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Background

Troponin is now the gold standard for the diagnosis of myocardial infarction. A consensus document authored by a joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) has redefined a myocardial infarction (MI) as any amount of myocardial necrosis as indicated by an elevation of troponin in the setting of clinical ischemia. It is a "maximal concentration of troponin T or I exceeding the decision limit (99th percentile of the values for a reference control group) on at least one occasion during the first 24 hours after the index clinical event" (see outline below for reference).

OUTLINE

Measurement  
Clinical Utility  
Interference  
Commonly Used Terms  
Internet Links  

ANALYTICAL METHOD  

Characterization of cardiac troponin subunit release into serum after acute myocardial infarction and comparison of assays for troponin T and I. American Association for Clinical Chemistry Subcommittee on cTnI Standardization.

Wu AH, Feng YJ, Moore R, Apple FS, McPherson PH, Buechler KF, Bodor G.

Department of Pathology, Hartford Hospital, CT 06102, USA.

Clin Chem 1998 Jun;44(6 Pt 1):1198-208 Abstract quote

We examined the release of cardiac troponin T (cTnT) and I (cTnI) into the blood of patients after acute myocardial infarction (AMI).

Three postAMI serum samples were applied in separate analytical runs onto a calibrated gel filtration column (Sephacryl S-200), and the proteins were separated by molecular weight. Using commercial cTnT and cTnI assays measured on collected fractions, we found that troponin was released into blood as a ternary complex of cTnT-I-C, a binary complex of cTnI-C, and free cTnT, with no free cTnI within the limits of the analytical methodologies. The serum samples were also examined after incubation with EDTA and heparin. EDTA broke up troponin complexes into individual subunits, whereas heparin had no effect on the assays tested. We added free cTnC subunits to 24 AMI serum samples and found no marked increase in the total cTnI concentrations, using an immunoassay that gave higher values for the cTnI-C complex than free cTnI. To characterize the cross-reactivity of cTnT and cTnI assays, purified troponin standards in nine different forms were prepared, added to serum and plasma pools, and tested in nine quantitative commercial and pre-market assays for cTnI and one approved assay for cTnT.

All nine cTnI assays recognized each of the troponin I forms (complexed and free). In five of these assays, the relative responses for cTnI were nearly equimolar. For the remainder, the response was substantially greater for complexed cTnI than for free cTnI. Moreover, there was a substantial difference in the absolute concentration of results between cTnI assays. The commercial cTnT assay recognized binary and ternary complexes of troponin on a near equimolar basis.

We conclude that all assays are useful for detection of cardiac injury. However, there are differences in absolute cTnI results due to a lack of mass standardization and heterogeneity in the cross-reactivities of antibodies to various troponin I forms.


Standardization of cardiac troponin I assays: round Robin of ten candidate reference materials.

Christenson RH, Duh SH, Apple FS, Bodor GS, Bunk DM, Dalluge J, Panteghini M, Potter JD, Welch MJ, Wu AH, Kahn SE.

Department of Pathology, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA.

Clin Chem 2001 Mar;47(3):431-7 Abstract quote

BACKGROUND: Cardiac troponin I (cTnI) results vary 100-fold among assays. As a step toward standardization, we examined the performance of 10 candidate reference materials (cRMs) in dilution studies with 13 cTnI measurement systems.

METHODS: Solutions of 10 cTnI cRMs, each characterized by NIST, were shipped to the manufacturers of 13 cTnI measurement systems. Manufacturers used their respective diluents to prepare each cRM in cTnI concentrations of 1, 10, 25, and 50 microg/L. For the purpose of ranking the cRMs, the deviation of each cTnI measurement from the expected response was assessed after normalization with the 10 microg/L cTnI solution. Normalized deviations were examined in five formats. Parameters from linear regression analysis of the measured cTnI vs expected values were also used to rank performance of the cRMs.

RESULTS: The three cRMs demonstrating the best overall rankings were complexes of troponins C, I, and T. The matrices for these three cRMs values differed; one was reconstituted directly from the lyophilized form submitted by the supplier; one was submitted in liquid form, lyophilized at NIST, and subsequently reconstituted; and the third was evaluated in the liquid form received from the supplier. The cRM demonstrating the fourth best performance was a binary complex of troponins C and I supplied in lyophilized form and reconstituted before distribution.

CONCLUSIONS: The cRMs demonstrating the best performance characteristics in 13 cTnI analytical systems will be included in subsequent activities of the cTnI Standardization Committee of the AACC.

BIOCHEMICAL THEORY

Troponin is found only within cardiac muscle and is released into the circulation during myocardial injury and death

Cardiac TnI circulates in the blood as a complex with TnC and TnT

HALF LIFE 96 hours to two weeks

 

CLINICAL IMPORTANCE CHARACTERIZATION
Association of mild transient elevation of troponin I levels with increased mortality and major cardiovascular events in the general patient population.

