. The heart in endocrine disorders.In Heart Disease, a Textbook of Cardiovascular Medicine, sixth edition.E. Braunwald, D. P. Zipes, and P. Libby, eds. W. B. Saunders,Philadelphia, 2001.

Valve DiseasesI. MurmursII. Causes and Consequences of Valve DiseaseIII. Rheumatic FeverIV. Specific Valve LesionsV. Prosthetic Valve ChoiceGLOSSARYangina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstruction ofthe artery supplying blood to the segment of cells.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.murmur a blowing sound heard with a stethoscope usuallycaused by obstruction of heart valves or leaking valves.The loudness of a murmur depends on the velocityof blood flow, the amount of blood passing across thedeformed valve, and the turbulence that occurs. A cardiologist,using the simple stethoscope and without expensivetests, can tell if a murmur is significant. An echocardiogramconfirms this observation, but is often unnecessaryif the doctor is well trained in the use of a stethoscope. Theechocardiogram may display murmurs that are not significantand may create unnecessary worry for individuals.Murmurs are most commonly systolic in time; that is,they occur during the contraction of the ventricles. Manysystolic murmurs are not significant in that they do notdisturb the function of the heart. Murmurs that occurwhen the ventricles are relaxed, that is, during diastole, aretermed diastolic murmurs and are always of significance.Over a period of 5–50 years, significant murmursincrease the work of the heart muscle and cause it toenlarge. The muscle finally becomes weak and heart failureoccurs. When severe heart failure occurs, disability occurs.(see the chapter Heart Failure.)THE VALVES OF THE HEART (SEE FIG. 1) ARElike automatic doors, which open when people want topass through and stay shut when not in use. When bloodmust be expelled from the left ventricle into the aorta, theaortic valve, the main valve, opens. The texture of valvesis as smooth as silk, thus blood particles and bacteria donot adhere to them. Valves may be the site of disease,however, thus the term valvular heart disease.I. MURMURSWhen affected by disease, the soft heart valve tissue getsrough, thick, swollen, and hard. As blood rushes throughthe obstructing or damaged valves, turbulence occurs. Thisturbulence sets up vibrations that are louder than normaland can be heard easily with a stethoscope. The soundheard by the stethoscope is called a murmur (see thechapter Murmurs).II. CAUSES AND CONSEQUENCESOF VALVE DISEASEA. CausesDamage to heart valves is caused by: Rheumatic fever Infections such as bacterial endocarditis and syphilis;viral infections, though extremely common, are notknown to cause valve disease Mitral valve prolapse Degenerative diseases due to age changes, such ascalcific aortic sclerosis Congenital heart disease (see the chapter CongenitalHeart Disease) Complications of coronary artery disease and cardiomyopathy599

600VALVE DISEASESFIGURE 1p. 267.)Structure of the heart. (From Khan, M. Gabriel and Marriott, H. J. L. (1996). Heart Trouble Encyclopedia, Toronto: Stoddart Publishing,B. ConsequencesBacterial endocarditis may occur in patients with valvedisease. Complications due to blockage of the valve(stenosis) or backward leak (regurgitation or incompetentvalve) of blood may cause severe shortness of breath.Roughness of the valve may also extend into the chamberof the left atrium and set up electrical discharges. Thusarrhythmias such as premature beats, paroxysmal atrialtachycardia, and atrial fibrillation may occur.The major symptoms of serious valve disease areincreasing shortness of breath on mild exertion and onlying flat, cough, and occasionally blood-tinged sputum(hemoptysis). Finally, signs of heart failure occur. Theseinclude severe shortness of breath, edema of the legs, andwater in and around the lungs (see the chapter HeartFailure).A tight valve is medically called a stenosis, thus the terms‘‘mitral stenosis’’ and ‘‘aortic stenosis.’’ A leaky valve indicatesregurgitation of blood, and the two common lesionsare mitral regurgitation and aortic regurgitation. Thepulmonary and tricuspid valves are rarely affected exceptwhen due to congenital heart disease or infection causedby endocarditis as seen in drug addicts.III. RHEUMATIC FEVERA. Types of Valve DamageDamage to heart valves often occurs during an attackof rheumatic fever. Rheumatic fever is most commonbetween the ages of 5 and 25 and occurs in susceptibleindividuals after a beta-hemolytic streptococcal sore throat.The streptococcus bacterium sets up an allergic-like reactionon the valves and in the joints. There is usually feverand joint pains and murmurs are heard over the swollenheart valves. A blood test to show a reaction to the streptococcususually confirms the diagnosis.Fortunately, sore throats caused by this particular strainof streptococcus have become much less common and thedisease is disappearing from North America. It still persistsin third-world countries.

IV. SPECIFIC VALVE LESIONS601Not all individuals who get rheumatic fever developdamage to the heart valves. Those who have severe feverwith severe joint pains lasting several months may neverget valve damage. The opposite is most likely to occur;it appears that when rheumatic fever ‘‘licks the joints itspares the heart.’’ More than 40% of patients may notrecall having had an illness with fever and joint pains yettheir valves may be affected by minor streptococcalinfection.The mitral valve is affected most often followed by theaortic valve, causing conditions called mitral stenosis andregurgitation or aortic stenosis and regurgitation. Othervalves rarely get damaged by rheumatic fever or degenerativedisease.B. Prevention of Rheumatic FeverRheumatic fever tends to recur in the same individualbecause of a predisposition to the disease. In order toprevent recurrence, the following is advised:1. If rheumatic fever was properly documented, but thereis no evidence of significant valve damage, penicillin isusually given for a minimum of 5 years or to age 20,whichever is longest.2. If the heart valve was damaged, penicillin is given fora minimum of 10 years or to age 40, whichever is thelongest.3. Depending on the state or country, and the prevalenceof beta-hemolytic streptococci and rheumatic fever,some physicians continue treatment beyond age 40.The dose of antibiotic is usually penicillin V 250 mgtwice daily.4. If the patient is allergic to penicillin, sulfadiazine isas effective and is given 1 g once daily for adults and0.5 g daily for patients weighing less than 60 pounds.If penicillin V is not given, then 1.2 million unitsof benzathine penicillin G intramuscularly is givenmonthly.IV. SPECIFIC VALVE LESIONSA. Mitral Stenosis1. SymptomsThe silky, soft leaflets of the mitral valve become thickened,rough, and hard, and over a few years the orifice of thevalve becomes tight. Blood in the left atrium has difficultygetting through the mitral valve to reach the left ventricle(see Fig. 1). Patients with mild mitral stenosis have avalve area 1.6 to 2 cm 2 and may develop mild shortnessof breath on moderate-to-severe exertion, but lifestyle isnot altered. Symptoms progress slowly over 5–10 years.Shortness of breath may worsen suddenly because of chestinfection, pregnancy, and tachycardias (atrial fibrillationis a common complication).Patients with moderately severe mitral stenosis with avalve area of 1–1.5 cm 2 usually have symptoms that affector interfere with daily living. Shortness of breath caused byprogressive pulmonary venous hypertension and congestionof blood in the lungs become bothersome. Breathlessnessis precipitated by moderate activity such as brisklywalking 100 yards or walking up two flights of stairs.Cough, shortness of breath, wheezing, and hemoptysismay mimic bronchitis for several months because the subtlesigns of mitral stenosis can be missed by the untrainedphysician.Severe mitral stenosis with a valve area less than 1 cm 2usually causes bothersome symptoms such as progressiveshortness of breath, palpitations, marked fatigue, cough,hemoptysis, and hoarseness may occur during mildactivity. Chest pain may be the presenting feature, butprogression may be rapid with development of heart failuremanifested by bilateral leg edema and shortness of breathin bed (orthopnea). The patient may awaken from sleepand may need to sit at the side of the bed for severalminutes to get relief (paroxysmal nocturnal dyspnea).Progression to heart failure with life-threatening pulmonaryedema may be precipitated by pregnancy or atrialfibrillation, a situation in which the rapid beating of theheart does not allow proper filling of the ventricle becauseof the tightly obstructed valve.2. Physical SignsOn examination of the heart particular signs of mitralstenosis are usually present. The apex beat is tapping inquality and is not usually displaced except if concomitantmitral regurgitation or other valve lesions are present.A lower left parasternal heave may be seen or felt caused byright ventricle hypertrophy brought on by the pulmonaryhypertension. Auscultation reveals a loud slapping firstheart sound that is typical with an opening snap thatis followed by a low-pitched murmur, and a mid-diastolicrumble that is a characteristic of mitral stenosis. If sinusrhythm is present the murmur increases intensity justprior to the first heart sound. This is called presystolicaccentuation. This murmur is best heard with the bell ofthe stethoscope with the patient lying on the left side.3. InvestigationsChest x-ray shows straightening of the left heart border dueto enlargement of the left atrium. ECG shows left atrialenlargement. Echocardiography is diagnostic and tightness

602VALVE DISEASES(stenosis) of the valve can be graded as mild (1.6–2 cm 2 ),moderate (1–1.5 cm 2 ), or severe (

IV. SPECIFIC VALVE LESIONS603common cause of aortic stenosis in developing countriessuch as Asia, Africa, the Middle East, and Latin America.Diagnosis before age 50 is typical of congenital aorticstenosis. In patients above age 70 calcific aortic stenosisdue to degenerative calcification is common and severestenosis develops in up to 10% of these individuals. Thislesion is now the most common reason for aortic valvereplacement in the United States. A recent clinical trialindicates that the use of a statin decreases calcification andthe degree of stenosis, and it is highly recommendedtherapy prior to development of moderate aortic stenosis.2. SymptomsThe patient may remain relatively asymptomatic untilsevere stenosis develops. Shortness of breath is usually thefirst symptom. In aortic stenosis, the aortic valve (see Fig. 1)is tight and obstructs the flow of blood from the leftventricle into the aorta with less blood reaching the head.Symptoms such as dizziness, fainting (syncope), shortnessof breath, and chest pain (angina) may occur. The leftventricle tries to overcome the obstruction by pumpingmore forcefully, and over the years the muscle becomesthick and enlarges and finally fails to pump efficiently.3. Physical SignsA systolic crescendo–decrescendo murmur is best heardat the left sternal border, the second right interspace, oroccasionally at the apex with radiation to the neck. Severestenosis is indicated by a murmur that is louder and peakslate in systole. A palpable thrill may result and this isusually a thrusting apex beat caused by left ventricularhypertrophy. The carotid pulse in patients below age 65shows a typical delayed upstroke.4. InvestigationsThe severity of aortic stenosis can be determined by continuouswave Doppler echocardiography. This techniqueagrees with the data obtained at catheterization in up to90% of cases. Mild aortic stenosis is indicated by a meanaortic valve pressure gradient of less than 20 mmHg anda valve area greater than 1.5 cm 2 . Moderate stenosis isindicated by a mean pressure gradient of 21–39 mmHgand a valve area greater than 0.9–1.4 cm 2 . Severe aorticstenosis is indicated by a pressure gradient greater than40 mmHg (40–120 mmHg) and a valve area less than0.75 cm 2 .5. TherapySevere shortness of breath, chest pains, fainting spells,enlargement of the left ventricle, or heart failure areindications for surgery. During surgery the diseased valve isremoved and an aortic valve prosthesis is usually inserted.This is extensive surgery and is done only when justifiable.Any patient over age 45 may have concomitant coronaryheart disease and may require valve replacement as well ascoronary artery bypass graft.D. Aortic Regurgitation1. Natural History and SymptomsIn this condition the aortic valve remains widely openwhen it should be tightly closed, therefore, blood regurgitatesor leaks from the aorta backward into the leftventricle (see Fig. 1). The main symptom is shortness ofbreath. The left ventricle, however, tolerates regurgitantvolume overload and compensates adequately for severalyears. An asymptomatic 10- to 20-year period is common.Many patients with a moderate degree of aortic regurgitationdeny shortness of breath on walking 2–5 miles orclimbing three flights of stairs. Complaints of shortness ofbreath on exertion, fatigue, palpitations, and dizziness aregenerally associated with moderate-to-severe regurgitationor severe regurgitation of recent onset.2. Diagnostic Physical SignsThe radial and brachial pulses have a typical collapsingboundingcharacter in aortic regurgitation. The bloodpressure shows a wide pulse pressure with diastolicpressures often less than 50 mmHg. A typical high-pitchedblowing decrescendo murmur begins immediately afterthe second heart sound. It is unmistakable to the trainedear and is best heard with the diaphragm of the stethoscopepressed firmly against the chest with the patient leaningforward and the breath held in deep expiration.3. InvestigationsColor flow Doppler echocardiography provides quantificationof aortic regurgitation and dimensions of the leftventricle. Marked changes or rate of change at 6-monthlyassessments should guide the timing for surgery in symptomaticpatients with moderate-to-severe regurgitation.Relatively asymptomatic patients with moderate-to-severeregurgitation are not offered surgery because of the highrisks involved.4. TherapyThe left ventricle has more work to do with aorticregurgitation and over several years dilates and enlarges.Surgery is not often required because the left ventricle

604VALVE DISEASEScopes with the extra work for many years and drugs suchas nifedipine appear beneficial in delaying surgery inpatients with a moderate degree of stenosis. Leaking valvesimpose less work on the heart than obstructed valves.When heart failure occurs due to a leaking valve, digoxinand diuretics are helpful as well as vasodilators such asACE inhibitors. Surgery is required to replace the valvebefore heart failure occurs. The timing for surgery can bevery difficult to estimate and surgical intervention is notwithout risks.Prosthetic heart valve surgery is a major undertakingand careful assessment by a cardiology team is necessary.Post surgery, the patient may need to take anticoagulantsto prevent clotting of the valve. Warfarin is given if amechanical valve is used or if atrial fibrillation is present.A bioprosthesis is advised in patients over age 65, and noblood thinners are required with these valves.E. Mitral Valve ProlapseThis is a common disease. The mitral valve leaflets becomestretched and floppy with redundant folds. The valve isdamaged by a degenerative myxomatous process.1. Physical SignsWhen a patient has mitral valve prolapse, the doctor hearsthe valves flapping like a sail in a crisp wind. The noiseheard is typical and is called a click and murmur. Theclick can be similar to a loud tick of a clock or at times likea musical sound. The systolic murmur is typically late intiming.This condition is somewhat more common in females,and about 5% of individuals over age 25 have this clickand murmur, which is produced by the mitral valve.Middle-aged men, however, develop a more complicatedvalve disturbance.2. Symptoms and Natural HistoryMitral valve prolapse is a benign condition; less than 1 inevery 100 cases may have a problem. But many peoplebecome anxious and nervous about this problem as it hasbecome exaggerated by physicians. Panic attacks mayoccur. A few individuals may have palpitations consistingchiefly of premature beats that rarely cause faintingspells. Beta-blockers are very useful in this condition torelieve bothersome palpitations and faint-like episodes.Chest pain occurs in a few, but the condition is notrelated to coronary heart disease and there is no relationbetween the disease and heart attacks. In less than 1 in100 cases, the valve leaflet may weaken or get a redundantfold and cause regurgitation of blood. In suchpatients mild and sometimes severe mitral regurgitationmay occur.In the western world, severe mitral prolapse is the mostcommon reason for repair or replacement of the mitralvalve in men and women. In third world countries, rheumaticfever remains the most common cause for mitralvalve replacement.Infection of the valve causing bacterial endocarditisand further damage may occur, particularly if a murmur ispresent. Thus, prophylaxis with antibiotics is advisablebefore dental work and surgical procedures, otherwise thepatient, who can live to over age 80, may have an abruptshortening of life (see the chapter Endocarditis).V. PROSTHETIC VALVE CHOICEProblems exist with all types of valve prosthesis; none isideal. More than one million valves have been implantedworldwide.A. Mechanical ProsthesesCommonly used mechanical valves are shown in Fig. 2.The bileaflet and floating disk designs are most popularin North America. Mechanical valves are the first choicein patients less than age 70 because of they last longer.When a mechanical valve is used anticoagulation withwarfarin is necessary to prevent thromboembolism. Inmost patients with atrial fibrillation the valve implantchosen is a mechanical one because anticoagulation isindicated in both instances.B. Tissue ProsthesesBioprosthetic valves are the first choice in patients over age70 because these valves are expected to only last from 15to 20 years. Anticoagulation is not required with bioprostheticvalves except when anticoagulation is necessary forthe management of atrial fibrillation to prevent stroke.Xenograft tissue valves are shown in Fig. 3. The vastmajority of biologic valves (bioprostheses) implantedsince 1960 are stented xenografts. Several manufacturershave recently introduced stentless xenografts. These graftswere designed to improve hemodynamics by eliminationof the bulky stent and sewing ring. Currently it isunclear whether the durability of stentless xenografts issuperior to that of stented valves. The implantation ofstentless grafts is much more complex than stentedvalves; the necessary subcoronary technique has a potential

V. PROSTHETIC VALVE CHOICE605FIGURE 2 Mechanical prostheses. (A) The Starr-Edwards ball-in-cage prosthesis was popular for many years and demonstrated excellent durability(photo courtesy of Edwards Lifesciences, LLC). (B) The Hall-Medtronic single tilting disc prosthesis is the dominant single-disc valve in the United States(photo courtesy of Medtronic Corp.). (C) The St. Jude bileaflet design is the most popular mechanical prosthesis in this country at the current time (imageis provided courtesy of St. Jude Medical, Inc. All rights reserved). (D) The Carbomedics ‘‘top-hat’’ bileaflet design is designed to permis supra-annularimplantation (photo courtesy of Carbomedics, Inc.).FIGURE 3 Xenograft tissue valves. (A) The Medtronic Hancock Bioprosthesis is constructed from a porcine aortic valve (photo courtesy of MedtronicCorp.). (B) The Baxter Perimount (Registered trademark, Edwards LLC) valve was engineered to optimize hemodynamics and durability with leaflets madefrom bovine pericardium (photo courtesy of Edwards LLC). (C) The Medtronic Freestyle stentless xenograft may be implanted as a free-standing rootreplacement or using a subcoronary technique (photo courtesy of Medtronic Corp.). (D) The St. Jude Toronto SPV (registered trademark of St. JudeMedical, Inc.) stentless xenograft must be implanted using the subcoronary technique (photo courtesy of St. Jude Medical Inc.).

606VALVE DISEASESdisadvantage of predisposing the patient to aorticregurgitation. Perhaps because of these complexities andthe as yet unproven advantage, stentless valves continueto search for their appropriate place in valve replacementsurgery.Homografts have better long-term performancethan stented xenografts; however, they still have limiteddurability. Their use is hindered by limited availabilityand necessity for liquid glycogen storage. Their implantationis also more complex than that for stented valvesand the surgical technique is complicated similar toimplantation of stented xenografts. They do possessremarkable flexibility and are useful to accommodate forcomplex root pathology, particularly following bacterialendocarditis.BIBLIOGRAPHYBiancaniello, T. et al. Innocent murmurs. Circulation, 111:e20–e22, 2005.Enriquez-Sarano, M., Tajik, A. J. et al. Aortic regurgitation. N. Engl. J.Med., 351:1539–1546, 2004.Fish, R. D. et al. Percutaneous heart valve replacement: Enthusiasmtempered. Circulation, [Editorial] 110:1876–1878, 2004.Khan, M. Gabriel. In Heart Disease Diagnosis and Therapy: Valvular heartdisease, second edition. Humana press, New Jersey, 2005.Khan, M. Gabriel. Evaluation and treatment of patients with murmurs.In On Call Cardiology, second edition. W. B. Saunders, Philadelphia,2001.Otto, C. M., Salerno, C. T. et al. Timing of surgery in asymptomaticmitral regurgitation. N. Engl. J. Med., [Editorial] 352:928–929, 2005.Rahimtoola, S. H. et al. The year in valvular heart disease. J. Am. Coll.Cardiol., 45:111–122, 2005.Sundt, T. M. Current options for replacing the aortic valve in adults.J. Am. Coll. Cardiol. ACC Curr. Rev., January/February, 78–82, 2002.

