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High-sensitivity troponin: where are we now and where do we go from here?

High-sensitivity troponin (hsTn) assays are used clinically in most parts of the world and are expected to be approved by the US FDA for clinical use in the USA soon. Clinical use of hsTn leads to improvements in the detection of myocardial injury, shorter time to ruling out acute myocardial infarction, improved risk-stratification of patients with heart failure and atrial fibrillation among others. HsTn may also guide strategies for primary and secondary prevention of cardiovascular disease. However, unmet challenges remain, including distinguishing between acute and chronic hsTn elevations, distinguishing between type 1 and type 2 acute myocardial infarction and determining whether to use gender-neutral or gender-specific reference values. Keywords:  acute coronary syndrome • cardiovascular disease prevention • high-sensitivity troponin • review • structural heart disease • troponin

High-sensitivity troponin (hsTn) assays are used clinically in most parts of the world and are expected to be approved by the US FDA for clinical use in the USA within 1–2 years (see Table 1 for list of hsTn assays). Although questions remain regarding the appropriate application of hsTn values in acute care settings and for guiding primary and secondary prevention of cardiovascular disease, emerging literature has improved our current understanding. In this review, we will discuss the roles of hsTn in both acute care and outpatient settings. We will also highlight important questions that remain unanswered regarding clinical use of hsTn. Improved analytical sensitivity at the expense of specificity for myocardial infarction Cardiac troponin (cTn) I and T are the preferred biomarkers for diagnosing acute myocardial infarction (AMI) [1] . They are predominantly expressed in cardiac myocytes, and their near-absolute cardiac specificity distinguishes them from previously used biomarkers of myocardial injury such as aspartate transaminase, lactate dehydrogenase, myo­

10.2217/BMM.14.54 © 2014 Future Medicine Ltd

globin and isoenzymes of creatinine kinase [2] . The near absolute cardiac specificity of cTnT has been recently challenged [3] . Early versions of troponin assays, although much less sensitive than current assays, measured elevated values in many more patients than creatinine kinase MB isoenzyme assays [4] . However, it was clear from the very start that in addition to detecting more patients with acute ischemic heart disease, these assays would also identify many new clinical situations where cardiac injury was present [5] . Many clinicians ignored this fact initially and considered elevations of cTn as synonymous with AMI. This has never been the case [6] . New hsTn assays measure tenfold or greater concentrations of cTn than current generation assays which themselves are substantially more sensitive than the original cTn assays. With hsTn, even more patients with disease processes that cause myocardial injury (including trauma, sepsis, respiratory distress, structural heart disease and AMI, among others) will have an elevated hsTn value. Thus, distinguishing elevations due to acute AMI from those due to chronic causes will become increasingly important. An idea of

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Frederick K Korley*,1 & Allan S  Jaffe2 Department of Emergency Medicine, Johns Hopkins University School of Medicine, Davis Building, Suite 3220, 5801 Smith Avenue, Baltimore, MD 21209, USA 2 Cardiovascular Division & Division of Core Clinical Laboratory Services, Departments of Medicine and Laboratory Medicine and Pathology, Mayo Clinic & Medical School, Rochester, MN, USA *Author for correspondence: Tel.: +1 410 735 6400 Fax: +1 410 735 6440 fkorley1@ jhmi.edu 1

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Table 1. High-sensitivity assays. Assay

% with values >LOD Classification 

ARCHITECT STAT hsTnI (Abbott Laboratories, IL, USA)

96

Level 4 hsTn

Access 2 hsTnI (Beckman Coulter Inc, CA, USA)

80

Level 3 hsTn

Erenna hsTnI (Singulex Inc, CA, USA)

100

Level 4 hsTn

Dimension Vista hsTnI (Siemens Healthcare Diagnostics Inc., DE, USA) 86

Level 3 hsTn

Elecsys hsTnT (Roche Diagnostics, IN, USA) 

Level 1 hsTn

25

Level 1 = 95% of a reference population of healthy individuals have measurable troponin values. hsTnI: High-sensitivity troponin I; LOD: Limit of detection. Data taken from [84].

