Mar-Apr 2013 - Indian Heart Journal

2 nd World Summit 

on Echocardiography 

October 25-27, 2013 | new delhi, india 

leela Kempinski Gurgaon Hotel 

REGISTRATION NOW OPEN | www.wsecho.org 

An EduCAtiOnAl COllAbOrAtiOn by: 

• American Society of Echocardiography • European Association of Cardiovascular Imaging, 

• Indian Academy of Echocardiography 

a branch of the European Society of Cardiology 

• Echocardiography Association of the 

Interamerican Cardiology Society 

• Japanese Society of Echocardiography 

• Korean Society of Echocardiography 

• Canadian Society of Echocardiography 

• Chinese Society of Echocardiography 

Abstract Submissions Accepted March 1 – May 31, 2013 

Partho P. Sengupta, MBBS, MD, DM, FASE 

International Chair 

Jagdish C. Mohan, md, dm 

Program Chair

indian heart journal 65 (2013) 152e157 

Available online at www.sciencedirect.com 

journal homepage: www.elsevier.com/locate/ihj 

Original article 

Comparative assessment of platelet Gp IIb/IIIa receptor 

occupancy ratio with Eptifibatide/Tirofiban in patients 

presenting with ACS and undergoing PCI 

Aniket Puri a, *, A. Bansal b , V.S. Narain c , R. Sethi d , S.K. Dwivedi c , V.K. Puri e , R.K. Saran f 

a Associate Professor, Department of Cardiology, CSM Medical University (Erst. King George Medical University), B-58 Sector A, Mahanagar, 

Lucknow, India 

b Senior Resident, Department of Cardiology, CSM Medical University (Erst. King George Medical University), Lucknow, India 

c Professor, Department of Cardiology, CSM Medical University (Erst. King George Medical University), Lucknow, India 

d Assistant Professor, Department of Cardiology, CSM Medical University (Erst. King George Medical University), Lucknow, India 

e Former Professor, Department of Cardiology, CSM Medical University (Erst. King George Medical University), Lucknow, India 

f Professor and Head, Department of Cardiology, CSM Medical University (Erst. King George Medical University), Lucknow, India 

article info 

Article history: 

Received 28 February 2012 

Received in revised form 

30 May 2012 

Accepted 12 August 2012 

Available online 27 August 2012 

Keywords: 

Glycoprotein IIb/IIIa (Gp IIb / IIIa ) 

antagonists 

Acute coronary syndrome 

Percutaneous coronary intervention 

abstract 

Background: The level of platelet inhibition by a Glycoprotein IIb/IIIa (Gp IIb/IIIa ) antagonist 

therapy necessary to minimize thrombotic complications in patients undergoing percutaneous 

coronary intervention (PCI) is a subject of debate. The degree of platelet inhibition 

obtained 10 min after start of Gp IIb/IIIa antagonist therapy predicts adverse events after PCI. 

The aim of this study was to look at platelet inhibition and to compare platelet Gp IIb/IIIa 

receptors occupancy ratio (GpRO) with Eptifibatide and Tirofiban using various dose regimens 

and correlate with 30-day clinical outcomes in patients presenting with high-risk 

acute coronary syndromes (ACS) and undergoing PCI. 

Methods: The patients were divided into four sub groups: (1) Eptifibatide two intracoronary 

bolus (180 mg/kg) alone (E B ); or (2) two intravenous bolus (180 mg/kg) followed by infusion at 

2 mg/kg/min for 24 h (E B þ Inf ); and (3) Tirofiban standard bolus dose (0.4 mg/kg) over 30 min 

followed by infusion at 0.1 mg/kg/min (T Std ); or (4) at ADVANCE dose bolus (25 mg/kg) over 

3 min, followed by infusion at 0.1 mg/kg/min (T Adv ). Number of Gp IIb/IIIa receptors was 

assessed by flow cytometry at baseline and 10 min after the bolus and percentage of free 

receptors was determined to calculate the GpRO. Patients were followed for 30 days for any 

major adverse cardiac events (MACE). 

Results: 200 consecutive patients (including 74% with ST-elevation ACS) were enrolled. 

GpRO in groups E B (n ¼ 48) and E B þ Inf (n ¼ 44) were 62.7% 27.2% and 61.4% 6.1% 

respectively while in the groups T Std (n ¼ 96) and T Adv (n ¼ 12) groups were 35.1% 17.74% 

and 68.8% 27.3% respectively. The GpRO was similar in E B ,E B þ Inf and T Adv groups and 

was significantly higher than T Std group (p < 0.0001). The 30-day MACE rates in E B (4.2%), 

E B þ Inf (4.5%) and T Adv (4.2%) were significantly lower than T Std group (12.5%) (p < 0.01). 

* Corresponding author. 

E-mail address: aniketpuri@hotmail.com (A. Puri). 

0019-4832/$ e see front matter Copyright ª 2012, Cardiological Society of India. All rights reserved. 

http://dx.doi.org/10.1016/j.ihj.2012.08.007

indian heart journal 65 (2013) 152e157 153 

Conclusions: Standard dose Tirofiban results in significantly lower rates of Gp IIb/IIIa receptor 

occupancy ratio and this correlated with higher incidence of 30-day MACE in high-risk ACS 

patients undergoing PCI. 

Copyright ª 2012, Cardiological Society of India. All rights reserved. 

1. Introduction 

The level of platelet inhibition induced by a Glycoprotein IIb/IIIa 

(Gp IIb/IIIa ) receptor antagonist therapy necessary to minimize 

thrombotic complications in patients undergoing percutaneous 

coronary intervention (PCI) has been the subject of various 

studies. Steinhubl et al, in the GOLD study, showed that the 

degree of platelet function inhibition obtained 10 min after the 

start of Gp IIb/IIIa receptor antagonist therapy is an independent 

predictor of the risk of major adverse cardiac events after PCl. 1 

It has been shown that the extent of inhibition of platelet aggregation 

depends on various factors like, (1) the clinical presentation, 

(2) the type of antiplatelet agents used and (3) the dose of the 

antiplatelet agent. However, considerable inter patient variability 

in the platelet inhibitory response has been observed in various 

studies. The effort to achieve and sustain optimal receptor 

blockade had led to various adjustments in the weight-based 

dosing strategies of the different Gp IIb/IIIa receptor antagonist 

drugs namely Abciximab, Eptifibatide and Tirofiban. Initial dose 

finding trials in humans attempted to identify the appropriate 

dosing regimen necessary to achieve and maintain >80% Gp IIb/IIIa 

receptor blockade, or achieve 80% 

of the receptors completely abolished ADP induced platelet 

aggregation, suggesting a steep doseeresponse curve. 2,3 

Quantitative flow cytometry allows platelet membrane 

receptor measurement in whole blood samples and Glycoprotein 

IIb/IIIa receptor occupancy (GpRO) ratio can be 

measured either directly or indirectly. Markers of platelet 

activation have been studied with flow cytometry to predict 

an increased risk of ischemic events after PCI. It has been 

shown that higher levels of platelet GpRO with Eptifibatide 

have been associated with improved myocardial perfusion 

among patients with ST-elevation myocardial infarction. It 

has also been shown that intracoronary administration of 

Eptifibatide results in a high local concentration, which in turn 

may lead to increased levels of platelet GpRO, cause more 

destabilization of platelet aggregates, and promote thrombus 

disaggregation, thereby improving myocardial perfusion. 4,5 

The aim of this study was to compare the platelet Gp IIb/IIIa 

receptors occupancy ratio with Eptifibatide and Tirofiban 

using flow cytometry and to correlate with 30-day clinical 

outcomes in patients undergoing PCI for established clinical 

indications also being treated with Gp IIb/IIIa receptor antagonist 

therapy. 

receiving a Gp IIb/IIIa receptor antagonist therapy in the form of 

either Eptifibatide or Tirofiban based on the treating clinician’s 

discretion. The index diagnosis of ACS included unstable angina, 

noneST-elevation myocardial infarction (NSTEMI), or STelevation 

myocardial infarction (STEMI). All STEMI patients 

included were treated as per best prevailing indications including 

with thrombolytic therapy and decision for PCI was based on the 

physician’s discretion, which in turn was based on current best 

clinical practice with most patients having routine angiography 

within 24 h and proceeding for PCI if needed. The exclusion 

criteria were multivessel PCI at the time of the index procedure; 

severe coronary calcification; unprotected left main stenosis 

>50%; target lesion in a saphenous vein graft; previous stenting 

at the target lesion; or a contraindication to Gp IIb/IIIa receptor 

antagonist therapy. The age, sex, detailed clinical history 

including that of diabetes mellitus, smoking, hypertension, 

family history of coronary artery disease (CAD), hospitalization 

for CAD were noted. At admission a thorough clinical examination 

including measuring the body weight (Wt), pulse rate (PR), 

systolic blood pressure (SBP), determination of Killip class (KC), 

and an electrocardiogram (ECG) was done. In addition to this, 

Troponin T, lipid profile, platelet count before and after PCI, CPK- 

MB the day following PCI were also recorded. 2D Echocardiogram 

was done for determination of left ventricular ejection fraction 

(EF) using Simpson’s method, along with LV end diastolic and end 

systolic volume noted. Informed consent for participation in the 

study was obtained by all patients prior to enrollment. 

During PCI, all of the patients were treated as per protocol 

with at least 325 mg aspirin before the procedure. A loading dose 

of Clopidogrel 300 mg was administered prior to the PCI. A 

weight-adjusted heparin regimen was used to titrate and achieve 

a minimum activated clotting time of 250 s. Guide wires and 

approved stents (drug-eluting or bare metal) were used according 

to standard techniques and based on the performing physician’s 

discretion. Stent was deployed after completion of the 

bolus dose of Gp IIb/IIIa receptor antagonist therapy, and choice of 

drug [Eptifibatide (Group E) or Tirofiban (Group T)] was left to the 

performing physicians discretion and hence the study was not 

randomized or blinded to one treatment or another upon 

enrollment. Each group was further divided into two subgroups 

each based on the dose regimen used viz (1) Eptifibatide two 

intracoronary bolus (180 mg/kg) alone (E B ); or (2) two intravenous 

bolus (180 mg/kg) followed by infusion at 2 mg/kg/min (E B þ Inf ); and 

(3) Tirofiban standard dose (T Std )(0.4mg/kg bolus over 30 min) 

followed by 0.1 mg/kg/min infusion; or (4) at ADVANCE dose (T Adv ) 

(25 mg/kg bolus over 3 min), followed by infusion at 0.1 mg/kg/min 

based on the dose used in the ADVANCE trial. 6 

2. Methods 

We included all consecutive patients admitted to our hospital 

undergoing PCI for an acute coronary syndrome (ACS) and 

3. Platelet aggregometry study 

Ten ml blood samples were taken in 3.8% sodium citrate vials, 

at baseline from the catheter prior to engaging the coronary

154 


ostia and 10 min after both boluses of Eptifibatide; or in case of 

Tirofiban 10 min after starting the infusion. Samples were 

analyzed at an ISO 9001:2000 and NABL certified laboratory by 

flow cytometry using platelet Gp IIb/IIIa Occupancy kit (PLT 

VASP/P2Y12, Biocytex, Marseille, France). At baseline, the 

numbers of Gp IIb/IIIa receptor/cell were calculated and the 

percentage of free receptors was determined. With the 2 nd 

sample, again percentage of free and bound receptors was 

calculated and subsequently Gp IIb/IIIa receptor occupancy 

(GpRO) ratio was determined. The flow cytometric method is 

based on binding of two monoclonal antibodies to platelet 

Gp IIb/IIIa viz Mab1 and Mab2. Monoclonal antibody 1 (Mab 1, 

Clone L4P18) is a murine monoclonal antibody to Gp IIb/IIIa 

complex and the monoclonal antibody 2 (Mab 2, Clone 4F8) is 

a murine monoclonal antibody to beta 3 subunits. Binding of 

these antibodies is used in a flow cytometric assay to directly 

quantify occupied and unoccupied Glycoprotein IIb/IIIa 

receptors. Eptifibatide binds with Mab 2 in a dose-dependent 

manner and has little effect on Mab 1 binding while Tirofiban 

binds with both Mab 1 and Mab 2. The total number of platelet 

Gp IIb/IIIa receptors and number of free Gp IIb/IIIa receptors are 

determined by converting the fluorescence intensity into the 

corresponding numbers of sites per platelet base on a calibrated 

bead standard curve. The final GpRO results for each 

patient were blinded till the end of study period. 

Major adverse clinical event (MACE) end points of recurrent 

ischemia, reinfarction, target vessel revascularization, worsening 

heart failure, repeat hospitalization for cardiovascular 

(CV) causes and CV Death during these 30 days were recorded. 

Worsening heart failure was defined as a worsening in Killip’s 

class of more than one grade. Recurrent ischemia was defined 

as those who had a worsening of NYHA functional class of 

more than one grade during the 30 days and required a step 

up of anti-anginal therapy. Those who could not be stabilized 

on medical therapy and required hospitalization either for 

recurrent ischemia or worsening heart failure, were included 

in the group of repeat hospitalizations. The entire study was 

cleared by the ethics committee of the university and conformed 

to the guidelines set for good clinical practice. 

3.1. Statistical analysis 

SPSS 11.5 software was used for analysis of the data obtained. 

The student t test, Fisher’s exact test and Chi square test were 

used to test the significance between the study groups. Risk 

analysis was carried out by calculating the odds ratio (OR) and 

95% confidence interval (CI). 

4. Results 

Two hundred consecutive patients were enrolled in the study. 

The mean age of the patients was 53 years. The index event 

and indication of PCl was ST-elevation myocardial infarction 

(STEMI) in 74% (38% with anterior wall myocardial infarction 

(AWMI), 36% with inferior wall myocardial infarction (IWMI)); 

noneST-elevation myocardial infarction (NSTEMI) in 22%, and 

unstable angina 4%; in the STEMI group 10% patients had 

primary PCI and 6% had rescue PCI following failed 

thrombolysis. 

Among the cohort 20% patients were diabetic, 32% were 

hypertensive, 32% had dyslipidemia, 50% were smokers and 

38% patients had 2 risk factors. The mean level of troponin 

T elevation on admission was 2.25 ng/ml. Baseline characteristics 

of the patient’s are shown in Table 1. 

Based on the drugs used the patients were divided into two 

groups i.e. the Eptifibatide group (Group E) and the Tirofiban 

group (Group T) and further subdivided into four subgroups 

i.e., (1) Eptifibatide two intracoronary bolus alone (Group E B ) 

which included 48 patients; (2) Eptifibatide intravenous bolus 

followed by infusion (Group E B þ Inf ) which included 44 

patients; (3) Tirofiban standard dose group (T Std ) which 

included 96 patients; and (4) Tirofiban ADVANCE dose (Group 

T Adv ) which included 12 patients. 

4.1. Gp IIb/IIIa occupancy ratio 

The average numbers of Gp IIb/IIIa receptors/cell at baseline was 

73,379 12,426 in the entire cohort. Based on patients 

risk factors in the diabetic subgroup the average number of 

Gp IIb/IIIa receptors/cell was 75,200 10,115; in hypertensive 

patients it was 71,437 11,225; in smokers it was 

72,920 10,246; and in the dyslipidemia group it was 

76,687 10,356. At baseline 6.12% 8.62% Gp IIb/IIIa receptors 

were occupied, which could be attributed to receptor binding 

with fibrinogen and von Willebrand factor. The GpRO ratio 

above baseline in Group E was 70.25% 19.11% while in the 

Group T was 38.20% 20.74% (p < 0.001). 

The absolute GpRO was significantly higher with Group E 

62.1% 17.1% as compared to Group T 38.8% 18.8% 

(p < 0.001). Across all patient risk groups Eptifibatide achieved 

significantly higher GpRO as compared with Tirofiban viz, in 

diabetic patients 61.16% 26% v/s 38.53% 22.23% (p < 0.05); 

in hypertensive patients 56.82% 21.56% v/s 37.57% 22.89% 

Table 1 e Baseline characteristics of patients (n [ 200). 

Patient 

demographics 

Eptifibatide 

(n ¼ 92) 

Tirofiban 

(n ¼ 108) 

Mean age 53 52 

Male 76 96 

Female 16 12 

Diabetes mellitus 24 16 

Hypertension 40 24 

Dyslipidemia 32 32 

Smoker 40 60 

Indications of PCI 

USA 0 8 

NSTEMI 12 32 

STEMI 80 68 

AWMI 56 20 

IWMI 24 48 

Urgency of PCI 

Elective PCI 72 96 

Primary PCI 12 8 

Rescue PCI 8 4 

PCI ¼ Percutaneous Coronary Intervention; USA ¼ unstable angina; 

NSTEMI ¼ noneST-elevation myocardial infarction; STEMI ¼ STelevation 

myocardial infarction; AWMI ¼ Anterior Wall myocardial 

infarction; IWMI ¼ Inferior Wall myocardial infarction.


(p < 0.05); in dyslipidemia patients 67.6% 13.49% v/s 

30.85% 17.31% (p < 0.05); while there was a non-significant 

increase in GpRO with Eptifibatide in smokers as compared 

to Tirofiban 53.31% 23.69% v/s 43.72% 18.02% (Table 2). In 

the presence of visible thrombus the GpRO was significantly 

lower as compared to without visible thrombus in Group E 

with visible thrombus 56.24% 22.96% v/s 75.74% 13.24% 

with no visible thrombus (p < 0.01); and in Group T with visible 

thrombus 29.60% 18.7% v/s 41.20% 18.84% with no visible 

thrombus (p < 0.01). 

The GpRO based on the index event of the patient was 

51.12% 23.75% in the STEMI patients; 38.61% 22.74% in the 

NSTEMI patients and 63.23% 18.7% in the unstable angina 

patients. Interestingly, there was a trend of increased GpRO in 

patients having platelet count greater than 250,000. The GpRO 

achieved according to weight showed significantly higher 

GpRO in the patients having less than 60 kg body weight in 

Group E 67.77% 27.74% v/s 59.78% 19.74% (p < 0.05) and in 

Group T 46.77% 20.13% v/s 31.56% 17.16% (p < 0.05). 

In the subgroup E B absolute GpRO was 62.7% 27.2% while 

in the subgroup E B þ Inf absolute GpRO was 61.4% 6.1%; 

whereas in subgroup T Std absolute GpRO was 35.1% 17.74% 

and in subgroup T Adv was 68.8% 27.3%. Therefore the 

absolute GpRO was similar in subgroups E B ,E B þ Inf and T Adv 

groups which was significantly higher than T Std group 

(p < 0.001). The percentage of patients achieving >80% GpRO 

was only seen with 13% in the E B þ Inf group, 9% in the E B group, 

8% in the T Adv group and in none of the patients in the T Std 

group. There was no difference in any bleeding side effects 

across all four subgroups following the procedure. 

The incidence of 30-day MACE rates in Group E was 4.3% 

(subgroup E B 4.2% and subgroup E B þ Inf 4.5%), while in Group T 

was 13% (subgroup T Adv 8.3% and subgroup T Std 12.5%). There 

was a trend for MACE to be lower with Eptifibatide as 

compared to Tirofiban although this did not reach statistical 

significance (p ¼ 0.06). MACE rates were lower in E B ,E B þ Inf and 

T Adv subgroups than T Std subgroup, however this did not 

reach statistical significance (Table 3). 

5. Discussion 

Glycoprotein IIb/IIIa receptor antagonists have been shown 

to therapeutically down regulate platelet function to prevent 

the thrombotic complications associated with coronary 

artery disease. 7 However, several individual studies, in 

specific patient populations or with suboptimal dosing regimens, 

have found a lack of effect in preventing thrombotic 

complications. 8 These results raise the question as to 

whether a specific dose of Gp IIb/IIIa receptor antagonist, 

adjusted only by patient weight, can provide the same level 

of platelet inhibition across all clinical syndromes and across 

all individuals. 

The GOLD multicenter study, 1 showed that patients who 

did not achieve >95% inhibition of Gp IIb/IIIa receptors after 

bolus of Gp IIb/IIIa receptor antagonist therapy experienced 

a significantly higher incidence of MACE rates (14.4% v/s 6.4%, 

p ¼ 0.006). Patients whose platelet function was 70% inhibition of platelet function 

(p ¼ 0.009) and on multivariate analysis it was found that 

platelet function inhibition >95% at 10 min after the start of 

therapy was associated with a significant decrease in the 

incidence of MACE. However, in our study only 7% of patients 

in the entire cohort achieved >80% GpRO (13% in the E B þ Inf 

group, 9% in the E B group, 8% in the T Adv group and in none of 

the patients in the T Std group) which may indicate suboptimal 

drug effect or variation in pharmacological response in our 

population. 

It has been suggested that the disaggregation of platelet 

thrombi may be a mechanism for the clinical benefits. Eptifibatide 

has demonstrated to reduce the occurrence of myonecrosis 

with PCI in acute coronary syndromes, a clinical 

scenario associated with platelet rich thrombus development. 

In an analysis of the Enhanced Suppression of the Platelet IIb/ 

IIIa Receptor With Integrilin Therapy (ESPRIT) trial, patients 

were then stratified into high- and low-risk groups in which 

thrombotic complications with the PCI were more likely 

during revascularization. High-risk characteristics included 

age >75 years, diabetes, ST-segment elevation within 7 days, 

or unstable angina within 48 h. The high-risk group demonstrated 

a reduction in the combined end point of death or 

myocardial infarction at both 30 days (6.2% v/s 12.4%; 

p < 0.001) and 12 months (8.0% v/s 15.9%; p < 0.001). 9 The lowrisk 

group demonstrated a trend toward benefit but did not 

achieve a statistically significant improvement with Eptifibatide 

thereby suggesting that higher risk groups benefit more. 

In our patient population, the GpRO achieved based on the 

Table 2 e Glycoprotein IIb/IIIa receptor occupancy ratio and 30-day major adverse clinical event across Eptifibatide group 

(Group E) and Tirofiban group (Group T). 

Results Group E, n ¼ 92 Group T, n ¼ 108 T value p Value 

GpRO above baseline 70.3% 19.1% 38.2% 20.7% 4.3

156 


Table 3 e Subgroups analysis of Glycoprotein IIb/IIIa receptor occupancy ratio and 30-day major adverse clinical event, 

across the four subgroups. 

Results Group E B , n ¼ 48 Group E B þ Inf , n ¼ 44 Group T Adv , n ¼ 12 Group T Std , n ¼ 96 p Value 

Absolute GpRO 62.7% 27.2% 61.4% 6.1% 68.8% 27.3% 35.1% 17.7% 80% 9% 13% 4% 0%


10. Deibele AJ, Jennings LK, Tcheng JE, Neva C, Earhart AD, 

Gibson CM. Intracoronary eptifibatide bolus administration 

during percutaneous coronary revascularization for acute 

coronary syndromes with evaluation of platelet glycoprotein 

IIb/IIIa receptor occupancy and platelet function: the 

intracoronary eptifibatide (ICE) trial. Circulation. 

2010;121:784e791. 

11. Fischell TA. “Bolus-only” glycoprotein IIb/IIIa inhibitor use for 

elective percutaneous coronary intervention: maybe less is 

more? Am Heart J. 2006;152:812e814.




Case report 

Absent pulmonary valve syndrome with tetralogy of Fallot 

detected at an early gestational age of 27 weeks e A case 

report 

Ashok N. Bhupali a,b , Kiran B. Patankar c , Sayi Prasad d , Jeetendra K. Patil e , 

Ajitey Tamhane f, * 

a Consultant Interventional Cardiologist and Head of Institute, Saraswati Hospital and Advanced Medical Care Center 

(Post Graduate Institute-DNB), Dasara Chowk, Kolhapur 416002, Maharashtra, India 

b Consultant Cardiologist, Apple Hospital and Research Institute, Diagnostic Center, Shahupuri, Kolhapur, Maharashtra, India 

c Director (Radiology), Apple Hospital and Research Institute, Diagnostic Center (Post Graduate Institute-DNB), Shahupuri, 

Kolhapur, Maharashtra, India 

d Consultant Physician and Intensivist, Saraswati Hospital and Advanced Medical Care Center (Post Graduate Institute-DNB), 

Dasara Chowk, Kolhapur 416002, Maharashtra, India 

e Head of Department of Advanced Imaging Radiology (CT & MRI), Apple Hospital and Research Institute Diagnostic Center 

(Post Graduate Institute-DNB), Shahupuri, Kolhapur, Maharashtra, India 

f Post Graduate Resident in Radiodiagnosis, Apple Hospital and Research Institute, Diagnostic Center (Post Graduate Institute-DNB), 

525, E, Vyapari Peth, Shahupuri, Kolhapur, Maharashtra, India 

article info 


Received 11 July 2012 

Accepted 23 October 2012 

Available online 29 October 2012 

Keywords: 

Absent pulmonary valve syndrome 

Tetralogy of Fallot 

Congenital heart Anomalies 

Fetal echocardiography 

abstract 

Objective: Absent pulmonary valve syndrome (APVS) is a rare congenital anomaly, usually 

seen in association with a ventricular septal defect. It has been reported to occur in 3e6% of 

cases of tetralogy of Fallot (TOF). In this case report we discuss a case of absent pulmonary 

valve syndrome with tetralogy of Fallot that was detected in utero by fetal echocardiography 

at 27 weeks of gestation. 

Case: A 20-year-old pregnant woman at 27 weeks of gestation referred to our Institute. She 

has no consanguineous history. We diagnosed the case as tetralogy of Fallot with absent 

pulmonary valves in fetal echocardiographic study. 

Conclusion: We conclude that when a paracardiac cystic, pulsatile lesion with dilated 

pulmonary arteries are seen in the fetus in utero then other features associated with the 

syndrome, such as TOF and the presence or absence of the ductus arteriosus should be 

looked for. In our case there was no ductus arteriosus. 

Copyright ª 2012, Cardiological Society of India. All rights reserved. 


Absent pulmonary valve syndrome (APVS) is a rare congenital 

anomaly, usually seen in association with a ventricular septal 

defect. It has been reported to occur in 3e6% of cases of 

tetralogy of Fallot (TOF). Absence of the pulmonary valve 

results in a dilated main pulmonary artery, which can be seen 

as a cystic, pulsatile, paracardiac lesion on antenatal USG. 

* Corresponding author. Tel.: þ91 231 2651207, þ91 9823265255 (mobile); fax: þ91 231 2654850. 

E-mail address: drtamhanes@hotmail.com (A. Tamhane). 

0019-4832/$ e see front matter Copyright ª 2012, Cardiological Society of India. All rights reserved. 

http://dx.doi.org/10.1016/j.ihj.2012.10.010

192 


Such a lesion, though rare, can easily be detected. We report 

a case of this rare anomaly which was present in association 

with a TOF. The case was detected at 27 weeks of gestation. 

The prognosis depends on the respiratory complications. 1 

When APVS is associated with a ventricular septal defect, 

the physiologic and anatomic repercussions affect both 

ventricles, and cardiac performance can be critically 

impaired. 2 We report a case of APVS that was detected by USG 

at 27 weeks of gestation; As of now the fetus is grossly normal 

and growth is corresponding to gestational age. 

2. Case report 

A 20-year-old primigravida presented for routine prenatal USG 

scanning. There was a single fetus of about 27 weeks gestation. 

The fetus showed a pulsatile cystic lesion located near 

the heart. We therefore performed a detailed fetal echocardiography, 

which revealed. The superior and inferior vena 

cava drained normally into the right atrium. Both Atria were 

normal. Atrioventricular concordance was noted. The 

tricuspid and mitral valves were normal. The right ventricle 

(RV) was seen to open into the pulsatile cystic lesion, which 

was thus confirmed to be the dilated main pulmonary artery 

along with the right and left pulmonary arteries. The pulmonary 

annulus showed no pulmonary valve (p-valve) echoes 

[Fig. 1]. There was back-and-forth flow across the RV and the 

dilated pulmonary artery during systole and diastole of the RV 

[Fig. 2]. The aorta was seen arising from the left ventricle (LV) 

and there was 50% overriding of aorta. A large subaortic 

ventricular septal defect (VSD) was seen [Fig. 3]. On Color 

Doppler study pulmonary regurgitation was noted [Fig. 4]. 

Other systems were unremarkable. Thus, a diagnosis of TOF 

with absent pulmonary valves was made. 

3. Discussion 

APVS is a complex syndrome comprising dysplasia/absence 

of pulmonary valvular leaflets, with resultant regurgitation 

Fig. 2 e An axial color Doppler image of the right 

ventricular outflow tract (arrows) shows the dilated 

pulmonary artery (PA) and the right ventricle (RV) with 

a mixed hue of colors suggesting to-and-fro random flow 

between the right ventricle and the pulmonary artery. 

and dilatation of the main and branch pulmonary arteries. 3 

The majority of these cases present with a VSD and features 

of TOF. The aneurysmal dilatation of the pulmonary artery 

often results in compression of the bronchial tree and 

esophagus, with consequent bronchomalacia and polyhydramnios. 

Volpe et al studied 21 fetuses with APVS for their 

associations and outcomes. Their study reveals an association 

of this syndrome with microdeletion of chromosome 

22q11 in 25% of cases. They also suggest that bronchomalacia 

is commonly associated with cardiomegaly and dilatation of 

the pulmonary artery and results in poor prognosis. 4 APVS, in 

the absence of VSD, is uncommon. As reported by Yeager 

et al, most of the cases presenting with an intact ventricular 

septum commonly reveal a patent ductus arteriosus, with 

relatively small pulmonary arteries and associated tricuspid 

atresia. 2 According to their study, the free communication 

Fig. 1 e An oblique coronal image of the fetal thorax reveals 

the aneurysmally dilated main pulmonary artery and 

absence of pulmonary valve echoes (arrow). 

Fig. 3 e Sagittal image of the fetal thorax reveals a large 

subaortic VSD (arrow) between the right ventricle (RV) and 

the left ventricle (LV). Aorta (AO) is seen arising from the LV.


by Callan et al, the presence of polyhydramnios may indicate 

a poor prognosis. 5 

4. Conclusion 

We conclude that when a paracardiac cystic, pulsatile lesion is 

seen in the fetus in utero, APVS is an important differential 

diagnosis and other features associated with the syndrome, 

such as TOF and the presence or absence of the ductus arteriosus 

should be looked for. 

references 

Fig. 4 e CW Doppler interrogation of RVOT/MPA showing 

pulmonary regurgitation. 

between the ventricles and the aorta causes the blood flow to 

the atria to be reduced, while there is an increase in the 

ventricular end diastolic pressure; this may in turn affect the 

cardiac function and the development of the atrioventricular 

valve. Yeager et al also suggest that in the presence of a VSD 

these changes affect both the ventricles, thereby resulting in 

a poor prognosis, 2 as seen in our case. A grossly dilated 

pulmonary artery can cause compression of the tracheobronchial 

tree and the esophagus. This obstructs the normal 

amniotic fluid circulation, causing polyhydramnios. As stated 

1. Yaman C, Arzt W, Tulzer G, Tews G. Tetralogy of Fallot with 

absent pulmonary valve e prenatal diagnosis and 

management in the 2nd trimester. Geburtshilfe Frauenheilkd. 

1996;56:563e565. 

2. Yeager SB, Van Der Velde ME, Waters BL, Sanders SP. Prenatal 

role of the ductus arteriosus in absent pulmonary valve 

syndrome. Echocardiography. 2002;19:489e493. 

3. Zucker N, Rozin I, Levitas A, Zalzstein E. Clinical presentation, 

natural history and outcome of patients with absent 

pulmonary valve syndrome. Cardiol Young. 2004;14:402e408. 

4. Volpe P, Paladini D, Marasini M, et al. Characteristics, 

associations and outcome of absent pulmonary valve 

syndrome in the fetus. Ultrasound Obstet Gynecol. 

2004;24:623e628. 

5. Callan NA, Kan JS. Prenatal diagnosis of tetralogy of Fallot 

with absent pulmonary valve. Am J Perinatol. 1991;8:15e17.

220 


resolution (STR) and 30-day MACE (w7% in all groups)/stent 

thrombosis/bleeding were not significantly different between 

the randomized groups. 

Two of the strongest baseline determinants of infarct size 

are: 1) anterior MI location and 2) abnormal TIMI flow. This 

trial was limited to patients with proximal or mid LAD 

occlusion and TIMI 0e2 flow. Moreover, it only enrolled 

patients who could be treated early, in whom time window for 

effective myocardial salvage had not closed. The median time 

from symptom onset to hospital arrival was only 99 min and 

the median D-to-B time was 45 min. Thus the study population 

represents a highly selected cohort of patients with 

large anterior MI, in whom infarct size reduction should be 

feasible given early presentation and rapid treatment. Infarct 

size was assessed by cMRI, which strongly correlates with 

subsequent mortality. Unlike prior studies, which measured 

infarct size at 2e7 days (a period during which substantial 

myocardial edema is present, thereby interfering with 

assessment of viable myocardium) in this study cMRI was 

done at 30 days when much of myocardial edema had 

resolved. 

These results need to be placed in the context of previous 

studies. A meta-analysis of 6 RCT’s (1246 patients) reported 

enhanced survival with bolus intracoronary abciximab. 

However, the recent AIDA-STEMI trial (2065 patients) found 

nearly identical rates of MACE with bolus intracoronary and 

intravenous abciximab. However, this trial differs from these 

earlier studies in many ways: 1) unlike prior studies which 

included routine post-PCI intravenous abciximab infusion in 

both the groups, in this trial only bolus intracoronary abciximab 

was given in the randomized groups. 2) In all prior trials 

(including AIDA-STEMI), intracoronary abciximab was infused 

proximally through the guide catheter thereby limiting its 

penetration into occlusive thrombus and allowing spillage of 

the drug to LCx or backflow into the aorta. In contrast, the 

local drug delivery catheter (clearway catheter) used in this 

study achieves high intra-clot concentration of abciximab at 

the site of LAD occlusion and prolongs drug residence time, 

which may enhance platelet disaggregation and thrombus 

resolution. In the present study, an abciximab bolus delivered 

directly to the infarct lesion site (without a 12-hour infusion) 

reduced infarct size at 30 days in patients with anterior STEMI 

reperfused early. 

Regarding aspiration thrombectomy, in TAPAS, 1071 

patients with anterior and non-anterior STEMI who presented 

within 12 h of symptoms at a single-center were randomized 

to manual aspiration vs. no aspiration before primary PCI; 

aspiration resulted in modest improvements in MBG and STR 

but a marked reduction in 1-year mortality. Other trials have 

reported conflicting results, and in contrast to single-center 

studies, multicenter aspiration trials have been largely negative. 

Moreover, in TAPAS, aspiration did not reduce infarct 

size as measured by cardiac biomarkers, calling into question 

the mechanism underlying the survival benefit. The present 

multicenter trial, in which only patients presenting early with 

anterior MI and coronary anatomy optimal for aspiration were 

enrolled, and in which cMRI was used to assess infarct size at 

30 days was specifically designed to overcome many of the 

limitations from these earlier studies. The fact that manual 

thrombus aspiration did not reduce infarct size in this study 

makes a substantial clinical benefit unlikely, questioning its 

routine use in STEMI. 

9. Our opinion 

Regarding use of GPIIb/IIIa inhibitors: a) I/V bolus and infusion 

is to be discouraged because it achieves very little intra-clot 

concentration and also increases the risk of systemic bleeding. 

b) Only bolus intracoronary drug should be used, that too 

not into the guide catheter, but via a clearway catheter (we can 

use a simple PTCA balloon by making multiple holes on its 

surface, in case clearway catheter is not available). 

Regarding manual aspiration via Export catheter: a) the 

symptom onset to hospital arrival and the D-to-B time were 

substantially shorter in this study which is next to impossible 

in our context. b) As time passes by after STEMI thrombus 

tends to get organized and hence thrombus aspiration might 

have some role to play in late presenters of STEMI. However, 

the last word in this matter is yet to be written. 

Suraj Khanal* 

Assistant Professor of Cardiology, Department of Cardiology, 

3rd Floor, Block-C, Advanced Cardiac Center, PGIMER, 

Chandigarh 160012, India 

Ajay Bahl 

Associate Professor of Cardiology, PGIMER, Chandigarh, India 

*Corresponding author. Tel.: þ91 09878222526. 

E-mail address: khanal.s@rediffmail.com 

Azeem Latib, Antonio Colombo, Fausto Castriota, 

Antonio Micari, Alberto Cremonesi, Francesco De Felice, 

Alfredo Marchese, Maurizio Tespili, Patrizia Presbitero, 

Gregory A. Sgueglia, Francesca Buffoli, Corrado Tamburino, 

Ferdinando Varbella, Alberto Menozzi, A randomized multicentre 

study comparing a paclitaxel drug-eluting balloon with 

a paclitaxel-eluting stent in small coronary vessels: The 

BELLO (Balloon Elution and Late Loss Optimization) study. J 

Am Coll Cardiol. 60 (2012) 2473e2480 

Objectives: The aim of this study was to evaluate the efficacy 

of drug-eluting balloons (DEB) compared with paclitaxel 

eluting stents (PES) for the reduction of restenosis in small 

vessels. 

Background: DEB have been shown to be effective in the 

treatment of coronary in-stent restenosis, but data are limited 

regarding their efficacy in de-novo disease. 

Methods: BELLO (Balloon Elution and Late Loss Optimization) 

is a prospective, multicentre trial that randomized 182 patients 

with lesions located in small vessels (reference diameter 


(2.15 0.27 mm vs. 2.25 0.24 mm; p ¼ 0.003). The majority 

(89%) of lesions involved vessels with a diameter




Original Article 

Coronary sinus filling time: A novel method to assess 

microcirculatory function in patients with angina and normal 

coronaries 

Vellani Haridasan a , Deepak Nandan a , Deepak Raju a , Gopalan Nair Rajesh a , C.G. Sajeev a , 

Desabandhu Vinayakumar a , Kader Muneer a , Kadangot Babu a , M.N. Krishnan b, * 

a Govt. Medical College, Kozhikode, India 

b Professor and HOD, Department of Cardiology, Govt. Medical College, Kozhikode 673017, Kerala, India 

article info 


Received 21 October 2012 

Accepted 14 February 2013 

Available online 21 February 2013 

Keywords: 

Syndrome X 

Coronary sinus filling time 

Coronary microcirculation 

abstract 

Objective: Dysfunction of the coronary microcirculation is considered as one of the factors 

responsible for symptoms and abnormal stress tests in patients with angina and normal 

coronaries (syndrome X). We sought to evaluate the usefulness of coronary sinus filling 

time (CSFT) to assess coronary microcirculation in this group of patients. 

Methods: We compared the CSFT of patients having definite angina or atypical angina with 

positive treadmill electrocardiography test (angina group), with that of patients undergoing 

coronary angiogram (CAG) prior to balloon mitral valvuloplasty (control group). During 

CAG, coronary sinus was visualized in appropriate views and CSFT in seconds was derived 

from frame count. Thrombolysis In Myocardial Infarction (TIMI) flow grade, corrected TIMI 

(cTIMI) frame count, TIMI Myocardial Perfusion grade (TMP) were assessed. 

Results: There were 41 patients in angina group and 16 in control group. Among the angina 

group 68.8% were females as against 81.8% in the control group. 87.8% (n ¼ 36) had typical 

angina. Mean CSFT was 4.25 0.72 s and 3.46 0.99 s in the angina group and control 

group respectively (p ¼ 0.001). No significant differences were found between the groups 

with respect to TMP (p ¼ 0.68) & cTIMI frame count (p ¼ 0.22). 

Conclusion: CSFT is a simple method to assess the transit time through coronary microcirculation. 

CSFT was significantly delayed in patients with angina and normal coronaries. 

TMP and cTIMI frame count were not significantly different between groups. 

Copyright ª 2013, Cardiological Society of India. All rights reserved. 


Twenty percent of all diagnostic angiograms in patients 

referred for evaluation of chest pain have normal epicardial 

coronary arteries. 1 First described by Kemp in 1973, syndrome 

X comprises of a heterogenous group presenting with typical 

angina, a positive exercise stress test, normal epicardial coronaries 

and no clinical or angiographic evidence of epicardial 

coronary artery spasm. 2 Dysfunction of the coronary microcirculation 

may be one of the factors responsible for persistent 

anginal symptoms and abnormal stress test. 3,4 Prognosis of 

these patients is not as benign as reported by preliminary 

* Corresponding author. Tel.: þ91 4952356120, þ91 9846697553. 

E-mail addresses: kedaram@gmail.com, dr.mn.krishnan@gmail.com (M.N. Krishnan). 

0019-4832/$ e see front matter Copyright ª 2013, Cardiological Society of India. All rights reserved. 

http://dx.doi.org/10.1016/j.ihj.2013.02.002


cohort studies. There are studies showing increased risk of 

myocardial infarction and cardiac death, especially in patients 

with positive stress test. 5,6 Women Ischemic Symptom Evaluation 

(WISE) trial showed that persistence of symptoms is 

associated with more than two-fold increase in cardiovascular 

events and concluded that such patients should undergo 

formal studies of vascular function and aggressive risk factor 

modification. 7 Noninvasive as well as invasive modes for 

assessing microcirculation have yielded inconsistent results 

and there is yet no simple method available at present to 

assess coronary microcirculation. 8e10 In this study, we have 

attempted to evaluate the usefulness of coronary sinus filling 

time (CSFT) for assessment of microcirculatory transit time in 

the coronary circulation. 

2. Patients and methods 

Adult patients presenting to the cardiology department of a 

major teaching hospital with angina-like chest pain from June 

2011 to January 2012 were screened for this study. 

The assessment of chest pain was done by two cardiologists 

of the department separately and doubtful cases were 

reviewed by a third cardiologist. Patients with chest pain were 

grouped into: 1) definite angina with/without positive TMT 2) 

probable angina with positive TMT and 3) non-cardiac chest 

pain. Definite (typical) angina was defined as substernal chest 

discomfort 1) of characteristic quality and duration 2) provoked 

by exertion or emotional stress 3) relieved by rest or 

sublingual nitrites. Probable angina was defined as those that 

met any two of the above characteristics; non-cardiac chest 

pain as those meeting one or none of the characteristics. 11 

Baseline evaluation, electrocardiogram (ECG) and echocardiography 

were done in all subjects. Definite and probable 

angina group underwent TMT. Patients were grouped as 

having either positive, negative or inconclusive test result 

based on standard criteria. 12 Patients with definite angina 

regardless of the result of TMT and patients with probable 

angina and a positive stress test were subjected to CAG. 

Among patients undergoing CAG, those with normal coronaries 

formed the angina group. The control group consisted 

of patients with mitral stenosis in sinus rhythm, normal coronary 

angiogram and normal left ventricular structure and 

function undergoing percutaneous balloon mitral valvuloplasty 

(BMV). The right atrial pressures and left ventricular 

end diastolic pressures were measured in all cases. Exclusion 

criteria were: 1) abnormal coronaries on angiography (any 

vascular irregularity/ectasia/stenoses), 2) patients with current 

or prior cardiovascular events by history, ECG or echocardiography, 

3) presence of cardiac diseases other than 

isolated mitral stenosis. Fig. 1 outlines the selection of patients 

for the study. 

Coronary angiogram was done with Philips Allura Xper 

FD20 (Philips Electronics, Eindhoven, The Netherlands) at a 

rate of 15 frames/s. Left coronary artery injection was taken 

with 7 mL contrast at 2 mL/s rate. A normal coronary artery 

was defined as epicardial coronary artery at angiography 

without any wall irregularities, ectasia or stenosis. TIMI 

Fig. 1 e Flow diagram showing the enrollment of patients for the study.

144 


frame count, TMP grade and CSFT were obtained offline. 

CSFT was defined as the time taken in seconds for the 

contrast agent in the epicardial coronary artery to traverse 

the coronary microvasculature and reach the coronary sinus 

origin. CSFT was estimated as the difference between the 

frame count of maximum left anterior descending artery 

(LAD) system opacification at first diagonal (D 1 )/first septal 

(S 1 ) to that of the starting point of opacification of coronary 

sinus origin. 

Frame count at the maximum opacification of LAD at D 1 or 

S 1 , whichever was earlier (first frame count), was noted. A 

column of fully concentrated dye must extend across the 

entire width of LAD at D 1 /S 1 and move forwards. The frame 

count in which dye is first seen at the origin of coronary sinus 

is counted as the last frame and the frame count was noted 

(last frame count). Coronary sinus origin is defined as the 

point where great cardiac vein joins the posterolateral vein 

(that is marked by the joining of oblique vein of Marshall to 

coronary sinus in whom it is seen). Coronary sinus was evaluated 

in at least two views, left anterior oblique (LAO) with 

appropriate cranial angulation and right anterior oblique 

(RAO) with caudal tilt. In these views, the tract and effluent 

were well visualized draining into the right atrium after 

sixeeight cycles on an average. The CSFT is calculated as: 

CSFT in seconds ¼ðlast frame count 

first frame count=15Þ 

TIMI Frame Count is defined as the number of angiographic 

frames elapsed from the first frame in which the contrast fully 

enters the artery to that in which it reaches the distal standardized 

landmark of the vessel of interest. 

For LAD, TIMI frame count [ Frame count at distal 

bifurcation e frame count at D 1 . 

The frame rates are corrected for the longer length of the 

LAD by dividing it by 1.7. 13 TMP is a simple descriptive score of 

myocardial opacification with contrast, distinct from the 

epicardial vessel, and provides a score of between 0 (no 

myocardial blush) and 3 (normal blush and clearance of dye 

from myocardium). 14,15 cTIMI frame count, TMP and CSFT in 

both the groups was compared and correlation analyzed. 

Analysis was done using two tailed t-test for equality of 

means. The demographic data was analyzed using Chi square 

test and Pearson correlation for correlation between CSFT 

frame count and cTIMI frame count. 

Table 1 e Baseline characteristics of patients and 

controls. 

Parameter 

21.84 5.0 in the control group p ¼ 0.224) or TMP (2.9 0.3 in 

angina group and 2.94 0.25 in control group p ¼ 0.68). 

4. Discussion 

Angina 

group n (%) 

Control 

group n (%) 

p value 

Sex 

M 13 (31.7) 3 (18.8) 

F 28 (68.3) 13 (81.2) 0.108 

Age e Mean (SD) 50.4 (7.6) 47.4 (9.6) 0.064 

Diabetes mellitus 16 (39) 2 (12.5) 0.053 

Hypertension 22 (53.7) 1 (6.2) 0.001 

Dyslipidemia 18 (43.9) 1 (6.2) 0.007 

Smoking 11 (26.8) 2 (12.5) 0.2 

Family history of CAD 6 (14.3) 0 0.11 

Heart rate e Mean (SD) 74 (12) 77 (14) 0.08 

RA pressure e Mean (SD) 3.4 (2.5) 5.3 (3.48) 0.06 

LV EDP 7 (3.6) 6 (2.4) 0.18 

Drugs 

1. Beta blockers 11 16 0.12 

2. CCB 8 2 0.04 

3. Statins 18 0 0.02 

4. Nitrates 32 0 0.003 

5. ACEI/ARB 18 4 0.03 

6. Aspirin 32 4 0.004 

RA ¼ Right atrium; LVEDP ¼ Left ventricular end diastolic pressure; 

CCB ¼ Calcium channel blocker; ACEI ¼ Angiotensin converting 

enzyme inhibitor; ARB ¼ Angiotensin receptor blocker. 

Our study demonstrated a delay in transit through microcirculation 

in patients with angina and normal coronaries. In a 

similar study, Sankareddi et al 16 have proposed that the time 

delay between LAD opacification and filling of coronary sinus 

would indicate the microcirculatory time. They went on to 

define CSFT as the difference in frame counts between 

maximum LAD opacification to the maximal opacification of 

the coronary sinus. They also calculated coronary sinus 

emptying time and coronary sinus emptying velocity as parameters 

to assess microcirculatory transit. In our study, we 

3. Results 

There were 41 cases in the angina group and 16 in the control 

group. Baseline data of both groups are given in (Table 1). 

Angina group and control group were compared with 

respect to following parameters e cTIMI frame, TMP Grade 

and CSFT. Mean CSFT frame count in angina group and in 

control group were 63.76 10.7 and 52.06 5.0 and mean CSFT 

were 4.2476 0.72 s and 3.4581 0.99 s, respectively (p ¼ 0.001) 

(Fig. 2). We could demonstrate a positive correlation between 

CSFT and cTIMI frame count in the angina group (correlation 

coefficient ¼ 0.7) (Fig. 3). 

No significant differences were found between the two 

groups with regard to cTIMI (23.97 6.2 in angina group and 

Fig. 2 e Coronary sinus filling time in angina group and 

control group.


Fig. 3 e Correlation of cTIMI frame count and CSFT. 

included only CSFT, since coronary sinus emptying time and 

velocity depend on the drainage characteristics of coronary 

sinus rather than that of the coronary microcirculation. We 

modified the definition of CSFT as the difference in frame 

counts between maximum LAD opacification to the beginning 

of filling of coronary sinus origin. The coronary sinus is a 

venous conduit, which drains between 80% and 85% of unsaturated 

blood of the left ventricle. 17 Studies have shown 

that there is dynamic variation of the coronary sinus lumen 

during normal cardiac cycle and has been categorized into 

passive, normal response and hyperactive. 18 An exaggerated 

response to this mechanism could potentially modify cyclic 

coronary circulation and perfusion, causing slow flow phenomena. 

19 Modulation of coronary sinus outflow pressure in 

normal canine hearts affects intramyocardial tissue pressure 

and has been shown to reduce blood flow in the subepicardial 

tissue layer independently of coronary artery pressure. 20 

Since the maximal opacification of the coronary sinus would 

depend on multiple factors other than the condition of the 

microcirculation, we decided to assess the filling at the origin 

of coronary sinus. Our study agrees with the previous study 

that CSFT is delayed in angina with normal coronaries. Our 

study had a larger study population (n ¼ 41) compared to the 

previous study (n ¼ 10). We also compared other parameters of 

perfusion, cTIMI frame count and TMP. These two parameters 

were not significantly different between angina group and 

control group as in other studies. 14,21,22 In our study there was 

a positive correlation between cTIMI frame count & CSFT in 

the case group (r ¼ 0.730). There was a trend toward delayed 

CSFT in those patients with an increased cTIMI frame count. 

Mahfouz et al could demonstrate a marked delay in cTIMI 

frame count in a group of syndrome X patients, even though 

other studies have yielded mixed results. 23 A few studies 

could demonstrate abnormal TMP as a surrogate marker for 

dysfunctional coronary microvasculature in syndrome X. 24 

We could not demonstrate any correlation between TMP and 

CSFT in this study. 

We have not been able to find any study examining the 

relation between CSFT and long-term outcomes; nor could we 

find any study on the effect of coronary dilators like adenosine 

or dipyridamole on CSFT. It would be worthwhile to study the 

differential power of CSFT on long-term outcomes in patients 

with angina and normal coronaries. 

There were several limitations in our study, as this was one 

of the pilot studies of CSFT. One of the limitations of this study 

was the small number of control population. We could not 

recruit absolutely normal subjects as control population 

because of ethical issues. We took mitral stenosis patients 

undergoing CAG prior to BMV as controls. In case of control 

population, we had to exclude patients with mean pulmonary 

artery pressure 25 mmHg, as elevated right atrial pressures 

prolonged coronary sinus filing time. Another limitation was 

that coronary spasm was not excluded. We did not standardize 

the injection speed and force as we used hand injection; 

this could have affected the results. However, Gibson 

et al have shown that the difference in hardware, injection 

methods and phase of cardiac cycle did not produce much 

variability in corrected frame count calculation. 13 Since we did 

not come across any study that used automated injectors for 

standardization our study used manual injections at prespecified 

rate and volume. Our study group and controls have 

a preponderance of female subjects; thus it is not clear 

whether the conclusions can be extended to male patients. 

