Point: Detection of Myocardial Infarction—Is It All Troponin?

Cardiac troponin is a cardiospecific protein that is detectable in the blood of patients with myocardial injury with sensitive and specific assays (1). Cardiac troponin is recommended as the preferred biomarker for the diagnosis of myocardial infarction (MI),2 for risk stratification, and for therapeutic guidance regarding anticoagulation therapy and invasive management (2–4). Assays should be appropriately precise to measure at the 99th-percentile value with a total imprecision of ≤10%. Until recently, assays were insufficiently precise, and rather than using the recommended 99th-percentile value, many clinicians had advocated the use of the lowest value at which an assay achieved a 10% CV as the decision cutoff. Manufacturers have refined their assays through improvements in reagent or antibody configuration, changes in the microparticle capture bed, introduction of a third antibody, increases in sample volume, and other modifications (5). For these reasons, newer generations of cardiac troponin assays now provide improved analytical sensitivity and precision. High-sensitivity cardiac troponin assays have reduced the time from symptom onset to detectable marker increases compared with former assays. Keller et al. (6) demonstrated that a contemporary sensitive cardiac troponin I (cTnI) assay allowed a diagnosis of MI on admission in an acute coronary syndrome (ACS) population with a sensitivity of 90.7% and a negative predictive value (NPV) of 96.4%. A second sample 3 h after symptom onset identified all patients with a final MI diagnosis, irrespective of the time delay from onset of symptoms to presentation. Reichlin et al. (7) evaluated 786 consecutive patients with suspected ACS and demonstrated better performance of 4 cardiac troponin assays more sensitive than the conventional fourth-generation cTnT assay, with sensitivities at presentation of between 84% and 95% (NPVs, 97%–99%). Both trials indicated that the benefits of earlier detection were most pronounced for patients presenting early after chest pain onset (6, 7). There is debate regarding the usefulness of additional biomarkers for detecting myocardial necrosis before measurable increases in cardiac troponin concentrations occur in the blood. Kurz et al. (8) provided evidence that use of a high-sensitivity assay to measure cTnT in admission samples proved at least as effective for predicting non–ST-elevation MI (non-STEMI) as measuring myoglobin or heart-type fatty acid–binding protein. Whether copeptin, a stable fragment of vasopressin that is rapidly released into the blood after life-threatening stress or hemodynamic compromise and returns to normal within a few hours, will add to the excellent NPV of cTnT measured with the high-sensitivity cTnT (hs-cTnT) assay is unclear. Given a reported NPV of >99% for the combination of cTnT measured by the fourth-generation cTnT assay and copeptin, this strategy is interesting for rapidly and safely ruling out non-STEMI from the initial blood draw in order to optimize the triage of patients in busy chest pain units or emergency departments and to avoid prolonged observation times or unnecessary hospitalizations (9). Precision is not the only variable useful in evaluating assays. There are differences related to the analytical performance of high-sensitivity cardiac troponin assays (10). Assays may be configured to provide improved imprecision by increasing the threshold of the assay, but this improvement comes at the expense of a decrease in diagnostic sensitivity. To address this issue, Apple proposed a scorecard grading system that considers both precision and analytical sensitivity (10). Whether differences related to analytical performance have an effect on clinical performance is still unclear. Reichlin et al. (7) tested 4 sensitive assays and reported comparable performance; all of the assays outperformed the fourth-generation cTnT assay that served as the reference. In contrast, unpublished findings from our group for 1386 patients with suspected ACS indicate a superior prognostic performance for the hs-cTnT assay (Fig. 1), compared with a contemporary sensitive cTnI assay (Siemens Ultra). Several preanalytical factors have also been reported to interfere with cardiac troponin measurements, particularly at low concentrations. These factors include cross-reactivity with heterophilic antibodies and autoantibodies, as well as severe hemolysis. Each of these factors can cause either overestimation or underestimation of cardiac troponin concentrations (11). For some, but not for all, assays (12), the use of different cutoff values for men and women may also be necessary. Values less than and greater or equal to the 99th-percentile are indicated by plus signs and minus signs, respectively. Indicated are rates of all-cause death and MI (left panel) and all-cause death (right panel) within 3 years. The use of biomarkers is not recommended for STEMI diagnosis, because it is based on electrocardiogram evidence. High-sensitivity cardiac troponin assays will facilitate the detection of all other non-STEMIs, including so-called microinfarcts. Application of the diagnostic criteria of the ESC/ACCF/AHA/WHF Task Force for infarct definition (3) will have a major impact on the numbers of non-STEMI diagnoses. Lowering the diagnostic threshold to the 99th-percentile value will decrease the numbers of patients with unstable angina and proportionately increase the number ruling in for non-STEMI (5). This reclassification of ACS patients is not a simple change in the prevalence of unstable angina and non-STEMI, but it is of high clinical relevance, because even minor increases in cardiac troponin above the 99th-percentile value are associated with adverse short- and long-term outcomes. The MERLIN-TIMI 36 trial (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes), a large-scale trial of 