Gudmundsson GS, Kahn SE, Moran JF.

Division of Cardiology, Loyola University Medical Center, Maywood, Ill, USA.
Arch Pathol Lab Med. 2005 Apr;129(4):474-80. Abstract quote  

CONTEXT: The prognostic value of mild elevation of cardiac-specific troponin I (cTnI) levels is poorly defined, which can make interpretation of such an elevation difficult.

OBJECTIVE: To study the prognostic value of transient mild elevation of cTnI levels in the hospitalized patient population.

DESIGN: We performed a case-control study that compared the outcome of patients hospitalized for any cause with at least 2 subsequent transient cTnI measurements of 0.1 ng/mL or higher and less than 1.5 ng/mL with matched controls with cTnI levels less than 0.1 ng/mL. A cohort of 118 patients (mean +/- SD age, 67.4 +/- 14.0 years; 35.6% men) was followed up for an average +/- SD of 11.9 +/- 7.9 months. Seventy-one cases were matched with 37 controls in terms of demographics, coronary artery disease risk factors, and reason for admission. End points were all-cause mortality and major cardiovascular end points, including cardiovascular mortality, myocardial infarction, and revascularization.

RESULTS: The total event rate was significantly increased in the case group compared with the control group at 12, 6, and 3 months (62.0% vs 24.3%, 59.2% vs 16.2%, and 47.9% vs 5.4%, respectively; P < .001). At 12, 6, and 3 months, the cases had a significant increase in all-cause mortality (43.7% vs 16.2%, 40.8% vs 8.1%, and 33.8% vs 0.0%, respectively; P = .005) and major cardiovascular end points (26.8% vs 8.1%, 26.8% vs 8.1%, and 21.1% vs 5.4%, respectively; P = .02) compared with controls.

CONCLUSION: Transient mild elevation of cTnI levels in hospitalized patients is associated with an increase in all-cause mortality and major cardiovascular complications. Such elevations of cTnI levels can be considered a marker for both all-cause and cardiovascular morbidity and mortality.

Diagnostic and prognostic value of cardiac troponin I assays in patients admitted with symptoms suggestive of acute coronary syndrome.

Apple FS, Quist HE, Murakami MM.

Department of Laboratory Medicine and Pathology, Hennepin County Medical Center, University of Minnesota School of Medicine, Minneapolis 55415, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):430-4. Abstract quote

CONTEXT: Increasing numbers of patients are presenting to emergency departments with symptoms suggestive of an acute myocardial infarction.

OBJECTIVE: To demonstrate the comparative performance of the Ortho Vitros Troponin I and Beckman Access AccuTnI assays used to detect myocardial infarction and to develop risk stratification schemes for all-cause death in patients who presented with myocardial ischemia symptoms that were suggestive of acute coronary syndrome (ACS).

DESIGN: The prospective enrollment of patients with ACS and the measurement of serial plasma samples by 2 commercial cardiac troponin I (cTnI) assays.

SETTING: A metropolitan medical center that admitted patients with ACS during a 2-month period.

PATIENTS: The study population consisted of 200 consecutively admitted patients who presented with symptoms that were suggestive of ACS.

RESULTS: Correlation scatterplots showed no significant bias between cTnI assays based on 659 specimens across the dynamic range of each assay. Only minor differences in slopes and intercepts were observed between assays when correlations were based across selected concentration ranges. The receiver operating characteristic curve areas for the detection of myocardial infarction were not significantly different (Ortho,.991; Beckman,.995). At the 99th percentile (Beckman, 0.04 microg/L; Ortho, 0.08 microg/L), each assay demonstrated 100% sensitivity with 78% and 80% specificity, respectively. Kaplan-Meier survival curves and the log-rank test were used to compare time-to-event data. Patients with increased baseline cTnI values had higher odds ratios of death than did those with normal concentrations. For Ortho, the 99th percentile cutoff was 5.9, and the 10% coefficient of variation cutoff was 10.3; for Beckman, the 99th percentile cutoff was 31.4, and the 10% coefficient of variation cutoff was 15.3.

CONCLUSIONS: Comparable diagnostic and risk stratification abilities were demonstrated in patients with ACS by the Ortho Vitros and Beckman Access cTnI assays, with no significant analytic bias between cTnI assays.

Biochemical markers of myocardial injury test turnaround time: a College of American Pathologists Q-Probes study of 7020 troponin and 4368 creatine kinase-MB determinations in 159 institutions.

Novis DA, Jones BA, Dale JC, Walsh MK; College of American Pathologists.