CSFT may be proposed as a method to risk-stratify patients 

with angina and normal coronaries. Moreover, CSFT may be 

used as a simple and quantitative test in percutaneous coronary 

intervention setting to assess myocardial reperfusion. 

Further studies are required to evaluate this proposition. 

5. Conclusion 

CSFT is a simple method to assess the transit time through 

coronary microcirculation. CSFT was significantly delayed in 

patients with angina and normal coronaries. TMP and cTIMI 

frame count did not differ significantly between the groups 

studied. 

Conflicts of interest 

All authors have none to declare. 

references 

1. Chierchia SL, Fragasso G. Angina with normal coronary 

arteries: diagnosis, pathophysiology and treatment. Eur Heart 

J. 1996;17:14e19. 

2. Kemp HG. Left ventricular function in patients with angina 

syndrome and normal coronary arteriograms. Am J Cardiol. 

1973;32:375e376. 

3. Opherk D, Zebe H, Weihe E, et al. Reduced coronary dilatory 

capacity and ultrastructural changes of the myocardium in 

patients with angina pectoris but normal coronary 

arteriograms. Circulation. 1981;63:817e825.

146 


4. Cannon III RO, Canici PG, Epstein SE. Pathophysiological 

dilemma of syndrome X. Circulation. 1992;85:883e892. 

5. Prognosis in women with myocardial ischemia in the absence 

of obstructive CAD: results from the National Institute of 

Health-National Heart, Lung, & Blood Institute e Sponsored 

Women Ischemic Syndrome Evaluation Trial (WISE). 

Circulation. 2004;109:2993. 

6. Bugiardini R. Women, “non specific” chest pain, normal or 

near normal CAG are not synonymous with favourable 

outcome. Eur Heart J. 2006;27:1387. 

7. Johnson BD, Pepera CJ, Reis SE, et al. Persistent chest pain 

predicts cardiovascular events in women without obstructive 

CAD: results from NIH-NHLBI-sponsored Women Ischemic 

Syndrome Evaluation (WISE) study. Eur Heart J. 2006;27:1408. 

8. Meller J, Goldsmith SJ, Rudin A, et al. Spectrum of exercise 

thallium-201 myocardial perfusion imaging in patients with 

chest pain and normal coronary angiograms. Am J Cardiol. 

1979;43:717e723. 

9. Rossetti E, Fragasso G, Vanzulli A, et al. Magnetic resonance 

contrast enhancement with gadolinium-DTPA in patients 

with angina and angiographically normal coronary arteries: 

effect of chronic beta-blockade. Cardiologia. 

1999;44(7):653e659. 

10. Dijkmans PA, Knaapen P, Sieswerda GT, et al. Quantification 

of myocardial perfusion using intravenous myocardial 

contrast echocardiography in healthy volunteers: comparison 

with positron emission tomography. J Am Soc 

Echocardiography. 2006;19:285e293. 

11. ACC/AHA updated guidelines for management of patients 

with stable chest pain syndromes and known or suspected 

ischemic heart disease. J Am Coll Cardiol. 2003;41(1):159e168. 

12. A report of the ACC/AHA Taskforce on practice guidelines 

(Committee to update the 1997 exercise testing guidelines). 

Circulation. 2002;106:1883e1892. 

13. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a 

quantitative method of assessing coronary artery flow. 

Circulation. 1996;93:879e888. 

14. Bertomeu-Gonzáleza Vicente, Bodía Vicent, Sanchis Juan. 

Limitations of myocardial blush grade in the evaluation of 

myocardial perfusion in patients with acute myocardial 

infarction and TIMI grade 3 flow. Esp Cardiol. 2006;59: 

575e581. 

15. Dibra A, Mehilli J, Dirschinger J, et al. Thrombolysis in 

myocardial infarction myocardial perfusion grade in 

angiography correlates with myocardial salvage in patients 

with acute myocardial infarction treated with stenting or 

thrombolysis. J Am Coll Cardiol. 2003;41:925e929. 

16. Sangareddi V, Alagesan R. Coronary Sinus Filling and 

Emptying Time: A New Parameter to Assess Coronary 

Microcirculation by a Simple Angiographic Frame Count; 59th 

Annual Conference of the Cardiological Society of India 

December 7e10, 2008 [abstract]. 

17. Singh Jagmeet P, Houser Stuart, Heist E Kevin, Ruskin Jeremy 

N. The coronary venous anatomy: a segmental approach to 

aid cardiac resynchronization therapy. J Am Coll Cardiol. 

2005;46:68e74. 

18. Barcelo A, De La Fuente LM, Stertzer SH. Anatomic and 

histologic review of the coronary sinus. Int J Morphol. 

2004;22(4):331e338. 

19. Krakover R, Blatt A, Hendler A, et al. Angiographic functional 

characterization of the coronary sinus. Isr Med Assoc J. 

2005;7:374e376. 

20. Rouleau JR, White M. Effects of coronary sinus pressure 

elevation on coronary blood flow distribution in dogs with 

normal preload. Can J Physiol Pharmacol. 1985;63:787e797. 

21. Chen YC, Hou CJ, Tsai CH, et al. Relationships of the 

thrombolysis in myocardial infarction frame count with 

clinical, hemodynamic and medicine variables in syndrome X 

patients. Int J Gerontol. 2008;2(3):109e114. 

22. Nihat S, Yusuf T, Ugurii H, et al. Coronary blood flow in 

patients with cardiac syndrome X. Coron Artery Dis. 

2007;18(1):45e48. 

23. Mahfouz Ragab A, Abdou Mohamed, Elsaeed Ashraf, 

Kandil Nader T. Cardiac syndrome-X: is it benign or malignant? 

An Egyptian follow-up study. Open J Cardiol. 2011;2:1. 

24. Atmaca Y, Zdemir AO. Angiographic evaluation of myocardial 

perfusion in patients with syndrome X. Am J Cardiol. 

2005;96(6):803e805.




Arrhythmia Graphics 

Nodal and infranodal atrioventricular conduction block: 

Electrophysiological basis to correlate the ECG findings 

Bharat K. Kantharia a,b,c, *, Arti N. Shah d 

a Professor of Medicine, The University of Texas-Health Science Center at Houston, 6431 Fannin Street, Suite MSB 1.246, Houston, 

TX 77030, USA 

b Director, Clinical Cardiac Electrophysiology Fellowship Training Program, 6431 Fannin Street, Suite MSB 1.246, Houston, TX 77030, USA 

c Director, Cardiac Electrophysiology Laboratories-Memorial Hermann Hospital, 6431 Fannin Street, Suite MSB 1.246, Houston, 

TX 77030, USA 

d Elmhurst Hospital Center, Mount Sinai School of Medicine, NY, USA 

article info 


Received 2 January 2013 



Keywords: 

HisePurkinje system 

Atrioventricular node 

2:1 block 

Atrioventricular nodal block 

Infra-Hisian block 

abstract 

A 68-year-old woman with a history of dilated non-ischemic cardiomyopathy presented 

with syncope. The index ECG showed sinus rhythm with left bundle branch block. 

On telemetry episodes of sinus rhythm with narrower QRS complexes conduced in 2:1 

pattern were noted. Invasive electrophysiological study was performed to determine cause 

of syncope. Normal conduction up to the AV node with an AH interval of 79 ms 

(normal ¼ 55e125 ms) was observed. However, every alternate sinus beat was blocked after 

the inscription of His deflection (infra-Hisian block). The narrow beats conducted through 

the His bundle with HV intervals of 54 ms (normal ¼ 35e55 ms). When 1:1 conduction 

resumed further abnormality of the HisePurkinje conduction system became evident with 

a QRS morphology that of an LBBB and prolongation of HV interval (HV ¼ 96 ms). Criteria to 

differentiate nodal versus infranodal block based on electrophysiological properties of the 

nodal and infranodal system are discussed. 


A 68-year-old woman with a history of dilated non-ischemic 

cardiomyopathy (left ventricular ejection fraction 40%), presented 

with syncope. Her physical examination was unremarkable. 

The index ECG showed sinus rhythm with left 

bundle branch block (LBBB). On telemetry episodes of sinus 

rhythm with narrower QRS complexes conduced in 2:1 pattern 

were noted. Invasive electrophysiological (EP) study was performed 

to determine cause of syncope. 

Relevant observations made during EP study are as shown 

in Fig. 1. Panels A and B: 12 lead ECGs are recorded at a paper 

speed of 25 mm/s. The baseline rhythm is sinus at a rate of 88 

beats per minute (bpm) [sinus cycle length of 680 ms (ms)] that 

has 1 to 1 atrioventricular (AV) conduction with QRS 

morphology of LBBB, PR intervals of 200 ms and QRS durations 

of 120 ms (Panel A). The rhythm spontaneously converts to 

sinus with 2:1 AV block (Panel B). During the 2:1 AV block 

rhythm, the conducted beats have PR intervals of 200 ms and 

the QRS complexes are narrower and measure 100 ms in 

duration. The intervals between the two consecutive P waves 

(PeP interval) remain fixed at 680 ms, The intervals between 

* Corresponding author. Tel.: þ1 713 500 6590; fax: þ1 713 500 6556. 

E-mail addresses: bharat.k.kantharia@uth.tmc.edu, bkantharia@yahoo.com (B.K. Kantharia). 



230 


Fig. 1 e Surface 12-lead ECGs (A and B) and the tracings of intracardiac electrograms (C and D) during AV block. 

the R wave to the next conducted P wave (R to P þ 1 interval) 

remain fixed at 1160 ms. Panels C and D: The tracings are 

recorded at a paper speed of 50 mm/s and 100 mm/s, respectively. 

From top to bottom, the tracings show surface ECG 

leads I, aVF and V1, intracardiac electrograms from the high 

right atrium (hRA) corresponding to the P waves, the AV nodal 

junction region covering the proximal, mid and distal His 

bundle (HISp, HISm and HISd, respectively) corresponding to 

the PR intervals, and the outflow tract region of the right 

ventricle (RVot) corresponding to the R waves. Each sinus beat 

is conducted normally up to the AV node with an AH interval 

of 79 ms (normal ¼ 55e125 ms). However, every alternate 

sinus beat is blocked after the inscription of His deflection 

(infra-Hisian block). The narrow beats conduct through the 

His bundle with HV intervals of 54 ms (normal ¼ 35e55 ms). 

When 1:1 conduction resumes (the last beat in Panel D) further 

abnormality of the HisePurkinje conduction system becomes 

evident with a QRS morphology that of an LBBB and prolongation 

of HV interval (HV ¼ 96 ms). 

1. Commentary 

On routine ECGs, right bundle branch block (RBBB) may be 

seen even in otherwise perfectly healthy individuals. On the 

other hand, the inscription of LBBB usually indicates abnormality 

of the HisePurkinje system, with the exception of LBBB 

that may be observed during rapid supraventricular tachycardia 

with aberrant conduction secondary to rate related 

functional conduction block/delay in the bundle. 

By ECG criteria alone, it can be very hard to determine the 

level of block, i.e. Mobitz I (AV nodal) or Mobitz II (infranodal) 

block in the presence of 2:1 AV conduction block. Although, for 

the most part wide QRS complexes suggest infranodal block, 

and narrow QRS complexes indicate AV nodal block, these 

criteria are not reliable. In the presence of 2:1 AV conduction 

block, if the PR intervals of the conducted beats remain short 

and fixed, the level of block may be considered infranodal 

(Mobitz II block). On the other hand, if the PR intervals of the 

conducted beats are longer and not fixed, the level of block 

may be considered AV nodal (Mobitz I block). In a typical 

Mobitz I (AV nodal Wenckebach) block, the PR interval of the 

first conducted complex after the dropped beat shortens due 

to recovery of normal AV nodal conduction. If the AV 

Wenckebach periodicity were to continue then the next PR 

interval would prolong considerably. The subsequent complexes 

although would have further prolongation of the PR 

intervals, the increments compared to the preceding intervals 

are less. Thus, the RR intervals may demonstrate apparent 

shortening with prolongation of the PR intervals. In case of 2:1 

AV block, if the PR intervals of the conducted beats remain 

short and fixed then it would be difficult to conceptualize that 

the AV node after conducting a sinus beat normally (normal 

PR interval) would impart so much conduction delay for the


very next sinus beat at an identical sinus cycle length that the 

beat would block within the AV node. However, in case of the 

HisePurkinje system dysfunction, conduction of sinus beats 

through the infranodal structures may be totally unreliable 

and only slight decrement in the conduction through the 

HisePurkinje system may result in total conduction block. 

On a surface ECG, prolongation of the PR interval and 

correspondingly a longer AH interval during EP study may be 

observed if there is a rapid input to the AV node by a shortcoupled 

premature beat that conducts through the AV node 

with decremental conduction physiology. Likewise, with recovery 

of the AV nodal conduction, shorter PR and AH intervals 

may be observed if there is a delayed input to the AV 

node by a long-coupled premature beat. Thus, during 2:1 AV 

block, if there is a reciprocal relationship between the R to 

P þ 1 interval and subsequent PR interval (shorter R to P þ 1 

interval resulting in a longer subsequent PR interval and vice 

versa) is observed then the level of block is most likely within 

the AV node. On the other hand, if the conduction block 

occurs in the His-Purkinje system (infranodal block) then 

irrespective of the variations in the R to P þ 1 interval, the 

subsequent PR intervals remain fixed. 

Of course, certain maneuvers and interventions to alter the 

vagal and sympathetic balance may help to differentiate AV 

nodal block from block in the infranodal HisePurkinje system. 

For example, although the carotid sinus massage which increases 

the vagal tone and slows the sinus rate and conduction 

through the AV node would further deteriorate nodal 

block, it may improve the infranodal block by improving the 

His-Purkinje conduction of slower sinus beats. Exercise, 

atropine and isoproterenol would improve nodal block but 

would deteriorate infranodal block. 


All authors have none to declare.




Case Report 

Constrictive pericarditis following Coronary Artery Bypass 

Grafting 

Anirban Kundu a, *, Om Prakash Yadava a , Arvind Prakash b 

a Department of Cardiac Surgery, National Heart Institute, New Delhi, India 

b Department of Cardiac Anesthesiology, National Heart Institute, New Delhi, India 

article info 





Keywords: 

Constrictive pericarditis 

Coronary Artery Bypass Grafting 

Thoracotomy 

Pericardiectomy 

abstract 

Constrictive pericarditis following Coronary Artery Bypass Surgery is an uncommon disorder. 

We report a patient who developed constrictive pericarditis after Coronary Artery 

Bypass Grafting. After an unsuccessful trial of medical management and pericardial tapping, 

he underwent pericardiectomy via a left posterolateral thoracotomy. 


1. Case report 

The patient was a 66-year-old normotensive, non-diabetic 

gentleman with normal left ventricular function, who underwent 

off-Pump CABG in January 2009, wherein he 

received three grafts. However, during sternal closure he had 

a sudden and unexplained hemodynamic collapse, necessitating 

emergent cardiopulmonary bypass (CPB) support. His 

subsequent post-operative course was uneventful and he was 

discharged on the 7 th post-operative day. Pre-discharge echo 

showed minimal pericardial effusion posterolateral to the left 

ventricle (LV). After 16 months, he presented with shortness of 

breath, pedal edema and easy fatigability. 2D echocardiography 

revealed biatrial dilatation, small LV, marked pericardial 

effusion with fibrous strands, no constriction, marked thickening 

of posterolateral pericardium, normal LV ejection fraction 

and raised LVEDP. 300 ml of hemorrhagic fluid was 

drained under echocardiographic guidance. However, he 

again presented with similar complaints after six months. 

This time, echocardiography showed a large pericardial 

collection causing posterolateral compression of the LV, with 

pericardium thickened to 7 mm and features of constrictive 

physiology. MRI of thorax showed a mass 8 cm in diameter 

compressing the LV. Keeping in mind the clinical and imaging 

findings and the history of recurrence, it was decided to 

operate. He underwent preoperative cardiac catheterization 

and coronary angiography, which confirmed the echocardiographic 

findings and demonstrated patent grafts. Based on the 

MRI findings which suggested a left lateral compression of the 

LV (Fig. 2), and the presence of patent grafts, our surgical 

approach was left posterolateral thoracotomy. There was a 

large pleural effusion of about 2 L of straw colored fluid. The 

LV was encased by 1 cm thick pericardium with 500 ml 

of altered blood and partially-organized clots (Fig. 1). Pericardiectomy 

over the LV was done with thorough removal of 

the clots and fluid, leaving a strip of pericardium along the 

* Corresponding author. Tel.: þ91 11 46600700 (Ext: 4098), þ91 11 46600700 (Ext: 4055); fax: þ91 11 2642 8372. 

E-mail addresses: dockundu@yahoo.com, drkundu@indiatimes.com, onku2@rediffmail.com (A. Kundu). 




Fig. 1 e Operative photograph showing partially opened 

thickened pericardium. 

phrenic nerve. Post-operative echocardiography showed mild 

posterolateral pericardial collection with no constriction and 

the patient was discharged after 4 days. 

2. Discussion 

Constrictive pericarditis as a complication following CABG is 

rare and was first reported in 1972. 1 Constrictive pericarditis is 

caused by adhesions and fibrous contracture of the pericardial 

sac. This impairs normal diastolic ventricular filling, causing a 

fall in stroke volume and elevation of systemic and pulmonary 

venous pressures. Fatigue, dyspnea and signs of congestive 

cardiac failure result. At our institution, at which almost 500 

major cardiac surgical proceduresdmainly CABGs e are performed 

annually; this was the first such case. While it is true 

that such cases eventually requiring pericardiectomy are rare, 

the true incidence of pericardial constriction post-surgery may 

be underestimated. Mild cases may mimic low cardiac output 

syndrome, with low systemic pressures and high venous 

pressures, especially post-valve surgeries, or following CABG 

with severe LV dysfunction. Patients with mild disease may 

respond well to diuretic treatment given for heart failure and 

thus never undergo investigations to establish the diagnosis, 

which requires a high degree of clinical suspicion. 2 Definitive 

factors that predispose to the development of constriction in 

patients after cardiac surgery are still not well known. Studies 

on animal models have demonstrated that pericardial adhesions 

will develop if spilled blood comes into contact with an 

injured serosal surface. 3 The volume of blood spillage during 

surgery is variable, but the initiation of inflammation and 

fibrosis depends on the presence of pericardial damage. Postpericardiotomy 

syndrome (PPS) has been postulated as a 

potential cause and has been found to occur in up to 30% of 

patients after cardiac surgery. 4 The presence of PPS does not 

necessarily predict which patients will develop constriction, 

and its absence does not preclude the development of 

constriction. However, PPS is an indication of inflammation in 

and around the pericardium, and perhaps these patients 

should be watched more closely for development of constrictive 

pericarditis. Definitive management of this condition remains 

re-do surgery with pericardiectomy. Patients who have 

undergone previous surgery, especially CABG, pose a greater 

risk with patent grafts lying just beneath the sternum, which 

are susceptible to injury during the procedure. Lee et al have 

recommended a non-midline sternotomy approach, to avoid 

damage to patent grafts. Patients in their series underwent 

pericardial stripping via right, left and bilateral thoracotomies, 

depending on the extent of constriction. 5 Our patient underwent 

CABG over two years ago, which had required CPB support. 

It is well known that CPB is associated with increased risk 

of bleeding complications and inflammatory response. 

Removal of drainage tubes following CABG might have been 

followed by gradual oozing from the raw surfaces caused by 

the surgery, which could have led to inflammation, fibrosis 

and constriction. Imaging studies revealed a marked thickening 

on the left lateral aspect of the heart. This correlates 

with the post-operative echocardiography findings of a 

posterolateral collection. Keeping in mind the site of 

compression and the fact that the patient was post-CABG with 

patent grafts, it was decided to use a left posterolateral thoracotomy. 

Apart from obviating the need for any extra precaution 

with regard to the grafts, this approach avoided the 

morbidity associated with a re-do sternotomy and very 

importantly, allowed for a satisfactory decompression of the 

LV, which was bearing the brunt of the constrictive process. 

3. Conclusion 

Fig. 2 e Preoperative MRI showing thickened pericardium. 

Based on the experience of this case, we conclude that pericardiectomy 

via lateral thoracotomy is a safe and effective 

approach in cases of post-CABG constrictive pericarditis, in 

view of the presence of patent grafts, and added morbidity of a 

re-do sternotomy. Also, this uncommon complication has to 

be considered in all post-cardiac surgery patients presenting 

with signs of unexplained myocardial failure, before ascribing 

them to the underlying cardiac disorder, or to post-cardiac 

surgery LV dysfunction.

200 




references 

1. Kendall ME, Rhodes GR, Wolfe W. Cardiac constriction 

following aorta to coronary bypass surgery. J Thorac Cardiovasc 

Surg. 1972;64:142e153. 

2. Killian DM, Furiasse JG, Scanlon PJ, et al. Constrictive 

pericarditis after cardiac surgery. Am Heart J. 

1989;118:563e568. 

3. Cliff WJ, Grobetz J, Ryan GB. Postoperative pericardial 

adhesions. The role of mild serosal injury and spilled blood. J 

Thorac Cardiovasc Surg. 1973;65:744e750. 

4. Drusin LM, Engle MA, Hagstrom JWC, et al. The 

postpericardiotomy syndrome. A six year epidemiologic study. 

N Engl J Med. 1965;272:597e602. 

5. Lee C, Yang S, Yang H, et al. Pericardiectomy through a right 

anterior thoracotomy for constrictive pericarditis after 

coronary artery bypass grafting. J Med Sci. 2007;27(2):085e088.




Case Report 

Intravascular ultrasound-guided revascularization of a 

chronically occluded left main coronary artery 

Alberto Ranieri De Caterina, Florim Cuculi, Adrian P. Banning* 

Oxford Heart Centre, Oxford University Hospitals, Headley Way, Oxford OX3 9DU, UK 

article info 


Received 19 September 2012 



Keywords: 

Left main coronary artery 

Chronic total occlusion 

Intravascular ultrasound 

abstract 

We describe a case of a left main coronary artery (LMCA) chronic total occlusion (CTO), 

which we elected to treat through percutaneous coronary intervention (PCI). In this case 

report, we briefly review the prevalence of LMCA CTO, discuss the feasibility of PCI versus 

surgical revascularization and highlight the importance of intravascular ultrasound in the 

guidance of these complex procedures. 


1. Background 

Chronic total occlusion (CTO) of the left main coronary artery 

(LMCA) is a rare finding in everyday practice. Here we describe 

a successful percutaneous revascularization of a LMCA CTO in 

a patient presenting with mild-to-moderate symptoms. Specifically, 

in this case we highlight the importance of intravascular 

ultrasound in the guidance of these complex procedures. 

2. Case presentation 

A 75-year-old lady was referred to our heart centre for the 

evaluation of breathlessness to minimal exertion, which had 

suddenly worsened after an episode of “unwellness” three 

months before. She denied chest pain, was overweight (Body 

Mass Index, BMI, of 43 kg/m 2 ) and had a history of 

well-controlled hypertension and hypercholesterolemia. An 

echocardiogram showed mildly impaired global left ventricular 

(LV) contractility (LV ejection fraction 46%) with hypokinetic 

anterior wall. Single photon emission computed 

tomography (SPECT) revealed severely impaired perfusion in 

the left anterior descendent (LAD) territory and inducible 

ischemia in the lateral wall. At coronary angiography an ostial 

LMCA occlusion with some antegrade vessel opacification 

through a microchannel and retrograde filling from a dominant 

right coronary artery (RCA) was found (Fig. 1). Syntax 

score was 27, while Euroscore II was 2.55%. 

The patient underwent percutaneous coronary intervention 

(PCI) through bilateral femoral approach for contralateral 

injection if needed. LMCA ostium was engaged with a Judkins 

left 4 6F guide catheter and the lesion successfully crossed 

engaging the microchannel with a Pilot 50 wire (Abbott 

Vascular, Canada). After multiple predilations with 1.5 and 2.5 

balloons, an intravascular ultrasound (IVUS) run from the 

proximal circumflex artery (Cx) was performed showing 

* Corresponding author. Tel.: þ44 1865 228934; fax: þ44 1865 220585. 

E-mail address: Adrian.Banning@ouh.nhs.uk (A.P. Banning). 




Fig. 1 e LMCA occlusion. Angiography shows eterocoronary retrograde vessel filling from RCA (panel A) and minimal 

antegrade filling (panel B, arrows). 

diffuse concentric atheroma extending from bifurcation to 

ostial LMCA (Fig. 2) with a native vessel diameter of 3.9 mm. A 

4 24 mm drug eluting stent (Promus Element, Boston 

Scientific) from proximal Cx to ostial LMCA was successfully 

implanted (Fig. 3, left panel). Post-stenting IVUS run from 

proximal LAD revealed mild ostial LAD disease, suboptimal 

stent struts expansion and coverage of LMCA ostium with 

minimal stent protrusion into aorta (Fig. 3, mid panels). Final 

kissing balloon with 4.0 12 mm (to Cx) and 3.0 12 mm 

(to LAD) non-compliant (NC) balloons (Fig. 3, right panel) 

followed by stent expansion of the body of LMCA with a 

5 8 mm NC balloon was performed. Excellent angiographic 

result was achieved and a final IVUS run confirmed optimal 

stent expansion (Fig. 4). The recovery after the procedure 

was uneventful, the patient was discharged the day after 

and was asymptomatic at clinical follow-up. 

3. Discussion 

Fig. 2 e LMCA recanalization. Angiographic (panel A) and 

IVUS (panel B and C) appearance after multiple balloon 

LMCA predilation. Diffuse circumferential atheroma is 

evident both at proximal (panel B) and mid left main 

coronary artery (panel C). 

CTO of the LMCA is a rare condition, with a reported prevalence 

ranging from 0.04 to 0.4%. 1,2 Two reasons can explain such a 

low prevalence. On the one hand, stable severe LMCA disease is 

almost always symptomatic, so that patients can be often 

diagnosed and treated before further progression. On the other 

hand, acute LMCA occlusion is frequently fatal and survival is 

possible only in patients with a dominant RCA providing sufficient 

collateral formation. Interestingly, our patient suffered 

mainly from shortness of breath and did not complain of 

angina, although SPECT demonstrated considerable inducible 

ischemia. Although this is not uncommon in diabetic patients 

it is surprising in a non-diabetic patient with LMCA occlusion. 

Although the recommendation for LMCA revascularization 

is still coronary artery bypass grafting (CABG), emerging evidence 

supports the feasibility of PCI in this setting. 3,4 Specifically, 

the pre-specified LMCA subgroup in the Syntax trial 

showed no significant difference for safety and efficacy endpoints 

compared to CABG at 1-year follow-up. 4 In the case here 

presented, although the high Syntax score would have 

indicated surgical revascularization, the poor functional 

status (NYHA III class) and severe obesity (BMI > 40 kg/m 2 ) 

suggested PCI as first attempt. In addition, PCI was a low risk 

option compared to surgery and we were reassured by 

option of surgical revascularization in case of failure. We 

also felt that PCI could provide the potential advantage of the 

reestablishment of normal coronary anatomy.

196 


Fig. 3 e IVUS-guided PCI optimization. After Cx-LMCA stenting (left panel) IVUS run shows suboptimal stent expansion at 

mid LMCA and good LMCA ostium coverage (mid panels). Final kissing balloon (right panel) allows PCI optimization. 

Fig. 4 e Final result. Excellent final angiographic (panel A) and IVUS (panel B) result with good LMCA stent expansion. 

New techniques and tools have allowed interventional 

cardiologists to tackle more and more complex lesions, but PCI 

to LMCA CTO represents a very rare situation. To the best of our 

knowledge, only 2 cases have been reported in the literature so 

far. 5,6 In order to warrant proper stent sizing and coverage of all 

diseased segments, IVUS generally plays a relevant role in the 

context of LMCA PCI. In the present case of a LMCA CTO, IVUS 

guidance revealed essential, as contrast opacification through 

the channel opened by multiple predilations did not clarify the 

real caliber and length of the vessel. Conversely, IVUS pullback 

allowed to visualize a concentric tubular disease from proximal 

Cx to ostial LMCA and guided the choice of the size and the 

length of the stent. Soon after stent deployment, IVUS run from 

LAD showed minor plaque shift to proximal LAD and ostial 

LMCA coverage but suboptimal stent expansion throughout all 

its length. PCI was then optimized with kissing balloon for LAD 

and Cx ostia and distal LMCA and with a large NC balloon for 

mid-to-proximal LMCA stent. Optimal stent apposition was 

confirmed by final IVUS run. 

4. Conclusions 

This case demonstrates CTO of the LMCA, although a rare 

finding, is compatible with life and can even present without 

typical angina in a non-diabetic patient. PCI of LMCA CTO is 

feasible in experienced hands and, owing to the reestablishment 

of normal anatomy, provides a more physiological 

revascularization than a surgical approach. In these procedures, 

IVUS guidance reveals of crucial importance to 

understand the anatomy and to guide stent sizing and 

placement.




references 

1. Greenspan M, Iskandrian AS, Segal BL, Kimbiris D, Bemis CE. 

Complete occlusion of the left main coronary artery. Am Heart 

J. 1979;98:83e86. 

2. Zimmern SH, Rogers WJ, Bream PR, et al. Total occlusion of the 

left main coronary artery: the coronary artery surgery study 

(CASS) experience. Am J Cardiol. 1982;49:2003e2010. 

3. Takagi H, Kawai N, Umemoto T. Stenting versus coronary 

artery bypass grafting for unprotected left main coronary 

artery disease: a meta-analysis of comparative studies. J Thorac 

Cardiovasc Surg. 2009;137:54e57. 

4. Morice MC, Serruys PW, Kappetein AP, et al. Outcomes in patients 

with de novo left main disease treated with either percutaneous 

coronary intervention using paclitaxel-eluting stents or coronary 

artery bypass graft treatment in the Synergy between 

Percutaneous Coronary Intervention with TAXUS and Cardiac 

Surgery (SYNTAX) trial. Circulation. 2010;121:2645e2653. 

5. Koster NK, White M. Chronic effort-induced angina as 

presentation of a totally occluded left main coronary artery: a 

case report and review. Angiology. 2009;60:382e384. 

6. Secco GG, Marino PN, Venegoni L, De Luca G. Percutaneous 

revascularization of chronic total occlusion of the left main 

coronary artery. Rev Esp Cardiol. 2011;64:431e433. 

Book Review 

Pediatric Cardiac Intensive Care. Pre and Postoperative 

Guidelines, Manoj Luthra. Elsevier A Division of Reed Elsevier 

India Pvt Ltd, 3, Tolstoy Marg, New Delhi, India, (2012). 

Pages: 314, Price: INR 475/- 

Pediatric Cardiac Intensive Care has seen a tremendous 

progress over the last few decades in our country. The centers 

providing this specialized care have increased steadily with 

newer centers being added every year across non-metro cities 

too. This has created a requirement of good pediatric cardiac 

intensive care services which most often is delivered by the 

team of pediatric cardiac surgeon, pediatric cardiac anesthetist, 

pediatric cardiologist, intensivist, pediatrician, registrars 

and nurses at various levels. With this scenario, there is an 

urgent need for a simple yet informative and concise handbook 

to enable provision of quality care to some of the sickest 

of children with cardiac problems across their peri-operative 

and post-operative period. 

‘The Manual of Pediatric cardiac intensive care e Pre and 

postoperative guidelines’ by Dr Manoj Luthra, an eminent 

pediatric cardiac surgeon of our country, is an excellent 

handbook which should enable the team of pediatric cardiac 

intensive care providers to handle most of the situations 

arising in the unit. It has chapters on almost all the relevant 

emergencies such as congestive cardiac failure, arrhythmias, 

hypertension, pulmonary hypertension, post-operative respiratory 

complications, ARDS, ventilator associated pneumonia, 

sepsis, seizures, acute kidney injury and 

coagulopathies. Besides these emergencies, many basic 

physiology topics such as fluid and electrolytes, ABG analysis, 

hemodynamic monitoring, parenteral and enteral nutrition 

have been discussed very succinctly .It also contains valuable 

chapters on important drugs used in the PCCU and has a well 

compiled set of appendices at the end. The book is handy, is 

well illustrated and the author has kept the language very 

simple so that it can be used by the different levels of child 

care providers. The book is likely to be useful to anyone 

involved in looking after the sick child in the pediatric cardiac 

care unit. 

It is a difficult task to convert volumes of information 

available on pediatric cardiac intensive care to a few hundred 

pages. However, the author has created an excellent handbook 

on the subject and reflects decades of experience in 

practical day to day management in the PCCU and toward 

which the book shall go a long way in fulfilling the requirements 

of the pediatric cardiac care provider. 

B.M. John*, Amit Devgan 

Associate Professor, Department of Pediatrics, AFMC, 

Sholapur Road, Pune 411040, India 


E-mail address: drbmj1972@yahoo.com (B.M. John)





Fractional Flow Reserve: Intracoronary versus intravenous 

adenosine induced maximal coronary hyperemia 

P.S. Sandhu a , Upendra Kaul a,b, *, R.K. Gupta a , Tapan Ghose a 

a Fortis Escorts Heart Institute and Research Center, Okhla Road, New Delhi, India 

b Executive Director and Dean, Fortis Flt. Lt Rajen Dhall Hospital & Fortis Escorts Heart Institute and Research Center, 

Okhla Road, New Delhi 1100, India 

article info 


Received 8 October 2012 



Keywords: 

Fractional Flow Reserve 

Adenosine 

Maximal hyperemia 

abstract 

Background: Fractional Flow Reserve (FFR), a measure of coronary stenosis severity is based 

on the achievement of maximal hyperemia of coronary microcirculation. The most widely 

used pharmacological agent is adenosine which is administered either by intra coronary or 

intra venous routes. IV route is time consuming, has more side effects and expensive. This 

study is undertaken to compare the two routes of administration. 

Methods: FFR was assessed in 50 patients with 56 intermediate focal lesions using both IV 

and intracoronary (IC) adenosine. FFR was calculated as the ratio of the distal coronary 

pressure to the aortic pressure at maximal hyperemia. 

Results: A total of 25 left anterior descending, 8 right, 21 circumflex, and 2 left main coronary 

arteries were evaluated. The mean percent stenosis was 63.91 13.13 SD and, the 

mean FFR was 0.831 0.0738 SD for IV and 0.832 0.0707 SD for IC adenosine. There was a 

strong and linear correlation between 2 sets of observations with IV dose and IC adenosine 

dose (R ¼ 0.964, y ¼ 0.065 þ 0.923x; p < 0.001) (y ¼ IV dose, x ¼ IC dose). The agreement 

between the two sets of measurements was also high, with a mean difference of: 

0.001 0.0197. The changes in heart rate and blood pressure were significantly higher in IV 

adenosine group. Different incremental doses were well tolerated, with fewer systemic 

adverse events with IC adenosine. Transient AV blocks were observed with both IV and IC 

adenosine. 

Conclusions: This study suggests that IC adenosine is equivalent to IV infusion for the 

determination of FFR. The administration of IC adenosine is easy to use, cost effective, safe 

and associated with fewer systemic events. 



The temporal and spatial resolution of coronary angiography 

(CAG) have meant that despite major advances in noninvasive 

cardiac imaging, CAG continues to remain the gold standard 

for the diagnosis and management of coronary artery disease. 

However, the 2-dimensional silhouette image provided by 

CAG has well recognized limitations; it does not accurately 


E-mail address: kaul.upendra@gmail.com (U. Kaul). 



148 


represent the true complexity of the coronary luminal 

morphology, and gives no indication of the functional influence 

of luminal changes on coronary blood flow. These limitations 

are more pronounced in angiographically intermediate 

stenosis (50e90%) and in patients in whom there is a clear 

discrepancy between the clinical picture and angiographic 

findings. 1e4 

The measurement of Fractional Flow Reserve (FFR) is used 

to determine the hemodynamic significance of epicardial 

coronary stenosis detected at CAG. 3 For an accurate calculation 

of FFR, the principle is to achieve a maximal hyperemia to 

minimize the contribution of microvascular resistance. 5 With 

suboptimal levels of coronary hyperemia, FFR will be artificially 

high, resulting in a potentially significant underestimation 

of the functional severity of the coronary stenosis. 

This physiologic method of assessing the severity of coronary 

lesions has become a very acceptable simple method utilized 

in a large numbers of cardiac catheterization laboratories 

world over after the results of FAME study were published. 4,5 

The method is being utilized in our country also increasingly. 

We have previously demonstrated its utility and cost 

saving advantage in our set. 6 

Although adenosine invariably intravenously (IV), has been 

recommended for FFR measurements, intracoronary (IC) 

administration of adenosine constitutes a valuable alternative 

in everyday practice. 4e9 Compared with the IC route, IV 

adenosine administration requires relatively large doses, and 

it is associated with more systemic adverse effects and 

costs. 10,11 However, several observations cast some doubts 

about the ability of the IC adenosine boluses to achieve 

maximal hyperemia in all patients. 11,12 

The aim of this study was to compare IV versus IC adenosine 

for calculating an accurate FFR at maximal hyperemia by 

two methods. The FFR was calculated by both methods in our 

setting at maximum hyperemia. 

of the procedure (5000 units). The heart rate and arterial 

pressure were continuously monitored throughout the procedure. 

After CAG, a 0.014-inch pressure-recording guidewire 

(PressureWire Certus, St. Jude Medical, USA) was introduced 

through a guiding catheter into the coronary artery. Arterial 

pressure wave damping or variation of the measured coronary 

guide pressure was avoided. The guidewire was externally 

calibrated and then advanced to the distal tip of the catheter. 14 

At this position, it was verified that both the catheter and the 

pressure wire recorded equal pressures. The pressure wire 

was subsequently advanced into the coronary artery with the 

pressure sensor placed beyond the lesion site. Distal coronary 

and aortic pressures were measured at baseline and at 

maximal hyperemia. Pressure signals were continuously 

recorded and a beat-to-beat analysis of mean pressure was 

performed automatically (RadiAnalyzer Xpress, St. Jude 

Medical, USA). 

2.3. Pharmacologic protocol 

All patients first received multiple IC adenosine boluses, 

which were then followed by IV adenosine. Incremental doses 

of IC adenosine (60, 100, and 120 mg for both coronary arteries) 

were administered. Each bolus was followed by a flush with 

5 ml saline. Subsequent doses were given after pressure 

curves returned to baseline values. Thereafter, adenosine 

infusion via a large systemic vein at incremental doses of 140, 

160, 180 mg/kg/min was administered until a steady-state hyperemia 

was achieved for a minimal duration of 1 min 15 The 

electrocardiogram was simultaneously recorded. 

2.4. Calculations of pressure-derived FFR 

FFR is defined as the ratio of the hyperemic flow in a stenotic 

artery to the hyperemic flow in the same artery in the 

2. Methods 

2.1. Study population 

FFR was assessed in a total of 50 patients enrolled prospectively. 

The study population consisted of 36 males and 14 females 

with a mean age of 62 8 years. Most patients had 

normal left ventricular function, and only focal or short 

segment of coronary artery stenosis ranging from 50e90%, as 

assessed by QCA, were analyzed. In all patients, FFR was 

determined for a target coronary lesion by both IV and IC 

adenosine. All patients were symptomatic with angina or 

angina equivalent and had been referred for a diagnostic or 

interventional cardiac catheterization. Exclusion criteria 

included culprit vessel in acute coronary syndrome, acute 

myocardial infarction, and atrioventricular conduction abnormalities 

in the electrocardiogram. All patients gave 

informed consent to participate in the study. 

2.2. Study protocol 

Coronary angiography (CAG) was performed from femoral or 

radial approach. Heparin was administered at the beginning 

Table 1 e Baseline demographic data of the study 

population. 

Study cohort (50 patients, 56 lesions) 

Age (yr.) 62 8 

Male/Female 36/14 

Risk factors 

Hypertension 18 (36%) 

Diabetes 21 (42%) 

Smoking 10 (20%) 

Dyslipidemia 15 (30%) 

Old MI 5 (10%) 

Angiographic parameters 

Single vessel disease 13 (26%) 

Double vessel disease 26 (52%) 

Triple vessel disease 11 (22%) 

Percent stenosis (%) 63.9 13.1 

Target vessel 

LAD 25 (44.6%) 

LCX 21 (37.5%) 

RCA 8 (14.3%) 

LM 2 (3.6%) 

Ejection fraction (%) 55 5% 

LAD, Left anterior descending artery; RCA, right coronary artery; 

LCx, left circumflex artery; LM, left main coronary artery.


Fig. 1 e Linear regression analysis of FFR measurements performed with intracoronary (IC) (dependent variable) and 

intravenous (IV) 9 independent variable adenosine. 

hypothetical case when there is no stenosis present. 16 FFR 

expresses maximum hyperemic blood flow in a stenotic vessel 

as a fraction of normal maximal blood flow in that vessel. FFR is 

calculated from intracoronary and aortic pressure measurements 

obtained during maximal hyperemia by the following 

equation: FFR ¼ P d P v /P a P v , or FFRyP d /P a (if P v is negligible), 

where P a is the mean proximal coronary pressure, P d is the 

mean distal coronary pressure, and P v is the mean central 

venous pressure. FFR measurement was done with IC adenosine 

at incremental doses. The values were taken at maximum 

hyperemia. This was compared with IV adenosine at sequentially 

increasing doses till maximum hyperemia was produced. 


Data are presented as mean SD. Student paired t test was 

used to compare FFR values after different hyperemic 

responses for IV and IC adenosine. Linear regression was 

calculated for FFR data derived from both hyperemic stimuli, 

and nonlinear regression was used for the relation of percent 

stenosis to the FFR. The mean SD of the signed differences 

between measurements of FFR with intravenous and intracoronary 

adenosine was used as an index of agreement between 

measurements. Results were considered statistically 

significant at p 0.05. 

3. Results 

3.1. Patient characteristics 

A total of 50 patients with 56 lesions were included in the 

analysis. Baseline demographic data is provided in Table 1. 

Procedural success was 100% for crossing the target lesion 

Fig. 2 e BlandeAltman agreement between 2 sets of measurements. Difference between measurements with intracoronary 

(IC) and intravenous (IV) adenosine plotted against mean.

150 


Table 2 e Hemodynamic data for intravenous and intracoronary adenosine. 

IC adenosine 

(mean SD) 

IV adenosine 

(mean SD) 

p value 

DHR (beats/min) 0.8 3.4 5 5.6



This study suggests that IC adenosine is equivalent to IV 

infusion for achievement of maximal hyperemia and the 

determination of FFR in short segment or focal lesions. The 

administration of IC adenosine is easy to use, cost effective, 

safe and associated with fewer systemic events. 



references 

1. Kern JM, De Bruyne B. From research to clinical practice: 

current role of intracoronary physiologically based decision 

making in the cardiac catheterization laboratory. JACC. 

1997;30:613e620. 

2. Kern JM. Coronary physiology revisited. Practical insights 

from the cardiac catheterization laboratory. Circulation. 

2000;101:1344e1351. 

3. Topol EJ, Nissen SE. Our preoccupation with coronary 

luminology: the dissociation between clinical and 

angiographic findings in ischemic heart disease. Circulation. 

1995;92:2333e2342. 

4. Tonino PA, De Bruyne B, Pijls NH, et al. FFR versus 

angiography for guiding PCI. NEJM. 2009;360:213e224. 

5. De Bruyne B, Pijls NH, Kalesan B, et al. FFR-guided PCI versus 

medical therapy in stable coronary disease. NEJM. 

2012;367:991e1001. 

6. Kaul U, Rastogi V, Seth A, et al. Role of fractional flow reserve 

(FFR) in decision making during multivessel PCI and the cost 

effectiveness. Our experience. IHJ. 2011;63:6. 

7. Jeremias A, Whitbourn RJ, Filardo SD, et al. Adequacy of IC vs 

IV adenosine-induced maximal coronary hyperemia for FFR 

measurements. AHJ. 2000;140:651e667. 

8. Casella G, Leibig M, Schiele TM, et al. Are high doses of IC 

adenosine an alternative to standard intravenous adenosine 

for the assessment of FFR? AHJ. 2004;148:590e595. 

9. Leone AM, Porto I, de Caterina AR, et al. IC vs IC sodium 

nitroprusside vs IV adenosine: the NASCI study. JACC Intv. 

2012;5:402e408. 

10. Wilson RF, Wyche K, Christensen BV, et al. Effects of 

adenosine on human coronary circulation. Circulation. 

1990;82:1595e1606. 

11. Kern MJ, Deligonul U, Tatineni S, et al. IV adenosine: 

continuous infusion and low dose bolus administration for 

determination of coronary vasodilator reserve in patients 

with and without coronary artery disease. JACC. 

1991;18:718e729. 

12. Jeremias A, Filardo SD, Whitbourn RJ, et al. Effect of IV and IC 

adenosine 5’- triphosphate as compared with adenosine on 

coronary flow and pressure dynamics. Circulation. 

2000;101:318e323. 

13. de Bruyne B, Bartunek J, Sys SU, et al. Simultaneous 

coronary pressure and flow velocity measurements in 

humans: feasibility, reproducibility, and hemodynamic 

dependence of coronary flow velocity reserve, hyperemic 

flow versus pressure slope index, and FFR. Circulation. 

1996;94:1842e1849. 

14. Pijls NH, van Gelder B, van der Voort P, et al. FFR: a useful 

index to evaluate the influence of an epicardial coronary 

stenosis on myocardial blood flow. Circulation. 

1995;92:3183e3193. 

15. Wilson RF, Wyche K, Christensen BV, et al. Effects of 

adenosine on human coronary arterial circulation. Circulation. 

1990;82:1595e1606. 

16. Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of 

determining maximum coronary, myocardial, and collateral 

blood flow by pressure measurements for assessing 

functional stenosis severity before and after percutaneous 

transluminal coronary angioplasty. Circulation. 

1993;87:1354e1367. 

17. Pijls NHJ, Klauss V, Siebert U, et al. Coronary pressure 

measurements after stenting predicts adverse events at 

follow-up: a multicenter registry. Circulation. 

2002;105:2950e2954.





Fragmented narrow QRS complex: Predictor of left ventricular 

dyssynchrony in non-ischemic dilated cardiomyopathy 

Jamal Yusuf a , Devendra Kumar Agrawal a,b, *, Saibal Mukhopadhyay a , Vimal Mehta a , 

Vijay Trehan a , Sanjay Tyagi a 

a Department of Cardiology, G.B. Pant Hospital, New Delhi, India 

b Senior Resident, Department of Cardiology, Maulana Azad Medical College and G.B. Pant Hospital, Jawaharlal Nehru Marg, 

New Delhi 110002, India 

article info 


Received 20 September 2012 


Available online 4 March 2013 

Keywords: 

Cardiomyopathy 

Intraventricular dyssynchrony 

Fragmented QRS complex 

Tissue Doppler imaging 

abstract 

Background: Cardiac resynchronization therapy is an important therapeutic modality in 

drug refractory symptomatic patients of heart failure with wide QRS (120 ms) on electrocardiogram. 

However, wide QRS (considered as a marker of electrical dyssynchrony) 

occurs in only 30% of heart failure patients, making majority of drug refractory heart failure 

patients ineligible for resynchronization therapy. Significant numbers of patients with 

narrow QRS have echocardiographic evidence of left ventricular dyssynchrony. However, 

there is sparse data about additional features on the surface ECG which can predict 

intraventricular dyssynchrony. This study was undertaken to assess the utility of fragmented 

narrow QRS complex to predict significant intraventricular dyssynchrony in 

symptomatic patients of non-ischemic dilated cardiomyopathy. 

Method: 100 symptomatic patients of non-ischemic dilated cardiomyopathy with narrow 

QRS complexes (50 each with fragmented and normal QRS) were recruited. Tissue Doppler 

imaging was used to assess intraventricular dyssynchrony as per ‘Yu index’. 

Results: 78% patients (n ¼ 39) in fQRS complex group and 14% (n ¼ 7) in normal QRS complex 

group had significant intraventricular dyssynchrony (c 2 ¼ 20.61; p < 0.000005). fQRS complexes 

had 84.78% sensitivity, 79.62% specificity, a positive predictive value of 78% and 

negative predictive value of 86% to detect intraventricular dyssynchrony. fQRS also had 

sensitivity and specificity of 93% and 90% respectively to localize the dyssynchronous 

segment. 

Conclusion: fQRS is a marker of electrical dyssynchrony, which results in significant intraventricular 

dyssynchrony in patients of non-ischemic dilated cardiomyopathy and a narrow 

QRS interval. fQRS localizes the dyssynchronous segment and might be useful in 

identifying patients who can benefit from cardiac resynchronization therapy. 


* Corresponding author. Department of Cardiology, Maulana Azad Medical College and G.B. Pant Hospital, Jawaharlal Nehru Marg, New 

Delhi 110002, India. 

E-mail addresses: drdevendra_123@yahoo.co.in, devendra.aiims@gmail.com (D.K. Agrawal). 





Cardiac resynchronization therapy (CRT) is a useful therapeutic 

strategy in drug refractory symptomatic patients of 

heart failure (HF) with wide QRS (120 ms) on electrocardiogram 

(ECG). 1 Though QRS duration 120 ms has been adopted 

as a marker of electrical dyssynchrony responsible for presence 

of left ventricular (LV) dyssynchrony and subsequent 

eligibility for CRT, studies suggest that QRS widening 120 ms 

occurs in only 30% of HF patients. 2,3 In patients of HF with 

normal QRS duration, LV dyssynchrony has been reported in 

20e50% patients. 4e7 However, there are not enough studies 

available analyzing additional features on the surface ECG that 

can be taken as marker of electrical dyssynchrony resulting in 

significant intraventricular dyssynchrony (IVD) in patients of 

HF with narrow QRS. Till date only two studies have reported 

that fQRS on the surface ECG is a predictor of significant IVD in 

patients of non-ischemic DCM. 8,9 We undertook this study to 

assess the sensitivity, specificity and positive predictive value 

(PPV) of fQRS complex on the surface ECG to detect significant 

IVD in symptomatic patients of non-ischemic DCM. 

2. Methods 

2.1. Patients selection 

This study was conducted in GB Pant Hospital, New Delhi, a 

tertiary care centre, located in the Northern part of India. The 

study protocol conforms to the ethical guidelines of the 1975 

Declaration of Helsinki as reflected in a priori approval by the 

institution’s human research committee. 

A total of 100 patients of chronic HF due to non-ischemic 

dilated cardiomyopathy (DCM), with LV ejection fraction of 

less than 35% and sinus rhythm having narrow QRS complexes 

(

174 


presence of significant (50% stenosis in any epicardial coronary 

artery) coronary artery disease (CAD). Patients with 

organic valvular heart disease, history suggestive of CAD, 

atrial fibrillation, kidney failure, liver failure and on permanent 

pacemakers were excluded from the study. The study 

protocol was approved by the institutional review board. 

Written informed consent was obtained from all participants. 

2.2. ECG 

The resting 12-lead ECG (filter range, 0.05e100 Hz; A.C. filter, 

60 Hz, 25 mm/s, 10 mm/mV) was analyzed by two independent 

clinicians who were blinded to echocardiographic data. 

The fQRS included various RSR’ patterns and was defined by 

the presence of an additional R-wave (R 0 prime), notching in 

nadir of the S-wave, notching of R-wave, or the presence of 

more than one R prime (fragmentation) in two contiguous 

leads corresponding to a major myocardial segment as previously 

described by Das et al (Fig. 1). 10 The presence of fQRS in 

2 contiguous anterior leads (V1eV5) were assigned to anterior 

myocardial segments, in 2 contiguous lateral leads (I, 

aVL, and V5, V6) to the lateral myocardial segments, in 2 

contiguous inferior leads (II, III, and aVF) to the inferior 

myocardial segments and in both V1 and V2 only to the posterior 

myocardial segments. 