Ventricular FibrillationI. Clinical FeaturesII. Genesis and CausesIII. ManagementGLOSSARYejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker ofventricular contractility.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.platelet aggregation clumping together of small particles in theblood; platelets increase clot formation.Wolff-Parkinson-White syndrome characterized by prematureexcitation of the ventricles due to an anomalous conductionbypass tract between the atria and ventricles; often leads torapid heart rates.I. CLINICAL FEATURESVentricular fibrillation (VF) results in sudden faintnessand loss of consciousness, cessation of respiration, anddeath. During VF the heart muscle does not contract but‘‘quivers’’; therefore, there is no heartbeat (cardiac arrest)and no blood is pumped out of the heart. Death occurswithin minutes if the abnormal heart rhythm is notcorrected. Ventricular fibrillation requires electrical countershockwithin three minutes to change this life-threateningrhythm to normal heartbeats. Cardiopulmonary resuscitation(CPR) must be instituted immediately to maintain ablood supply to the brain until a defibrillator is available,hopefully within a few minutes. Note that in atrial fibrillation,the atrium fibrillates but the ventricles contractnormally although faster than normal. This condition isusually not life-threatening and is easily controlled with thedigoxin or a beta-blocker and anticoagulants.More than 75% of patients resuscitated from out-ofhospitalcardiac arrest have VF. Occasionally VF ispreceded by ventricular tachycardia (VT). Figure 1 showsthe bizarre, irregular undulations of varying contour andamplitude. Distinct QRS complexes, ST segments, andT waves are absent and the irregular undulating baselineis diagnostic of VF.II. GENESIS AND CAUSESA. GenesisThe onset of VF is believed to involve the disintegrationof a single spiral wave into many self-perpetuating waves.It appears that the breakup of spiral waves is precipitatedby oscillations of action potential duration that are ofsufficiently large amplitude to cause conduction blockalong the spiral wavefront.Intracellular calcium accumulation, the action of freeradicals, metabolic alterations, and autonomic modulationare some of the factors that are associated with thedevelopment of VF during severe ischemia.B. Causes1. Coronary Artery DiseaseVF is observed in individuals with coronary artery diseaseand as a terminal event. VT commonly precedes the onsetof VF but often there are no consistent premonitorywarning signals observed. Approximately 75% of patientsresuscitated from VF have significant coronary arterydisease and acute myocardial infarction develops inapproximately 30%. Acute coronary artery thrombosishas been noted in up to 70% of patients with VF.Individuals resuscitated from VF in whom acute myocardialinfarction does not develop have an increased ratefor sudden cardiac death or VF. Predictors of deathfor patients resuscitated from VF include a reduced607

608VENTRICULAR FIBRILLATIONFIGURE 1 Ventricular flutter and ventricular fibrillation. (A) The sine wave appearance of the complexes occurring at a rate of 300 beats per minute ischaracteristic of ventricular flutter. (B) The irregular undulating baseline typifies ventricular fibrillation.ejection fraction, congestive heart failure, history ofmyocardial infarction, and the presence of ventriculararrhythmias.VF causing sudden cardiac death occurs most frequentlyin the early morning and appears to be related to increasedplatelet aggregation. Sudden death from VF occurs moreoften in winter months and appears to be related to thesudden exposure to cold temperatures which influenceplatelet aggregation.VF can occur during antiarrhythmic drug therapy orafter electrical shock is applied during cardioversion. It isalso observed during competitive ventricular pacing toterminate VT. Sudden death in cardiomyopathy anddilated cardiomyopathy is often precipitated by VF.III. MANAGEMENTImmediate, non-synchronized DC electrical shock using350–400 J should be rapidly applied without attemptingto obtain an ECG or palpating pulses. VF rarely convertsspontaneously to normal rhythm and shock must be appliedimmediately. CPR is used only until the equipment isready and the shock usually terminates VF. This may causethe asystolic heart to beat and time should not be wastedwith CPR if defibrillation can be accomplished rapidly.If a defibrillator is used within 60 seconds significantmetabolic acidosis does not occur and sodium bicarbonateshould be withheld. Intravenous calcium is administeredto treat hypocalcemia, hyperkalemia, or calcium antagonistoverdose.C. Other CausesOther disturbances associated with VF include Brugadasyndrome and arrhythmogenic right ventricular dysplasia.Stokes-Adams attacks are caused by complete heart blockthat culminates in VF. Rapid ventricular rates such as inWolff-Parkinson-White syndrome, hypoxia, and rarelyatrial fibrillation can be associated with it as well. Also,improperly grounded equipment and electrocution duringan electrical storm can cause VF.BIBLIOGRAPHYOlgin, J. E., and Zipes, D. P. Specific arrhythmia: Diagnosis andtreatment. In Heart Disease, sixth edition. E. Braunwald, D. P. Zipes,and P. Libby, eds. W. B. Saunders, Philadelphia, 2001.Witkowski, F. X., Leon, L. J., Penkoske, P. A. et al. Spatiotemporalevolution of ventricular fibrillation. Nature, 392:78–82, 1998.Wenzel, V., Krismer, A. C., Arntz, H. R. et al. For the EuropeanResuscitation Council Vasopressor during Cardiopulmonary ResuscitationStudy Group A Comparison of Vasopressin and Epinephrine forOut-of-Hospital Cardiopulmonary Resuscitation. N. Engl. J. Med.,350:105–113, 2004.

Women and Heart DiseaseI. Relevant Statistics and PerspectivesII. Recognized Differences in Women and MenIII. Hormone TherapyIV. Pregnancy and Heart DiseaseGLOSSARYaneurysm a ballooning of the wall of an artery or heart musclecaused by severe weakening of the walls of the artery or theheart muscle.arrhythmia general term for on the irregularity or rapidity of theheartbeat, an abnormal heart rhythm.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wall ofarteries that obstruct the lumen and the flow blood; the plaqueof atheroma hardens the artery, hence the term atherosclerosis(sclerosis ¼ hardening).heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.myocardial infarction death of an area of heart muscle due toblockage of a coronary artery by blood clot and atheroma;medical term for a heart attack or coronary thrombosis.I. RELEVANT STATISTICS ANDPERSPECTIVESThere is a false notion that cardiovascular disease is morecommon in men than in women. After age 65, one in threewomen have some form of cardiovascular disease. Morethan 350,000 women die of a heart attack and morethan 120,000 die of a stroke in the United States each year.This situation is occurring because of the relatively largepopulation of older women who are at high risk forcardiovascular events. The National Center for HealthStatistics indicates that for the 12 months ending in August1994, deaths from cardiovascular disease in the UnitedStates were 944,280 and more women died of cardiovasculardisease than men and women accounted for morethan 490,000 of these deaths. The 1990 statistics revealedthat of all cardiovascular deaths, 56% occurred in womenand 44% in men. The 1992 statistics indicate that 52%(479,000) occurred in women and 48% (444,000)occurred in men; with 246,000 deaths from all forms ofcancer (43,100 breast cancer and 55,900 lung cancer).Cardiovascular disease is a much more common causeof death and disability in women than all forms of cancer,pneumonia, and AIDS. Women incorrectly perceive theirrisk of cancer of the breast and uterus as much greaterthan that of heart disease or stroke. More than twice asmany women die of cardiovascular disease than all forms ofcancer in United States.Fortunately, most women are protected from the riskof heart attack up to age 48 because of their hormonalstatus. It is extremely rare for a normal menstruatingwoman to have a heart attack prior to age 47 except inthose who have blood cholesterol at levels greater than260 mg (6.5 mmol) or in diabetics, whereas many men diefrom myocardial infarction between age 35 and 48. Theincidence of heart attack in men and women at age 35, 40,50, 65, 70, and 75 is about 100:1, 20:1, 10:1, 5:2, 5:4,1:1. Because more men age 35–65 than women have heartattacks and angina, there are more clinical studies done onmen using drugs and undergoing coronary bypass surgeryand angioplasty. Women believe they are not treatedequally by the medical profession particularly in the areaof heart disease. Women are not excluded from studies, themajority fortunately do not manifest coronary arterydisease until after age 70 and long-term trials for soundreasons often include patients up to the age 70.Women believe that there is some bias attached tothe treatment of men versus women with heart problems.Some doctors are proclaiming that women with heartdisease have different symptoms from men and responddifferently to drugs, angioplasty, and bypass surgery. Thisassumption is incorrect. Because an insufficient amountof women age 35–65 were available to be included in the609

610WOMEN AND HEART DISEASEstudies, information on women and heart disease isdeficient. Patients age 71–80 are not usually entered intolong-term follow-up studies. It is obvious that there aremore 75- to 85-year-old women with heart attacks thanmen as the population of elderly women is increasingrelative to men.Symptoms of a genuine heart attack are not significantlydifferent in women and men. Some women suffer withshortness of breath or nausea instead of pain during a heartattack, but so do a few men. Diagnosis of a heart attackis similar in women and men. An ECG records the sameinformation for both.The medical treatment for heart attack is virtually thesame for both women and men and the response isthe same. All blood pressure lowering medications workequally well in women and men to prevent stroke or heartfailure. Bypass surgery and angioplasty in the elderly carrya greater risk, and the results of angioplasty appear to beless impressive in women. Women age 60–70 who needbypass surgery do just as well as men. Complications ofbypass surgery are said to be slightly higher in women, butthe women are older than age 75. There are no studiesdone to compare 71- and 81-year-old men and womenundergoing bypass surgery and angioplasty. Bypass surgeryis done more often in men at a younger age, because thistreatment is performed to relieve angina. Angina interfereswith lifestyle, particularly the ability to work, between age40 and 65. This is an age at which women are lesssubjected to disabling angina.II. RECOGNIZED DIFFERENCES INWOMEN AND MENApart from heart disease in pregnancy and coronary arterydisease there is very little difference between the incidence,symptoms, signs, and therapy for various heart and othercardiovascular diseases in men and women.A. Atypical Chest Pain versus AnginaThere is greater difficulty diagnosing nonspecific symptomsthat are angina-like between men and women. Thereis no difficulty with the diagnosis of acute myocardialinfarction, heart failure, arrhythmias, pericarditis, valvularheart disease, or stroke. Women do present at age 45–65with nonspecific chest pain, angina-like symptoms, chestwall pain, pain caused by gastroesophageal reflux (GER),esophageal spasm, and other noncardiac causes of chestpain. A few of these patients have genuine coronary arterydisease. Thus, caution is required because women mayhave atypical chest discomfort (not the typical chest painof angina) when they have angina caused by obstructiveatheromatous coronary artery disease (see the chapterAngina).Symptoms of angina pectoris are recurrent pain ordiscomfort of short duration arising in the chest, throat,jaw, or arms caused by severe but temporary lack of bloodand oxygen. This is precipitated by a particular exertionalactivity and is quickly relieved within minutes of cessationof the precipitating activity. Some women present withtypical angina but some describe the pain as a peculiarfeeling of unpleasant yet mild discomfort, and a knot orbothersome discomfort in the neck or ache in the left arm.If the discomfort is associated with brisk walking orwalking up an incline and relieved within a few minutesby stopping the walk, then angina caused by coronaryartery disease should be strongly suspected.1. Exercise Testing and Nuclear ImagingThere are many reasons why exercise treadmill testingwith conventional ST segment analysis is believed toprovide less accurate diagnoses for coronary artery diseasein women than in men. Some of these differences may beexplained by differences in the disease prevalence andseverity of the disease from age 40 to 70. Women havea lower prevalence and severity of the disease prior to age70 when most exercise testing is performed. Womenyounger than age 65 have a low prevalence of multivesseldisease; single-vessel disease is more common in womenand multivessel and left main disease is more common inmen at this age. Obviously, patients with more severedisease have a higher incidence of abnormal exercise testresults. Compared with men of the same age (50–70),women are less likely to achieve more than 9 minutes ofexercise using the Bruce protocol and achieving anadequate heart rate response to exercise. Women withcoronary artery disease usually present at a later age thanmen and after age 70 have a greater number of comorbiditiesthat significantly reduce the ability to perform anadequate exercise stress test. Nonetheless, a negative testresult in a woman or man who has completed more than9 minutes of the Bruce protocol and achieved more than85% maximal heart rate is a powerful tool for excludingthe presence of significant ischemia caused by atherothromboticcoronary artery disease.Several meta-analyses of treadmill testing indicate differencesbetween men and women, but these reports aremisleading. The false-negative rate for women is low(12–22%) and is comparable to that for men (12–40%).Thus treadmill testing that achieves more than 85%

III. HORMONE THERAPY611maximal heart rate reliably excludes the presence of significantcoronary artery disease in women with negativeresults just like it does in men. The treadmill results in580 women from the CASS trial showed a 3% falsepositiverate for men and a 14% rate for women. When thesame population was matched for differences in demographicsand clinical characteristics, however, the differencesin the false-positive rates were no longer detected.The lower sensitivity of exercise testing in womencompared with men adjusted for age and the presence ofdiabetes appears to relate to the finding of less ST-segmentdepression in women compared with men. The differencesmay be related in part to lower exercise tolerance inwomen, which causes lower maximal heart rates andsystolic blood pressures at peak exercise. Also, studies haveindicated that estrogen affects coronary vasomotor toneand may play a role in alteration of ST-T wave changes.There is little doubt that the sensitivity and specificityof treadmill exercise testing for the detection of coronaryartery disease in women are improved when combinedwith myocardial perfusion imaging. Yet the lack of efforttolerance to achieve an adequate heart rate response andthe presence of comorbidities in women older than age70 that limit exercise duration add limitations to theseexpensive tests. Adenosine or dipyridamole is used inindividuals who are unable to complete an exercise stresstest, but good sensitivity and specificity are lacking.Stress echocardiography is claimed by some to bemore accurate than exercise testing in women suspected ofcoronary artery disease, but these small studies do notinclude nuclear imaging.B. Innovative TechnologyClearly technologic advances are necessary to provide othermethods of noninvasive testing currently used for detectingthe presence of atheromatous coronary artery disease.Currently used investigative methods that have manydrawbacks and are unsatisfactory diagnostic tools includetreadmill exercise testing, nuclear imaging, treadmill stresstesting combined with nuclear imaging, adenosine ordipyridamole cardiac nuclear imaging, echocardiography,Stress echocardiography, PET scan, and electron beamCT scan for coronary calcification (see the chapter Testsfor heart diseases).C. Acute Myocardial InfarctionWomen appear to experience more severe consequencesof myocardial infarction than men. In every age groupwomen with coronary artery disease have a higher risk ofdeath from coronary events than men. Older women aretwice as likely as older men to die within weeks after aheart attack. In the first year after a heart attack 27% ofmen and 44% of women are expected to die, but thisaccounting is not age specific. The risk of death is equal inwomen and men with ejection fractions less than 35%.Sudden cardiac death is reportedly more common in menthan in women.Ventricular septal and free wall rupture following acutemyocardial infarction occur more often in women thanin men. From age 75 to 85, women may have a slightlyhigher risk of bleeding with thrombolytic therapy anddoctors need to reduce the dose of thrombolytic drugs tomatch the age and weight of women.D. DyslipidemiaGenerally, levels of low-density lipoprotein (LDL) cholesterolare lower in women than in men until the age of50, after which LDL levels increase. An exception to thisfinding is in patients with genetic familial hypercholesterolemiaand in diabetics. High-density lipoprotein (HDL)cholesterol levels are approximately 10 mg/dl (0.3 mmol/L)higher in women than in men of all ages. The combinationof a lower LDL cholesterol and slightly higher HDLcholesterol from age 35 to 55 in women compared withmen is believed to account for the lower prevalence ofcoronary artery disease and coronary events in womencompared with men from age 35 to 65. Atherothromboticdisease progresses from age 55 in women and culminates inserious events that include angina, acute myocardialinfarction, and heart failure mainly from age 70 onward.The use of oral contraceptive pills has been associatedwith increased risk of stroke, myocardial infarction,and thromboembolism (see the chapter Contraception andCardiovascular Disease).III. HORMONE THERAPYA. Premenopausal ProtectionAtherothrombotic cardiac disease is rare in women aged30–50 before menopause when compared with men. Thisprotection from atherothrombotic disease is due to veryhigh estrogen levels that maintain LDL cholesterol at verylow levels and increase HDL levels considerably.Atherothrombotic coronary artery disease, however,occurs in women age 35–50 who have undergone surgicalor chemical oophorectomy, a condition in which there isa documented accelerated rate of atherosclerosis. Coronary

612WOMEN AND HEART DISEASEartery disease also occurs in women who have diabetes orgenetic familiar hypercholesterolemia, and progression ofdisease is increased in smokers and with the presenceof hypertension.After menopause estrogen levels fall drastically, and thisresults in an increase in LDL cholesterol levels and a milddecrease in HDL levels. Because of this change atheromatousobstructive disease of the coronary arteriesdevelops gradually from age 50 to 70 and culminates inangina or myocardial infarction mainly during age 65–85.This progressive atherothrombotic disease is not prevented,however, by exogenous hormone replacement (HRT). Thefindings of recent randomized clinical trials show nobeneficial cardiac effects of HRT. These findings arenot surprising because HRT causes only a modest 11%reduction in LDL cholesterol and only a 10% increase inHDL cholesterol. This is a change in lipid levels that isunlikely to accomplish regression of disease or causea decrease in mortality. A 10% increase in HDL cholesterolhas been overrated as a measure of cardioprotection, andis unlikely to ameliorate the progression of atherothromboticdisease when this is already present in women atage 60 and beyond. The statins are capable of reducingLDL cholesterol 20–40% and have shown decreasedcardiac mortality in several randomized clinical trials. InThe Lipid Research Clinic trial cholestyramine causedabout a 13% reduction in total cholesterol and showed nodecrease in total or cardiac mortality. A total cholesteroldecrease of more than 33% sustained for several yearsappears to be necessary for the prevention of atherothromboticcoronary disease and its complications. Thepremenopausal hormonal status in women does notprotect from atherothrombotic stroke, however. Thereason why a woman’s premenopausal hormonal statusprotects her from coronary artery disease and not cerebralartery disease remains unclear, and has received littleattention in various publications.B. Clinical Studies1. Heart and Estrogen/Progestin Replacement StudyThe Heart and Estrogen/Progestin Replacement Study(HERS) evaluated 2763 women with known coronarydisease who were postmenopausal and had an intact uterus.After a 4-year follow up HRT resulted in an 11% reductionin LDL cholesterol and a 10% increase in HDLcholesterol, but the overall rate of coronary artery diseaseevents was not decreased. There was a statistically significanttime trend with more coronary artery disease eventsoccurring in the HRT group at one year and fewer eventsin years four to five. Most important, thromboembolicevents were increased by HRT. There was no significanteffect on the risk of stroke.2. Estrogen Replacement and Atherosclerosis TrialThe Estrogen Replacement and Atherosclerosis (ERA) trialdemonstrated that estrogen replacement with or withoutprogestin did not significantly improve the angiographicprogression of atherosclerotic disease in postmenopausalwomen who had known coronary artery disease whencompared with placebo.3. Woman’s Health Initiative StudyThe Women’s Health Initiative (WHI) study randomlyassigned 16,608 postmenopausal women 50–79 years ofage with an intact uterus to estrogen 0.625 mg plusmedroxyprogesterone 2.5 mg or placebo. After three years’follow up HRT did not have a clinically meaningful effecton health-related quality of life issues such as generalhealth, vitality, mental health, depressive symptoms, orsexual satisfaction. Treatment resulted in a small benefit interms of sleep disturbance, but no benefit in terms of otherquality of life outcomes.After a mean follow up of 5.2 years, the data and safetymonitoring board recommended terminating the estrogenplus progestin trial because the overall risks exceeded thebenefits.It was concluded that estrogen plus progestin does notconfer cardiac protection and may increase the risk ofcoronary artery disease among generally healthy postmenopausalwomen. This treatment should not be prescribedfor the prevention of cardiovascular disease.Other studies have recently confirmed an increasedrisk of breast cancer with the use of HRT and it is nolonger recommended for the primary and secondaryprevention of coronary artery disease or prevention ofstroke. The WHI randomized trial of conjugated equineestrogen alone, in postmenopausal women with hysterectomy,showed an increase in stroke but no increase incoronary disease or breast cancer. The follow up, however,was only 6.8 years and caution is required.IV. PREGNANCY AND HEART DISEASEPregnancy imposes an internal workload on the cardiovascularsystem similar to that of endurance exercise.The placenta and fetus require a huge blood supply thatmust be pumped through a large circuit of blood vessels,