Department of Pathology, Wentworth Douglass Hospital, Dover, NH 03820, USA.
Arch Pathol Lab Med. 2004 Feb;128(2):158-64. Abstract quote  


CONTEXT: Rapid diagnosis of acute myocardial infarction in patients presenting to emergency departments (EDs) with chest pain may determine the types, and predict the outcomes of, the therapy those patients receive. The amount of time consumed in establishing diagnoses of acute myocardial infarction may depend in part on that consumed in the generation of the blood test results measuring myocardial injury.

OBJECTIVE: To determine the normative rates of turnaround time (TAT) for biochemical markers of myocardial injury and to examine hospital and laboratory practices associated with faster TATs.

DESIGN: Laboratory personnel in institutions enrolled in the College of American Pathologists Q-Probes Program measured the order-to-report TATs for serum creatine kinase-MB and/or serum troponin (I or T) for patients presenting to their hospital EDs with symptoms of acute myocardial infarction. Laboratory personnel also completed detailed questionnaires characterizing their laboratories' and hospitals' practices related to testing for biochemical markers of myocardial injury. ED physicians completed questionnaires indicating their satisfaction with testing for biochemical markers of myocardial injury in their hospitals.

SETTING: A total of 159 hospitals, predominantly located in the United States, participating in the College of American Pathologists Q-Probes Program.

RESULTS: Most (82%) laboratory participants indicated that they believed a reasonable order-to-report TATs for biochemical markers of myocardial injury to be 60 minutes or less. Most (75%) of the 1352 ED physicians who completed satisfaction questionnaires believed that the results of tests measuring myocardial injury should be reported back to them in 45 minutes or less, measured from the time that they ordered those tests. Participants submitted TAT data for 7020 troponin and 4368 creatine kinase-MB determinations. On average, they reported 90% of myocardial injury marker results in slightly more than 90 minutes measured from the time that those tests were ordered. Among the fastest performing 25% of participants (75th percentile and above), median order-to-report troponin and creatine kinase-MB TATs were equal to 50 and 48.3 minutes or less, respectively. Shorter troponin TATs were associated with performing cardiac marker studies in EDs or other peripheral laboratories compared to (1) performing tests in central hospital laboratories, and (2) having cardiac marker specimens obtained by laboratory rather than by nonlaboratory personnel.

CONCLUSION: The TAT expectations of the ED physicians using the results of laboratory tests measuring myocardial injury exceed those of the laboratory personnel providing the results of those tests. The actual TATs of myocardial injury testing meet the expectations of neither the providers of those tests nor the users of those test results. Improving TAT performance will require that the providers and users of laboratory services work together to develop standards that meet the needs of the medical staff and that are reasonably achievable by laboratory personnel.


Cardiac troponin T and C-reactive protein for predicting prognosis, coronary atherosclerosis, and cardiomyopathy in patients undergoing long-term hemodialysis.

deFilippi C, Wasserman S, Rosanio S, Tiblier E, Sperger H, Tocchi M, Christenson R, Uretsky B, Smiley M, Gold J, Muniz H, Badalamenti J, Herzog C, Henrich W.

Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.

JAMA. 2003 Jul 16;290(3):353-9. Abstract quote

CONTEXT: Cardiac troponin T (cTnT) and C-reactive protein (CRP) are prognostic markers in acute coronary syndromes. However, for patients with end-stage renal disease (ESRD) the ability of combinations of these markers to predict outcomes, and their association with cardiac pathology, are unclear. O

OBJECTIVE: To investigate the association between levels of cTnT and CRP and long-term risk of cardiac pathology and death in patients with ESRD.

DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study initiated February through June 1998 and enrolling 224 patients with ESRD from 5 hemodialysis centers in the Houston-Galveston region of Texas. Levels of cTnT and CRP were analyzed at study entry in patients without ischemic symptoms.

MAIN OUTCOME MEASURES: All-cause mortality during a mean follow-up of 827 (range, 29-1327) days. Secondary outcomes in predefined substudies were coronary artery disease (CAD), decreased (< or =40%) left ventricular ejection fraction (LVEF), and presence of left ventricular hypertrophy (LVH).

RESULTS: One hundred seventeen (52%) patients died during follow-up. For levels of cTnT and CRP, progressively higher levels predicted increased risk of death compared with the lowest quartile (for cTnT quartile 2: unadjusted hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1; quartile 3: HR, 2.7; 95% CI, 1.5-4.9; quartile 4: HR, 3.0; 95% CI, 1.6-5.3. For CRP quartile 2: HR, 0.9; 95% CI, 0.5-1.6; quartile 3: HR, 1.8; 95% CI, 1.1-3.1; quartile 4: HR, 1.8; 95% CI, 1.1-3.2). Both cTnT and CRP remained independent predictors of death after adjusting for a number of potential confounders. The combination of cTnT and CRP results provided prognostic information when patients were divided into groups at or above and below the biomarker medians (high cTnT/high CRP levels vs low cTnT/low CRP levels for risk of death: HR, 2.5; 95% CI, 1.5-4.0). Elevated levels of cTnT, but not CRP, were strongly associated with diffuse CAD (n = 67; 0%, 25%, 50%, and 62% prevalence of multivessel CAD across progressive cTnT quartiles, P<.001). An LVEF of 40% or less was identified in 4 (9%), 3 (8%), 10 (27%), and 7 (19%) of patients across cTnT quartiles (P =.07). No trend for cTnT levels was found among patients with LVH (P =.45); similarly, no trend for CRP was found among patients with LVH (P =.65) or an LVEF of 40% or less (P =.75).