2.3. Echocardiography 

Standard echocardiography with Doppler studies was performed 

by using a commercially available system (Philips iE33 

system, Andover, Massachusetts, USA). LV dimensions were 

measured by two-dimensional guided M-mode echocardiography 

according to the guidelines of the American Society of 

Echocardiography. 11 LV volumes were determined by the use 

of biplane Simpson’s method of disks, and the ejection fraction 

was calculated with a formula calling for the subtraction 

of the end-systolic volume from the end-diastolic volume and 

the difference divided by the end-diastolic volume. The 

effective orifice area and the regurgitant volume of the functional 

mitral regurgitation jet (MR volume) were calculated by 

‘proximal iso-velocity surface area’ method. 12 

Tissue Doppler imaging (TDI) was performed in the apical 

views (four-chamber, two-chamber and long-axis) for the long 

axis motion of the left ventricle. Two-dimensional echocardiography 

with tissue Doppler color imaging was performed 

with a 2.5 MHz phase array transducer. Myocardial regional 

velocity curves were constructed from the digitized images as 

previously described 13 (Fig. 2B). In this way septal, anteroseptal, 

anterior, lateral, inferior and posterior segments 

Fig. 1 e Various morphologies of QRS on 12-lead ECG 

defined as fQRS in present study originally proposed by 

Das et al. 10 

were interrogated at both basal and middle levels. Aortic 

opening and closure were determined by sampling the flow 

through the LV outflow tract with the use of pulsed Doppler 

echocardiography. For the purpose of measurement, the 

beginning of the QRS complex was used as the reference 

point, from where the time to peak myocardial sustained 

systolic (T s ) and early diastolic (T e ) velocities were calculated. 

The higher peak in velocity was selected when double peaks 

were encountered within the aortic ejection period. 

To assess global LV function, the myocardial sustained 

systolic (s), early diastolic (e) and late diastolic (a) velocities 

from the basal septal and basal lateral segments were calculated. 

For the assessment of synchronicity, the standard deviations 

of T s (T s -SD) of all 12 LV segments were calculated. 

Significant systolic IVD was defined as T s -SD >32.6 ms proposed 

by Yu et al and popularly known as ‘Yu index’. 14 Fig. 2B 

depicts color coded TDI (post processing image) of a patient 

with the ECG shown in Fig. 2A, showing systolic dyssynchronous 

inferior wall segments. 

We also looked for the association of fQRS and the most 

delayed contracting LV segment on echocardiography. ‘Dyssynchronic 

segments’ were defined as those LV segments that 

contracted later than 100 ms following the earliest contracting 

LV segment (which had the earliest T s ) and ‘most delayed 

segment’ was the last contracting myocardial segment (which 

had the latest T s ). 


Analysis was performed using a statistical software program 

(SPSS for windows, version 17.0, SPSS Inc. Chicago, IL, USA). 

Data has been presented as mean SD and compared using 

the paired student’s t test. ManneWhitney U test has been 

used when the distribution was not normal. Categorical data 

between two or more groups were compared by Pearson c 2 

test. P value of


Fig. 2 e (A): 12-lead ECG showing fragmented narrow QRS complexes in inferior leads (B): Colour coded TDI (post processing 

image) of the same patient showing systolic dyssynchronous inferior wall segments. 

Table 2 e Comparison of time to peak myocardial sustained systolic velocity (T s ) (in ms) between patients with fQRS and 

without fQRS. 

Segment Fragmented QRS (n ¼ 50) Normal QRS (n ¼ 50) p value 

Basal septal 158.52 37.86 160.26 33.09 0.80 

Mid septal 156.24 37.56 160.80 33.75 0.52 

Basal lateral 177.28 49.88 164.88 34.25 0.15 

Mid lateral 182.18 49.23 164.16 32.79 0.03* 

Basal inferior 187.48 48.44 169.64 32.64 0.03* 

Mid inferior 188.18 47.05 169.08 29.24 0.01* 

Basal anterior 177 47.21 161.36 28.38 0.048* 

Mid anterior 183.24 50.14 162.18 29.55 0.01* 

Basal posterior 172.16 40.25 167.08 29.08 0.47 

Mid posterior 173.76 45.23 169.84 31.05 0.61 

Basal anteroseptal 170.04 37.11 162.94 26.94 0.27 

Mid anteroseptal 169.7 38.52 169.90 34.23 0.98 

T s -SD (Yu index) 35.64 12.79 20.45 11.17

176 


significant difference in severity of LV dilatation, LV ejection 

fraction and mitral regurgitation between the two groups. 

However, there was significant difference in the QRS 

duration in patients with fQRS complexes as compared to 

those with normal QRS, though QRS duration in both the 

groups was 32.6 ms) was seen in 39 patients (78%) in 

fQRS complex group and 7 patients (14%) in normal QRS 

complex group (Pearson’s c 2 ¼ 20.61; p < 0.000005) [Table 2]. 

The presence of fQRS complexes in the basal ECG was 

found to detect systolic IVD as defined by the ‘Yu index’ (T s - 

SD > 32.6 ms) with sensitivity of 84.78%, specificity of 79.62%, 

positive predictive value (PPV) of 78% and a negative predictive 

value (NPV) of 86% (Table 3). 

The 50 patients with fQRS complexes were sub-divided 

into two groups with either significant systolic dyssynchrony 

(group 1, n ¼ 39) or without dyssynchrony (group 2, 

n ¼ 11) on the basis of T s -SD greater than or lesser than 

32.6 ms. Table 4 shows the clinical, demographic and echocardiographic 

characteristics of patients in group 1 and 2. The 

demographic and clinical parameters between the two groups 

were not statistically different. The patients in group 1 had 

significantly longer isovolumetric relaxation time (IVRT) in 

comparison to patients in group 2 (105.23 20.36 vs. 

72.00 8.90 ms; p < 0.001). There was no significant difference 

in any other echocardiographic parameters between the two 

groups. Among 39 patients of group 1 with significant systolic 

dyssynchrony, 30 (76.92%) patients had ECG fragmentation in 

the maximal dyssynchronic segment and six (15.39%) patients 

had ECG fragmentation in one of the dyssynchronic segments. 

In three (7.69%) patients, fragmented segments and dyssynchronic 

segments did not correlate. Among the dyssynchronic 

patients, the sensitivity and specificity of a 

fragmented segment on ECG to detect the most dyssynchronic 

segment or one of the dyssynchronic segments were 93% and 

88%, respectively. 

Table 3 e Relationship between fragmented QRS and 

intraventricular systolic dyssynchrony. 

Group 

Significant 

systolic 

dyssynchrony 

present (n) 

No significant 

systolic 

dyssynchrony 

(n) 

Total (n) 

Fragmented QRS 39 (true positives) 11 (false positives) 50 

Normal QRS 7 (false negatives) 43 (true negatives) 50 

Total 46 54 100 

4. Discussion 

CRT is an established treatment option for patients with drug 

refractory heart failure. The predominant mechanism of benefit 

from CRT appears to be related to the presence of IVD due to 

electrical conduction delay and subsequent resynchronization 

after CRT. 15e19 The presence of significant IVD at baseline secondary 

to electrical dyssynchrony is therefore, mandatory for 

the response to CRT. QRS duration of 120 ms has been adopted 

as a cut-off point for electrical dyssynchrony resulting in LV 

systolic dyssynchrony in CRT trials 20,21 and subsequently by 

treatment guidelines. 1 However, studies suggest that QRS 

widening of 120 ms occurs in only 30% of HF patients making 

majority of HF patients ineligible for CRT. On the other hand, 

significant IVD by TDI has been reported in 36e51% 14,22 of patients 

with HF and QRS 150 ms, the ‘Yu index’ has a sensitivity and 

specificity of 100% and 78%, respectively to predict reverse 

remodeling, while in patients with QRS duration of 

120e150 ms the sensitivity is 83% and specificity is 86%. 30 So 

we decided to use ‘Yu index’ to assess mechanical dyssynchrony 

in patients with fQRS and drug refractory symptomatic 

non-ischemic dilated cardiomyopathy as it may also serve as 

a predictor of response to CRT in this subgroup of patients 

with narrow QRS. Yu et al 14 developed this twelve segment


Table 4 e Characteristics of patients with fQRS with (group 1) and without (group 2) significant systolic dyssynchrony. 

Characteristic 

Group 1 (with systolic 

dyssynchrony) (n ¼ 39) 

Group 2 (no systolic 

dyssynchrony) (n ¼ 11) 

Chi square value p value 

Age (in years) 46.13 14.24 45.00 12.20 0.80 

Sex (M:F) 23:16 9:2 0.43 0.51 

NYHA class n (%) 2.74 0.09 

II 23 (59%) 4 (57%) 

III-IV 16 (41%) 7 (43%) 

Heart rate (BPM) 91.67 17.74 98.09 14.91 0.24 

PR interval (ms) 148.59 29.52 155.82 31.49 0.51 

QRS duration (ms) 99.08 13.32 100.64 12.62 0.72 

LVEF % (Simpson’s) 22.31 5.30 22.00 4.43 0.85 

EPSS (mm) 20.47 3.44 21.33 1.70 0.26 

MR regurgitant volume (ml) 31.61 13.45 30.66 22.41 0.90 

TR jet gradient (mm Hg) 27.09 9.40 31.10 7.46 0.18 

Mitral E/A 2.29 1.39 3.03 1.70 0.21 

IVRT (ms) 105.23 20.36 72.00 8.90

178 


patients with non-ischemic DCM and a narrow QRS interval. 

fQRS on the surface ECG is also helpful for localizing the 

dyssynchronous segment. In future, studies are needed to 

assess the beneficial effects of CRT in drug refractory, symptomatic 

HF patients with narrow fragmented QRS complexes 

and significant IVD. 



references 

1. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 

2008 guidelines for device-based therapy of cardiac rhythm 

abnormalities: a report of the American College of Cardiology/ 

American Heart Association Task Force on Practice 

Guidelines (Writing Committee to Revise the ACC/AHA/ 

NASPE 2002 Guideline Update for Implantation of Cardiac 

Pacemakers and Antiarrhythmia Devices) developed in 

collaboration with the American Association for Thoracic 

Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 

2008;51:e1ee62. 

2. Kashani A, Barold SS. Significance of QRS complex duration 

in patients with heart failure. J Am Coll Cardiol. 2005;46: 

2183e2192. 

3. Freudenberger R, Sikora JA, Fisher M, et al. Electrocardiogram 

and clinical characteristics of patients referred for cardiac 

transplantation: implications for pacing in heart failure. Clin 

Cardiol. 2004;27:151e153. 

4. Bleeker G, Schalij M, Molhoek S, et al. Frequency of left 

ventricular dyssynchrony in patients with heart failure and a 

narrow QRS complex. Am J Cardiol. 2005;95:140e142. 

5. Auricchio A, Yu CM. Beyond the measurement of QRS 

complex toward mechanical dysynchrony: cardiac 

resynchronization therapy in heart failure patients with a 

normal QRS duration. Heart. 2004;90:479e481. 

6. Dohi K, Suffoletto M, Murali S, et al. Benefit of cardiac 

resynchronization therapy to a patient with a narrow 

QRS complex and ventricular dyssynchrony identified by 

tissue synchronization imaging. Eur J Echocardiogr. 

2005;6:455e460. 

7. Yu CM, Chan YS, Zhang Q, et al. Benefits of cardiac 

resynchronization therapy for heart failure patients with 

narrow QRS complexes and coexisting systolic asynchrony 

by echocardiography. J Am Coll Cardiol. 2006;48:2251e2257. 

8. Tigen K, Karaahmet T, Gurel E, et al. The utility of fragmented 

QRS complexes to predict significant intraventricular 

dyssynchrony in nonischemic dilated cardiomyopathy 

patients with a narrow QRS interval. Can J Cardiol. 2009;25(9): 

517e522. 

9. Basaran Y, Tigen K, Karaahmet T, et al. Fragmented QRS 

Complex are associated with cardiac fibrosis and significant 

intraventricular systolic dyssynchrony in nonischemic 

dilated cardiomyopathy patients with a narrow QRS interval. 

Echocardiography. 2011;28(1):62e68. 

10. Das M, Khan B, Jacob S, et al. Significance of a fragmented 

QRS complex versus a Q wave in patients with coronary 

artery disease. Circulation. 2006;113:2495e2501. 

11. Schiller NB, Shah PM, Crawford M, et al. Recommendations 

for quantitation of the left ventricle by two-dimensional 

echocardiography: American Society of Echocardiography 

Committee on Standards, Subcommittee on Quantitation of 

the Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 

1989;2:358e367. 

12. Shiota T, Jones M, Teien DE, et al. Evaluation of mitral 

regurgitation using a digitally determined colour Doppler flow 

convergence ‘centerline’ acceleration method: studies in an 

animal model with quantified mitral regurgitation. Circulation. 

1994;89:2879e2886. 

13. Gorcsan 3rd J, Strum DP, Mandarino WA, et al. Quantitative 

assessment of alterations in regional left ventricular 

contractibility with color-coded tissue Doppler 

echocardiography. Comparison with sonomicrometry and 

pressure volume relations. Circulation. 1997;95:2423e2433. 

14. Yu CM, Lin H, Zhang Q, et al. High prevalence of left 

ventricular systolic and diastolic asynchrony in patients with 

congestive heart failure and normal QRS duration. Heart. 

2003;89:54e60. 

15. Bax JJ, Marwick TH, Molhoek SG, et al. Left ventricular 

dyssynchrony predicts benefit of cardiac resynchronization 

therapy in patients with end-stage heart failure before 

pacemaker implantation. Am J Cardiol. 2003;92:1238e1240. 

16. Yu CM, Fung WH, Lin H, et al. Predictors of left ventricular 

reverse remodeling after cardiac resynchronization therapy 

for heart failure secondary to idiopathic dilated or ischemic 

cardiomyopathy. Am J Cardiol. 2003;91:684e688. 

17. Breithardt OA, Stellbrink C, Kramer AP, et al. 

Echocardiographic quantification of left ventricular 

asynchrony predicts an acute hemodynamic benefit of 

cardiac resynchronization therapy. J Am Coll Cardiol. 

2002;40:536e545. 

18. Bordachar P, Lafitte S, Reuter S, et al. Echocardiographic 

parameters of ventricular dyssynchrony validation in 

patients with heart failure using sequential biventricular 

pacing. J Am Coll Cardiol. 2007;44:2157e2165. 

19. Bax JJ, Bleeker GB, Marwick TH, et al. Left ventricular 

dyssynchrony predicts response and prognosis after cardiac 

resynchronization therapy. J Am Coll Cardiol. 

2004;44:1834e1840. 

20. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac 

resynchronization on morbidity and mortality in heart 

failure. N Engl J Med. 2005;352:1539e1549. 

21. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization 

therapy with or without an implantable 

defibrillator in advanced chronic heart failure. N Engl J Med. 

2004;350:2140e2150. 

22. Haghjoo M, Bagherzadeh A, Fazelifar AF, et al. Prevalence of 

mechanical dyssynchrony in heart failure patients with 

different QRS durations. Pacing Clin Electrophysiol. 

2007;30:616e622. 

23. Bleeker GB, Holman ER, Steendijk P, et al. Cardiac 

resynchronization therapy in patients with a narrow QRS 

complex. J Am Coll Cardiol. 2006;48:2243e2250. 

24. Achilli A, Sassara M, Ficili S, et al. Long-term effectiveness of 

cardiac resynchronization therapy in patients with refractory 

heart failure and "narrow" QRS. J Am Coll Cardiol. 

2003;42:2117e2124. 

25. Takemoto Y, Hozumi T, Sugioka K, et al. Beta-blocker therapy 

induces ventricular resynchronization in dilated 

cardiomyopathy with narrow QRS complex. J Am Coll Cardiol. 

2007;49:778e783. 

26. Marcassa C, Campini R, Verna E, et al. Assessment of cardiac 

asynchrony by radionuclide phase analysis: correlation with 

ventricular function in patients with narrow or prolonged 

QRS interval. Eur J Heart Fail. 2007;9:484e490. 39. 

27. Timonen P, Magga J, Risteli J, et al. Cytokines, interstitial 

collagen and ventricular remodelling in dilated 

cardiomyopathy. Int J Cardiol. 2008;124:293e300. 

28. Marijianowski MM, Teeling P, Mann J, et al. Dilated 

cardiomyopathy is associated with an increase in the type


I/type III collagen ratio: a quantitative assessment. J Am Coll 

Cardiol. 1995;25:1263e1272. 

29. Gorcsan J, Abraham T, Agler DA, et al. Echocardiography for 

cardiac resynchronization therapy: recommendations for 

performance and reportingea report from the American Society 

of Echocardiography Dyssynchrony Writing Group endorsed by 

the Heart Rhythm Society. JAmSocEchocardiogr. 2008;21:191e213. 

30. Yu CM, Fung JW, Chan CK, et al. Comparison of efficacy of 

reverse remodeling and clinical improvement for relatively 

narrow and wide QRS complexes after cardiac 

resynchronization therapy for heart failure. J Cardiovasc 

Electrophysiol. 2004;15:1058e1065. 

31. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiacresynchronization 

therapy in heart failure with narrow QRS 

complexes. N Engl J Med. 2007;357:2461e2471. 

32. Chung ES, Leon AR, Tavazzi L, et al. Results of the predictors 

of response to CRT (PROSPECT) trial. Circulation. 

2008;117:2608e2616.




Review Article 

“On” or “Off” pump coronary artery bypass grafting e Is the 

last word out? 

O.P. Yadava*, Anirban Kundu 

Department of Cardiac Surgery, National Heart Institute, New Delhi-110065, India 

A glance at the history of the development of Coronary Artery 

Bypass Surgery (CABG) throws up the interesting finding that 

the first milestones were without cardiopulmonary bypass 

(CPB) support. Off-pump CABG (OPCAB), having predated Onpump 

surgery, has had a roller coaster ride for want of a clean, 

still and bloodless field, culminating in the introduction of 

CABG on CPB (On-pump) by Favaloro in 1967. This development 

profoundly “democratised” the CABG procedure in that 

now a broad number of surgeons could achieve better and 

reproducible results with considerably more optimum operating 

conditions. The initial enthusiasm for On-pump CABG 

gradually gave way to concerns regarding its safety, especially 

with regard to complications arising from CPB, and not CABG 

per se. Foremost of these relate to microembolic showering 

during manipulation of the aorta and neurocognitive 

dysfunction. In addition, CPB triggers a whole-body inflammatory 

response caused by contact activation of the complement 

cascade. This leads to multiple organ dysfunction 

affecting the kidneys, liver, lungs, brain and heart itself. 1 

Studies published over a decade and a half ago questioned 

the safety of On-pump CABG. The proportion of patients 

recovering without any complication was found to be only 

64.3%. 2 In addition, health insurance data and data from 

clinical studies showed that 10.2% did not leave the hospital 

within 14 days after the operation and 3.6% of the patients 

were discharged to a non-acute care facility. 3 These and other 

observations, pari passu with the development of mechanical 

and pharmacological organ stabilizers and intracoronary 

shunts, resurrected OPCAB in the early 1990s. 

As regards surgical technique, the actual suture anastomosis 

of the vessels follows the same technique both in Onand 

Off-pump surgery. The difference is that unlike On-pump 

surgery, where the heart is arrested by means of cardioplegia, 

in Off-pump surgery the area of interest is kept immobile with 

the help of organ stabilizers while the anastomosis is being 

performed. Pharmacologic agents like short-acting betablockers 

(e.g. Esmolol) or Adenosine are used in conjunction 

with these mechanical stabilizers to achieve the goal of a 

relatively motionless field. Exposure of the heart is aided by 

retraction devices like the “Starfish”, which lift up the apex 

from the pericardial cavity (Table 1). Retraction can also be 

achieved by means of folded sponges placed in the pericardial 

sac to lift the heart, or by pericardial hitching sutures. Distal 

coronary perfusion is maintained by means of flexible intracoronary 

shunts introduced into the coronary vessel prior to 

commencement of the anastomosis (Fig. 1). Although these 

devices are designed for one-time use, they may be reused 

after ETO sterilization. This assumes importance as far as 

cost-containment in a country like India is concerned, giving a 

further fillip to Off-pump surgery. 

Numerous large observational studies and small randomized 

controlled trials (RCT) have been published in the past 18 

years suggesting benefits from OPCAB. Among these are, a 

reduction in stroke, duration of post-operative ventilation, 

need for reoperation, bleeding, wound infection, renal failure, 

post-operative length of stay 4 and decreased atrial fibrillation 

and inotrope requirement. 5 A major study published in 2001 

(the Octopus trial), showing no major differences in cardiac, 

neurological and neuropsychological outcomes in patients 

operated On- and Off-pump was also a shot in the arm for Offpump 

surgery. 6 However, as with any new technique, initial 

enthusiasm was somewhat dampened by reports of incomplete 

revascularization using OPCAB. 7 This and other reports 

led to the first RCT comparing the two procedures, the Randomized 

On/Off bypass study (ROOBY) in 2009. At 1-year of 

follow-up, Off-pump patients had worse composite outcomes 


E-mail address: op_yadava@yahoo.com (O.P. Yadava). 



188 


Table 1 e Commonly used stabilizer/retraction devices. 

Name of stabilization 

device 

Stabilization 

mechanism 

Pros 

Cons 

Medtronic-Utrecht Octopus Ò 

tissue stabilization system 

Suction Good stabilization for LAD Difficulty in LCx territory, 

cumbersome 

(discontinued) 

Octopus 1 Suction Good stabilization for LAD Bulky, cumbersome, difficulty in 

LCx, long arm causes less stability; 


Octopus 2 Suction Better stabilization, lesser pod 

height 

Octopus 3 Suction Malleable suction pods, better 

adaptation to heart contour 

Stiff pods may cause heart injury 


Increased horizontal motion; (in 

use) 

Octopus 4 Suction 360 arm movement (in use) 

Genzyme Elite stabilizer 

Compression of coronary 

between tapes 

No need for shunt 

Damage to coronary endothelium, 

possibility of catching back wall 

during anastomosis; (not widely 

used) 

Guidant system Suction High flexibility of arm Usable only on custom-made 

retractor (in use) 

Starfish positioning system Suction Allows for posterior vessel access May cause apical ischemia, injury 

(in use) 

of death, myocardial infarction (MI), graft patency and repeat 

revascularization. 8 The conversion rate from Off- to On-pump 

procedures was 12.4%, a figure 5 times that reported in the 

National Database of Thoracic Surgeons! This was bandied as 

glaring evidence of the participant practitioners’ inexperience. 

9 The authors had addressed the prickly issue of surgeon 

experience by doing a sensitivity analysis based on high volume 

(>50 pre-study cases) versus low volume operators, and 

had found no significant difference in outcomes. Nonetheless, 

many have questioned the figure of 50 cases as being insufficient 

to indicate surgeon experience, 10 whilst disregarding 

anesthesiologist experience. 

As if this was not enough, another nail in the coffin of 

OPCAB was driven by a recent Cochrane review meta-analysis 

11 from Copenhagen considering 10 low-bias trials 

(n ¼ 4950) of a total of 86 RCTs comparing Off-pump with Onpump 

surgery, which found 30% higher risk of all-cause 

mortality with Off- vs. On-pump CABG. Other adverse 

events like MI, stroke, renal insufficiency or repeat revascularization 

were similar despite a slightly lower number of 

distal anastomoses Off-pump versus On-pump. In fact the 

authors, Moller et al hazard to state, “findings suggest that 

funding sources matter, with the device industry-funded 

trials less apt to show harm from Off-pump CABG,” thereby 

suggesting that vested interests may be at play. But a major 

issue with the Cochrane review is that it included just one 

additional study to the meta-analysis by Afilalo et al (vide 

infra) which incidentally had showed clear superiority of 

Off-pump CABG. This additional study, ironically of Moller 

himself, had a staggering 25% mortality Off-pump, which 

obviously seriously skewed the results of the review to suggest 

harm with OPCAB. 

Fig. 1 e Diagrammatic representation of use of stabilizer & retraction/positioning devices and intracoronary shunts in 

Off-pump surgery. Reprinted from Verma S et al Off pump coronary artery bypass surgery. Fundamentals for the clinical 

cardiologist. Circulation. 2004;109:1206-1211.


Angelini et al analyzed 2 RCTs comparing Off-pump and 

On-pump patients 6e8 years following surgery to assess graft 

patency, major adverse cardiac-related events (MACE), and 

health-related quality of life. The patient cohort followed up 

was from the Beating Heart Against Cardioplegic Arrest 

Studies (BHACAS) 1 and 2 trials. 12 Overall, 10.8% of grafts were 

occluded across both groups. Further, logistic regression 

analysis showed no evidence that grafts were more likely to be 

occluded in OPCAB than in On-pump patients. The differences 

in MACE-free survival and quality of Life indicators did not 

approach statistical significance. Although these findings 

greatly bolstered the case of the proponents of OPCAB surgery, 

some shortcomings pointed out were that the modality of 

assessment of graft patency was non-invasive (MDCTA) as 

against the gold standard of coronary angiography; also, the 

study was a single center study by a single surgical team, and 

hence could not necessarily be extrapolated to other surgeons 

and centers. Another concern with OPCAB is the lesser number 

of grafts put. But this has long been disproved by a review 

of 22 RCTs which showed only 0.2 fewer grafts being put in 

this group compared with On-pump. 13 

A meta-analysis published by Afilalo et al included 

all published and unpublished RCTs of Off-pump versus 

On-pump CABG from the MEDLINE, EMBASE and Cochrane 

databases. It took into consideration a total of 59 trials, 

encompassing 8961 patients. There was a significant 30% 

reduction in post-operative strokes with Off-pump surgery 

[risk ratio (RR) 0.70, 95% CI: 0.49e0.99]. There was no significant 

difference in mortality (RR: 0.90, 95% CI: 0.63e1.30) or MI 

(pooled RR: 0.89, 95% CI: 0.69e1.13). In the meta-regression 

analysis, the effect of OPCAB on all of the clinical outcomes 

was similar regardless of mean age, proportion of females in 

the trial, number of grafts per patient, and trial publication 

date. 13 

The most recent comparison study of the two techniques 

is the CABG Off or On pump revascularization study (CORO- 

NARY Study) published in March this year. 14 The trial randomized 

4752 patients undergoing CABG to Off-pump or 

On-pump groups. There was no significant difference seen 

in the primary end-points of death, MI, stroke, or new renal 

failure requiring dialysis at 30 days (Table 2). 

There were, however, some differences in secondary outcomes 

(Table 3), with the Off-pump group showing advantages 

of less bleeding, respiratory infections, and acute kidney 

injury, but this group also had fewer grafts performed and had 

more repeat revascularizations thereby mandating longer 

term follow-ups before a final verdict. 

Table 2 e CORONARY: primary outcomes. 

Endpoint 

Off-pump 

(%) 

On-pump 

(%) 

HR (95% CI) 

Primary composite 9.8 10.3 0.95 (0.79e1.14) 

end point 

Death 2.5 2.5 1.02 (0.71e1.46) 

MI 6.7 7.2 0.93 (0.75e1.15) 

Stroke 1.0 1.1 0.89 (0.51e1.54) 

New renal failure 1.2 1.1 1.04 (0.61e1.76) 

Table 3 e CORONARY: secondary outcomes. 

End point 

Off-pump 

(%) 

On-pump 

(%) 

HR (95% CI) 

Repeat revascularization 0.7 0.2 4.01 (1.34e12.0) 

Respiratory failure 

5.9 7.5 0.79 (0.63e0.98) 

or infection 

Acute kidney injury 28.0 32.1 0.87 (0.80e0.96) 

Blood transfusion 50.7 63.3 0.80 (0.75e0.85) 

Reoperation for 

perioperative bleeding 

1.4 2.4 0.61 (0.40e0.93) 

The investigators thus struck a middle path by recommending 

either of the two techniques based on patient factors, 

provided the surgeon was competent in both. For 

example, if a patient had renal dysfunction or a heavily 

calcified aorta, OPCAB would be preferred. 

Much like the proverbial see-saw, a 1-year follow-up 

angiographic study of the ROOBY cohort was reported this 

year by Hattler at the AHA Congress in Orlando. He revealed 

that Off-pump patients had a lower saphenous vein patency 

than On-pump, but a similar arterial graft patency rate, 

leading to less effective revascularization. Grover in an 

editorial tried to reconcile the difference between the ROOBY 

and CORONARY trial findings. 15 The latter involved only surgeons 

experienced in Off-pump surgery, whereas the ROOBY 

trial also had trainees as operating surgeons. On a conservative 

note however, he cautioned that any firm conclusions 

would have to await long term follow-up results. 

Training of surgeons in OPCAB techniques has been an 

issue as it requires a great deal of focus and enthusiasm, apart 

from safety concerns. However, even this issue has been laid 

to rest by a recent study from the Bristol Heart Institute 16 that 

Off-pump surgery is not only safe and reproducible, but the 

technique can be taught effectively and safely to trainees with 

clinical outcomes unrelated to either the level of supervision 

or the seniority of the trainees. 

The final frontier for the Off-pump coronary surgeon remains 

the patient with left main disease as well as those with 

severely depressed LV function. Here too, lower mortality and 

complication rates have been demonstrated. 17 OPCAB has 

been validated with results quite similar to the CORONARY 

trial in left main stem disease also. Murzi et al showed that 

OPCAB was associated with lower in-hospital mortality (0.5% 

vs. 2.9%; p ¼ 0.001) and morbidity in terms of stroke, renal 

dysfunction and pulmonary complications/infections. 18 But 

the biggest bugbear of OPCAB, viz. fewer grafts (2.7 0.7 vs. 

3 0.7; p ¼ 0.001) and lower rate of complete revascularization 

(88.3% vs. 92%; p ¼ 0.04) continue to remain. On multivariate 

analysis, CPB was confirmed to be an independent predictor of 

in-hospital mortality (OR 5.74; p ¼ 0.001). The countervailing 

pros and cons negating each other lead to similar survivals at 

1.5 and 10 years, a fact validated by Cheng et al. 19 OPCAB has 

also been shown to give superior results in patients with 

chronic kidney disease. 20 

The International Society for Minimally Invasive Cardiothoracic 

Surgery (ISMICS) recommendations state that the use 

of Off-pump bypass reduces perioperative morbidity, neurocognitive 

dysfunction and hospital length of stay and should 

be considered especially in high-risk patients, for example,

190 


those with severe ascending aortic calcification, liver disease, 

renal insufficiency or other systemic processes that may be 

exacerbated by CPB, in order to reduce morbidity and 

mortality. 21 

A balanced approach has been advocated by the American 

Heart Association in their 2011 Guidelines. 22 Based on available 

data, the guidelines contend, both approaches are 

reasonable, with certain factors tilting the balance one way or 

the other. For example, the oft-quoted instance of a patient 

with a heavily diseased aorta being more amenable to Offpump 

surgery. The European Guidelines (2010) on the other 

hand make no mention of Off-pump surgery, stating instead 

that over 70% of bypass surgeries worldwide are conducted 

On-pump 23 (perhaps a diplomatic way of making an undiplomatic 

point!). 

As for our experience at the National Heart Institute in 

Delhi of over 5000 cases done Off-pump with a conversion rate 

of less than 1% and mortality of 1.6%, we can safely state that 

this is an effective technique, provided it is adopted and 

practiced in spirit as well as letter. The surgeon, and perforce 

the team, should be well conversant with the nuances of Offpump 

techniques, besides being motivated, focused and inclined, 

and not be a proponent just to join the bandwagon and 

be counted, whilst jeopardizing the patient’s interest. In the 

end, a doctor’s reputation lives through his/her patients, and 

this is no truer than for a cardiac surgeon. The best technique 

is that which works best for that particular patient, in the 

context of his clinical setting and his treating surgeon’s 

repertoire lending credence to our strong belief that it is the 

surgeon and not the technique, which is at the heart of the 

problem. 

references 

1. De Jaegere PP, Suyker WJL. Off pump coronary artery bypass 

surgery. Heart. 2002;88(3):313e318. 

2. Duhaylongsod F. Minimally invasive cardiac surgery defined. 

Arch Surg. 2000;135:296e301. 

3. Roach G, Kanchuger M, Mangano C, et al. Adverse cerebral 

outcomes after coronary bypass surgery. N Engl J Med. 

1996;335:1857e1863. 

4. Cleveland Jr JC, Shroyer AL, Chen AY, et al. Off-pump 

coronary artery bypass grafting decreases risk-adjusted 

mortality and morbidity. Ann Thorac Surg. 2001;72:1282e1288. 

5. Angelini GD, Taylor FC, Reeves BC, et al. Early and midterm 

outcome after off-pump and on-pump surgery in Beating 

Heart against Cardioplegic Arrest Studies (BHACAS 1 and 2): a 

pooled analysis of two randomised controlled trials. Lancet. 

2002;359:1194e1199. 

6. Van Dijk D, Nierich AP, Eefting FD, et al. The Octopus Study: 

rationale and design of two randomized trials on medical 

effectiveness, safety, and cost-effectiveness of bypass surgery 

on the beating heart. Control Clin Trials. 2000;21(6):595e609. 

7. Hannan EL, Wu C, Smith CR, et al. Off-pump versus on-pump 

coronary artery bypass graft surgery: differences in shortterm 

outcomes and in long-term mortality and need for 

subsequent revascularization. Circulation. 

2007;116:1145e1152. 

8. Shroyer AL, Grover FL, Hattler B, et al, for the Veterans Affairs 

Randomized On/Off Bypass (ROOBY) Study Group. On-pump 

versus off-pump coronary artery bypass surgery. N Engl J Med. 

2009;361:1827e1837. 

9. Puskas JD, Mack MJ, Smith CR. On-pump versus off-pump 

CABG. N Engl J Med. 2010;362:851e854. 

10. Kieser TM. On-pump versus off-pump CABG. N Engl J Med. 

2010;362:852e854. 

11. Møller CH, Penninga L, Wetterslev J, et al. Off-pump versus 

on-pump coronary artery bypass grafting for ischaemic heart 

disease. Cochrane Database Syst Rev 2012;(3):CD007224. 

12. Angelini GD, Culliford L, Smith DK, et al. Effects of on- and 

off-pump coronary artery surgery on graft patency, survival, 

and health-related quality of life: long-term follow-up of 2 

randomized controlled trials. J Thorac Cardiovasc Surg. 

2009;137(2):295e303. 

13. Afilalo A, Rasti M, Ohayon SM, et al. Off-pump vs. on-pump 

coronary artery bypass surgery: an updated meta-analysis 

and meta-regression of randomized trials. Eur Heart J. 

2012;33(10):1257e1267. 

14. Lamy A, Devereaux PJ, Prabhakaran D, et al. Off-pump or onpump 

coronary- artery bypass grafting at 30 days. N Engl J 

Med. 2012;366:1489e1497. 

15. Grover FL. Current status of off-pump coronary-artery bypass 

[Editorial]. N Engl J Med. March 26, 2012;366. Published in 

NEJM.org. 

16. Murzi M, Caputo M, Aresu G, et al. Training residents in offpump 

coronary artery bypass surgery: a 14 year experience. 

J Thorac Cardiovasc Surg. 2012;143(6):1247e1253. 

17. Caputti GM, Palma JH, Gaia DF, et al. Off-pump coronary 

artery bypass surgery in selected patients is superior to the 

conventional approach for patients with severely depressed 

left ventricular function. Clinics (Sao Paulo). 2011 

December;66(12):2049e2053. 

18. Murzi M, Caputo M, Aresu G, et al. On-pump and off-pump 

coronary artery bypass grafting in patients with left main 

stem disease: a propensity score analysis. J Thorac Cardiovasc 

Surg. 2012;143(6):1382e1388. 

19. Cheng DC, Bainbridge D, Martin JE, et al, Evidence Based 

Perioperative Clinical Outcomes Research Group. Does offpump 

coronary artery bypass reduce mortality, morbidity, 

and resource utilization when compared with conventional 

coronary artery bypass? A meta-analysis of randomized 

trials. Anesthesiology. 2005;102:188e203. 

20. Schroeder ME, Chawla L, Zhao Y, et al. Effect of off-pump 

versus on-pump coronary artery bypass grafting in patients 

with chronic kidney disease. Crit Care. 2012;16(suppl 1):347. 

21. Puskas J, Cheng D, Knight J, et al. Off-pump versus 

conventional coronary artery bypass grafting: a metaanalysis 

and consensus statement from the 2004 ISMICS 

consensus conference. Innovations. 2005;1(1):3e27. 

22. ACCF/AHA Practice Guidelines. 2011 ACCF/AHA guideline 

for coronary artery bypass graft surgery. Circulation. 

2011;124:e659. 

23. The Task Force on Myocardial Revascularization of the 

European Society of Cardiology (ESC) and the European 

Association for Cardio-Thoracic Surgery (EACTS). Guidelines 

on myocardial revascularization. Eur Heart J. 

2010;31:2501e2555.





Oral flecainide is effective in management of refractory 

tachycardia in infants 

Vikas Kohli* 

Pediatric Cardiology & Congenital Cardiac Surgery, Indraprastha Apollo Hospital, New Delhi, India 

article info 





Keywords: 

Flecainide 

Tachycardia 

Digoxin 

abstract 

Background: Propranolol and digoxin have been used as first line drugs for treatment of 

supraventricular tachycardia (SVT) in infants. Flecainide and other drugs have been 

effective as a second line treatment for controlling refractory SVT. 

Material and methods: This is a prospective study without randomization and control. The 

inclusion criteria were: infants (12 months) with tachyarrhythmia who failed to respond 

to first line drugs. Patients having post-surgical arrhythmias were excluded from the study. 

Results: A total of 8 infants were treated with flecainide for refractory tachyarrhythmia’s. 

Diagnosis on electrocardiogram (ECG) was atrioventricular reentry tachycardia (AVRT) in 5, 

atrial ectopic tachycardia (AET) in 2, a combination of AVRT and atrioventricular nodal 

reentry tachycardia (AVNRT) in 1. All patients had failed trial of antiarrhythmic drugs prior 

to presentation: digoxin and propranolol in 7, amiodarone in 3, cardioversion in 1. Flecainide 

(80e130 mg/m 2 orally) resulted in termination of the tachycardia in all 8 patients. 

Acute pharmacological termination of arrhythmia occurred with oral flecainide loading in 

1 and temporarily with intravenous esmolol loading in 1 patient. Adjuvant therapy in form 

of propranolol was used in 5 and digoxin in 2. There were no side effects noted. Four episodes 

of recurrence were noted in 3 patients over 2 years, all of which responded to dose 

increase. Mean follow up time is 24.75 months. 

Conclusion: This small case series indicates that flecainide is an effective antiarrhythmic 

agent, free of side effects and when used orally is capable of terminating and controlling 

relatively resistant supraventricular tachycardia in children. 



Approximately, 60% of children with supraventricular tachycardia 

(SVT) develop their initial episode by 1 year of age. 1 

Most often it is managed with a single drug. Spontaneous 

resolution occurs in 50e80% of infants by 1 year of age. 2 In 10% 

of patients, first line drugs in the form of digoxin and/or betablocker 

may not be effective. These patients need second line 

drugs like flecainide, amiodarone, sotalol or propafenone. 

These drugs can be used either as monotherapy or in combination 

for control of tachycardia. 3e7 A few patients in this 

group may not be controlled with drugs and may rarely 

require radiofrequency ablation. 

Flecainide has been effective in controlling refractory SVT 

when used as a monotherapy or with other antiarrhythmics 

in children. 3,5e7 Flecainide has been effectively used 

* C-116 Sarita Vihar, New Delhi 110044, India. Tel.: þ91 9891362233; fax: þ91 11 26941746. 

E-mail addresses: vkohli_md@yahoo.com, pedsheart@gmail.com. 




intravenously for acute termination of arrhythmia, followed by 

oral maintenance for prevention of recurrence. Its use has been 

variable depending on a variety of factors. In a North American 

survey, less than 5% of patients received flecainide. 7 In India, 

intravenous flecainide is not available while the oral form is 

available only at limited locations. We present our experience 

with oral flecainide in acute and medium term control of 

arrhythmia in infants with SVT not controlled with first line 

drugs. Since intravenous flecainide is not available in India, we 

used oral flecainide. Sotalol and amiodarone would then have 

been used as the last line therapy, a strategy used by others too. 3 

2. Methods 

Data was prospectively collected, however, there was no 

randomization and there were no controls. The inclusion 

criteria were: infants (12 months) with a diagnosis of 

tachyarrhythmia with a failure to control SVT with first line 

drugs i.e. propranolol and digoxin in standard dosages and no 

history of cardiac surgery. The parameters recorded are 

shown in Tables 1 and 2. The QTc was calculated from surface 

electrocardiograms using Bazett’s formula. 

Echocardiogram was performed on all patients before 

initiation of therapy to assess anatomy as well as ventricular 

size and function. Twenty-four hour ambulatory ECG monitoring 

(Holter) was done prior to discharge and subsequently 

at 1 month follow up and then 3 monthly to assess efficacy of 

treatment in the first year of follow up following which at 6 

monthly intervals. This was done since follow up only on 

basis of history may not be reliable in infants. The objective of 

treatment was to get complete suppression of arrhythmia. 

Effective control of arrhythmia was defined as complete suppression 

of tachyarrhythmia on Holter monitoring. 

3. Results 

3.1. Patient profile 

A total of 8 patients met the inclusion criteria during the study 

period (January 2006 to December 2010). The mean age of 

patients was 5.1 months with the range of 2 monthse12 

months (Table 1). Seven infants had normal ventricular 

function by echocardiography and one had an ejection fraction 

of 40% of left ventricular function (patient no. 3), not low 

enough to contraindicate flecainide therapy. The decreased 

function was due to tachyarrhythmia associated cardiomyopathy 

which improved completely once the rate was 

controlled. At the time of presentation to our institution, all 

patients had a failed trial with more than one drug (4 had 2 

antiarrhythmics tried, 4 had 3 antiarrhythmics tried and in 

addition 1 had attempted cardioversion). All patients were in 

tachycardia when they presented to us. Three patients were 

on our follow up from neonatal period and had failure of first 

line medications when they were included in our study. 

3.2. Dosages and monitoring 

All patients were hemodynamically stable at presentation; 

oral maintenance dose was started in all except one (patient 

no. 4) where oral loading of flecainide was performed. Oral 

loading was done in the one patient with 120 mg/m 2 /day of 

flecainide divided in three doses over 12 h which resulted in 

termination of arrhythmia. No side effects were noted with 

oral loading. The median dose of flecainide at initiation of 

therapy was 80 mg/m 2 /day (range 70e100 mg/m 2 /day) and 

was given in two to three divided doses. Corrected QTc interval 

was noted prior to discharge and subsequently at follow 

up visits. The median dose required for the efficacy was 

100 mg/m 2 /day (range: 80e130 mg/m 2 /day). QTc was not 

allowed to increase beyond 0.46 ms and drug dose increase 

was stopped if QTc reached or exceeded 0.46 ms. 

Efficacy was defined as complete suppression of 

arrhythmia. Therapy was initiated in the hospital, and all infants 

were monitored as inpatients for 3e5 days prior to 

discharge. In view of the known interference of milk with 

flecainide absorption, we disallowed feeds half an hour before 

and after administration of flecainide. 8 Dose was adjusted for 

the body surface area as the baby grew. The dose was recalculated 

at monthly follow up visits and was rounded off 

to convenient dispensing dose (with the dilution of 10 mg/ml). 

3.3. Response to therapy 

All the patients reverted to normal sinus rhythm (8/8). Sinus 

rhythm was restored in less than 3 days in 2/8 patients and 

Table 1 e Study patient profiles. 

Patient Age (months) Cardiac anatomy ECG diagnosis Previous drugs used/ 

cardioversion 

1 2 Normal AVRT & AVNRT D,P,A 

2 3 Ebstein’s AVRT D,E,A 

3 2 Normal AET D,P 

4 12 Normal AVRT D,P,A 

5 2 Normal AVRT D,P,CV 

6 12 Normal AVRT D,P 

7 6 Normal AVRT D,P, A 

8 2 Normal AET D,P 

Abbreviations: AVRT ¼ atrioventricular reentry tachycardia, AVNRT ¼ atrioventricular nodal reentry tachycardia, AET ¼ Atrial ectopic tachycardia, 

VT ¼ Ventricular tachycardia. 

D ¼ digoxin; P ¼ propranolol; E ¼ esmolol; A ¼ amiodarone; CV ¼ cardioversion.

170 


Table 2 e Response to therapy. 

Patient Maximum dosage of 

flecainide used mg/m 2 

Time to complete 

control 

Additional 

drugs used 

Length 

of f/u (mo) 

Recurrences (months 

after therapy started) 

1 80 3 days P 48 1 (1 mo) 

2 120 3 days E b ,P,D,A a 36 2 (1 mo; 6 mo) 

3 100 1 day P,D 24 1 (3 mo) 

4 110 1 day e 36 0 

5 100 1 day P 12 0 

6 200 1 day P 24 0 

7 120 1 day P 6 0 

8 120 1 day P 12 0 

D ¼ digoxin; P ¼ propranolol; E ¼ esmolol; A ¼ amiodarone; mo ¼ months. 

a Starred indicates trial of this drug was given but stopped in few weeks. 

b Indicates use only on day 1. 

within 24 h in 6/8 patients. Holter recordings prior to discharge 

showed complete control of arrhythmia in 8/8 patients. 

Recurrences were noted in 3 patients, 1 month after the 

control in one and 3 months later in another, whereas in third 

patient there were 2 recurrences: the first one occurred after 1 

months of follow up and the second after 6 months. All the 

recurrences responded to dose increase, none requiring hospitalization. 

The median duration of therapy was 24 months 

(range: 12e48 months). One patient in the series is currently 

off all medications and has had no recurrence of arrhythmia 

(patient no. 1). 

3.4. Additional drugs 

Additional drugs were used in 7/8 patients. Esmolol was used 

in 1 for acute control of arrhythmia which was continued as 

propranolol; propranolol was used in 7/8 patients (in most as a 

continuation of therapy initiated prior to presentation). In 7/8 

patients, the desired control was achieved with flecainide and 

propranolol combination and in 1 with flecainide alone. In 1 

patient (patient no. 2 with Ebstein’s anomaly), amiodarone 

was tried for a short period during one of the recurrences 

without any effect and was discontinued. The recurrence was 

subsequently controlled by increasing the dosage of flecainide. 

Digoxin was used in 2/6 patients along with propranolol 

and flecainide. 

3.5. Follow-up 

All patients have been in sinus rhythm for a range of 6 

monthse48 months (mean 24.75 months). No pro-arrhythmic 

side effects were observed with flecainide. There was no 

episode of bradycardia or AV block. Echocardiograms 

demonstrated normal ventricular function in all infants while 

on flecainide. None of the patients had inadvertent prolongation 

of QTc (>0.48 s). Holter monitoring was performed at a 

6 monthly interval did not reveal recurrence of arrhythmia 

after the first 3 months in any of the patients except one. 

4. Discussion 

Supraventricular tachycardia in infants is usually controlled 

using digoxin or beta-blockers as first line therapy. 7 However, 

in about 10% of infants, second line therapy drugs like flecainide, 

propafenone, amiodarone or sotalol are needed as single 

agents or in combination. 3e7 Flecainide has been used as a 

second line agent, most often intravenously with a loading 

dose which would terminate the arrhythmia, followed by oral 

maintenance dosage. 9 Though Flecainide is a safe and effective 

drug its use is much less than anticipated especially in the 

North American continent mainly due to the results of the 

CAST trial in the late 80’s which showed a significant increase 

in mortality with Flecainide in myocardial infarction patients 

when it was used to prevent arrhythmias. 10 We have in this 

paper reported our experience with oral flecainide and noted 

good response in a small group of patients. This small study 

reinforces that oral flecainide provides a good intermediate 

option. There was only one patient in our series that did not 

respond to flecainide and went on to require amiodarone for 

control of his arrhythmia. Amiodarone has also been studied 

as a second line drug. 4,11 The intravenous amiodarone study 

group conducted a randomized double blinded trial of use of 

amiodarone in 61 children. The adverse event rate was 87% in 

this group. 11 Burri et al reported 23 infants with lifethreatening 

incessant tachycardia, predominantly supraventricular. 

4 Intravenous amiodarone was used as a single antiarrhythmic 

agent. In this study, amiodarone was effective in 

19/23 infants. Significant side effects were however noted: 

neurological side effects in one infant; liver enzyme elevation 

necessitating stopping amiodarone administration and sinus 

bradycardia requiring dose change in two patients. In 

contrast, our small group of patients using flecainide exhibited 

no side effects. A staged approach has recently been reported 

by Drago et al. 3 They tried a stepwise protocol on a 

study group of 55 infants. Initial treatment was with propafenone, 

flecainide or propranolol and only if not controlled 

with these was amiodarone used. 

Only about 30% patients required amiodarone alone or in 

combination. Others have tried Flecainide as first line therapy 

in newborns and it has worked successfully in 85% of the 

babies over a 24 month period. 12 Other reports include successful 

control of arrhythmia with a combination of amiodarone 

and flecainide or amiodarone and sotalol in this age 

group of patients. 5,6 In our study, we have used flecainide by 

the oral route which has been easy to administer and overcomes 

the problem of non-availability of intravenous flecainide 

in our part of the world. We have used propranolol and


digoxin in addition in some patients, for a short duration as an 

overlap with flecainide. The limitations of this study include 

the small number of patients enrolled. A larger study would be 

required in order to more conclusively validate the use of oral 

flecainide. In addition, our patients, though presenting in 

tachycardia, were hemodynamically stable. This implies that 

there is an internal bias of non-critical patients in our subset. 

Non-availability of drug level monitoring has also been a 

limitation of this study. Esmolol and oral loading of flecainide 

were used when urgent control was required. The advantage 

offered by oral flecainide is the ease of administration and the 

degree of control of arrhythmia. Significantly, side effects 

were not an issue in this series and similar series reported by 

other authors using flecainide. 4e6 


In this study, oral flecainide has been shown to be useful 

either alone or in combination as second line management in 

difficult to treat arrhythmia in infants less than 12 months 

age. Flecainide is safe and has shown good control of the 

arrhythmia even when given orally. It has also been safely 

administered in small children in this study over a long period 

of time. Apart from being useful for acute control, it is also 

effective in preventing the recurrence of arrhythmia in majority 

of the cases. 


The author has none to declare. 

references 

1. Tortoriello TA, Snyder CS, Smith EO, Fenrich Jr AL, 

Friedman RA, Kertesz NJ. Frequency of recurrence among 

infants with supraventricular tachycardia and comparison 

of recurrence rates among those with and without 

preexcitation and among those with and without response 

to digoxin and/or propranolol therapy. Am J Cardiol. 

2003;92(9):1045e1049. 

2. Garson Jr A, Gillette PC, McNamara DG. Supraventricular 

tachycardia in children: clinical features, response to 

treatment, and long-term follow-up in 217 patients. J Pediatr. 

1981;98(6):875e882. 

3. Drago F, Silvetti MS, De Santis A, et al. Paroxysmal 

reciprocating supraventricular tachycardia in infants: 

electrophysiologically guided medical treatment and longterm 

evolution of the re-entry circuit. Europace. 

2008;10:629e635. 

4. Burri S, Hug MI, Bauersfeld U. Efficacy and safety of 

intravenous amiodarone for incessant tachycardias in 

infants. Eur J Pediatr. 2003;162(12):880e884. 

