Cardiac troponin (ctn) testing is an

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1 CLINICIAN UPDATE How to Interpret Elevated Cardiac Troponin Levels Vinay S. Mahajan, MD, PhD; Petr Jarolim, MD, PhD Cardiac troponin (ctn) testing is an essential component of the diagnostic workup and management of acute coronary syndromes (ACS). Although over the past 15 years the diagnostic performance of the previous gold-standard assay, creatine kinase- MB, has not changed appreciably, the ever-increasing sensitivity of ctn assays has had a dramatic impact on the use of ctn testing to diagnose ACS. 1 Here, we present 3 recent clinical cases from the emergency department with acute chest discomfort that exemplify the challenges introduced by highsensitivity ctn assays: a 48-year-old man who presented to the emergency department with chest discomfort lasting 2 hours and a 3-day history of flu-like symptoms whose ECG showed diffuse ST-segment changes, a 60- year-old woman with a medical history of heart failure who presented to the emergency department with chest pain lasting 1.5 hours whose ECG was nondiagnostic, and a 54-year-old man with a medical history of diabetes mellitus who presented with chest discomfort lasting 1 hour whose ECG was normal. Cardiac troponin I (ctni) testing (TnI- Ultra assay on the ADVIA Centaur XP immunoanalyzer, both Siemens Healthcare Diagnostics) was ordered on all 3 patients. The laboratory results were reported as positive in all 3 cases, with the reported values being 0.05, 0.06, and 0.06 ng/ml, respectively, all just above the diagnostic limit of 0.04 ng/ml. Assays for ctn, namely ctni and cardiac troponin T (ctnt), are the preferred diagnostic tests for ACS, in particular non ST-segment elevation myocardial infarction, because of the tissue-specific expression of ctni and ctnt in the myocardium. The results of ctn testing often guide the decision for coronary intervention. However, although the increasing sensitivity of ctn assays lowers the number of potentially missed ACS diagnoses, it presents a diagnostic challenge because the gains in diagnostic sensitivity have inevitably come with a decrease in specificity. For instance, the replacement of the ctn assay (Siemens Healthcare Diagnostics) by the more sensitive TnI-UItra assay in the Brigham and Women s Hospital Clinical Laboratories in early 2007 resulted in a doubling of positive ctn results in samples collected in the emergency department 2 even though there was no change in the frequency of final diagnoses of ACS. What Is a High-Sensitivity Troponin Test? Rapid advances in immunoassay technologies and the international adoption of traceable troponin calibration standards have allowed manufacturers to develop and calibrate troponin assays with unprecedented analytic sensitivity and precision. Thus, a contemporary ctni assay such as TnI-Ultra detects plasma ctn levels as low as ng/ml with an assay range that spans 4 orders of magnitude ( ng/ ml). Similarly, the limit of detection of a contemporary ctnt assay (Elecsys TnT-hs, Roche Diagnostics; approved for clinical use in Europe but not yet in the United States) is as low as ng/ml. 3 Although ctni and ctnt concentrations correlate to some extent, the numeric values can be quite different in a given patient, with ctnt readings generally being lower. Between 1995 and 2007, the limit of detection fell from 0.5 ng/ml for some ctn assays to ng/ml for TnI- Ultra, an 100-fold improvement in analytic sensitivity (Figure 1). Remarkably, the use of contemporary high-sensitivity ctn assays makes it possible to detect low levels of ctn even in plasma from healthy subjects. Indeed, high-sensitivity ctn assays are designated as such on the basis of their ability to detect ctns even in healthy individuals. The latest generation of high-sensitivity ctn assays can detect ctn in 95% of a reference popula- From the Brigham and Women s Hospital, Harvard Medical School, Boston, MA. Correspondence to Petr Jarolim, MD, PhD, Brigham and Women s Hospital, 75 Francis St, Boston, MA pjarolim@partners.org (Circulation. 2011;124: ) 2011 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 Mahajan and Jarolim Interpretation of Elevated Troponin Levels 2351 Figure 1. Evolution of the cardiac troponin (ctn) assays and their diagnostic cutoffs. A hypothetical case of acute coronary syndrome is depicted with the earliest times of potential diagnosis corresponding to the diagnostic cutoffs of more sensitive ctn assays. The years correspond to the availability of the respective assays in the US market. tion. 4 The ability to detect ctns in healthy individuals made it imperative to define a clinical decision limit for ctn concentration, ie, a positive ctn result. What Is a Positive Troponin Result? The 99th Percentile Rule The National Academy of Clinical Biochemistry issued a guideline in 2007 that stated that in the presence of a clinical history suggestive of ACS, the following is considered indicative of myocardial necrosis consistent with myocardial infarction: maximal concentration of ctn exceeding the 99th percentile of values (with optimal precision defined by total c.v. [coefficient of variation] 10%) for a reference control group on at least one occasion during the first 24 hours after the clinical event. 5 This guideline provides the framework for determining the decision limit or a positive troponin result. Based on the 99th percentile rule, troponin decision limits of several high-sensitivity ctn assays can be set as low as 0.01 ng/ml. 6 This makes it possible to identify patients with ACS earlier, enabling earlier coronary intervention (Figure 2). However, while improving clinical sensitivity for the diagnosis of myocardial infarction, the