CONCLUSIONS: Among stable patients with ESRD, increasing levels of cTnT and CRP are associated with increased risk of death. Furthermore, higher levels of cTnT may identify patients with severe angiographic coronary disease.

Prognostic Value of the Ortho Vitros Cardiac Troponin I Assay in Patients With Symptoms of Myocardial Ischemia
Risk Stratification Using European Society of Cardiology/American College of Cardiology Recommended Cutoff Values


Fred S. Apple, PhD,1 MaryAnn M. Murakami,1 Heidi H. Quist,1 Lesly A. Pearce, MS,2 Stacey Wieczorek, PhD,3 and Alan H.B. Wu, PhD

Am J Clin Pathol 2003;120:114-120 Abstract quote

We evaluated the risk assessment value of a commercial cardiac troponin (cTn; Ortho Vitros ECi, Ortho-Clinical Diagnostics, Raritan, NJ) I assay in patients with symptoms of myocardial ischemia suggestive of acute coronary syndrome and compared findings with those for a commercial cTnT assay in the same population.

The cTn levels were measured by both assays in plasma samples from 273 patients during 24 hours after admission. Baseline and maximum concentrations were used for risk stratification; cutoffs were the 99th percentile and 10% coefficient of variation. End points were all-cause death and cardiac events within 60 days. Relative risks (RRs) were estimated using Cox proportional hazards regression models and Kaplan-Meier curves. RRs of cardiac events and death were significantly higher with increased baseline and maximum concentrations using either cTnI cutoff.

The respective mortality rates for baseline cTnI of more than 0.08 µg/L vs 0.08 µg/L or less were 17.4% vs 2.9% (P = .001); cardiac event rates were 11.5% vs 3.6% (P = .03). Exclusion of patients with ST-segment elevation had no significant effect on rates for either assay.

Mortality was higher in the intermediate (0.09-0.2 µg/L) than in the low (£0.08 µg/L) group for cTnI, with directionally similar results for cTnT.

Cardiac troponin T and cardiac troponin I: relative values in short-term risk stratification of patients with acute coronary syndromes. GUSTO-IIa Investigators.

Christenson RH, Duh SH, Newby LK, Ohman EM, Califf RM, Granger CB, Peck S, Pieper KS, Armstrong PW, Katus HA, Topol EJ.

Department of Pathology, University of Maryland School of Medicine, Baltimore, USA.

Clin Chem 1998 Mar;44(3):494-501 Abstract quote

We compared cardiac troponins T (cTnT) and I (cTnI) collected within 3.5 h of ischemic symptoms for predicting clinical outcomes in 770 patients.

cTnT (cutoff > 0.1 microgram/L) and cTnI (cutoff > 1.5 micrograms/L) were concordant (both positive or negative) in 90.4% of patients. Among discordant results, 66 were cTnT positive and cTnI negative vs 8 who showed the reverse (P < 0.001). Five cTnT-positive and cTnI-negative patients died within 30 days; none who were cTnT negative and cTnI positive died. cTnT showed a slightly greater association (chi 2 = 18.0, P < 0.001) with 30-day mortality than cTnI (chi 2 = 12.5, P = 0.002). The area of the ROC curve for predicting 30-day mortality was significantly larger (Z = 2.08; P = 0.0375) for cTnT, at 0.68 [95% confidence interval (CI) 0.60-0.75], compared with cTnI, at 0.64 (95% CI 0.56-0.72).

When cTnI and the electrocardiogram (ECG) were put in a logistic multiple regression model, cTnT added significant information (chi 2 = 8.03, P = 0.045); however, cTnI did not add to a model containing cTnT and the ECG (chi 2 = 0.84, P = 0.657). cTnT provided more information than cTnI for predicting 30-day mortality early after presentation with acute coronary syndromes.