5. Price JF, Kertesz NJ, Snyder CS, Friedman RA, Fenrich AL. 

Flecainide and sotalol: a new combination therapy for 

refractory supraventricular tachycardia in children





Effects of a yoga intervention on lipid profiles of diabetes 

patients with dyslipidemia 

Nisha Shantakumari a, *, Shiefa Sequeira b , Rasha El deeb a 

a Department of Physiology, Gulf Medical University, Ajman, P.O. Box 4184, UAE 

b Fetal Medicine Genetic Center, Dubai Healthcare City, UAE 

article info 


Received 18 June 2012 



Keywords: 

Yoga 

Cholesterol 

Triglycerides 

Lipoproteins 

abstract 

Objective: The present study was conducted to assess the effectiveness of yoga in the 

management of dyslipidemia in patients of type 2 diabetes mellitus. 

Methods: This randomized parallel study was carried out in Medical College Trivandrum, 

Kerala, India. Hundred type 2 diabetics with dyslipidemia were randomized into control 

and yoga groups. The control group was prescribed oral hypoglycemic drugs. The yoga 

group practiced yoga daily for 1 h duration along with oral hypoglycemic drugs for 3 

months. The lipid profiles of both the groups were compared at the start and at the end of 3 

months. 

Results: After intervention with yoga for a period of 3 months the study group showed a 

decrease in total cholesterol, triglycerides and LDL, with an improvement in HDL. 

Conclusion: Yoga, being a lifestyle incorporating exercise and stress management training, 

targets the elevated lipid levels in patients with diabetes through integrated approaches. 



The major risk factor for cardiovascular disease in diabetes 

mellitus is dyslipidemia. 1 The characteristic features of diabetic 

dyslipidemia are a high plasma triglyceride concentration, 

low high-density lipoprotein (HDL) concentration and 

increased concentration of small dense low-density lipoprotein 

(LDL) particles. Insulin resistance leads to increased flux 

of free fatty acids and hence the lipid changes. 2 Reports from 

the National Health and Nutrition Examination Survey 

(NHANES) 1999e2000 indicate that 55% of the U.S. general 

population and 51% of adults aged 20e59 years with diabetes 

have hypercholesterolemia. 3,4 

Caloric restriction and weight loss for the overweight 

individual with diabetes mellitus have been of proven 

therapeutic value. However, there is no consensus on the ideal 

dietary composition for these patients. Genetic factors and the 

lipid phenotype of the individual determine the way the 

plasma lipid profiles change in these patients. 5 Lifestyle 

changes, including increased physical activity and dietary 

modifications have, however, been the cornerstones of management 

of dyslipidemia in diabetes. 6 

Mahajan conducted a study on subjects with mild to 

moderate hypertension and reported that yoga can play an 

important role in risk modification for cardiovascular diseases. 

7 Another study had reported a better lipid profile in 

long and medium term mediators when compared to nonmeditators. 

8 In view of these observations, the present study 

was undertaken to assess the effect of yoga practice on the 

lipid profile in patients with type 2 diabetes mellitus (DM). 


E-mail address: nisha@gmu.ac.ae (N. Shantakumari). 



128 


2. Materials and methods 

2.1. Setting 

Patients reporting to the out-patient department of Holistic 

Medicine and in the Diabetic clinic, Medical College Trivandrum, 

Kerala, India, in the year 2005 were the participants of 

this randomized parallel study. The Holistic Medicine 

department aims at bringing lifestyle modifications in patients 

with non-communicable diseases and also offers regular 

yoga classes for all the patients in its care. The study was 

conducted after the approval of the Ethics Committee of the 

Medical faculty and all subjects volunteered for the trial. 

2.2. Study sample 

The guidelines of the National Diabetes Data Group and the 

third set of the Adult Treatment Panel of the National 

Cholesterol Education Program (NCEP ATP III) were used to 

recruit one hundred patients with type 2 diabetes and dyslipidemia. 

9,10 Known diabetic patients who were on treatment 

with sulphonylureas were included in the study. Patients who 

are smokers, alcoholics, pregnant, on long-term steroids and 

those with known retinopathy, nephropathy, coronary artery 

disease and cerebrovascular diseases were excluded from the 

study. 

One hundred patients with type 2 DM attending the Diabetic 

clinic were randomized into control group of 27 males 

and 23 females and experimental group of 24 males and 26 

females. The experimental group was prescribed oral hypoglycemic 

drugs and in addition followed lifestyle modification 

in the form of 1 h daily practice of yoga for a period of 3 

months at the Holistic Medicine department. The control 

group was prescribed oral hypoglycemic drugs only and did 

not perform yogic exercises during this period. 

The experimental group was taught a series of yoga postures 

in groups of 25 patients each. They were instructed to practise 

them daily for 1 h duration and were asked to record the 

number of minutes they engaged in yoga per day. Yoga 

treatment consisted of practice of 1) asanas (Body postures), 2) 

pranayama (Breathing exercises) and 3) meditation techniques 

(Table 1), to be practiced for 1 h duration. At the end of 

2 weeks of supervised yogic training each subject was given 

advice on ongoing medical treatment and was given a booklet 

illustrating personalized yoga program to practice regularly at 

home. All subjects were required to contact the Holistic 

Medicine department once every month for follow up advice. 

The control group was asked to report to Diabetic clinic every 

month for their follow up after being given advice on ongoing 

medical treatment at the start of the study. There were no 

alterations made in the treatment and dietary habits of either 

group during the study period. Both the groups were advised 

to continue with their carbohydrate restricted fiber rich diet. 

The BMI, W/H circumference and lipid profile of all the 

participants were measured at the end of 3 months. Data were 

entered in Microsoft Excel and SPSS Version 12 was used for 

analysis. Paired and unpaired t tests were employed to 

compare measures. A p value of


Table 2 e Baseline characteristics of the participants. 

Parameters Control group Study group 

The study showed that 3 months of yoga practice resulted 

in a non-significant decrease in BMI from 25.12 1.54 to 

23.59 1.38 kg/m 2 . A significant decrease in the weight from 

62.20 4.45 to 59.60 4.65 kg and W/H ratio from 0.94 þ 0.07 to 

0.89 þ 0.07 was recorded. 

There was a significant reduction in total cholesterol, triglycerides 

and LDL cholesterol. Mean total cholesterol before 

yoga was 244.86 28.09 mg% and was reduced to a mean of 

219.56 32.02 mg%. Triglycerides showed a significant 

reduction from 151.88 43.08 mg% to 130.11 28.82 mg% 

while the LDL reduced from 144.74 28.45 to 120.51 34.31 mg 

%. There was a non-significant elevation in HDL from 

44.63 9.35 mg% to 47.15 8.17 mg % (Table 3). 

After a period of 3 months the control group showed a 

significant increase in body weight, non-significant increase 

in BMI, total cholesterol, triglycerides and LDL and a decrease 

in HDL (Table 4). 

4. Discussion 

(Medication 

only) n ¼ 50 

(Medication þ 

Yogic intervention) 

n ¼ 50 

Mean age (years) 44.46 10.98 45.51 7.98 

Sex (M/F) 23 F, 27 M 26 F, 24 M 

Wt (kg) 62.20 4.45 62.17 4.67 

BMI (kg/m 2 ) 23.2 2.14 22.9 2.15 

W/H ratio 0.93 þ 0.07 0.94 þ 0.07 

FBS (mg/dl) 181.57 66.25 155.86 60.53 

PPBS (mg/dl) 265.31 74.70 240.31 79.42 

Total cholesterol (mg/dl) 225.74 37.60 244.86 28.09* 

Triglyceride (mg/dl) 172.74 52.55 151.89 43.08 

LDL cholesterol (mg/dl) 126.11 30.41 144.74 28.46* 

HDL cholesterol (mg/dl) 44.23 5.21 44.63 9.35 

*p < 0.05. 

The present study was aimed at studying the effect of practicing 

yoga in patients with type 2 DM for 3 months. The 

practice of yoga in these patients resulted in a decrease in BMI, 

body weight, W/H ratio, total cholesterol, triglycerides and 

LDL cholesterol and an increase in HDL. 

Table 3 e Comparison of pre-yoga and post-yoga values 

in experimental group. 

Parameters n ¼ 50 

Pre-yoga 

(mean SD) 

Post-yoga 

(mean SD) 

WT(kg) 62.20 4.45 59.60 4.65* 

BMI (kg/m 2 ) 25.12 1.54 23.59 1.38 

W/H ratio 0.94 þ 0.07 0.89 þ 0.07* 

Total cholesterol (mg/dl) 244.86 28.09 219.54 32.02** 

Triglycerides (mg/dl) 151.88 43.08 130.11 28.82* 

LDL cholesterol (mg/dl) 144.74 28.45 120.51 34.31** 


*p < 0.05, **p < 0.01. 

Table 4 e Comparison of initial values of parameters and 

follow up values of the control group. 

Parameters n ¼ 50 

Initial value 

(mean SD) 

Follow up 

(mean SD) 

WT (kg) 62.17 4.67 63.03 5.10* 

BMI (kg/m 2 ) 24.73 1.87 25.03 2.14 

W/H ratio 0.93 þ 0.07 0.91 þ 0.05 

Total cholesterol (mg/dl) 225.74 37.60 235.23 26.64 

Triglycerides (mg/dl) 172.74 52.55 197.91 130.11 

LDL cholesterol (mg/dl) 126.11 30.41 126.60 22.84 


*p < 0.05. 

Improving glycemic control has not yet been shown to 

prevent development of macro-vascular complications in type 

2 DM. Alternately, carefully controlled treatment measures 

with exercise, dietary modification and oral drugs can be expected 

to improve diabetic lipid disorder. 14 

The effect of exercise on blood lipid profiles has been 

widely reported. 15,16 Physical activity raises HDL levels and 

decreases the concentration of very low-density lipoprotein 

cholesterol and triglycerides. 17 Physical activity and HDL 

appear to be linked via HDL’s role in triglyceride metabolism. 18 

It is, however, seen that diabetic patients usually cannot 

sustain the levels of recommended physical activity for them 

due to varied reasons like age, obesity, cardiovascular disease 

and other complications. Compliance and motivation for 

performing activity at 50e70% of maximum aerobic capacity 

regularly is quite poor. 19 

Yoga has a beneficial effect on insulin kinetics and the lipid 

profile resulting from it. A decrease inwaist hip ratio inthis study 

is consistent with that reported by Sahay et al, who also reported 

an associated increase in lean body mass and reduction in skin 

fold thickness. Yoga helps in redistribution of body fat and 

reduction in central obesity which leads to insulin resistance. A 

decrease in insulin resistance, increase in insulin receptors and 

sensitivity,shift of peak level of insulinto leftwithnormalization 

of insulin glucagon ratio was also reported. 20 

The dynamic stretching of the body during yoga asanas is 

postulated to rejuvenate pancreatic cells, increase insulin 

secretion and hence correct the impaired insulin secretion in 

chronic diabetes. 21 

Various studies have reported physical, physiological, 

psychological and endocrinological changes with the practice 

of yoga. Manchanda and Narang found that after one year of 

yoga therapy, patients with coronary artery disease (CAD) 

showed significant reduction in serum total cholesterol, triglycerides 

and LDL cholesterol. The patients showed a significant 

reduction in the number of angina episodes and 

required revascularization procedures less frequently. Angiography 

after one year showed regression of lesions. 22 The 

practice of Raja yoga meditation was found to lower serum 

cholesterol by Vyas, 23 while Sahay 20 and Bijlani 24 noted that 

yoga practice causes significant reduction in free fatty acids, 

LDL, VLDL and an increase in HDL. 

The beneficial effect of yoga in the management of 

hyperlipidemia and obesity cannot just be attributed alone to 

the simple excess calorie expenditure as there is no rapid 

muscle activity and energy generation involved in yoga.

130 


Repeated stress is known to lead to persistent elevation of 

cortisol which causes central obesity and insulin resistance. 25 

It increases gluconeogenesis and diminishes peripheral uptake 

of glucose. 26 Decreased glucose uptake and insulin 

secretion can also occur due to stress induced release of 

growth hormone and b endorphin. 27 Elevated cortisol is also 

linked to dyslipidemia, and higher blood pressure. 28 Yoga has 

been reported to lower levels of sympathetic hormones and 

reduce cortisol. Pranayama reduces sympathetic tone, increases 

parasympathetic activity and also helps an individual 

reduce stress. 8,29,30 Meditation also brings about a hypometabolic 

state and reduces stress induced sympathetic over 

activity. 31 Better ability to overcome stress resulting in lowered 

cortisol levels can be cited as possible mechanism for 

improvement in lipid profile in patients practicing yoga. 

Dyslipidemia is usually associated with the abnormalities 

in lipolysis; triglyceride metabolism and free fatty acid turn 

over in a case of insulin resistance. Impaired lipoprotein lipase 

and increased hepatic lipase activity is thought be a resulting 

from insulin resistance in diabetes. Chronic exposure to 

elevated free fatty acids have been associated with impaired 

insulin secretion. 32 The improvement in lipid profile with 

practice of yoga could be due to increased hepatic lipase and 

lipoprotein lipase. This would increase the uptake of triglycerides 

by adipose tissue and affect the lipoprotein 

metabolism. 33 

Yoga practice is also proved to affect mental balance of an 

individual allaying apprehension, stress and bringing about 

hormonal balance and feelings of well being. This sense of 

well being is attributed to its ability to increase endogenous 

melatonin secretion. 34 This can explain the probability of 

greater compliance with its practice even in long-term and its 

use as an effective intervention in control of the disease. 

5. Conclusion 

The present study has shown an efficacy of improving the 

dyslipidemic state associated with diabetes. Yoga, being a 

lifestyle incorporating exercise and stress management 

training, targets the elevated lipid through integrated approaches 

resulting in improved lipid profiles, lower BMI, and 

macro-vascular complications in diabetes. 

5.1. Strength of study 

The yoga package was designed after extensive literature review 

by yoga specialists and was a perfect combination of 

asana and breathing exercises targeted at the disease under 

study. Excellent compliance of study sample and there were 

no drop outs. Experimental group patients voluntarily reported 

to Holistic medicine department and were self motivated 

for the practice of yoga. The control group was also 

under constant surveillance by the Diabetic care clinic. 

5.2. Limitations of the study 

Direct supervision of the patients was not possible for the 

entire period of the study. Dietary data were not recorded. 

Long-term study was not possible due to threat of noncompliance 

of the patients. 



references 

1. Taskinen MR. Diabetic dyslipidemia. Atheroscler Suppl. 

2002;3(1):47e51. 

2. Mooradian Arshag D. Dyslipidemia in type 2 diabetes 

mellitus. Nat Clin Pract Endocrinol Metab. 2009;5:150e159. 

3. Ford ES, Mokdad AH, Giles WH, Mensah GA. Serum total 

cholesterol concentrations and awareness, treatment, and 

control of hypercholesterolemia among US adults: findings 

from the National Health and Nutrition Examination Survey, 

1999 to 2000. Circulation. 2003;107:2185e2189. 

4. Imperatore G, Cadwell BL, Geiss L, et al. Thirty year trends in 

cardiovascular risk factor levels among US adults with 

diabetes: National Health and Nutrition Examination Surveys, 

1971e2000. Am J Epidemiol. 2004;160:531e539. 

5. Krauss RM. Dietary and genetic probes of atherogenic 

dyslipidemia. Arterioscler Thromb Vasc Biol. 2005;25: 

2265e2272. 

6. Expert Panel on Detection, Evaluation, and Treatment of High 

Blood Cholesterol in Adults. Executive summary of the third 

report of the National cholesterol education program (NCEP) 

expert Panel on detection, evaluation, and treatment of high 

blood cholesterol in adults (Adult treatment Panel III). JAMA. 

2001;285:2486e2497. 

7. Mahajan AS, Reddy KS, Sachdeva U. Lipid profile of coronary 

risk subjects following yogic lifestyle intervention. Indian 

Heart J. 1999;51:37e40. 

8. Damodaran A, Malathi A, Patil N, Shah N, Suryananshi, 

Marathe S. Therapeutic potential of yoga practices in 

modifying cardiovascular risk profile in middle aged men and 

women. J Assoc Physicians India. 2002;50:633e640. 

9. Vyas R, Dikshit N. Effect of meditation on respiratory system, 

cardiovascular system and lipid profile. Ind J Physiol Pharmacol. 

2002;46(4):487e491. 

10. National Diabetes Data Group. Classification and diagnosis of 

diabetes mellitus and other categories of glucose intolerance. 

Diabetes. 1979;28:1039e1057. 

11. Expert Panel on Detection, Evaluation and treatment of high 

blood cholesterol in adults (Adult treatment Panel III). JAMA. 

2001;285:2486e2497. 

12. Mc Gowan MW, Artiss JD, Strandbergh DR, Zak B. A peroxidasecoupled 

method for the colorimetric determination of serum 

triglycerides. Clin Chem. 1983;29:538e542. 

13. Trider P. Clinical chemistry. Ann Clin Biochem. 1969;6:24e27. 

14. Burstein M, Scholnic HR, Morfin R. Rapid method for the 

isolation of lipoproteins from human serum with polyanions. 

J Lipid Res. 1970;11:583e595. 

15. Pyorala k, Laakso M, Ustipa M. Diabetes and atherosclerosis; 

an epidemiological view. Diabetes Metab Rev. 1987;3:463e524. 

16. Szapary PO, Bloedon LT, Foster GD. Physical activity and its 

effects on lipids. Curr Cardiol Rep. 2003;5:488e492. 

17. Asikainen TM, Miilunpalo S, Kukkonen-Harjula K, et al. 

Walking trials in postmenopausal women: effect of low doses 

of exercise and exercise fractionization on coronary risk 

factors. Scand J Med Sci Sports. 2003;13:284e292. 

18. Clearfield Michael B. The national cholesterol education 

program adult treatment Panel III guidelines. JAOA; 2003.


19. Thompson PD. What do muscles have to do with 

lipoproteins? Circulation. 1990;81:1428e1430. 

20. Skarfors ET, Wegener TA, Lithell H, Selinus I. Physical training 

as treatment for Type 2 (non-insulin-dependent) diabetes in 

elderly men. A Feasibility Study Over 2 Years. Diabetologia. 

1987;30(12):930e933. 

21. Sahay BK. Role of yoga in diabetes. J Assoc Physicians India. 

2007;55:121e126. 

22. Singh S, Malhotra V, Singh KP, Madhu SV, Tandon OP. Role of 

yoga in modifying certain cardiovascular functions in Type 2 

diabetic patients. J Assoc Physicians India. 2004;52:203. 

23. Manchnada SC, Narang R, Reddy KS, Sachdev V. Retardation 

of coronary atherosclerosi with yoga lifestyle intervention. 

J Asso Physiocians in India. 2000;48:487e494. 


cardiovascular system and lipid profile. Indian J Physio 

Pharmacol. 2001;45(4):493e496. 

25. Bijlani RL, Vempati RP, Yadav RK, et al. A brief but 

comprehensive lifestyle education program based on yoga 

reduces risk factors for cardiovascular disease and diabetes 

mellitus. J Altern Complement Med. 2005;11(2):267e274. 

26. Bjorntorp P. Metabolic implications of body fat distribution. 

Diabetes Care. 1991;14:1132e1143. 

27. Chrousos GP, Gold PW. A healthy body in a healthy mind and 

vice versa: the damaging power of uncontrollable stress. J Clin 

Endocrinol Metab. 1998;83:1842e1845. 

28. Giugliano D. Morphine, opioid peptides, and pancreatic islet 

function. Diabetes Care. 1984;7:92e98. 

29. Udupa K, Madanmohan, Ananda BB, Vijayalakshmi P, 

Krishnamoorthy N. Effect of pranayama training on cardiac 

function in normal young volunteers. Indian J Physiol 

Pharmacol. 2003;47:27e33. 

30. Raghuraj P, Ramakrishnan AG, Nagendra HR, Telles S. Effect 

of two selected yogic breathing techniques on heart rate 

variability. Indian J Physiol Pharmacol. 1998;42:467e472. 

31. Sandeep B, Pandey US, Verma NS. Improvement in oxidative 

status with yogic breathing in young healthy males. Indian J 

Physiol Pharmacol. 2002;46:349e354. 

32. Perez-De-Albeniz A, Holmes J. Meditation:concepts, effects 

and uses in therapy. Int J Psychotherapy. 2000;5:49e58. 

33. Shradha Bisht, Sisodia SS. Diabetes, dyslipidemia, antioxidant 

and status of oxidative stress. IJRAP. 2010;1(1):33e42. 

34. Harinath K, Malhotra AS, Pal K, et al. Effects of hatha yoga 

and omkar meditation on cardiorespiratory performance, 

psychological profile and melatonin secretion. J Altern 

Complement Med. 2004;10(2):261e268.





Comparison of diagnostic utilities of ankleebrachial index 

and Carotid intima-media thickness as surrogate markers of 

significant coronary atherosclerosis in Indians 

Babu Ezhumalai c, *, Subrahmanyam Dharanipragada Krishnasuri b , 

Balachander Jayaraman a 

a Dept. of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India 

b Dept. of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India 

c Senior Resident, Dept. of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Dhanvantri Nagar, Gorimedu, 

Pondicherry 605006, India 

article info 





Keywords: 

Coronary artery disease 

Ankleebrachial index 

Carotid intima-media thickness 

Atherosclerosis 

abstract 

Aim: We aimed to compare Ankleebrachial index (ABI) and Carotid intima-media thickness 

(CIMT) as surrogate markers of significant coronary atherosclerosis in South Indians with 

coronary artery disease (CAD). 

Methods and results: There were two groups: CAD group (n ¼ 59) and Control group (n ¼ 55). 

Mean ABI (0.82 0.06 vs. 1.16 0.11, p < 0.0001) and mean CIMT (0.74 0.22 mm vs. 

0.45 0.09 mm, p < 0.0001) were statistically different between two groups. ABI < 0.9 

(sensitivity: 91.53%, specificity: 100%) and CIMT > 0.63 mm (sensitivity: 61.02%, specificity: 

98.18%) implied significant CAD. ABI and CIMT were negatively correlated to one another. 

With increasing severity of CAD, ABI decreased but CIMT increased. 

Conclusion: ABI and CIMT are simple noninvasive tools providing insight into coronary 

atherosclerosis. They can be done at bedside and easily repeated than coronary angiography. 

ABI < 0.9 is a better surrogate marker of significant coronary atherosclerosis than 

CIMT > 0.63 mm in South Indians with CAD. 



Coronary artery disease (CAD) imposes significant economic 

burden throughout the world. Coronary angiography remains 

the gold standard investigation for identifying CAD. In fact, it 

is a luminogram and may not detect the abluminal plaque 

growth in the initial stages of coronary atherosclerosis. 

Moreover, it is invasive associated with significant interobserver 

variability and underestimation of stenosis in the 

presence of diffuse disease. 

Atherosclerosis is the major etiology of CAD and it is a 

generalized process simultaneously involving multiple arteries 

in the body. Hence, analysis of peripheral arteries in an 

individual with CAD may throw some light upon the degree 

of atherosclerosis at the level of coronaries. Ankleebrachial 

index (ABI) and Carotid intima-media thickness (CIMT) are 

simple noninvasive tools developed based on this principle. 

The use of ABI in peripheral arterial disease is well established. 

As the same pathogenesis primarily involves coronary 

vasculature, ABI (0.9 or

138 


cardiovascular events and death. 1e3 Abnormal ABIs, both low 

(


The differences in mean ABI (CAD group: 0.82 0.06 and 

Control group: 1.16 0.11, unpaired Student’s t test p < 0.0001) 

and mean CIMT (CAD group: 0.74 0.22 mm and Control 

group: 0.45 0.09 mm, unpaired Student’s t test p < 0.0001) 

between the two groups were statistically highly significant 

(Table 2). Overall, in the CAD group, there were 54 (91.53%) 

cases with ABI < 0.9 and 5 (8.47%) cases with ABI 0.9 (Table 

2). Similarly, there were 36 (61.02%) cases with 

CIMT > 0.63 mm and 23 (38.98%) cases with CIMT 0.63 mm in 

the CAD group. There were 22 (37.29%) cases with carotid 

plaques in CAD group while none in the Control group had 

plaque. There was significant difference (Fisher’s Exact test, 

p < 0.0001) between the two groups with respect to the presence 

of carotid plaques. 

Subgroup analysis (Table 3) between diabetics (n ¼ 28) and 

non-diabetics (n ¼ 31) within CAD group did not show significant 

difference in the mean values of ABI (0.82 0.06 and 

0.82 0.05, p ¼ 0.714) or CIMT (0.75 0.24 and 0.73 0.20, 

p ¼ 0.679) using unpaired Student’s t test. 

The mean ABI was 0.87, 0.82 and 0.75 in cases with single 

vessel, double vessel and triple vessel diseases in CAD group 

respectively. One-way ANOVA showed that these values were 

statistically different (F ¼ 42.487, p < 0.0001) between these 

subgroups. The mean CIMT was 0.6, 0.73 and 0.94 mm in these 

subgroups respectively and they were statistically different 

(F ¼ 44.552, p < 0.0001, one-way ANOVA). The posthoc test 

performed along with ANOVA was Turkey Kramer Multiple 

Comparisons test and this also showed statistical significance 

( p < 0.001) with respect to ABI and CIMT in these subgroups. 

With increase in severity of CAD, ABI decreased (Fig. 1) while 

CIMT increased (Fig. 2). Pearson correlation test showed statistically 

significant negative correlation between ABI and 

CIMT (r ¼ -0.780). 

5. Discussion 

Routine screening tests such as resting electrocardiography, 

treadmill test and electron-beam computed tomography are 

inaccurate in predicting cardiovascular events in adults with 

low risk for CAD or asymptomatic persons because many 

acute events result from sudden occlusion of a previously 

unobstructed coronary artery. 12 Therefore, in our study, the 

participants in Control group were not routinely subjected to 

Table 2 e Ankleebrachial index and Carotid intimamedia 

thickness in CAD and Control groups. 

Parameter 

CAD group 

n ¼ 59 

Control group 

n ¼ 55 

ABI 

Mean SD* 0.82 0.06 1.16 0.11 

0.63 36 (61.02%) 1 (1.82%) 

0.63 23 (38.98%) 54 (98.18%) 

*p < 0.0001 using unpaired Student’s t test. 

Table 3 e Ankleebrachial index and carotid intima-media 

thickness between diabetics and non-diabetics within 

CAD group. 

Parameter 

Diabetics 

n ¼ 28 

Mean SD 

Non-diabetics 

n ¼ 31 

Mean SD 

ABI* 0.82 0.06 0.82 0.05 

CIMT # (mm) 0.75 0.24 0.73 0.20 

*p ¼ 0.714 and # p ¼ 0.679 using unpaired Student’s t test. 

these screening tests but recruited based on Framingham risk 

scoring with 10-year risk of developing myocardial infarction 

and coronary death less than 10%. 

Prior studies have concluded that a low ABI is highly specific 

but not sensitive for predicting future cardiovascular risk 

in individuals with peripheral arterial diseases. 13 There is one 

trial where ABI was assessed using automated oscillometric 

method and it was found that the sensitivity, specificity, and 

positive and negative predictive values of ABI < 0.9 in predicting 

multivessel CAD were 22%, 96%, 93%, and 34%, 

respectively. 14 In contrast with this trial, another study done 

in African-American population, proved that an ABI 0.90 

predicted the presence of 3-vessel or left main CAD with a 

sensitivity of 85% and specificity of 77%. 15 In patients with 

PAD diagnosed based on ABI < 0.9, the prevalence of CAD is 

46.88%. 16 

The normal range (mean 2SE, 95% confidence interval) of 

ABI for healthy adults in our study is from 0.94 to 1.38. Taking 

0.94 as the lower limit of normal range for ABI, we would obtain 

a sensitivity of 100% and specificity of 96.36%. Since many 

studies have shown that ABI < 0.9 is a marker of increased 

cardiovascular events, 1e3 we took ABI < 0.9 as a surrogate 

marker of CAD and found a sensitivity of 91.53%, specificity of 

100%, pretest probability of 51.75%, positive predictive value of 

100% and a negative predictive value of 91.67%. 

0.9 

0.85 

0.8 

Mean 

ABI 

5 

0.7 

0.65 

0.87 

Single Vessel 

Disease 

0.82 

Double Vessel 

Disease 

0.75 

Triple Vessel 

Disease 

Fig. 1 e Ankleebrachial index and severity of coronary 

artery disease. One-way ANOVA: F [ 42.48, p < 0.0001. 

Posthoc test: TurkeyeKramer Multiple Comparisons test, 

p < 0.001.

140 


1 

0.9 

0.8 

Mean 

CIMT 0.7 

(mm) 0.6 

0.6 

0.5 

0.4 

Single Vessel 

Disease 

0.73 

Double Vessel 

Disease 

0.94 

Triple Vessel 

Disease 

Fig. 2 e Carotid intima-media thickness and severity of 

coronary artery disease. One-way ANOVA: F [ 44.552, 

p < 0.0001. Posthoc test: TurkeyeKramer Multiple 

Comparisons test, p < 0.001. 

Prior studies had no unanimous opinion about the cut-off 

value of CIMT for CAD. According to one study conducted in 

Japanese diabetics, CIMT 1.1 mm represents CAD. 10 The 

maximum values of CIMT for normal Indian population and 

CAD are 0.80 and 1.02 mm, respectively. 17 There is one more 

study which states that the risk of first myocardial infarction 

increases with a CIMT 0.822 mm. 18 In our study, the 

normal range (mean 2SE, 95% confidence interval) of CIMT 

for healthy adults is from 0.27 to 0.63 mm. We took 

CIMT > 0.63 mm as a surrogate marker of CAD and found a 

sensitivity of 61.02%, specificity of 98.18%, pretest probability 

of 51.75%, positive predictive value of 97.3% and a negative 

predictive value of 70.13%. In published studies, CIMT cut-off 

value of 0.67 mm yielded a sensitivity and specificity of 85% 

and 72%, respectively, for predicting obstructive coronary 

atherosclerosis 19 while the cut-off value of 0.87 mm for 

maximum CIMT obtained a sensitivity and specificity of 90 

and 64%, respectively for the detection of left main CAD. 5 In 

our study, when a higher cut-off value of 0.8 mm was 

considered the upper limit of normal CIMT, specificity 

increased to 100% but sensitivity decreased markedly to 

16.95%. Hence we took 0.63 mm as the upper limit of normal 

CIMT. This cut-off value is lower than that found in other 

studies. The probable explanation for a lower cut-off value for 

CIMT in our study is that other studies had matched cases and 

controls with respect to risk factors like diabetes, hypertension, 

dyslipidemia, smoking, obesity etc. On the other hand, 

the controls in our study were matched with cases only in age 

and sex but not for risk factors. Patients with diabetes were 

excluded from the control population. Moreover, the inclusion 

criteria for Control group incorporated Framingham risk 

scoring to calculate 10-year risk of developing cardiovascular 

events less than 10% and this was hardly used by other 

studies. Another explanation could be that South Indians may 

have a lower CIMT than other populations. Our study is 

limited by small sample size which could have also contributed 

to the lower cut-off value for CIMT. 

Based on sensitivity and specificity, ABI < 0.9 is a better 

surrogate marker of CAD than CIMT > 0.63 mm. In our study, 

all assessments were performed by a single operator so as to 

avoid interobserver variation and multiple readings were 

taken in order to avoid intraobserver variation. Earlier done 

study also did not show any significant interobserver or 

intraobserver variation on repeatedly measuring ABI. 20 

Studies have shown that significant reduction in CIMT occurs 

by one year of therapy with statins 21 and maximum 

regression occurs by 2 years. 22 So we excluded all those cases 

on statins for more than one year. 

As per ATP III guidelines, diabetes mellitus is considered a 

CAD equivalent. 11 Hence, ABI is expected to be low and CIMT to 

be high in diabetics compared to non-diabetics. The abnormalities 

in ABI and CIMT are expected to be more pronounced 

in diabetics with CAD than in non-diabetics with CAD. On the 

contrary, in our study, there was no significant difference in 

ABI or CIMT between diabetics and non-diabetics within CAD 

group. The major reason for this interesting observation is the 

quantum of atherosclerosis needed for developing CAD will 

not differ between diabetics and non-diabetics. Other reasons 

could be the interplay of multiple risk factors in non-diabetics 

within CAD group and small sample size. 

As mentioned earlier, in our study, the term ‘severity’ of 

CAD referred only to the number of major epicardial coronary 

arteries having at least 50% stenosis. We did not take into 

consideration the degree of stenosis beyond 50% and the type 

of coronary artery involved. There was significant difference 

in ABI and CIMT among cases with single vessel disease, 

double vessel disease and triple vessel disease within the CAD 

group. With increase in severity of CAD, ABI decreased but 

CIMT increased in our study. Prior studies had shown similar 

variation of ABI and CIMT with respect to severity of 

CAD. 8,10,23e25 A few studies differed in this view; one study 

found a weak correlation between CIMT and severity of CAD 26 

and a couple of studies could not establish a direct association 

between ABI and significant CAD. 27,28 We also found that ABI 

and CIMT were negatively correlated to one another; i.e. with 

increase in CIMT there was a decrease in ABI and vice versa. 

The definition of carotid plaque is highly variable. In our 

study, carotid plaque was defined as a localized thickening of 

the intima of carotid artery greater than 1.5 mm. 5,29 Carotid 

arteries were scanned from the clavicle to the angle of 

mandible for luminal plaques, while maximal CIMT was 

measured in the far wall of common carotid artery around 

10 mm below the bifurcation. Around 37.29% of cases in CAD 

group had plaques in carotid artery while none in the Control 

group had plaques. Using Fisher’s exact test we found that 

there was highly significant difference between CAD and 

Control groups with respect to the presence of carotid plaques. 

Hence, the value of CIMT as a surrogate marker of CAD is 

emphasized by the presence of plaque in carotid arteries. 

6. Conclusion 

Ankleebrachial index and Carotid intima-media thickness are 

simple noninvasive diagnostic tools capable of providing 

insight into the burden of atherosclerosis at the level of coronaries. 

Hence they are surrogate markers of significant


coronary atherosclerosis. They are very simple to do at 

bedside and more easily repeatable than coronary angiography. 

They provide key information even during the early 

phase of coronary atheroma formation particularly during the 

stage of positive remodeling when the atheromatous plaque 

abluminally encroaches on the coronary arteries. This 

compensatory hyperenlargement is usually not discernible in 

coronary angiography. Moreover there is no place for issues 

like radiation hazard, contrast induced nephropathy or 

vascular complications which may be encountered during 

coronary angiography. ABI < 0.9 is a better surrogate marker 

of significant coronary atherosclerosis than CIMT > 0.63 mm 

in South Indians with CAD. The presence of carotid plaque 

may endorse CIMT as a surrogate marker of CAD. ABI and 

CIMT are negatively correlated to one another. Therefore, ABI 

decreases but CIMT increases with increasing burden of coronary 

atherosclerosis. 



references 

1. Lee AJ, Price JF, Russell MJ, et al. Improved prediction of fatal 

myocardial infarction using the ankle brachial index in 

addition to conventional risk factors: the Edinburgh Artery 

Study. Circulation. 2004;110(19):3075e3080. 

2. Leng GC, Fowkes FG, Lee AJ, et al. Use of ankle brachial 

pressure index to predict cardiovascular events and death: a 

cohort study. BMJ. 1996;313:1440e1444. 

3. Papamichael CM, Lekakis JP, Stamatelopoulos KS, et al. 

Ankle-brachial index as a predictor of the extent of coronary 

atherosclerosis and cardiovascular events in patients with 

coronary artery disease. Am J Cardiol. 2000;86(6):615e618. 

4. Criqui MH, McClelland RL, McDermott MM, et al. The anklebrachial 

index and incident cardiovascular events in the 

MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll 

Cardiol. 2010;56(18):1506e1512. 

5. Kasliwal RR, Bansal M, Gupta H, et al. Association of carotid 

intima-media thickness with left main coronary artery 

disease. Indian Heart J. 2007;59(1):50e55. 

6. Wang D, Yang H, Quinones MJ, et al. A genome-wide scan for 

carotid artery intima-media thickness: the MexicaneAmerican 

Coronary Artery Disease Family Study. Stroke. 2005;36(3): 

540e545. 

7. Liviakis L, Pogue B, Paramsothy P, et al. Carotid intima-media 

thickness for the practicing lipidologist. J Clin Lipidol. 2010;4(1): 

24e35. 

8. Kablak-Ziembicka A, Tracz W, Przewlocki T, et al. Association 

of increased carotid intima-media thickness with the extent 

of coronary artery disease. Heart. 2004;90(11):1286e1290. 

9. Heuten H, Goovaerts I, Ennekens G, et al. Carotid artery 

intima-media thickness is associated with coronary artery 

disease. Acta Cardiol. 2008;63(3):309e313. 

10. Hayashi C, Ogawa O, Kubo S, et al. Ankle brachial pressure 

index and carotid intima-media thickness as atherosclerosis 

markers in Japanese diabetics. Diabetes Res Clin Pract. 

2004;66(3):269e275. 

11. Third report of the National Cholesterol Education Program 

(NCEP) expert panel on detection, evaluation and treatment 

of high blood cholesterol in adults (Adult Treatment Panel III). 

Final report. Circulation. 2002;106(25):3143e3421. 

12. U.S. Preventive Services Task Force. Screening for coronary 

heart disease: recommendation statement. Ann Intern Med. 

2004;140(7):569e572. 

13. Doobay AV, Anand SS. Sensitivity and specificity of the 

ankleebrachial index to predict future cardiovascular 

outcomes: a systematic review. Arterioscler Thromb Vasc Biol. 

2005;25(7):1463e1469. 

14. Su HM, Voon WC, Lin TH, et al. Ankle-brachial pressure index 

measured using an automated oscillometric method as a 

predictor of the severity of coronary atherosclerosis in 

patients with coronary artery disease. Kaohsiung J Med Sci. 

2004;20(6):268e272. 

15. Otah KE, Madan A, Otah E, et al. Usefulness of an abnormal 

ankle-brachial index to predict presence of coronary artery 

disease in African-Americans. Am J Cardiol. 2004;93(4):481e483. 

16. Sarangi S, Srikant B, Rao DV, et al. Correlation between 

peripheral arterial disease and coronary artery disease using 

ankle brachial index e a study in Indian population. Indian 

Heart J. 2012;64(1):2e6. 

17. Hansa G, Bhargava K, Bansal M, et al. Carotid intima-media 

thickness and coronary artery disease: an Indian perspective. 

Asian Cardiovasc Thorac Ann. 2003;11(3):217e221. 

18. Aminbakhsh A, Mancini GB. Carotid intima-media thickness 

measurements: what defines an abnormality? A systematic 

review. Clin Invest Med. 1999;22(4):149e157. 

19. Djaberi R, Schuijf JD, de Koning EJ, et al. Usefulness of carotid 

intima-media thickness in patients with diabetes mellitus as 

a predictor of coronary artery disease. Am J Cardiol. 

2009;104(8):1041e1046. 

20. Endres HG, Hucke C, Holland-Letz T, et al. A new efficient trial 

design for assessing reliability of ankle-brachial index 

measures by three different observer groups. BMC Cardiovasc 

Disord. 2006;6:33. 

21. Corti R, Fuster V, Fayad ZA, et al. Effects of aggressive versus 

conventional lipid-lowering therapy by simvastatin on 

human atherosclerotic lesions: a prospective, randomized, 

double-blind trial with high-resolution magnetic resonance 

imaging. J Am Coll Cardiol. 2005;46(1):106e112. 

22. Crouse JR, Raichlen JS, Riley WA, et al. Effect of rosuvastatin 

on progression of carotid intima-media thickness in low-risk 

individuals with subclinical atherosclerosis: the METEOR 

Trial. JAMA. 2007;297(12):1344e1353. 

23. Coskun U, Yildiz A, Esen OB, et al. Relationship between 

carotid intima-media thickness and coronary angiographic 

findings: a prospective study. Cardiovasc Ultrasound. 2009;7:59. 

24. Matsushima Y, Kawano H, Koide Y, et al. Relationship of 

carotid intima-media thickness, pulse wave velocity, and 

ankle brachial index to the severity of coronary artery 

atherosclerosis. Clin Cardiol. 2004;27(11):629e634. 

25. Sukhija R, Aronow WS, Yalamanchili K, et al. Association of 

ankle-brachial index with severity of angiographic coronary 

artery disease in patients with peripheral arterial disease and 

coronary artery disease. Cardiology. 2005;103(3):158e160. 

26. Adam MR, Nakagomi A, Keech A, et al. Carotid intima-media 

thickness is only weakly correlated with the extent and 

severity of coronary artery disease. Circulation. 

1995;92(8):2127e2134. 

27. Hakeem F, Siddique S, Saboor QA. Abnormal ankle brachial 

index and the presence of significant coronary artery disease. 

J Coll Physicians Surg Pak. 2010;20(2):79e82. 

28. Pearson TL. Ankle brachial index as a prognostic tool for 

women with coronary artery disease. J Cardiovasc Nurs. 

2010;25(1):20e24. 

29. Vicenzini E, Ricciardi MC, Puccinelli F, et al. Common carotid 

artery intima-media thickness determinants in a population 

study. J Ultrasound Med. 2007;26(4):427e432.





Polymorphisms of MDR1, CYP2C19 and P2Y 12 genes in Indian 

population: Effects on clopidogrel response 

Kavita K. Shalia d, *, Vinod K. Shah b , Poonam Pawar a , Siddhi S. Divekar a , 

Satchidanand Payannavar c 

a Sir H.N. Medical Research Society, Sir H.N. Hospital and Research Centre, Raja Rammohan Roy Road, Mumbai 400 004, India 

b Dept. of Cardiology, Sir H.N. Hospital and Research Centre, Raja Rammohan Roy Road, Mumbai 400 004, India 

c Dept. of Cardiology, Rajawadi Municipal Hospital, Ghatkopar (East), Mumbai, India 

d Research Scientist, Sir H.N. Medical Research Society, Sir H.N. Hospital and Research Centre, Raja Rammohan Roy Road, Mumbai, 

Maharashtra 400 004, India 

article info 





Keywords: 

Clopidogrel 

CYP2C19 

Gene polymorphisms 

MDR1 

P2Y 12 

abstract 

Aims/objective: Influence of genetic variations on the response of clopidogrel, an antiplatelet 

drug is implicated. In the present study, the prevalence of single nucleotide polymorphisms 

of MDR1 (C3435T), CYP2C19 [CYP2C19*2 CYP2C19*3, CYP2C19*17] and P2Y 12 

(i-T744C) in Indian population and their effects on clopidogrel response was analyzed. 

Methods and results: To analyze the prevalence of polymorphisms, 102 healthy individuals 

were recruited. Clopidogrel response was assessed by ADP induced platelet aggregation in 

clopidogrel naïve acute myocardial infarction (AMI) patients (n ¼ 26) screened from 100 AMI 

cases, before loading dose of 300 mg, at 24 h before next dose and 6 days after on 75 mg per 

day and platelet aggregation inhibition (PAI) was calculated between these time intervals. 

Genotyping was carried out by PCR-based restriction enzyme digestion method for C3435T 

of MDR1 and i-T744C of P2Y 12 , by multiplex PCR for CYP2C19*2 (G681A) and CYP2C19*3 

(G636A) and by nested PCR for CYP2C19*17 (C806T). The effect of the above mentioned 

genetic variations on PAI was analyzed. Variant allele of CYP2C19*3 was not observed while 

the prevalence of 3435T of MDR1 (0.524), CYP2C19*2 (681A, 0.352); i-744C of P2Y 12 (0.088), as 

well as wild type allele CYP2C19*17 (C806, 0.897) associated with decrease clopidogrel 

response were observed. Trend toward poor response to clopidogrel was observed at 24 h 

with the variant genotypes of CYP2C19*2 and i-T744C of P2Y 12 as compared to wild type. 

Conclusion: The present study did show a trend toward impaired response of clopidogrel to 

inhibit platelet aggregation with variant genotypes of CYP2C19*2 and iT744C of P2Y 12 

compared to respective wild type genotype at 24 h. 


* Corresponding author. Tel.: þ91 (0) 22 66106308/387; fax: þ91 (0) 22 66106212. 

E-mail addresses: Kavita_shalia@hnhospital.com, kavitashalia@hotmail.com (K.K. Shalia). 




1. Background 

It has become extensively clear over the past decade that millions 

of loci within the human genome can vary from person to 

person which affect gene and subsequent protein expression 

and influence our metabolism. Among our many happening 

metabolic processes, the action of drug is dependent on various 

metabolic processes that includes its activation and metabolism; 

thus determining its efficacy. For a drug like clopidogrel, 

a highly prescribed antiplatelet agent, a genetic testing 

which is able to predict variability in drug response has found 

its place in the field of pharmacogenomics. 

Clopidogrel, alone or combined with aspirin, is routinely 

used to treat patients with a variety of vascular disorders. It is 

a thienopyridine derivative; a prodrug activated in the liver by 

cytochrome P450 (CYP) enzymes mainly by CYP2C19. This 

active metabolite of the drug then binds irreversibly to the 

platelet adenosine diphosphate (ADP) receptor P2Y 12 which 

inhibits platelet degranulation, glycoprotein IIb/IIIa (GPIIbIIIa) 

receptor activation and thus platelet aggregation. 1e3 The 

pharmacodynamic response to clopidogrel varies widely from 

subject to subject, and about 25% of patients treated with 

standard clopidogrel doses display low ex vivo inhibition of 

ADP-induced platelet aggregation. Generally patients with 

160 


prevalence of the polymorphisms. Of these subjects, blood 

sample was also collected of randomly selected 10 healthy 

individuals for platelet aggregation study. 

To analyze the effect of these polymorphism on platelet 

aggregation only those AMI cases (n ¼ 26) were selected and 

recruited who were not on clopidogrel before and were prescribed 

clopidogrel later. They were clopidogrel naïve patients 

screened from 100 AMI patients in the span of two years 

(2009e2011). The platelet aggregation of these patients was 

compared before and after the intake of the drug and thus 

platelet aggregation inhibition (PAI) was calculated and the 

effect of genotypes on PAI was analyzed. AMI patients were 

those who suffered an AMI with prolonged chest pain more 

than 30 min and ST segment elevation more than 0.1 mv on at 

least two adjacent ECG leads with elevated cardiac enzymes 

from ICCU ward. These AMI patients were with first episode of 

chest pain and had neither past history of such clinical 

symptoms nor were on any known medications for the same. 

AMI patients on prior clopidogrel treatment at the time of 

admission were excluded as their basal platelet aggregation 

could not be obtained which was essential to compare the 

extent of PAI after the intake of clopidogrel. Other exclusion 

criteria were valvular heart disease, known cardiomyopathy, 

malignancy, renal or liver diseases as well as subjects with 

systemic inflammatory disease to exclude any other complications 

and keep the patient population homogenous. These 

AMI patients at presentation were given 300 mg loading dose 

of clopidogrel and aspirin (150 mg) along with the standard 

treatment of nitrates antiarrhythmics, antifailures, statins 

and proton pump inhibitors (PPI) and subsequently were on 

maintenance dose of 75 mg clopidogrel per day. PPIs, 

frequently used in patients receiving clopidogrel and aspirin, 

are also metabolized by CYP2C19 and CYP3A4. 7 In our study, 

pantoprazole 40 was used as PPI for all the patients. In 

contrast to the reported negative omeprazole-clopidogrel drug 

interaction, the intake of pantoprazole or esomeprazole has 

been demonstrated, not to interfere with the activation of 

clopidogrel and was therefore not associated with impaired 

response. 26,27 The subjects were recruited in study only after 

obtaining informed consent. Information regarding their demographic 

status, clinical history, family history and medications 

were noted down in detail. The ethical committee of 

Sir H. N. Hospital and Research Centre and Rajawadi Municipal 

Hospital approved the study protocol. The analyzes of the 

samples were carried out at Sir H. N. Medical Research Society 

at Sir H. N. Hospital and Research Centre, Mumbai. 

2.2. Sample collection 

Blood samples of 102 healthy individuals were collected in the 

plain and EDTA anti-coagulated vacutainer after overnight, 

12 h fast for analyzing biochemical parameters and complete 

blood count respectively. Of these subjects, 10 healthy individuals 

were randomly selected and their blood sample was 

also collected in Na-Citrate vacutainer (3.2%) for platelet aggregation 

test. Peripheral blood samples of AMI patients were 

collected at presentation for routine analysis such as electrolytes, 

cardiac enzymes, complete blood count and prothrombin 

time. Remaining serum was stored at 80 C and 

EDTA blood sample at 4 C for further analysis. Peripheral 

blood of each AMI patient was collected in Na-Citrate vacutainer 

(3.2%) for platelet aggregation test at three different 

point of time e (1) baseline or 0 h e before clopidogrel loading 

dose (300 mg) administration, (2) 24 h after loading dose 

(300 mg) administration and before the next dose of 75 mg and 

(3) at 6 days when the patient was on 75 mg maintenance dose 

of clopidogrel. 

2.3. Platelet aggregation by turbidometric method 

Platelet aggregation test was carried out at the earlier mentioned 

three different point of time within 4 h of blood collection. 

Platelet rich plasma (PRP) and platelet poor plasma (PPP) were 

separated from each Na-citrated blood and then the test was 

carried out in duplicates using ADP (10 mM) as agonist in a two 

chambered Chronolog Platelet Aggregometer (model 490-2D). 

With the help of AggroLink software package, platelet aggregation 

was expressed as the maximal percent change in light 

transmittance from baseline in PRP with PPP used as a reference. 

All the patients were administered aspirin along with clopidogrel. 

The predominant antiplatelet effect of aspirin is mediated 

through its irreversible inactivation of cyclooxygenase (COX) 1, 

which is responsible for the formation of thromboxane A2, a 

potent vasoconstrictor and platelet aggregator, from arachidonic 

acid. 27 In the present study, final concentration of 10 mM 

ADP was chosen for platelet aggregation because at this concentration 

ADP induces complete platelet aggregation in a 

manner independent of thromboxane A2 production. 14,28,29 

2.4. Genotyping of polymorphisms 

DNA was extracted from peripheral leukocytes by modified 

Miller et al’s salting out procedure. 30 Genotyping was carried 

out by polymerase chain reaction (PCR) e based restriction 

enzyme digestion method for C3435T of MDR1 31 and i-T744C 

of P2Y 12 . 32 A multiplex PCR was standardized for CYP2C19*2 

and CYP2C19*3 using primer sequence of Pang et al 33 while 

CYP2C19*17 was genotyped using nested PCR. 34 The primers 

used for PCR of each polymorphism are given in Table 1. The 

Table 1 e Primers sequence. 

Gene 

Primer sequence 

MDR1 31 

(C3435T) 

CYP2C19*2 33 

(G681A) 

CYP2C19*3 33 

(G636A) 

CYP2C19*17 34 

(C806T) 

P2Y 12 

32 

(i-T744C) 

5 0 TGT TTT CAG CTG CTT GAT GG 3 0 

5 0 AAG GCA TGT ATG TTG GCC TC 3 0 

5 0 CAG AGC TTG GCA TAT TGT ATC 3 0 

5 0 GTA AAC ACA CAA CTA GTC AAT G 3 0 

5 0 AAA TTG TTT CCA ATC ATT TAG CT 3 0 

5 0 ACT TCA GGG CTT GGT CAA TA 3 0 

SET 1 

5 0 GCC CTT AGC ACC AAA TTC TC 3 0 

5 0 ATT TAA CCC CCT AAA AAA ACA CG 3 0 

SET 2 

5 0 AAA TTT GTG TCT TCT GTT CTC AAT G 3 0 

5 0 AGA CCC TGG GAG AAC AGG AC 3 0 

5 0 TCA CTT ATC TCT GGT GAA ATA AAA 

AGA TTA CGT A 3 0 

5 0 GTC AGA AAT GGC CTG TGT ATA TAT 

GGT CAT GAG 3 0


content of the master mix and PCR conditions are depicted in 

Table 2. Taq polymerase and dNTPs were from FermentaseMBI. 