3 2352 Circulation November 22, 2011 Figure 2. Cardiac troponin I (ctni) levels in a healthy reference population and in an acute coronary syndrome (ACS) population. Top, Frequency histograms of real TnI levels (blue filled) in healthy reference controls are shown, along with the distribution of the same TnI levels as measured with a less precise ctni (green) and the more precise TnI- Ultra (blue) assay for comparison. In practice, the values below the assay detection threshold (dashed portions of the histogram plots) cannot be distinguished from one another. Note how the 99th percentile decision limits decrease with increased assay precision. Bottom, Hypothetical frequency histograms of ctni concentrations in individuals with ACS 2, 2 to 3, or 3 to 4 hours after the onset of symptoms. The decision limits (dashed vertical lines) for the contemporary high-sensitivity ctni assays are based on the 99th percentile in a healthy reference population. Note the impact of decreased diagnostic cutoffs of the newer ctni assays on the fraction of acute myocardial infarctions diagnosed at earlier time intervals. (All frequency histograms in this figure are hypothetical and for illustrative purposes only.) increased analytic sensitivity has come at the cost of reduced specificity, thus presenting an additional diagnostic challenge for clinicians. The Specificity of a Troponin Test for ACS The use of the 99th percentile cutoff for ctn positivity does not imply that 1% of the population suffers from myocardial damage. Rather, this cutoff is useful only when applied to patients with a high pretest probability of ACS. The clinician must interpret ctn results in the context of clinical history, ECG findings, and possibly cardiac imaging to establish the correct diagnosis. A positive troponin in the setting of a low pretest probability for ACS may be suggestive but clearly is not indicative of a coronary event. Unfortunately, the pressure to avoid malpractice litigation forces many clinicians to order comprehensive panels of laboratory tests, including ctn, for patients with a very low pretest probability of ACS, which adversely affects the positive predictive value of ctn assays for diagnosing myocardial infarction. Traditional wisdom, before the advent of high-sensitivity ctn assays, held that troponins do not appear in the circulation of individuals with a healthy myocardium. These levels used to be considered indicative of myocardial necrosis. However, with high-sensitivity troponin assays, circulating ctnt or ctni can be found in the plasma as a result of transient ischemic or inflammatory myocardial injury. Thus, elevated ctn may be detected in conditions other than ACS (the Table), including heart failure, cardiomyopathies, myocarditis, renal failure, tachyarrhythmias, and pulmonary embolism, and even after strenuous exercise in healthy individuals. 8 The Need for Serial Troponin Testing In addition to the absolute level of ctn in plasma or serum above the decision limit, a critical component of the diagnosis of ACS is ctn kinetics. This was reiterated in the current universal definition of myocardial infarction adopted in Although absolute ctn elevations are seen in multiple chronic cardiac and noncardiac conditions, a rise or fall in serial ctn levels strongly supports an acutely evolving cardiac injury such as, most commonly, acute myocardial infarction. Serial ctn testing helped establish final diagnoses in our 3 patients. Patient 1 (Figure 3, top) had a steady but relatively slow increase in ctni with a peak value of 0.9 ng/ml. The findings of acute dilated cardiomyopathy and global ventricular dysfunction on echocardiography were consistent with a diagnosis of acute myocarditis. Patient 2 (Figure 3, middle) had modest ctn elevations fluctuating just above the decision limit in the 0.05 to 0.09 ng/ml range. She was diagnosed with acutely decompensated heart fail-