Gold Standard for the diagnosis of acute myocardial infarction Eur Heart J 2000;21:1502
J Am Coll Cardiol 2000;36:959
Consensus document authored by a joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC)

Acute Coronary Syndrome consisting of unstable angine (UA) or
non-Q-wave MI
Also known as UA/non-ST-elevation MI

20 to 30 percent of patients with unstable angina have elevated troponin

Increased risk of MI or mortality in the 30 to 45 days after discharge

Several trials (CAPTURE, TIMI, PRISM, PURSUIT, FRISC) using glycoprotein IIb/IIIa inhibitors or low-molecular-weight (LMW) heparins, either as primary therapy or in conjunction with angioplasty, have validified the utility of using troponin to identify at risk patients

C-Reactive protein and cardiac troponin T in risk stratification: differences in optimal timing of tests early after the onset of chest pain.

de Winter RJ, Fischer J, Bholasingh R, van Straalen JP, de Jong T, Tijssen JG, Sanders GT.

Departments of Cardiology, Clinical Chemistry, and Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands.

Clin Chem 2000 Oct;46(10):1597-603 Abstract quote

BACKGROUND: Increased C-reactive protein (CRP) is an important prognostic indicator for early risk stratification in patients with an acute coronary syndrome (ACS), independent of, and in combination with, increased cardiac troponin T (cTnT). However, increases in both cTnT and CRP also occur secondary to myocardial damage.

METHODS AND RESULTS: In 156 consecutive patients, early release kinetics of CRP and cTnT were analyzed. The cutoff values were 3.0 mg/L for CRP and 0.1 microgram/L for cTnT. In the 75 patients with a CRP below the cutoff on admission, there was little change in CRP until 8 h after the onset of symptoms. At 12 h after the onset of symptoms, the cumulative proportions of abnormal CRP and cTnT in non-ST elevation ACS patients were 27% and 89%, respectively (P <0.01). During the first 24 h after the onset of symptoms, the median time above the cutoff was 20 h for CRP and 5 h for cTnT (P <0.0001). CRP was below the cutoff on admission significantly more often among patients receiving thrombolytic therapy than in patients without an indication for reperfusion therapy (51% vs 28%; P = 0.004).

CONCLUSIONS: Increased CRP as an early independent risk indicator should be measured as soon as possible after the onset of symptoms, whereas increased cTnT is most reliable at 12 or more hours after the onset of symptoms.

Cardiac troponin T and C-reactive protein as markers of acute cardiac allograft rejection.

Chance JJ, Segal JB, Wallerson G, Kasper E, Hruban RH, Kickler TS, Chan DW.

Department of Pathology, Johns Hopkins Hospital, 600 N. Wolfe Street/Meyer B-125, 21287-7065, Baltimore, MD, USA

Clin Chim Acta 2001 Oct;312(1-2):31-9 Abstract quote

Due to myocyte damage and an associated inflammatory response, it is possible that cardiac troponin T and C-reactive protein (CRP) concentrations may correlate with the histologic grade of rejection in endomyocardial biopsy samples obtained from patients who have received a heart transplant. In this study, 704 blood samples were obtained from 145 different heart transplant recipients just prior to endomyocardial biopsy. Plasma specimens were assayed for troponin T and CRP concentration and the results compared with the assigned International Society of Heart and Lung Transplantation (ISHLT) histologic grade. Rejection was defined as an ISHLT grade of 3A or higher. The negative predictive values were near 80% in all cases, and a statistically significant increase in median troponin T concentration was observed across ISHLT grades. After the first month posttransplantation, the specificity of the troponin T test (cutoff 0.1 ng/ml) was 95% and increased to 98% when false positives seen in renal disease patients were excluded. Both tests demonstrated poor sensitivity and positive predictive value for rejection. Neither CRP nor troponin T had sufficient sensitivity to serve as an alternative to endomyocardial biopsy in the diagnosis of acute cardiac allograft rejection. However, the troponin T test had a high specificity, especially when patients with renal insufficiency were excluded, and could serve as an adjunct test in this setting. When combined with a normal serum creatinine, a troponin T>/=0.1 ng/ml prior to endomyocardial biopsy correlated with graft rejection in almost all cases, making biopsy unnecessary.

Clinical Significance of Low-Positive Troponin I by AxSYM and ACS:180

James S. Lewis, Jr, MD
James F. Taylor
Andrew Z. Miklos, MD
Katherine S. Virgo, PhD
Michael H. Creer, MD
Detlef G. Ritter, MD

Am J Clin Pathol 2001;116:396-402 Abstract quote

We compared troponin I (TnI) assays (AxSYM [Abbott]; ACS:180 [Bayer]) in blood samples with concentrations less than 10 ng/mL (<10 g/L).

Discordant results were evaluated by linearity studies and by testing for rheumatoid factor. Patients with discordant TnI results were compared with patients with concordant results and patients with negative TnI who had a new myocardial infarction or died within 2 months of initial testing. Positive TnI cutoffs by AxSYM and ACS:180 were 0.7 ng/mL (0.7 g/L) and 0.13 ng/mL (0.13 g/L), respectively.