PCR was carried out in thermal cycler “T Gradient” 

from “Biometra” (Genetix Biotech Asia Pvt. Ltd.). Each sample 

was run in duplicates with a positive and negative control for 

each for a batch of samples. Amplified PCR product was then 

run on Agarose gel electrophoresis. Finally, the PCR products 

were subjected to restriction digestion with the enzymes Sau 

3A1, Sma I, Bam HI, Nsi I and Rsa I for identifying genotypes of 

C3435T of MDR1, CYP2C19*2, CYP2C19*3, CYP2C19*17 and 

i-T744C of P2Y 12 respectively. Fig. 1 shows the restriction 

digestion pattern of C3435T of MDR1, Fig. 2 shows CYP2C19*2 

and CYP2C19*3 genotypes of multiplex PCR, Figs. 3 and 4 show 

that of CYP2C19*17, and i-T744C of P2Y 12 , respectively on 10% 

polyacrylamide gel electrophoresis. 

in platelet aggregation between groups was assessed by 

ManneWhitney U test. 

3. Results 

3.1. Characteristics of the study population 

Demographic data and routine pathology data of 102 healthy 

individuals and 26 AMI patients is given in Table 3 and Table 4 

respectively. There was no significant difference in the age, 

body mass index and blood pressure amongst AMI patients. 

Six out of 26 patients were hypertensive while 4 were diabetic. 

3.2. Allelic frequencies 


Genotype frequencies were estimated by the gene-counting 

method. Allelic frequencies were calculated from genotype 

frequencies. Genotypes were tested for deviations from HardyeWeinberg 

equilibrium. The change in platelet aggregation 

within a group from baseline to 24 h or 6th day was assessed 

using Wilcoxon Signed Rank test. The comparison of change 

The genotype and allele frequencies for all the polymorphisms 

studied are given in Table 5 and Table 6 for 

healthy individuals and AMI patients, respectively. The study 

population did not show the presence of the variant allele of 

CYP2C19*3. The observed genotype distributions did not 

deviate from HardyeWeinberg equilibrium. 

As the sample size of healthy individuals (n ¼ 102) and that 

of AMI patients (n ¼ 26) differed, the significance of difference 

Table 2 e Details of the PCR protocol for genotyping polymorphisms. 

Genotype Content of the PCR reaction PCR conditions PCR amplified 

product 

MDR1 (C3435T) 

1 U Taq DNA polymerase, 2.5 ml of 10X 

Buffer with 25 mM MgCl 2 , 0.5 ml of10mM 

dNTPs, 10 pmoles of primers and 100 ng 

of genomic DNA 

Initial denaturation at 95 C for 5 min 

followed by 30 cycles of denaturation 

at 95 C for 45 s, annealing at 62 C 

for 30 s and extension at 72 C for 

30 s followed by final extension at 

72 C for 5 min. 

The PCR amplification conditions 

consisted 3 steps e an initial 

denaturation step at 95 C for 5 min 

followed by 30 cycles of denaturation 

at 95 C for 45 s, annealing at 58 C 

for 50 s and extension at 72 C for 1 

min followed by final extension at 

72 C for 3 min 

An initial denaturation step at 95 C 

for 5 min followed by 30 cycles of 

denaturation 95 C for 45 s, annealing 

at 62 C for 30 s and denaturation at 

72 C for 30 s followed by final 

extension at 72 C for 5 min. 

Second PCR 

Initial denaturation step at 95 C for 5 

min followed by 30 cycles of 

denaturation at 95 C for 45 s, 

annealing at 62 C for 30 s and 

extension at 72 C for 30 s followed 

by final extension at 72 C for 3 min 

Initial denaturation step at 95 C for 5 

min followed by 30 cycles of 

denaturation at 95 C for 45 s, 

annealing at 60 C for 2 min and 

extension at 72 C for 2 min followed 

by final extension at 72 C for 5 min 

197 base pair (bp) 

CYP2C19*2 and 

CYP2C19*3 

polymorphisms 

by multiplex PCR 

The 50 ml reaction mixture contained 2 U 

Taq DNA polymerase, 5 ml 10X Buffer with 

25 mM MgCl 2 ,1ml 10 mM dNTPs and 15 

pmoles of each specific primers and 100 ng 

of genomic DNA 

321 bp of CYP2C19*2 

(G681A) and 271 bp of 

CYP2C19*3 (G636A) 

CYP2C19*17 

polymorphism 

by nested PCR 

First PCR 

The first 25 ml reaction mixture contained 1 U 

Taq DNA polymerase, 2.5 ml of 10X buffer 

with 25 mM MgCl 2 , 0.5 ml of 10 mM dNTPs 

and 10 pmoles of each specific primers and 

100 ng of genomic DNA 

Second PCR 

The next 50 ml reaction mixture contained 1U 

Taq DNA polymerase, 5 ml of 10X Buffer with 

25 mM MgCl 2 , 0.5 ml of 10 mM dNTPs and 10 

pmoles of each specific primers. For each 

sample to be genotyped 1 ml of earlier amplified 

PCR product was added later. 

2 U Taq DNA polymerase (Fermentas - MBI), 

2.5 ml 10X Buffer with 25 mM MgCl 2 , 0.5 ml of 

10 mM dNTPs and 10 pmoles of each specific 

primers and 100 ng of genomic DNA. 

473bp 

143bp 

P2Y 12 

(i-T744C) 

220bp

162 


Fig. 1 e The restriction digestion pattern of MDR1 [C3435T] 

on 10% polyacrylamide gel electrophoresis. Lane 1: PCR 

product of 197 bp. Lane 2 and 4: heterozygous genotype 

(C3435T) showing two bands of 197 bp and 158 bp. Lane 3: 

O 0 Range Ruler, 20 bp, ready to use DNA Ladder from MBI 

Fermentas. Lane 4: homozygous mutant genotype 

(T3435T) showing one band of 158 bp. Lane 6: wild type 

genotype (C3435C) showing one band of 197 bp. 

Fig. 3 e The restriction digestion pattern of CYP2C19*17 on 

10% polyacrylamide gel electrophoresis. Lane 1: PCR 

products of 143 bp. Lane 2: wild type genotype (*1 3 *1) 

showing one band of 116 bp. Lane 3: Heterozygous 

genotype (*1 3 *17) showing two bands 143 bp and 116 bp. 

Lane 4 to 6: homozygous mutant genotype (*17 3 *17) 

showing one band of 143 bp. Lane 7: O 0 Range Ruler, 20 bp, 

ready to use DNA Ladder from MBI Fermentas. 

of prevalence of the genotypes and alleles (using Chi Square 

statistics with Yates Corrections) was not calculated. However, 

it was observed that the prevalence of wild type allele 

frequency of CYP2C19*17 (C806, 0.897 > 0.865) and the variant 

allele frequency of 3435T of MDR1 (0.576 > 0.524), CYP2C19*2 

(681A, 0.423 > 0.352) as well as i744C of P2Y 12 (0.173 > 0.088) of 

AMI patients although marginal, were more as compared that 

of healthy individuals (Tables 5 and 6). 

3.3. Platelet aggregation 

The platelet aggregation of healthy individuals (n ¼ 10) was in 

the range of 60e80% (70.4 8.87) almost similar to average 

Fig. 2 e The restriction digestion pattern of CYP2C19*2 and 

CYP2C19*3 on 10% polyacrylamide gel electrophoresis. 

Lane 1: PCR products of 321 bp and 271 bp for CYP2C19*2 

and CYP2C19*3 respectively. Lane 2eLane 4: wild type 

genotype (*1 3 *1) of CYP2C19*2 showing two bands 212 bp 

and 109 bp and wild type genotype (*1 3 *1) of CYP2C19*3 

showing two bands 175 bp and 196 bp. Lane 3: 

Heterozygous genotype (*1 3 *2) of CYP2C19*2 showing 

three bands 321 bp, 212 bp and 109 bp and wild type 

genotype (*1 3 *1) of CYP2C19*3 showing two bands 175 bp 

and 196 bp. Lane 4: homozygous mutant genotype (*2 3 *2) 

showing one band of 321 bp and wild type genotype 

(*1 3 *1) of CYP2C19*3 showing two bands 175 bp and 196 

bp. Lane 5: O 0 Range Ruler, 20 bp, ready to use DNA Ladder 

from MBI Fermentas. 

Fig. 4 e The restriction digestion pattern of P2Y 12 [i-T744C] 

on 10% polyacrylamide gel electrophoresis. Lane 1: PCR 

products of 220 bp. Lane 2: wild type genotype (i-T744T) 

showing one band of 220 bp. Lane 3: heterozygous 

genotype (i-T744C) showing two bands 220 bp and 196 bp. 

Lane 4: Homozygous mutant genotype (i-C744C) showing 

one band of 196 bp. Lane 5: O 0 Range Ruler, 20 bp, ready to 

use DNA Ladder from MBI Fermentas.


Table 3 e Demographic data. 

Parameters 

Healthy individuals 

(n ¼ 102) 

AMI patients 

(n ¼ 26) 

M:F 47: 55 19:7 

Age [years] 43.59 10.74 51 10 

BMI [kg/m 2 ] 24.4 4.53 23.98 2.12 

SBP [mmHg] 118 9.23 135 29 

DBP [mmHg] 78.96 6.73 82 17 

Smoking 14 14 

Alcohol consumption 15 8 

Hypertension e 6 

Diabetes mellitus e 4 

baseline platelet aggregation (0 h) of 26 AMI patients (69.16%). 

The platelet aggregation of all AMI patients (n ¼ 26) dropped to 

45.6% at 24 h subsequent to the administration of 300 mg 

loading dose with PAI of only 23.56%. Further, platelet aggregation 

dropped to 43.4% at 6 days on further 75 mg maintenance 

dose per day of clopidogrel demonstrating PAI of only 

25.76%. 

Among 26 AMI patients, none demonstrated homozygous 

mutant (T806T) genotype of CYP2C19*17. All the patients were 

associated with either wild type or heterozygous genotypes 

associated with decreased enzyme function. Also there were 

only 4 patients each with wild type (C3435C) genotype of MDR1 

and rests were with variant genotypes associated decrease 

intestinal absorption. Therefore, further analysis of effect of 

polymorphisms on response to clopidogrel was carried out 

with respect to CYP2C19*2 genotypes and patients were 

grouped according to common genotypes as depicted in 

Table 7. Group I, II and III were with wild type (G681G), heterozygous 

(G681A) and homozygous mutant (A681A) genotype 

of CYP2C19*2 respectively and wild type genotype (i-T744T) of 

P2Y 12 . Subsequently, subjects were grouped as per variant 

genotypes of i-T744C of P2Y 12. Group IV was one case having 

homozygous mutant genotype (A681A) of CYP2C19*2 and 

heterozygous genotype (i-T744C) of P2Y 12 while three cases 

with heterozygous genotype (G681A) of CYP2C19*2 and homozygous 

mutant genotype (i-C744C) of P2Y 12 were included 

Table 4 e Routine pathology data. 

Parameters 

Healthy 

individuals 

(n ¼ 102) 

AMI patients 

(n ¼ 26) 

Total cholesterol (TC) (mg/dl) 188.5 35.38 172.5 44.4 

HDL-cholesterol (HDL-C) (mg/dl) 44.63 9.29 38.4 7.65 

TC/HDL-C 4.31 0.86 4.47 0.74 

LDL cholesterol (LDL-C) (mg/dl) 124.8 25.5 105.9 40.1 

LDL-C/HDL-C 2.8 0.71 2.8 0.6 

Triglycerides (mg/dl) 102.6 41.5 127.4 61.02 

VLDL cholesterol (mg/dl) 22.24 13.11 25.5 12.2 

Glucose (mg/dl) 95.1 10.1 154.2 68.3 

SGOT U/L 16 3.25 51.4 30.12 

SGPT U/L 20.1 2.3 38.2 15.8 

BUN (mg/dl) 8.1 2.37 10.1 7.32 

Creatinine (mg/dl) 0.7 0.12 0.98 0.24 

Uric acid (mg/dl) 4.0 1.3 4.95 1.84 

Total WBC count/mL 6975 1602 11 210 2926 

Platelet count 10 3 /mL 259 109.5 328 137 

in Group V. There was only one case with wild type genotype 

(G681G) of CYP2C19*2 and homozygous mutant genotype 

(i-C744C) of P2Y 12 (Group VI). The PAI at 24 h was in the 

decreasing order; 37%, 22%, 18.5%, 18.0%, 14.3% and 11.0% for 

Group I, II, III, IV, V and VI respectively. 

Statistical analysis of Group I and Group II with 6 and 13 

cases, respectively demonstrated that decrease in platelet 

aggregation i.e. PAI of Group I from 0 h to 24 h (37%, p ¼ 0.002) 

and 0 to 6th day (27%, p ¼ 0.027) was significant. The same was 

also observed for Group II for PAI from baseline to 24 h (22.0%, 

p ¼ 0.001) as well as from baseline to 6th day (24.3%, p ¼ 0.001). 

PAI at 24 h of Group II (22.0%) was less by 15% as compared to 

Group I (37.0%) but this decrease in PAI did not reach statistical 

significance of p< 0.05 (p ¼ 0.072). PAI at 6 days from baseline 

of Group I and II were almost similar 27% and 24.3%, respectively 

and did not reach statistical significance of p < 0.05 

(p ¼ 0.639). There were 3 hypertensives and one diabetic patient 

in Group I while in Group II there were 2 hypertensives 

and 2 diabetic patients. After excluding these patients, the 

difference in the PAI between Group I and II was 16.0% almost 

similar to that obtained on including these patients (15.0%). 

There was no significant difference in the BMI or age between 

the two patient groups (data not shown). 

Table 7 also depicts the CYP2C19*17 and C3435T genotypes 

of MDR1. In Group I, out of 6 patients, 5 had wild type genotype 

(C806C) for CYP2C19*17 while just one showed heterozygous 

genotype (C806T) for the same. Whereas in Group II, 11 out of 

13 had wild type genotype for CYP2C19*17 and just 2 showed 

heterozygous genotype for the same. On the other hand, in 

Group I out of 6 patients 2 were heterozygous (C3435T) and 4 

were homozygous mutant (T3435T) thus all were with variant 

genotypes of C3435T polymorphism of MDR1. In Group II, out 

of 13 patients, 7 were heterozygous and 3 each showed homozygous 

mutant and wild type genotype (C3435C) for C3435T 

polymorphism of MDR1. 

Remaining 7 patients could not be included in Group I or II 

and therefore in Table 7 they are grouped separately. Their PAI 

at 24 h was less as compared to Group I. Of these notably, 3 

patients of Group V with not only heterozygous genotype for 

CYP2C19*2 but also homozygous mutant genotype (i-C744C) of 

P2Y 12 demonstrated further (22.0%e14.3%) 7.7% less PAI as 

compared to Group II at 24 h. One patient with wild type 

genotype of CYP2C19*2 and homozygous mutant genotype 

(i-C744C) of P2Y 12 demonstrated only 11% PAI at 24 h. At 6th 

day, the PAI for all seven patients was either similar or near to 

Group I patients. 

4. Discussion 

The present study demonstrated the prevalence of polymorphisms 

of drug-efflux transporter protein responsible for 

drug absorption (MDR1), one of the metabolizing enzymes of 

clopidogrel (CYP2C19) and its target (P2Y 12 ), in our study 

population. Its effect was demonstrated on antiplatelet activity 

of clopidogrel in AMI patients assessed ex vivo by 

ADP-induced platelet aggregation. 

In our study population variant allele frequency of 3435T of 

MDR1 affecting intestinal absorption was found to be 52.4% 

(0.524) nearing to that reported for Indian population

164 


Table 5 e Genotype and allele frequencies of healthy individuals (n [ 102) for all the polymorphisms studied. 

Genotype frequency 

Allele frequency 

Wild type Heterozygous Homozygous Wild type allele Mutant allele 

MDR1 

(C3435T) 

CYP2C19*2 

(G681A) 

CYP2C19*3 

(G636A) 

CYP2C19*17 

(C806T) 

P2Y 12 

(i-T744C) 

26.4% (27) 42.1% (43) 31.4% (32) 3435C ¼ 0.475 3435T ¼ 0.524 

46% (47) 37% (38) 16.7% (17) 681G ¼ 0.647 681A ¼ 0.352 

100% (102) 0 0 636G ¼ 1.0 e 

81.4% (83) 16.7% (17) 1.96% (2) 806C ¼ 0.897 806T ¼ 0.102 

85.2% (87) 11.8% (12) 2.94% (3) i744T ¼ 0.911 i744C ¼ 0.088 

(0.61e0.62). 21,22 In African, 35 Asian and Caucasian 36 population, 

allele frequency of 3435T of MDR1 has been reported to be 

21.0%, 42.0% and 55.0%, respectively. The variant allele frequency 

of CYP2C19*2 (681A) associated with poor metabolizer 

type, was observed to be 35.2% (0.352) in the present study 

which is similar to that reported by Adithan et al 23 for 

Tamilian population (37.9%) and Mizutani et al 36 who have 

reported 30e35% in Asians and is greater than reported for 

African (17e20%) 35 and Caucasians (13e18%). 36 In the present 

study, the presence of CYP2C19*3 variant allele (636A), also 

associated with poor metabolizer type, was not observed 

which has also been reported by Pang et al 33 in Malaysian 

subjects. However, Adithan et al 22 have reported CYP2C9*3 

variant allele frequency as 2.2% in Tamilian population. In 

African, 35 Asians and Caucasians, 36 the variant allele frequency 

of CYP2C19*3 has been reported to be


Table 7 e Platelet aggregation, platelet aggregation inhibition (PAI) of AMI patients (n [ 26) grouped as per genotypes. 

Groups 

Platelet 

Platelet aggregation 

Genotypes 

aggregation (%) 

inhibition (PAI) (%) 

CYP2C19 P2Y 12 CYP2C19 MDR 1 

0 h 24 h 6 days At 0 h At 6 days *2 *3 -i T744C *17 C3435T 

Group I (n ¼ 6) 67.8 30.7 40.3 37 27.3 W W W W HMM 

W W W W HMM 

W W W W HMM 

W W W W HMM 

W W W W HZ 

W W W HZ HZ 

Group II (n ¼ 13) 67.15 45.15 42.15 22 24 HZ W W W HZ 

HZ W W W HZ 

HZ W W W HZ 

HZ W W W HMM 

HZ W W W HZ 

HZ W W HZ W 

HZ W W W HMM 

HZ W W W W 

HZ W W W HMM 

HZ W W HZ HZ 

HZ W W W W 

HZ W W W HZ 

HZ W W W HZ 

Group III (n ¼ 2) 71.5 53 51 18.5 20.5 HMM W W HZ HZ 

HMM W W HZ HZ 

Group IV (n ¼ 1) 79 61 47 18 32 HMM W HZ W HZ 

Group V (n ¼ 3) 76.7 62.3 50 14.3 26.7 HZ W HMM HZ HMM 

HZ W HMM HZ HZ 

HZ W HMM W W 

Group VI (n ¼ 1) 64 53 33 11 31 W W HMM W HZ 

Wewild type genotype, HZeheterozygous genotype, HMMehomozygous mutant genotype. 

were on maintenance dose of 75 mg clopidogrel per day, 

indicating that a part of low pharmacodynamic response of 

clopidogrel due to the CYP2C19*2 polymorphism may be 

reversed to some extent by repeated dosing. 

Fontana et al 20 have identified a P2Y 12 receptor haplotype 

H2 to be strongly associated with an increase in ADP-induced 

platelet aggregation. In 2008, Malek et al 32 reported that the 

co-existence of the variant i-744C allele of P2Y 12 and the 

variant 681A allele of CYP2C19*2 is associated with persisting 

platelet activity in patients with acute coronary syndrome 

(ACS) on clopidogrel treatment. Similar to this finding, in the 

present study, there were three patients with homozygous 

mutant genotype (i-C744C) for P2Y 12 receptor in combination 

with heterozygous genotype for CYP2C19*2 (Group V) who 

showed additional 7.7% decreased PAI as compared to patients 

of Group II with wild type genotype (i-T744T) of P2Y 12 

receptor and heterozygous genotype (G681A) of CYP2C19*2. 

Further Malek et al 32 have reported that the carriers of i-744C 

allele of P2Y 12 without variant allele of CYP2C19*2 did not have 

significantly decreased platelet response to ADP suggesting 

that i-T744C polymorphism of P2Y 12 could also independently 

elevate platelet reactivity. In the present study we had only 

one case with homozygous mutant (i-C744C) genotype of 

P2Y 12 and wild type of CYP2C19*2 which was also associated 

with increased response to ADP with PAI of only 11% at 24 h. 

Small study population for analyzing the platelet aggregation 

effect is the major limitation of our study which was 

further affected by variations in genotypes. To see the extent 

of clopidogrel to inhibit the platelet aggregation, it was very 

important that these patients were without any prior antiplatelet 

intake. For this reason, patients with prior antiplatelet 

treatment were excluded and these 26 AMI clopidogrel naïve 

patients were screened from 100 AMI patients in the span of 

two years from January 2009 to March 2011. 

5. Conclusion 

In our study the occurrence of variant alleles of MDR1 (3435T), 

CYP2C19*2 (681A), P2Y 12 (i-744C) as well as wild type allele of 

CYP2C19*17 (C806) associated with decreased clopidogrel 

response were observed. The present study did show a trend 

toward impaired response of clopidogrel to inhibit platelet 

aggregation with variant genotypes of CYP2C19*2 and iT744C 

of P2Y 12 compared to respective wild type genotype at 24 h. 

Similar studies of larger sample size and of longer follow-up 

may strengthen our view for individualized antiplatelet 

treatment based on genotypic analysis for patients with ACS 

and those undergoing PCI who receive loading dose of 300 mg 

of clopidogrel. 

Funding source 

The work is being supported by the grants from Sir H. N. 

Medical Research Society.

166 




Acknowledgment 

Authors would like to acknowledge Sir H. N. Hospital and 

Research Centre, and Rajawadi Municipal Hospital for 

recruitment of the patients and Sir H. N. Medical Research 

Society for the financial support. 

references 

1. Yusuf S, Zhao F, Mehta SR, et al. Effects of Clopidogrel in 

addition to aspirin in patients with acute coronary syndromes 

without ST-segment elevation. N Engl J Med. 

2001;345:494e502. 

2. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of 

clopidogrel to aspirin and fibrinolytic therapy for myocardial 

infarction with ST-segment elevation. N Engl J Med. 

2005;352:1179e1189. 

3. King 3rd SB, Smith Jr SC, Hirshfeld Jr JW, et al. 2007 focused 

update of the ACC/AHA/SCAI 2005 Guideline Update for 

Percutaneous Coronary Intervention: a report of the 

American College of Cardiology/American Heart Association 

Task Force on Practice Guidelines: 2007 Writing Group to 

Review New Evidence and Update the ACC/AHA/SCAI 2005 

Guideline Update for Percutaneous Coronary Intervention, 

Writing on behalf of the 2005 Writing Committee. Circulation. 

2008;117:261e295. 

4. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for 

coronary stenting: response variability, drug resistance, and 

the effect of pretreatment platelet reactivity. Circulation. 

2003;107:2908e2913. 

5. Muller I, Besta F, Schulz C, Massberg S, Schomig A, Gawaz M. 

Prevalence of Clopidogrel non-responders among patients 

with stable angina pectoris scheduled for elective coronary 

stent placement. Thromb Haemost. 2003;89:783e787. 

6. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a 

review of the evidence. J Am Coll Cardiol. 2005;45:1157e1164. 

7. Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter 

in a fast-moving story. Circulation. 2004;109:3064e3067. 

8. Taubert D, von Beckerath N, Grimberg G, et al. Impact of 

P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 

2006;80:486e501. 

9. Fung KL, Gottesman MM. A synonymous polymorphism in a 

common MDR1 (ABCB1) haplotype shapes protein function. 

(BBA)dProteins and Proteomics. 2009;1794:860e871. 

10. Tang K, Wong LP, Lee EJD, Chong SS, Lee CGL. Genomic 

evidence for recent positive selection at the human MDR1 

gene locus. Hum Mol Genet. 2004;13:783e797. 

11. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the 

human cytochrome P450 enzymes involved in the two 

oxidative steps in the bioactivation of clopidogrel to its 

pharmacologically active metabolite. Drug Metab Dispos. 

2010;38:92e99. 

12. De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, 

Nakamura K, Goldstein JA. Identification of a new genetic 

defect responsible for the polymorphism of (S)-mephenytoin 

metabolism in Japanese. Mol Pharmacol. 1994;46:594e598. 

13. De Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, 

Meyer UA, Goldstein JA. The major genetic defect responsible 

for the polymorphism of S-mephenytoin metabolism in 

humans. J Biol Chem. 1994;269:15419e15422. 

14. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 lossof-function 

polymorphism is a major determinant of 

clopidogrel responsiveness in healthy subjects. Blood. 

2006;108:2244e2247. 

15. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms 

of CYP2C19 and CYP2C9 affect the pharmacokinetic and 

pharmacodynamic response to clopidogrel but not prasugrel. 

J Thromb Haemost. 2007;5:2429e2436. 

16. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 

2C19 681G>A polymorphism and high on-Clopidogrel platelet 

reactivity associated with adverse 1-year clinical outcome of 

elective percutaneous coronary intervention with drug 

eluting or bare-metal stents. J Am Coll Cardiol. 

2008;51:1925e1934. 

17. Sim SC, Risinger C, Dahl ML, et al. A common novel CYP2C19 

gene variant causes ultrarapid drug metabolism relevant for 

the drug response to proton pump inhibitors and 

antidepressants. Clin Pharmacol Ther. 2006;79:103e113. 

18. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 

allelic variant, platelet aggregation, bleeding events, and 

stent thrombosis in clopidogrel-treated patients with 

coronary stent placement. Circulation. 2010;121:512e518. 

19. Hollopeter G, Jantzen HM, Vincent D, et al. Identification of 

the platelet ADP receptor targeted by antithrombotic drugs. 

Nature. 2001;409:202e207. 

20. Fontana P, Dupont A, Gandrille S, et al. Adenosine 

diphosphate e induced platelet aggregation is associated 

with P2Y12 gene sequence variations in healthy subjects. 

Circulation. 2003;108:989e995. 

21. Balram C, Sharma A, Sivathasan C, Lee EJ. Frequency of 

C3435T single nucleotide MDR1 genetic polymorphism in an 

Asian population: phenotypicegenotypic correlates. Br J Clin 

Pharmacol. 2003;56:78e83. 

22. Ashavaid T, Raje H, Shalia K, Shah B. Effect of gene 

polymorphisms on the levels of calcineurin inhibitors in 

Indian renal transplant recipients. Indian J Nephrol. 

2010;20:146e151. 

23. Adithan C, Gerard N, Vasu S, Rosemary J, Shashindran CH, 

Krishnamoorthy R. Allele and genotype frequency of CYP2C19 

in a Tamilian population. Br J Clin Pharmacol. 2003;56:331e333. 

24. Panchabhai TS, Noronha SF, Davis S, Shinde VM, 

Kshirsagar NA, Gogtay J. Evaluation of the activity of CYP2C19 

in Gujrati and Marwadi subjects living in Mumbai (Bombay). 

BMC Clin Pharmacol. 2006;24:6e8. 

25. Ellis KJ, Souffer GA, McLeod HL, Lee CR. Clopidogrel 

pharmacogenomics and risk of inadequate platelet 

inhibition: US FDA recommendations. Pharmacogenomics. 

2009;10:1799e1817. 

26. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, 

Jilma B. Effects of pantoprazole and esomeprazole on 

platelet inhibition by clopidogrel. Am Heart J. 

2009;157:148e1e148e5. 

27. Cattaneo M. Aspirin and clopidogrel: efficacy, safety and the 

issue of drug resistance. Arterioscler Thromb Vasc Biol. 

2004;24:1980e1987. 

28. Dörr G, Schmidt G, Gräfe M, Regitz-Zagrosek V, Fleck E. Effects 

of combined therapy with clopidogrel and acetylsalicylic acid 

on platelet glycoprotein expression and aggregation. J 

Cardiovasc Pharmacol. 2002;39:523e532. 

29. Wilkinson GR. Drug metabolism and variability among 

patients in drug response. N Engl J Med. 2005;352:2211e2221. 

30. Miller SA, Dykes DD, Polesky HF. A simple salting out 

procedure for extracting DNA from human nucleated cells. 

Nucleic Acids Res. 1988;16:1215.


31. Cizmarikova M, Wagnerova M, Schonova L, Habalova V, 

Kohut A, Linkova A. MDR1 (C3435T) polymorphism: relation 

to the risk of breast cancer and therapeutic outcome. 

Pharmacogenomic J. 2010;10:62e69. 

32. Malek LA, Kisiel B, Spiewak M, et al. Coexisting 

polymorphisms of P2Y12 and CYP2C19 genes as a risk factor 

for persistent platelet activation with clopidogrel. Circ J. 

2008;72:1165e1169. 

33. Pang YS, Wong LP, Lee TC, Mustafa AM, Mohamed Z, Lang CC. 

Genetic polymorphism of Cytochrome P450 2C19 in healthy 

Malaysian subjects. Br J Clin Pharmacol. 2004;58:332e335. 

34. Baldwin RM, Ohlsson S, Pedersen RS, et al. Increased 

omeprazole metabolism in carriers of the CYP2C19*17 allele; a 

pharmacokinetic study in healthy volunteers. Br J Clin 

Pharmacol. 2008;65:767e774. 

35. Xie H-G, Kim RB, Wood AJJ, Stein CM. Molecular basis of 

ethnic differences in drug disposition and response. Annu Rev 

Pharmacol Toxicol. 2001;41:815e850. 

36. Mizutani T. PM frequencies of major CYPs in Asians and 

Caucasians. Drug Metabol Rev. 2003;35(2e3):99e106. 

37. Giusti B, Gori AM, Marcucci R, et al. Cytochrome P450 2C19 

loss-of-function polymorphism, but not CYP3A4 IVS10 þ 12G/ 

A and P2Y12 T744C polymorphisms, is associated with 

response variability to dual antiplatelet treatment in highrisk 

vascular patients. Pharmacogenet Genomics. 

2007;17:1057e1064.





Association between erectile dysfunction and coronary artery 

disease and it’s severity 

A. Sai Ravi Shanker a, *, B. Phanikrishna b , C. Bhaktha Vatsala Reddy c 

a Cardiologist, Department of Cardiology, Narayana Medical College, Chinta Reddy Palem, Nellore 524003, Andhra Pradesh, India 

b Associate Professor, Narayana Medical College, Chinta Reddy Palem, Nellore 524003, Andhra Pradesh, India 

c Assistant Professor, Narayana Medical College, Chinta Reddy Palem, Nellore 524003, Andhra Pradesh, India 

article info 





Keywords: 

Erectile dysfunction 

Coronary artery disease 

Acute coronary syndrom 

Gensini’s score 

International Index of Erectile 

dysfunction 

abstract 

Background/aims: To investigate the prevalence of erectile dysfunction (ED) in patients with 

coronary artery disease (CAD), its relationship between the severity of ED and the extent of 

coronary vessel involvement and to register the mean time interval between them. 

Methods: 240 patients with CAD divided into three age-matched groups: Group 1 (n ¼ 60), 

ACS with one-vessel disease (1VD); group 2 (n ¼ 60), ACS with 2,3VD; group 3 (n ¼ 60), CSA. 

Control group (C, n ¼ 60) was composed of patients with suspected CAD who were found to 

have entirely normal coronary arteries by angiography. ED as any value


endothelial dysfunction, leading to restrictions in blood 

flow. 5,6 Prevalence of ED as high as 75% has been reported in 

the established CAD patients. 7e12 

Atherosclerosis can play a major role in the development 

of ED both in the general population and in diabetic 

patients. 13e17 In the diabetic population, the prevalence of 

silent CAD is particularly high. 18,19 

Evidence to support ED as a predictor of CAD is: 

A significant proportion of men with ED exhibit early signs 

of CAD. 

Men with pre-existing ED may develop more severe CAD 

than those without ED. 

The interval between the onset of ED symptoms and the 

occurrence of CAD symptoms is estimated at 2e3 years and 

a cardiovascular event at 3e5 years. 

There is a common endothelial pathology underlying both 

ED and CAD. 

Erectile dysfunction is associated with increased all-cause 

mortality primarily through its association with CAD 

mortality. 

Erectile dysfunction is associated with significant changes 

in established cardiovascular risk factors such as fasting 

lipids, fasting glucose, body mass index (BMI), C-reactive 

protein (CRP) and homocysteine. 20e23 Men with ED generally 

exhibit more severe CAD and left ventricular dysfunction than 

those without ED, 24e26 and the severity of ED may also be 

correlated with the severity of CAD. 27 It should be noted, 

however, that penile Doppler testing cannot be reliably used 

to identify at-risk men because of its average sensitivity and 

specificity, low positive predictive value and high negative 

predictive value. 28 In around two-thirds of men, the onset of 

CAD is preceded by ED (Montorsi et al.). A number of studies 

have estimated the interval between the onset of ED symptoms 

and the occurrence of CAD symptoms as 2e3 years and a 

cardiovascular event [myocardial infarction (MI) or stroke] as 

3e5 years, 29,30 although longer time frames have been 

reported. 31 

Using Framingham risk scores, the relative risk of developing 

CAD within 10 years in men with moderate-severe ED 

has been estimated as 4.9% in those aged 30e39 years, 

increasing to 21.1% in those aged 60e69 years. 32 This compares 

with 4.3% and 16.6% in men without ED for the same age 

groups, i.e. an increase in relative risk of 1.14 and 1.27 

respectively. The risk of experiencing a cardiovascular event 

within a 10-year timeframe is increased by 1.3e1.6 times in 

men with ED vs. men without ED. 33,34 

2. Aims and objectives of the study 

To investigate the prevalence of ED in patients with CAD and 

to evaluate the relationship between the severity of ED and 

the extent of coronary vessel involvement and to register the 

first symptom and the mean time interval between them. 

We tested the hypothesis that ED prevalence is related to 

coronary atherosclerotic burden that in turn is related to the 

type of clinical presentationdacute coronary syndrome (ACS) 

vs. chronic coronary syndrome (CCS). As atherosclerosis is a 

systemic disorder, penile circulation might be involved to a 

similarly different extent as coronary circulation in ACS vs. 

CCS patients. If true, ED prevalence should be low in the 

former and high in the latter. 35,36 

3. Methods 

180 patients with CAD divided into three age-matched groups: 

Group 1 (G1, n ¼ 60), ACS with one-vessel disease (1-VD); 

Group 2 (G2, n ¼ 60), ACS with 2, 3-VD; Group 3 (G3, n ¼ 60), 

chronic stable angina, along with Control group (C, n ¼ 60) was 

composed of patients with suspected CAD who were found to 

have entirely normal coronary arteries by angiography. 

International Index of Erectile Function (IIEF) questionnaires 

were used to assess extent of ED. ED as any value 2 months). 

We have excluded: 

1. Patients with previous percutaneous or surgical myocardial 

revascularization procedures. 

2. Patients with diseases that could alter sexual activity, such 

as liver cirrhosis, renal failure, thyroid disease (hypo- and 

hyperthyroidism on replacement treatment), major 

depression on long-term pharmacological treatment, and 

spinal cord injuries, and those with previous pelvic, penile, 

urethral, or prostate trauma or surgery. 

3. Patients with primary erectile dysfunction were excluded. 

All patients underwent complete routine laboratory tests, 

included lipid profile, fasting glucose, and total and freeplasma 

testosterone levels. Diagnostic coronary angiography 

was carried out in all patients by the standard technique. If 

required, percutaneous transluminal coronary angioplasty 

(PTCA) or coronary artery bypass graft surgery was carried out 

during the hospital stay. Risk factors (when not previously 

known) were defined according to the ESC/ACC/AHA guidelines 

as follows 38 hypertension as blood pressure >140/ 

90 mmHg in three consecutive readings, at rest; hypercholesterolemia 

as total cholesterol level >200 mg/dL and/or LDL 

cholesterol level >130 mg/dL, diabetes as fasting glucose level 

>126 mg/dL; obesity as body mass index (BMI) >30 kg/m 2 ; and 

family history of CAD as parents with CAD at age

182 


the indexes obtained for the two legs was used as the measure 

of disease severity. 42 

The Narayana medical college ethics committee approved 

the study protocol and each patient gave written informed 

consent. 

IIEF-EFD questionnaire for ED (questions 1e5 and 15) 

(1) Q: how often were you able to get an erection during sexual 

activity? A: no sexual activity (0), almost never/never (1), a 

few times (much less than half of the time) (2), sometimes 

(about half of the time) (3), most times (much more than 

half the time) (4), almost always/always (5). 

(2) Q: when you had an erection with sexual stimulation, how 

often were your erections hard enough for penetration? A: 

no sexual activity (0), almost never/never (1), a few times 

(much less than half of the time) (2), sometimes (about half 

of the time) (3), most times (much more than half the time) 

(4), almost always/always (5). 

(3) Q: when you attempted sexual intercourse, how often 

were you able to penetrate your partner? A: no sexual activity 

(0), almost never/never (1), a few times (2), sometimes 

(about half of the time) (3), most times (much more 

than half the time) (4), almost always/always (5). 

(4) Q: during sexual intercourse, how difficult was it to 

maintain your erection after you had penetrate your 

partner? A: no sexual activity (0), almost never/never (1), a 

few times (2), sometimes (about half of the time) (3), most 

times (much more than half the time) (4), almost always/ 

always (5). 

(5) Q: during sexual intercourse, how difficult was it to 

maintain your erection to completion of intercourse? A: 

did not attempt intercourse (0), extremely difficult (1), very 

difficult (2), difficult (3), slightly difficult (4), not difficult (5). 

(6) Q: how do you rate your confidence that you could get and 

keep an erection? A: very low (1), low (2), moderate (3), high 

(4), very high (5) 

Fig. 1 e Schematic drawing of the GENSINI score (left). The 

method assigns a different severity score depending on the 

degree of stenosis, its location (proximal, middle or distal 

tract) along the target vessel and the type of coronary 

vessel involved (left anterior descending, left CX or RCA). 

An example of Gensini score calculation is shown on the 

right part of the figure. MLCA, main left coronary artery; 

LAD, left anterior descending; CFx, left circumflex; RCA, 

right coronary artery. 

3.1. Quantitative coronary angiography 

3.3. Erectile function evaluation 

Coronary angiography analysis was performed by the 

cardiologist who is unaware of the patient’s ED. IIEF-EFD 

questionnaire, using ARTREK Quantum IC (Image Comm. 

System Inc, Sunnyvale, CA, USA). 39 The outer diameter of 

the contrast-filled catheter was used for calibration. The lesions 

were analyzed in multiple projections, and reference 

vessel diameter, minimal lumen diameter, and percent 

diameter stenosis were measured from the ‘worst’ angiographic 

view. Significant angiographic narrowing was 

defined as >50% diameter stenosis involving either one 

major epicardial vessel at any site or any collaterals with 

>0.3 mm diameter. Patients were classified as having 1-VD, 

2-VD, or 3-VD, if they had a single lesion in 1, 2, or 3 coronary 

vessels. 


3.2. Gensini’s score 

The method assigns a different severity score depending on 

the degree of stenosis, its location (proximal, middle or distal 

tract) along the target vessel and the type of coronary vessel 

Erectile function was evaluated by IIEF-EFD, a validated 

15-item self-administered questionnaire. 41 Erectile function is 

specifically addressed by six questions that form the so called 

‘erectile function domain’ of the questionnaire. Each question 

is scored 0 to 5. ED is defined as any value


Table 1 e Baseline characteristics with risk factors. 

Control (n ¼ 60) Gr-I (n ¼ 60) Gr-II (n ¼ 60) Gr-III (n ¼ 60) p value 

Age (years) 48.5 9 52 8.4 53 8.3 55.4 5.7 0.21 

BMI (kg/m 2 ) 26.7 1.2 26.9 1.3 26.4 1.3 26.9 2.1 0.86 

Symptom onset (months) 28 12 22 13 18 12 16 9 0.008 

Risk factors 

Hypertension 57% 56% 54% 55% 0.13 

Diabetes 15% 16% 32% 38% 0.06 

Hypercholesterolemia 61% 78% 76% 84% 0.06 

Smoking 28% 45% 52% 58% 0.08 

Obesity 12% 15% 21% 18% 0.07 

F/H of CAD 6% 28% 38% 29% 0.005 

>3 Risk factor 26% 42% 48% 52% 0.52 

mean þ SD, unless otherwise stated. A two tailed P-value 

3 risk factors. Overall ED 

prevalence was 47%. When separately considered, ED prevalence 

was 24%, 56%, and 64% in G1, G2, and G3, respectively 

(p < 0.0001 for G1 vs. G2 and G1 vs. G3; p < 0.45 for G2 vs. G3). 

ED prevalence in Controls was 22%. ED prevalence was lower 

in G1 vs. G3 (24 vs. 64%, p

184 


70 

70 

ED prevalence (%) 

60 

50 

40 

30 

20 

10 

0 

C G1 ACS G2 ACS G3 CCS 

60 

65 

66 

62.5 

50 

52 58 

40 

30 

20 22 

10 

0 

1VD 2VD 3VD 1VD 2VD 3VD 

Fig. 2 e Prevalence of ED in the four groups of patients. ACS CSA 

Fig. 3 e Prevalence of ED in the ACS and CSA groups. 

5. Discussion 

ED prevalence (%) 

A significant proportion of men with ED exhibit early signs of 

CAD, and this group may develop more severe CAD than men 

without ED. Prevalence of ED differs across subsets of patients 

with CAD and is related to extent of CAD. In group I, ED 

prevalence was 24%. This value was similar to that obtained in 

age-matched controls with normal coronary arteries. 15 Thus, 

most patients with ACS and 1-VD do not complain of ED as 

result of an overall low coronary and penile atherosclerotic 

burden. 

The finding that patients with CCS and 1-VD had higher ED 

rate (65 vs. 22%, p < 0.0001) when compared with patients with 

ACS and 1-VD, confirms the role of different pathophysiological 

background and related atherosclerotic burden at work in 

CCS (Fig. 3). Infact, multivariate analysis showed that patients 

with CCS presentation had a 2.3-fold increase in relative risk 

of ED when compared with those with ACS, independently of 

other conventional risk factors. The lower ankle-brachial 

index (0.98 þ 0.10 vs.0.80 0.28, p < 0.0001), an accurate and 

reliable marker of generalized atherosclerosis, supported a 

more advanced vascular involvement in CCS. The time interval 

between the onset of ED symptoms and the occurrence 

of CAD symptoms and cardiovascular events is estimated at 

2e3 years and 3e5 years, respectively; this interval allows for 

risk factor reduction. 

According to this finding, we evaluated whether ED may 

predict coronary artery involvement in ACS. Interestingly 

enough, this suggests that the IIEF questionnaire may be a 

useful ‘bedside’ test to predict the extension of CAD in ACS: 

according to positive predictive value seven out of 10 patients 

with ED turned out to have angiographic multivessel disease. 

ED-coronary atherosclerosis’ relationship by assessing ED 

rate according to CAD extension is being evaluated in this 

Table 3 e ED prevalence. 

ACS 

CCS 

1 VD 2 VD 3VD 1VD 2VD 3VD 

ED prevalence (%) 22 52 58 65 62.5 66 

study. Interesting enough, having 2- or 3-VD did not significantly 

increased ED prevalence as compared to 1-VD in both 

ACS and CCS patients with similar age (Fig. 2) suggesting ED as 

a sort of ‘on-off’ phenomenon that we hypothesized takes 

place when 0.50% angiographic obstruction of at least one 

major coronary vessel occurs. If true, having 2- or 3-VD would 

not add to ED prevalence. Almost 30% of patients with proved 

CAD did not complain of ED. Age may be an explanation. We 

found age to be independent predictor of ED in the whole 

study patient population, with a 10% per patient increase in 

the yearly relative risk of ED. ED significantly increased over 

time being 30% under 50 years and close to 100% over 60 years 

of age. At any age ED rate was similar regardless extent of 

CAD, confirming the ‘on-off’ phenomenon. 

We found that severe ED (a score


ED prevalence is related to extent of CAD. (3) ED symptoms 

come prior to CAD symptoms in virtually all patients with a 

mean time-interval of 3 years. (4) All men with ED should 

undergo a thorough medical assessment, including testosterone, 

fasting lipids, fasting glucose and blood pressure 

measurement. (5) Following assessment, patients should be 

stratified according to the risk of future cardiovascular events. 

(6) Those at high risk of cardiovascular disease should be 

evaluated by stress testing with selective use of computed 

tomography (CT) or coronary angiography. (7) Improvement in 

cardiovascular risk factors such as weight loss and increased 

physical activity has been reported to improve erectile function. 

(8) In men with ED, hypertension, diabetes and hyperlipidemia 

should be treated aggressively, bearing in mind the 

potential side effects. (9) Management of ED is secondary to 

stabilizing cardiovascular function, and controlling cardiovascular 

symptoms and exercise tolerance should be established 

prior to initiation of ED therapy. (10) Clinical evidence 

supports the use of phosphodiesterase 5 (PDE5) inhibitors as 

first-line therapy in men with CAD and comorbid ED and those 

with diabetes and ED. (11) Review of cardiovascular status and 

response to ED therapy should be performed at regular 

intervals. 



references 

1. Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802e1813. 

2. Aytac IA, McKinlay JB, Krane RJ. The likely worldwide increase 

in erectile dysfunction between 1995 and 2025 and some 

possible policy consequences. Br J Urol Int. 1999;84:50e56. 

3. Feldman HA, Goldstein I, Hatzichristou D, Krane RJ, 

McKinlay JB. Impotence and its medical and psychological 

correlates: results of the Massachusset Male Aging Study. 

J Urol. 1994;151:54e61. 

4. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. 

Development and evaluation of an abridged, 5-item version of 

the International Index of Erectile Function (IIEF-5) as a 

diagnostic tool for erectile dysfunction. Int J Impot Res. 

1999;11:319e326. 

5. Chiurlia E, D’Amico R, Ratti C, Granata AR, Romagnoli R, 

odena MG. Subclinical coronary artery atherosclerosis in 

patients with erectile dysfunction. J Am Coll Cardiol. 

2005;46:1503e1506. 

6. Vlachopoulos C, Rokkas K, Ioakeimidis N, Stefanadis C. 

Inflammation, metabolic syndrome, erectile dysfunction, and 

coronary artery disease: common links. Eur Urol. 

2007;52:1590e1600. 

7. Solomon H, Man JW, Wierzbicki AS, Jackson G. Relation of 

erectile dysfunction to angiographic artery disease. Am J 

Cardiol. 2002;91:230e231. 

8. Montorsi F, Briganti A, Salonia A, et al. Erectile dysfunction 

prevalence, time of onset and association with risk factors in 

300 consecutive patients with acute chest pain and 

angiographically documented coronary artery disease. Eur 

Urol. 2003;44:360e365. 

9. Kloner RA, Mullin S, Shook T, et al. Erectile dysfunction in the 

cardiac patient: how common and should we treat? J Urol. 

2003;170:S46eS50. 

10. Wabrek AJ, Burchell C. Male sexual dysfunction associated 

with coronary artery disease. Arch Sex Behav. 1980;9:69e75. 

11. Diokno AC, Brown MB, Herzog R. Sexual function in the 

elderly. Arch Intern Med. 1990;150:197e200. 

12. Dhabuwala CB, Kumar A, Pierce JM. Myocardial infarction and 

its influence on male sexual function. Arch Sex Behav. 

1986;15:499e504. 

13. Welt FGP, Simon DI. Atherosclerosis and claque rupture. 

Catheter Cardiovasc Interv. 2001;53:56e63. 

14. Fedele D, Bortolotti A, Coscelli C, et al, on behalf of Gruppo 

Italiano Studio Deficit Erettile nei Diabetici. Erectile 

dysfunction in Type 1 and Type 2 diabetics in Italy. Int J 

Epidemiol. 2000;29:524e531. 

15. Feldman JA, Goldstein I, Hatzichristou DG, et al. Impotence 

and its medical and physiological correlates: results of the 

Massachusetts Male Aging Study. J Urol. 1994;151:54e61. 

16. Adams PF, Marano MA. Current estimates from the National 

Health Interview Survey. Vital Health Stat. 1995;10:83e84. 

17. Greenstein A, Chen J, Miller H, et al. Does severity of ischemic 

coronary disease correlate with erectile function? Int J Impot 

Res. 1997;9:123e126. 

18. Koistinen MJ. Prevalence of asymptomatic myocardial 

ischaemia in diabetic subjects. BMJ. 1990;301:92e95. 

19. Ashley EA, Raxval V, Finlay M, et al. Diagnosing coronary 

artery disease in diabetic patients. Diabetes Metab Res Rev. 

2002;18:201e208. 

20. Billups KL, Kaiser DR, Kelly AS, et al. Relation of C-reactive 

protein and other cardiovascular risk factors to penile 

vascular disease in men with erectile dysfunction. Int J Impot 

Res. 2003;15:231e236. 

21. Roumeguere T, Wespes E, Carpentier Y, Hoffmann P, 

Schulman CC. Erectile dysfunction is associated with a high 

prevalence of hyperlipidemia and coronary heart disease risk. 

Eur Urol. 2003;44:355e359. 

22. El-Sakka AI, Morsy AM, Fagih BI, Nassar AH. Coronary artery 

risk factors in patients with erectile dysfunction. J Urol. 

2004;172:251e254. 

23. Vlachopoulos C, Aznaouridis K, Ioakeimidis N, et al. 

Unfavourable endothelial and inflammatory state in erectile 

dysfunction patients with or without coronary artery disease. 

Eur Heart J. 2006;27:2640e2648. 1503e6. 

24. Min JK, Williams KA, Okwuosa TM, Bell GW, Panutich MS, 

Ward RP. Prediction of coronary heart disease by erectile 

dysfunction in men referred for nuclear stress testing. Arch 

Intern Med. 2006;166:201e206. 

25. Montorsi P, Ravagnani PM, Galli S, et al. Association between 

erectile dysfunction and coronary artery disease. Role of 

coronary clinical presentation and extent of coronary 

vessels involvement: the COBRA trial. Eur Heart J. 2006;27: 

2632e2639. 

26. Ward RP, Weiner J, Taillon LA, Ghani SN, Min JK, Williams KA. 

Comparison of findings on stress myocardial perfusion 

imaging in men with versus without erectile dysfunction and 

without prior heart disease. Am J Cardiol. 2008;101:502e505. 

27. Salem S, Abdi S, Mehrsai A, et al. Erectile dysfunction severity 

as a risk predictor for coronary artery disease. J Sex Med. 

2009;6:3425e3432. 

28. Montorsi P, Ravagnani PM, Galli S, et al. Association between 

erectile dysfunction and coronary artery disease: matching 

the right target with the right test in the right patient. Eur 

Urol. 2006;50:721e731. 

29. Baumhakel M, Bohm M. Erectile dysfunction correlates with 

left ventricular function and precedes cardiovascular events 

in cardiovascular high-risk patients. Int J Clin Pract. 2007;61: 

361e366.