IV. PREGNANCY AND HEART DISEASE613and the altered vasculature is similar to that found witha large arteriovenous fistula. Redistribution of the greatlyexpanded blood volume occurs and an increase in cardiacoutput that begins around the fifth week of conceptionpeaks between the 20th to 24th week. A resultanthyperdynamic state occurs with increased heart rate anda bounding pulse that has a collapsing character becauseof a fall in diastolic pressure and widened pulse pressure.Fortunately serious cardiovascular disturbances rarelyoccur during pregnancy and mainly in women who haveunderlying heart or hypertensive disease. The main disordersof concern include accelerated hypertension causedby preeclampsia, life-threatening pulmonary edema, orheart failure in patients with tight mitral stenosis or othersevere valvular disorder, arrhythmias that may be bothersome,pulmonary hypertension, cerebrovascular accident,aortic dissection in those with Marfan syndrome, and therare peripartum cardiomyopathy. Maternal heart diseaseoccurs in approximately 2% of pregnancies in the westernworld.A. HypertensionNormally blood volume increases by 130–150% of nonpregnancyvalues and cardiac output increases by up to50% commencing soon after conception. There is amarked reduction in peripheral vascular resistance causedby widespread systemic arterial vasodilatation that occursas a result of increased levels of gestational hormonesincluding progesterone, circulating prostaglandins, andatrial natriuretic factor. Thus, blood pressure decreasesslightly despite the increased cardiac output. This reductionin systemic vascular resistance allows the heart topump the increased volume of blood against less resistancewith less work and oxygen requirement.A diagnosis of chronic hypertension is based on theconfirmed existence of hypertension before conceptionand particularly prior to the 20th week of pregnancy; atwhich stage a blood pressure greater than 140/90 mmHgis considered abnormal. Fortunately a mild or moderatedegree of hypertension causes minimal complications tomother or fetus even when drug therapy is withheld.Superimposed preeclampsia occurs in about 6% of pregnantwomen regardless of blood pressure control.1. Clinical Study: Mabie et al.Treatment with methyldopa with added hydrochlorothiazidewas administered to 82 women and no therapy wasgiven to 82 women with chronic hypertension seen beforethe 20th week. Triple therapy with added propranolol wasnecessary in five women. There was the difference inperinatal mortality, but there was an increase in fetalgrowth restriction in the treatment group.2. Clinical Study: Sibai et al.This study randomized 263 women with mild-to-moderatehypertension to methyldopa, labetalol, or no treatmentat 6–13 weeks to achieve a blood pressure of less than140/90 mmHg. There was no significant difference ingestational age at delivery, premature delivery, mean birthweight, superimposed preeclampsia, placental abruption,or perinatal mortality. If preeclampsia develops and itscomplications occur, drug therapy is necessary for controlof blood pressure.3. Drug TherapyMethyldopa at a dose of 500–1500 mg daily is the mostwidely used agent and its relative safety has been recognizedover the past 40 years. During the past decade,however, many obstetricians have replaced methyldopawith labetalol or atenolol, because methyldopa causesdepression in up to 25% of patients, sedation, posturalhypotension, and a positive direct Coombs test.Atenolol 25–75 mg once daily is a relatively safe andeffective agent for the control of mild-to-moderatehypertension from the 16th week to 1 week prior tolabor. Labetalol is reported in many publications to be safe,but this author cautions that fatal or nonfatal hepaticnecrosis has been reported in nonpregnant hypertensives.Also, a lupus-like illness, a lichenoid rash, abnormal liverfunction tests, and postural hypotension not observedwith pure beta-adrenergic blocking agents may occur.Labetalol is a most useful agent for short-term use such asfor hypertensive emergencies, accelerated hypertension,and emergencies in preeclampsia and can be used priorto delivery and during delivery if required.Hydralazine, a pure arteriolar vasodilator, has been usedextensively for the acute control of severe hypertensionin the third trimester and predelivery. Its chronic use isnot recommended because the drug causes sodium andwater retention that may necessitate the use of a diuretic.For hypertensive crisis a 5- to 10-mg bolus is injectedintravenously. It is given orally 25 mg twice daily increasingto 100 mg daily used in combination with other agentsfor one to two weeks if needed for emergency control ofhypertension associated with preeclampsia.Diuretics are not generally recommended because fetaloutcome is usually worse in women with preeclampsia

614WOMEN AND HEART DISEASEwho fail to expand the plasma volume that is reduced bydiuretics.Nifedipine has been used effectively for short-termemergency control of accelerated hypertension. Cautionis required because the drug occasionally causes a precipitous fall in blood pressure, and this is more likely to occurif magnesium sulfate is added concomitantly. Nimodipinehas special vasodilator effects on human cerebral vessels,and it has been used effectively to control blood pressure inpatients with subarachnoid hemorrhage. This drug mayprove useful in treating severe hypertension of preeclampsiaand for the prevention of seizures in eclampsia, whichare associated with cerebral vasospasm and cerebralischemia.B. Valvular Heart Disease1. Mitral StenosisIn mitral stenosis left atrial pressure rises and diastolicblood flow through the tight mitral valve is slowed. Inaddition, cardiac output and intravascular volume reacha peak by weeks 20–24. A 50% increase in cardiac outputduring pregnancy may cause a marked increase in thepressure gradient across the valve. Patients with moderateto-severemitral stenosis and a mitral valve area less than1.2 cm 2 are at increased risk of dramatic and at times fatalpulmonary edema. The heart rate increases an averageof 10 beats per minute. Increases in heart rates causea shortened ventricular filling time and a marked increasein left atrial pressure. Sinus tachycardia, thus, mayprecipitate pulmonary edema which may be fatal. Reductionof resting heart rate from a mean of 90 to 75 beatsper minute is associated with a marked improvement inleft ventricular filling and prevention or amelioration ofpulmonary edema. Also, with atrial fibrillation and a fastventricular response beta-blockers are useful when tryingto achieve a ventricular rate less than 80 beats minute.Digoxin does not reduce the heart rate sufficiently withatrial fibrillation. If pulmonary edema develops diureticsare added to beta-blocker therapy followed at theopportune time by valvuloplasty or surgery to relievemitral stenosis. A valve area of less than 1 cm 2 or valvearea corrected for body surface area (valve area index

IV. PREGNANCY AND HEART DISEASE615HERS. Randomized trial of estrogen plus progestin for secondaryprevention of coronary heart disease in postmenopausal women. Heartand estrogen/progestin replacement study (HERS) research group.JAMA, 280:650, 1998.Hulley, S. B., and Grady, D. Editorial: The WHI estrogen-alone trial —Do things look any better? JAMA, 291:1769–1771, 2004.Jacobs, A. K., Eckel, R. H. et al. Evaluating and managing cardiovasculardisease in women: Understanding a woman’s heart. Circulation,111:383–384, 2005.Johnson, P. A., Manson, J. E. et al. How to make sure the beat goes on:Protecting a woman’s heart. Circulation, 111:e28–e33, 2005.Kannel, W. B., and Abbott, R. D. Incidence and prognosis of myocardialinfarction in women. The Framingham study. In Coronary HeartDisease in Women. E. D. Eaker, B. Packard, N. K. Wenger et al., eds.Haymarket Doyma Inc., New York, 1987, p. 208.Lansky, A. J., Hochman, J. S., Ward, P. A. et al. Endorsed by theAmerican College of Cardiology Foundation: Percutaneous coronaryintervention and adjunctive pharmacotherapy in women: A statementfor healthcare professionals from the American Heart Association.Circulation, 111:940–953, 2005.Lerner, D. J., and Kannel, W. B. Patterns of coronary heart diseasemorbidity and mortality in the sexes: A 26 year follow-up of theFramingham population. Am. Heart J., 111:383, 1986.Lipid Lowering Hormone Atherosclerosis Regression Trial ResearchGroup. Hormone therapy and the progression of coronary arteryatherosclerosis in postmenopausal women. N. Engl. J. Med.,349:535–45, 2003.Mabie, W. C., Pernoll, M. L., and Biswas, M. K. Chronic hypertension inpregnancy. Obstet. Gynecol., 67:197, 1986.Mieres, J. H., Shaw, L. J., Arai, A. et al. Role of noninvasive testing inthe clinical evaluation of women with suspected coronary arterydisease: Consensus statement from the Cardiac Imaging Committee,Council on Clinical Cardiology, and the Cardiovascular Imagingand Intervention Committee, Council on Cardiovascular Radiologyand Intervention, American Heart Association. Circulation,111:682–696, 2005.Mosca, L., Manson, J. E., Sutherland, S. E. et al. Cardiovascular disease inwomen: A statement for healthcare professionals from the AmericanHeart Association. Circulation, 96:2468, 1997.Mosca, L., Merz, N. B., Blumenthal, R. S. et al. Opportunity forintervention to achieve American Heart Association guidelines foroptimal lipid levels in high-risk women in a managed care setting.Circulation, 111:488–493, 2005. doi:10.1161/01.CIR.0000153859.66086.85.Sharkey, S. W., Lesser, J. R., Zenovich, A. G. et al. Acute and reversiblecardiomyopathy provoked by stress in women from the United States.Circulation, 111:472–479, 2005.Sibai, B. M., Mabie, W. C., Shamsa, F., et al. A comparison of nomedication versus methyldopa or labetalol in chronic hypertensionduring pregnancy. Am. J. Obstet. Gynecol., 162:960, 1990.van der Schouw, Y. T., Kreijkamp-Kaspers, S., Peeters, P. H. M. et al.Prospective study on usual dietary phytoestrogen intake and cardiovasculardisease risk in western women. Circulation, 111:465-471,2005. doi:10.1161/01.CIR.0000153814. 87631.WHI: Estrogen plus progestin in the risk of coronary heart disease.N. Engl. J. Med., 49: 523–34, 2003.Wilansky, S., and Willerson, J. T. Heart Disease in Women. ChurchillLivingstone, New York, 2002.Women’s Health Initiative WHI; Investigators. Effects of estrogen plusprogestin on health-related quality-of-life. N. Engl. J. Med.,348:1839–54, 2003.Women’s Health Initiative (WHI) Steering Committee: Effects ofconjugated equine estrogen in postmenopausal women with hysterectomy.JAMA, 291:1701–1712, 2004.Writing Group For the PEPI trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausalwomen. The postmenopausal estrogen progestin interventions(PEPI) trial. JAMA, 273:199, 1995.

APPENDIX AGenericBLOOD PRESSURE PILLSBeta-BlockersAcebutololAtenololCarvedilolBisoprololLabetalolMetoprololNadololPindololPropranololTimololSotalolDiureticsThiazidesChlorothiazideHydrochlorothiazideBendrofluazideMetolazoneStrong DiureticsFurosemide, frusemideBumetanideEthacrynic acidTorsemidePharmaceutical Trade NameMonitan, SectralTenorminCoreg, EucardicZebeta, Monocor, EmcorNormodyne, TrandateBetaloc, Lopressor, Toprol XLCorgardViskenInderal, Inderal LABlocadren, BetimSotacorDiuril, SaluricHydroDiuril, Esidrix, Oretic,DiremaAprinox, Berkozide, Centyl,Neo-NaclexZaroxolyn, MetenixLasix, DryptalBurinex, BumexEdecrinDemadexDiuretics that Retain PotassiumAmilorideMidamorEplerenoneInspraSpironolactone AldactoneTriamtereneDyrenium, DytacThiazide Combined with Potassium-Retaining DiureticNongeneric names AldactazideDyazideModuretic, ModuretVasodilators (Dilate Arteries)ACE InhibitorsBenazeprilCaptoprilLotensinCapotenGenericPharmaceutical Trade NameCilazaprilInhibaceEnalaprilVasotecFosinoprilMonoprilLisinoprilPrinivil, ZestrilPerindoprilCoversylQuinaprilAccuprilRamiprilAltaceSpiraprilRenpress, Sandopril,TrandolaprilMavik, GoptenZofenopril —Angiotensin II Receptor Blocker (ARBs)CandesartanAtacand, AmiasEprosartanTevetenIrbesartanAvapro, AprovelTelmisartanMicardisValsartanDiovanLosartanCozaarLosartan plusHyzzarhydrochlorothiazideCalcium AntagonistsAmlodipineNifedipineNimodipineDiltiazemFelodipineVerapamilOther AntihypertensivesClonidineGuanabenzMethyldopaReserpineNorvascAdalat XL, Procardia XLNimotopCardizem CDPlendil, RenedilIsoptinCatapresWytensinAldomet, DopametAbicol, Decaserpyl, Raudixin,SerpasilDRUGS USED FOR ANGINANitratesNitroglycerinNitrostat, Nitro-Bid,(sublingual)Nitrolingual SprayIsosorbide dinitrate Coronex, Isordil, Sorbitrate,othersIsosorbide mononitrate ImdurIsmo617

618APPENDIX AGenericBeta-Blockers. See above.Calcium AntagonistsDiltiazemNifedipineVerapamilPharmaceutical Trade NameAnginyl, Cardizem,Cardizem CDAdalat XL, Procardia XLCalan, Cordilox, Isoptin,Isoptin SR, IsoptinoDRUGS FOR HEART FAILUREDigoxinLanoxin, othersFurosemide andother diuretics.See aboveACE Inhibitors such ascaptopril and enalapril.See aboveARBs if ACE inhibitorscause adverse effectsDRUGS FOR ABNORMAL HEART RHYTHMS(ARRHYTHMIAS)AmiodaroneCordarone, Cordarone XBeta-Blockers. See above.DigoxinLanoxinDisopyramideNorpace, RythmodanMexiletineMexitilProcainamidePronestylQuinidineCardioquin, QuinidexQuinate, Biquin, DurulesSotalolSotacorGenericPharmaceutical Trade NameDRUGS THAT AFFECT BLOOD CLOTTINGBlood Thinners: AnticoagulantsWarfarinCoumadin, Warfilone, Marevan,othersDrugs that Reduce Stickiness of Blood Platelets(Not Blood Thinners)Acetylsalicylic acid Aspirin, enteric coated aspirin:Entrophen, NovasenClopidogrelPlavixDipyridamolePersantin, PersantinePotassium supplementsDRUGS THAT REDUCE CHOLESTEROLFibratesBezafibrateBezalip, Bezalip-MonoGemfibrozilLopidFenofibrateLipidil, Lipidil-MicroResinsCholestyramineColestipolStatinsAtorvastatinFluvastatinLovastatinPravastatinRosuvastatinSimvastatinQuestranColestidLipitorLescolMevacorPravacholCrestorZocorCholesterol Absorption InhibitorsEzetimibeZetia, Ezetrol

APPENDIX Bmg/dL = milligram per 100 mL of bloodmEq/L = milliequivalent per liter of bloodmmol/L = millimole per liter of bloodNormal Values or Normal Range of Some Blood ConstituentsUnited StatesCanada, U.K. (S.I.)Cholesteral 150 to 200 mg/dL U38.5 = 3.9 to 5.19 mmol/LHDL cholesterol 40 to 80 mg/dL U38.5 = 1.03 to 2.07 mmol/LLDL cholesterol 60 to 160 mg/dL U38.5 = 1.55 to 4.15 mmol/LLDL cholesterol (optimal) less than 130 mg/dL U38.5 = less than 3.37 mmol/LLDL cholesterol (if heart trouble) less than 100 mg/dL U38.5 = less than 2.59 mmol/LLDL cholesterol (serious heart attack) less than 80 mg/dL U38.5 = less than 2.07 mmol/LPotassium 4 to 5 mEq/L 4 to 5 mmol/LTriglycerides 50 to 300 mg/dL U100 = 0.5 to 3 mmol/L619

GLOSSARYAACE angiotensin-converting enzyme.action potential voltage changes generated across the membraneof a nerve or muscle cells when the cell is activated througha variety of stimuli (electrical, chemical, or mechanical).acute coronary syndrome this syndrome defines patients withacute chest pain caused by myocardial infarction or unstableangina.adventitia the outer most lining of the vessel wall.afterload arterial impedance, restriction to blood flow deliveredfrom the left ventricle; force against which the myocardiumcontracts in systole; a major determinant of wall stress.aggregation platelet clumping.aldosterone a hormone produced by the adrenal glands.allograft a graft between animals of the same species, but ofdifferent genotype.aneurysm a ballooning of the wall of an artery or the heartcaused by severe weakening of the walls of the artery or theheart muscle.angina chest pain caused by temporary lack of blood to an areaof heart muscle cells, usually caused by severe obstructionof the artery supplying blood to the segment of cells.angina pectoris short duration, recurrent chest pain or pressureoften accompanied by feelings of suffocation and impendingdoom; most frequently associated with lack of blood andoxygen to the heart muscle.angiogenesis functional new blood vessel growth.anomaly marked deviation from normal, especially as a resultof congenital or hereditary defects.antiarrhythmic agents cardioactive drugs used to prevent andtreat arrhythmias.anticoagulants blood thinners.anticoagulation to decrease the tendency of the blood to forma clot, thrombosis.AOO a pacemaker that stimulates the atrium as a fixed rate,independent of atrial activity.aorta main artery arising from the heart; the branches of theaorta take blood to all parts of the body.apnea cessation of airflow for at least 10 seconds.arcomere the contractile unit of a myofibril; sarcomeresare repeating units, delimited by the Z bands, along thelength of the myofibril that make up the myocardium ofthe heart.arrhythmia general term for an irregularity or rapidity of theheartbeat, an abnormal heart rhythm.arterial dilatation enlargement or increase in the luminaldiameter of the artery.arterioles small branches of arteries.arteriosclerosis loss of elasticity and hardening of the arterydue to several causes, particularly age change and depositsof calcium; an artery with pipe-like rigidity.artery blood vessels that carry blood away from the heartto organs, tissues, and cells throughout the body, as opposedto veins, which carry blood from the tissues back to the heart.artium one of the two upper chambers of the heart.ascites accumulation of serous fluid in the abdominal cavity.atheroma same as atherosclerosis, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis = hardening).atheromatous same as atherosclerotic, a plaque that juts intothe lumen and obstructs the flow of blood in arteries.atherosclerosis same as theroma, raised plaques filled withcholesterol, calcium, and other substances on the inner wallof arteries that obstruct the lumen and the flow of blood;the plaque of atheroma hardens the artery, hence the termatherosclerosis (sclerosis = hardening).atherothrombosis when a plaque of atheroma is fissuredor ruptures, the contents of the plaque are highly thrombogenicand a clot (thrombus) forms rapidly causing completeocclusion of arteries leading to myocardial infarction, stroke,or other cardiovascular events (atheroma plus thrombosis ¼atherothrombosis).atrial fibrillation the most common, persistent arrhythmiathat is seen in medical practice; it may precipitate thromboembolicstroke.atrial septal defect a hole in the wall of the heart (septum) thatdivides the left and right atrium.621