We identified 173 specimens that were repeatedly positive by at least 1 assay; 143 specimens were positive by both assays. Twenty samples positive for TnI by AxSYM were negative by ACS:180, while 10 samples positive by ACS:180 were negative by AxSYM. The discordant samples showed no evidence of interfering substances, including rheumatoid factor. Clinical follow-up showed that 26% of patients with elevated TnI by both assays, 33% with TnI positive only by AxSYM, 22% with TnI positive only by ACS:180, and 8% with negative TnI by AxSYM encountered at least 1 clinical end point.

Variable detection rates by these assays for low-positive TnI represent a clinically significant problem.

Coronary Angiographic Findings in Patients With Clinical Unstable Angina According to Cardiac Troponin I and T Concentrations in Serum
A Comparative Analysis


Mauro Panteghini, MD, Claudio Cuccia, MD, Franca Pagani, MD, Claudia Turla, MD, Graziella Bonetti, MD, and Elena Bonini, MD

From the Laboratorio Analisi Chimico Cliniche 1 (Drs Panteghini, Pagani, and Bonetti) and the Cattedra and Divisione di Cardiologia (Drs Cuccia, Turla, and Bonini), Azienda Ospedaliera Spedali Civili and Universitá, Brescia, Italy

 

Arch Pathol Lab Med 2002;Vol. 126, No. 4, pp. 448–451. Abstract quote

Context.—Elevated cardiac troponin levels have been reported to identify unstable angina patients at high risk.

Objective.—To examine the relation of cardiac troponin I (cTnI) and cardiac troponin T (cTnT) levels to findings of coronary angiography in these patients.

Methods.—Samples for troponin estimation were taken every 4 hours throughout the first 48 hours after admission before angiography in 34 patients with primary unstable angina. Patients were considered to be troponin positive if the marker was increased (>0.04 g/L for cTnT and >0.03 g/L for cTnI) in at least one sample collected.

Results.—An increased troponin (I or T) concentration was documented in 14 patients (41.2%). Twelve patients (35.3%) had elevations of both markers, whereas the remaining 2 patients had elevations of cTnI or cTnT alone. Patients with or without increased troponin levels did not differ with respect to degree of coronary disease at angiography. However, patients with elevated troponin concentrations had more complex lesion characteristics. In 69% of patients with increased cTnI levels and in 77% of patients with increased cTnT levels, type B2 or C lesions were documented with presence of ulcerated plaques and thrombus formation. In contrast, only 23% of the patients with elevated cTnI or cTnT levels had type A lesions compared with 71% of patients with negative troponin concentrations.

Conclusions.—Patients with unstable angina who have significant release of cTnI and/or cTnT have evidence of more complex lesions on coronary angiography, supporting the hypothesis that both troponins might be used without distinction as surrogate markers for microembolization from thrombus formation on a disrupted plaque.



Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction.

Aviles RJ, Askari AT, Lindahl B, Wallentin L, Jia G, Ohman EM, Mahaffey KW, Newby LK, Califf RM, Simoons ML, Topol EJ, Berger P, Lauer MS.

Department of Cardiology, the Cleveland Clinic Foundation, Cleveland, OH 44951, USA.

N Engl J Med 2002 Jun 27;346(26):2047-52 Abstract quote

BACKGROUND: Among patients with suspected acute coronary syndromes, cardiac troponin T levels have prognostic value. However, there is concern that renal dysfunction may impair the prognostic value, because cardiac troponin T may be cleared by the kidney.

METHODS: We analyzed the outcomes in 7033 patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries IV trial who had complete base-line data on troponin T levels and creatinine clearance rates. The troponin T level was considered abnormal if it was 0.1 ng per milliliter or higher, and creatinine clearance was assessed in quartiles. The primary end point was a composite of death or myocardial infarction within 30 days.

RESULTS: Death or myocardial infarction occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 ml per minute, an abnormally elevated troponin T level was predictive of an increased risk of myocardial infarction or death (7 percent vs. 5 percent; adjusted odds ratio, 1.7; 95 percent confidence interval, 1.3 to 2.2; P<0.001). Among patients with a creatinine clearance in the lowest quartile, an elevated troponin T level was similarly predictive of increased risk (20 percent vs. 9 percent; adjusted odds ratio, 2.5; 95 percent confidence interval, 1.8 to 3.3; P<0.001). When the creatinine clearance rate was considered as a continuous variable and age, sex, ST-segment depression, heart failure, previous revascularization, diabetes mellitus, and other confounders had been accounted for, elevation of the troponin T level was independently predictive of risk across the entire spectrum of renal function.

CONCLUSIONS: Cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of their level of creatinine clearance.