186 


30. Hodges LD, Kirby M, Solanki J, O’Donnell J, Brodie DA. The 

temporal relationship between erectile dysfunction and 

cardiovascular disease. Int J Clin Pract. 2007;61:2019e2025. 

31. Chew KK, Finn J, Stuckey B, et al. Erectile dysfunction as a 

predictor for subsequent atherosclerotic cardiovascular 

events: findings from a linked-data study. J Sex Med. 

2010;7:192e202. 

32. Ponholzer A, Temml C, Obermayr R, Wehrberger C, 

Madersbacher S. Is erectile dysfunction an indicator for 

increased risk of coronary heart disease and stroke? Eur Urol. 

2005;48:512e518. 

33. Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, 

Moinpour CM, Coltman CA. Erectile dysfunction and 

subsequent cardiovascular disease. JAMA. 

2005;294:2996e3002. 

34. Schounten BW, Bohnen AM, Bosch JL, et al. Erectile 

dysfunction prospectively associated with cardiovascular 

disease in the Dutch general population: results from the 

Krimpen Study. Int J Impot Res. 2008;20:92e99. 

35. Montorsi P, Montorsi F, Schulman C. Is erectile dysfunction 

the tip of the iceberg of a systemic vascular disorder? Eur Urol. 

2003;44:352e354. 

36. Montorsi P, Ravagnani P, Galli S, et al. Association between 

erectile dysfunction and coronary artery disease: a case 

report study. J Sex Med. 2005;2:575e582. 

37. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European 

guidelines on cardiovascular disease prevention in clinical 

practice. Eur Heart J. 2003;24:1601e1610. 

38. Braunwald E. Unstable angina. Circulation. 1989;80:410e414. 

39. Mancini GBJ, Simon SB, McGillem MJ, LeFree MT, Friedman HZ, 

Vogel RA. Automated quantitative coronary arteriography: 

morphologic and physiologic validation in vivo of a rapid 

digital angiographic method. Circulation. 1987;75:452e460. 

40. Gensini G. A more meaningful scoring system for 

determining the severity of coronary artery disease. Am J 

Cardiol. 1983;51:606. 

41. Jackson G, Betteridge J, Dean J, et al. A systematic approach to 

erectile dysfunction in the cardiovascular patient: a 

consensus statement e update 2002. Int J Clin Pract. 

2002;56:663e671. 

42. Bird CE, Criqui MH, Fronek A, Denenberg JO, Klauber MR, 

Langer RD. Quantitative and qualitative progression of 

peripheral arterial disease by non-invasive testing. Vasc Med. 

1999;4:15e21.


(2.15 0.27 mm vs. 2.25 0.24 mm; p ¼ 0.003). The majority 

(89%) of lesions involved vessels with a diameter

222 


patients without baseline “SCD-HeFT criteria” (left ventricular 

ejection fraction >0.35 or NYHA class I), 125 were 

evaluated after 5.5 2 months. Of these 227 patients, 13 

(10%) developed “SCD-HeFT criteria” (group B1), 111 (89%) 

remained without “SCD-HeFT criteria” (group B2), and 1 

(1%) had worsened to NYHA class IV. The 10-year mortality/heart 

transplantation and sudden death/sustained 

ventricular arrhythmia rate was 57% and 37% in group A1, 

23% and 20% in group A2 (p < 0.001 for mortality/heart 

transplantation and p e 0.014 for sudden death/sustained 

ventricular arrhythmia vs. group A1), 45% and 41% in group 

B1 ( p e NS vs. group A1), 16% and 14% in group B2 ( p e NS 

vs. group A2), respectively. 

Conclusion: Two thirds of patients with idiopathic 

dilated cardiomyopathy and “SCD-HeFT criteria” at presentation 

did not maintain implantable cardioverterdefibrillator 

indications 3e9 months later with optimal 

medical therapy. Their long-term outcome was excellent, 

similar to that observed for patients who had never met the 

“SCD-HeFT criteria.” 

1. Perspective 

Since the publication of the SCD-HeFT and the DEFINITE 

trials, treatment with ICD for the primary prevention of 

sudden cardiac death (SCD) has been extended to patients 

with idiopathic dilated cardiomyopathy (IDC), who have a 

LVEF of 0.35 and who are classified as NYHA II or III (“SCD- 

HeFT criteria,” class I B indication). The appropriate timing 

for ICD implantation, however, is still uncertain. Current 

guidelines suggest that an ICD should be considered in 

addition to medical therapy, but many patients are treated 

with an ICD without evidence-based indications, mainly 

because of newly diagnosed heart failure and before treatment 

optimization. This study evaluated the proportion of 

patients with and without potential indications for ICD 

implantation at presentation and the long-term prognosis of 

patients with initial ICD indications but who improved after 

optimization of medical treatment. It also compared the 

long-term outcome of “improved” patients to those maintaining 

“SCD-HeFT criteria” and those who never met “SCD- 

HeFT criteria.” 

This trial included only patients who were not on beta 

blockers. After initial assessment, optimization of medical 

treatment was achieved with gradually up-titrating doses of 

beta blockers and ACEI/ARB at the highest tolerated dose over 

a period of 3e9 months. 

The main results of the present study are: 1) 50% patients 

had SCD-HeFT criteria at first assessment and would have 

otherwise received an ICD. 2) 2/3rd of patients with SCD-HeFT 

criteria at baseline “improved” and no longer maintained SCD- 

HeFT criteria 5.5 months after starting beta blocker and ACEI 

treatment. 3) The long-term SCD were similar in “improved” 

patients and in those without SCD-HeFT criteria, suggesting 

ICD implantation should not be done in most patients with 

low LVEF and HF symptoms before optimization of medical 

treatment. 4) SCD (4 patients e 2%) was similar in patients 

both with and without SCD-HeFT criteria before second 

evaluation at 3e9 months, confirming the difficulty of stratifying 

risk of SCD at first evaluation. 

This study emphasizes how important is the optimization 

of medical therapy in patients initially presenting with ICD 

indications and ICD implantation can be avoided in the 

majority of such patients. Even in USA, nearly 22.5% of 

patients with an ICD did not meet the evidence-based criteria 

for implantation, mainly because of newly diagnosed 

HF (62%). Such unnecessary ICD implantations should be 

avoided because of economic issues (especially in a developing 

country like India), the risk of complications associated 

with implantation and inappropriate shocks (in w25% 

of patients). 

What then is the waiting period for ICD implantation after 

onset of HF symptoms in patients with LVEF 35%? Well, we 

have no clear-cut answer. Data from DEFINITE trial suggest 

early ICD implantation (




Letter to the Editor 

Association between blood glucose level and in-hospital 

mortality in patients with acute myocardial infarction 

Dear Editor, Diabetes mellitus increases cardiovascularrelated 

morbidity and mortality and high blood glucose even 

before it reaches the threshold to diagnose diabetes is associated 

with higher cardiovascular risk. 

Several studies previously reported that adverse cardiac 

events increased in patients with acute myocardial infarction. 

However, the association between admission blood glucose 

level and cardiac-related mortality and morbidity was not 

studied in Iranian population. 

Therefore, we conducted a study to assess the association 

between on admission blood glucose level and in-hospital 

cardiac mortality and prognosis in these patients. 

The study designed prospectively and performed on 

patients presenting to the emergency department of our 

center with acute ST elevation myocardial infarction 

(STEMI) between April, 2008 and April, 2010. STEMI was 

diagnosed based on the acute rise and gradual fall of cardiac 

enzymes with ischemic symptoms and ECG changes (ST 

segment elevation or new left bundle branch block). Exclusion 

criteria were severe co-morbidities, history of valvular 

heart disease, and low ejection fraction before infarction 

(EF


Hooman Bakhshandeh, Tahereh Zandi, Majid Maleki, 

Anoushiravan Vakili-Zarch 

Rajaei Heart Center, Tehran University of Medical Sciences, Iran 

*Corresponding author. Assistant Professor of Cardiology, 

Valiasr Ave., Niyayesh Exp., Shaheed Rajaei Cardiovascular 

and Medical Research Center, Tehran, Iran. 

Tel.: þ98 (21) 23922176; fax: þ98 (21) 22055594. 

E-mail address: negar70049@gmail.com (N. Salehi) 


0019-4832/$ e see front matter 

Copyright ª 2013, Cardiological Society of India. All rights 

reserved. 






Association between blood glucose level and in-hospital 

mortality in patients with acute myocardial infarction 

Dear Editor, Diabetes mellitus increases cardiovascularrelated 

morbidity and mortality and high blood glucose even 

before it reaches the threshold to diagnose diabetes is associated 

with higher cardiovascular risk. 

Several studies previously reported that adverse cardiac 

events increased in patients with acute myocardial infarction. 

However, the association between admission blood glucose 

level and cardiac-related mortality and morbidity was not 

studied in Iranian population. 

Therefore, we conducted a study to assess the association 

between on admission blood glucose level and in-hospital 

cardiac mortality and prognosis in these patients. 

The study designed prospectively and performed on 

patients presenting to the emergency department of our 

center with acute ST elevation myocardial infarction 

(STEMI) between April, 2008 and April, 2010. STEMI was 

diagnosed based on the acute rise and gradual fall of cardiac 

enzymes with ischemic symptoms and ECG changes (ST 

segment elevation or new left bundle branch block). Exclusion 

criteria were severe co-morbidities, history of valvular 

heart disease, and low ejection fraction before infarction 

(EF


Hooman Bakhshandeh, Tahereh Zandi, Majid Maleki, 

Anoushiravan Vakili-Zarch 

Rajaei Heart Center, Tehran University of Medical Sciences, Iran 

*Corresponding author. Assistant Professor of Cardiology, 

Valiasr Ave., Niyayesh Exp., Shaheed Rajaei Cardiovascular 

and Medical Research Center, Tehran, Iran. 

Tel.: þ98 (21) 23922176; fax: þ98 (21) 22055594. 

E-mail address: negar70049@gmail.com (N. Salehi) 




reserved. 





Journal Reviews 

Gregg W. Stone, Akiko Maehara, Bernhard Witzenbichler, 

Jacek Godlewski, Helen Parise, Jan-Henk E. Dambrink, 

Andrzej Ochala, Trevor W. Carlton, Ecaterina Cristea, 

Steven D. Wolff, Sorin J. Brener, Saqib Chowdhary, 

Magdi El-Omar, Thomas Neunteufl, D. Christopher Metzger, 

Theodore Karwoski, Jose M. Dizon, Roxana Mehran, C. 

Michael Gibson, for the INFUSE-AMI Investigators, Intracoronary 

abciximab and aspiration thrombectomy in patients 

with large anterior myocardial infarction: the INFUSE-AMI 

randomized trial. JAMA 307 (17) (2012) 1817e1826 

1. Context 

Thrombus embolization during percutaneous coronary intervention 

(PCI) in ST-segment elevation myocardial infarction 

(STEMI) is common and results in suboptimal myocardial 

perfusion and increased infarct size. Two strategies proposed 

to reduce distal embolization and improve outcomes after 

primary PCI are bolus intracoronary abciximab and manual 

aspiration thrombectomy. 

2. Objective 

To determine whether bolus intracoronary abciximab, manual 

aspiration thrombectomy, or both reduce infarct size in 

high-risk patients with STEMI. 

3. Design, setting, and patients 

Between November 28, 2009, and December 2, 2011, 452 

patients presenting at 37 sites in 6 countries within 4 h of 

STEMI due to proximal or mid left anterior descending artery 

occlusion undergoing primary PCI with bivalirudin anticoagulation 

were randomized in an open-label, 22 factorial 

design to bolus intracoronary abciximab delivered locally at 

the infarct lesion site vs no abciximab and to manual aspiration 

thrombectomy vs no thrombectomy. 

4. Interventions 

A 0.25 mg/kg bolus of abciximab was administered at the site 

of the infarct lesion via a local drug delivery catheter. Manual 

aspiration thrombectomy was performed with a 6 F aspiration 

catheter. 

5. Main outcome measures 

Primary end point: infarct size (percentage of total left ventricular 

mass) at 30 days assessed by cardiac magnetic 

resonance imaging (cMRI) in the abciximab vs no abciximab 

groups (pooled across the aspiration randomization); major 

secondary end point: 30-day infarct size in the aspiration vs 

no aspiration groups (pooled across the abciximab 

randomization). 

6. Results 

Evaluable cMRI results at 30 days were present in 181 and 172 

patients randomized to intracoronary abciximab vs no 

abciximab, respectively, and in 174 and 179 patients 

randomized to manual aspiration vs. no aspiration, respectively. 

Patients randomized to intracoronary abciximab 

compared with no abciximab had a significant reduction in 

30-day infarct size (median, 15.1%; interquartile range [IQR], 

6.8%e22.7%; n ¼ 181, vs. 17.9% [IQR, 10.3%e25.4%]; n ¼ 172; 

p ¼ 0.03). Patients randomized to intracoronary abciximab 

also had a significant reduction in absolute infarct mass 

(median, 18.7 g [IQR, 7.4e31.3 g]; n ¼ 184, vs. 24.0 g [IQR, 

12.1e34.2 g]; n ¼ 175; p ¼ 0.03) but not abnormal wall motion 

score (median, 7.0 [IQR, 2.0e10.0]; n ¼ 188, vs. 8.0 [IQR, 

3.0e10.0]; n ¼ 184; p ¼ 0.08). Patients randomized to aspiration 

thrombectomy vs no aspiration had no significant difference 

in infarct size at 30 days (median, 17.0% [IQR, 9.0%e22.8%]; 

n ¼ 174, vs. 17.3% [IQR, 7.1%e25.5%]; n ¼ 179; p ¼ 0.51), absolute 

infarct mass (median, 20.3 g [IQR, 9.7e31.7 g]; n ¼ 178, vs. 21.0 g 

[IQR, 9.1e34.1 g]; n ¼ 181; p ¼ 0.36), or abnormal wall motion 

score (median, 7.5 [IQR, 2.0e10.0]; n ¼ 186, vs. 7.5 [IQR, 

2.0e10.0]; n ¼ 186; p ¼ 0.89). 

7. Conclusion 

In patients with large anterior STEMI presenting early after 

symptom onset and undergoing primary PCI with bivalirudin 

anticoagulation, infarct size at 30 days was significantly 

reduced by bolus intracoronary abciximab delivered to 

the infarct lesion site but not by manual aspiration 

thrombectomy. 


In this multicenter, prospective, randomized trial in patients 

with large anterior STEMI presenting early after infarct onset 

and undergoing primary PCI with bivalirudin anticoagulation, 

the principal findings were: 1) bolus intracoronary abciximab 

delivered to the site of the lesion via a clearway catheter significantly 

but modestly reduced the infarct size at 30 days 2) 

thrombus aspiration with export catheter had no effect on 

infarct size and 3) indices of myocardial reperfusion, ST

220 


resolution (STR) and 30-day MACE (w7% in all groups)/stent 

thrombosis/bleeding were not significantly different between 

the randomized groups. 

Two of the strongest baseline determinants of infarct size 

are: 1) anterior MI location and 2) abnormal TIMI flow. This 

trial was limited to patients with proximal or mid LAD 

occlusion and TIMI 0e2 flow. Moreover, it only enrolled 

patients who could be treated early, in whom time window for 

effective myocardial salvage had not closed. The median time 

from symptom onset to hospital arrival was only 99 min and 

the median D-to-B time was 45 min. Thus the study population 

represents a highly selected cohort of patients with 

large anterior MI, in whom infarct size reduction should be 

feasible given early presentation and rapid treatment. Infarct 

size was assessed by cMRI, which strongly correlates with 

subsequent mortality. Unlike prior studies, which measured 

infarct size at 2e7 days (a period during which substantial 

myocardial edema is present, thereby interfering with 

assessment of viable myocardium) in this study cMRI was 

done at 30 days when much of myocardial edema had 

resolved. 

These results need to be placed in the context of previous 

studies. A meta-analysis of 6 RCT’s (1246 patients) reported 

enhanced survival with bolus intracoronary abciximab. 

However, the recent AIDA-STEMI trial (2065 patients) found 

nearly identical rates of MACE with bolus intracoronary and 

intravenous abciximab. However, this trial differs from these 

earlier studies in many ways: 1) unlike prior studies which 

included routine post-PCI intravenous abciximab infusion in 

both the groups, in this trial only bolus intracoronary abciximab 

was given in the randomized groups. 2) In all prior trials 

(including AIDA-STEMI), intracoronary abciximab was infused 

proximally through the guide catheter thereby limiting its 

penetration into occlusive thrombus and allowing spillage of 

the drug to LCx or backflow into the aorta. In contrast, the 

local drug delivery catheter (clearway catheter) used in this 

study achieves high intra-clot concentration of abciximab at 

the site of LAD occlusion and prolongs drug residence time, 

which may enhance platelet disaggregation and thrombus 

resolution. In the present study, an abciximab bolus delivered 

directly to the infarct lesion site (without a 12-hour infusion) 

reduced infarct size at 30 days in patients with anterior STEMI 

reperfused early. 

Regarding aspiration thrombectomy, in TAPAS, 1071 

patients with anterior and non-anterior STEMI who presented 

within 12 h of symptoms at a single-center were randomized 

to manual aspiration vs. no aspiration before primary PCI; 

aspiration resulted in modest improvements in MBG and STR 

but a marked reduction in 1-year mortality. Other trials have 

reported conflicting results, and in contrast to single-center 

studies, multicenter aspiration trials have been largely negative. 

Moreover, in TAPAS, aspiration did not reduce infarct 

size as measured by cardiac biomarkers, calling into question 

the mechanism underlying the survival benefit. The present 

multicenter trial, in which only patients presenting early with 

anterior MI and coronary anatomy optimal for aspiration were 

enrolled, and in which cMRI was used to assess infarct size at 

30 days was specifically designed to overcome many of the 

limitations from these earlier studies. The fact that manual 

thrombus aspiration did not reduce infarct size in this study 

makes a substantial clinical benefit unlikely, questioning its 

routine use in STEMI. 

9. Our opinion 

Regarding use of GPIIb/IIIa inhibitors: a) I/V bolus and infusion 

is to be discouraged because it achieves very little intra-clot 

concentration and also increases the risk of systemic bleeding. 

b) Only bolus intracoronary drug should be used, that too 

not into the guide catheter, but via a clearway catheter (we can 

use a simple PTCA balloon by making multiple holes on its 

surface, in case clearway catheter is not available). 

Regarding manual aspiration via Export catheter: a) the 

symptom onset to hospital arrival and the D-to-B time were 

substantially shorter in this study which is next to impossible 

in our context. b) As time passes by after STEMI thrombus 

tends to get organized and hence thrombus aspiration might 

have some role to play in late presenters of STEMI. However, 

the last word in this matter is yet to be written. 

Suraj Khanal* 

Assistant Professor of Cardiology, Department of Cardiology, 

3rd Floor, Block-C, Advanced Cardiac Center, PGIMER, 

Chandigarh 160012, India 

Ajay Bahl 

Associate Professor of Cardiology, PGIMER, Chandigarh, India 


E-mail address: khanal.s@rediffmail.com 

Azeem Latib, Antonio Colombo, Fausto Castriota, 

Antonio Micari, Alberto Cremonesi, Francesco De Felice, 

Alfredo Marchese, Maurizio Tespili, Patrizia Presbitero, 

Gregory A. Sgueglia, Francesca Buffoli, Corrado Tamburino, 

Ferdinando Varbella, Alberto Menozzi, A randomized multicentre 

study comparing a paclitaxel drug-eluting balloon with 

a paclitaxel-eluting stent in small coronary vessels: The 

BELLO (Balloon Elution and Late Loss Optimization) study. J 

Am Coll Cardiol. 60 (2012) 2473e2480 

Objectives: The aim of this study was to evaluate the efficacy 

of drug-eluting balloons (DEB) compared with paclitaxel 

eluting stents (PES) for the reduction of restenosis in small 

vessels. 

Background: DEB have been shown to be effective in the 

treatment of coronary in-stent restenosis, but data are limited 

regarding their efficacy in de-novo disease. 

Methods: BELLO (Balloon Elution and Late Loss Optimization) 

is a prospective, multicentre trial that randomized 182 patients 

with lesions located in small vessels (reference diameter 




references 

1. Greenspan M, Iskandrian AS, Segal BL, Kimbiris D, Bemis CE. 

Complete occlusion of the left main coronary artery. Am Heart 

J. 1979;98:83e86. 

2. Zimmern SH, Rogers WJ, Bream PR, et al. Total occlusion of the 

left main coronary artery: the coronary artery surgery study 

(CASS) experience. Am J Cardiol. 1982;49:2003e2010. 

3. Takagi H, Kawai N, Umemoto T. Stenting versus coronary 

artery bypass grafting for unprotected left main coronary 

artery disease: a meta-analysis of comparative studies. J Thorac 

Cardiovasc Surg. 2009;137:54e57. 

4. Morice MC, Serruys PW, Kappetein AP, et al. Outcomes in patients 

with de novo left main disease treated with either percutaneous 

coronary intervention using paclitaxel-eluting stents or coronary 

artery bypass graft treatment in the Synergy between 

Percutaneous Coronary Intervention with TAXUS and Cardiac 

Surgery (SYNTAX) trial. Circulation. 2010;121:2645e2653. 

5. Koster NK, White M. Chronic effort-induced angina as 

presentation of a totally occluded left main coronary artery: a 

case report and review. Angiology. 2009;60:382e384. 

6. Secco GG, Marino PN, Venegoni L, De Luca G. Percutaneous 

revascularization of chronic total occlusion of the left main 

coronary artery. Rev Esp Cardiol. 2011;64:431e433. 

Book Review 

Pediatric Cardiac Intensive Care. Pre and Postoperative 

Guidelines, Manoj Luthra. Elsevier A Division of Reed Elsevier 

India Pvt Ltd, 3, Tolstoy Marg, New Delhi, India, (2012). 

Pages: 314, Price: INR 475/- 

Pediatric Cardiac Intensive Care has seen a tremendous 

progress over the last few decades in our country. The centers 

providing this specialized care have increased steadily with 

newer centers being added every year across non-metro cities 

too. This has created a requirement of good pediatric cardiac 

intensive care services which most often is delivered by the 

team of pediatric cardiac surgeon, pediatric cardiac anesthetist, 

pediatric cardiologist, intensivist, pediatrician, registrars 

and nurses at various levels. With this scenario, there is an 

urgent need for a simple yet informative and concise handbook 

to enable provision of quality care to some of the sickest 

of children with cardiac problems across their peri-operative 

and post-operative period. 

‘The Manual of Pediatric cardiac intensive care e Pre and 

postoperative guidelines’ by Dr Manoj Luthra, an eminent 

pediatric cardiac surgeon of our country, is an excellent 

handbook which should enable the team of pediatric cardiac 

intensive care providers to handle most of the situations 

arising in the unit. It has chapters on almost all the relevant 

emergencies such as congestive cardiac failure, arrhythmias, 

hypertension, pulmonary hypertension, post-operative respiratory 

complications, ARDS, ventilator associated pneumonia, 

sepsis, seizures, acute kidney injury and 

coagulopathies. Besides these emergencies, many basic 

physiology topics such as fluid and electrolytes, ABG analysis, 

hemodynamic monitoring, parenteral and enteral nutrition 

have been discussed very succinctly .It also contains valuable 

chapters on important drugs used in the PCCU and has a well 

compiled set of appendices at the end. The book is handy, is 

well illustrated and the author has kept the language very 

simple so that it can be used by the different levels of child 

care providers. The book is likely to be useful to anyone 

involved in looking after the sick child in the pediatric cardiac 

care unit. 

It is a difficult task to convert volumes of information 

available on pediatric cardiac intensive care to a few hundred 

pages. However, the author has created an excellent handbook 

on the subject and reflects decades of experience in 

practical day to day management in the PCCU and toward 

which the book shall go a long way in fulfilling the requirements 

of the pediatric cardiac care provider. 

B.M. John*, Amit Devgan 

Associate Professor, Department of Pediatrics, AFMC, 

Sholapur Road, Pune 411040, India 


E-mail address: drbmj1972@yahoo.com (B.M. John)

228 


H.M. Mardikar* 

Director, Spandan Heart Institute & Research Center, 

31, Off Chitale Marg, Dhantoli, 

Nagpur 440010, India 

*Corresponding author. Tel.: þ91 9823082609 (mobile), þ91 (0) 

712 2443333; fax: þ91 (0) 712 2443426. 

E-mail address: drmardikar@cadindia.co.in 

Conclusions: Control patients who crossed over to renal 

denervation with the Symplicity system had a significant drop 

in blood pressure similar to that observed in patients receiving 

immediate denervation. Renal denervation provides safe and 

sustained reduction of blood pressure to 1 year. 

Clinical trial registration: URL: http://www.clinicaltrials. 

gov. Unique identifier: http://www.clinicaltrials.gov. (Circulation. 

2012;126:2976e2982.) 

Murray D. Esler, Henry Krum, Markus Schlaich, Roland E. 

Schmieder, Michael Böhm, Paul A. Sobotka, for the Symplicity 

HTN-2 Investigators. Renal sympathetic denervation for 

treatment of drug-resistant hypertension one-year results 

from the Symplicity HTN-2 randomized, controlled trial. 

Background: Renal sympathetic nerve activation contributes 

to the pathogenesis of hypertension. Symplicity HTN-2, a 

multicenter, randomized trial, demonstrated that catheterbased 

renal denervation produced significant blood pressure 

lowering in treatment-resistant patients at 6 months after the 

procedure compared with control, medication-only patients. 

Longer-term follow-up, including 6-month crossover results, 

is now presented. 

Methods and results: Eligible patients were on 3 antihypertensive 

drugs and had a baseline systolic blood pressure 

160 mm Hg (150 mm Hg for type 2 diabetics). After the 

6-month primary end point was met, renal denervation in 

control patients was permitted. One-year results on patients 

randomized to immediate renal denervation (n ¼ 47) and 

6-month postprocedure results for crossover patients are 

presented. At 12 months after the procedure, the mean fall in 

office systolic blood pressure in the initial renal denervation 

group ( 28.1 mm Hg; 95% confidence interval, 35.4 to 20.7; 

p < 0.001) was similar to the 6-month fall ( 31.7 mm Hg; 95% 

confidence interval, 38.3 to 25.0; p < 0.16 versus 6-month 

change). The mean systolic blood pressure of the crossover 

group 6 months after the procedure was significantly lowered 

(from 190.0 19.6 to 166.3 24.7 mm Hg; change, 23.7 27.5; 

p < 0.001). In the crossover group, there was 1 renal artery 

dissection during guide catheter insertion, before denervation, 

corrected by renal artery stenting, and 1 hypotensive 

episode, which resolved with medication adjustment. 

1. Clinical perspective 

The efficacy and safety of the Renal sympathetic Denervation 

(RDN) by utilizing the Symplicity Renal Denervation 

System in patients with uncontrolled resistant hypertension 

have been documented earlier. It has been shown that 

activation of the sympathetic nervous system is involved in 

the pathogenesis and maintenance of hypertension. Renal 

denervation with the Symplicity catheter is a minimally 

invasive procedure based on the premise that interruption 

of renal afferent and efferent nerves with resultant decrease 

in sympathetic outflow to the kidneys should reduce renin 

release and sodium retention, increase renal blood flow, and 

lower blood pressure. One-year follow-up data of The Symplicity 

HTN-2 trial demonstrates two points: (1) that the 

initial significant lowering of blood pressure achieved by the 

RDN procedure was maintained at the end of one year and 

no procedure-related side effect was revealed by that time; 

and (2) the control patients maintained on medical therapy 

and whose blood pressure was not adequately controlled 

were now permitted to switch over to RDN procedure. These 

patients again showed significant drop in blood pressure, 

which was maintained at the end of six months. Renal 

sympathetic Denervation by radiofrequency ablation thus 

may provide a safe and effective adjunctive therapy for 

treatment-resistant hypertensive patients. 

Contributed by: 

Arup Dasbiswas 

Professor and HOD, Department of Cardiology, 

NRS Medical College, Kolkata, India 

E-mail address: arup.dasbiswas@gmail.com




Editorial 

Yoga e an ancient solution to a modern epidemic. Ready for 

prime time? 

Harinder K. Bali 

Director, Department of Cardiology, Fortis Hospital, Mohali 160062, Punjab, India 

Cardiovascular disease (CVD), the leading cause of morbidity 

and mortality worldwide, is clearly of pressing clinical and 

economic significance, underscoring the need for effective 

primary prevention. 1 Although genetic predisposition plays 

an important role, the main culprit responsible for the burgeoning 

epidemic of CVD are the modifiable risk factors 

related to lifestyle. They not only aid in the initiation but also 

in the progression and complications of atherosclerosisrelated 

diseases. Hypertension, dyslipidemia and diabetes 

are all lifestyle-related conditions and are, therefore, modifiable. 

Metabolic syndrome has recently been recognized as an 

important risk factor particularly in the Indian subcontinent. 

Increased sympathetic activity, enhanced cardiovascular 

reactivity and reduced parasympathetic tone have been 

strongly implicated in the pathogenesis of metabolic syndrome 

and in the development and progression of atherosclerosis 

and cardiovascular disease. Recent research offers 

compelling evidence that chronic psychological stress and 

negative affective states contribute significantly to the pathogenesis 

and progression of insulin resistance, glucose 

intolerance, hypertension, dyslipidemia and other metabolic 

syndrome-related conditions and ultimately increase the risk 

for CVD morbidity and mortality. 

In the light of evidence of strong influence of psychosocial 

factors on the development of CVD, mind-body therapies 

may have considerable potential in its prevention and 

treatment. Of particular interest in this regard is Yoga, an 

ancient mind-body discipline which originated in our country 

almost 4000 years ago and has been widely used in the 

management of hypertension, diabetes and related chronic 

insulin resistance conditions. Of the seven major branches of 

yoga, Hatha (or forceful), Raja (or classical) and Mantra yoga 

are the best known and most widely practiced forms. Both 

Hatha and Raja yoga emphasize specific postures (asanas), 

including both active and relaxation poses as well as breath 

control (pranayama), concentration (dharanas) and meditation 

(dhyana). 

Yoga is a safe, simple-to-learn, noninvasive and inexpensive 

practice requiring little in way of equipment or professional 

training. However, as with most practices originating 

from the east, it was initially met with a lot of reluctance and 

resistance in Western countries. Moreover, lack of systemic 

studies did not help its cause. This has changed steadily in the 

last few decades with a growing body of evidence 2e6 suggesting 

that practice of yoga may reduce risk factors for CVD and 

may attenuate signs, reduce complications and improve the 

prognosis of those with frank or underlying disease. 

Since 1970, more than 50 studies from different countries 

have been published in peer reviewed journals investigating 

the potential influence of yoga and yoga-based programs on 

one or more core indices of CVD including measures of insulin 

resistance, lipid profiles, body weight and composition and on 

blood pressure. Interventions ranged in length from 40 days to 

12 months in various studies and they were carried out on 

healthy young adults as well as in patients with type II diabetes, 

hypertension and coronary artery disease. 

1. Glucose intolerance and diabetes 

Most of the studies in patients with glucose intolerance and 

frank diabetes have shown significant improvement postintervention 

in indices of insulin resistance relative to baseline 

values. Overall yoga practice was associated with 5.4%e 

33.4% reduction in fasting glucose, 24.5%e27% reduction in 

post-prandial glucose and 13.3%e27.3% reduction in glycohemoglobin 

with the percentage varying by study population 

and design. 7 In the present issue of the journal, Shantakumari 

et al 8 have reported the results of their study of effect of yoga 

on lipids in diabetic patients. Although it is a well-conducted 

randomized study, it is limited by the fact that during three 

months of yogic intervention, subjects were under supervision 

for only the initial 2 weeks raising concerns about 

compliance to the yogic protocol during the unsupervised 

E-mail address: hkbalipgi@gmail.com. 




period. Despite this limitation, the results are encouraging 

and consistent with other studies 7 on similar subject. Yogic 

intervention showed significant improvement in body weight 

and also in total cholesterol, LDL, triglycerides and nonsignificant 

elevation in HDL level in the intervention group as 

compared to controls. 

Although the evidence for beneficial effect has been 

observed consistently across studies, these results are 

tempered by the fact that most of the studies did not include 

control subjects. 

2. Lipid profile 

Practice of yoga and yoga-based programs may improve lipid 

profile in healthy adults and in patients with hypertension, 

diabetes and coronary artery disease. Four uncontrolled 

studies 3,9e11 and three controlled non-randomized 

studies 6,12,13 that ranged from six weeks to 12 months in 

duration showed significant improvement in lipid profile 

(reduction in total cholesterol, low density lipoproteins and 

triglyceride values and increase in HDL cholesterol) over control 

values and in comparison to control group as a result of 

yoga-based interventions. Several RCTs investigating the effect 

of yoga in combination with diet, 6,14,15 education, 16 stress 

management 6,16,17 and other therapies 6,14,17 have likewise 

demonstrated significant improvement in lipid profiles relative 

to controls receiving enhanced usual care, exercise and/or 

dietary interventions. Of the 5 RCTs identified in adults with 

hypertension, CVD or risk factors for CVD, three 14e16 documented 

improvement in all indices of dyslipidemia examined 

and one 17 reported significantly greater reduction in triglycerides 

but not in cholesterol or LDL. Patel et al 16 studied the 

long-term effect of yogic intervention on lipids and concluded 

that improvement in lipid profile persisted at 8 months but not 

at 4 years. Of those studies demonstrating positive effect, yoga 

practice was associated with 5.8%e25.2% decrease in total 

cholesterol, 22.0%e28.5% decrease in triglycerides and a 

12.8%e26.0% in LDL reduction. 7 The magnitude of the difference 

varies from study population and design. 

3. Body weight and composition 

Body weight and composition is uniformly improved by yogic 

interventions. Five RCTs 14,15,17e19 demonstrated improvement 

in body weight and/or composition relative to usual care, 14,17,19 

diet and exercise 15 and no intervention 18 controls. Studies 

reporting improvement in anthropometric indices included 

investigations of healthy individuals, 9,13,18,20e23 as well as those 

with hypertension, 19 and/or other CVD risk factors, 15 coronary 

artery disease 6,14,17 and diabetes. 24,25 In these studies yogic 

intervention was associated with 1.5%e13.6% improvement in 

body weight. 7 

4. Blood pressure 

A number of studies including seven uncontrolled studies of 

healthy 10,22,26 individuals and hypertensive 11,27e29 adults and 

eleven RCTs of healthy 30e33 adults and patients with hypertension 

or other CVD risk factors 16,19,34e38 have reported 

consistent beneficial effect of even relatively short-term 

practice of yoga and yoga-based programs on blood pressure. 

The duration of yogic intervention studied in these studies has 

ranged from 3 weeks to 6 months. Overall, these studies 

demonstrated a 4.6%e24.3% decline in diastolic blood pressure 

and 2.6%e21.3% decline in systolic blood pressure with 

yoga. The magnitude of decline in blood pressure varied with 

the study design and sample population. In a cross-sectional 

study of healthy mid-life men with similar lifestyle characteristics, 

Vyas et al found that those with both short term and 

long term experience in Raja yoga meditation had reduced 

diastolic blood pressure as compared to those naïve to 

meditation. 39 

5. Procoagulant changes and oxidative 

stress 

Procoagulant changes and damage caused by oxidative stress 

have a pivotal role to play in the causation of metabolic syndrome 

and in the development and progression of diabetes and 

CVD. 40 In an uncontrolled study, it was observed that four 

months yogic intervention caused a significant decline in 

fibrinogen and an increase in fibrinolytic activity. 41 In a nonrandomized 

controlled study of healthy German adults, 

Schmidt et al 13 documented a significant fall in fibrinogen 

among participants completing a 3-month residential Kriya 

yoga program relative to community controls matched on age, 

gender, and baseline fibrinogen levels. These trials suggest that 

yoga may foster beneficial changes in the coagulation and 

fibrinolytic systems in healthy adults. Results of some small 

studies 3,13,17,42e44 provide evidence that it may reduce oxidative 

stress in both healthy populations and those with chronic 

insulin resistance related disorders. Observed changes in other 

oxidative stress indices include increase in antioxidants 44 and 

antioxidative enzymes, 44 and reductions in free radicals. 43 

6. Stress 

There is a strong experimental evidence to suggest that yoga 

can lead to improvement in both cardiovascular response to 

stress and cardiovascular recovery from stress. Cardiovascular 

reactivity to stress is strongly associated with insulin 

resistance. 45 In addition, it is a major independent predictor of 

hypertension, stroke, myocardial infarction and cardiovascular 

mortality. 46 Cardiovascular recovery from stress similarly 

has been strongly associated with CVD risk. 47 

7. Other effects 

Population based studies 48e54 have shown that participation 

in yoga and yoga-based programs promotes significant 

reduction in respiratory rate, heart rate, cortisol concentration, 

catecholamine levels, renin activity, and accelerated recovery 

time from stress as well as significant improvement in 

heart rate variability and baroreceptor sensitivity in both

134 


healthy 48e53 and hypertensive 54 populations. Collectively, 

these studies prove that even short-term practice of yoga may 

produce marked reduction in sympathoadrenal activation, 

enhance cardio-vagal tone and promote sympatho-vagal 

balance. 

8. CVD clinical end-points 

Large studies that have directly studied the effect of yogic 

interventions on clinical end-points of cardiovascular disease 

in populations suggest that yoga and yoga-based programs 

may attenuate signs, reduce complications and improve the 

prognosis of those with frank or underlying disease. In an RCT 

of Indian men with coronary artery disease, 14 those enrolled 

in a 12-month comprehensive yoga program showed retardation 

of coronary atherosclerosis, increased regression 

and reduced progression of vascular lesions, and reduced 

anginal episodes relative to usual care controls. In a study 

amongst American seniors, 34 those completing a 12-month 

comprehensive yoga-based program demonstrated a decline 

in carotid intimal media thickness, an indicator of carotid 

atherosclerosis, relative to those receiving usual care or a 

comprehensive medical, diet, and exercise intervention. The 

decline was correlated inversely with adherence, suggesting a 

direct relation between the practice of this program and 

atherosclerotic change. There is also some evidence that the 

clinical benefits observed following yoga-based programs 

might persist long term. In a 4-year follow-up of an earlier RCT 

in hypertensive adults, Patel et al 16 found that those who had 

participated in an 8-week comprehensive yoga relaxation 

program were less likely than usual care controls to be 

receiving treatment for CVD related complications, to have 

experienced a serious coronary event, or to have electrocardiographic 

evidence of ischemia. 

significant issues which need to be addressed particularly 

about the methodology of many of these trials. 

Interpretation of many existing studies is limited by small 

sample sizes, lack of appropriate control groups, inadequate 

description of methods, selection bias, failure to adjust for 

lifestyle characteristics and other potential confounders, 

exposure to multiple interventions, inadequacies in statistical 

analysis and presentation, or other methodological problems. 

In many of the controlled trials, treatment allocation was not 

randomized, and direct statistical comparisons were not 

made to control groups, potentially biasing the findings. In 

addition, the large variation in the nature, duration, intensity, 

and delivery methods of the yoga-based interventions used, 

even among studies using yoga practice alone, renders comparison 

across studies difficult. Therefore, although existing 

RCTs have yielded results consistent overall with those of 

non-randomized and uncontrolled studies, additional high 

quality RCTs are warranted. 

11. Present state and future direction 

Yoga is an inexpensive method of addressing the major 

epidemic of CVD sweeping our country. It has no known side 

effects, requires no infrastructure or maintenance charges 

and can easily be practiced even by the chronically ill and the 

elderly. Time has come for it to be included regularly in our 

prescription for primary and secondary prevention of CVD. It 

is likely to be even more effective when combined with other 

lifestyle measures like exercise and dietary modification. It 

should be inculcated in the school curriculum for long-term 

benefit and various community centers should offer free yoga 

classes to the community. Large multicenter multinational 

scientifically conducted studies will go a long way in establishing 

its definitive role in CVD prevention and treatment. 

9. Possible mechanisms of action of yoga 

Although the mechanisms underlying the putative beneficial 

effects of yoga therapy on cardiovascular risk profiles are not 

yet well understood, the observed changes probably occur primarily 

through two pathways. First, by reducing the activation 

and reactivity of the sympatho-adrenal system and the hypothalamic 

pituitary adrenal (HPA) axis and promoting feelings of 

well-being, yoga may alleviate the effects of stress and foster 

multiple positive downstream effects on neuroendocrine status, 

metabolic function and related inflammatory responses. 

Second, by directly stimulating the vagus nerve, yoga may 

enhance parasympathetic output and thereby shift the autonomic 

nervous system balance from primarily sympathetic to 

parasympathetic leading to positive changes in cardiac-vagal 

function, in mood and energy state, and in related neuroendocrine, 

metabolic, and inflammatory responses. 

10. Limitations of studies 

Although there is a wealth of data available to support the 

efficacy of yoga and yoga related interventions, there are 

references 

1. American Heart Association. 2012 Heart and Stroke Statistical 

Update. American Heart Association; 2012. 

2. Pandya D, Vyas V, Vyas S. Mind-body therapy in the 

management and prevention of coronary disease. Compr Ther. 

1999;25:283e293. 

3. Damodaran A, Malathi A, Patil N, Shah N, Suryavansihi 

Marathe S. Therapeutic potential of yoga practices in 

modifying cardiovascular risk profile in middle aged men 

and women. J Assoc Physicians India. 2002;50:633e640. 

4. Sahay B, Sahay R. Lifestyle modification in man e agement of 

diabetes mellitus. J Indian Med Assoc. 2002;100:178e180. 

5. Raub J. Psychophysiologic effects of hatha yoga on 

musculoskeletal and cardiopulmonary function: a literature 

review. J Altern Complement Med. 2002;8:797e812. 

6. Yogendra J, Yogendra H, Ambardekar S, et al. Beneficial 

effects of yoga lifestyle on reversibility of ischaemic heart 

disease: Caring Heart Project of International Board of Yoga. 

J Assoc Physicians India. 2004;52:283e289. 

7. Innes KE, Bourguignon C, Taylor AG. Risk indices associated 

with the insulin resistance syndrome, cardiovascular disease, 

and possible protection with yoga: a systematic review. JAm 

Board Fam Pract. 2005;18:491e519.


8. Shantakumari N, Sequeria S, Eldeep Rasha. Effects of a yoga 

intervention on lipid profiles of diabetes patients with 

dyslipidemia. Indian Heart J. 2013;65:127e131. 

9. Udupa KN, Singh RH. The scientific basis of yoga. JAMA. 

1972;220:1365. 

10. Joseph S, Sridharan K, Patil S, et al. Study of some 

physiological and biochemical parameters in subjects 

undergoing yogic training. Indian J Med Res. 

1981;74:120e124. 

11. Patel C. Reduction of serum cholesterol and blood pressure in 

hypertensive patients by behaviour modification. J Roy Coll 

Gen Pract. 1976;26:211e215. 

12. Naruka J, Mathur R, Mathur A. Effect of pranayama practices 

on fasting blood glucose and serum cholesterol. Indian J Med 

Sci. 1986;40:149e152. 

13. Schmidt T, Wijga A, Muhlen Von Zur, et al. Changes in 

cardiovascular risk factors and hormones during a 

comprehensive residential three month kriya yoga training 

and vegetarian nutrition. Acta Physiol Scand Suppl. 

1997;640:158e162. 

14. Manchanda S, Narang R, Reddy K, et al. Retardation of 

coronary atherosclerosis with yoga lifestyle intervention. 

J Assoc Physicians India. 2000;48:687e694. 

15. Mahajan A, Reddy K, Sachdeva U. Lipid profile of coronary 

risk subjects following yogic lifestyle intervention. Indian 

Heart J. 1999;51:37e40. 100. 

16. Patel C, Marmot M, Terry D, et al. Trial of relaxation in 

reducing coronary risk: four year follow-up. Br Med J. 

1985;290:1103e1106. 

17. Jatuporn S, Sangwatanaroj S, Saengsiri A, et al. Short-term 

effects of an intensive lifestyle modification program on lipid 

peroxidation and antioxidant systems in patients with 

coronary artery disease. Clin Hemorheol Microcirc. 

2003;29:429e436. 

18. Bera TK, Rajapurkar MV. Body composition, cardiovascular 

endurance and anaerobic power of yogic practitioner. Indian J 

Physiol Pharmacol. 1993;37:225e228. 

19. Murugesan R, Govindarajulu N, Bera T. Effect of selected yogic 

practices on the management of hypertension. Indian J Physiol 

Pharmacol. 2000;44:207e210. 

20. Udupa KN, Singh RH, Settiwar RM. Physiological and 

biochemical studies on the effect of yogic and certain other 

exercises. Indian J Med Res. 1975;63:620e624. 

21. Satyanarayana M, Rajeswari KR, Rani NJ, Krishna CS, Rao PV. 

Effect of santhi kriya on certain psychophysiological 

parameters: a preliminary study. Indian J Physiol Pharmacol. 

1992;36:88e92. 

22. Telles S, Nagarathna R, Nagendra HR, Desiraju T. 

Physiological changes in sports teachers following 3 months 

of training in yoga. Indian J Med Sci. 1993;47:235e238. 

23. Raju PS, Prasad KV, Venkata RY, Murthy KJ, Reddy MV. 

Influence of intensive yoga training on physiological changes 

in 6 adult women: a case report. J Altern Complement Med. 

1997;3:291e295. 

24. Divekar M, Bhat M, Mulla A. Effect of yoga therapy in diabetes 

and obesity. J Diab Assoc Ind. 1978;17:75e78. 

25. Jain S, Uppal A, Bhatnagar S, Talukdar B. A study of response 

pattern of non-insulin dependent diabetics to yoga therapy. 

Diabetes Res Clin Pract. 1993;19:69e74. 

26. Anantharaman R, Kabir R. A study of yoga. J Psychol Res. 

1984;28:97e101. 

27. Mogra A, Singh G. Effect of biofeedback and yogic 

relaxation exercise on the blood pressure levels of 

hypertensives: a preliminary study. Aviation Med. 

1986;30:68e75. 

28. Lakshmikanthan C, Alagesan R, Thanikachalam S, et al. 

Long term effects of yoga on hypertension and/or coronary 

artery disease. J Assoc Physicians India. 1979;27:1055e1058. 

29. Sundar S, Agrawal S, Singh V, Bhattacharya S, Udupa K, 

Vaish S. Role of yoga in management of essential 

hypertension. Acta Cardiol. 1984;39:203e208. 

30. Bagga OP, Gandhi A. A comparative study of the effect 

of Transcendental Meditation (T.M.) and shavasana 

practice on cardiovascular system. Indian Heart J. 

1983;35:39e45. 

31. Cusumano JA, Robinson SE. The short-term 

psychophysiological effects of hatha yoga and progressive 

relaxation on female Japanese students. Appl Psychol. 

1992;42:77e90. 

32. Ray U, Mukhopadhyaya S, Purkayastha S, et al. Effect of 

yogic exercises on physical and mental health of young 

fellowship course trainees. Indian J Physiol Pharmacol. 

2001;45:37e53. 

33. Harinath K, Malhotra AS, Pal K, et al. Effects of hatha yoga 

and omkar meditation on cardiorespiratory performance, 

psychologic profile, and melatonin secretion. J Altern 

Complement Med. 2004;10:261e268. 

34. Fields JZ, Walton KG, Schneider RH, et al. Effect of a 

multimodality natural medicine program on carotid 

atherosclerosis in older subjects: a pilot trial of Maharishi 

Vedic Medicine. Am J Cardiol. 2002;89:952e958. 

35. Patel C, Marmot MG, Terry DJ. Controlled trial of biofeedbackaided 

behavioural methods in reducing mild hypertension. Br 

Med J (Clin Res Ed). 1981;282:2005e2008. 

36. Patel C, Marmot M. Can general practitioners use training in 

relaxation and management of stress to reduce mild 

hypertension? Br Med J (Clin Res Ed). 1988;296:21e24. 

37. Patel C, North WR. Randomised controlled trial of yoga and 

bio-feedback in management of hypertension. Lancet. 

1975;2:93e95. 

38. Broota A, Varma R, Singh A. Role of relaxation in 

hypertension. J Indian Acad Appl Psychol. 1995;21:29e36. 


cardiovascular system and lipid profile. Indian J Physiol 

Pharmacol. 2002;46:487e491. 

40. Ceriello A, Motz E. Is oxidative stress the pathogenic 

mechanism underlying insulin resistance, diabetes and 

cardiovascular disease? the common soil hypothesis 

revisited. Arterioscler Thromb Vasc Biol. 2004;24:816e823. 

41. Chohan IS, Nayar HS, Thomas P, Geetha NS. Influence of 

yoga on blood coagulation. Thromb Hemost. 1984;51:196e197. 

42. Singh S, Malhotra V, Singh K, Sharma S. A pre-liminary 

report on the role of yoga asanas on oxi-dative stress in noninsulin 

dependent diabetes. Indian J Clin Biochem. 

2001;16:216e220. 

43. Bhattacharya S, Pandey U, Verma N. Improvement in 

oxidative status with yogic breathing in young healthy males. 

Indian J Physiol Pharmacol. 2002;46:349e354. 

44. Sharma H, Sen S, Singh A, Bhardwaj NK, Kochupillai V, 

Singh N. Sudarshan kriya practitioners exhibit better 

antioxidant status and lower blood lactate levels. Biol Psychol. 

2003;63:281e291. 

45. Moan A, Nordby G, Rostrup M, Eide I, Kjeldsen SE. 

Insulin sensitivity, sympathetic activity, and 

cardiovascular reactivity in young men. Am J Hy-pertens. 

1995;8:268e275. 

46. Jennings JR, van der Molen MW, Somsen RJ, Graham R, 

Gianaros PJ. Vagal function in health and disease: studies in 

Pittsburgh. Physiol Behav. 2002;77:693e698. 

47. Mezzacappa ES, Kelsey RM, Katkin ES, Sloan RP. Vagal 

rebound and recovery from psychological stress. Psychosom 

Med. 2001;63:650e657. 

48. Bernardi L, Sleight P, Bandinelli G, et al. Effect of 

rosary prayer and yoga mantras on autonomic 

cardiovascular rhythms: comparative study. BMJ. 

2001;323:1446e1449.

136 


49. Konar D, Latha R, Bhuvaneswaran JS. Cardiovascular 

responses to head down-body-up postural ex-ercise 

(sarvangasana). Indian J Physiol Pharmacol. 2000;44:392e400. 

50. Bowman A, Clayton R, Murray A, Reed J, Subhan M, Ford G. 

Effects of aerobic exercise training and yoga on the baroreflex 

in healthy elderly persons. Eur J Clin Invest. 1997;27:443e449. 

51. Udupa K, Madanmohan, Bhavanani AB, Vijayalakshmi P, 

Krishnamurthy N. Effect of pranayam training on cardiac 

function in normal young volunteers. Indian J Physiol 

Pharmacol. 2003;47:27e33. 

52. Vempati R, Telles S. Baseline occupational stress 

levels and physiological responses to a two day 

stress management program. JIndianPsychol. 2000; 

18:33e37. 

53. Vempati R, Telles S. Yoga-based guided relaxation reduces 

sympathetic activity judged from baseline levels. Psychol Rep. 

2002;90:487e494. 

54. Selvamurthy W, Sridharan K, Ray U, et al. A new 

physiological approach to control essential hypertension. 

Indian J Physiol Pharmacol. 1998;42:205e213.