622GLOSSARYautograft a tissue graft transferred from one part of the patientsbody to another part.automaticity the ability to generate a spontaneous actionpotential.Bblastula usually spherical body produced by cleavage of a fertilizedovum, consisting of a single layer of cells (blastoderm)surrounding a fluid-filled cavity (blastocele).brachial artery the artery of the arm and forearms that suppliesblood to the upper limb including the hands.bradycardia heart rate less than 60 beats a minute.Brugada P. Brugada described the syndrome and its electrocardiographicchanges.Ccalorie a unit of energy; one calorie represents the amountof heat required to raise the temperature of one kilogram ofwater by one degree.capillaries fine, thin-walled blood vessels that branch fromarterioles and feed the tissues and cells with blood and fluids.capillaries minute, thin-walled blood vessels which connect thearterioles and the venules, forming a network in nearly allorgans and tissues of the body.cardiac arrest cessation of the heartbeat.cardiac catheterization a cardiac catheter is inserted through avein or artery and pushed and propelled to reach inside theheart. The progress of the catheter is watched on a fluoroscope.cardiac dysfunction the normal function of the heart isreduced; abnormal heart function.cardiac output the volume of blood pumped by the ventricleper unit time expressed in liters per minute; it is a functionof the stroke volume multiplied by the heart rate.cardiac tamponade compression of the heart by fluid in thepericardial sac causing hemodynamic compromise that leadsto cardiogenic shock and death if not immediately corrected.cardiogenic shock extremely low blood pressures in the arteriescaused by failure of the heart to eject blood; systolic bloodpressure is usually less than 90 mmHg.cardiomyopathy heart muscle disease.cardioprotection protection of the heart from serious eventsthat include coronary artery disease and its complications,angina, myocardial infarction, and heart failure.catheter a flexible tube that can be inserted into body organs toachieve drainage, treatment, or diagnosis.caudal pertaining to toward the tail or distal end of the body.cephalic pertaining to the head or to the head end of the body.cholesterol a lipid, or fat-like substance, made by animal cells.commissures a site of union of corresponding par especially thesites of junction between the adjacent cusps of the heart valves.concentric hypertrophy diffuse generalized thickening of themyocardium with little or no change in dimensions of the leftventricular cavity as seen in pressure overload of the left ventricle.converting enzyme the same as kininase II.coronary arteries the arteries that supply the heart muscle andother parts of the heearet with blood.coronary heart disease obstruction of the coronary arteries withsymptoms such as chest pain, angina, or heart attacks.coronary thrombosis a blood clot in a coronary artery, blockingblood flow to a part of the heart muscle. Also called a heartattack or myocardial infarction.creatinine breakdown of proteins excreted into the urine by thekidneys so that the composition in the bloodstream remainsrelatively constant.cryptogenic of obscure or doubtful origin.cyanosis purplish-blue discoloration of the lips, tongue, mucousmembranes, ear lobes, extremities, fingers, and toes.Ddemand or inhibited pacemaker any pacemaker that inhibitsits output upon sensing a natural or paced event and firesat the preset rate when the sinus rate falls below thepacemaker’s programmed escape rate.diapedese the passage of blood cells through intact vessel walls.distal further away from the heart and near to the feet or fingers.dyslipidemia the same as hyperlipidemia, elevated blood cholesterol,LDL cholesterol, triglycerides, or low HDL cholesterol.dyspnea shortness of breath, usually on exertion.Eeccentric hypertrophy hypertrophy with concomitant enlargementor dilatation of the ventricular cavity, as seen in volumeoverload of the left ventricle.edema accumulation of fluid.effusions accumulation of fluid.ejection fraction the fraction of blood ejected from the heartinto the arteries, normally this ranges from 60 to 75%; a lowejection fraction is less than 40%; often used as a marker ofleft ventricular contractility.electrocardiogram test used to diagnose myocardial infarction;EKG or ECG.embolism, embolus sudden blocking of an artery by a clotor foreign material which has been brought to its site oflodgement by the circulating blood. Pulmonary embolism isoften caused by a clot (thrombus) that dislodges from a veinin the thigh or pelvis and shoots into a pulmonary artery.embolization encrusted material, particularly small clots orbacterial vegetation on the heart valves, heart chambers,or veins which may dislodge and fly off into the circulation;they are swiftly carried to other organs, for example,pulmonary embolism.

GLOSSARY623embryo developing human from conception until the end of the8th week by which time all organ systems have been formed.endocarditis infection on deformed or damaged valves in theheart, or at the site of a hole in the heart (ventricular septaldefect).endocardium internal lining of the heart.endothelial pertaining to the innermost part of the intima thatcomes in contact with circulating blood.endothelial dysfunction endothelium (lining of the arteries) isinfluenced by many substances some of which derange thefunction of the endothelial cells.endothelium the innermost part of the intima that comesin contact with circulating blood, a silky smooth layer ofepithelial cells.epistaxis hemorrhage from the nose.Ffibrin an insoluble protein that is essential to clotting of blood,formed from fibrinogen by action of thrombin.fitness ability to undertake physical exercise without unduefatigue; the several types of fitness include aerobic, strength,coordination, and flexibility.Flavonoid any of a large group of crystalline compounds foundin plants.free radical an atom or group of atoms that is highly chemicallyreactive, because it has at least one unpaid electron; freeradicals can attack cells.free radical scavenger a substance that removes or destroysfree radicals.Ggynecomastia enlargement of the breast, usually seen in men.HHDL cholesterol high density lipid; the good cholesterol.heart the size of a closed fist, it lies within the chest cavity,directly under the breastbone (sternum); the shape of the heartis conical with the apex pointing downward to the left edgeof the diaphragm.heart failure failure of the heart to pump sufficient blood fromthe chambers into the aorta; inadequate supply of bloodreaches organs and tissues.hemodynamics the study of the movement of blood and theforces involved in the circulation of the blood.hemoglobin heme – ‘‘iron,’’ globin – ‘‘protein;’’ an iron-proteinsubstance present in red blood cells that carries oxygen to thecells of the body.heterograft a graft of tissue taken from a donor of one speciesand grafted into a recipient of another species, also called axenograft.Holter monitor a machine, the size of a handbook, that iscapable of recording 24–48 hr of continuous electrocardiographicmonitoring; the tracing is used to assess abnormalheart rhythms, particularly serious arrhythmias.homograft a graft of tissue taken from a donor of the samespecies as the recipient.hydrodynamics a branch of the science of mechanics whichtreats of liquids.hypercholesterolemia high levels of cholesterol in the blood.hypercoagulability increased clotting of blood.hyperglycemia high blood glucose levels.hyperkalemia high levels of serum potassium.hyperplasia abnormal increase in the number of normal cells innormal arrangement in an organ or tissue which increases itsvolume.hypertension high blood pressure.hypertriglyceridemia elevated triglyceride level.hypertrophy increase in thickness of muscle.hypocapnia deficiency of carbon dioxide in the blood.hypoglycemia low blood glucose.hypokinesis decreased myocardial contraction usually caused bydamage and weakness of the heart muscle due to coronaryartery disease and cardiomyopathies.hypopnea abnormal decrease in depth and rate of respiration.hypotension marked decrease in blood pressure, usually lessthan 95 mmHghypoxemia severe lack of oxygen in the blood.hypoxia low levels of oxygen in the blood (hypoxemia).hypoxia, hypoxemia severe lack of oxygen in the blood.Iinfarct an area of cardiac necrosis caused by a disruption ofblood supply due to blockage of the supply artery.infarction death of cells (necrosis) caused by a marked deficitin blood supply to the area of cells.infective endocarditis infection of the endocardial lining ofheart valves with microorganisms.inotropic an effect that affects the force of muscular contractions;negative inotropic refers to decreased myocardialcontractility that may lead to poor pumping of blood, reducedejection fraction, and heart failure.intima the innermost lining of the vessel wall that is in contactwith flowing blood.ischemia temporary lack of blood and oxygen to an area ofcells, for example, the heart muscle, usually due tosevere obstruction of the artery supplying blood to this areaof cells.ischemic heart disease atherosclerosis (atheromatous plaques)causes obstruction to coronary arteries depriving the myocardiumof blood containing oxygen and necessary nutrients.

624GLOSSARYKkaryotype chromosomal characteristics of an individual orcell line.Lleft ventricular assist device a device that can replace a leftventricle that is no longer able to pump blood into the aorta.left ventricular dysfunction poor contractility of the leftventricle, this leads to heart failure.leukocytes white blood cells, with monocytes that are scavengerwhite blood cells.Lupus short for systemic lupus erythematosus (SLE).Mmacrovascular damage damage to arteries, arterioles (smallarteries), and small vessels.macula densa specialized cells in the kidney that control sodiumbalance.malignant tumor the tumor that spreads to other organs.maximal oxygen consumption the most oxygen that the bodycan use in aerobic exercise; synonymous with maximal aerobicfitness.media the middle wall of the arteries.metastases distant spread of cancer to various organs.microvascular damage damage to capillaries.mitochondria small spherical cytoplasmic organelles; mitochondriaare the principal sites of ATP synthesis and containenzymes of the citric acid cycle for fatty acid oxidation,oxidative phosphorylation, and other biochemical pathways.They contain their own DNA and ribosomes, replicateindependently, and synthesize some of their own proteins.mitral regurgitation the mitral valve remains open when itshould be completely shut; blood rushes backwards from theleft ventricle into the left atrium.monocytes white blood cells.murmur a blowing sound heard with a stethoscope usuallycaused by obstruction of heart valves or leaking valves.mutations a permanent transmissible change in the geneticmaterial.myocardial infarction death of an area of heart muscle dueto blockage of a coronary artery by blood clot andatheroma; medical term for a heart attack or coronarythrombosis.myocarditis damage to the heart muscle caused by microorganismsor autoimmune and other undefined processes.myocardium the heart muscle.myocytes single muscle cells.myopathy disease of muscle.myopericarditis specific or nonspecific infection of both thepericardium and the myocardium.Nnecrosis cell death.necrotic dead.nephropathy kidney disease.neutrophils white blood cells.New York Heart Association class IV heart failure the worststage, end-stage, severely symptomatic at rest.nosocomial pertaining to or originating in a hospital.notropic an effect that affects the force of muscular contractions;negative inotropic refers to decreased myocardialcontractility that may lead to poor pumping of blood, reducedejection fraction, and heart failure.Ooligohydramnios Deficiency in the amount of amniotic fluid.outflow tract gradient marked thickness of the left ventricularseptum obstructs the blood flow from the left ventricle thatis to be delivered into the aorta.Ppalpitations rapid heart rate; the patient feels the heartbeat.paroxysmal nocturnal dyspnea patient awakens at night fromsleep with severe shortness of breath and must dangle the legsor walk to an open window; relief occurs only after severalminutes.pathogenesis the development of morbid conditions or ofdisease, particularly the cellular events and reactions and otherpathologic mechanisms occurring in the development ofdisease.PCI percutaneous coronary intervention; percutaneous transluminalcoronary angioplasty (PTCA), often involving the useof intracoronary stents.pericardial effusion excess fluid within the pericardial sac.pericarditis inflammation of the pericardium or sac surroundingthe heart; this is not a heart attack.pericardium the thin, tough membrane or sac that surroundsthe heart.phlebitis inflammation of the wall of a vein.plaque of atheroma same as atherosclerotic, a plaque that jutsinto the lumen and obstructs the flow of blood in arteries.platelet aggregation clumping together of small particles in theblood; platelets increase clot formation.platelets very small disk-like particles that circulate in theblood alongside red and white blood cells initiating theformation of blood clots; platelets clump and form littleplugs called platelet aggregation, thus causing minor bleedingto stop.

GLOSSARY625preload the degree of ventricular muscle stretch present at theonset of myocardial contraction; often expressed as enddiastolic volume or pressure.prophylaxis prevention of disease; preventive treatment.proteinuria a leak of protein from the kidney tubules into theurine.proximal near to a center point of the body such as the heart.pulmonary edema fluid in the air sacs and alveoli; the lungsbecome congested and severe shortness of breath occurs.Purkinje fibers the terminal branches of the cardiac conductingsystem that run along the subendocardium.Rrenoprotection protection o f the nephrons of the kidney fromdamage, destruction, and amelioration of albuminuria.retinopathy noninflammatory disease of the retina, particularlycaused by diabetes or hypertension.revascularization procedures that include coronary artery bypasssurgery to bypass obstructive atheromatous plaques or percutaneouscoronary intervention (PCI) using balloon angioplastywith or without stents.rhabdomyolysis disintegration of striated muscle fibers withexcretion of myoglobin in the urine.SS1 the first heart sound caused by closure of the mitral andtricuspid valves.S2 the second heart sound caused by closure of the aortic andpulmonary valves.sarcomere the contractile unit of a myofibril; sarcomeres arerepeating units, delimited by the Z bands, along the lengthof the myofibril that make up the myocardium of the heart.smooth muscle cells cells that are predominant in the middlewall of arteries, the media; these cells migrate into the intimato strengthen the wall that is injured during the developmentof atheroma or following trauma from balloon angioplasty orintracoronary stenting. The strong smooth muscle cells arenature’s effective band-aid that help to fortify the damagedwall of arteries.sodium cardiac channels cardiac cells possess channels throughwhich sodium and potassium flow inward and outward; theexchange of positive and negative charge produces a smallcurrent.stroke damage of part of the brain due to blockage or ruptureof an artery in the brain, which leads to weakness or paralysisof limbs with or without disturbances of speech or consciousness.A stroke or cerebrovascular accident is not a form ofheart attack.sudden cardiac death death from cardiac causes that occursinstantaneously or within the hoursupraventricular tachycardia tachycardia arising in the atrium,that is above the ventricle.sympathomimetic impulses from the sympathetic nervoussystem, adrenergic.syncope temporary loss of consciousness caused by lack ofblood supply to the brain; fainting describes a simple syncopalattack.systole period of contraction of the heart muscle especially ofthe ventricles; blood is ejected from the ventricles.Ttachycardia increase in heart rate exceeding 100 beats perminute.tachypnea increased respiratory rate.thrombi blood clots.thrombocythemia increased levels of circulating bloodplatelets.thrombocytopenia a mild decrease in platelet counts.thromboembolic clots or thrombi that break off from theinterior lining of the heart; they are propelled by the bloodand become lodged in an artery supplying blood to an organor to the extremities.thromboembolism formation of a blood clot and a subsequentdislodgment; the thrombus is carried in the circulating bloodand obstructs an artery.thrombogenic causes clotting of the blood.thrombus (thrombi) blood clot(s).TIA transient ischemic attack; transient lack of blood supply(ischemia) to the brain causing symptoms of mild stroke thatrecover within 24 h.tissues an aggregation of specialized cells which togetherperform certain special functions.torsades de pointes a very serious, life-threatening ventriculararrhythmia.transvenous anything that passes through a vein (catheter orpacemaker lead)tricuspid regurgitation tricuspid valve leaks and blood is propelledbackwards from the right ventricle into the right atriumand into the neck veins.unstable angina severe angina usually occurring at rest.UVvalvular pertaining to the heart valves.valvular disorders disease of heart valves, particularly mitralstenosis, mitral regurgitation, aortic stenosis, and aorticregurgitation.

626GLOSSARYvalvular heart disease pertaining to diseases of the heart and theheart valves.vasculitis inflammation of the walls of a blood vessel.vasoconstriction narrowing, decrease in the diameter of veinsor arteries.vasodilatory dilatation of the lumen of arteries or veins; thisincreases blood flow.venodilatation dilation of veins, as may occur during hotweather, hot baths, and by some drugs such as ACE inhibitorsand nitroglycerin.ventricle one of the two lower chambers of the heart.ventricular cavity the chamber of the ventricle.ventricular dysfunction poor contractility of the ventricleusually causing a decrease in ejection fraction.ventricular fibrillation the heart muscle does not contractbut quivers; therefore, there is no heartbeat (cardiac arrest)and no blood is pumped out of the heart; death occurswithin minutes if the abnormal heart rhythm is notcorrected. Note that in atrial fibrillation, the atrium fibrillatesbut the ventricles contract normally although faster thannormal; this condition is usually not life-threatening and iseasily controlled with the commonly known heart drugdigoxin.ventricular septal defect a hole in the septum, that divides theleft and right ventricles.visceral adiposity marked accumulation of fat that covers theabdominal organs, often termed abdominal obesity; the fataround the waistline also covers the internal organs withinthe abdomen.Wwall tension force exerted on the vessel or chamber wallacting to pull it apart in a circumferential direction; it is afunction of the radius and the pressure within the lumen orchamber.Wolff-Parkinson-White syndrome characterized by prematureexcitation of the ventricles due to an anomalous conductionbypass tract between the atria and ventricles; often leads torapid heart rates.Xxenobiotic compound that is foreign to the body, such as a drugor an environmental pollutant.

INDEXAbciximab, as antiplatelet agent, 82Abdominal aortic aneurysmclinical studies, 30from hypertension, 477pathogenesis, 27–28signs and symptoms, 28–29treatment, 29–30AbioCor, 106ACE, see Angiotensin-converting enzymeAcebutololas beta-blocker, 166for hypertension, 484Acetazolamide, for high-altitude pulmonary edema, 10Acquired immunodeficiency syndromeand heart, 463and left ventricular systolic dysfunction, 464and myocarditis, 464, 541pericardial effusion, 463–464Acromegaly, features and management, 363–364ACTC, see Alpha cardiac actinACTH-dependent adenoma,see Adrenocorticotropic hormone-dependent adenomaAction potential, 87Acute atrial fibrillation, 143–145Acute coronary syndromecharacteristics and treatment, 54–55definition, 79, 169, 515Acute heart attacks, indications, 58Acute myocardial infarctionACE inhibitor indications, 63beta-blocker therapy, 161in coronary artery bypass surgery, 271electrocardiography, 343–344, 346in women, 611Adalat XL, see nifedipineAdenoma, ACTH-dependent,see Adrenocorticotropic hormone-dependentadenomaAdenovirus Gene Therapy Trial, 394Adrenal disorders, and heart, 364–365Adrenaline, see Epinephrinefrom stress, 569–571AAdrenocorticotropic hormone-dependent adenoma, 364Adventitia, 101Aerobic exercisecaloric costs of work, 377–378cardiopulmonary physiology, 376–377cardiovascular training, 378–380effect, 377overview, 376physiologic hypertrophy, 380Aesculus hippocastanum, see Horse chestnut seedAfrican-Americanscoronary artery disease, 556heart failure, 554–556hypertension, 553–554stroke, 556Afterloadin aerobic exercise, 376definition, 35, 61, 159, 229, 375, 469, 493AGENT, see Adenovirus Gene Therapy TrialAggrastat, see TirofibanAggregation, 79Aging heartassociated changes, 1–2and atherosclerosis risk, 126basic problem, 1cardiovascular therapy, 2–3research implications, 3AHA, see American Heart AssociationAIDS, see Acquired immunodeficiency syndromeAlcoholand abnormal heart rhythms, 7and cardiomyopathy, 6–7and coagulation factors, 7and coronary heart disease, 5–6and heart failure, 6and hypertension, 6, 480post-heart failure, 444–445and stroke, 7wine comparisons, 7–8Aldactone, see SpironolactoneAldosterone, 61Aldosterone antagonistsas diuretics, 317–318heart failure treatment, 443627

628INDEXAldosterone receptor blocking agents,and heart hypertrophy, 498–499Aliskiren, for hypertension, 490ALLHAT, see Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack TrialAllograft, 277Alpha-blockersand heart hypertrophy, 498for hypertension, 489Alpha cardiac actin, in young athlete hypertrophiccardiomyopathy, 133Alpha Tocopherol Beta-Carotene Cancer Prevention Trial, 72–73Altace, see RamiprilAlteplase, heart attack therapy, 416Alternative therapy, history and regulation, 453–454Ambulance transport, and heart attack, 407–409American Beta-Blocker Heart Attack Trial, for beta-blockers, 164American Heart Associationhomocystinemia screening, 467ventricular fibrillation guidelines, 216Amiloride, as diuretic, 317Amiodaroneas antiarrhythmic agent, 97–98for cardiac arrest, 220induced thyroid dysfunction, 598for paroxysmal atrial fibrillation, 145–146Amlodipineas angina treatment, 50–51as calcium antagonists, 194–195for hypertension, 488Amplatzer spetal occluder, for atrial septal defect, 151–152Anabolic steroidsand athletes, 460in athlete sudden cardiac death, 135Anderson-Fabry disease, 23Anemiaclinical studies, 25–26and heart function, 25severe anemia, 41Aneurysmsabdominal aortic aneurysm, 27–30, 477aortic dissection, 31–32atrial septal aneurysms, 536–537berry aneurysm, 32definition, 27, 175, 609dissecting aneurysm, 162thoracic aortic aneurysm, 30–31Angina, see also Coronary artery diseaseanti-inflammatory agent treatments, 52aspirin treatment, 51–52atheroma, 37–38beta-blocker therapy, 47–50, 161CAD as cause, 35–36calcium blocker treatments, 50–51coronary arteriograms, 592coronary artery bypass graft, 268definition, 25, 79, 85, 159, 227, 233, 267, 277,307, 363, 397, 453, 539, 569, 589, 597, 599diagnosis, 39–40, 42diseases causes, 40–41and heart failure, 53and hypertension, 53men vs. women, 610–611Nicorandil treatment, 52nondrug treatment, 42–44overview, 36–37pain mechanism, 38–39precipitation, 40Prinzmetal’s angina, 53–54Ranolazine treatment, 52–53and silent ischemia, 53stable angina, 41–42, 58, 113, 268statin treatments, 52from stress, 569unstable angina, 41–42, 54–55, 58, 113, 268, 277variant angina, 40Anginal pain, and smoking, 337–338Angina pectorischaracteristics, 40definition, 57, 193, 375, 391Angiogenesisand atherosclerotic plaques, 126definition, 117Angiogramsfor angina, 42for pulmonary embolism, 551Angiopeptin, in drug-eluting stents, 567Angioplasty,see Percutaneous transluminal coronary angioplastyfor angina treatment, 55heart attack therapy, 416–417Angiotensin-converting enzyme, 61Angiotensin-converting enzyme inhibitorsadverse effects, 65for African-American heart failure, 555–556and anthracycline-induced heart disease, 230associated research, 63–65and atrial fibrillation, 142available blockers, 62and heart attack, 415for heart failure, 419, 440–441and heart hypertrophy, 498for hypertension, 487hypertension treatment, 480–481indications, 62–63interactions, 65mechanism of action, 61–62Angiotensin II, and hypertrophy, 494Angiotensin II receptor blockersavailable blockers, 65–66clinical trials, 66in heart failure treatment, 440–442

