Clinical Biochemistry 47 (2014) 319–320

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Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem

Editorial

Diagnosis of myocardial infarction: Cardiac troponin I or troponin T?

Over the last half-century serum biomarkers have become an integral component of the clinical diagnosis of myocardial infarction, with cardiac troponins now established as the biomarker of choice [1,2]. Troponin is a complex of three proteins — troponin I, T and C — found within the sarcomere where it regulates calcium that mediated both cardiac and skeletal muscle contractions. The genes for troponin I and T are distinct in cardiac and skeletal muscles, and therefore immunoassays are able to quantify cardiac isoforms of both. Cardiac troponin I and T are therefore highly specific markers of myocardial injury. Contemporary cardiac troponin I and T assays have greatly enhanced the diagnosis of myocardial infarction. However, the majority of assays are not able to meet the analytical precision recommended in the Third Universal Definition of Myocardial Infarction [2] to permit the 99th centile of a healthy reference population to be adopted as the diagnostic threshold for myocardial infarction. The diagnostic community has therefore sought to improve analytical precision, with the development of the latest generation of high-sensitivity troponin assays. The International Federation of Clinical Chemistry Task Force on Clinical Applications of Cardiac Biomarkers defines a ‘high-sensitivity’ assay by the following criteria: a) the total imprecision (coefficient of variation) at the 99th centile should be b 10%, and b) troponin should be measureable above the assay's limit of detection for at least 50% (and ideally 95%) of healthy individuals [3]. It is hoped that high-sensitivity troponin assays will permit more laboratories to adopt the universal definition of myocardial infarction and improve clinical outcome in patients with chest pain through more accurate diagnosis. High-sensitivity assays to measure both cardiac troponin I and T are now available for clinical use in many countries, yet few studies have directly compared these assays. As such, guidelines do not make a distinction between cardiac troponin I and T, and whether one is more effective than the other is not known. There are important differences in the molecular structure, biology and release kinetics of troponin I and T in health and disease [4–6]. Studies evaluating whether these characteristics translate into differences in diagnostic performance of these assays are therefore important and timely. Cullen and colleagues evaluate the performance of a high-sensitivity troponin I and a high-sensitivity troponin T assay in 1571 patients with symptoms suggestive of cardiac ischemia presenting to the Emergency Department in Christchurch, New Zealand and Brisbane, Australia [7]. The diagnosis of myocardial infarction was independently adjudicated using the contemporary troponin I assays which were measured on

☆ Relationship with industry: NLM and AS have received honoraria from Abbott Diagnostics and NLM has acted as a consultant for Beckman-Coultar and Abbott Diagnostics. All other authors have no conflict of interest or financial disclosures to declare.

http://dx.doi.org/10.1016/j.clinbiochem.2014.03.002 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc.

admission and that 6–12 h later were used to guide clinical care. Blood was collected and stored on admission and at 2 h as part of the study protocol. The authors compare diagnostic performance of highsensitivity troponin I and T assays on admission and at 2 h to peak troponin concentration determined by the contemporary assay. Cullen et al. make two important observations. First, both highsensitivity troponin I and high-sensitivity troponin T assays have excellent sensitivity for the diagnosis of myocardial infarction when measured as early as 2 h after presentation. These observations add to a growing body of evidence supporting a role for high-sensitivity troponin assays in the early diagnosis myocardial infarction [8,9]. The proportion of patients with myocardial infarction was 12.9% in this study population, and sensitivities were comparable for the high-sensitivity troponin I and T assays at 96%, 95% confidence interval [CI] 92 to 98%, and 94%, 95% CI 90 to 97%, respectively. Second, while sensitivities were similar, specificity was significantly lower for the highsensitivity troponin T assay (79%, 95% CI 77 to 81%) compared to the high-sensitivity troponin I assay (93%, 95% CI 91 to 94%). The impact of high-sensitivity troponin assays on specificity for myocardial infarction and the effect that reduced specificity has on clinical practice has been underestimated and has received little attention. Identifying an increasing number of patients with myocardial injury has the potential to result in inappropriate hospital admission, misdiagnosis, initiation of potentially detrimental therapies and poorer clinical outcomes for patients. Are differences in specificity between these troponin I and T assays real and of clinical relevance? It is important to highlight that specificity will inevitably reduce with high-sensitivity troponin assays as we lower the diagnostic threshold to improve the early diagnosis of myocardial infarction [10]. However, the impact of identifying an additional 14% of patients as having myocardial injury not due to myocardial infarction could be clinically significant. If the high-sensitivity troponin T assay was used to guide patient care in the study population it is likely that more patients would have been admitted to hospital and would have undergone additional cardiac investigation. Were these findings to be replicated, differences in assay specificity may have health economic consequences and influence practice guidelines. There are a number of plausible explanations for differences in specificity between the high-sensitivity troponin T and I assays. First, the adjudication of myocardial infarction was based on contemporary troponin I assays used in clinical practice. As the authors acknowledge, this may have introduced a systematic bias that would favor the diagnostic performance of the high-sensitivity troponin I assay. The effect of this potential source of bias should not be overstated though as a recently published analysis from a European cohort also reported lower specificity for troponin T compared to troponin I despite the use of the

