Curr Cardiol Rep (2014) 16:471 DOI 10.1007/s11886-014-0471-x


Making Sense of High Sensitivity Troponin Assays and their Role in Clinical Care Lori B. Daniels

# Springer Science+Business Media New York 2014

Abstract Cardiac troponin assays have an established and undisputed role in the diagnosis and risk stratification of patients with acute myocardial infarction. As troponin assays gets more sensitive and more precise, the number of potential uses has rapidly expanded, but the use of this test has also become more complicated and controversial. Highly sensitive troponin assays can now detect troponin levels in most individuals, but accurate interpretation of these levels requires a clear understanding of the assay in the context of the clinical scenario. This paper provides a practical and up-to-date overview of the uses of highly sensitive troponin assays for diagnosis, prognosis, and risk stratification in clinical practice. Keywords Diagnosis . Prognosis . Risk stratification . Myocardial infarction . Prediction . High sensitivity troponin assays . Clinical care

improved sensitivity and precision. The current generation of troponin assays in use throughout most of the United States, the “contemporary sensitive” assays, yield very precise measures of cardiac troponin at even very low levels, and are detectable in a small percentage of the general population [1, 2]; but do not signify the end of the troponin evolution. The most recent generation of troponin assays, the “highly sensitive” assays, can detect circulating cardiac troponin levels in most (and in some cases, all) of the population. The emergence of these highly sensitive cardiac troponin (hsTn) assays has elicited both enthusiasm and skepticism. A thorough understanding of the strengths and pitfalls of these assays is essential for clinicians to fully capitalize on their beneficial aspects, while minimizing the confusion they might otherwise engender.

The Biology of Cardiac Troponin Introduction Cardiac troponin assays have become an indispensable mainstay for cardiologists and other clinicians over the past few decades. The use of cardiac troponin assays has indisputably improved the way we diagnose and risk stratify patients with suspected myocardial infarction (MI). When cardiac troponin assays were first introduced, they were not very sensitive, though they were an improvement over creatinine kinaseMB, the gold-standard at the time. New iterations of the cardiac troponin assay periodically materialized with This article is part of the Topical Collection on Interventional Cardiology L. B. Daniels (*) Division of Cardiology, Department of Medicine, University of California at San Diego, Mail Code 7411,9444 Medical Center Drive, La Jolla, CA 92037-7411, USA e-mail: [email protected]

Troponin I and troponin T are proteins that help modulate the interaction between actin and myosin within the contractile apparatus in striated muscle. In the heart, cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are found both as part of the structural apparatus of cardiomyocytes, as well as within a smaller early-releasable pool possibly in the cytoplasm [3, 4]. While cTnI appears to be specific to the heart, very small amounts of cTnT may be expressed in skeletal muscle [5], though this subfraction is not detected by the available cTnT assays except in rare cases [6]. Measurement of cardiac troponin is therefore believed to be highly specific for cardiomyocyte injury [7]. Detection of troponin in the blood has classically been thought to represent irreversible cardiomyocyte injury [8], though this concept has been called into question. Some evidence suggests that troponin may be released after reversible ischemia [9–14] or in the setting of other conditions such

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as sepsis [15]. One hypothesis is that ischemia causes increased membrane permeability and/or “bleb” formation [16], a reversible form of cell injury, which leads to release of the cytosolic pool of troponin despite an intact cell membrane and intact contractile apparatus [17•, 18]. This theory is used to explain an observed rapid rise and fall in highly sensitive troponin values described in some settings of ischemia, including cardiac stress-test induced ischemia [12] and with rapid atrial pacing [14]. Meanwhile, a more prolonged troponin elevation as seen with irreversible cardiomyocyte damage could be due to degradation of the contractile apparatus and release of the larger, bound pool of cardiac troponin. As the sensitivity of troponin assays has improved, measurable levels of circulating troponin can now be detected even in “normal” individuals. With the contemporary troponin assays, only a very small percentage of healthy individuals have detectable levels of cardiac troponin [1, 2]. In contrast, with emerging highly sensitive troponin assays, troponin levels are detectable in most, or all, of the population [19–22]. The etiology of this detectable troponin in “normal” individuals is a matter of some controversy and active investigation. Finally, while hsTnT and hsTnI are both thought to reflect similar pathophysiologic pathways, a recent study of patients with stable coronary heart disease found that the 2 tests had only modest correlation with each other (r=0.44), and actually had different clinical correlates and different associations with incident cardiovascular disease [23]. Highly sensitive TnI, but not hsTnT, was independently associated with prior MI and with incident MI. Thus, hsTnT and hsTnI may reflect slightly different pathophysiologic disturbances.

Analytical Considerations By definition, a “highly sensitive” troponin assay is one that can detect troponin in >50 % of the normal population [24•]. With these assays, the population distribution of troponin values follows a near-Gaussian distribution, and individuals vary in their “normal” level of troponin [24•]. Because different individuals have different normal levels of troponin, some have suggested that optimal use of hsTn assays in the acute care setting may require knowing an individual’s baseline, or “homeostatic,” troponin level during health [17•]. A major problem with this approach is that cardiac troponin assays are not standardized; each uses a different set of antibodies, and reports troponin values on a different scale. So even if a baseline troponin value were known, it would only provide a useful comparison in clinical settings using the same assay. Although cTn assays are believed to be nearly 100 % specific to myocardial insult, a few caveats are worthy of mention. Highly sensitive troponin assays may be somewhat more prone to analytic problems because even small

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differences can represent a large relative change. Factors that can artificially reduce troponin levels include hemolysis, which can reduce low levels of hsTnT near the 99th percentile but can sometimes artificially raise levels in various hsTn assays as well [25, 26], though this is controversial [27], and interfering autoantibodies [17•, 28]. Conversely, troponin levels can be falsely elevated in the setting of heterophilic interfering antibodies [26], and hsTnT levels may show rare false elevations due to skeletal muscle disease [5], though myocardial involvement causing a true troponin elevation cannot be excluded [29]. Defining the true 99th percentile troponin cut-point of a “healthy” population is very dependent on the population being measured. Although highly sensitive assays can detect troponin in most individuals, the true prevalence of detectable troponin depends in large measure upon the age and comorbidities of the population being studied. For instance, when imaging is used to exclude individuals with subclinical disease, the prevalence of detectable troponin and the 99th percentile cut-point both decrease [30, 31]. Since men tend to have higher levels of hsTn than women, it is best to utilize sexspecific 99th percentile cut-points.

Diagnosis of MI The universal definition of MI, updated in 2012, recommends a minimum standard of precision for any troponin assay used to diagnose MI. Specifically, guidelines recommend a coefficient of variation (CV) of 5× the 99th percentile ULN, and which also required additional clinical corroborating evidence to be present [32••]. In patients with an abnormal troponin level at baseline, the Task Force recommended using a rise in troponin >20 % of the baseline, as long as values were stable or falling prior to PCI. Even with this higher threshold, controversy about the prognostic significance of post-PCI troponin elevations remains. Delayed-enhancement MRI studies have confirmed that there is irreversible myocardial injury associated with and proportional to biomarker elevations [44], though some have found that CK-MB levels correlate better than troponin levels [45]. It is likely that MRI is less sensitive than the sensitive troponin assays, and the key question is whether troponin elevations are detecting clinically relevant risk that CK-MB (and MRI) is not. There is now a significant amount of data that post-PCI troponin levels do carry prognostic significance, when used correctly [46–48]. Even among patients with elevated baseline troponin levels, post-PCI levels of troponin carry significant prognostic information, but they must be interpreted correctly [46]. Specifically, the baseline troponin value must be taken into account, and if the baseline level is above the 99th percentile ULN, a 20 % relative increase rather than an absolute cut-point must be used. Further, these criteria are only applicable in patients with stable or falling levels prior to PCI. A recent study of patients with NSTEMI undergoing PCI confirmed the value of post-PCI troponin levels even among patients with elevated levels at baseline, and independent of the risk associated with the initial MI event [46]. In this study, there was a highly significant relationship between post-PCI troponin levels and 1-year mortality. Since these were MI patients, they all had elevated levels of troponin at baseline, and individuals with levels that were still rising at the time of PCI were appropriately excluded. A noteworthy finding from this study was that an elevation of troponin >20× the ULN seemed to have an equivalent incidence (~14 %) and 1-year mortality risk (5 %) as a CK-MB level >3× the ULN. Similarly, a troponin level >100× the ULN was similar to a CK-MB >5× ULN, with an incidence of 8 %–9 % and a 1-year mortality risk of about 6 %. Other studies have also found that the use of higher troponin cut-points might provide better correlation with traditional CK-MB cut-points than simply using 3× the ULN irrespective of the biomarker [47].

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Diagnosing and Understanding Type 2 MIs Patients with demand-related acute MI, also known as a type 2 MI, develop elevated levels of troponin when a condition other than an acute coronary atherothrombotic event contributes to an imbalance between myocardial oxygen supply and demand [32••]. Although troponin is specific for myocardial injury, it does not provide information regarding the etiology of the injury, and cannot distinguish between an acute thrombotic event (type 1 MI) and a type 2 MI. Regardless of whether the acute rise in troponin is due to tachycardia, hypertension, sepsis, pulmonary embolism, or some other condition, clinicians should recognize that the rising troponin levels in type 2 MIs are associated with an increased risk of adverse outcomes [49–56]. Even so, without plaque rupture, patients with a type 2 MI are not likely to benefit from the same aggressive treatment with antithrombotic medications that is proven to improve outcomes in patients with a type 1 MI. In fact, the optimal treatment of a type 2 MI varies depending upon the clinical scenario, and must be highly individualized to the patient with a focus on treating the precipitating conditions that led to the myocardial oxygen imbalance. With hsTn assays, the relative percentage of type 2 MIs is likely to increase [57]. Clinicians will need to remain cognizant of the fact that rising troponin levels are not always due to an acute coronary syndrome, or else risk misdiagnosis and mismanagement with inappropriate therapies and potential delays in establishing alternate diagnoses [58]. Although this is also true of CK-MB levels, the greater sensitivity of troponin means that this scenario will occur much more frequently.

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to directly target elevated troponin levels and improve outcomes in chronic CAD or heart failure patients, closer followup and astute attention to guideline-based medical therapy is probably especially important in these individuals. Patients with chronic kidney disease are another subgroup that frequently has persistent low-level troponin elevations. A recent study showed that with hsTn assays, essentially all patients with end stage renal disease on hemodialysis have elevated troponin levels above the 99th percentile: 94 % had an elevated baseline measure, but 100 % had an elevated measure when sampled bimonthly over a 6 month period [61]. Even in the setting of end stage renal disease, an elevated troponin level carries a worse prognosis, and the higher the level, the higher the risk of an adverse outcome [62–65]. In each of these settings, detecting a rising and/or falling pattern of troponin levels and evaluating for additional symptoms or signs of ischemia will be crucial to determining whether an individual who presents with new symptoms is having an acute MI vs a stable, chronic troponin elevation. It may turn out that knowing an individual’s baseline troponin value can also be of some help in this regard. Although this is hypothetical and remains to be proven, establishing a baseline hsTn value in selected high-risk outpatients (ie, those with chronic heart failure, chronic coronary disease, renal disease, or diabetes) may help reduce confusion when they present acutely in the future. One caveat, as noted above, is that the utility of this approach is dependent upon standardization of the troponin assay used in the outpatient setting with the one used for acute evaluations.

Emerging Uses for Highly Sensitive Troponin Testing Troponin Elevations in Chronic Diseases and Other Conditions

The improved performance of the hsTn assays has opened the door to new clinical applications for this biomarker.

With the increased sensitivity of troponin tests, a growing number of medical conditions are recognized as being associated with detectable and/or elevated troponin levels. Although many of these conditions are related to chronic cardiovascular disease, non-cardiovascular elevations are also represented, and even apparently healthy individuals in the general population may have elevated hsTn levels. In the settings of stable coronary artery disease (CAD) and chronic heart failure, persistent low-level troponin elevations are common, and will be more common with hsTn assays. Despite how ubiquitous these low-level elevations seem to be, they nonetheless carry important prognostic information, even at low levels that were previously undetectable with conventional troponin assays [59]. The prognostic value of troponin elevations holds true in both acute and chronic heart failure, across a spectrum of presentations, and independent of other risk factors [60]. Although no specific therapy has been found

HsTn for Improving Cardiovascular Stress Testing A recent study of 984 patients with stable coronary heart disease found that hsTnT levels were associated with greater inducible ischemia and worse treadmill exercise capacity [66]. Even so, hsTnT levels provided information above and beyond the stress test. They were predictive of recurrent cardiovascular events, independent of clinical factors, stress echocardiogram test results, and other cardiovascular biomarkers. These findings lend credibility to the hypothesis that hsTn assays, used in conjunction with cardiovascular stress tests, may help improve the accuracy and prognostic value of stress tests. Using an hsTnI assay measured immediately before exercise treadmill testing, and again at 2 h and 4 h post-test, Sabatine et al found that patients with transient stress testinduced myocardial ischemia have a quantifiable increase in circulating troponin at 4 h, and that levels increase more in

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patients with moderate/severe ischemia compared with those with only mild ischemia [12]. Levels were unchanged in patients without evidence of ischemia on nuclear perfusion imaging. Moreover, a rise in hsTn after stress testing was predictive of ischemia independent of traditional measures like limiting angina and ST-segment depression. Whether real-world use of pre- and post-test measurements of hsTn can improve upon current stress test accuracy and/or limit the need for concurrent imaging remains to be studied. HsTn to Guide Therapy in Acute Coronary Syndromes As a strong marker of risk, a number of studies have shown that individuals who present with a non ST-elevation ACS (NSTEACS) and who have elevated troponin levels have improved outcomes with more aggressive treatment. Such patients benefit from an early invasive approach [67, 68], and from more aggressive antithrombotic therapy, including glycoprotein IIb/ IIIa inhibitors [69] and low molecular weight heparins [70]. A recent study that utilized hsTnT provides further insight on how troponin may help guide the choice of antiplatelet agents. In a substudy of 9946 NSTE-ACS patients from the Platelet Inhibition and Patient Outcomes (PLATO) trial, Wallentin et al found that the baseline hsTnT level could help determine which patients were most likely to benefit from ticagrelor compared with clopidogrel [71]. Overall, the PLATO study, which randomized patients to either ticagrelor or clopidogrel (in addition to standard treatment with aspirin and antithrombin therapy), found that use of ticagrelor reduced the primary composite endpoint (vascular death, myocardial infarction, and stroke) by 16 % [72]. Further investigation revealed that, among patients treated noninvasively, the benefit with ticagrelor was only seen among individuals with a baseline hsTnT level ≥ 14 ng/L. For patients with a low or normal hsTnT level at baseline, the hazard ratios slightly favored clopidogrel, though these patients had a low event rate regardless of which antiplatelet agent they received. This study highlights the potential to utilize hsTn levels to streamline the care of lower risk patients, while optimizing the care of higher risk patients. HsTn to Predict Cardiotoxicity in Chemotherapy Troponin is already considered by some to be the gold standard for the early detection of chemotherapy-mediated myocardial injury [73]. The improved sensitivity of hsTn assays may make this application even more successful. A recent small study of 81 breast cancer patients who underwent chemotherapy with anthracyclines, taxanes, and trastuzumab found that hsTnI levels measured at the completion of anthracycline treatment predicted the subsequent development of cardiotoxicity [74]. Even more importantly, troponin levels may be able to identify a subgroup of patients in whom early institution of angiotensin converting enzyme (ACE)

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inhibitors can prevent the development of cardiotoxicity [75]. In a randomized trial, 114 patients with an elevated troponin level within 72 h after chemotherapy were randomized to receive enalapril for 1 year vs placebo. Over the 1-year follow-up period, 43 % of the patients receiving placebo developed cardiotoxicity (defined as an absolute drop in left ventricular EF of 10 %, to a value

Making sense of high sensitivity troponin assays and their role in clinical care.

Cardiac troponin assays have an established and undisputed role in the diagnosis and risk stratification of patients with acute myocardial infarction...
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