INDEX629mechanism of action, 65Ankylosing spondylitis, 507Anomalous coronary arteries, as angina cause, 41Anomaly, 131Anorectic agents, and coronary artery disease, 310–311Anthracyclines, in heart damage, 229–231Antiarrhythmic agentsamiodarone, 97–98beta-blockers, 96definition, 281digoxin, 96disopyramide, 98lidocaine, 98mexiletine, 98overview, 95–96procainamide, 98–99quinidine, 99–100sotalol, 96–97Antibiotics, for endocarditis, 360Anticoagulantsfor atrial fibrillation, 148–149definition, 169garlic activity, 456–457Anticoagulation, 77Antidepressant heart attack randomized trial, 291–292Antihistamine, 69Antihypertensive and Lipid-Lowering Treatmentto Prevent Heart Attack Trial, 3Antihypertensive agentsexamples, 483–490hypertension with coexisting diseases, 482Anti-inflammatory agents, for angina treatment, 52Antioxidants, see specific antioxidantsbeta-carotene, 73–74dietary plant-derived flavonoids, 74French red wine, 74–75Mediterranean diet effects, 74overview, 71probucol, 75statins, 71vitamin C, 73vitamin E, 72–73Antiphospholid antibody syndromediagnosis, 77management, 77Antiplatelet agentsaspirin, 80–81blood clot treatment, 171–172Clopidogrel, 81–82garlic as, 456–457indications, 80mechanism of action, 79–80Anxiety, post-heart attack, 420–421AOO, 525Aortaand atherosclerosis, 125in athlete sudden cardiac death, 134coarctation in CHD, 254–255definition, 27in heart disease, 119–120and Marfan syndrome, 505and secondary hypertension, 472Aortic dissectiondiagnostic testing, 31–32management, 32signs and symptoms, 31Aortic regurgitation, 603–604Aortic semilunar valve, anatomy, 18fAortic stenosisas angina cause, 41characteristics, 602–603congenital heart disease, 254Aortic valve stenosis, echocardiography, 329APBs, see Atrial premature beatsAPLA, see Antiphospholid antibody syndromeApnea, 559Aprovel, see IrbesartanARBs, see Angiotensin II receptor blockersArgatroban, blood clot treatment, 173–174L-Arginineas angina treatment, 44and cardiovascular disease, 459for primary pulmonary hypertension, 547Arginine, clinical studies, 85Arm pain, as heart attack mimic, 407Arrhythmiasautomatic implantable cardioverter defibrillator, 100beta-blocker therapy, 162in coronary artery bypass surgery, 272definition, 5, 25, 35, 61, 69, 79, 131, 139, 159, 175, 189,193, 223, 313, 335, 341, 353, 363, 375, 397, 449,453, 463, 493, 515, 539, 559, 575, 581, 599, 609electrocardiographic detection, 347, 349from hypertension, 477and ischmemic zone, 399in myocardial infarction, 418–419, 420and pregnancy, 614and sleep apnea, 563Arrhythmogenic right ventricular dysplasiain athlete sudden cardiac death, 135and ventricular fibrillation, 608Arterial blood gas analysis, for pulmonary embolism, 550Arterial dilatation, 453, 501Arteriesabdominal aortic aneurysm, 28anomalous coronary arteries, 41and atherosclerosis, 125–126brachial arteries, 85carotid arteries, 120–121coronary, see Coronary arteriesin heart disease, 119–121hypertension effects, 476–477

630INDEXArteries [continued ]internal mammary arteries, 269left anterior descending arteries, 267, 269, 333leg arteries, 121pulmonary arteries, 121, 125radial arteries, 269renal arteries, 121trauma from stress, 569upper limb arteries, 125Arterioles, 391Arteriosclerosisdefinition, 175diseases causing, 101–102Arteriovenous malformations, in adults, 256Artificial heartclenbuterol treatment, 109electric total artificial heart, 105–107left ventricular assist device, 107–108overview, 105post-heart failure, 444ventricular assist devices, 107–108ASA, see Atrial septal aneurysmsAscites, 543Asian Indians, heart disease, 556–557ASO, see Amplatzer spetal occluderAspirinas angina treatment, 51–52as antiplatelet agent, 80–81blood clot treatment, 171coronary artery bypass surgery, 273historical overview, 111–112indications and dose, 113–114for Kawasaki syndrome, 502mechanism of action, 112Atacand Amias, see CandesartanATBC, see Alpha Tocopherol Beta-CaroteneCancer Prevention TrialAtenololfor angina treatment, 49–50as beta-blocker, 166for hypertension, 484–485post-heart attacks, 425pregnancy hypertension, 613Atheroma, see also Atherosclerosisassociated arteries, 119–121causes, 36characteristics, 37–38definition, 27, 35, 57, 111, 117, 119, 131, 169, 233, 267,277, 293, 375, 397, 465, 565, 575, 581, 589, 609exercise effects, 381–382history, 118Atheromatous, definition, 201Atheromatous plaquesanti-inflammatory agent effects, 52and blood clots, 170characteristics, 37definition, 227hemorrhage, 127lining erosion, 127rupture, 127Atherosclerosis, see Atheromain angina, 40associated arteries, 119–121, 125–126characteristics, 102–103and cigarette smoke, 337clinical studies, 127–128definition, 13, 71, 79, 105, 119, 159, 227, 335,391, 469, 515, 519, 569and gene therapy, 394–395HDL effects, 238history, 118hydrodynamic forces, 124–125incidence, 117–118pathogenic theories, 121–124research studies, 118, 128–130risk factors, 126Atherosclerotic plaques, and angiogenesis, 126Atherothrombosisdefinition, 117, 575NSAID effects, 516in women, 611–612Athletesdietary supplements, 460normal heart vs. hypertrophic cardiomyopathy, 136sudden cardiac death, 132–135Atkins-type dietfor heart disease, 307for obesity, 523–524Atorvastatin, for cholesterol lowering, 244ATP, in cardiovascular training, 379–380Atrial fibrillation, see also Ventricular fibrillationacute atrial fibrillation, 143–145anticoagulant treatments, 148–149causes, 141–143characteristics, 93in coronary artery bypass surgery, 272definition, 267diagnosis, 140in elderly, 1electronic pacing, 149epidemiology, 140idiopathic atrial fibrillation, 143overview, 139paroxysmal atrial fibrillation, 145–146pathophysiology, 143permanent atrial fibrillation, 148persistent atrial fibrillation, 147–148and ventricular fibrillation, 608Atrial myxoma, 509Atrial pacingfor atrial fibrillation, 149and sleep apnea, 562

INDEX631Atrial premature beats, diagnosis, 89Atrial septal aneurysms, and patent foramen ovale, 536–537Atrial septal defectclinical study, 151–152definition, 319overview, 151Atrioventricular nodal reentrant tachycardia, 90–93Atrioventricular nodefor atrial fibrillation, 149function, 139–140second degree block, 528third degree block, 527–528Atropine, for cardiac arrest, 221Autograft, 251Automated external defibrillator, 216Automatic implantable cardioverter defibrillator, 100Automaticity, 87Avapro, see IrbesartanAVMs, see Arteriovenous malformationsAV node, see Atrioventricular nodeAVNRT, see Atrioventricular nodal reentrant tachycardiaBad cholesterol, see Low-density lipoproteinsBARI, see Bypass Angioplasty Revascularization InvestigationBehavior, type A, and stress, 572Belgian-Netherlands stent study, and stent acceptance, 565Belladonna, 460BENESTENT, see Belgian-Netherlands stent studyBenzothiazepines, 195Beriberi heart disease, 157Berry aneurysm, 32Beta-1 receptors, 160Beta-2 receptors, 160Beta-blockersfor acute atrial fibrillation, 143adverse effects, 164and African-Americans, 556agent differences, 165–166for angina treatment, 47–50as antiarrhythmic agent, 96and atrial fibrillation, 142for cardiac arrest, 220–221in cardiomyopathy sudden death, 208–209classification, 164–165clinical trials, 163–164coronary artery bypass surgery, 273cytochrome P-450 interactions, 285examples, 166–167and heart attack, 415for heart attack pain, 414–415for heart failure, 419, 442–443and heart hypertrophy, 498for hypertension, 483–486hypertension treatment, 481–482Bindications, 161–163mechanism of action, 160for non-ST elevation myocardial infarction, 418for paroxysmal atrial fibrillation, 145–146for permanent atrial fibrillation, 148post-heart attacks, 424–426research implications, 164salutary effects, 160–161therapy in elderly, 2thoracic aortic aneurysm treatment, 31Beta-carotene, antioxidant effects, 73–74Betaloc, see MetoprololBeta myosin heavy chain genein hypertrophic cardiomyopathy, 204in young athlete hypertrophic cardiomyopathy, 133Beta-receptors, 160Bezafibratefor cholesterol lowering, 245for dyslipidemia, 325BHAT, see American Beta-Blocker Heart Attack TrialBicuspid aortic valve, congenital heart disease, 254Bile acid sequestrant resin, 326Bioprosthetic valves, 604–606Bisoprololfor angina treatment, 50as beta-blocker, 166for hypertension, 485post-heart attack, 425Bivalirudin, blood clot treatment, 173–174Black tea, and cardiovascular disease, 460Blastula, 353Bleeding, in coronary artery bypass surgery, 272Blood clotsantiplatelet agent treatments, 171–172causes, 169–170in heart attack, 398heparin treatment, 173–174nondrug treatments, 170oral anticoagulant treatments, 172–173overview, 169thrombolytic agent treatment, 170–171Blood-clotting factors, exercise effects, 382–383Blood flowcaffeine effects, 190exercise effects, 382–383heart as pump, 21Blood pressurecaffeine effects, 190classification, 178daytime and nighttime variability, 179early measurement methods, 175–178early sphygmomanometry, 175exercise effects, 381–382finger cuff measurement, 180as heart attack warning, 404high pressure effects, 180

632INDEXBlood pressure [continued ]home measurements, 179–180level conventions, 471marked variability, 178–179measurement techniques, 180, 469–471pseudohypertension, 179systolic and diastolic, 178white-coat hypertension, 179Blood supply, and stress, 569–570Blood testsfor Chagas disease, 225for extra heartbeats, 88HDLs, 241for heart attacks, 412–413for hypertension, 477–478LDL, 240–241total cholesterol, 240Blood vessels, caffeine effects, 190BNP, see B-type natriuretic peptideBody temperature, in blood clots, 169–170Brachial arteries, 85Bradyarrhythmiasin myocardial infarction, 419in syncope, 583–584Bradychardiadefinition, 581in syncope, 587Bradytachy syndrome, 142Brain-acting drugs, and hypertension, 489–490BreathingCPR steps, 217as heart attack warning, 403–404shortnesss, see Shortness of breathBretylium, for cardiac arrest, 221Bronchitis, in cor pulmonale, 506Brugada syndromein athlete sudden cardiac death, 135clinical features, 183–184definition, 183overview, 183research perspective, 184in syncope, 584and ventricular fibrillation, 608B-type natriuretic peptideclinical studies, 153–154diagnostic perspective, 154–155in heart failure diagnosis, 438overview, 153Bundle branch block, 185–187Bypass Angioplasty Revascularization Investigation, 303Bypass surgery, for angina treatment, 55CABG, see Coronary artery bypass graft surgeryCAD, see Coronary artery diseaseCCaffeineassociated biochemistry, 189cardiovascular effects, 190–191overview, 189Calcificationaging heart, 2in arteriosclerosis, 102Calcium, coronary, evaluation, 593Calcium antagonistsfor angina treatment, 50–51and atrial fibrillation, 142benzothiazepines, 195coronary artery bypass surgery, 273dihydropyridines, 194–195in elderly, 2–3and heart hypertrophy, 498for hypertension, 480, 488mechanism of action, 193–194next generation agents, 196–197for paroxysmal atrial fibrillation, 145–146phenylalkylamines, 195–196for primary pulmonary hypertension, 546therapeutic benefits, 196Caloric costs, in aerobic exercise, 377–378Cambridge Heart Antioxidant Study, 72Canadian Cardiac Randomized Evaluation ofAntidepressant and Psychotherapy Efficacy, 292Canadian Task Force, homocystinemia screening, 467Candesartan, heart failure treatment, 441Capillariesdefinition, 13, 391rupture, 399Capoten, see CaptoprilCAPRICORN Studyfor beta-blockers, 164heart failure treatment, 442CAPRIE study, for Clopidogrel, 81Captim, heart attack clinical trials, 417Captoprilheart failure treatment, 441for hypertension, 487Capture, definition, 525Carace, see LisinoprilCarbohydrates, and obesity, 522Carbon monoxideand blood clots, 170in cigarette smoke, 336–337Carcinoid heart diseaseclinical study, 200diagnosis, 199heart damage, 199overview, 199treatment, 200Cardiac arrestand CPR, 216drugs for, 220–221

INDEX633in loss of consciousness, 216out-of-hospital outcomes, 221–222recognition in CPR, 217Cardiac catheterizationhistorical overview, 591indications, 592–593technique, 591–592Cardiac dysfunction, 25Cardiac enzymes, and heart attacks, 412–413Cardiac nuclear scans, for angina, 42Cardiac outputin aerobic exercise, 376definition, 189, 215, 511Cardiac resynchronization therapy, 443–444Cardiac tamponadecharacteristics, 540definition, 215Cardiac troponin-Tin hypertrophic cardiomyopathy, 204in young athlete hypertrophic cardiomyopathy, 133Cardiogenic shockcauses, 201definition, 157management, 202pathophysiology, 201–202research implications, 202Cardiomyopathyand alcohol, 6–7definition, 5, 87, 139, 223, 293, 363, 433, 449,463, 493, 581dilated cardiomyopathy, 209–211as heart failure cause, 435hypertrophic, see Hypertrophic cardiomyopathyoverview, 203–204peripartum cardiomyopathy, 614restrictive cardiomyopathy, 211sudden death, 207–209Cardioprotectiondefinition, 5, 71, 515Framingham Offspring Cohort, 6Cardiopulmonary resuscitationcardiac arrest recognition, 217cardiac arrest rhythms, 216circulation, 217–219defibrillation, 219–220out-of-hospital outcomes, 221–222overview, 216research implications, 221steps, 217Cardiotoxicity, in anthracycline-induced heart disease, 230Cardiovascular disease effectsL-arginine, 459Danshen, 454Ephedra sinica, 454–455erectile dysfunction, 369feverfew, 457–458garlic, 456–457ginger, 457ginkgo biloba, 455–456ginseng, 457gugulipid, 458hawthorn, 458hellebore, 459historical remedies, 453horse chestnut seed, 458kava, 459licorice, 459linoleic acid, 459natural product, 460St. John’s wort, 459supplements for, 453–454in syncope, 583–584yohimbine, 459–460Cardiovascular magnetic resonance imaging, 593–594Cardiovascular systemnormal sleep effects, 559stress effects, 569–571Cardiovascular therapy, in elderly, 2–3Cardiovascular training, training effect, 378–380Cardizem, see DiltiazemCARE, see Cholesterol and Recurrent EventsCARET, see Carotene and Retinol Efficacy TrialCardizem, see DiltiazemCarotene and Retinol Efficacy Trial, 73Carotid arteries, in heart disease, 120–121Carotid endarterectomy, 577–578Carotid sinus, hypersensitivity in syncope, 583Carvedilol, for angina treatment, 50as beta-blocker, 166for hypertension, 485post-heart attacks, 425Catecholaminesdefinition, 159in myocardial infarction, 398–399in vasovagal syncope, 582–583Catheterizationhistorical overview, 591indications, 592–593technique, 591–592Caudal, 353CCU, see Coronary care unitsCentral retrosternal chest pain, 401Central sleep apnea, 560Cephalic, 353Cerebral infarction, 576Cerebrovascular accident, 575CETP, see Cholesteryl ester transfer proteinChagas diseaseacute phase, 223–224in complete heart block, 527diagnosis, 225latent and chronic phases, 224–225

634INDEXChagas disease [continued ]management, 225transmission, 223CHAOS, see Cambridge Heart Antioxidant StudyCHARM Program, 66, 441–442CHD, see Congenital heart disease; Coronary heart diseaseChelation, clinical study and research, 227–228Chemical septal ablation, in cardiomyopathysudden death, 209Chemotherapeutic agentsas angina cause, 41heart disease induction, 229Chemotherapy-induced heart diseasefrom anthracyclines, 229–231chemotherapeutic agents, 229cyclophosphamide, 2315-fluorouracil, 231–232Chest compression, in CPR, 217–219Chest painas heart attack mimic, 407men vs. women, 610–611Chest X-rayfor Chagas disease, 225in heart failure diagnosis, 438and mitral stenosis, 601–602overview, 590primary arterial hypertension, 544Chlamydia pneumoniae, in atherosclerosis, 122Cholesterolabsorption inhibitors, 245and atheroma, 118bad, 237blood tests, 240–241caffeine effects, 191combination therapy, 245–246coronary artery disease risk, 241–242diet advice, 243–244drugs for lowering, 244–245good, 237–240high-density, see High-density lipoproteinshistorical and clinical trials, 233–235and linolenic acid, 242low-density, see Low-density lipoproteinsand nuts, 243overview, 233and polyunsaturates, 242and saturated fats, 242size of problem, 233total, 237types, 236–237very-low-density lipoproteins, 240Cholesterol absorption inhibitors, for dyslipidemia, 325Cholesterol and Recurrent Events, 235Cholesteryl ester transfer proteinand atherosclerosis, 128and dyslipidemia management, 302Cholestyraminefor cholesterol lowering, 245dyslipidemia treatment, 326Chronic bronchitis, in cor pulmonale, 506Chronic coronary artery disease, in atrial fibrillation, 142Chronic kidney diseases, in secondary hypertension, 472Chronic obstructive lung disease, in cor pulmonale, 506CIBIS-II trial, heart failure treatment, 442–443Cigarette smoking, see also Smokingand atherosclerosis, 126, 337carbon monoxide, 336–337HDL level variability, 239nicotine, 336overview, 335tar fraction, 337Circulationand CPR, 217–219and heart anatomy, 16CKIs, see Cyclin-dependent kinase inhibitorsClenbuterol, and artifical hearts, 109Clonidine, for hypertension, 489Clopidogrelblood clot treatment, 172clinical studies, 81–82for non-ST elevation myocardial infarction, 418ticlopidine comparison, 82CMR, see Cardiovascular magnetic resonance imagingCMV, see CytomegalovirusCoagulation factorsand alcohol, 7in deep vein thrombosis, 288oral contraceptive risk, 263Cocaine, in athlete sudden cardiac death, 135Coenzyme Q10actions, 247clinical study, 247–249research implications, 249Coffeediabetes type 2 risk, 302–303and hypertension, 480Colesevelam, dyslipidemia treatment, 326Collagen, in Ehlers-Danlos syndrome, 506Collagen vascular disease, 527COMET trial, 443Commiphora mukul, see GugulipidCommissures, 251Commotio cordis, in athlete sudden cardiac death, 135Compensatory hypertrophy, 493–494Complete heart block, 526–528Computed tomographyfor aortic dissection, 32primary arterial hypertension, 544Concentric hypertrophy, 493Congenital cyanotic heart disease, 256–258Congenital heart diseaseaorta coarctation, 254–255