4513 patients with ACS, demonstrated a 3-fold higher adjusted risk of death and recurrent MI at 30 days and a 2.7-fold higher risk at 12 months, when cTnI values exceeded the 99th percentile (13). The low residual risk for adverse short- and long-term outcomes in chest pain patients who show no increase in cardiac troponin to ≥99th percentile is equally important. It appears that these patients have much better outcomes and do not derive benefit from aggressive diagnostic and therapeutic procedures, observations that prompt one to ask whether these patients should be labeled as having ACS. It is very likely that the use of hs-cTnT and hs-cTnI assays will improve early rule in and rule out of suspected MI and will allow a more accurate and sensitive diagnosis of MI; however, the use of such assays requires scrutiny and a high level of professional experience for proper interpretation. The higher proportion of increased cardiac troponin in asymptomatic and symptomatic patients not due to acute MI (AMI) has started to confuse physicians. The term “false-positive cardiac troponin result” should be used cautiously for patients without clinical proof of AMI. As may be expected, lowering a test's diagnostic threshold will inherently increase the diagnostic sensitivity for myocardial injury but decrease the diagnostic specificity for MI (14). When increased cardiac troponin values are encountered in the absence of myocardial ischemia, a careful search for other possible etiologies of cardiac damage should be undertaken, because an increased high-sensitivity cardiac troponin value is associated with an adverse prognosis in almost all situations. Overdiagnosis of MI, workup bias, and overtreatment can be avoided with simple measures, including a strict adherence to the clinical definition of MI and consideration of kinetic changes. Although increased cardiac troponin results with conventional assays usually have meant sending patients to the catheterization laboratory, the results of high-sensitivity cardiac troponin assays require scrutiny and clinical experience for proper interpretation. Whether there is a distinct cardiac troponin threshold that is helpful for guiding anticoagulation treatment or selecting patients who will derive benefit from early coronary angiography is as yet unclear. Cardiac troponin results from the large prospective PLATO (Platelet Inhibition and Patient Outcomes) trial (15) evaluating the effects of ticagrelor, a novel direct-acting reversible ADP receptor inhibitor, are expected to be published soon. Cardiac troponin concentrations were measured with conventional, contemporary sensitive, and high-sensitivity cardiac troponin assays in >18 000 patients with non–ST-elevation ACS and STEMI who received ticagrelor or clopidogrel and underwent medical, interventional, or surgical treatment. According to the universal definition, AMI is defined by an increasing and/or decreasing pattern of cardiac troponin concentrations, with at least 1 value above the 99th percentile in the setting of a patient with clinical features of myocardial ischemia (3). The interpretation of changes (δ values) cannot be done in isolation from the clinical situation and requires consideration of several variables that influence the slope and pattern (increase or decrease). These variables include time from the onset of chest pain to cardiac troponin testing and reperfusion success. In addition, the definition requires serial sampling with an appropriately timed interval between at least 2 consecutive blood draws and the point in time from the onset of symptoms to account for the time-dependent kinetic changes in AMI and other acute or chronic injuries of the heart. The magnitude of the concentration change that best discriminates between acute and chronic increases has not been defined yet, and it is still a matter of debate whether one should prefer relative changes, absolute changes, or the reference change value, a metric calculated from short-term or intermediate-term biological variation in cardiac troponin. Considering future perspectives, the number of indications for testing of cardiac troponin in settings other than ACS will increase. The PEACE (Prevention of Events with Angiotensin Converting Enzyme Inhibition) study of 3679 patients with stable coronary artery disease and a preserved left ventricular function demonstrated that small increases in cTnT measured with the hs-cTnT assay were associated with a higher risk of death and rehospitalization for heart failure (16). Our group demonstrated an association between cTnT concentrations (measured with the hs-cTnT assay) and the presence and composition of coronary plaque detected with multislice coronary computed tomography (17). These observations suggest that high-sensitivity cardiac troponin assays should be incorporated into the routine clinical workup of patients with stable coronary artery disease. Furthermore, the Dallas Heart Study found that increases in cardiac troponin are seen more frequently with the hs-cTnT assay in noncoronary heart disease (18). Given that an increased cardiac troponin concentration is almost always associated with an adverse prognosis (19), regardless of whether the underlying cause is acute or chronic, measurement of cardiac troponin with high-sensitivity assays should be considered for risk stratification in cases of acute or chronic heart disease, because previous reports have suggested a performance similar to that of natriuretic peptides, heart-type fatty acid–binding protein, or growth differentiation factor 15 (20). myocardial infarction cardiac troponin I acute coronary syndrome negative predictive value ST-elevation MI high-sensitivity cardiac troponin T (assay) Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes (trial) acute MI Platelet Inhibition and Patient Outcomes (trial) Prevention of Events with Angiotensin Converting Enzyme Inhibition (trial).