Troponin - Non-MI Causes of Troponin Elevation

Common Causes of Troponin Elevationsin the Absence of Acute MyocardialInfarction*Incidence and Clinical SignificanceChanwit Roongsritong, MD; Irfan Warraich, MD; and Charles Bradley, PhDCardiac troponin is a preferred biomarker of acute myocardial infarction (MI). Unfortunately,elevation of troponin can be detected in a variety of conditions other than acute MI. This reviewfocuses on the incidence and clinical significance of increased troponin in conditions commonlyassociated with troponin elevations, particularly in those that may resemble acute MI.(CHEST 2004; 125:1877–1884)Key words: false-positive; heart failure; pericarditis; pulmonary embolism; sepsis; troponinAbbreviations: CAD coronary artery disease; CK creatinine kinase; HF heart failure; MI myocardial infarction;PE pulmonary embolism; TnI troponin I; TnT troponin T*From the Cardiovascular Division, Department of InternalMedicine (Dr. Roongsritong), and Department of Pathology(Drs. Warraich and Bradley), Texas Tech University HealthSciences Center, Lubbock, TX.Manuscript received April 8, 2003; revision accepted August 6,2003.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (e-mail:permissions@chestnet.org).Correspondence to: Chanwit Roongsritong, MD, Department ofInternal Medicine, Texas Tech University Health Sciences Center,3601 Fourth St, Lubbock, TX 79430Cardiac troponins are the most sensitive andspecific biochemical markers of myocardialdamage. 1 In patients with clear-cut unstable angina,cardiac troponin measurements provide superiorprognostic information over creatinine kinase (CK). 2The current guidelines 3 from the Joint EuropeanSociety of Cardiology/American College of CardiologyCommittee for the redefinition of myocardialinfarction (MI) state that cardiac troponins are thepreferred markers for detecting myocardial cell injury.Therefore, one of the cardiac troponins isroutinely measured in patients presenting with acutechest pain syndrome, acute dyspnea, or other complaintsin which acute MI is one of the differentialdiagnoses. However, troponin elevations indicate thepresence but not the mechanism of myocardialinjury, and myocardial damage can occur from avariety of mechanisms other than acute ischemia.Although a thorough clinical evaluation and the timecourse of troponin elevation will often help discriminateacute MI from other causes, knowledge aboutthe potential elevations of troponin in these conditionsmay minimize unnecessary discomfort and costassociated with cardiac testing to exclude coronaryartery disease (CAD).Furthermore, all of the currently available troponinmeasurements utilize two-site immunoassays.Similar to other immunoassays, spurious elevationsof cardiac troponin from interference in the absenceof MI, known as false-positive troponin, have beenreported. 4–5 This review will focus on the incidence,magnitude, and clinical significance of troponin elevationsin conditions other than acute MI, particularlyin those conditions that may resemble acutecoronary syndrome (Table 1), and the commoncauses of false-positive troponin.Acute PericarditisPatients with acute pericarditis usually presentwith chest pain and ST-segment changes on ECG.Modest elevation of the MB fraction of CK (CK-MB) has been found in patients with acute pericarditis.6 Troponin elevation has also been reported inpatients with acute pericarditis. 7–8 However, theavailable data on the prevalence and extent of troponinelevation in this condition are limited.Bonnefoy et al 8 reported that approximately onehalf of their 69 consecutive patients (49%) with acuteidiopathic pericarditis had troponin I (TnI) levels 0.5 ng/mL. Twenty-two percent had TnI levels 1.5 ng/mL, their cut-off level for acute MI. Theaverage TnI level was 8 12 ng/mL (range, 0 to 48ng/mL). The median level was, however, only 1www.chestjournal.org CHEST / 125 /5/MAY, 2004 1877

Table 1—Conditions Commonly Associated WithCardiac Troponin Elevations in the Absence ofAcute MIAcute PEAcute pericarditisAcute or severe HFMyocarditisSepsis and/or shockRenal failureFalse-positive troponinng/mL. ST-segment elevation was found in almostevery patient (93%) with TnI levels 1.5 ng/mL,compared to 65% in the entire group. A troponinlevel above the cut-off for acute MI was morecommon in younger patients (37 years vs 52 years,p 0.002) and in those with a history of recentinfection (66% vs 31%, p 0.01). Elevation of troponinin acute pericarditis is believed to representinjury of the epicardial layer of myocardium adjacentto visceral pericardium where the active inflammationoccurs.Acute Pulmonary EmbolismPatients with acute pulmonary embolism (PE)often present with acute dyspnea and/or chest pain.Echocardiographic evidence of right ventricular dysfunctionwas reported in 40 to 55% of patients withacute PE. 9–10 Right ventricular dysfunction in acutePE has been associated with increased mortality. 