the magnitude of this increased sensitivity can be found in a recent study of Korley et al. [7] , who demonstrated that approximately 10–13% of emergency department patients evaluated for suspected acute coronary syndrome (ACS) had elevated hsTnI without an elevation in one of the more sensitive contemporary cTnI assays (Beckman). Only a few of these new hsTnI elevations were due to ACS. The majority were due to heart failure and other primary noncardiac conditions. As a result, clinicians will be challenged to determine which elevations are due to ACS, other acute processes, or chronic structural heart disease. This distinction will be important to the timing of further cardiovascular evaluations and whether they need occur in an inpatient or an outpatient setting. Unsettled analytical considerations concerning high-sensitivity troponin assays Prior to discussing the clinical use of hsTn, a number of unsettled analytical considerations are worth mentioning. Analytical confounds that exist with current generation troponin assays will be amplified with clinical use of hsTn. Hemolysis artificially decreases hsTnT but increases values for some hsTnI assays [8,9] . Even relatively low degrees of hemolysis can have a significant effect. As a result, clinical chemistry laboratories will need to continue active monitoring of samples for hemolysis and clinicians will need to make sure that high-quality samples are obtained for analysis. This is particularly difficult when so many samples are obtained from indwelling lines [10] . Interfering antibodies including heterophilic antibodies, human antianimal antibodies and autoimmune antibodies are all potential causes of falsely elevated hsTn [11] . With hsTn assays, even smaller amounts of these antibodies may be of significance. However, in settings where antibodies cause hsTn elevations, they are unlikely to cause changing hsTn values. Thus, high values that fail to change and are inconsistent with the clinical picture should be questioned. Laboratories have access to heterophilic blocking tubes to use in this situation. Addi-

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tionally, dilution studies can be performed and they are often abnormal in this situation [12] . Abnormal hsTn values should always be interpreted within the existing clinical context and a changing pattern of values should reduce the suspicion for analytical confounds. Finally, there are anti-cTnI and anti-cTnT antibodies that have been described. These have the potential to lower cTn values and this confound has been described for presentday cTnI assays [13] . Since these antibodies are likely to have a greater effect when concentrations are low, they may be more common with hsTn assays. Severe renal dysfunction has been a common cause for chronically elevated cTn values and this will be more pronounced with hsTnT than with hsTnI. In a study of stable outpatients with end-stage chronic kidney disease, 38% had elevated hsTnI, whereas 68% had elevated hsTnT [14] . Potential contributors to elevations in hsTn among patients with reduced renal function include an increased prevalence of multi-vessel coronary artery disease [15] , volume overload with or without cardiac failure [16] , left ventricular hypertrophy in this population [17] and the abnormal metabolic profile that exists in such patients [18] . One explanation that has been advanced has to do with renal clearance of cTn. However, cTn has not been found in the urine, making renal clearance doubtful. The majority of the troponin I and T in human blood occur as binary and ternary complexes with troponin C [19] . These complexes are relatively large molecules (troponin C is 18 kDa, cTnI is 23 KDa and cTnT is 35 KDa [20] ; for comparison, albumin is 66 KDa), making them less likely to be cleared by the kidney. It has been hypothesized without evidence that smaller molecular weight degradation products of troponin I and T might be cleared renally  [21] . In hemodialysis patients, differences in degradation result in the accumulation of these smaller fragments (8–25 KDa) [22] . This alternative degradation pattern is more apt to be detected with cTnT because the epitopes for detection are much closer together and therefore are not lost, whereas those of cTnI are further apart and

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High-sensitivity troponin: where are we now & where do we go from here? 