 

INTERFERING DISEASES OR SUBSTANCES THAT ALTER LEVELS CHARACTERIZATION
DEGRADATION  

Degradation of cardiac troponin I in serum complicates comparisons of cardiac troponin I assays.

Shi Q, Ling M, Zhang X, Zhang M, Kadijevic L, Liu S, Laurino JP.

Spectral Diagnostics Inc., 135-2 The West Mall, Toronto, Ontario, Canada M9C 1C2.

Clin Chem 1999 Jul;45(7):1018-25 Abstract quote

BACKGROUND: Up to a 20-fold variation in serum cardiac troponin I (cTnI) concentration may be observed for a given patient sample with different analytical methods. Because more limited variation is seen for control materials and for purified cTnI, we explored the possibility that cTnI was present in altered forms in serum.

METHODS: We used four recombinantly engineered cTnI fragments to study the regions of cTnI recognized by the Stratus(R), Opus(R), and ACCESS(R) immunoassays. The stability of these regions in serum was analyzed with Western blot.

RESULTS: The measurement of several control materials and different forms of purified cTnI using selected commercial assays demonstrated five- to ninefold variation. Both the Stratus and Opus assays recognized the N-terminal portion (NTP) of cTnI, whereas the ACCESS assay recognized the C-terminal portion (CTP) of cTnI. Incubation of recombinant cTnI in normal human serum produced a marked decrease in cTnI concentration as determined with the ACCESS, but not the Stratus, immunoassay. Western blot analysis of the same samples using cTnI NTP- and CTP-specific antibodies demonstrated preferential degradation of the CTP of cTnI.

CONCLUSIONS: The availability of serum cTnI epitopes is markedly affected by the extent of ligand degradation. The N-terminal half of the cTnI molecule was found to be the most stable region in human serum. Differential degradation of cTnI is a key factor in assay-to-assay variation.

FIBRIN CLOTS  
HEPARIN  

Lower cardiac troponin T and I results in heparin-plasma than in serum.

Stiegler H, Fischer Y, Vazquez-Jimenez JF, Graf J, Filzmaier K, Fausten B, Janssens U, Gressner AM, Kunz D.

Institut fur Klinische Chemie und Pathobiochemie, Medizinische Klinik I, and Klinik fur Thorax-, Herz- und Gefasschirurgie, Universitatsklinikum der RWTH Aachen, 52074 Aachen, Germany.

Clin Chem 2000 Sep;46(9):1338-44 Abstract quote

BACKGROUND: The use of plasma rather than serum for determination of cardiac troponins can improve turnaround time and potentially avoid incomplete serum separation that may produce falsely increased results. We investigated the influence of incomplete serum separation and the effect of heparin-plasma on cardiac troponin concentrations.

METHODS: Serum and heparin-plasma samples were drawn simultaneously from 100 patients (50 patients with acute coronary syndrome and 50 patients after open heart surgery) and measured on three different analytical systems, two for determination of cardiac troponin I (cTnI; Abbott AxSYM and Bayer ACS:Centaur) and one for cardiac troponin T (cTnT; Roche Elecsys cTnT STAT). Serum samples were reanalyzed after a second centrifugation to assess the influence of incomplete serum separation.

RESULTS: Mean results (+/- 95% confidence interval) in heparin-plasma compared with serum were 101% +/- 2% (AxSYM cTnI), 94% +/- 3% (ACS:Centaur cTnI), and 99% +/- 3% (Elecsys cTnT). Differences >20% were seen in 11% of results on the ACS:Centaur, 9% of results on Elecsys cTnT, and 2% of results on the AxSYM. For the Elecsys cTnT assay, the magnitude of the difference between serum and plasma was independent of the absolute concentration and confined to individual samples, and was reversed by treatment with heparinase. A second centrifugation had no effect on serum results by any of the assays.

CONCLUSION: The concentrations of troponins measured in heparin-plasma are markedly lower than in serum in some cases.

HETEROPHILIC ANTIBODIES  

Performance of the enhanced Abbott AxSYM cardiac troponin I reagent in patients with heterophilic antibodies.

Yeo KT, Storm CA, Li Y, Jayne JE, Brough T, Quinn-Hall KS, Fitzmaurice TF.

Department of Pathology, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA.

Clin Chim Acta 2000 Feb 25;292(1-2):13-23 Abstract quote

The presence of heterophilic antibodies in the serum of a small subpopulation of individuals continues to cause false results for modern-day immunoassays. In order to determine the frequency of heterophilic antibody (HA)-related false positives within our population of positive cardiac troponin I (cTnI) patients, we assayed 200 samples using the original in-house cTnI assay (Abbott AxSYM) and the Bayer ACS:180 cTnI, which we had previously observed to be more effective at blocking HA interference.