9–10Elevation of CK-MB has been reported in acutemassive PE. 11–12 Since cardiac troponins are moresensitive than CK-MB in detecting myocardial injury,measurement of cardiac troponin may providesuperior information for the management of patientswith PE.Giannitis et al 13 reported the incidence and prognosticsignificance of troponin T (TnT) elevation inpatients with confirmed acute PE. Of the 56 patients,32% had elevated TnT levels ( 0.1 ng/mL).In contrast, only 7% had CK levels above twice theupper limit of normal. Using a clinical gradingsystem adapted from Goldhaber, 14 23%, 46%, and30% of the patients were classified as having smallPE, moderate-to-large PE, and massive PE, respectively.Elevated TnT was only observed in patientswith either moderate-to-large PE or massive PE.None of those with small PE had increased TnT.TnT-positive patients were more likely to haveright ventricular dysfunction, severe hypoxemia, prolongedhypotension, or cardiogenic shock. They alsomore often required inotropic therapy or mechanicalventilation than those with negative TnT. Completeor incomplete right bundle-branch block or ST-Tchanges on ECG were also more prevalent in TnTpositivesubgroup. More importantly, TnT positivitywas associated with approximately 30-fold increasedrisk of in-hospital mortality. In addition, TnT levelwas found to be an independent predictor of the30-day outcome. Survival rates at 30 days were 60%and 95%, respectively, for those with and withoutTnT elevation (Table 2).Right ventricular dilation and strain from suddenincrease in pulmonary arterial resistance is believedto be the cause of troponin release in acute PE. 15Unfortunately, coexisting CAD is not uncommon inpatients with acute PE. In the study by Giannitis etal, 13 a 20% incidence of previous MI was reported.Twelve percent of their patients had previous coronaryrevascularization. Significant CAD, defined as a 50% luminal diameter stenosis, was also morecommon in TnT-positive than TnT-negative patients(40% vs 27%, respectively). Although left ventricularinfarction may not be completely excluded in patientswith concomitant CAD, troponin elevationswere observed even in those without CAD. Moreover,a recent study 15 in patients with submassivePE, defined as all confirmed PE except massive PEassociated with hypotension, cardiogenic shock, orrespiratory failure, has strongly suggested that myocardialischemia from CAD is not the major cause oftroponin elevation in acute PE. In this study byDouketis et al, 15 patients with a history of confirmedCAD, congestive heart failure, or cardiomyopathywere excluded. Of 24 patients, 21% had TnI levels 0.4 ng/mL. TnI levels above the cut-off for acuteMI in their laboratory (2.3 ng/mL) were detected in4% of the patients. The lower incidence of troponinelevation in the latter study is likely due to theexclusion of patients with massive PE.Acute or Severe Heart FailureAcute coronary syndrome occasionally presentswith a sudden increase of dyspnea without typicalangina. In elderly, dyspnea is a major complaint in alarge number of patients with acute MI. 16 In patientswith severe but stable heart failure (HF), a modestincrease of cardiac troponin has been reported. 17Using a highly sensitive TnI assay with a lowerdetection limit at 3 pg/mL, Missov et al 17 found asignificantly higher level of TnI in patients withstable HF than in control subjects (72 pg/mL vs 25pg/mL, p 0.01). However, a TnI level 0.1 ng/mL, a normal detectable level on standard assay, wasfound in only 1 of their 35 patients (0.206 ng/mL). Amuch higher incidence of detectable TnI has beenreported in a combined population of hospitalized1878 Reviews

Table 2—Incidence and Clinical Significance of Troponin Elevations in Various Conditions*ConditionsTroponinSubunitCut-offs,ng/mLIncidence,% Clinical Significance of Troponin ElevationAcute pericarditis TnI 0.5 49 Correlates with recent infection1.5 22Acute PEOverall TnT 0.1 32 Increased risk of in-hospital mortality, poor30-d outcome, right ventriculardysfunction, shock/hypotension, andneed for mechanical ventilationMassive 53Small 0Submassive TnI 0.4 212.3 4HFSevere but stable TnI 0.1 3 Independent predictor of long-termsurvival or readmission for HF;correlates with worse functional class,and lower ejection fractionTnT 0.1 151.0 3Hospitalized HF TnT 0.1 71.0 2Stable or unstable TnI 0.3 231.0 0Acute left HF TnI 1.0 20TnT 0.1 551.0 7Cor pulmonale TnI 1.0 0Myocarditis TnI 3.1 34 Correlates with recent onset of HF andmore diffuse myocarditisSevere sepsis/shock TnI 0.1 58–85 Correlates with APACHE II score anddegree of hypotension; increased inhospitalmortality; independent predictorof left ventricular dysfunction0.4 50TnT 0.1 36–69Renal failure TnI 0.1 6 Independent predictor of poor long-termoutcome0.4 1TnT 0.03 530.1 20*APACHE acute physiology and chronic health evaluation.HF and stable HF patients seen in the outpatientclinic. 18 Using Stratus II (Dade International; Deerfield,IL) TnI assays, La Vecchia et al 18 found TnIlevels above the detection limit (0.3 ng/mL) in 23%of their 26 patients. Unfortunately, the proportionsof patients with stable and unstable HF were notreported. Nevertheless, the degree of TnI elevationwas similarly modest, with the highest level of only0.8 ng/mL.The incidence of elevated TnT in chronic HF hasalso been reported. 19–20 In 33 patients with stableHF, Missov and Mair 19 found that 15% had detectableTnT ( 0.1 ng/mL). However, only 9% and 3%of their patients had TnT levels 0.5 ng/mL and 1.0 ng/mL, respectively.Setsuda et al 20 reported TnT levels of at least 0.02ng/mL in 52% of their 58 patients hospitalized forHF. Of all patients with detectable TnT in the latterstudy, 87% had TnT levels between 0.02 ng/mL and0.1 ng/mL, 10% had TnT levels between 0.1 ng/mLand 1.0 ng/mL, and only 3% had TnT levels 1ng/mL.Published data on troponin elevations in patientswith acute HF, particularly right HF from corpulmonale, are limited. Perna et al 21 recently reporteda 55% incidence of TnT of 0.1 ng/mL inpatients with acute cardiogenic pulmonary edema.The highest level of TnT in these patients was 2.6ng/mL, and 7% of the patients had TnT levels 1ng/mL. Guler et al 22 studied 41 patients with acuteleft heart failure and 17 patients with worsening ofright HF. In 23 of 41 patients with left HF, CAD waswww.chestjournal.org CHEST / 125 /5/MAY, 2004 1879

published. 25–28 Ammann et al 25 evaluated patientswith sepsis, 40% of whom were in shock. Seventeenof their 20 patients (85%) had TnI elevation. TnIlevels ranged from 0.17 to 15.4 ng/mL, with amedian value of 0.57 ng/mL. ver Elst et al 26 foundTnI levels of at least 0.4 ng/mL in 50% of their 46patients with early septic shock. Similarly, a relativelylow median level (1.4 ng/mL) of the peak concentrationsof TnI was observed in this study. In patientswith severe sepsis, septic shock, or hypovolemicshock, Arlati et al 27 found elevated TnI elevation in74% of the cases. All of their 12 patients withhypovolemic shock and 58% of those with severesepsis or septic shock had elevated TnI.Elevation of TnT in sepsis has also been reported.26,28 ver Elst et al 26 found cardiac TnT elevations( 0.1 ng/mL) in 36% of their cases. A muchhigher incidence of TnT elevation was reported bySpies et al 28 ; in their 26 patients with sepsis, 69% hadTnT levels 0.2 ng/mL.Furthermore, elevations of troponin in these patientsappear to correlate with severity of the diseaseprocess. TnI levels were found to correlate with thedegree of hypotension 27 and APACHE (acute physiologyand chronic health evaluation) II score. 26The causes of troponin elevations in these criticallyill patients are not well understood. Thesereports, in general, had a relatively small sample sizeand included a heterogeneous group of patients.Some of these patients had CAD, and stress-inducedMI may have been responsible for troponin releasein this particular subgroup of patients. Acute coronaryevents have, however, been excluded in some ofthese patients. For example, Ammann et al 25 wereable to exclude CAD in 10 of 17 TnI-positivepatients. These findings indicated that other mechanismsare also involved.In one study, 26 patients with elevated troponinlevels are older and more likely to have hypertensionor previous history of MI, suggesting that theirunderlying cardiovascular disease may, to some degree,contribute to troponin elevation. However,these findings were not observed in another study. 28It also remains unclear whether infection with anyspecific pathogens is more likely to result in troponinelevations. Streptococcal pneumoniae infection wasthe cause of sepsis in 41% of TnI-positive patients inone study, 25 whereas Gram-negative bacteria werethe offending pathogens in 63% of cases in anotherstudy. 26 Spies et al 28 found no difference in terms ofthe causes of sepsis between patients with or withouttroponin elevation.Nevertheless, there are several potential mechanisms,other than acute MI, for troponin release inseptic patients. First, it is well known that a numberof local and circulating mediators (eg, cytokines orreactive oxygen species) possess direct cardiac myocytoxicproperties. 26 Secondly, myocardial injuryfrom the effect of bacterial endotoxins has beendemonstrated. Finally, dysfunction of the microcirculationhas been described in sepsis. 29 This microvasculardysfunction can lead to ischemia and reperfusioninjury of the myocardial cell.More importantly, troponin measurements inthese patients appear to provide valuable prognosticinformation. ver Elst et al 26 reported that both TnIand TnT were independent markers of left ventriculardysfunction in patients with sepsis. They detectedleft ventricular dysfunction by transesophagealechocardiography in 78% and 9% of patientswith and without TnI elevation, respectively(p 0.001). Several studies 26,28,30 also found a weakcorrelation between elevated cardiac troponin andhospital mortality.Renal FailureThe prevalence and clinical significance of elevatedtroponins in patients with renal failure havebeen recently reviewed elsewhere. 