therefore are more likely to be lacking on smaller fragments. The lack of renal clearance need not be invoked. End-stage renal disease patients who receive renal transplant have lower troponin values post-transplant than pretransplant, suggesting that this process might be related to reversible abnormalities in metabolism associated with renal failure. A potential explanation for the higher levels of cTnT in renal failure compared with cTnI is the fact that there is somewhat more cTnT than cTnI per gram of myocardium [23] . Therefore myocardial injury may result in a release of more cTnT than cTnI. Irrespective of potential explanations, the important long-term prognostic significance of hsTn elevations in renal failure should be recognized [24] . Because the definition of elevated versus nonelevated hsTn rests on the 99th percentile (upper reference limit) of a reference population of healthy individuals [1] , the constitution of reference populations is critically important. First, demographics of the reference population should closely mimic the target population in which the assay will be used [25] . Second, laboratory and, whenever possible, imaging-based assessment of reference population subjects to provide objective evidence that they are truly ‘healthy’ is preferable to selfreport of health status alone. Significant differences in the 99th percentile are observed when objective criteria rather than subjective patient reports alone are used [26] . Acute usage: distinguishing between acute & chronic hsTn elevations In addition to an elevated hsTn, a rise and/or fall in hsTn is necessary for diagnosing AMI in the appropriate clinical context [1] . Elevated troponin values suggest myocardial injury; however, they are not indicative of AMI. In patients with clear cut and recent AMI, serial troponin changes are quite marked [27] . Several papers have reported the superiority of absolute δ hsTn over relative δ hsTn changes, for discriminating between AMI and non-AMI patients [28–30] . It appears that near the 99th percentile upper reference limit, these approaches provide similar results. However, at values significantly greater than the 99th percentile, absolute changes may provide better accuracy. In some studies, the diagnostic accuracy of absolute 2–3 h changes in hsTn is similar to that of absolute 3 and 6 h changes [29] . However, in such studies, late samples are often missing so that those who rule in later than 3 h are less likely to be included. It is often wrongly assumed that biomarker release, which is blood flow dependent, is consistent over time in patients with acute coronary disease. Kagen and others have described a staccato pattern of myoglobin release indicative of intermittent rather than continuous release in patients with AMI [31] . In addition, most studies in this area have used

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less than sensitive gold standards and thus included larger AMIs resulting in a distortion of the magnitude of the elevations, the magnitude of the serial changes and how rapidly patients rule in [32] . Thus, more data are needed in this important area. Finally, calculation of delta changes must take into account: • Assay: optimal δ concentrations will be assay dependent. Thus, each assay will need a unique concentration cutoff for maximizing sensitivity and specificity; • Clinical outcome(s): the optimal δ for discriminating between acute versus chronic hsTn elevation, AMI versus non-AMI and for predicting shortand long-term cardiovascular risk may be different. Furthermore, to rule in AMI, specificity needs to be maximized, whereas sensitivity needs to be maximized to rule out AMI. Thus, the optimal δ could be different for each of these; • Initial hsTn value: at elevated values of hsTn, some of the recommended δ changes may be within the limit of conjoint assay imprecision and biological variation [33] . Thus, there likely will be a trade-off between sensitivity and specificity in this situation; • Timing of symptom onset: the discriminative ability of absolute δ hsTn will depend on the time elapsing between onset of symptoms and hospital presentation. AMI patients who are late presenters may have lower absolute changes and may be misclassified as chronic elevations. In one report, 26% of Non-ST elevation myocardial infarction (NSTEMI) patients did not manifest a marked change in values because they presented late after the onset of symptoms [34] . This is obviously a critical issue. It has been suggested that the combination of absolute and relative δ hsTn may yield improved discriminative ability [33] . This has been found to be true for hsTnT but not yet for hsTnI [35] . To rule in AMI, the European Society of Cardiology recommends that patients with an initial hsTn 99th percentile, in addition to an increase of >50% of the 99th percentile. Similarly, for patients with an initial hsTn >99th percentile, the 3 or 6 h hsTn has to increase by >20% or greater to rule in AMI (Figure 1) [36] . These recommendations were based on currently available literature and are very likely to change as the data for defining the optimal δ hsTn continue to evolve. Acute usage: novel strategies for rapidly ruling out AMI One of the advantages of using hsTn in acute care settings is the ability to rapidly identify a subgroup of

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Review  Korley & Jaffe low-risk individuals in whom AMI can be safely and expeditiously ruled out. A number of strategies have been suggested for achieving this. Body et al., using the hsTnT assay, reported that an initial hsTnT 50% of URL

Initial hs-cTn value >URL

Myocardial necrosis

hs-cTn value at 3 h >URL + increase >20% of initial value

Optional 6 h later

hs-cTn value at 6 h >URL + increase >50% of URL

Evidence of ischemia†

hs-cTn value at 6 h >URL + increase >20% of initial value

Myocardial infarction Figure 1. Algorithm for rule in of AMI with hsTn. † Evidence of ischemia by symptoms and/or new electrocardiogram changes and/or new imaging corroboration. AMI: Acute myocardial infarction; hs-cTn: high-sensitivity cardiac troponin; URL: Upper reference limit. Reproduced with permission from [36].]