Four samples were identified as false positives based on discordant results between the two assays, as well as the correction of the false positives by treatment of the samples with heterophilic antibody blocking reagent (HBR). An 'enhanced' version of the AxSYM cTnI reagent was designed to greatly reduce or eliminate HA interference, and has now replaced the original reagents. The present study shows that the enhanced reagent significantly reduced or eliminated much of the HA interference.

Comparative studies between the enhanced cTnI reagent and the original Abbott AxSYM cTnI reagent showed excellent correlation and equivalent diagnostic concordance, when HA samples were excluded from the analysis.

CHRONIC RENAL FAILURE  

Cardiac troponin elevations in chronic renal failure: prevalence and clinical significance.

Musso P, Cox I, Vidano E, Zambon D, Panteghini M.

Department of Cardiology, Ospedale Civile, Ivrea, Italy.

Clin Biochem 1999 Mar;32(2):125-30 Abstract quote

OBJECTIVES: The aim of the study was investigate the prevalence of abnormal values of cardiac troponin T (cTnT) and cardiac troponin I (cTnI) in patients with chronic renal failure (CRF) and their clinical significance.

DESIGN AND METHODS: We investigated the concentrations of cTnT and cTnI in 49 CRF patients without heart disease or diabetes. Cardiac TnT values were measured with a second generation immunoassay and cTnI with two immunoassays with different analytical sensitivity. All CRF patients underwent regular clinical follow-up over a 18-month period.

RESULTS: No patients with CRF had elevated values of cTnI when measured with one assay and only 2 patients displayed minimally elevated values with the second assay. In contrast, 23 CRF patients (47%) displayed cTnT concentrations elevated above the upper reference limit. The elevated cTnT values observed were below the values detected in acute myocardial infarction and were not associated with adverse cardiac events during follow-up.

CONCLUSIONS: Mildly elevated cTnT concentrations are common in patients with CRF and do not appear to be associated with adverse coronary events.

HETEROPHILE ANTIBODIES  


False-positive AxSYM cardiac troponin I results in a 53-year-old woman.

Knoblock RJ, Lehman CM, Smith RA, Apple FS, Roberts WL.

Division of Clinical Pathology, Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah 84108, USA.

Arch Pathol Lab Med 2002 May;126(5):606-9 Abstract quote

A number of classes of endogenous antibodies, including heterophile, rheumatoid factor, and autoantibodies, can interfere with immunoassay measurements of many different analytes. Heterophile and rheumatoid factor antibody interferences have been described previously for the AxSYM cardiac troponin I assay. Several commercial products have been developed to neutralize heterophile antibody interferences.

We describe a patient with multiple apparently falsely elevated cardiac troponin I results that were unique to the AxSYM analyzer. These cardiac troponin I results diluted linearly. When treated with 2 different heterophile-blocking reagents, the magnitudes of the falsely elevated results increased 17- and 26-fold, and these results also demonstrated dilution linearity. This interfering substance could be removed by passage through an immobilized protein A column and by polyethylene glycol precipitation. It does not appear to be a classic heterophile antibody, nor is it a paraprotein.

Laboratorians must remain constantly vigilant for immunoassay interferences that lead to clinically significant inaccurate results and must recognize that accepted methods for detecting and neutralizing the interference may be ineffective.

RHEUMATOID FACTOR  

False-positive troponin I in the MEIA due to the presence of rheumatoid factors in serum. Elimination of this interference by using a polyclonal antisera against rheumatoid factors.

Dasgupta A, Banerjee SK, Datta P.

Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School 77030, USA.

Am J Clin Pathol 1999 Dec;112(6):753-6 Abstract quote

We report false-positive cardiac troponin (cTn) I results in the microparticle enzyme immunoassay (MEIA) using the AxSYM analyzer.

We studied serum samples from 12 patients with positive rheumatoid factor but with no indication of myocardial infarction (MI); 2 also had positive antinuclear antibody (ANA) titers. Serum samples from 7 patients with positive ANA titers and negative rheumatoid factors also were studied. Total creatine kinase (CK) was run using a Hitachi 747 analyzer, cTnT using an Elecsys 2010 analyzer, and cTnI and CK-MB using an AxSYM analyzer.

We observed no measurable cTnI and cTnT concentrations in 12 control samples or in specimens with positive ANA titers and negative rheumatoid factors. In contrast, samples from 7 of 12 patients containing rheumatoid factors had measurable cTnI concentrations. Four specimens showed cTnI concentrations more than 2.0 micrograms/L, the suggested diagnostic cutoff for MI. None of the specimens showed detectable cTnT. The concentrations of total CK and CK-MB were within normal ranges in all specimens. False-positive results were observed only with the MEIA for cTnI.

This interference can be eliminated by using a polyclonal antisera against rheumatoid factor. The chemiluminescent assay for cTnI showed no detectable cTnI concentration in any specimen.

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