INDEX635aortic stenosis, 254bicuspid aortic valve, 254classification, 251in complete heart block, 527in Down syndrome, 319echocardiography, 330patent ductus arteriosus, 253–254and patent foramen ovale, 533and pregnancy, 258, 261in right bundle branch block, 186ventricular septal defects, 252–253Connective tissue, and heart hypertrophy, 495Conn’s syndrome, see HyperaldosteronismConstrictive pericarditis, characteristics andmanagement, 540–541Converting enzyme, 61COPD, see Chronic obstructive lung diseaseCOPERNICUS trial, heart failure treatment, 442–443Coreg, see CarvedilolCorgard, see NadololCoronary angiograms, for angina, 42Coronary angioplasty, heart attack therapy, 416–417Coronary arteriesadult anomalies, 255–256anatomy, 18f, 19–21and atherosclerosis, 125in athlete sudden death, 134definition, 13in heart disease, 120overview, 267spasm in variant angina, 40transthoracic visualization, 333Coronary arteriographyhistorical overview, 591indications, 592–593technique, 591–592Coronary artery bypass graft surgeryangioplasty comparison, 59aspirin treatment, 113complications, 271–272contraindications, 273in elderly, 272–273first time, 267indications, 268life prolongation, 270–271medication advice, 273–274mortality and morbidity factors, 271PCI comparison, 274–275perioperative medications, 273postoperative maintenance, 273survival, 270symptomatic relief, 271types, 268–269Coronary artery disease, see also Anginain African-Americans, 556as angina cause, 35–36in Asian Indians, 556–557in athlete sudden death, 134in atrial fibrillation, 142and B-type natriuretic peptide, 154cholesterol risk, 241–242in complete heart block, 527controversial diets, 307definition, 307, 321diet-drug valvulopathy, 310–311echocardiography, 330and fish oils, 311as heart failure cause, 434–435left main, bypass graft, 268recommended diets, 307–308in right bundle branch block, 186and trans fatty acids, 308–310in ventricular fibrillation, 607–608Coronary calcium, evaluation, 593Coronary care units, heart attacks, 410–411Coronary heart disease, see also Coronary artery diseaseand alcohol, 5–6and atheroma, 37–38definition, 1, 233and obesity, 521Coronary thrombosis, 1Cor pulmonale, diagnosis and management, 505–506Corticosteroids, for Kawasaki syndrome, 502Coughas heart attack warning, 404from high-altitude pulmonary edema, 9Coumadin, blood clot treatment, 172–173COX, see CyclooxygenaseCPR, see Cardiopulmonary resuscitationCrataegus species, see HawthornC-reactive proteinclinical studies, 278–279research implications, 279–280as risk marker, 277–278CREATE, see Canadian Cardiac RandomizedEvaluation of Antidepressant and PsychotherapyEfficacyCreatineand athletes, 460definition, 25CREDO Trial, for Clopidogrel, 81–82CRP, see C-reactive proteinCryptogenic, 533CSA, see Central sleep apneaCT, see Computed tomographyCURE Trial, for Clopidogrel, 81Cushing’s syndromeand heart, 364and secondary hypertension, 473Cyanosis, 251Cyclin-dependent kinase inhibitors, and genetherapy, 395

636INDEXCyclooxygenaseand aspirin mechanism, 112NSAID effects, 80Cyclooxygenase inhibitors, 515Cyclophosphamide, heart disease induction, 231Cyclosporine, type 1 diabetes studies, 305Cytochrome P-450beta-adrenergic blocking agent interactions, 285definition, 281functions, 281–283regulation, 283statin interactions, 283, 285Cytomegalovirusin atherosclerosis, 122and NSAIDs, 516–517Dacron, abdominal aortic aneurysm treatment, 29Danshen, and cardiovascular disease, 454DCM, see Dilated cardiomyopathyDean Ornish program, for heart disease, 307Deathfrom high-altitude pulmonary edema, 9sudden cardiac death, see Sudden cardiac deathDeep vein thrombosisdiagnosis, 288–289incidence and location, 287management, 289–290and oral contraceptives, 264and patent foramen ovale, 536pathogenesis, 287–288Defibrillationin CPR, 219–220errors, 220Definitive medical management, aortic dissection, 32Demand pacemaker, 525Depressiondrug management, 291–292overview, 291pathophysiologic mechanisms, 291post-heart attack, 420–421Dextrocardia, in adults, 256Diabetes mellitusand atherosclerosis risk, 126beta-blocker therapy, 163caffeine effects, 191coronary artery bypass graft, 268in erectile dysfunction, 369HDL level variability, 239incidence, 293–294vascular abnormalities, 298Diabetes Prevention Trial-Type I, 305Diabetes type 1management, 305Dpathogenesis, 303–304pathologic features, 304–305research studies, 305–306symptoms and complications, 305Diabetes type 2clinical studies, 302coffee consumption risk, 302–303diagnosis, 294–295dyslipidemia, 298–299, 301–302features, 295fibrinolysis defect, 299genetic abnormalities, 299hyperglycemic hyperosmolar coma, 301insulin effects, 298insulin resistance, 303insulin secretion, 295–297management, 299–301mechanisms, 297–298nephropathy, irbesartan effects, 66symptoms, 294thrombosis defect, 299Diabetic distress, and cardiovascular disease, 294Diapedese, 117Diastolic blood pressure, 178Diastolic heart murmurs, 514Dietantioxidant effects, 74cholesterol advice, 243–244controversial diets, 307for heart attack prevention, 428–429and obesity, 521–523, 523–524post-heart attack, 421post-heart failure, 444–445recommended diets, 307–308Dietary supplementsathletes, 460and cardiovascular disease, 454–460regulation, 453–454Diet-drug valvulopathy, 310–311Digitalisfor African-American heart failure, 556as antiarrhythmic agent, 96heart failure treatment, 438–439for paroxysmal atrial fibrillation, 145–146Digitoxin, heart failure treatment, 439–440Digoxin, see DigitalisDihydropyridines, as calcium antagonists, 194–195Dilated cardiomyopathy, 209–211Diltiazemas angina treatment, 51as calcium antagonist, 195for hypertension, 488D-Dimer, in deep vein thrombosis diagnosis,288–289Dipyridamole, blood clot treatment, 171–172Disopyramide, as antiarrhythmic agent, 98

INDEX637Dissecting aneurysm, beta-blocker therapy, 162Distal, definition, 287Diureticsfor African-American heart failure, 555aldosterone antagonists, 317–318and atrial fibrillation, 142for heart failure, 419, 442and heart hypertrophy, 498for hypertension, 486–487indications, 313loop diuretics, 316–317potassium-sparing diuretics, 317–318pregnancy hypertension, 613–614thiazides, 315–316Dizziness, as heart attack warning, 404DNA, gene therapy strategies, 391–392Door-to-needle time, for heart attacks, 400Doppler echocardiography, 603Down syndromecongenital heart malformations, 319genetics, 319Drug-eluting stentscoronary bypass surgery, 274types, 566–567Drug interactionsDanshen, 454Ephedra sinica, 454–455Drug therapyfor cardiac arrest, 220–221for cholesterol lowering, 244–246in complete heart block, 527cytochrome P-450 interactions, 283, 285for depression management, 291–292for dyslipidemia, 324–326HDL level variability, 239for heart failure, 438–443for hypertension, 480–482nitrate treatment, 45–47in pericarditis, 539post-heart failure, 444–445pregnancy hypertension, 613–614for type 2 diabetes, 299–300for unstable angina treatment, 55Dual-chamber pacemaker, in cardiomyopathysudden death, 209DVT, see Deep vein thrombosisDyazide, for hypertension, 486Dyslipidemiaabnormalities, 323–324bile acid sequestrant resin treatment, 326cholesterol absorption inhibitor treatment, 325definition, 159, 233, 277, 321, 367, 453, 519diabetes type 2, 301–302fibrate treatment, 325statin treatment, 324–325torcetrapib treatment, 326and type 2 diabetes, 298–299in women, 611Dyspnea, 153, 543Ebstein’s anomaly, 507EBT, see Electron beam tomographyEccentric hypertrophy, 493ECG, see ElectrocardiographyEchocardiographyfor Chagas disease, 225clinical indications, 332congenital heart disease, 330coronary artery disease, 330Doppler echocardiography, 603examination technique, 328–329handheld instruments, 333heart attacks, 413heart failure, 330, 438historical background, 327–328instrumentation, 328overview, 590primary arterial hypertension, 544research studies, 332in syncope diagnosis, 585thrombus, 329transthoracic visualizations, 333valvular heart disease, 329ED, see Erectile dysfunctionEdemadefinition, 153, 287, 293and diuretics, 313high-altitude, see High-altitude pulmonary edemapulmonary edema, 9, 157, 159, 193, 247EF, see Ejection fractionEffusions, 157Ehlers-Danlos syndrome, 30, 506Ejection fractiondefinition, 25, 35, 57, 193, 223, 267, 397, 433,449, 463, 553, 559, 607in heart disease test, 591Elderlyaortic dissection, 31atrial fibrillation, 1cardiovascular therapy, 2–3coronary artery bypass surgery, 272–273type 2 diabetes complications, 301Electrical conduction systemin aging heart, 2in athlete sudden cardiac death, 135defects, 346Electric total artificial heartAbioCor, 106Lionheart, 106–107overview, 105–106E

638INDEXElectrocardiographyacute myocardial infarction, 343–344, 346and alcohol, 7for angina, 42arrhythmia, 347, 349and atrial fibrillation, 139–141Brugada syndrome, 183characteristics, 589in coronary care unit, 410definition, 35electrical conduction defects, 346during exercise, 387general applications, 342–343heart attacks, 409–410, 411–412heart hypertrophy, 346historical background, 341–342left bundle branch block diagnosis, 187microvolt T-wave alternans, 349and mitral stenosis, 601–602NIH studies, 349normal type, 343for pericarditis, 540primary arterial hypertension, 544for pulmonary embolism, 551right bundle branch block, 185in syncope diagnosis, 584–585Electrolytes, 313Electron beam tomography, coronary calciumevaluation, 593Electronic pacing, for atrial fibrillation, 149Electrophysiologic testing, in syncope diagnosis, 586ELISA, see Enzyme-linked immunosorbent assayEmbolismdefinition, 263, 267, 287, 533, 575pulmonary, see Pulmonary embolismEmbolization, 151Embolus, see EmbolismEmbryodefinition, 353heart development, 353–357Emotional state, post-heart attack, 420Emphysema, in cor pulmonale, 506Enalaprilheart failure treatment, 441for hypertension, 487Endarteritis obliterans, 102Endocarditisdefinition, 251, 359diagnosis, 359–360infection sites, 359infective endocarditis, 463prevention, 360–361therapy, 360Endocardium, 199, 229, 359Endocrine diseasesin erectile dysfunction, 369and secondary hypertension, 472–473Endothelial dysfunction, 293Endothelial injury, in atherosclerosis, 121–122Endothelial nitric oxide synthaseFrench red wine, 74in penile erection, 367and wine effects, 7Endothelin-1 receptor antagonists, 546–547Endothelium, 85, 117, 367, 465Endovascular stent grafts, for abdominal aorticaneurysm, 29–30eNOS, see Endothelial nitric oxide synthaseEnzyme-linked immunosorbent assay, for pulmonaryembolism, 550–551Ephedra sinica, 454–455EPHESUS, see Eplerenone post myocardial infarctionand heart failure efficacy and survival studyEpilepsyand complete heart block, 526in loss of consciousness, 215Epinephrinefor cardiac arrest, 220in cardiovascular training, 380Epistaxis, 101Eplerenonefor African-American heart failure, 556as diuretic, 317–318heart failure treatment, 443and heart hypertrophy, 499for hypertension, 487post-heart attacks, 426Eplerenone post myocardial infarction and heartfailure efficacy and survival studyfor diuretics, 318heart failure treatment, 443EP testing, see Electrophysiologic testingEptifibatide, as antiplatelet agent, 82ERA, see Estrogen Replacement and Atherosclerosis TrialErectile dysfunctioncauses, 369definition, 367phosphodiesterase inhibitor treatment, 369–370sildenafil treatment, 370–372Tadalafil treatment, 372–373Vardenafil treatment, 372–373Esophageal spasm, as heart attack mimic, 406–407Estrogen Replacement and Atherosclerosis Trial, 612Euroinject, 394European International Task Force, 467Event recorders, in syncope diagnosis, 585Everolimus, in drug-eluting stents, 567Exerciseadvice for starting, 385–386as angina treatment, 44atheroma effects, 381–382benefits, 375–376

INDEX639blood effects, 382–383blood pressure effects, 381–382HDL level variability, 239heart disease studies, 383–384heart rate during, 386–387hypertension treatment, 479overview, 385post-heart failure, 444–445and weight reduction, 381Exercise stress testfor angina, 42characteristics, 387, 589–590men vs. women, 610–611stress test, 589–590Eyes, and Marfan syndrome, 505Ezetimibefor cholesterol absorption inhibition, 245for dyslipidemia, 325Ezetrol, see EzetimibeFACIT, see Folate therapy after coronary intervention trialFactor V, oral contraceptive risk, 264Factor VIII, exercise effects, 382–383Fainting, in loss of consciousness, 215Familial hypercholesterolemia, 235–236Familial predisposition, and atherosclerosis risk, 126Fats, and cholesterol, 242FDA, see Food and Drug AdministrationFeeling of doom, as heart attack warning, 404Felodipine, as calcium antagonists, 195Fenfluramine, and coronary artery disease, 310Fenofibratefor cholesterol lowering, 245for dyslipidemia, 325Fetal alcohol syndrome, 507Fever, from high-altitude pulmonary edema, 9Feverfew, and cardiovascular disease, 457–458Fibratesfor cholesterol lowering, 245for dyslipidemia, 325for dyslipidemia management, 302Fibrin, 287Fibrinolysis, in type 2 diabetes, 299Fibrosis, aging heart, 2Fibrous tissue, and atheroma, 37Finger cuff method, Penaz, 180Fish oils, and coronary artery disease, 311Fitness, 375Flavonoidsantioxidant effects, 74definition, 71, 4535–Fluorouracil, heart disease induction, 231–232Fluvastatin, for cholesterol lowering, 244Foam cells, in atherosclerosis, 122FFolate, for restenosis prevention, 568Folate therapy after coronary intervention trial, 467–468Folic acid, and hyperhomocystinemia, 467Food and beverages, HDL level variability, 238–239Food and Drug Administration, and abdominalaortic aneurysm treatment, 29–30Framingham Offspring Cohort, 6Framingham Point Scores, coronary artery diseaserisk, 241–242Framingham Study, obesity and heart disease, 521Free fatty acids, in type 2 diabetes, 298–299Free radical, 453Free radical scavengerDanshen as, 454definition, 453French red wineantioxidant effects, 74–75German white wine comparison, 7Furosemideheart failure treatment, 442for hypertension, 486as loop diuretic, 316–317Gamma butyrolactone, and athletes, 460–461Gamma globulin therapy, for Kawasaki syndrome, 502Garlic, and cardiovascular disease, 456–457Gemfibrozilfor cholesterol lowering, 245for dyslipidemia, 325Gene therapyadverse outcomes, 394–395clinical application, 392–394strategies, 391–392Geneticsin abdominal aortic aneurysm, 28cigarette smoke and atherosclerosis, 337dilated cardiomyopathy, 209–210Down syndrome, 319hemochromatosis, 449hypertrophic cardiomyopathy, 204type 2 diabetes abnormalities, 299in young athlete hypertrophic cardiomyopathy, 133Genotyping, in cardiomyopathy sudden death, 207German white wine, French red wine comparison, 7Giant cell arteritisas angina cause, 41definition, 501Ginger, and cardiovascular disease, 457Ginkgo bilobaand cardiovascular disease, 455–456for high-altitude pulmonary edema, 10Ginseng, and cardiovascular disease, 457Global Utilization of Streptokinase and t-PAfor Occluded Coronary Arteries, 170G

640INDEXGlyceryl trinitrate, see NitroglycerinGood cholesterol, see High-density lipoproteinsGore-Tex, abdominal aortic aneurysm treatment, 29Grafts, coronary artery bypass surgery, 268–269Grapefruit, and cardiovascular disease, 460Gugulipid, and cardiovascular disease, 458GUSTO, see Global Utilization of Streptokinase andt-PA for Occluded Coronary ArteriesGynecomastia, 313Hallmark Scandinavian Simvastatin Survival Study, 234Hawthorn, and cardiovascular disease, 458HCM, see Hypertrophic cardiomyopathyHeart attacks, see also Myocardial infarctionacute, 58ambulance transport, 407–409arm pain mimic, 407associated symptoms, 403–405beta-blocker treatments, 424–426blood tests, 412–413caffeine effects, 190and cardiac enzymes, 412–413causes, 398–400chest wall pain mimic, 407clinical trials, 405, 417depression and anxiety, 420–421diet after, 421door-to-needle time, 400echocardiography, 413electrocardiogram, 411–412emotional impact, 420eplerenone after, 426hospital expectations, 409–411lung infection mimic, 407mimics, 405–407overview, 397–398pain location, 401–402pain management, 413–415pain severity and duration, 402–403pain types, 400–401patient case history, 426–427pericarditis mimic, 407physical signs, 405prevention diet, 428–429rehabilitation, retirement, travel, 421–422retirement and travel, 423risk factors and prevention, 427–428sexual activity after, 423–424warning attacks, 403Heartbeat, origin, 87–88Heart blockaging heart, 2bundle branch block, 185–187complete heart block, 526–528Hincomplete right bundle branch block, 186left anterior hemiblock, 186left bundle branch block, 187right bundle branch block, 185–186Heart damagefrom anthracycline, 229–231from carcinoid heart disease, 199in hemochromatosis, 450–451Heart developmentanomalies, 355–357biophysical development, 35414 to 18 days, 354post-gastrulation, 353second month, 354–355stages, 35510 to 14 days, 353–354tube elongation, 355Heart and Estrogen/Progestin Replacement Study, 612Heart failureACE inhibitors, 63, 440–441African-American population, 554–556in African-Americans, 554–556aging effects, 1and alcohol, 6aldosterone antagonist treatment, 443in angina patients, 53angiotensin receptor blocker treatment, 440–442artificial heart, 444in atrial fibrillation, 142basic causes, 434–435beta-blocker therapy, 162, 442–443cardiac resynchronization therapy, 443–444in coronary artery bypass surgery, 271–272definition, 1, 5, 25, 27, 35, 61, 105, 139, 153, 159,175, 185, 189, 193, 203, 229, 247, 267, 313, 327,363, 367, 397, 449, 453, 463, 469, 493, 511, 515,519, 539, 543, 553, 559, 597, 599, 609diagnosis, 438digitalis treatment, 438–439digitoxin treatment, 439–440discharge from hospital, 445–446and diuretics, 313diuretic treatment, 442echocardiography, 330from hypertension, 476–477incidence and pathogenesis, 433–434in myocardial infarction, 419natural defense mechanisms, 436–437nitrate treatment, 442nondrug therapy, 444–445NSAID effects, 517and obesity, 521precipitating factors, 435–436and sleep apnea, 560–562symptoms and signs, 437–438terminology, 437