31 In brief, TnT ismore commonly elevated in patients with renalfailure than TnI. Although the exact causes of troponinelevation in renal failure remain debatable,patients with elevated troponin generally have worseclinical outcome than those without it.False-Positive TroponinTroponin complex is located on the thin filamentof skeletal and myocardial muscle. An importantfeature of troponin complex is that its I and Tsubunits are sufficiently unique so that specificantisera can differentiate these two tissue forms. Thehigh sensitivity and specificity of cardiac troponin fordetecting myocardial injury is well documented. 32–33However, various factors can interfere with the TnIassay, leading to falsely elevated levels (Table 3).These include heterophilic antibodies, 34 rheumatoidfactor, 35 fibrin clots, 36 microparticles, 36 and malfunctionof the analyzer itself. 37The role of heterophilic antibodies in causinginterference in immunoassays has been reported in aTable 3—Common Causes of False-Positive TroponinHeterophilic antibodiesRheumatoid factorFibrin clotsMicroparticlesAnalyzer malfunctionwww.chestjournal.org CHEST / 125 /5/MAY, 2004 1881

number of studies. 34,38–41 The incidence of thisinterference varies considerably in the literature,40–43 ranging from 0.17 to 40%. Various sourceshave been proposed to give rise to heterophilicantibodies, and these include the use of mousemonoclonal antibodies in diagnostic imaging andcancer therapy, 44 exposure to microbial antigens, 39,45exposure to foreign animal proteins, 41 and autoimmunediseases such as rheumatoid arthritis. 38,40Recognizing the significance of this interferenceby heterophilic antibodies, the manufacturers recommendusing the antibody blocking agents alongwith their cardiac troponin immunoassays wheneverthis interference is suspected. 46–47 However, theresults of these blocking agents are not very convincing.34,37,48–53 Therefore, it is important that themanufacturers continue to improve their assays. Inthis regard, Kim et al 43 evaluated the performance ofthe revised Dimension cardiac TnI assay (DadeBehring; Deerfield, IL). They found that the revisedDimension cardiac TnI assay removed the interferencein most of the samples with which the originalDimension cardiac TnI assay had given falsely elevatedlevels, and greatly decreased the interferencein the remaining samples.Rheumatoid factor is another cause of interferencein the immunoassays. It has been reported that5% of healthy patients might have circulating rheumatoidfactor, and approximately 1% of patients withelevated cardiac TnI levels may have this elevationsolely because of the rheumatoid factor. 54 When thisscenario is suspected, a rheumatoid factor-blockingagent can be used. 38Excess fibrin is another well-reported source offalsely elevated cardiac TnI levels. 36 Roberts et al 55observed that incompletely clotted specimencontributed to the false elevations in cardiac TnIlevels with the Stratus II batch analyzer (DadeInternational). The manufacturers mention this possibilityin the package insert and advise care with thespecimens from patients receiving anticoagulanttherapy. The investigators found three approaches tobe useful to correct this interference: (1) heparinizingthe tubes before analysis, (2) removing excessfibrin by repeating the centrifugation, and (3) addingSuperSerum (TTC; Edison, NJ), which containsprotamine sulfate, thrombin, and snake venom toenhance coagulation.In addition, Roberts et al 55 found that some of theinterference due to free fibrin and microparticles canbe avoided with repeat centrifugation of the sampleand/or the use of a clot activator. However, Beyne etal, 56 in an open comparative study, found that asingle centrifugation of collection tubes containingthrombin as a clot activator is not enough to avoidfalse-positive cardiac TnI results on the ACCESSanalyzer (Beckman Coulter; Fullerton, CA).Finally, malfunction of the analyzer itself is anotherreported cause of false elevations in cardiacTnI results. Galambos et al 37 reported several casesof falsely elevated plasma cardiac TnI levels due to atemporary malfunction of the AxSYM analyzer (AbbottLaboratories; Abbott Park, IL). The operationmanual provided by the manufacturer mentions thepossibility of a solution dispenser misalignment ifthe dispensers are repositioned incorrectly duringthe weekly maintenance. 57 The authors recommendrunning quality-control samples after each maintenanceof the analyzer.ConclusionsCardiac troponin can be elevated in a variety ofconditions other than acute MI. 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