4 Mahajan and Jarolim Interpretation of Elevated Troponin Levels 2353 Table. Causes of Elevated Plasma Cardiac Troponin Other Than Acute Coronary Syndromes Cardiac Causes Noncardiac Causes Cardiac contusion resulting from trauma Pulmonary embolism Cardiac surgery Severe pulmonary hypertension Cardioversion Renal failure Endomyocardial biopsy Stroke, subarachnoid hemorrhage Acute and chronic heart failure Infiltrative diseases, eg, amyloidosis Aortic dissection Cardiotoxic drugs Aortic valve disease Critical illness Hypertrophic cardiomyopathy Sepsis Tachyarrhythmia Extensive burns Bradyarrhythmia, heart block Extreme exertion Apical ballooning syndrome Post percutaneous coronary intervention Rhabdomyolysis with myocyte necrosis Myocarditis or endocarditis/pericarditis Adapted from Jaffe et al 7 with permission of the publisher. Copyright 2006, Elsevier. Figure 3. Troponin kinetics in the index cases. Plasma cardiac troponin I (ctni) values in the 3 index cases. The cutoff for the TnI assay (0.04 ng/ml) is indicated with a dashed horizontal line. See the text for detailed description. ure. Additional TnI testing did not provide evidence of ACS. TnI levels in patient 3 (Figure 3, bottom) rose to a peak of 53 ng/ml within 24 hours. He was diagnosed with non ST-segment elevation myocardial infarction when the second ctn result of 6.3 ng/ml was obtained after 6 hours. The rapid, steep increase from the initial barely positive value of 0.06 ng/ml to the 6-hour value of 6.3 ng/ml illustrates that more frequent testing during the first several hours may be sufficient to detect a diagnostic rise in ctn levels that is eventually destined to increase by a few orders of magnitude such as the peak of 53 ng/ml in this patient. Fortunately, simultaneous improvements in contemporary assay sensitivity and precision allow 2 ctn values with a difference as small as a few hundredths of 1 ng/ml to be distinguished reliably. This has significant implications for serial ctn testing. Previously, clinicians often had to wait an average of 6 hours with the lower-sensitivity, lower-precision ctn assays to see a conclusive increase in plasma ctn levels after the first troponin measurement, but today s highsensitivity ctn tests that are separated by a mere 2 to 3 hours can be highly informative. Given the urgent need for early diagnosis of ACS and appropriate emergency intervention, as well as the ease of performing this relatively inexpensive assay, clinicians do not need to wait 6 to 8 hours before ordering a second troponin test to rule in ACS. We recommend collecting a second specimen for ctn testing within 2 to 3 hours from the collection of the blood sample at presentation to help confirm the diagnosis of MI. Conclusions Commenting on the ever-increasing sensitivity and decreasing specificity of ctn assays, Robert Jesse quipped, When troponin was a lousy assay it was a great test, but now that it s becoming a great assay, it s getting to be a lousy test. 9 However, frequent monitoring of ctn kinetics, along with

5 2354 Circulation November 22, 2011 careful attention to the noncoronary causes of ctn elevations, will keep the high-sensitivity ctn assays in the class where they rightfully belong among the greatest, most useful assays in clinical chemistry laboratories. Disclosures Dr Jarolim has research grants from Roche Diagnostics, Siemens Healthcare Diagnostics, Ortho Clinical Diagnostics, Beckman Coulter, Inc, and Amgen, as well as honoraria from Ortho Clinical Diagnostics and Roche Diagnostics. Dr Mahajan reports no conflicts. References 1. Melanson SEF, Morrow DA, Jarolim P. Earlier detection of myocardial injury in a preliminary evaluation using a new troponin I assay with improved sensitivity. Am J Clin Pathol. 2007;128: Melanson SEF, Conrad MJ, Mosammaparast N, Jarolim P. Implementation of a highly sensitive cardiac troponin I assay: test volumes, positivity rates and interpretation of results. Clin Chim Acta. 2008;395: Saenger AK, Beyrau R, Braun S, Cooray R, Dolci A, Freidank H, Giannitsis E, Gustafson S, Handy B, Katus H, Melanson SE, Panteghini M, Venge P, Zorn M, Jarolim P, Bruton D, Jarausch J, Jaffe AS. Multicenter analytical evaluation of a high-sensitivity troponin T assay. Clin Chim Acta. 2011;412: Apple FS. A new season for cardiac troponin assays: it s time to keep a scorecard. Clin Chem. 2009;55: Thygesen K, Alpert JS, White HD, Jaffe AS, Apple FS, Galvani M, Katus HA, Newby LK, Ravkilde J, Chaitman B, Clemmensen PM, Dellborg M, Hod H, Porela P, Underwood R, Bax JJ, Beller GA, Bonow R, Van der Wall EE, Bassand JP, Wijns W, Ferguson TB, Steg PG, Uretsky BF, Williams DO, Armstrong PW, Antman EM, Fox KA, Hamm CW, Ohman EM, Simoons ML, Poole-Wilson PA, Gurfinkel EP, Lopez-Sendon JL, Pais P, Mendis S, Zhu JR, Wallentin LC, Fernández- Avilés F, Fox KM, Parkhomenko AN, Priori SG, Tendera M, Voipio-Pulkki LM, Vahanian A, Camm AJ, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Morais J, Brener S, Harrington R, Morrow D, Lim M, Martinez-Rios MA, Steinhubl S, Levine GN, Gibler WB, Goff D, Tubaro M, Dudek D, Al-Attar N. Universal definition of myocardial infarction. Circulation. 2007;116: Apple FS, Parvin CA, Buechler KF, Christenson RH, Wu AHB, Jaffe AS. Validation of the 99th percentile cutoff independent of assay imprecision (CV) for cardiac troponin monitoring for ruling out myocardial infarction. Clin Chem. 2005;51: Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease: the present and the future. J Am Coll Cardiol. 2006;48: Mingels AMA, Jacobs LHJ, Kleijnen VW, Laufer EM, Winkens B, Hofstra L, Wodzig WK, van Dieijen-Visser MP. Cardiac troponin T elevations, using highly sensitive assay, in recreational running depend on running distance. Clin Res Cardiol. 2010;99: Jesse RL. On the relative value of an assay versus that of a test: a history of troponin for the diagnosis of myocardial infarction. JAm Coll Cardiol. 2010;55: