Detection of circulating troponins has traditionally been used as the gold standard for the diagnosis of acute myocardial infarction (AMI) in patients presenting to the emergency department with chest pain. Advancements in technology have led to the development of high-sensitivity assays detecting troponin at levels 10- to 100-fold lower than levels measured by contemporary troponin assays. This marked increment in sensitivity has the potential to significantly alter our current approach to diagnosis of AMI.

Assays are defined as high sensitivity if they fulfill the following two conditions: 1) a coefficient of variance less than 10% at the 99th percentile value of the reference healthy population and 2) concentrations above the assay's limit of detection are measurable in greater than 50% of healthy individuals.¹ Several assays have been developed that fulfill the two criteria and are actively used in Europe and Asia.

Multiple studies have demonstrated an increased sensitivity and better early discrimination of AMI with high-sensitivity assays compared with contemporary assays.^2,3 This has allowed for a shortening of the period for "rule out" of AMI and initiation of treatment.⁴ The current European Society of Cardiology Acute Coronary Syndrome guidelines recommend algorithms incorporating high-sensitivity troponin assays for quicker AMI rule-in/rule-out (1-3 hours) compared with traditional assays (6-12 hours).⁵ Additionally, high-sensitivity troponins assays have excellent negative predictive values (~99%) for events at 1 hour, allowing for rapid exclusion of AMI and the potential for facilitated throughput of patients with chest pain through the emergency department.⁶ Moreover, there have been a number of encouraging studies suggesting that very low values of high-sensitivity cardiac troponin can effectively rule out myocardial infarction (MI) with a single blood draw (i.e., without a requirement for serial measurements).^7,8 The single blood draw strategy, however, should not be applied to patients with recent symptom onset and should probably be restricted to individuals without electrocardiographic changes or other high-risk features.

In spite of these potential advantages, there is some skepticism toward the widespread implementation of high-sensitivity assays. A troponin value is considered to be elevated if the measured value is noted to be higher than the 99th percentile upper reference value for a specific assay within a normal reference population. A major issue is how the reference population is defined. If the reference value is younger and with fewer comorbidities compared with the typical population that develops MI, the 99th percentile value may be inappropriately low, resulting in misleading increases in sensitivity and decreases in specificity for the high-sensitivity assay. For example, the recommended cut-off for 99th percentile is 14 ng/L for the high-sensitivity cardiac troponin assay. This was derived from a reference normal population that consisted of 616 apparently healthy volunteers with a mean age of 44 years.⁹ In a recent study involving 3 large community-based cohorts and more than 12,000 participants, we found that the 99th percentile upper reference limit for this assay varied across different age, sex, and racial groups¹⁰ and was notably higher than 14 ng/L, particularly in older men. For example, ~10% of men over the age of 65 years without any evidence of ischemia had levels of high-sensitivity cardiac troponin above the MI threshold. This study highlights the importance of precise delineation of the 99th percentile value with consideration for age, sex, and comorbidity burden. Moreover, the study serves as a reminder of the critical importance of serial changes in troponin for the diagnosis of MI.

Detection of troponins in the blood per se is not sufficient for a diagnosis of AMI because elevated levels only indicate myocardial damage without regard to the underlying etiology. The 2012 Universal Definition of Myocardial Infarction requires not only the presence of elevated troponin (above the 99th percentile cutpoint) but also a rise and fall in levels over serial measurement along with supportive evidence of ischemia from the history, electrocardiogram, or imaging studies.¹¹ Thus, elevated troponins require integration and interpretation of all of the clinical data and, as a consequence, potentially increase clinical workload for practicing cardiologists. Even with evidence of ischemia, discerning the pathophysiology leading to ischemia (i.e., true atherosclerotic plaque rupture [Type 1 AMI] vs. supply/demand mismatch [Type 2 AMI]) will be required, which can be challenging. For example, Shah et al. demonstrated that for every 1 additional patient diagnosed with Type 1 MI with a high-sensitivity troponin assay, 3 patients with Type 2 MI were also diagnosed.¹² Importantly, in this study, patients diagnosed with Type 2 AMI incurred longer hospitalization stays and underwent invasive cardiac therapies without affecting outcomes.