How Do I Do It 

Stepwise evaluation of left to right shunts by 

echocardiography 

Neeraj Awasthy a , S. Radhakrishnan b, * 

a Associate Consultant, Department of Pediatric and Congenital Heart Diseases, Fortis Escorts Heart Institute, Delhi, India 

b Director, Department of Pediatric and Congenital Heart Diseases, Fortis Escorts Heart Institute, Delhi, India 

Echocardiography has revolutionized the practice of pediatric 

cardiology. The addition of Doppler and color flow mapping 

also gives physiological information about flow and pressures 

and enables the pediatric cardiologist to refer patients for 

surgical treatment without cardiac catheterization, especially 

in neonate and infants. In this communication echocardiographic 

findings of common shunt lesions are discussed. 

1. General features: shunt lesions 

arteries or obstruction in pulmonary vascular bed (as in 

pulmonary arterial hypertension). 

- Increase in pressures in RV and beyond may be seen in 

large VSD, similarly a large PDA would lead to significant 

increase in PA pressures 

4) The magnitude of the gradient from a chamber outflow 

would be dependent on the magnitude of shunt into the 

chamber. 

- This may lead to exaggerated gradients even in hemodynamically 

scuttle lesions viz. exaggerated pulmonary 

There are a few salient features of all the shunt lesions: 

1) The shunt would lead to volume overloads of the chambers 

it feeds (particularly in relation to the tricuspid 

valves) e.g. while a shunt proximal to the tricuspid valve 

would lead to volume overloading of the right atrium and 

right ventricle and further (Fig. 1). A lesion beyond the 

tricuspid valve would lead to the volume overloading of 

the left atrium (LA) and left ventricle (LV). 

2) The magnitude of the chamber enlargement depends 

upon the magnitude of the shunt. Thus significant right 

atrium (RA) and right ventricle (RV) enlargement would be 

a feature of pretricuspid shunt, while a significant LA and 

LV enlargement would be a feature of post-tricuspid 

shunt. 

3) The pressure of the investigated chamber would rise not 

only on account of distal obstruction (obstruction of the 

outflow of the chamber) or it would be because of the 

transmitted pressures from the adjacent chambers on 

account of the shunt. 

- Increase in RV pressures may be because of distal pulmonary 

stenosis, obstruction in branch pulmonary 

Fig. 1 e 4 Chamber view showing prominent right atrium 

and right ventricle. The image has been taken from a case 

of 15-year-old child with large atrial septal defect. 

* Corresponding author. Tel.: þ91 (0) 9811962775. 

E-mail addresses: n_awasthy@yahoo.com, n_awasthy@yahoomail.com (N. Awasthy), samurai43@yahoo.com (S. Radhakrishnan). 



202 


Fig. 2 e Perimembranous defect shown with anterior tilt 

from 4c view. 

stenosis gradients in associated pretricuspid shunts 

(like ASD), exaggerated mitral and aortic valve gradients 

in associated post-tricuspid shunts like VSD 1 or PDA in 

absence of significant stenosis. For example gradients 

upto 60 mmHg have been reported across pulmonary 

valve in patients of atrial septal defect in absence of 

pulmonary stenosis (Fig. 2). 

5) The secondary manifestations of the shunt lesions may 

themselves lead to exaggerated secondary effects e.g. the 

mitral annular dilatation on account of post-tricuspid 

shunt may lead to mitral regurgitation and this may 

further lead to mitral valve dilatation and LV dilatation. 

6) Since a shunt lesion almost always signifies a communication 

between 2 chamber the gradient between the 2 

chambers can guide as to the magnitude of the shunt 

lesion or the size of the defect (Fig. 3A and B). 

7) The size of the defect in 2 dimensions may be a useful 

guide in deciding the degree of shunt. It also is useful to 

help the interventional modality 

- The size of the VSD may be compared to the size of the 

Aortic root for classifying the size of the VSD. 

- The size of defects like ASD, coronary AV fistulae, VSD, 

RSOV etc would help in deciding the size of the device 

which may be used. 

Fig. 3 e Echocardiographic imaging with continuous wave Doppler gradient across the PDA, showing the PDA gradient of 

89 mmHg against systemic pressures of 100 mmHg. The PA pressures from the gradient is systemic pressures (100 mmHg) 

PDA gradient (89 mmHg) [ 11 mmHg. B shows the gradient across the VSD of 98 mmHg against systemic pressures of 

120 mmHg. By the observation the predicted RV pressures are 22 mmHg (100e98).


Fig. 4 e Transesophageal echocardiography showing the dimensions of ASD in various TEE planes. The view is obtained by 

keeping the endoscope in the middle of the esophagus and rotating the icon four chamber view, A: (showing atrial and 

atrioventricular valve rims), Basal short axis view, B: shows the atrial and aortic rims, basal long axis view, C: shows the 

superior vena cava (SVC) and inferior vena cava (IVC) rims. For optimum device placement the rims should be adequate (at 

least 5 mm) and supportive. The size of the ASD has to be seen in all the planes to decide the size of the ASD device. The 

same (D) has to be viewed on color Doppler to ascertain the flow and the visualization of additional defect. 

8) Echocardiography should focus, not only on the characteristics 

of the primary lesion, but also on the adjacent 

structures of the defect e.g. distances from the adjoining 

valves 

- VSD, it is important to note the distances from the aortic 

valve when considering for device closure. It is also 

important from the surgical point of view. 

Fig. 5 e An interesting case of ALCAPA with masked manifestations. In view of associated large VSD leading to pulmonary 

artery hypertension the flow in the anomalous coronary artery from the pulmonary artery on color flow was normal (A). Thus 

2d echocardiography (B) becomes important in such cases demonstrating the origin of the left main coronary artery (LMCA) 

from pulmonary artery (PA).

204 


Fig. 6 e An interesting case of coronary sinus type of ASD with mitral stenosis and unroofed ASD. The interesting case 

demonstrated that because of associated large coronary sinus ASD (A), mitral gradients were underestimated on color 

Doppler echocardiography (B) with mean gradient of 3 mmHg inspite of severe mitral stenosis (mitral valve area on


Table 1 e Stepwise evaluation for ASD. 

1) Initial indication is the volume overload of the chambers (RA 

and RV) in 4c view 

2) Visualize the defect from subcostal view (Sagittal and coronal) 

3) Determine the site of defect: fossa ovalis or others (others being 

not suitable for device) 

4) Determine the direction of shunting of the defect 

5) Look for the associated structures particularly pulmonary veins 

and AV valves 

6) Look for the pulmonary artery pressures: TR and PR gradients 

7) Determine suitability for device closure 

Table 3 e Stepwise evaluation for a PDA. 

1) Visualize the ductus ostium and aortic isthmus from the parasternal 

short axis, high parasternal short axis and suprasternal 

views 

2) Determine the direction of shunt by color flow mapping and 

Doppler 

3) Take the peak velocity of the PDA signal which will give the 

pressure difference between the aorta and pulmonary artery 

and obtain the aortic, RVOT and PA velocities 

4) Take the measurements of the left ventricle and left atrium as 

these will reflect the volume of the left to right shunt 

5) Specifically look for associated defects like coarctation of aorta 

(suprasternal view), aortic interruption and aortopulmonary 

window (communication between the ascending aorta and 

pulmonary artery) 

Table 2 e Stepwise evaluation for VSD. 

1) Initial indication is the volume overload of the chambers (LA 

and LV) 

2) Visualize the defect from all possible windows to look for the 

defect 

3) Determine the presence of additional defects (screening the 

septum e septal sweep in subcostal view, apical 4c view and 

parasternal short and long axis sweep in color and 2d) 

4) Determine the direction of shunting of the defect 

5) Look for the associated structures particularly outflows 

6) Look for the pulmonary artery pressures: VSD gradients, TR and 

PR gradients 

7) Determine the volume overload of chambers (Z scores of LV, 

particularly in M mode) 

8) Determine suitability for device closure 

- For ASD, the rims are seen not only for their adequacy, 

but also the adjoining structures being encroached 

upon, whenever contemplating a device closure 

(Fig. 4AeD). 

- For AP window, the distance from coronaries and valves 

becomes important 

- The post-tricuspid shunt is known to mask the manifestations 

of Anomalous left coronary artery from pulmonary 

artery (ALCAPA), and thus one should keenly 

look at the 2d anatomy and origin of the coronary 

arteries whenever investigating an associated shunt 

lesion 2,3 (Fig. 5A and B). 

9) Whenever investigating a shunt at multiple sites or an 

associated lesion, one must remember that the shunt flow 

may be modified by the presence of distal obstruction and 

also by the associated shunt. 

- The associated post-tricuspid shunt may lead to exaggerated 

manifestations of a pretricuspid shunt lesions 

(viz ASD). Thus RA and RV may be unduly dilated even in 

the presence of small ASD, with the associated presence 

of post-tricuspid shunt (VSD or PDA) or associated 

presence of mitral stenosis. 

- The associated aortic stenosis or coarctation of aorta 

may exaggerate the shunt across the ventricular septal 

defect. 

10) The associated lesions being drained off by the shunt lesions 

may become masked and may manifest themselves 

only after the shunt lesion is closed. 

- Mitral stenosis may not manifest itself in the presence 

of ASD (although it may exaggerate the shunt flow 

across it) (Fig. 6AeF). 

- The manifestations of significant mitral regurgitation 

may get unmasked after ASD closure. 4 

- High LVedp may not only exaggerate ASD shunt, they 

may manifest themselves as pulmonary edema after 

ASD closure. 

- VSD or PDA may mask the gradients across the aortic 

stenosis or coarctaion of aorta and this may manifest 

itself after the treatment of the underlying shunt 

lesion. 5 

11) Systemic disorders and conditions may exaggerate or 

confound the features and even echocardiographic features 

of a shunt lesion. 

- Anemia may exaggerate the gradients across any shunt 

lesion or across valves. Anemia may lead to LV dilatation 

thus confounding the assessment of associated 

post-tricuspid shunt lesion. 

- Systemic hypertension may not only lead to exaggerated 

shunt gradients, it may also lead to secondary 

ventricular hypertrophy thus leading to high LVedps 

and exaggerating ASD shunt. 

- Hyperdynamic states such as fever, anemia, thyroid 

disorders may exaggerate the shunt gradients. 

Assessment of shunt lesions must be preceded by a 

complete clinical information, chest X-ray and electrocardiogram. 

There would be a situation when information 

gained by these investigations will lead to clinical decision 

when echocardiographic findings are equivocal. 

planimetry of 0.7 cm 2 ) (C). The another interesting hemodynamic aspect of the lesion was associated unroofed coronary 

sinus ASD leading to right to left shunting and hence systemic desaturation. This shunting was clearly demonstrated by 

contrast injection in left brachial artery (D and E). The injection showed early filling of the left atrium and left ventricle (D) 

followed by right atrium and right ventricle (via coronary sinus ASD): (F). The draining of the LSVC to left atrium can be 

confirmed by computed tomography scan.

206 


Fig. 7 e 2d echocardiography with subcostal view showing 

bicaval view with SVC and IVC rims and left to right shunt. 

1.1. Stepwise approach (on echocardiography) 

Stepwise approach (on echocardiography) for evaluation of 

any shunt lesion involves: 

1) Determine the presence of shunt lesion 

2) Determine the volume overload (and complication) on account 

of the shunt lesion 

3) Defining the size of the lesion and its location 

4) Define the lesion on echocardiography for operability 

5) If suitable to decide the relevant modality of treatment 

The essential approach to any lesion should not be directed 

at the shunt lesion, rather it should be a standardized 

sequential analysis, as it is not the shunt lesion in isolation 

that exist and one needs to evaluate all the structural heart 

Fig. 9 e Apical 4 chamber view showing large ostium 

primum ASD defect in lower part of the interatrial septum 

marked by the arrow. 

defects. A few salient features of the important shunt 

lesionseASD, VSD, PDA and AP window are illustrated below 

Table 1. 

1.1.1. Step 1: suspect the shunt lesion 

Visualization of an accessory flow into the chamber 

Any shunt lesion will lead to the chamber enlargement into 

which it drains 

Tricuspid valve an important landmark 

A pretricuspid shunt would lead to right atrium and right 

ventricular chamber enlargement 

Fig. 8 e 2d echocardiography with color comparison showing the SVC type of sinus venosus ASD. There is overlapping of 

the SVC over the defect with partial anomalous pulmonary venous drainage of right upper pulmonary vein to SVC (PAPVC).


fistulae and RSOV to any structure beyond tricuspid valve, 

aorta e LV tunnel, aortopulmonary collaterals 

1.1.3. Step 3: critically see the chamber enlargement 

The enlargement of the innominate vein and superior vena 

cava (SVC) will point toward a flow into the SVC 

Enlargement of the isolated SVC in the absence of innominate 

vein dilatation will point toward a shunt in SVC or an AV 

malformation draining to SVC 

2. Atrial septal defects (Table 1) 

2.1. Objectives on echocardiography 

Fig. 10 e Transesophageal echocardiography at the level of 

basal long axis view showing the characteristics of SVC 

type of sinus venosus ASD. There is clearly a defect with 

overlying of the SVC over the defect. At times slight 

retroflexion of the probe may profile the defect well. 

1. To diagnose atrial septal defect, asses its anatomical site 

and size. 6e8 

2. To assess the direction and quantum of flow. 

3. To assess the degree of pulmonary arterial hypertension. 

4. To assess atrioventricular valve anomalies, pulmonary 

veins and pulmonary valve stenosis. 

2.2. ASD classification 

A post-tricuspid shunt would lead to left atrial and left 

ventricular enlargement 

1.1.2. Step 2: a recall of the shunt lesions 

Pretricuspid shunts: atrial septal defect (ASD), interatrial 

communication, anomalous pulmonary venous drainage, 

systemic AV fistulae, Ruptured sinus of Valsalva to right 

atrium, Coronary AV fistulae to right atrium, Gerbode defect 

(left ventricle to right atrial shunt) 

Post-tricuspid shunt: Ventricular septal defect (VSD) 

Table 2, aortopulmonary window (APW), Patent ductus arteriosus 

(PDA) Table 3, pulmonary AV fistulae, coronary AV 

Defects of atrial septum are classified into: a. patent foramen 

ovale (PFO), b. fossa ovalis atrial septal defect (Fig. 7), c. sinus 

venosus defect (Fig. 8), d. Coronary sinus atrial septa defect 

(Fig. 6A, DeF), e. ostium primum atrial septal defect (Fig. 9). 

2.3. Evaluation on echocardiography 

The abnormal interventricular septal motion and enlarged 

right atrium and ventricle are indirect evidence of left to right 

shunt at atrial level. 

The best views to directly visualize the atrial septal defect 

are subcostal coronal and sagittal views. 

Fig. 11 e 2d echocardiography with subcostal sagittal view showing the case of total anomalous pulmonary venous 

drainage with right to left shunt across atrial septal defect.

208 


most part of the interatrial septum with atrioventricular 

valves attached at the same level are designated as ostium 

primum defects. 

It should also be viewed in apical four chamber and short 

axis views. 

The four chamber view will also show the attachments of 

the atrioventricular valves. These will be at the same level in 

ostium primum defect. 

The color flow mapping across the defect will show the 

direction of flow and also presence or absence of any 

regurgitation. 

Doppler velocities across all valves should be taken, in 

particular the pulmonary valve to look for any pulmonary 

stenosis. 

False positive and false negatives 

Fig. 12 e Schematic diagram of the interventricular septum 

with removed RV cavity from the RV side. Various part of 

the septum are profiled: blue (muscular septum) this forms 

the region of the muscular VSD. The muscular septum can 

further be classified with respect to the muscular 

moderator and septal band. Yellow region signifies the 

perimembranous region, purple color signifies the inlet 

septum and green color the outlet septum. 

Atrial septal defect will be diagnosed by a dropout in the 

interatrial septum with flow across the defect on Doppler 

interrogation. 

When the defect is visualized its relationship to the SVC and 

inferior vena Cava (IVC) should be evaluated. If the SVC 

forms the roof of the defect, the defect is SVC sinus venous 

type. If the IVC straddles the defect, it is IVC type. The defects 

in the center of the atrial septum involving the fossa 

ovalis area are fossa ovalis defects. The defect in the lower 

Apical four chamber views are notorious in giving false echo 

dropouts and false positive impression of a defect. 

Apical four chamber view can completely miss an SVC type 

defect because of its very superior location. Transesophageal 

echo will resolve this issue (Fig. 10). 

Hugely dilated coronary sinus (as in coronary sinus TAPVC) 

has been mistaken for ostium primum ASD in inexperienced 

hands because of its very posterior location. 

The inflow velocities of the AV valves should be seen to rule 

out any mitral valve obstruction. The associated mitral 

obstruction may get missed unless specifically seen on 2 

dimensional echocardiography, as there may not be significant 

gradient across the mitral valve even with significant 

obstruction because of associated ASD (true for all Lutembacher 

cases) (Fig. 6 AeF). 

All pulmonary veins should be specifically imaged to see if 

they are abnormally connected or not and to look for any 

pulmonary vein stenosis. The pulmonary veins are best 

seen in subcostal coronal and sagittal, apical four chamber 

and short axis and suprasternal short axis views. 

Fig. 13 e 2d echocardiography with four chamber view with anterior tilt showing the perimembranous VSD defect getting 

restricted by septal leaflet of the tricuspid valve in 2d (A) and color Doppler (B).


Fig. 14 e 2d echocardiography with subcostal coronal view with anterior tilt with opening of the aortic outflow showing the 

outlet muscular VSD with left to right shunt in 2d (14A) and color mapping (B). 

3. Direction of shunt 

Dominant shunt occurs from left to right. Left to right shunt 

occurs mainly during mid to late systole as ‘v’ wave of left atria 

is larger than right atria (Fig. 7). 8e11 The second wave of left to 

right shunt occur with atrial contraction. The following 

pattern of shunting can be appreciated in patient of ASD. 

1) Left to right shunt: In associated ASD without pulmonary 

artery hypertension (PAH) this is a commonest pattern of 

shunting. Onset of atrial fibrillation even in absence of PAH 

can cause bidirectional shunt. 

2) Right to left shunt: In ASD right to left shunting will occur in 

following situation (Fig. 11): 

a) Severe PAH. 

b) Hypoplasia of right sided chambers which may rarely 

be isolated but more often as a part of more complex 

anomalies. 

c) Severe pulmonary stenosis with right ventricular hypertrophy 

or hypertension. 

d) Obligatory right to left shunt even in absence of significant 

PAH is seen in tricuspid atresia, TAPVC. 

3) Bidirectional shunting across atrial septal defect is seen 

most commonly during the stage of progression of PAH 

For the estimation of pulmonary arterial pressure the peak 

gradient of tricuspid regurgitation should be taken. If pulmonary 

regurgitation is present the pressure derived from the 

peak diastolic velocity will reflect the pulmonary arterial 

mean pressure. 

3.1. Calculation of shunt in ASD 

Because of its fallacy calculation of shunts by echocardiography 

is rarely practiced. More often quantitative assessment of 

significant shunt is assessed by its impact on right atrial or 

right ventricular chamber size. Thus a “significant” shunt is 

Fig. 15 e 2d echocardiography with parasternal long axis view showing the apical muscular type of trabecular muscular 

VSD with left to right shunt in 2d (A) and color mapping (B).

210 


Fig. 16 e 2d echocardiography with parasternal long axis view showing the doubly committed VSD with left to right shunt 

in 2d (A) and color flow mapping (B). 

will be associated with dilated right atrium and ventricle. The 

disadvantage of this visual assessment is that progressive 

enlargement of RA and RV can occur with increasing pulmonary 

artery pressures. Thus hugely dilated right atrium and 

ventricle will persist even with Eisenmenger state where there 

is only right to left shunt. Diagnostic cardiac catheterization in 

atrial septal defects is indicated when required to measure 

pulmonary artery pressures or to evaluate pulmonary 

vascular resistance. 

3.2. Evaluation of atrial septum by transesophageal 

echocardiography (Fig. 4AeD) 

Views, which are most useful for evaluation of atrial septal 

defect on TEE, 6,7,10 are 

a. Basal short axis view, b. bicaval or basal long axis view, 

c. Four chamber view. 

3.2.1. Basal short axis view 

Obtained by keeping the endoscope at the middle part of 

esophagus. 

The aortic and atrial rims can be best seen in this view. 

The fossa ovalis defect is seen in middle part of defect while 

sinus venosus defect is seen in the upper part of defect. 

3.2.2. Basal long axis or bicaval view 

Fig. 17 e 2d echocardiography shows in 4 chamber view 

shows the large inlet VSD getting partially restricted by 

septal leaflet of tricuspid valve. Such partial closure of VSD 

is more commonly a feature of perimembranous VSD and 

is very rarely seen in the inlet VSD as in the present case. 

Endoscope at the same level and rotating the icon to 80e100 0 . 

Fossa ovalis defect is seen in middle part of septum, while 

sinus venosus defect is seen in relation to superior vena 

cava with superior vena cava type of defect or in relation to 

inferior vena cava with inferior vena cava type of defect 

along with partial anomalous venous drainage of pulmonary 

vein. 

SVC and IVC rims can be accurately assessed in this view. 

3.2.3. Four-chamber view 

Obtained by keeping the endoscope at the lower part of 

esophagus.


Atrial and atrioventricular valve rims of fossa ovalis defect 

are visualized and volume overloaded right atrium and right 

ventricle. 

By rotating the endoscope we can see the attachment of 

right and left pulmonary veins to left atrium. 

4. Ventricular septal defect (Table 2) 

4.1. Objectives of echocardiography 

Confirm ventricular septal defect (VSD). 

Determine the size and morphological location of VSDs. 

Rule out associated lesions. 

Assessment of chamber size and wall thickness. 

Estimation of shunt size (pulmonary/systemic flow ratio). 

Estimate right ventricular and pulmonary arterial pressures. 

4.2. Classification of VSD (Fig. 12) 

Ventricular septal defects can be classified into following 

types 12,13 : a e perimembranous ventricular septal defect 

(Figs. 13 and 18), b e muscular ventricular septal defect 

(Figs. 14 and 15): i. muscular inlet, ii. muscular outlet (Fig. 14), 

iii. trabecular defect (Fig. 15), c e doubly committed ventricular 

septal defect (Figs. 16 and 19), d e inlet ventricular septal 

defect (Fig. 17). 

4.3. Size of ventricular septal defect 

The judgment of size of defect is generally made on hemodynamic 

grounds (degree of left to right shunt, presence of 

volume overload, and pulmonary artery pressure). 

Comparative size: According to some authors a VSD size is 

defined in relation to aortic root size. Small ventricular septal 

defect are defined if less than 1/3rd of aortic root diameter, 1/ 

3rd to 2/3rd of aortic root diameter considered as moderate 

sized defect, and the lesions that are approximate to the size 

of aortic root are defined as large VSD. The disadvantage of the 

method of classifying defects is that some defects which are 

anatomically large can be restricted in terms of shunt and 

pressure because of reduction in size by tricuspid valve or 

aortic valve. 

Hemodynamic classification uses the pressure differential 

across the left to right ventricle to classify defects. With isolated 

defects, when there is equalization of pressure between 

Fig. 18 e 2d echocardiography with various view shows the profilation of perimembranous VSD. A: shows the 

perimembranous defect with anterior tilt in subcostal coronal view with anterior tilt showing the defect. B: shows the 

parasternal short axis view shows the location of the perimembranous defect from 9 o’clock to 11 o’clock position, C1: 

shows the location of the perimembranous VSD with slight posterior tilt toward the tricuspid valve in 2d and color flow 

mapping (C2).

212 


pulmonary stenosis. With severe right ventricular outflow 

obstruction, if ventricular septal defect is small, one can get 

a turbulent jet of right to left shunt with suprasystemic right 

ventricle systolic pressure (Fig. 21). 

With the use of color flow mapping with careful interrogation, 

one should also look for any left ventricle to right 

atrial shunt as high velocity of left ventricle to right atrial 

jet can be misinterpreted as elevated right ventricle pressure. 

This can happen particularly with ventricular septal 

defect which are getting smaller by septal leaflet of 

tricuspid valve. 

4.5. Direction of shunt 

Fig. 19 e 2d echocardiography with parasternal long axis 

view shows the doubly committed VSD getting restricted 

with right coronary cusp of the aortic valve with significant 

prolapse of the right coronary cusp. Though such prolapse 

may significantly decrease the left to right shunting and 

hence volume overload, it by itself because of the 

significant prolapse is an indication of surgery to prevent 

the damage to the aortic valve. 

two ventricles in absence of pulmonary stenosis, then it is 

called as large or nonrestrictive defect. Since right and left 

ventricles do not contract exactly simultaneously, there is 

always some inequality in the ventricular pressures as estimated 

by Doppler technique since it measures instantaneous 

pressure difference. A restrictive defect is one in which right 

ventricular and pulmonary artery pressures are lower than 

left ventricle with pressure gradient of more than 60 mmHg 

(ventricular septal defect peak velocity more than 4 m/s), and 

moderately restrictive ventricular septal defect with pressure 

difference of 25e60 mmHg (ventricular septal defect peak 

velocity 2.5e4 m/s). 

The VSD may be associated with anterior or posterior 

malalignment and these VSDs in the region of the perimembranous 

area are generally large VSDs. Those with anterior 

malalignment may be associated with narrowing of the 

anterior outflow tract (generally pulmonary) as in Tetralogy of 

Fallot. Those VSDs associated with posterior malalignment 

are associated with narrowing of the posterior outflow 

(generally aorta) (Fig. 20 AeC). 

4.4. Patterns of shunting across VSD 

Nonrestrictive ventricular septal defect with high pulmonary 

vascular resistance, direction of flow can be bidirectional 

or dominantly right to left depending upon the 

severity of pulmonary vascular obstructive disease. 

With associated pulmonary stenosis, there may be isolated 

right to left shunt depending upon the severity of 

With isolated uncomplicated nonrestrictive VSD, pressure 

between the two ventricles is similar. 

In patients with low pulmonary vascular resistance, dominant 

shunt occurs from left to right during systole, and with 

increase in left ventricle end diastolic pressure left to right 

shunt will persist during diastole also. 

A typical ‘M’ shaped flow pattern is being described in 

patients with nonrestrictive VSD, explanation for which ise 

as left ventricle contraction starts early and last longer than 

right ventricle, so with onset of systole flow occur from left 

to right, with decrease in degree of shunt during mid systole 

as pressure between two ventricles equalized, and in later 

part of systole as right ventricle relaxes left to right shunt 

dominates. 

With restrictive VSD, left to right shunting occurs 

throughout systole. In some small muscular VSD, left to 

right shunt occurs only during a portion of systole, presumably 

because of closure of muscular ventricular septal 

defect in mid systole with ventricular contraction. Bidirectional 

or right to left shunting can occur with restrictive and 

nonrestrictive VSD as described earlier. 

4.6. Continuous and pulsed wave Doppler examination 

Pulsed and continuous wave Doppler examination is used to 

assess 14e16 : 

- Direction of shunt across VSD. 

- Pressure gradient across the defect (difference of left ventricleeright 

ventricle systolic pressure). 

- Right ventricle pressure (by VSD gradient and peak gradient 

of tricuspid regurgitation jet). 

- Diastolic function of both ventricles. 

4.7. Pressure gradient across ventricular septal defect 

(Fig. 3b) 

While taking continuous wave Doppler across VSD, the 

cursor should be well aligned with VSD jet on color flow 

mapping. 

The velocity of the VSD shunt can be determined using the 

Bernoulli’s equation. This will give the difference between 

the left and right ventricular systolic pressure. 

The left ventricular systolic pressure is derived from the 

systolic blood pressure (provided there is no left ventricular


Fig. 20 e A and B shows a large malaligned ventricular septal defect with anterior malalignment of the septum leading to 

associated pulmonary stenosis profiled in parasternal long axis view (A) and subcostal view (B). C shows the large 

malaligned VSD with anterior malalignment leading to subaortic narrowing profiled in parasternal long axis view. 

out flow obstruction), which should be recorded at the time 

of Doppler study using appropriate sized BP cuffs. 

Right ventricular pressure ¼ Systolic blood pressure VSD jet 

peak gradient 

This equation has been found to have good correlation 

with cardiac catheterization derived right ventricle systolic 

pressure. 

However, sometimes the jet velocity may not reflect the 

interventricular pressure gradient accurately because 

proper alignment of the Doppler beam with the jet is not 

possible, and that if the defect has some length to it, the 

viscous frictional forces make the application of the modified 

Bernoulli’s equation inappropriate. 

Determining the right ventricular pressure from tricuspid 

insufficiency jet velocity (which may be found in some 

cases) is also very useful. 

4.8. M mode echocardiography (Fig. 22) 

Assess the left atrial and left ventricular size to quantitate 

shunt across ventricular septal defect. 

Right ventricular size and wall thickness, which will reflect, 

elevated right ventricular systolic pressure. 

For direction of shunt, this is rarely used in daily practice but 

depicts best the direction of shunting during the various 

phases of a cardiac cycle. 

4.9. Interrogation of the atrioventricular and semilunar 

valves for regurgitation and stenosis 

The tricuspid regurgitation velocity should always be obtained 

to predict the right ventricular systolic pressure and 

hence indirectly the pulmonary artery pressure if there is no 

pulmonary stenosis. 

Presence of pulmonary stenosis, and aortic regurgitation 

should be evaluated. 

Fig. 21 e 2d echocardiography with parasternal long axis 

view of a case of doubly committed VSD in a 25-year-old 

man with Eisenmenger syndrome showing significant 

right to left shunt. The LV dimensions were normal in the 

present case with Z score of 1.1. 

Fig. 22 e M mode echocardiographic evaluation of a case of 

VSD taken in parasternal long axis view. The LV end 

diastolic dimensions (LVIDd) is compared to expected for 

the weight of the child and a dilated LV with Z score of 

more than 2 signifies significant left to right shunt (>2:1) 

and hence an indication for intervention.

214 


The velocities of both atrioventricular valves and semilunar 

valves should be taken to rule out any associated abnormality. 

The mitral valve gradients may get exaggerated in 

the presence of VSD (Fig. 23). 

4.10. Pulmonary blood flow to systemic blood flow ratio 

As regards quantifying pulmonary and systemic shunt flow 

using Doppler echocardiography several methods currently 

exists, although none is widely used due to variable 

results. 

4.11. Assessment of suitability for device closure 

Percutaneous closure for mid muscular VSD and perimembranous 

VSD can be done. While assessing the child for device 

closure of muscular defect, the defect should be at least 5 mm 

away from atrioventricular valves and semilunar valves and 

there should not be associated other defects requiring cardiopulmonary 

bypass. The softer variety of ADOII series can 

be used to close the defects in perimembranous region 

(particularly in a defect with good aneurysm) and also in 

muscular VSD. 

4.12. Utility of transesophageal echocardiography 

Transesophageal echocardiography has helped in better 

visualization of VSD, especially when transthoracic window 

is poor, like in adolescents and adults. Straddling and 

overriding of the atrioventricular defect can be better 

detected by transesophageal echocardiography. 

5. Patent ductus arteriosus (PDA) (Table 3) 

5.1. Objectives of echocardiography 

The presence of a duct 

Detailed definition of ductus 

B Size of the duct 

B Type of duct 

The hemodynamic significance of a duct 

B Direction of shunt 

B Pulmonary arterial pressure 

B Quantification of shunt 

Associated defects 

5.2. Method 

Various views to define the ductus are as under 17e20 : 

1) Ductal View (Fig. 24) e this uses the high parasternal window 

just beneath the left clavicle. After obtaining the short 

axis cut of the great vessel visualizing the pulmonary artery 

bifurcation the transducer is rotated anticlockwise in 

gradual motion. At one point the left pulmonary artery goes 

away from view and the duct with adjacent descending 

aorta opens. This view in neonates and infants also visualizes 

the origin of the left subclavian artery. In patients 

with associated coarctation the posterior shelf is also well 

visualized. 

2) Suprasternal view e 

a) Suprasternal long axis view e This is the best view for 

visualizing the vertical duct arising from the undersurface 

of the transverse arch in patients with pulmonary 

atresia. The origin of such ductii is well seen 

Fig. 23 e 2d echocardiography with color compare showing the well open mitral valve in 2d (A) and turbulence across mitral 

valve in B. The turbulence in color flow mapping across the mitral valve is essentially because of the increased flow across 

the mitral valve because of the associated nonrestricted VSD extending from the perimembranous to the inlet septum.


insertion. In the usual duct, this can be accurately 

measured in the ductal view or the modified arch view. 

b) Size of the ampulla of duct e it can be best measured in the 

modified ductal view. 

c) The length of the duct that is necessary to determine adequacy 

of coil/device/stent placement and also the need 

for evaluation for ADOII series of PDA devices. It is again 

best determined by the modified ductal view. 

In patients with inadequate windows, the size of the duct 

can be determined by the narrowest width of the color flow 

across the duct. This, however, always overestimates the 

ductal size and gives only a rough estimate. 

5.4. Hemodynamic significance 

Hemodynamic significance of ductus arteriosus can be 

assessed by evidence of volume overload of LA and LV, direction 

of shunt, and pulmonary arterial pressure. 

Fig. 24 e 2d echocardiography with color flow mapping in a 

high parasternal view (ductal view) showed the PDA with 

left to right shunt across. There is a good ampulla of the 

ductus with narrowing of the ductus before its insertion 

into the pulmonary artery. 

but the insertion point at the pulmonary artery 

required further anterior tilt. This is because of the 

tortuous nature of such ductii. In patients with 

discordant ventriculo-arterial connection (e.g. transposition 

of great vessels), the duct can be visualized 

very well in its entire length in this view. 

b) Suprasternal short axis view e this is the classical 

short axis arch view and can visualize those rare ductii 

which arises form the base of the left subclavian artery 

and descends straight down to insert into the left 

pulmonary artery. If aortic arch is right sided and the 

patient has pulmonary stenosis physiology. The entire 

length of the duct can be seen in one view because 

unlike in those patients with vertical duct it does not 

follow a tortuous course. 

c) Modified ductal view e this a less well described view 

to visualize the usual duct. It has the advantage of 

visualizing the duct in its entire length and most 

closely mimics the lateral angiogram performed during 

cardiac catheterization. From the usual suprasternal 

long axis view the transducer is rotated 

anticlockwise. A slight anterior tilt then shows the 

duct from its ampullary part to its insertion and accurate 

measurements can be made. 

5.3. Measurements of the duct 

Various measurements on the duct by echocardiography 

include: 

a) Size of the narrowest part of the duct e in the majority of 

cases this would be at the site of pulmonary artery 

Chamber dimensions: 

Left atrial enlargement signifies increased pulmonary 

venous return because of left-to-right ductal shunting. 

The reference measure is the ratio of the left atria to aorta 

at the level of the aortic valve (the LA: Ao ratio) by M mode 

echocardiography in parasternal long axis view. 

The aortic root does not enlarge significantly with even 

extremely large patent ductus arteriosus. 

A LA: Ao ratio >1.3:1 indicates a significant shunt. 

LV will enlarge as cardiac output increases with both 

increased pulmonary venous return and with increased 

diastolic run-off from the systemic circulation. 

5.5. Direction of shunt and pulmonary arterial pressure 

On color flow mapping, small duct with normal pulmonary 

artery pressure is displayed as a mosaic flow from 

descending aorta to pulmonary artery. With large duct, and 

low pulmonary vascular resistance, the duct jet appears as 

predominantly red flow with minimal aliasing. 

In patients with severe pulmonary arterial hypertension, on 

color flow mapping, there will be bidirectional shunt. 

With suprasystemic pulmonary artery pressure as in 

obstructed total anomalous pulmonary venous connection 

a restrictive duct will show turbulent high velocity right to 

left flow in systole and diastole in the descending aorta. This 

can give signals very similar to coarctation of aorta. 

5.6. Continuous wave Doppler examination of ductus 

arteriosus (Fig. 3A) 

By the use of continuous wave Doppler, direction of shunt in 

relation to cardiac cycle and pulmonary arterial pressure 

(systolic blood pressure minus pressure gradient cross 

duct ¼ systolic pulmonary arterial pressure) can be detected 

accurately. 

With isolated left to right shunt, with small to moderate 

sized patent ductus arteriosus and normal or mildly 

elevated pulmonary artery pressure, Doppler examination

216 


of duct shows continuous flow toward the transducer with 

peak in late systole. 

In large duct with pulmonary arterial hypertension, there 

will be bi-directional shunting on Doppler imaging of duct, 

right to left in systole and left to right in diastole. 

With increasing pulmonary vascular resistance as with no 

step up in oxygen saturation above and below the duct, peak 

of right to left shunt appear early in systole. 

With further rise in pulmonary vascular resistance, right to 

left shunt begins in diastole extending to systole and right to 

left shunt if present occurs only in late systole to early 

diastole. 

With duct dependent systemic circulation and severe pulmonary 

arterial hypertension, there will be isolated right to 

left shunting across the duct. 

5.7. Limitations of echocardiographic imaging of the 

duct 

There are several limitations of profilation of duct by twodimensional 

imaging 

1) The primary limitation of echocardiography is the restriction 

imposed by limited acoustic windows. The duct is 

profiled in the direction of lateral resolution of the transducer, 

so it is difficult to visualize with certainty very small 

duct in small babies. High frequency probe with excellent 

lateral resolution is needed. 

2) If the duct is long and tortuous, it may be difficult to profile 

whole length of the duct 

3) Poor acoustic windows as in adults with thick chest. 

6. Aortopulmonary window (Fig. 25) 

Aortopulmonary window or aortopulmonary septal defect 

accounts for 0.2e0.6% of patients with congenital heart 

defects. Nearly half of all patients have associated cardiac 

lesions, including aortic origin of the right pulmonary artery, 

type A interruption of the aortic arch, Tetralogy of Fallot, and 

anomalous origin of the right or left coronary artery from the 

pulmonary artery and right aortic arch. More rarely, it is 

associated with ventricular septal defect, pulmonary or aortic 

atresia, D-transposition, and tricuspid atresia 

Objectives of echocardiography 

Diagnosis 

Type of aortopulmonary window 

Associated heart defects 

Operability 

Two-dimensional echocardiography usually can accurately 

diagnose the aortopulmonary septal defect. 

Views, which are most useful for diagnosis, are parasternal 

short axis at the level of great vessels, subcostal coronal 

view of left ventricular outflow tract and the suprasternal 

views. 

In all these views, the wall separating aorta and pulmonary 

artery is aligned in the direction of lateral resolution, so 

great care is needed to differentiate true defect from artifactual 

dropout. A ‘T’ artifact at the edges of the defect will 

distinguish it from normal dropout. 

Color flow mapping: Color flow mapping is used to 

demonstrate flow through the defect. 

With large defect, which is usually the case, the flow appear 

laminar, low velocity, bidirectional flow across the defect. 

Smaller defect, a continuous high velocity left to right jet is 

usually present. 

With low pulmonary vascular resistance, evidence of aortic 

run-off can be detected in ascending and descending aorta 

in contrast to patent ductus arteriosus. 

Fig. 25 e 2d echocardiography with color comparison in parasternal short axis view showing a large AP widow in 2d (A)and 

color Doppler (B).


Fig. 26 e 2d echocardiography with color mapping comparison showing the Gerbode defect with left to right shunt. 

7. Gerbode defect (Figs. 26 and 27) 

The lesions such as Gerbode defect suggest LV to RA shunt and 

essentially lead to volume overload of the RA and the RV. 

In such cases the RA dimensions and features of right atrial 

volume overload need to be looked at. The features are 

essentially same as that of the atrial septal defect. 

The point to remember is that the pressure difference across 

tricuspid valve taken in these circumstances may be 

fallacious as one may pick up the left ventricle to RA 

gradient which will be systemic (mistaking it to be that of 

the tricuspid velocity signal). 

The shunt lesions such as pulmonary AV fistulas and 

coronary AV fistulas and systemic AV fistulas are not specifically 

covered in the present section. For the purpose of 

completion, they will represent the left to right shunt and 

would lead to the chamber enlargement of the chamber into 

which they drain. 

Fig. 27 e 2d echocardiography with color flow comparison in parasternal short axis view shows the Gerbode defect with left 

to right shunt.

218 




references 

1. Awasthy N, Radhakrishnan S, Shrivastava S. Double orifice 

mitral valve with PDA. J Indi Acad Echo. 2013;24:48e50. 

2. Awasthy N, Marwah A, Sharma R, Dalvi B. Anomalous origin 

of the left coronary artery from the pulmonary artery with 

patent ductusarteriosus: a must to recognize entity. Eur J 

Echocardiogr. 2010;11:E31. 

3. Awasthy N, Marwah A, Sharma R. Occult anomalous 

origin of the left coronary artery from the pulmonary 

artery with ventricular septal defect. Ann Pediatr Cardiol. 

2011;4:62e64. 

4. Awasthy N, Ambadkar P, Radhakrishnan S, Iyer KS. 

Lutembacher syndrome with unroofed left superior vena 

cava: a diagnostic dilemma. Pediatr Cardiol. 2012;24:1e2. 

5. Awasthy N, Tomar M, Radhakrishnan S, Iyer KS. Constriction 

juxta-ductal aorta rapid progression obstruction a newborn. 

Ann Pediatr Cardiol. 2010;3(2):181e183. 

6. Shrivastava S, Radhakrishnan R, Tomar M, eds. 

Echocardiography in Pediatric Heart Disease. 1st ed. Siddharth 

Publications; 2009. 

7. Vermilion PR. Basic physical principles. In: Snider AR, 

Serwer AG, Ritter SB, eds. Echocardiography in Pediatric Heart 

Disease. 2nd ed. Mosby; 1997:1e10. 

8. Dillon JC, Wayman AE, Feigenbaum H, Eggleton RC, 

Johnston K. Cross-sectional echocardiographic 

examination of the interatrial septum. Circulation. 

1977;55:115e120. 

9. Child JS. Echo-Doppler and color-flow imaging in congenital 

heart disease. Cardiol Cln. 1990;8:289e313. 

10. Nasser FN, Tajik AJ, Seword JB, Hagler DJ. Diagnosis of sinus 

venosus atrial septal defect by two-dimensional 

echocardiography. Mayo Clin Proc. 1981;56:568e572. 

11. Assessment of right to left shunt flow in atrial septal defect by 

transesophageal color and pulsed Doppler echo cardiography. 

J Am Soc Echocardiogr. 1994;7(5):506e515. 

12. Bierman FZ, Fellows K, Williams RG. Prospective identification 

of ventricular septal defect in infancy using subxiphoid twodimensional 

echocardiography. Circulation. 1980;6:807e817. 

13. Capelli H, Andrads JL, Somerville J. Classification of the site of 

ventricular septal defect by two-dimensional 

echocardiography. Am J Cardiol. 1983;51:1474e1480. 

14. Ortiz E, Robinson PJ, Deanfield JE, Franklin R, Macartney FJ, 

Wyse RK. Localization of ventricular septal defects by 

simultaneous display of superimposed colour Doppler and 

cross sectional echocardiographic images. Br Heart J. 

1985;54:53e60. 

15. Helmcke F, de Souza A, Nanda NC, et al. Two-dimensional 

and color Doppler assessment of ventricular septal defect of 

congenital origin. Am J Cardiol. 1989;63:1112e1116. 

16. Murphy DJ, Ludomirsky A, Huhta JC. Continuous wave 

Doppler in children with ventricular septal defect: 

noninvasive estimation of interventricular pressure gradient. 

Am J Cardiol. 1986;57:428e432. 

17. Huhta JC, Cohen M, Gutgesell HP. Patency of the ductus 

arteriosus in normal neonates: two dimensional 

echocardiography vs Doppler assessment. J Am Coll Cardiol. 

1984;4:561e564. 

18. Silverman NH. Patent ductus arteriosus. In: Pediatric 

Echocardiography. Baltimore, MD: Williams & Wilkins; 

1993:167e177. 

19. Liao PK, Su WJ, Hung JS. Doppler echocardiographic flow 

characteristic of isolated patent ductus arteriosus: better 

delineation by Doppler color flow mapping. J Am Coll Cardiol. 

1988;12:1285e1291. 

20. Swensson RE, et al. Real time Doppler color flow mapping for 

detection of patent ductus arteriosus. Pediatr Cardiol. 

1986;8:1105.

222 


patients without baseline “SCD-HeFT criteria” (left ventricular 

ejection fraction >0.35 or NYHA class I), 125 were 

evaluated after 5.5 2 months. Of these 227 patients, 13 

(10%) developed “SCD-HeFT criteria” (group B1), 111 (89%) 

remained without “SCD-HeFT criteria” (group B2), and 1 

(1%) had worsened to NYHA class IV. The 10-year mortality/heart 

transplantation and sudden death/sustained 

ventricular arrhythmia rate was 57% and 37% in group A1, 

23% and 20% in group A2 (p < 0.001 for mortality/heart 

transplantation and p e 0.014 for sudden death/sustained 

ventricular arrhythmia vs. group A1), 45% and 41% in group 

B1 ( p e NS vs. group A1), 16% and 14% in group B2 ( p e NS 

vs. group A2), respectively. 

Conclusion: Two thirds of patients with idiopathic 

dilated cardiomyopathy and “SCD-HeFT criteria” at presentation 

did not maintain implantable cardioverterdefibrillator 

indications 3e9 months later with optimal 

medical therapy. Their long-term outcome was excellent, 

similar to that observed for patients who had never met the 

“SCD-HeFT criteria.” 


Since the publication of the SCD-HeFT and the DEFINITE 

trials, treatment with ICD for the primary prevention of 

sudden cardiac death (SCD) has been extended to patients 

with idiopathic dilated cardiomyopathy (IDC), who have a 

LVEF of 0.35 and who are classified as NYHA II or III (“SCD- 

HeFT criteria,” class I B indication). The appropriate timing 

for ICD implantation, however, is still uncertain. Current 

guidelines suggest that an ICD should be considered in 

addition to medical therapy, but many patients are treated 

with an ICD without evidence-based indications, mainly 

because of newly diagnosed heart failure and before treatment 

optimization. This study evaluated the proportion of 

patients with and without potential indications for ICD 

implantation at presentation and the long-term prognosis of 

patients with initial ICD indications but who improved after 

optimization of medical treatment. It also compared the 

long-term outcome of “improved” patients to those maintaining 

“SCD-HeFT criteria” and those who never met “SCD- 

HeFT criteria.” 

This trial included only patients who were not on beta 

blockers. After initial assessment, optimization of medical 

treatment was achieved with gradually up-titrating doses of 

beta blockers and ACEI/ARB at the highest tolerated dose over 

a period of 3e9 months. 

The main results of the present study are: 1) 50% patients 

had SCD-HeFT criteria at first assessment and would have 

otherwise received an ICD. 2) 2/3rd of patients with SCD-HeFT 

criteria at baseline “improved” and no longer maintained SCD- 

HeFT criteria 5.5 months after starting beta blocker and ACEI 

treatment. 3) The long-term SCD were similar in “improved” 

patients and in those without SCD-HeFT criteria, suggesting 

ICD implantation should not be done in most patients with 

low LVEF and HF symptoms before optimization of medical 

treatment. 4) SCD (4 patients e 2%) was similar in patients 

both with and without SCD-HeFT criteria before second 

evaluation at 3e9 months, confirming the difficulty of stratifying 

risk of SCD at first evaluation. 

This study emphasizes how important is the optimization 

of medical therapy in patients initially presenting with ICD 

indications and ICD implantation can be avoided in the 

majority of such patients. Even in USA, nearly 22.5% of 

patients with an ICD did not meet the evidence-based criteria 

for implantation, mainly because of newly diagnosed 

HF (62%). Such unnecessary ICD implantations should be 

avoided because of economic issues (especially in a developing 

country like India), the risk of complications associated 

with implantation and inappropriate shocks (in w25% 

of patients). 

What then is the waiting period for ICD implantation after 

onset of HF symptoms in patients with LVEF 35%? Well, we 

have no clear-cut answer. Data from DEFINITE trial suggest 

early ICD implantation (


patients who were on dialysis. This study compared Cinacalcet 

with placebo in 3883 patients undergoing dialysis. Limited 

number of interventions are found to improve cardiovascular 

health in CKD undergoing dialysis. Secondary hyperparathyroidism 

has emerged as one of the most important 

risk factors for cardiovascular disease and thus, high rate of 

death and cardiovascular events in end stage renal disease. 3 

Although this trial result is non-definitive but after adjustment 

to the baseline characteristics there was nominally significant 

12% reduction in cardiovascular risk, 15% reduction in 

primary composite end point and 17% reduction in mortality. 

One has to understand the context of the patients who are 

on dialysis, frequently have poor health and high mortality 

(20% in United States) and morbidity (median 2 hospitalization 

and 12 hospital days per year). Patients have multi organ 

involvement with average pill burden of 19. Cinacalcet 

reduces parathyroidectomy by 50%. The study includes 

Cohorts from various geographic area, race, ethnicity, age and 

underlying kidney and cardiovascular diseases. 

Analysis adjusted for baseline characteristics on taking 

into account the effect of parathyroidectomy and kidney 

transplantation a nominally significant reduction on death on 

first Myocardial Infarction, hospitalization for unstable 

angina, heart failure and peripheral vascular disease (risk 

reduction 10e15% and absolute reduction of 2e3%). 

references 

1. Kidney disease improving global outcomes (KDIGO) CKD-MBD 

Work Group. Kidney Int Suppl. 2009;76:S1eS130. 

2. Cunningham J, et al. Kidney Int. 2005;68:1793. 

3. Chertow GM, et al. Am Soc Nephrol. 2007;2:898e905. 

Ajay Kumar Sinha 

Associate Editor, IHJ, India 

E-mail address: sinha_ajaykr@yahoo.co.in 

Gregg W. Stone, Alexandre Abizaid, Sigmund Silber, et al., 

Prospective, randomized, multicenter evaluation of a polyethylene 

terephthalate micronet mesh-covered stent 

(MGuard) in ST-segment elevation myocardial infarction: the 

MASTER trial. J Am Coll Cardiol 60 (2012) 1975e1984 


The enemy of revascularization using primary PCI during 

STEMI intervention is risk of distal embolization with capillary 

plugging which leads to reduced tissue reperfusion. Several 

pharmacological agents, as well as mechanical devices (i.e. 

manual aspiration catheters/mechanical thrombectomy, 

proximal and distal protection devices) were introduced, in 

the last years, to reduce the risk of angiographic complications 

during percutaneous coronary intervention and to 

improve myocardial reperfusion. 1,2 Despite the use of these 

agents still distal embolization is common which leads to noreflow 

phenomenon. 1,2 

Recently, the MGuard stent (InspireMD, Tel Aviv, Israel), a 

bare metal stent covered by micron level mesh, which allows 

to prevent distal embolization by blocking the athero-thrombi 

prolapse through the stent struts during deployment. 3 

Dr. Gregg W. Stone presented the late-breaking findings 

from the MASTER study were presented in a late-breaking 

session at TCT 2012 that revealed a new stent in STEMI 

patients undergoing emergent PCI to increase the rate of complete 

ST-segment resolution compared with conventional BMS 

and DES. 

2. Objectives 

MASTER study sought to evaluate the potential utility of a 

novel polyethylene terephthalate micronet mesh-covered 

stent (MGuard) in patients with acute ST-segment elevation 

myocardial infarction (STEMI) undergoing percutaneous coronary 

intervention (PCI). 

3. Study design 

The MASTER trial is a prospective, multicenter, randomized 

study designed to compare the incidence of complete 

(70%) ST-segment resolution with PCI using bare metal or 

drug-eluting stents (the control arm) versus PCI with the 

MGuard stent, measured 60e90 min after the last angiogram 

(primary endpoint). 

Secondary endpoints include the rates of TIMI flow and 

myocardial blush, and clinical outcomes through 1-year 

follow-up. 