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Editorial

troponin T assay to adjudicate the study diagnosis [11]. Second, differences in assay specificity may reflect differences in the biology and release kinetics of troponin I and T from the injured myocardium. The protein content of ventricular myocardium is 5.0 mg/g for troponin I and 10.8 mg/g for troponin T [3]. While most troponin complex is bound within the cytoskeletal structure, ~ 3.5% of troponin I and ~ 7% of troponin T is found in the cytosolic pool. Any systemic insult that altered the integrity of the cardiomyocyte cell membrane may release more cytosolic troponin T than troponin I into the circulation. Lower specificity with the high-sensitivity troponin T assay could theoretically reflect differences in the detection of myocardial injury due to noncoronary pathologies between the two assays. Perhaps the most likely explanation for the differences in specificity observed by Cullen et al. relate to the appropriateness of the recommended 99th centile values for each assay or to assay precision at these concentrations. While the authors used the 99th centile reference limits recommended by each manufacturer in this analysis, these limits were determined in different reference populations that may not be truly comparable. Furthermore, no assessment of assay precision was undertaken in the research laboratory and we can therefore only assume that precision was comparable at the respective 99th centile limits. In a recent analysis from the Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) study, comparing the sensitivity and specificity of the admission troponin measurement alone, differences in specificity were also reported for the same high-sensitive troponin I and T assays. Specificities were similar to those reported by Cullen et al. at 93% for troponin I and 78% for troponin T [11]. In this study, two prototype high-sensitivity troponin I assays were also evaluated using a lower 99th centile value of 9 ng/L compared to 26 ng/L for the assay in clinical use. For these prototype troponin I assays specificity for myocardial infarction was significantly lower (71 to 75%) and comparable to the high-sensitivity troponin T assay. A recent evaluation of cardiac troponin T across three well characterized population-based studies suggested that the recommended 99th centile value of 14 ng/L may lead to over-diagnosis of myocardial infarction particularly in men and the elderly [12]. Taken together these observations perhaps suggest differences in the biology and release kinetics of troponin I and T have a less important effect on assay specificity than the selection of appropriate reference populations and therefore diagnostic thresholds. Further studies are required to determine whether the diagnostic performance of high-sensitivity troponin T and I assays are equivalent. It is now clear that the upper reference limit for troponin differs in men and women for both troponin I and T assays, with the 99th centile nearly two-fold higher in men than in women [13]. The prevalence of myocardial injury is also higher in elderly patients who have more

comorbid illness. Further comparisons of high-sensitivity troponin assays are needed and should stratify patients by age and sex, and address the impact of high-sensitivity assays on clinical outcomes in addition to diagnostic performance. References [1] Coudrey L. The troponins. Arch Intern Med 1998;158:1173–80. [2] Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012;33:2551–67. [3] Apple FS, Collinson PO. Analytical characteristics of high-sensitivity cardiac troponin assays. Clin Chem 2012;58:54–61. [4] Dean KJ. Biochemistry and molecular biology of troponins I and T. Cardiac MarkersPathology and Laboratory Medicine; 1998 193–204. [5] Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W. Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am J Cardiol 1991;67:1360–7. [6] Wu AH, Feng YJ, Moore R, et al. Characterization of cardiac troponin subunit release into serum after acute myocardial infarction and comparison of assays for troponin T and I. Clin Chem 1998;44:1198–208. [7] Cullen L, Aldous S, Than M, et al. Comparison of high sensitivity troponin T and I assays in the diagnosis of non-ST elevation acute myocardial infarction in emergency patients with chest pain. Clin Biochem 2014;47:321–6. [8] Cullen L, Mueller C, Parsonage WA, et al. Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome. J Am Coll Cardiol 2013;62:1242–9. [9] Keller T, Zeller T, Ojeda F, et al. Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction. JAMA 2011;306:2684–93. [10] Mills NL, Lee KK, McAllister DA, et al. Implications of lowering threshold of plasma troponin concentration in diagnosis of myocardial infarction: cohort study. BMJ 2012;344: e1533. [11] Hoeller R, Rubini Giménez M, Reichlin T, et al. Normal presenting levels of highsensitivity troponin and myocardial infarction. Heart 2013;99:1567–72. [12] Gore MO, Seliger SL, Defilippi CR, et al. Age and sex dependent upper reference limits for the high sensitivity cardiac troponin T assay. J Am Coll Cardiol Jan 30 2014 [epublication]. [13] Apple FS, Ler R, Murakami MM. Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin Chem 2012;58:1574–81.

Kuan Ken Lee Royal Infirmary of Edinburgh, Edinburgh, United Kingdom Anoop S.V. Shah Nicholas L. Mills⁎ BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom E-mail address: [email protected]. ⁎ Corresponding author at: BHF/University Centre for Cardiovascular Science, Chancellor's Building, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SB, United Kingdom. Fax: +44 131 242 6379. 11 March 2014

Diagnosis of myocardial infarction: cardiac troponin I or troponin T?

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