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more open arteries and more endothelial dysfunction. The 2012 revision of the universal definition of MI recommends considering gender-specific cutoffs for diagnosing myocardial infarctions with hsTn [1] . Mills et al. studied 1126 subjects (518 women) evaluated for suspected ACS and reported that the frequency of diagnosing AMI increased from 13% (contemporary cTnI; single reference value) to 23% (hsTnI; gender-specific reference values) in women [51] . However, in men, the frequency of diagnosing AMI did not change significantly (23% with cTnI vs 24% with hsTnI and gender-specific reference values). Importantly, this study suggests that the use of gender-specific cutoffs will significantly improve the detection of AMI in women. It remains unclear whether the AMI patients diagnosed only with a gender-specific cutoff and not with a gender-neutral cutoff have worse outcomes than non-AMI patients. More data in this important area are needed [46] . At least two studies have reported high rates of adverse cardiovascular events in men determined to have elevated hsTnI only when a single reference value is used (lower cutoff for men), and not when gender-specific reference values are used [7,50] . It is possible that using gender-specific reference values for females and gender-neutral reference values for males will maximize sensitivity in diagnosing AMI and improve accuracy in predicting adverse cardiac events. Large, multicenter studies are needed to answer this question definitively. Acute usage: distinguishing between type 1 & type 2 AMIs Distinguishing between type 1 and type 2 AMIs has become all the more important in the era of hsTn [52] . Type 1 AMI is due to plaque rupture, ulceration, fissuring, erosion, or dissection in a coronary vessel, with resultant myonecrosis, whereas type 2 AMI occurs when a noncoronary artery condition causes a mismatch between myocardial oxygen demand and supply  [1] . Currently, as many as one out of every four AMIs may be a type 2 AMI [53] . Single point determinations of hsTnT [54] and hsTnI [55] correlate closely with infarct size. This relationship is negatively impacted albeit modestly by the presence of left ventricular hypertrophy [56] . Since type 2 AMIs are smaller and thus elaborate less cTn, they are expected to increase with the use of hsTn [57] . Although guidelines recommend invasive management as the preferred treatment strategy for the majority of patients with AMI [58] , only patients with type 1 AMI, specifically, the ones with acute obstructive coronary artery disease, are likely to derive consistent benefit from invasive management. Invasive management places

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patients at risk for procedural complications, severe bleeding and subsequent thrombotic events. Patients clinically diagnosed with type 2 AMI may have severe coronary artery disease or no coronary disease and the prognosis within different subsets may be variable. It is likely that most type 2 AMIs will be best managed with guideline-directed medical therapy at least initially. Thus, making the distinction between type 1 and type 2 AMIs has important implications for the selection of appropriate treatment strategies. There is an unmet clinical need for novel noninvasive approaches that distinguish between type 1 and type 2 AMIs. It is unlikely that a changing pattern of values will be capable of distinguishing between type 1 and type 2 AMIs. The main role of troponin is to diagnose myocardial injury. Thus, for now, the distinction between type 1 and type 2 AMI will have to be made based on clinical history, objective evidence of supply–demand mismatch, for example, tachycardia, hypotension etc, and diagnostic imaging modalities such as coronary angiography. Risk stratification in heart failure With clinical use of hsTn, many more patients with acute heart failure (AHF) will have troponin elevations. In a recent study, Korley et al. reported that the proportion of AHF patients with elevated cTnI is 23% with conventional assays but, with the use of hsTnI, it increases to 48% [7] . hsTn also has prognostic value in patients with heart failure. It is an independent predictor of mortality among patients hospitalized acutely, [59] and it outperforms current generation troponin assays in risk-stratifying heart failure patients  [60] . Longitudinal changes in hsTn are also predictive of adverse cardiovascular events in heart failure  [61] . These findings suggest a role for hsTn in the monitoring of disease progression in heart failure. hsTn may also help guide management of acute heart failure. In the RELAX-AHF trial [62] , increases in hsTnT within 2 days of hospitalization predicted all-cause mortality. Additionally, the administration of an experimental therapy for AHF (serelaxin) was associated with decreases in hsTnT and ultimately, decreases in all-cause mortality (Figure 2) . These findings suggest a role for hsTn as a surrogate marker for the effectiveness of both conventional and novel AHF treatment strategies. Risk stratification in atrial fibrillation In addition to risk stratification in NSTEMI and heart failure, hsTn also improves risk stratification in patients with atrial fibrillation, beyond traditional risk factor scores [63,64] . In two studies that examined

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Ratio of follow-up to baseline