Use of high-sensitivity troponin assays have revealed mechanisms of troponin release not explained entirely by necrosis. The assays have the ability to detect very minute levels of troponin in otherwise healthy people. Research has demonstrated mechanisms aside from myonecrosis that lead to detectable troponin, such as apoptosis, increased cell wall permeability with stress or stretch, and the production of membranous blebs containing troponins that could lead to the release of troponins in the bloodstream.¹³ The presence of these detectable but not elevated troponins in healthy individuals has the potential for adding to the complexity surrounding interpretation of a positive troponin in the clinical setting.

Another challenge involving routine use of high-sensitivity troponins is the increased prevalence of elevated troponins in patients with existing diabetes, heart failure, and chronic kidney disease. Although the presence of elevated troponins denotes a worse prognosis in these select patient populations, the specificity for the diagnosis of acute coronary syndromes is decreased. The use of serial testing of troponin values has been proposed to increase its specificity. Multiple studies have validated this approach using shorter sampling durations (1-3 hours).^2,3 Additionally, use of absolute changes in troponin values increase discriminatory power compared with relative changes (c-statistic, 0.898 vs. 0.752, p < 0.001).¹⁴ Standardization of appropriate thresholds for different assays across a variety of populations is imperative before widespread implementation of these more sensitive assays. Finally, the Bayesian approach dictates that the diagnosis of AMI depends on the pretest probability for AMI, highlighting the concept that a positive or negative high-sensitivity troponin must always be interpreted in the appropriate clinical context.¹⁵

In summary, high-sensitivity troponin assays represent a significant technological milestone in the diagnosis and management of AMI. This technological advancement will likely increase the frequency of correct Type I MI diagnosis and expedite care; however, implications for the entire health care system must be considered because the identification of Type II MI and troponin elevations from conditions other than MI will also increase, with the potential to increase subsequent testing and prolong inpatient care.

References

1. Apple FS, Collinson PO, IFCC Task Force on Clinical Applications of Cardiac Biomarkers. Analytical characteristics of high-sensitivity cardiac troponin assays. Clin Chem 2012;58:54-61.
2. Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. New Engl J Med 2009;361:868-77.
3. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. New Engl J Med 2009;361:858-67.
4. Mills NL, Churchhouse AM, Lee KK, et al. Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA 2011;305:1210-6.
5. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267-315.
6. Shah AS, Anand A, Sandoval Y, et al. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet 2015;386:2481-8.
7. Carlton EW, Cullen L, Than M, Gamble J, Khattab A, Greaves K. A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin. Heart 2015;101:1041-6.
8. Zhelev Z, Hyde C, Youngman E, et al. Diagnostic accuracy of single baseline measurement of Elecsys Troponin T high-sensitive assay for diagnosis of acute myocardial infarction in emergency department: systematic review and meta-analysis. BMJ 2015;350:h15.
9. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem 2010;56:254-61.
10. 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 2014;63:1441-8.
11. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation 2012;126:2020-35.
12. Shah AS, McAllister DA, Mills R, et al. Sensitive troponin assay and the classification of myocardial infarction. Am J Med 2015;128:493-501.e3.
13. White HD. Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis? J Am Coll Cardiol 2011;57:2406-8.
14. Mueller M, Biener M, Vafaie M, et al. Absolute and relative kinetic changes of high-sensitivity cardiac troponin T in acute coronary syndrome and in patients with increased troponin in the absence of acute coronary syndrome. Clin Chem 2012;58:209-18.
15. Diamond GA, Kaul S. How would the Reverend Bayes interpret high-sensitivity troponin? Circulation 2010;121:1172-5.

Keywords: Acute Coronary Syndrome, Algorithms, Apoptosis, Bayes Theorem, Blister, Cell Wall, Chest Pain, Comorbidity, Diabetes Mellitus, Electrocardiography, Healthy Volunteers, Heart Failure, Hospitalization, Inpatients, Myocardial Infarction, Myocardium, Permeability, Plaque, Atherosclerotic, Prognosis, Reference Values, Renal Insufficiency, Chronic, Troponin

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