INDEX641transplantation, 444vitamine E role, 73Heart hypertrophyin aerobic exercise, 380affecting factors, 495angiotensin II, 494causes and complications, 495compensatory hypertrophy, 493–494concentric hypertrophy, 493definition, 1, 23, 61, 131, 185, 341, 469diagnostic overview, 495–497eccentric hypertrophy, 493electrocardiographic detection, 346left ventricular hypertrophy, 207–208mitochondria, 495prevention and management, 497–499RNA, 494–495HeartMate, 107Heart murmurscharacteristics, 511, 599classification, 513–514clinical cases, 511–512definition, 151, 251, 599diagnostic clues, 512–513investigative tests, 514Heart muscleand acromegaly, 363–364aging effects, see Aging heartand anemia, 25angina overview, 36–37aortic semilunar valve, 18farginine role, 85beta-blocker effects, 49caffeine effects, 190chambers, 13, 18–19coronary arteries, 17f, 19–21and Cushing’s syndrome, 364definition, 13and depression, 291–292and hyperaldosteronism, 365hypertension effects, 476–477and hypothyroidism, 364internal anatomy, 15fand Marfan syndrome, 505myocardium, 13overview, 13pericardium, 13and pheochromocytoma, 365and pulmonary circulation, 16fas pump, 21rhythm, and alcohol, 7and surronding structures, 14fsystemic veins, 20fand thyrotoxicosis, 364Heart Outcomes Prevention Evaluation Trial, 73Heart ratecaffeine effects, 190as heart attack warning, 404–405maximum during exercise, 386–387Heimlich Maneuver, 222Helicobacter pylori, in atherosclerosis, 122Hellebore, 459Hemochromatosisdefinition, 449diagnosis, 451genetics, 449incidence, 449iron overload, 449management, 451myocardial damage mechanisms, 450–451signs and symptoms, 451Hemodynamics, 117, 203Hemorrhagein atheromatous plaques, 127in gene therapy, 395and ginkgo biloba, 455–456Hemostatic factors, and alcohol consumption, 6Heparinsfor acute atrial fibrillation, 144blood clot treatment, 173–174in deep vein thrombosis management, 289heart attack therapy, 416low molecular weight heparins, 173, 289–290, 416unfractionated heparin, 173, 416Herbal stimulants, in athlete sudden cardiac death, 135Herbal supplementsand cardiovascular disease, 454–460regulation, 453–454HERS, see Heart and Estrogen/Progestin Replacement StudyHeterograft, 251Hiatus hernia, as heart attack mimic, 406High-altitude pulmonary edemaclinical study, 10management, 10mechanisms, 9–10research implications, 10–11signs and symptoms, 9High-density lipoproteinsand alcohol, 5–6and atherosclerosis, 128atherosclerosis effect, 238blood tests, 241coronary artery disease risk, 242definition, 5exercise effects, 382and hormone therapy, 612level variability, 238–240metabolism, 237–238oral contraceptive risk, 264overview, 237trans fatty acids and CAD, 309in type 2 diabetes, 299

642INDEXHigh thyroid, see HyperthyroidismHippocrates, early disease remedies, 111Hirudin, blood clot treatment, 173–174HIV, see Human immunodeficiency virusHMC-CoA reductase inhibitors, for cholesterollowering, 244–245Holter monitordefinition, 131overview, 590in syncope diagnosis, 584–585Holt-Oram syndrome, 507Homocysteineand atherosclerosis risk, 126benefits of decrease, 467blood levels, 467clinical studies, 465–466, 467–468metabolism, 465and vascular disease, 465Homograftdefinition, 251for valve damage, 606HOPE Trial, see Heart Outcomes PreventionEvaluation TrialHormone therapy, women, 611–612Horse chestnut seed, and cardiovascular disease, 458Hospitalsdischarge post-heart failure, 445–446heart attack expectations, 409–411Human immunodeficiency virusand heart, 463in myocarditis, 541Hydralazinefor hypertension, 489pregnancy hypertension, 613Hydrochlorothiazide, for hypertension, 486Hydrodynamicsin atherosclerosis, 124–125definition, 117Hyperaldosteronismand heart, 365and secondary hypertension, 473Hypercholesterolemiacauses, 235–236characteristics, 323–324definition, 5, 321in hyperthyroidism, 598Hypercoagulability, 287Hyperglycemia, 293Hyperglycemic hyperosmolar coma, in elderlytype 2 diabetes, 301Hyperhomocystinemiaassociated conditions, 466management, 467screening, 466–467Hyperkalemia, 61, 215Hyperplasia, 101HypertensionACE inhibitors, 62–63, 487in African-Americans, 553–554and alcohol, 6, 480alpha-blockers, 489and angina, 53artery and heart effects, 476–477and atrial fibrillation, 140, 142available drugs, 480–482beta-blocker therapy, 161–162, 483–486blood pressure level conventions, 471blood pressure measurement, 469–471brain-acting drugs, 489–490calcium antagonists, 488causes, 471–474and coexisting diseases, 482and coffee, 480in coronary artery bypass surgery, 272definition, 1, 313, 453and diuretics, 313diuretics, 486–487and exercise, 479as heart attack risk factor, 427as heart failure cause, 435and kidney damage, 477malignant hypertension, 473–474nondrug treatment, 478NSAID effects, 517and obesity, 521oral contraceptive risk, 264and organ damage, 482–483overview, 469and pregnancy, 613–614primary essential hypertension, 471–472, 474–475,475–476primary pulmonary hypertension, 545–546, 546–547pseudohypertension, 179pulmonary arterial hypertension, 543–544, 544–545secondary hypertension, 472–473and sleep apnea, 563and smoking, 480sodium restriction, 478–479and stress, 479and stroke, 477symptoms, 477tests for, 477–478vasodilators, 489and weight reduction, 479white-coat hypertension, 179Hypertensive arterioslcerosis, 101Hypertensive heart diseaseechocardiography, 332in right bundle branch block, 186Hyperthyroidismand secondary hypertension, 473signs, symptoms, treatment, 597

INDEX643Hypertriglyceridemiacharacteristics, 323definition, 321in hyperthyroidism, 598Hypertrophic cardiomyopathyas angina cause, 41athlete heart comparison, 136beta-blocker therapy, 163clinical features, 207features, 204genetics, 204pathophysiology, 207sudden death, 207–209in young adult sudden cardiac death, 255in young athlete sudden cardiac death, 132–134Hypocapnia, 549Hypoglycemia, 293Hypokinesis, 223, 327Hypopnea, 559Hypotensiondefinition, 25, 27, 61, 229, 453, 539, 581management, 586in syncope, 583Hypothyroidismand heart, 364signs, symptoms, treatment, 597–598Hypoxemia, 9, 251Hypoxiadefinition, 9, 549and high-altitude pulmonary edema, 9–10and ventricular fibrillation, 608Iatrogenic, in complete heart block, 528Ibutilide, for acute atrial fibrillation, 143ICAM-I, see Intracellular adhesion molecule-IIdiopathic atrial fibrillation, in atrial fibrillation, 143Idiopathic degenerative disease, in complete heart block, 527Iliac vesselsand atherosclerosis, 125in heart disease, 121Imdur, see Isorbide mononitrateImmobilization, in deep vein thrombosis, 287–288Impotence, smoking, 338Incomplete right bundle branch block, 186Inderal, see PropranololIndigestion, as heart attack mimic, 406Indo-Mediterranean Diet, coronary artery disease, 308Infarct, definition, 61Infarctioncerebral infarction, 576definition, 575myocardial, see Myocardial infarctionInfectionin atherosclerosis, 122–124Iin complete heart block, 527in coronary artery bypass surgery, 272as heart attack mimic, 407and mitral valve prolapse, 604in pericarditis, 539sites in endocarditis, 359Infective endocarditis, 463Infiltrative diseases, in complete heart block, 527Inflammatory response, in atherosclerosis, 121–122Inhibited pacemaker, 525Injury, during jogging, 385iNOS, see Nitric oxide synthaseInotropic, 193, 433, 453Inspra, see EplerenoneInsulinresistance in diabetes type 2, 303in type 2 diabetes, 295–297, 298for type 2 diabetes management, 299–300Integrilin, see EptifibatideINTERHEART, smoking study, 337Internal mammary arteries, grafts, 269International Study of Infarct Survival, 112Intima, 27, 101, 117, 565Intracellular adhesion molecule-I, 279Intracoronary stent, 416–417Intracranial hemorrhage, 578Irbesartanfor diabetic nephropathy, 66heart failure treatment, 441Iron, in hemochromatosis, 449Irregular beats, causes and diagnosis, 88–89Ischemiadefinition, 25, 57, 85, 117, 159, 229, 251, 327, 341,367, 391, 575and lethal arrhythmias, 399myocardial ischemia, 38silent ischemia, 53Ischemic heart disease, 353Ischemic strokecausation, 576signs and symptoms, 576ISIS-2, see International Study of Infarct SurvivalIsometric exercise, 380–381Isoptin, see VerapamilIsorbide mononitrate, for angina treatment, 47Isordil, see Isosorbide dinitrateIsosorbide dinitrate, for angina treatment, 46–47Jogging, associated injuries, 385Karyotype, 353Kava, and cardiovascular disease, 459JK

644INDEXKawasaki syndromeas angina cause, 41causation, 502clinical features, 501diagnosis, 501–502management, 502overview, 501Kidney, associated physiology, 314–315Kidney damage, from hypertension, 477Kidney diseasein edema, 313in secondary hypertension, 472Lacidipineas calcium antagonist, 197for hypertension, 488LAD, see Left anterior descending coronary arteriesLanoxin, see Digitalis, digoxinLasix, see Furosemide, frusemideLBBB, see Left bundle branch blockLDL, see Low-density lipoproteinsLeft anterior descending coronary arteriesgrafts, 267robotic bypass surgery graft, 269visualization, 333Left anterior hemiblock, and right bundle branchblock, 186Left bundle branch block, causes and diagnosis, 187Left main coronary artery disease, coronary arterybypass graft, 268Left ventricular assist device, 105Left ventricular dysfunction, 341, 397, 420, 464, 553Left ventricular hypertrophy, 207–208Leg arteries, in heart disease, 121Lercanidipineas calcium antagonist, 197for hypertension, 488Lesionsin atherosclerosis, 121in paroxysmal atrial fibrillation, 146in right bundle branch block, 186in Takayasu, 508Leukocytesin atherosclerosis, 121–122definition, 117Levitra, see VardenafilLicorice, and cardiovascular disease, 459Lidocaine, as antiarrhythmic agent, 98Lifestyle, causing hyperhomocystinemia, 466Light-headedness, as heart attack warning, 404Linoleic acidand cardiovascular disease, 459and cholesterol, 242Lionheart, 106–107LLIPID, see Long-Term Intervention with Pravastatinin Ischemic DiseaseLipid Research Clinics Program, 234Lipidsin atherosclerosis, 122garlic effects, 456trans fatty acids and CAD, 309–310Lipoproteinsabnormalities, 323–324exercise effects, 382function, 321high-density, see High-density lipoproteinslow-density, see Low-density lipoproteinsparticles in atherosclerosis, 121size, 321types, 321–323Lisinopril, heart failure treatment, 441Liver disease, in edema, 313LMWHs, see Low molecular weight heparinsLong QT syndrome, in athlete sudden cardiac death, 135Long-Term Intervention with Pravastatin in IschemicDisease, as cholesterol study, 235Loop diuretics, 316–317Lopressor, see MetoprololLosartan Heart Failure Survival Study ELITE II, 66Loss of consciousness, causes, 215–216Lovastatin, 244Low-carbohydrate diet, 524Low-density lipoproteinsin atherosclerosis, 122blood tests, 240–241characteristics, 237and coronary artery bypass surgery, 271coronary artery disease risk, 241and C-reactive protein studies, 280exercise effects, 382and hormone therapy, 612and ischemic stroke, 576oral contraceptive risk, 264oxidation, 337and TIA management, 578trans fatty acids and CAD, 309in type 2 diabetes, 299Low-fat diet, 524Low molecular weight heparinsblood clot treatment, 173for deep vein thrombosis management, 289–290heart attack therapy, 416Low thyroid, see HypothyroidismLung diseases, in cor pulmonale, 506Lung infection, as heart attack mimic, 407Lungs, beta-blocker effects, 49Lung scan, for pulmonary embolism, 551Lung transplantation, for primary pulmonary hypertension, 547Lupus, 77, 508Lyon Diet Heart Study, coronary artery disease, 308

INDEX645MMacrophage-colony stimulating factor,in atherosclerosis, 122Macrovascular damage, 293Macula densa, 61Magnesium sulfate, for cardiac arrest, 221Magnetic resonance angiographyclinical studies, 594overview, 593–594Magnetic resonance imaging, for aortic dissection, 32Ma Huang, see Ephedra sinicaMalignant hypertension, causes, 473–474Malignant tumor, 199Manidipineas calcium antagonist, 197for hypertension, 488Marfan syndromebeta-blocker therapy, 163symptoms and management, 505Maturity onset diabetes of the young, 299Maximal oxygen consumption, 375MCP-1, see Monocyte chemoattractant protein-1M-CSF, see Macrophage-colony stimulating factorMechanical heart valves, 604Media, 27, 61, 101Medications, causing hyperhomocystinemia, 466Mediterranean dietantioxidant effects, 74for coronary artery disease, 307–308Men, women’s heart comparison, 610–611Menopause, and cardiac disease protection, 611–612MERIT-HF trial, heart failure treatment, 442–443Messenger ribonucleic acid, and wine effects, 7Metabolic syndrome, and obesity, 519Metastases, 229Methyldopafor hypertension, 489–490pregnancy hypertension, 613Metoprololfor angina treatment, 50as beta-blocker, 166for hypertension, 485post-heart attacks, 425Metropolitan height and weight tables, and obesity, 519Mexiletine, as antiarrhythmic agent, 98Microvascular damage, 293Microvolt T-wave alternans, 349Mitochondriadefinition, 375in hypertrophy, 495Mitral regurgitationbeta-blocker therapy, 162–163characteristics, 602definition, 327echocardiography, 329Mitral stenosisbeta-blocker therapy, 162–163characteristics, 601–602echocardiography, 329and pregnancy, 614Mitral valve disease, echocardiography, 329Mitral valve prolapsein athlete sudden cardiac death, 135characteristics, 604Mobile coronary care ambulance, post-heartattack, 408–409Moduretic, for hypertension, 486MODY, see Maturity onset diabetes of the youngMonckeberg’s sclerosis, in arteriosclerosis, 102Monitan, see AcebutololMonocyte chemoattractant protein-1, 122Monocytes, 117Morbidityin coronary artery bypass surgery, 271reduction in heart attack, 415Morphine, for heart attack pain, 413–414Mortalityin coronary artery bypass surgery, 271reduction in heart attack, 415MRI, see Magnetic resonance imagingmRNA, see Messenger ribonucleic acidMuscular system, beta-blocker effects, 49Mutations, 203MYH7, see Beta myosin heavy chain geneMyocardial infarction, see also Heart attacksacute, see Acute myocardial infarctionbeta-blocker therapy, 161bradyarrhythmia complications, 419and catecholamine, 398–399in complete heart block, 527and coronary arteries, 20definition, 1, 13, 35, 57, 61, 71, 79, 87, 111, 117, 139,159, 169, 175, 185, 193, 201, 215, 227, 233, 251,263, 267, 277, 307, 321, 327, 335, 341, 363, 367,375, 391, 433, 453, 465, 469, 493, 501, 515, 519,539, 559, 569, 589, 607, 609heart failure complications, 419from hypertension, 476non-ST elevation, 417–418oral contraceptive risk, 264papillary rupture, 399right ventricular infarction complications,419–420risk assessment, 420tachyarrhythmia complications, 418–419Myocardial ischemia, process, 38Myocarditisand AIDS, 464in athlete sudden cardiac death, 134–135causes, signs, management, 541definition, 463

646INDEXMyocardiumdefinition, 1, 13, 25, 35, 57, 87, 131, 153, 223,341, 353, 363, 391, 449as heart component, 13Myocytes, 193Myofibrillar ATPase, in heart hypertrophy, 495Myopathy, 281Myopericarditis, 229Myosin, in heart hypertrophy, 495Myotonic muscular dystrophy, 508Myxedema, see HypothyroidismNadololfor angina treatment, 50for hypertension, 485National Cholesterol Education Program, 241–242National Institutes of Health, ECG studies, 349Natural products, and cardiovascular disease, 460Nausea, as heart attack warning, 404NCEP, see National Cholesterol Education ProgramNebivolol, as beta-blocker, 166Necrotic, definition, 61, 229Nephropathydefinition, 61types II diabetes, 66Nervous system, beta-blocker effects, 49Neurally mediated syncope, 586Neurologic, in coronary artery bypass surgery, 272Neuromuscular disease, in complete heart block, 527Neutrophils, 9New York Heart Association, heart failure definition,105, 438Niacin, for cholesterol lowering, 245Nicorandil, for angina treatment, 52Nicotineand blood clots, 170as cigarette smoke component, 336Nicotinic acid, see NiacinNifedipineas calcium antagonist, 195for high-altitude pulmonary edema, 10for hypertension, 488Nitratesfor angina treatment, 45–47for heart failure, 419heart failure treatment, 442Nitric oxideand ACE inhibitors, 62and vasodilatory function, 337Nitric oxide synthase, and cardiogenic shock, 202Nitroglycerinfor angina treatment, 45–46for heart attack pain, 415NO, see Nitric oxideNNonrapid eye movement, cardiovascular systemeffects, 559Non-ST elevation myocardial infarction, 417–418Nonsteroidal anti-inflammatory drugsatherothrombosis effect, 516cardiovascular effects, 515–517cautions, 517cyclooxygenase effects, 80and heart failure, 517and hypertension, 517mechanism of action, 112overview, 515prostacyclin effects, 516viral load effects, 516–517Noonan syndrome, 506–507Noradrenaline, from stress, 569–571Norepinephrine, in cardiovascular training, 380Norvasc, see AmlodipineNorwegian Postinfarction Timolol Trial, 163–164Nosocomial, 359Novacor, as artifical heart device, 107NREM, see Nonrapid eye movementNSAIDs, see Nonsteroidal anti-inflammatory drugsNuclear scansfor heart disease, 590–591men vs. women, 610–611Numbness, as heart attack mimic, 407Obesityand African-American hypertension, 554Atkins-type diet, 523–524cardiovascular system effects, 521diet comparison, 524HDL level variability, 239incidence, 519management, 521–523treatment recommendations, 524Obstructive sleep apnea, 560Oligohydramnios, 251Oral agents, antiplatelet activity, 83Oral anticoagulants, blood clot treatment, 172–173Oral contraceptivescoagulation factor effects, 263deep vein thrombosis, 264hypertension, 264myocardial infarction, 264research studies, 264–265risks, 263Organ damage, and hypertension therapy, 482–483Orthostatic hypotensionmanagement, 586in syncope, 583OSA, see Obstructive sleep apneaOutflow tract gradient, 203O