The study has enrolled 432 patients with STEMI undergoing 

primary or rescue angioplasty within 12 h of symptom 

onset, and includes sub studies with cardiac magnetic resonance 

imaging and quantitative coronary angiography to 

evaluate infarct size, micro vascular obstruction and 

angiographic restenosis. 

Study population for trial enrolled a total 433 STEMI patients 

who presented within 12 h of symptom onset, at 50 sites in 9 

countries. 

These enrolees were randomly assigned to receive commercially 

available stents (n ¼ 216; 60% BMS; 40% DES) or 

MGuard (n ¼ 217). The two groups had equal baseline 

characteristics. 3 

4. Results 

Significantly more patients treated with the MGuard 

EPS achieved the primary endpoint of post-procedure 

of complete ST resolution (a measure of blood flow 

restoration to the heart muscle) compared to control arm 

(57.8% vs. 44.7%, p ¼ 0.008), a relative improvement of 29% 

[Fig. 2]. 

When compared to control, the MGuard EPS showed a significant 

improvement in coronary artery blood flow, 

including (1): superior rates of restoring normal blood flow 

(TIMI 3 flow) (91.7% vs. 82.9%, p ¼ 0.006, a relative 

improvement of 10.6%); and (2) significantly less incomplete 

blood flow (TIMI 0/1 flow) post PCI (1.8% vs. 5.6%, p ¼ 0.01, a 

relative improvement of 67.9%). 

The trial showed a trend toward lower mortality (0% vs. 

1.9%, p ¼ 0.06) at 30 days and smaller infarct size as


patients who were on dialysis. This study compared Cinacalcet 

with placebo in 3883 patients undergoing dialysis. Limited 

number of interventions are found to improve cardiovascular 

health in CKD undergoing dialysis. Secondary hyperparathyroidism 

has emerged as one of the most important 

risk factors for cardiovascular disease and thus, high rate of 

death and cardiovascular events in end stage renal disease. 3 

Although this trial result is non-definitive but after adjustment 

to the baseline characteristics there was nominally significant 

12% reduction in cardiovascular risk, 15% reduction in 

primary composite end point and 17% reduction in mortality. 

One has to understand the context of the patients who are 

on dialysis, frequently have poor health and high mortality 

(20% in United States) and morbidity (median 2 hospitalization 

and 12 hospital days per year). Patients have multi organ 

involvement with average pill burden of 19. Cinacalcet 

reduces parathyroidectomy by 50%. The study includes 

Cohorts from various geographic area, race, ethnicity, age and 

underlying kidney and cardiovascular diseases. 

Analysis adjusted for baseline characteristics on taking 

into account the effect of parathyroidectomy and kidney 

transplantation a nominally significant reduction on death on 

first Myocardial Infarction, hospitalization for unstable 

angina, heart failure and peripheral vascular disease (risk 

reduction 10e15% and absolute reduction of 2e3%). 

references 

1. Kidney disease improving global outcomes (KDIGO) CKD-MBD 

Work Group. Kidney Int Suppl. 2009;76:S1eS130. 

2. Cunningham J, et al. Kidney Int. 2005;68:1793. 

3. Chertow GM, et al. Am Soc Nephrol. 2007;2:898e905. 

Ajay Kumar Sinha 

Associate Editor, IHJ, India 

E-mail address: sinha_ajaykr@yahoo.co.in 

Gregg W. Stone, Alexandre Abizaid, Sigmund Silber, et al., 

Prospective, randomized, multicenter evaluation of a polyethylene 

terephthalate micronet mesh-covered stent 

(MGuard) in ST-segment elevation myocardial infarction: the 

MASTER trial. J Am Coll Cardiol 60 (2012) 1975e1984 


The enemy of revascularization using primary PCI during 

STEMI intervention is risk of distal embolization with capillary 

plugging which leads to reduced tissue reperfusion. Several 

pharmacological agents, as well as mechanical devices (i.e. 

manual aspiration catheters/mechanical thrombectomy, 

proximal and distal protection devices) were introduced, in 

the last years, to reduce the risk of angiographic complications 

during percutaneous coronary intervention and to 

improve myocardial reperfusion. 1,2 Despite the use of these 

agents still distal embolization is common which leads to noreflow 

phenomenon. 1,2 

Recently, the MGuard stent (InspireMD, Tel Aviv, Israel), a 

bare metal stent covered by micron level mesh, which allows 

to prevent distal embolization by blocking the athero-thrombi 

prolapse through the stent struts during deployment. 3 

Dr. Gregg W. Stone presented the late-breaking findings 

from the MASTER study were presented in a late-breaking 

session at TCT 2012 that revealed a new stent in STEMI 

patients undergoing emergent PCI to increase the rate of complete 

ST-segment resolution compared with conventional BMS 

and DES. 

2. Objectives 

MASTER study sought to evaluate the potential utility of a 

novel polyethylene terephthalate micronet mesh-covered 

stent (MGuard) in patients with acute ST-segment elevation 

myocardial infarction (STEMI) undergoing percutaneous coronary 

intervention (PCI). 

3. Study design 

The MASTER trial is a prospective, multicenter, randomized 

study designed to compare the incidence of complete 

(70%) ST-segment resolution with PCI using bare metal or 

drug-eluting stents (the control arm) versus PCI with the 

MGuard stent, measured 60e90 min after the last angiogram 

(primary endpoint). 

Secondary endpoints include the rates of TIMI flow and 

myocardial blush, and clinical outcomes through 1-year 

follow-up. 

The study has enrolled 432 patients with STEMI undergoing 

primary or rescue angioplasty within 12 h of symptom 

onset, and includes sub studies with cardiac magnetic resonance 

imaging and quantitative coronary angiography to 

evaluate infarct size, micro vascular obstruction and 

angiographic restenosis. 

Study population for trial enrolled a total 433 STEMI patients 

who presented within 12 h of symptom onset, at 50 sites in 9 

countries. 

These enrolees were randomly assigned to receive commercially 

available stents (n ¼ 216; 60% BMS; 40% DES) or 

MGuard (n ¼ 217). The two groups had equal baseline 

characteristics. 3 

4. Results 

Significantly more patients treated with the MGuard 

EPS achieved the primary endpoint of post-procedure 

of complete ST resolution (a measure of blood flow 

restoration to the heart muscle) compared to control arm 

(57.8% vs. 44.7%, p ¼ 0.008), a relative improvement of 29% 

[Fig. 2]. 

When compared to control, the MGuard EPS showed a significant 

improvement in coronary artery blood flow, 

including (1): superior rates of restoring normal blood flow 

(TIMI 3 flow) (91.7% vs. 82.9%, p ¼ 0.006, a relative 

improvement of 10.6%); and (2) significantly less incomplete 

blood flow (TIMI 0/1 flow) post PCI (1.8% vs. 5.6%, p ¼ 0.01, a 

relative improvement of 67.9%). 

The trial showed a trend toward lower mortality (0% vs. 

1.9%, p ¼ 0.06) at 30 days and smaller infarct size as

224 


Fig. 1 e AeD The MGuard stent has a 316L stainless steel frame with 100-mm strut thickness. It is manufactured in 

diameters ranging from 2.0 to 4.0 mm and in lengths ranging from 11 to 39 mm. The crossing profile ranges from 1.0 to 

1.3 mm. The MGuard prime stent is the MGuard prime stent is similar in configuration, but has an L605 cobalt chromium 

alloy frame with 80-mm strut thickness and slightly lower crossing profile. It is manufactured in diameters ranging from 2.5 

to 4.0 mm and in lengths ranging from 13 to 38 mm. The polyethylene terephthalate micronet is identical on both stents and 

has a fiber width of 20 mm and an expanded aperture size of 150 3 180 mm. 

measured by post-procedure cardiac MRI (17.1 g vs. 22.3 g, 

p ¼ 0.27) in the MGuard EPS arm versus control. 

There was no difference between the groups in the secondary 

endpoint of myocardial blush grade (MBG), which is an 

angiographic measure of blood flow to the cardiac muscle 

(MBG2/3 83.9% vs. 84.7%, p ¼ 0.81). 3 


Among patients with acute STEMI undergoing emergent 

PCI, the MGuard micronet mesh-covered stent com e pared 

with conventional metal stents resulted in superior rates 

of epicardial coronary flow and complete ST-segment 

resolution. 


Suboptimal myocardial reperfusion after PCI in STEMI is 

common and results in increased infarct size and mortality 

(5-year mortality 18.2% with no-reflow vs. patients with good 

reflow9.5%). The no-reflow is strong predictor of 5-year mortality[Fig. 

3]. 2 

Fig. 2 e The primary endpoint of complete ST resolution 

was achieved in 29% more compared to routine PCI using 

BMS/DES [control arm] while partial and absent ST 

resolution comparable to control arm. 

Fig. 3 e No-reflow defined as TIMI 0/1/2, or TIMI 3 

with MBG 0/1. G. Ndrepepa et al compared 5-year 

outcome of 410 patients with no-reflow vs. 996 

patients with reflow. (Kaplan-Meier estimates of 5-year 

mortality 18.2% and 9.5%, respectively; odds ratio: 2.02; 

95% confidence interval: 1.44 to 2.82; p < 0.001).


Covered stents have been tried for embolic protection 

before but they used a tightly woven material that ended up 

squeezing friable material out like toothpaste rather than 

trapping it. 4 The high density of the covered stent is detrimental 

to healing and endothelization process, and also 

blocks all side branches large and small. 

7. MGuard stent: the technology 

InspireMD has developed its proprietary stent system technology, 

MGuardä which is CE-Mark approved. 

The MGuard is a novel thin-strut metal stent [a balloonexpandable 

metallic scaffold] with mesh sleeve fibers of 

polyethylene terephthalate micronet attached to its outer 

surface designed to trap and exclude thrombus and friable 

atheromatous debris to prevent distal embolization 

[Fig. 1AeD]. 

The net is made of a single knitted PET fiber, and it is 

attached only to the proximal and distal edges of the stent. 

The net expands seamlessly during stent deployment. 

MGuard’s net is completely bio-stable. 5 

MGuard is deployed exactly like a typical balloon inflated 

stent after pre-dilatation if necessary and post dilatation is 

recommended whenever there is situation of incomplete 

apposition after stent deployment. 

The net reduces the risk of plaque rupture and embolization 

providing double protection during and post-procedure. 

MGuard addresses risks associated with distal embolization 

and no-reflow which simplifies primary PCI and SVG interventions 

as it is designed for thrombus containing lesions. 

Currently, MGuard is not recommended to be used in bifurcation 

lesions. 4 

8. MGuard stent: evidence 

After successful use of MGuard in First in Man trial in 2008, 

11 Single-Arm Trials are done with 630 patients with 458 

STEMI patients. They evaluated blush grade, ST-segment 

resolution and MACE from 30 days to 1 year. Some of the 

important trials are summarized in Table 1. The Landmark 

trials were the INSPIRE trial 6 which addressed SVG and ACS 

Fig. 4 e A showing comparison of blush grade and their 

predictor for adverse events for bare metal stent [BMS], 

thrombo-aspiration [TA] and MGuard. B showing 

comparison of ST resolution and their predictor for adverse 

events for bare metal stent [BMS], thrombo-aspiration [TA] 

and MGuard. Data on this slide for bare metal stent [BMS], 

thrombus aspiration [TA] and MGuard are derived from 

different sources. Please note a head to head study has not 

been conducted. BMS (n [ 665, TAPAS & EXPORT Trials) TA 

(n [ 655, TAPAS & EXPORT trial aspiration arm) MGuard 

(n [ 234, MAGICAL, Piscione, iMOS, Lindefjeld, Gaul). 

patients using MGUARD stent and MAGICAL trial 

7 had 

STEMI patients but their sample volume was small. Piscione 

et al 9 showed complete ST resolution with 100% device 

success rate. 

The iMOS registry is single arm prospective ‘real world’ 

registry which is ongoing registry with target population of 

Table 1 e Summery of trials of MGuard stent. 

Author/PI Patients Year of publication Highlights 

MASTER trial Gregg Stone et al 3 433 2012 RCT, STEMI patients, randomized 1:1 MGuard vs. BMS/DES. 

Superior rates of complete ST resolution (57.8% vs. 44.7%, 

p ¼ 0.008). Superior rates of TIMI 3 (91.7% vs. 82.9%, p ¼ 0.006), 

0% mortality at 30 days 

INSPIRE trial A. Abizaid et al 6 30 2010 SVG and native coronaries including ACS, no EPD used, 3.3% 

MACE at 30 days, 17% TVR at 1 year 0% death at 1 year 

MAGICAL trial D. Dudek et al 7 60 2010 STEMI patients, multicenter, 90% TIMI flow 3, 73% blush grade 

3, 0% MACCE at 30 days, 1.7% MACCE at 6 months* 

Interim analysis of a real world 

registry (iMOS registry) 

A. Danzi et al 8 211 2010 77% STEMI, 87% visible thrombus, 96% TIMI 3 flow, 98% 

procedural success, 3.8% MACE at 30 days 

Federico Piscione et al 9 100 2009 STEMI patients (n ¼ 84, excluding cardiogenic shock) 100% 

device success, final cTFC ¼ 17.2, 90% MBG 3 90% complete 

ST-segment resolution

226 


1000 patients. Primary endpoint at 6 months of MACE of 

Ischemia related death, myocardial infarction (Q wave and 

non-Q wave), target lesion revascularization (PTCA or CABG). 

They enrolled 81% of AMI patients with 77% of STEMI. 

Thrombus was visible in 87% of the cases and 65% of the 

patients showed initial TIMI flow of 0/1. Device success was 

98% and 96% of the patients gained TIMI 3 flow postprocedure. 

STEMI subgroup clinical analysis revealed a 30 

days accumulative MACE of 2.5% with 0% TLR. 8 

As shown in Fig. 4 which compares outcomes of MGuard 

stent versus bare metal stent and thrombus aspiration trials 

which clearly shows benefit of use of MGuard stent in terms of 

blush grade and ST-segment resolution. Though this comparison 

is not head to head comparison but trials using bare 

metal stent and thrombus aspiration were compared with 

similar parameters of myocardial blush grade and ST-segment 

resolution. This comparison showed 84.6% MBG grade 3 

with MGuard as compared to only 44% with use of thrombus 

aspiration catheter and >70% ST resolution was seen in 79.6% 

compared to 56.6% in patients of trials of thrombus aspiration. 

But these data need careful assessment with statistical analysis 

and there is further need of RCTs comparing them. 10 

Based on these earlier trials Gregg Stone et al conducted 

MASTER trial to prove use of novel stenteMGuard and recommended 

in any PCI when a stent implantation is needed 

and there is a risk of complication due to distal embolization 

of plaque or thrombus. 3 

Results of the study showed >70% resolution of STsegment 

in MGuard 29% relative to control arm of routine PCI 

using either BMS or DES in patients undergoing primary PCI 

with thrombus containing lesions but partial or absent resolution 

of ST-segment was comparable to control arm. 

But this study was limited by the fact that the operators 

and research coordinators were not blinded to stent assignment, 

which possibly introduced some bias. The MGuard 

stent e which has a higher profile and is less flexible than 

standard stents e was unable to reach or cross the lesion in 

4.1% of patients while there were no device failures in the 

control group. 

There were no significant differences at 30 days in rates of 

mortality (0% versus 1.9%, p ¼ 0.06), major adverse cardiac 

events (1.8% versus 2.3%, p ¼ 0.75), or any other clinical outcome. 

The authors noted, however, that the study was 

underpowered to evaluate differences in clinical events or 

infarct size and/or improved clinical outcomes and concluded 

that there is need for further experience with this device with 

larger trial. 

references 

1. Abbate A, Kontos MC, Biondi-Zoccai GGL. No-reflow: the next 

challenge in treatment of ST-elevation acute myocardial 

infarction. Eur Heart J. 2008;29(15):1795e1797. 

2. Ndrepepa G, Tiroch K, Fusaro M, et al. 5-Year Prognostic Value 

of no-reflow phenomenon after percutaneous coronary 

intervention in patients with acute myocardial infarction. 

J Am Coll Cardiol. 2010;55(21):2383e2389. 

3. Stone GW, Abizaid A, Silber S, et al. Prospective, randomized, 

multicenter Evaluation of a polyethylene terephthalate 

micronet mesh-covered stent (MGuard) in ST-segment 

elevation myocardial infarction: the MASTER trial. J Am Coll 

Cardiol. 2012;60(19):1975e84. 

4. http://www.inspire-md.com/site_en e Official website of 

InspireMD Inc. 

5. Grube E. New alternative in embolic protection: the mesh 

covered MGuard stent. TOUCH BRIEFINGS. Interv Cardiol. 2007: 

46e48. 

6. Maia F, Ribamar Costa J, Abizaid A, et al. Preliminary results 

of the INSPIRE trial with the novel MGuardä stent system 

containing a protection net to prevent distal embolization. 

Catheter Cardiovasc Interv. 2010;76(1):86e92. 

7. Dudek D, Dziewierz A, Rzeszutko q Legutko J, et al. Mesh 

covered stent in ST-segment elevation myocardial infarction. 

Eurointervention. 2010;6(5):582e589. 

8. Danzi A, et al, SOLACI EuroPCR. The International Mguard iMOS 

Registry; 2010. 

9. Piscione F, Danzi GB, Cassese S, et al. Multicentre experience 

with MGuardä net protective stent in ST-elevation 

myocardial infarction: safety, feasibility, and impact on 

myocardial reperfusion. Catheter Cardiovasc Interv. 2010;75(5): 

715e721. 

10. The Promise for Life. InspireMD Publication; 2012. 

Compiled by 

Pankaj V. Jariwala* 

Consultant Interventional Cardiologist, Apollo Hospitals, 

Hyderguda, Hyderabad, Andhra Pradesh, India 

*Tel.: þ91 4064503561, þ91 9393178738 (mobile). 

E-mail address: pankaj_jariwala@hotmail.com 

M.T. Roe, P.W. Armstrong, K.A. Fox, et al., TRILOGY ACS 

Investigators, Prasugrel versus clopidogrel for acute coronary 

syndromes without revascularization. N Engl J Med 367 (2012) 

1297e1309 

1. Background 

The effect of intensified platelet inhibition for patients with 

unstable angina or myocardial infarction without ST-segment 

elevation who do not undergo revascularization has not been 

delineated. 

2. Methods 

In this double-blind, randomized trial, in a primary analysis 

involving 7243 patients under the age of 75 years receiving 

aspirin, we evaluated upto 30 months of treatment with prasugrel 

(10 mg daily) versus clopidogrel (75 mg daily). In a secondary 

analysis involving 2083 patients 75 years of age or older, 

we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. 

3. Results 

At a median follow-up of 17 months, the primary end point of 

death from cardiovascular causes, myocardial infarction, or 

stroke among patients under the age of 75 years occurred in 

13.9% of the prasugrel group and 16.0% of the clopidogrel 

group (hazard ratio in the prasugrel group, 0.91; 95% confidence 

interval [CI], 0.79 to 1.05; p ¼ 0.21). Similar results were 

observed in the overall population. The prespecified analysis

226 


1000 patients. Primary endpoint at 6 months of MACE of 

Ischemia related death, myocardial infarction (Q wave and 

non-Q wave), target lesion revascularization (PTCA or CABG). 

They enrolled 81% of AMI patients with 77% of STEMI. 

Thrombus was visible in 87% of the cases and 65% of the 

patients showed initial TIMI flow of 0/1. Device success was 

98% and 96% of the patients gained TIMI 3 flow postprocedure. 

STEMI subgroup clinical analysis revealed a 30 

days accumulative MACE of 2.5% with 0% TLR. 8 

As shown in Fig. 4 which compares outcomes of MGuard 

stent versus bare metal stent and thrombus aspiration trials 

which clearly shows benefit of use of MGuard stent in terms of 

blush grade and ST-segment resolution. Though this comparison 

is not head to head comparison but trials using bare 

metal stent and thrombus aspiration were compared with 

similar parameters of myocardial blush grade and ST-segment 

resolution. This comparison showed 84.6% MBG grade 3 

with MGuard as compared to only 44% with use of thrombus 

aspiration catheter and >70% ST resolution was seen in 79.6% 

compared to 56.6% in patients of trials of thrombus aspiration. 

But these data need careful assessment with statistical analysis 

and there is further need of RCTs comparing them. 10 

Based on these earlier trials Gregg Stone et al conducted 

MASTER trial to prove use of novel stenteMGuard and recommended 

in any PCI when a stent implantation is needed 

and there is a risk of complication due to distal embolization 

of plaque or thrombus. 3 

Results of the study showed >70% resolution of STsegment 

in MGuard 29% relative to control arm of routine PCI 

using either BMS or DES in patients undergoing primary PCI 

with thrombus containing lesions but partial or absent resolution 

of ST-segment was comparable to control arm. 

But this study was limited by the fact that the operators 

and research coordinators were not blinded to stent assignment, 

which possibly introduced some bias. The MGuard 

stent e which has a higher profile and is less flexible than 

standard stents e was unable to reach or cross the lesion in 

4.1% of patients while there were no device failures in the 

control group. 

There were no significant differences at 30 days in rates of 

mortality (0% versus 1.9%, p ¼ 0.06), major adverse cardiac 

events (1.8% versus 2.3%, p ¼ 0.75), or any other clinical outcome. 

The authors noted, however, that the study was 

underpowered to evaluate differences in clinical events or 

infarct size and/or improved clinical outcomes and concluded 

that there is need for further experience with this device with 

larger trial. 

references 

1. Abbate A, Kontos MC, Biondi-Zoccai GGL. No-reflow: the next 

challenge in treatment of ST-elevation acute myocardial 

infarction. Eur Heart J. 2008;29(15):1795e1797. 

2. Ndrepepa G, Tiroch K, Fusaro M, et al. 5-Year Prognostic Value 

of no-reflow phenomenon after percutaneous coronary 

intervention in patients with acute myocardial infarction. 

J Am Coll Cardiol. 2010;55(21):2383e2389. 

3. Stone GW, Abizaid A, Silber S, et al. Prospective, randomized, 

multicenter Evaluation of a polyethylene terephthalate 

micronet mesh-covered stent (MGuard) in ST-segment 

elevation myocardial infarction: the MASTER trial. J Am Coll 

Cardiol. 2012;60(19):1975e84. 

4. http://www.inspire-md.com/site_en e Official website of 

InspireMD Inc. 

5. Grube E. New alternative in embolic protection: the mesh 

covered MGuard stent. TOUCH BRIEFINGS. Interv Cardiol. 2007: 

46e48. 

6. Maia F, Ribamar Costa J, Abizaid A, et al. Preliminary results 

of the INSPIRE trial with the novel MGuardä stent system 

containing a protection net to prevent distal embolization. 

Catheter Cardiovasc Interv. 2010;76(1):86e92. 

7. Dudek D, Dziewierz A, Rzeszutko q Legutko J, et al. Mesh 

covered stent in ST-segment elevation myocardial infarction. 

Eurointervention. 2010;6(5):582e589. 

8. Danzi A, et al, SOLACI EuroPCR. The International Mguard iMOS 

Registry; 2010. 

9. Piscione F, Danzi GB, Cassese S, et al. Multicentre experience 

with MGuardä net protective stent in ST-elevation 

myocardial infarction: safety, feasibility, and impact on 

myocardial reperfusion. Catheter Cardiovasc Interv. 2010;75(5): 

715e721. 

10. The Promise for Life. InspireMD Publication; 2012. 

Compiled by 

Pankaj V. Jariwala* 

Consultant Interventional Cardiologist, Apollo Hospitals, 

Hyderguda, Hyderabad, Andhra Pradesh, India 

*Tel.: þ91 4064503561, þ91 9393178738 (mobile). 

E-mail address: pankaj_jariwala@hotmail.com 

M.T. Roe, P.W. Armstrong, K.A. Fox, et al., TRILOGY ACS 

Investigators, Prasugrel versus clopidogrel for acute coronary 

syndromes without revascularization. N Engl J Med 367 (2012) 

1297e1309 

1. Background 

The effect of intensified platelet inhibition for patients with 

unstable angina or myocardial infarction without ST-segment 

elevation who do not undergo revascularization has not been 

delineated. 

2. Methods 

In this double-blind, randomized trial, in a primary analysis 

involving 7243 patients under the age of 75 years receiving 

aspirin, we evaluated upto 30 months of treatment with prasugrel 

(10 mg daily) versus clopidogrel (75 mg daily). In a secondary 

analysis involving 2083 patients 75 years of age or older, 

we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. 

3. Results 

At a median follow-up of 17 months, the primary end point of 

death from cardiovascular causes, myocardial infarction, or 

stroke among patients under the age of 75 years occurred in 

13.9% of the prasugrel group and 16.0% of the clopidogrel 

group (hazard ratio in the prasugrel group, 0.91; 95% confidence 

interval [CI], 0.79 to 1.05; p ¼ 0.21). Similar results were 

observed in the overall population. The prespecified analysis


of multiple recurrent ischemic events (all components of the 

primary end point) suggested a lower risk for prasugrel among 

patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 

0.72e1.00; p ¼ 0.04). Rates of severe and intracranial bleeding 

were similar in the two groups in all age groups. There was no 

significant between-group difference in the frequency of nonhemorrhagic 

serious adverse events, except for a higher frequency 

of heart failure in the clopidogrel group. 


Among patients with unstable nonangina or myocardial 

infarction without ST-segment elevation, prasugrel did not 

significantly reduce the frequency of the primary end point, as 

compared with clopidogrel, and similar risks of bleeding were 

observed. 

4.1. Clinical perspective 

Prasugrel is the more potent alternative antiplatelet drug as 

compared to clopidogrel in the treatment of invasively managed 

NSTEMI or STEMI as shown in TRITON TIMI 38 in patients 

who were treated with invasive strategy. The TRIOLOGY ACS 

has tried to answer the use of prasugrel in unstable angina or 

NSTEMI patients who are managed medically. The study 

population was at high risk, including NSTEMI or UA with 

>1 mm of ST depression plus 1 of 4 additional risk criteria: 

age 60 years, diabetes, prior MI, prior revascularisation 

(percutaneous coronary interventions or coronary artery 

bypass grafting). The trial is negative in terms primary end 

point of cardiovascular death, MI, or stroke as compared to 

clopidogrel. The important limitation of trial was inclusion 

criteria as it was not mandatory to do troponin T or I level for 

diagnosis and risk stratification of ACS, the troponin T or I 

assay was not done in central laboratory, patients were 

randomized upto 7 days of acute event and coronary angiography 

was not mandatory. The really high risk ACS patient 

with proved CAD might have been treated with invasive 

strategy and may not have been included in the trial. 

There are two important observations from this trial which 

has different implications particularly in Indian scenario. 

The use of Prasugrel in patients who underwent coronary 

angiography and had more than 30% coronary stenosis i.e. a 

group of patients with definitive CAD but are being managed 

conservatively. In this subgroup of patient, there was 23% 

reduction in primary end point of cardiovascular death, MI, or 

stroke. Thus the patients who have established coronary 

artery disease and who are at risk of future cardiac event are 

benefited with more potent antiplatelet drug. 1 

Second important observation of the trial was potent 

antiplatelet activity of prasugrel as compared to clopidogrel. 

The platelet function sub study 2 of TRIOLOGY ACS have 

shown that the platelet function inhibition was more with 

prasugrel than clopidogrel at 30 days among participants 

younger than 75 years and weighing 60 kg or more, a significant 

difference that persisted through all time points. Thus 

it points out that there is no significant difference in ischemic 

outcomes through the first 12 months despite clinical observations 

of greater P2Y12 inhibition with prasugrel than with 

clopidogrel but there is increased risk of bleeding. Thus the 

risk of bleeding outweighs the benefit of more potent antiplatelet 

activity of prasugrel in treatment of patient subset 

included in TRIOLOGY ACS. 

In the trial the dose of prasugrel was reduced to 5 mg in 

patients more than 75 years of age and body weight less than 

60 kg. The question of efficacy of low dose prasugrel have been 

tested in recently published FEATHER trial 3 that has shown 

that prasugrel 5 mg in low body weight (60 kg), supporting the use of prasugrel 5 mg in 

low body weight patients by doing platelet function assay. 

In India we have large number of patients who had ACS 

who are troponin positive and angiographically proved CAD 

but are managed medically because of financial or other reasons. 

This subset resembles the angiographically proved CAD 

subgroup of TRIOLOGY ACS. Hence the use of body weight 

adjusted dose of prasugrel may be extrapolated for conservatively 

managed ACS patients who have significant coronary 

artery disease and had suffered moderate to high risk 

ACS. It will be very interesting to study the medically managed 

NSTEMI or UA patients and who have angiographically proven 

significant coronary artery disease with use of either prasugrel 

or clopidogrel in addition to aspirin. For this the following 

study design can be suggested. 

Aspirin (75 mg) OD plus Clopidogrel (75 mg) 

OD plus standard medical therapy 

references 

UA or NSTEMI with angiographically 

proven CAD & advised PCI/CABGS, but 

who have opted for medical management 

Aspirin (75mg) OD plus Prasugrel (5 mg) 

OD plus standard medical therapy 

All patients are followed up for end points like death, non fatal myocardial infarction, heart 

failure, stroke and major or minor bleeding or any revascularisation. 

1. Wiviott SD. TRILOGY ACS Angiographic Cohort: a Prospective, 

Randomized Trial of Prasugrel vs. Clopidogrel in Patients with 

Non-ST-Segment-Elevation ACS who are Medically Managed 

after Coronary Angiography. TCT 2012; October 24, 2012. 

Miami, FL. 

2. Gurbel PA, Erlinge D, Ohman EM, et al, For the TRILOGY ACS 

platelet function Substudy Investigators. Platelet function 

during extended prasugrel and clopidogrel therapy for patients 

with ACS treated without revascularization: the TRILOGY ACS 

Platelet Function Substudy. JAMA. 2012 Nov 4:1e10. 

3. Erlinge D, Berg J, Foley D, et al. Prasugrel 5 mg in low body 

weight patient reduces platelet reactivity to a similar extent as 

prasugrel 10 mg in higher body weight patients: results from 

FEATHER trial. JACC. 2012;60(20):2032e2040. 

Parag Admane, N.V. Deshpande 

Spandan Heart Institute & Research Center, 31, 

Off Chitale Marg, Dhantoli, Nagpur 440010, India

228 


H.M. Mardikar* 

Director, Spandan Heart Institute & Research Center, 

31, Off Chitale Marg, Dhantoli, 

Nagpur 440010, India 

*Corresponding author. Tel.: þ91 9823082609 (mobile), þ91 (0) 

712 2443333; fax: þ91 (0) 712 2443426. 

E-mail address: drmardikar@cadindia.co.in 

Conclusions: Control patients who crossed over to renal 

denervation with the Symplicity system had a significant drop 

in blood pressure similar to that observed in patients receiving 

immediate denervation. Renal denervation provides safe and 

sustained reduction of blood pressure to 1 year. 

Clinical trial registration: URL: http://www.clinicaltrials. 

gov. Unique identifier: http://www.clinicaltrials.gov. (Circulation. 

2012;126:2976e2982.) 

Murray D. Esler, Henry Krum, Markus Schlaich, Roland E. 

Schmieder, Michael Böhm, Paul A. Sobotka, for the Symplicity 

HTN-2 Investigators. Renal sympathetic denervation for 

treatment of drug-resistant hypertension one-year results 

from the Symplicity HTN-2 randomized, controlled trial. 

Background: Renal sympathetic nerve activation contributes 

to the pathogenesis of hypertension. Symplicity HTN-2, a 

multicenter, randomized trial, demonstrated that catheterbased 

renal denervation produced significant blood pressure 

lowering in treatment-resistant patients at 6 months after the 

procedure compared with control, medication-only patients. 

Longer-term follow-up, including 6-month crossover results, 

is now presented. 

Methods and results: Eligible patients were on 3 antihypertensive 

drugs and had a baseline systolic blood pressure 

160 mm Hg (150 mm Hg for type 2 diabetics). After the 

6-month primary end point was met, renal denervation in 

control patients was permitted. One-year results on patients 

randomized to immediate renal denervation (n ¼ 47) and 

6-month postprocedure results for crossover patients are 

presented. At 12 months after the procedure, the mean fall in 

office systolic blood pressure in the initial renal denervation 

group ( 28.1 mm Hg; 95% confidence interval, 35.4 to 20.7; 

p < 0.001) was similar to the 6-month fall ( 31.7 mm Hg; 95% 

confidence interval, 38.3 to 25.0; p < 0.16 versus 6-month 

change). The mean systolic blood pressure of the crossover 

group 6 months after the procedure was significantly lowered 

(from 190.0 19.6 to 166.3 24.7 mm Hg; change, 23.7 27.5; 

p < 0.001). In the crossover group, there was 1 renal artery 

dissection during guide catheter insertion, before denervation, 

corrected by renal artery stenting, and 1 hypotensive 

episode, which resolved with medication adjustment. 


The efficacy and safety of the Renal sympathetic Denervation 

(RDN) by utilizing the Symplicity Renal Denervation 

System in patients with uncontrolled resistant hypertension 

have been documented earlier. It has been shown that 

activation of the sympathetic nervous system is involved in 

the pathogenesis and maintenance of hypertension. Renal 

denervation with the Symplicity catheter is a minimally 

invasive procedure based on the premise that interruption 

of renal afferent and efferent nerves with resultant decrease 

in sympathetic outflow to the kidneys should reduce renin 

release and sodium retention, increase renal blood flow, and 

lower blood pressure. One-year follow-up data of The Symplicity 

HTN-2 trial demonstrates two points: (1) that the 

initial significant lowering of blood pressure achieved by the 

RDN procedure was maintained at the end of one year and 

no procedure-related side effect was revealed by that time; 

and (2) the control patients maintained on medical therapy 

and whose blood pressure was not adequately controlled 

were now permitted to switch over to RDN procedure. These 

patients again showed significant drop in blood pressure, 

which was maintained at the end of six months. Renal 

sympathetic Denervation by radiofrequency ablation thus 

may provide a safe and effective adjunctive therapy for 

treatment-resistant hypertensive patients. 

Contributed by: 

Arup Dasbiswas 

Professor and HOD, Department of Cardiology, 

NRS Medical College, Kolkata, India 

E-mail address: arup.dasbiswas@gmail.com





Characterization of lipid profile in coronary heart disease 

patients in Sudan 

Dear Editor, 

Although the burden of cardiovascular disease (CVD) states 

is stabilizing in high-income countries, in low-to-middleincome 

countries it continues to rise. 1 Lifestyle, environmental 

and genetic factors play an important role in coronary 

heart disease (CHD) development. 2 Previous studies have 

shown that blacks have one of the highest rates of coronary 

artery disease in the world. 3 However, Caucasians generally 

have higher mean total cholesterol (TC) concentrations than 

do populations of Asian or African origin. 4 

Hospital based case control study was design to study lipid 

profile in coronary heart disease patients in Sudan. Among the 

total population studied (104 cases and 105 controls) 53.1% 

were male, 45% were from Northern Sudan and 72.7% were 

residing in urban areas. About 26.8% of the most infected age 

group was less than 40 years, 22% had strong family history of 

CHD, 42.6% had hypertension and 41.6% had diabetes mellitus. 

Smoking and alcohol consumption are very low among 

population represent 18.2% and 5.3%, respectively. 

Lipid profiles were analyzed using standard enzymatic 

methods on a MINDRAY BS-200 analyzer (MINDRAY, Shenzhen, 

China). General linear model and correlation between 

serum biochemical profiles were performed using SPSS15.0. 

The results showed that Sudanese patients had significantly 

lower TC and LDL-C levels and non-significantly lower triglycerides, 

HDL-C and VLDL levels compared with controls 

(Table 1). Age has a significant (p < 0.05) effect on LDL-C, while 

sex, race or ethnic, family history, residence, smoking, alcohol 

consumption has no significant (p < 0.05) effect on lipid profiles. 

Hypertension has no significant (p < 0.05) effect on lipid 

profiles, while diabetes mellitus has a significant (p < 0.05) 

effect on total cholesterol, and LDL-C (data not shown). Among 

patients TC was significantly (p < 0.05) and positively correlated 

with LDL and HDL, while VLDL was positively correlated with 

triglycerides. In contrast, triglycerides and VLDL were negatively 

correlated with LDL and HDL similarly VLDL was positively 

correlated with triglycerides (Table 2). In control group 

total cholesterol was significantly (p < 0.05) and positively 

correlated with triglycerides, LDL and VLDL. Triglyceride was 

negatively correlated with HDL and positively with VLDL and 

HDL was negatively correlated with LDL and VLDL (Table 2). 

Blacks had nominally higher adjusted HDL-C levels, and significantly 

lower triglyceride levels than whites. 5 African 

ancestry was significantly associated with decreased total 

cholesterol, LDL-C and triglycerides. 6 These observed 

Table 1 e Baseline characteristics and risk factors for 

coronary heart disease in cases and controls subjects. 

Traits 

Over all 

(n ¼ 209) 

Case 

(n ¼ 104) 

Control 

(n ¼ 105) 

p Value 

Age (yrs) 

70 (%) 11.5 17.3 5.7 0.014 

Ethnic 

Northern 

45.0 58.7 31.4 0.004 

Sudan (%) 

Western 

34.0 19.2 48.6 0.000 

Sudan (%) 

Eastern 

2.4 2.9 1.9 0.655 

Sudan (%) 

Southern 

1.4 3.8 2.9 0.705 

Sudan (%) 

Central 

17.2 15.4 15.2 1 

Sudan (%) 

Gender 

Male (%) 53.1 56.7 49.5 0.506 

Female (%) 46.9 43.3 50.5 0.419 

Residence 

Urban (%) 72.7 73.1 72.4 1 

Rural (%) 27.3 26.9 27.6 0.895 

Hypertension (%) 42.6 56.7 28.6 0.002 

Diabetes (%) 41.6 40.4 42.9 0.748 

Family history (%) 22.0 32.7 11.4 0.001 

Smoking (%) 18.2 22.1 14.3 0.196 

Alcohol (%) 5.3 7.7 2.9 0.132 

TC mg/dL 

158.82 9.75 220.90 8.94 0.000 

(X SE) 

TG mg/dL 

243.52 17.23 250.75 15.80 0.749 

(X SE) 

LDL mg/dL 

63.29 8.56 132.22 7.85 0.000 

(X SE) 

HDL mg/dL 

45.91 3.08 46.23 2.82 0.851 

(X SE) 

VLDL mg/dL 

(X SE) 

48.78 3.39 51.19 3.11 0.603 

TC: total cholesterol mg/dL, TG: triglyceride mg/dL, LDL: low density 

lipoprotein mg/dL, HDL: high density lipoprotein mg/dL, VLDL: 

very low density lipoprotein mg/dL, CI: 95% confidence interval. 

No. of samples for lipid profile for cases and controls were 65 and 

78, respectively.


Table 2 e Correlation coefficient matrixes of cholesterol, triglycerides, and lipoprotein indices in case and control 

population. 

Traits TC mg/dL TG mg/dL LDL mg/dL HDL mg/dL VLDL mg/dL 

TC mg/dL 1 0.214 0.719 a 0.403 a 0.218 

TG mg/dL 0.516 a 1 0.070 0.153 0.999 a 

LDL mg/dL 0.747 a 0.168 1 0.142 0.065 

HDL mg/dL 0.189 0.100 0.039 1 0.153 

VLDL mg/dL 0.520 a 0.987 a 0.174 0.103 1 

Cases were above the diagonal, and controls were below the diagonal. 

a Correlation is significant at the 0.01 level (2-tailed). 

associations between African ancestry and several lipid traits 

are consistent with the general tendency of individuals of 

African descent to have healthier lipid profiles compared to 

EuropeaneAmericans. 6 Our results confirm a high prevalence 

of conventional risk factors of coronary heart disease as well as 

the association between these factors with lipid profiles in 

Sudanese population. However, sample size used was very 

small of the general population, other studies using large 

sample size were needed to provide more accuracy and predictive 

value of coronary heart disease risk factors. 

Acknowledgments 

This study was supported by a grant from the Ministry of 

Higher Education, Sudan. 

references 

1. Abegunde DO, Mathers CD, Adam T, Ortegon M, Strong K. The 

burden and costs of chronic diseases in low-income and 

middle-income countries. Lancet. 2007;370:1929e1938. 

2. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially 

modifiable risk factors associated with myocardial infarction 

in 52 countries (the INTERHEART study): case-control study. 

Lancet. 2004;364(9438):937e952. 

3. Kountz DS, Levine SL. Cardiovascular risk profiling in blacks: 

don’t forget the lipids. Am Fam Physician. 1998;58:1541e1542. 

4. Tolonen H, Keil U, Ferrario M, Evans A. Prevalence, awareness 

and treatment of hypercholesterolaemia in 32 populations: 

results from the WHO MONICA project. Int J Epidemiol. 2005; 

34(1):181e192. 

5. Aiyer AN, Kip KE, Marroquin OC, Mulukutla SR, 

Edmundowicz D, Reis SE. Racial differences in coronary 

artery calcification are not attributed to differences in 

lipoprotein particle sizes: the Heart Strategies Concentrating 

on Risk Evaluation (Heart SCORE) Study. Am Heart J. 2007;153: 

328e334. 

6. Reiner AP, Carlson CS, Ziv E, Iribarren C, Jaquish CE, 

Nickerson DA. Genetic ancestry, population sub-structure, 

and cardiovascular disease-related traits among African- 

American participants in the CARDIA Study. Hum Genet. 2007; 

121:565e575. 

Hassan Hussein Musa* 

Faculty of Medical Laboratory Sciences, University of Khartoum, 

Sudan 

Etayeb Mohamed Ahmed Tyrab 

Faculty of Medical Laboratory Science, National Ribat University, 

Sudan 

Muzamil Mahdi Abdel Hamid 

Institute of Endemic Diseases, University of Khartoum, Sudan 

Elbagire Abdel Rahman Elbashir 

Sudan Heart Center, Khartoum, Sudan 

Lemya Mohammed Yahia, Nihad Mohammed Salih 

Faculty of Medical Laboratory Science, National Ribat University, 

Sudan 

*Corresponding author. 

E-mail address: hassan_hm30@yahoo.com 

Available online 7 March 2013 



reserved. 


indian heart journal 65 (2013) 236 



Cardiology News 

Dr. Venkat S. Ram awarded Padmashri 

Dr. Venkat S. Ram has been awarded 

Padmashri recently. He is the 

President and CEO of MediCiti Hospitals 

and MediCiti Institute of Medical 

Sciences, Hyderabad. 

He is also Chairman, Board of Governors, 

American Society of Hypertension 

and Vice-President of 

American Society of Hypertension 

specialists. 

He is a graduate of Osmania Medical College, Hyderabad. 

Subsequently, he completed his residency in medicine at 

Brown University in Providence, Rhode Island and a fellowship 

at the Hospital of the University of Pennsylvania. 

Dr. Ram’s professional career has centered on the management 

of hypertension and he is one of the very few individuals 

who have combined clinical practice with an 

academic career. 

Dr. Ram served on the Faculty of University of Texas for 

many years and was the head of the hypertension clinical 

services. He is a prolific writer. He authored more than 310 

articles and a book on the treatment of hypertension. He is 

also a renowned speaker in the field. Dr. Ram has made 

numerous contributions to our understanding of both the 

physiology and the management of hypertension. For more 

than three decades, Dr. Ram’s work has explored the mechanisms 

of action of various antihypertensive drugs. In addition 

to expertise in clinical research and medical practice, 

Dr. Ram is considered a uniquely skilled communicator of 

scientific advances. Dr. Ram was the youngest person ever to 

become the Master of American College of Physicians. Dr. Ram 

is on the editorial boards of numerous national and international 

medical journals. Dr. Ram is now completing a 

handbook of hypertension for European use and another book 

on hypertension in special populations for Jaypee Brothers 

publishers. 

Dr. Ram served as the president of American Association of 

Physicians from India and also as the president of medical 

staff, University Hospital, Dallas, USA. Dr. Ram has been 

repeatedly named year after year by the medical students and 

residents at the University of Texas Medical School as the 

“most skilled teacher of clinical medicine.” The Dallas County 

Medical Society, USA has named Dr. Ram as one of the five 

individuals in the history of Dallas to make the city as a center 

of excellence in medicine. World Telugu Conference bestowed 

him the title of the “most outstanding doctor globally of 

Telugu origin”daward given by the then Chief Minister, late 

N. T. Rama Rao. 

He is a founding patron of MediCiti. He conducted several 

CME programs and particularly HDL e Hypertension, Diabetes 

and Lipids e conferences have been outstanding. Above all he 

is a great humanist. Whatever he does as a doctor, specialist, 

executive or a friend, it is embellished by his outstanding 

humanistic skills. The Cardiological Society of India congratulates 

Dr. Venkat S. Ram on receiving this coveted award. 

Compiled by 

Dr. P.S. Reddy 

Hyderabad 






Obituary 

The sudden and tragic demise of 

Dr Prasanna Nyayadhish on 3rd 

January’2013 has been a devastating 

blow for the Cardiology community all 

over the country. A brilliant career has 

been cut short at its peak, plunging all 

his friends, colleagues, and students 

into a deep sense of gloom. 

Dr Nyayadhish spent his formative 

years at the village of Sakharwadi in 

district Satara, near Pune. After a bachelor’s degree from BJ 

Medical College, Pune in 1992, he received his MD degree in 

Medicine from the University of Pune in 1996. Always a brilliant 

student, he was one of the top rankers at the All India Superspeciality 

Entrance Exam held in 1996. He completed his residency 

in DM Cardiology in 2000. He also successfully obtained 

the Diplomate of the National Board of Examinations (DNB in 

Cardiology). Dr Nyayadhish joined as a full time faculty 

member in the Department of Cardiology, KEM Hospital in 

2001, eventually rising to the post of Professor and Unit Head in 

2008 e a post he held till his demise. 

Dr Nyayadhish was an excellent all round Cardiologist. He was 

a fine clinician with great powers of observation and analytical 

skills. He had a deep knowledge of echocardiography, and was 

especially renowned for his abilities in performing and interpreting 

echocardiograms in complex congenital heart diseases. In 

addition, he was a highly skilled interventionist e performing the 

full gamut of cardiac procedures, ranging from balloon atrial 

septostomies in one-day-old neonates to complex coronary interventions 

in octogenarians. Along with other faculty, he was 

responsible for taking Pediatric and Structural heart services at 

the KEM hospital to newer heights, making the department one of 

its kind in the public health centers in Western India. 

Dr Nyayadhish had a friendly and jovial nature. His keen 

sense of humor and brilliant repartees made him the life and 

soul of gatherings, and his circle of friends extended far 

beyond the narrow confines of the medical profession. He was 

generous to a fault, warm hearted, and ever ready to help his 

colleagues and patients in their times of need. In private 

practice, he was respected as much for his ethical and rational 

decision making as for his interventional skills. 

Dr Nyayadhish was always supportive of research, and 

encouraged his residents and faculty to find time from their 

clinical work to present and publish research papers. He was a 

superb teacher. Along with other senior teachers, he had set up a 

teaching academy in the city of Mumbai, for training DM and 

DNB students in clinical cardiology, echocardiography, and cardiac 

catheterization e all free of charge. The sessions held by this 

academy proved to be hugely popular over the last seven to eight 

years with trainees all over the country. Dr Nyayadhish was a fine 

speaker e his deep knowledge of the subject and unique presentationstylemadehimaregularfixtureasaspeakerorfaculty 

in all the important Cardiology conferences and workshops. 

The passing of Dr Nyayadhish has been a personal blow for 

me e I have lost one of my most valuable faculty members and 

a close personal friend. The thoughts of all of us are with his 

wife Mrs Lovlyn Nyayadhish and their two young sons in this 

difficult time. Let us pray to the Almighty to grant us strength in 

bearing this loss. May the departed soul rest in eternal peace. 

Compiled by 

Dr. Praful Kerkar 

Mumbai 


http://dx.doi.org/10.1016/j.ihj.2013.03.009 

Obituary 

Dr. N.N. Asokan, a long-standing member of Cardiological Society of India from Muvattupuzha, Kerala expired recently following 

a brief illness. 

Compiled by 

Dr. K. Sarat Chandra 

Hony. Editor, Indian Heart Journal, India 






Obituary 

The sudden and tragic demise of 

Dr Prasanna Nyayadhish on 3rd 

January’2013 has been a devastating 

blow for the Cardiology community all 

over the country. A brilliant career has 

been cut short at its peak, plunging all 

his friends, colleagues, and students 

into a deep sense of gloom. 

Dr Nyayadhish spent his formative 

years at the village of Sakharwadi in 

district Satara, near Pune. After a bachelor’s degree from BJ 

Medical College, Pune in 1992, he received his MD degree in 

Medicine from the University of Pune in 1996. Always a brilliant 

student, he was one of the top rankers at the All India Superspeciality 

Entrance Exam held in 1996. He completed his residency 

in DM Cardiology in 2000. He also successfully obtained 

the Diplomate of the National Board of Examinations (DNB in 

Cardiology). Dr Nyayadhish joined as a full time faculty 

member in the Department of Cardiology, KEM Hospital in 

2001, eventually rising to the post of Professor and Unit Head in 

2008 e a post he held till his demise. 

Dr Nyayadhish was an excellent all round Cardiologist. He was 

a fine clinician with great powers of observation and analytical 

skills. He had a deep knowledge of echocardiography, and was 

especially renowned for his abilities in performing and interpreting 

echocardiograms in complex congenital heart diseases. In 

addition, he was a highly skilled interventionist e performing the 

full gamut of cardiac procedures, ranging from balloon atrial 

septostomies in one-day-old neonates to complex coronary interventions 

in octogenarians. Along with other faculty, he was 

responsible for taking Pediatric and Structural heart services at 

the KEM hospital to newer heights, making the department one of 

its kind in the public health centers in Western India. 

Dr Nyayadhish had a friendly and jovial nature. His keen 

sense of humor and brilliant repartees made him the life and 

soul of gatherings, and his circle of friends extended far 

beyond the narrow confines of the medical profession. He was 

generous to a fault, warm hearted, and ever ready to help his 

colleagues and patients in their times of need. In private 

practice, he was respected as much for his ethical and rational 

decision making as for his interventional skills. 

Dr Nyayadhish was always supportive of research, and 

encouraged his residents and faculty to find time from their 

clinical work to present and publish research papers. He was a 

superb teacher. Along with other senior teachers, he had set up a 

teaching academy in the city of Mumbai, for training DM and 

DNB students in clinical cardiology, echocardiography, and cardiac 

catheterization e all free of charge. The sessions held by this 

academy proved to be hugely popular over the last seven to eight 

years with trainees all over the country. Dr Nyayadhish was a fine 

speaker e his deep knowledge of the subject and unique presentationstylemadehimaregularfixtureasaspeakerorfaculty 

in all the important Cardiology conferences and workshops. 

The passing of Dr Nyayadhish has been a personal blow for 

me e I have lost one of my most valuable faculty members and 

a close personal friend. The thoughts of all of us are with his 

wife Mrs Lovlyn Nyayadhish and their two young sons in this 

difficult time. Let us pray to the Almighty to grant us strength in 

bearing this loss. May the departed soul rest in eternal peace. 

Compiled by 

Dr. Praful Kerkar 

Mumbai 


http://dx.doi.org/10.1016/j.ihj.2013.03.009 

Obituary 

Dr. N.N. Asokan, a long-standing member of Cardiological Society of India from Muvattupuzha, Kerala expired recently following 

a brief illness. 

Compiled by 

Dr. K. Sarat Chandra 

Hony. Editor, Indian Heart Journal, India

Mar-Apr 2013 - Indian Heart Journal

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?