INDEX647Oxidation, LDL, 337Oxygenin cardiovascular training, 378–380for heart attack pain, 415Oxygen consumption, in aerobic exercise, 376Pacemakersfor atrial fibrillation, 149for complete heart block, 526–528conditions not used for, 532electrical safety, 530general complications, 530–531historical overview, 525–526malfunction, 531patient activities, 532for sinus node dysfunction, 528–529temporary pacing, 531–532types, 529–530Pacemaker syndrome, 531Paclitaxel-eluting stent, 567Paget’s disease, 507PAH, see Pulmonary arterial hypertensionPainin angina, 38–39, 337–338angina diagnosis, 39–40chest, men vs. women, 610–611as heart attack mimic, 407heart attacks, 400–403, 413–415Palpitationscauses and diagnosis, 88–89definition, 35, 69Panax ginseng, see GinsengParoxysmal atrial fibrillation, 145–146Paroxysmal atrial tachycardia, 90Paroxysmal nocturnal dyspnea, 203Partial thromboplastin time, oral contraceptive risk, 263Patent ductus arteriosus, in CHD, 253–254Patent foramen ovaleclinical features, 535developmental features, 533–535research implications, 537in stroke, 535–537Pathogenesis, 117Pausinystalia yohimbe, see YohimbinePCI, see Percutaneous coronary interventionPCI CURE, for Clopidogrel, 81Penile erection, associated physiology, 367–369Percutaneous coronary interventionbeta-blocker therapy, 162coronary bypass surgery, 274–275in coronary care unit, 411definition, 79, 169in heart attack clinical trials, 417and stents, 565PPercutaneous intervention, in elderly, 2Percutaneous transluminal coronary angioplastycontraindications and limitations, 58–59outcome, 59procedure, 57–58and restenosis, 566and stents, 565Pericardial effusionand AIDS, 463–464definition, 463Pericarditiscauses, 539definition, 341, 539diagnosis, 539–540as heart attack mimic, 407types, 540–541Pericardiumdefinition, 463as heart component, 13Perioperative mortality, beta-blocker therapy, 163Peripartum cardiomyopathy, and pregnancy, 614Permanent atrial fibrillation, 148Persistent atrial fibrillation, 147–148PET, see Positron emission tomographyPhentermine, and coronary artery disease, 310Phenylalkylamines, as calcium antagonist, 195–196Pheochromocytomaand heart, 365and secondary hypertension, 473Phlebitis, 287Phosphodiesterase inhibitorsfor erectile dysfunction, 369–370for primary pulmonary hypertension, 547Pindolol, for hypertension, 485Piper methysticum, see KavaPKC, see Protein kinase CPlaquesatheromatous plaques, 37, 52, 127, 170, 227atherosclerotic, and angiogenesis, 126Platelet aggregation, 453, 607Platelet glycoprotein IIb/IIIa receptor blockersblood clot treatment, 172for non-ST elevation myocardial infarction, 418types, 82–83Plateletsin blood clots, 169cigarette smoke and atherosclerosis, 337definition, 77, 79, 111, 117, 169, 569Plendil, see FelodipinePolygenic hypercholesterolemia, 236Polypharmacy, aging heart research, 3Polyphenols, in wine comparison, 7Polyunsaturates, and cholesterol, 242Population groups, HDL level variability, 238Positron emission tomography, as heart diseasetest, 590

648INDEXPotassium, post-heart failure, 444–445Potassium-sparing diuretics, 317–318PPH, see Primary pulmonary hypertensionPrague-2 trial, for heart attacks, 417Pravastatin, for cholesterol lowering, 244Prazosin, for hypertension, 489Prednisone, for restenosis prevention, 568Pregnancyand arrhythmias, 614and congenital heart disease, 258, 261heart disease overview, 612–613and hypertension, 613–614and peripartum cardiomyopathy, 614and valvular heart disease, 614Preloaddefinition, 35, 159, 397, 581in vasovagal syncope, 582Premature beats, causes and diagnosis, 88–89Primary essential hypertensioncauses, 471–472, 475–476salt hypothesis, 474–475Primary pulmonary hypertensiondiagnosis, 545risk factors, 545–546therapy, 546–547Prinivil, see LisinoprilPrinzmetal’s angina, 53–54Probucol, antioxidant effects, 75Procainamide, as antiarrhythmic agent, 98–99Procardia, see NifedipineProcardia XL, see NifedipineProphylaxisin deep vein thrombosis management, 289–290definition, 287Propranololas beta-blocker, 166–167for angina treatment, 50for hypertension, 483–484post-heart attacks, 425ProstacyclinNSAID effects, 516for primary pulmonary hypertension, 546Prostaglandin endoperoxidase H synthase inhibitors, 515Prosthetic valvechoices, 604–606murmurs, 514Protein kinase C, and diabetes vascular abnormalities, 298Proteinuria, 61Proximal, 287Pseudohypertension, in blood pressure variability, 179Pseudoxanthoma elasticum, 507–508PTCA, see Percutaneous transluminal coronary angioplastyPTT, see Partial thromboplastin timePulmonary angiogram, for embolism, 551Pulmonary arterial hypertensionlaboratory studies, 544–545risk factors, 543signs and symptoms, 543–544Pulmonary arteriesand atherosclerosis, 125in heart disease, 121Pulmonary circulation, and heart anatomy, 16Pulmonary edemadefinition, 9, 157, 159, 193, 247high-altitude, see High-altitude pulmonary edemaPulmonary embolismdiagnosis, 550incidence, 549investigations, 550–551management, 551pathogenesis, 549pathophysiology, 549–550Pulmonary vein ablation, in paroxysmal atrialfibrillation, 146Pulsatile blood flow, in atherosclerosis, 124–125Pulse, in CPR, 217Purkinje fibers, 87Purple grape juiceantioxidant studies, 74and cardiovascular disease, 460QQT syndromeacute atrial fibrillation, 143–144beta-blocker therapy, 163Quinidine, as antiarrhythmic agent, 99–100RAAS, see Renin angiotensin aldosterone systemRaceand coronary artery disease, 556–557and heart failure, 554–556and hypertension, 553–554and stroke, 556–557Radial arteries, grafts, 269Radiation, in pericarditis, 539Ramipril, for hypertension, 487Ranolazine, for angina treatment, 52–53RAVE, see Regional angiogenesis with vascular endothelialgrowth factor in peripheral arterial diseaseRAVEL studyand restenosis, 566for sirolimus-eluting stents, 566RBBB, see Right bundle branch blockReactive oxygen species, in atherosclerosis, 124–125Red wine, white wine comparison, 7–8Reflex-mediated syncopecarotid sinus hypersensitivity, 583vasovagal syncope, 581–583Reflux esophagitis, as heart attack mimic, 406R

INDEX649Regional angiogenesis with vascular endothelial growthfactor in peripheral arterial disease, 394Renal arteries, in heart disease, 121Renin angiotensin aldosterone system, 494Renin inhibitor, for hypertension, 490Renoprotection, 469ReoPro, see AbciximabResins, for cholesterol lowering, 245Resistance exercise, isometric exercise comparison, 380Responsiveness, CPR steps, 217Restenosisoverview, 565–566as PTCA limitation, 59Restlessness, as heart attack warning, 404Restrictive cardiomyopathy, 211Retinopathy, 101Revascularization, 201REVERSAL, see Reversing atherosclerosis with aggressivelipid-loweringReversing atherosclerosis with aggressive lipid-lowering, 128Rhabdomyolysis, 281Rheumatic fever, in valve damage, 600–601Right bundle branch block, 185–186Right heart failure, 435Right ventricular infarction, 419–420Risk assessmentangina, 54atherosclerosis, 126for atrial fibrillation, 141fcholesterol and coronary artery disease, 241–242coffee and type 2 diabetes, 302–303C-reactive protein as marker, 277–278heart attacks, 427–428myocardial infarction, 420nuts and cholesterol, 243obstructive sleep apnea, 560oral contraceptives, 263–264prevention with aspirin, 113–114primary arterial hypertension, 543primary pulmonary hypertension, 545–546vigorous exercise, 384–385Risk of death, in young athlete hypertrophiccardiomyopathy, 133–134Riva-Rocci sleeve, 177–178RNA, and hypertrophy, 494–495Robotic bypass surgery, LAD graft, 269ROS, see Reactive oxygen speciesRosuvastatinfor cholesterol lowering, 245for dyslipidemia, 325Rubella syndrome, 507S. aureus, in endocarditis, 360S. bovis, in endocarditis, 360SS. durans, in endocarditis, 360S. fecalis, in endocarditis, 360S. fecium, in endocarditis, 360S. viridans, in endocarditis, 360S1, definition, 511S2, definition, 511Salmeterol, for high-altitude pulmonary edema, 10Saltpost-heart failure, 444–445in primary essential hypertension, 474–475restriction in hypertension, 478–479Salvia miltiorrhiza, see DanshenSA node, see Sinoatrial nodeSaphenous vein, grafts, 268–269Sarcoidosis, 509Sarcomere, 131, 203, 493Saturated fatsand cholesterol, 242and obesity, 522Scandinavian Simvastatin Survival Study, 324–325SCD, see Sudden cardiac deathSecondary hypertension, 472–473Secondary Prevention and Antioxidants ofCardiovascular Disease in End-StageRenal Disease, 72Sectral, see AcebutololSeizure, in loss of consciousness, 215Selective serotonin reuptake inhibitors, 291–292Seven Countries Study, cholesterol, 234Severe anemia, as angina cause, 41Sexual activity, post-heart attack, 423–424SHOCK trial, for cardiogenic shock, 202Shortness of breathin aortic stenosis, 603as heart attack warning, 404from high-altitude pulmonary edema, 9Sick sinus syndromeaging heart, 2in atrial fibrillation, 142Sildenafil, for erectile dysfunction, 370–372Silent ischemia, and angina, 53Simvastatin, for cholesterol lowering, 245Single photon emission computerized tomography, 590Sinoatrial node, and calcium antagonists, 194Sinus node dysfunction, 528–529Sinus tachycardia, 90SIRIUS trial, for sirolimus-eluting stents, 566Sirolimus-eluting stents, 566Skeleton, and Marfan syndrome, 505Sleep, cardiovascular effects, 559Sleep apneasand arrhythmias, 563and atrial pacing, 562and heart failure, 560–562and hypertension, 563overview, 559–560

650INDEXSmoking, see also Cigarette smokingin abdominal aortic aneurysm, 27–28angina effects, 44anginal pain, 337–338habituation and cessation, 338and hypertension, 480impotence, 338Smooth muscle cellsin atherosclerosis, 122definition, 565Sodium bicarbonate, for cardiac arrest, 221Sodium cardiac channels, 183Sodium restriction, hypertension treatment, 478–479Sotalolas antiarrhythmic agent, 96–97as beta-blocker, 167SPACE study, see Secondary Prevention andAntioxidants of Cardiovascular Disease inEnd-Stage Renal DiseaseSpecific heart muscle disease, 211–212SPECT, see Single photon emission computerizedtomographySphygmomanometryblood pressure measurement, 469–470historical overview, 175Spironolactonefor African-American heart failure, 556as diuretic, 317heart failure treatment, 443and heart hypertrophy, 498–499SPORTIF, for atrial fibrillation, 149Sports, and stress, 571SSRIs, see Selective serotonin reuptake inhibitorsSt. John’s wort, 459Stable anginaaspirin treatment, 113coronary artery bypass graft, 268Static exercise, see Isometric exerciseStatinsfor angina treatment, 52characteristics, 71for cholesterol lowering, 244–245coronary artery bypass surgery, 273cytochrome P-450 interactions, 283, 285for dyslipidemia, 301–302, 324–325for primary pulmonary hypertension, 547Stent restenosis study, 565Stentsas cardiology advance, 565drug-eluting, see Drug-eluting stentsheart attack therapy, 416–417long-term studies, 567–568Stokes-Adams syndromeand complete heart block, 526and ventricular fibrillation, 608Stomach problems, as heart attack mimic, 406Streptokinaseblood clot treatment, 170–171heart attack therapy, 416STRESS, see Stent restenosis studyStressand atherosclerosis risk, 126cardiovascular system effects, 569–571definition, 569how to handle, 572and hypertension, 479signs and symptoms, 571–572and sports, 571testing in syncope diagnosis, 586and type A behavior, 572Strokein African-Americans, 556and alcohol, 7from hypertension, 477in loss of consciousness, 215–216patent foramen ovale role, 535–537Subarachnoid hemorrhage, 578Subclavian steal syndrome, in syncope, 584Sudden cardiac deathathletesaortic stenosis, 134commotio cordis, 135coronary artery anomalies, 134coronary artery disease, 134from hypertrophic cardiomyopathy, 132–134overview, 131–132ruptured aorta, 134various causes, 134–135definition, 131, 185, 493in hypertrophic cardiomyopathy, 207–209and vigorous exercise, 384–385in young adults, 255Supplementsand cardiovascular disease, 454–460regulation, 453–454Supraventricular tachchardia, 581Surgery, for abdominal aortic aneurysm, 29Surgical management, aortic dissection, 32Surgical myomectomy, in cardiomyopathy sudden death, 209Survival, coronary artery bypass graft, 270Sweating, as heart attack warning, 403Swedish angina pectoris aspirin trial, 112Sympathomimetic, 453Synchronized DC conversion, for persistent atrialfibrillation, 147–148Syncopecardiac causes, 587from cardiac disorders, 583–584causes, 581definition, 27, 131, 183, 215, 251, 463, 543, 581diagnostic evaluation, 584–586in loss of consciousness, 215

INDEX651management, 586–587from orthostatic hypotension, 583reflex-mediated syncope, 581–583unexplained types, 587Syndrome X, as angina cause, 41Syphilis, 30, 509Systemic veins, anatomy, 20fSystole, 159Systolic blood pressure, 178Systolic heart murmurs, 513–514Tachyarrhythmiasin myocardial infarction, 418–419in syncope, 584, 587Tachycardiacharacteristics, 89definition, 35, 139, 363Tachypnea, 543, 549Tadalafil, erectile dysfunction treatment, 372–373Takayasu, lesions and management, 508Tanacetum parthenium, see FeverfewTar fraction, in cigarette smoke, 337TEE, see Transesophageal echocardiographyTenecteplaseblood clot treatment, 171heart attack therapy, 416Tenormin, see AtenololTeratogensand CHD in pregnancy, 258, 261and heart development, 356Terazosin, for hypertension, 489TET, see Transcutaneous energy transferTetralogy of Fallot, 256–258Thiazides, as diuretics, 315–316Thiazolidinediones, for type 2 diabetes management, 301Thoracic aortic aneurysm, 30–31Thoratec, as artifical heart device, 107Thrombin inhibitors, blood clot treatment, 173–174Thromboangiitis obliterans, in arteriosclerosis, 102Thrombocythemia, 549Thrombocytopenia, 77Thromboembolism, 105, 263Thrombogenic, definition, 117Thrombolytic therapyfor blood clots, 170–171in elderly, 2for heart attacks, 415–416Thrombosis, in type 2 diabetes, 299Thrombotic factors, cigarette smoke and atherosclerosis, 337Thrombusdefinition, 79, 287echocardiography, 329Thyroid diseases, and heart, 364Thyroid dysfunction, types and characteristics, 597–598TThyrotoxicosisin atrial fibrillation, 143and heart, 364TIA, see Transient ischemic attackTiazac, see DiltiazemTiclopidineblood clot treatment, 172Clopidogrel comparison, 82Tilt-table testing, in syncope diagnosis, 586Timololfor hypertension, 485–486post-heart attacks, 425Tingling, as heart attack mimic, 407Tirofiban, as antiplatelet agent, 82–83Tissues, 13, 201TNNT2, see Cardiac troponin-TToprol XL, see MetoprololTorcetrapib, for dyslipidemia, 302, 326Torsades de Pointes, 95, 139Total cholesterolblood tests, 240characteristics, 237coronary artery disease risk, 242t-PA, see AlteplaseTranscutaneous energy transfer, AbioCor, 106Transesophageal echocardiographyfor aortic dissection, 31for endocarditis, 360and mitral stenosis, 602overview, 329patent foramen ovale, 533–534Trans fatty acids, and coronary artery disease, 308–310Transient ischemic attackdefinition, 533management, 577–578outcome, 577prevention with aspirin, 114signs and symptoms, 577in syncope, 586–587Transplantationlung transplantation, 547post-heart failure, 444type 1 diabetes studies, 305Transthoracic echocardiogram, 329Transthoracic visualizations, coronary artery, 333Transvenous, 525Triamterene, as diuretic, 317Tricuspid regurgitation, 199Turner syndrome, 507T wave alternans, in myocardial infarction, 420Type A behavior, and stress, 572Ubiquinone, see Coenzyme Q10UKPDS, for beta-blockers, 164U

652INDEXUltrasonographyin deep vein thrombosis diagnosis, 289for echocardiography, 328for pulmonary embolism, 551Unfractionated heparinblood clot treatment, 173heart attack therapy, 416Unstable anginaaspirin treatment, 113characteristics and treatment, 54–55coronary artery bypass graft, 268definition, 277Upper limb arteries, and atherosclerosis, 125Urgent medical management, aortic dissection, 32Urine tests, for hypertension, 477–478VAD, see Ventricular assist deviceVagus nerve, in cardiovascular training, 378Valve damage, from rheumatic fever, 600–601Valve diseasescauses and consequences, 599–600prosthetic valve choice, 604–606Valve disorders, 139, 584Valve lesionsaortic regurgitation, 603–604aortic stenosis, 602–603mitral regurgitation, 602mitral stenosis, 601–602mitral valve prolapse, 604Valvotomy, and mitral stenosis, 602Valvular, definition, 23Valvular heart diseasein atrial fibrillation, 142definition, 581echocardiography, 329as heart failure cause, 435and pregnancy, 614Valvular lesions, in right bundle branch block, 186Valvuloplasty, and mitral stenosis, 602Vardenafil, erectile dysfunction treatment, 372–373Variant angina, disease cause, 40Vascular cell adhesion molecule-1, 121–122Vascular disease, and homocysteine, 465Vascular system, aging effects, 1–2Vasculitis, see Giant cell arteritisVasoconstriction, 453Vasodepressors, in vasovagal syncope, 582Vasodilation, and nitric oxide, 337Vasodilators, for hypertension, 489Vasodilatory, definition, 293Vasopressin, 220Vasotec, see EnalaprilVasovagal syncopemechanisms, 582Voverview, 581–582triggers, 582–583VCAM-1, see Vascular cell adhesion molecule-1Veinsand atherosclerosis, 125pulmonary vein ablation, 146saphenous vein, 268–269systemic veins, 20Venodilatation, 397Venography, in deep vein thrombosis diagnosis, 289Venous ultrasonography, for pulmonary embolism, 551Ventricular assist device, 107–109Ventricular cavity, 131Ventricular dysfunction, 463Ventricular fibrillationclinical features, 607and CPR, 216definition, 87, 131, 159, 183, 215, 375genesis and causes, 607–608management, 608Ventricular premature beatsbeta-blocker treatments, 96diagnosis, 89Ventricular septal defectsas congenital heart disease, 252–253definition, 319and tetralogy of Fallot, 256–257Ventricular tachycardiacharacteristics, 93–95and CPR, 216Verapamilas angina treatment, 51as calcium antagonist, 195–196for hypertension, 488Veratrum, see HelleboreVery-low-density lipoproteins, 240Vesselsand atherosclerosis, 125beta-blocker effects, 49caffeine effects, 190VF, see Ventricular fibrillationVigorous exercise, risk, 384–385Viral infections, in pericarditis, 539Viral load, NSAID effects, 516–517Viral pericarditis, 540Visceral adiposity, 293VISP, see Vitamin Intervention for Stroke PreventionVitamin C, antioxidant effects, 73Vitamin E, clinical studies, 72–73Vitamin Intervention for Stroke Prevention, 126, 468Vitamin supplements, regulation, 453–454VLDL, see Very-low-density lipoproteinsVomiting, as heart attack warning, 404VPBs, see Ventricular premature beatsVSDs, see Ventricular septal defectsVT, see Ventricular tachycardia

INDEX653WWall tension, 27Warfarinfor atrial fibrillation, 148blood clot treatment, 172–173Weakness, as heart attack warning, 404Weight reductionas angina treatment, 42–44and exercise, 381hypertension treatment, 479and obesity, 521–523West of Scotland Coronary Prevention Study, 234–235WHI, see Woman’s Health Initiative StudyWhite-coat hypertension, in blood pressure variability, 179White wine, red wine comparison, 7–8Wine, consumption comparison, 7–8Wolff-Parkinson-White syndromein acute atrial fibrillation, 145in athlete sudden cardiac death, 135characteristics, 93definition, 139, 607and ventricular fibrillation, 608Woman’s Health Initiative Study, 612Womenacute myocardial infarction, 611dyslipidemia, 611heart disease statistics, 609–610hormone therapy, 611–612men’s heart comparison, 610–611pregnant, see Pregnancyand testing technology, 611Work, in aerobic exercise, 377–378WPW, see Wolff-Parkinson-White syndromeXXenobiotic, 281Ximelagatranfor atrial fibrillation, 148–149blood clot treatment, 173–174X-ray, see Chest X-rayYohimbine, and cardiovascular disease, 459–460Zestril, see LisinoprilZetia, see EzetimibeZingiber officinale, see GingerYZ