A 1.10

*

1.05 1.00 0.95 0.90 0.85 0.80 0.75

Placebo 0

2

Serelaxin 5 Days

14

Figure 2. Changes in high-sensitivity troponin T from baseline in the placebo and serelaxin groups. Changes in high-sensitivity troponin T values during treatment with serelaxin or placebo in the RELAX-AHF trial. *p-value of the difference in ratios of follow-up to baseline high-sensitivity troponin T between the serelaxin and placebo groups at 2 days is 7.5–11

Group 1: ≤7.5 Group 3: >11–16.7

Group 4: >16.7

0.045

0.040

Cumulative hazard rate

0.035

0.030

0.025

0.020

0.015

0.010

0.005

0.000 0

6

12

18

24

30

Months Figure 3. Association between high-sensitivity troponin T and the occurrence of adverse outcomes in atrial fibrillation. Association between quartiles of high-sensitivity troponin T and the composite outcome of stroke and systemic embolism among patients enrolled in the ARISTOTLE trial. Reproduced with permission from [63] .

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Review  Korley & Jaffe GUSTO IV cohort [82] . However, in the Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) cohort hsTnT outperformed hsTnI (Beckman–Coulter and Siemens) in prediction of mortality at 2 years [83] . Blood samples used for these studies were stored for many years, so fresh sample comparisons would be important to confirm this finding, especially since the data on the percentage of normal subjects who can be assigned as value would suggest that the hsTnI assays should, by this metric, be more sensitive. There is currently insufficient evidence for determining whether hsTnI or hsTnT has superior prognostic ability. Conclusion hsTn facilitates improved detection of myocardial injury and thus AMI and the expedited rule out of AMI. So far, its greatest strength lies in improved prediction of adverse cardiovascular events. hsTn augments substantially the risk stratification of acute and chronic heart failure and atrial fibrillation, and the

primary and secondary prevention of cardiovascular disease. Additional data are needed to further refine guidance regarding the specifics of its c­linical use. Future perspective As the literature on the use of hsTn evolves, hsTn continues to hold promise for the acute diagnosis of cardiovascular conditions, and for the primary and secondary diagnosis and prevention cardiovascular disease and associated sequelae. Clinical use of hsTn will necessitate a change in the mindset of clinicians from the dichotomous use of troponin values (positive/negative or elevated/nonelevated) to a better appreciation of the full spectrum of hsTn values and associated changes during serial sampling. Using hsTn for risk stratification of cardiac conditions such as heart failure and atrial fibrillation will become almost as important as its use in diagnosing myocardial infarction. Although there are currently insufficient data, there is high likelihood that hsTn will be used to guide the treatment of cardiovascu-

Executive summary Improved analytical sensitivity at the expense of specificity for myocardial infarction (MI) • High-sensitivity troponin (hsTn) will detect more patients with acute ischemic heart disease but also many new clinical situations where cardiac injury is present.

Unsettled analytical considerations concerning hsTn assays • The interference of analytical confounds (hemolysis, heterophilic antibodies, human anti-animal antibodies, autoimmune antibodies and anti-cTn antibodies) will be more important with hsTn. • The effect of renal dysfunction on troponin will be more pronounced with hsTn (especially hsTnT values). • Careful definition of the reference population of healthy individuals is critically important.

Acute usage: distinguishing between acute and chronic hsTn elevations • The optimal change value for distinguishing between acute and chronic hsTn elevation will depend on assay type, relevant clinical characteristics of the patients, the initial hsTn value and the timing of symptom onset. • Criteria combining absolute and relative changes may be preferable.

Acute usage: novel strategies for rapidly ruling out acute myocardial infarctions (AMIs) • It is clear that with hsTn the rule out of AMI might be accomplished within a shorter time frame.

Acute usage: gender considerations • The use of gender-specific reference values will be critically important for optimizing the diagnosis of AMI and the prediction of adverse cardiac events.

Acute usage: distinguishing between type 1 & type 2 MIs • Distinguishing between type 1 and type 2 MIs is based on clinical history, objective evidence of supply– demand mismatch, for example, tachycardia, hypotension etc, and diagnostic imaging modalities such as coronary angiography and is key to defining the appropriate treatment of patients.

Risk stratification in heart failure • hsTn will play a role in diagnosing heart failure and monitoring its progression.

Risk stratification in atrial fibrillation • hsTn will improve the prediction of adverse cardiovascular events in patients with atrial fibrillation, over traditional risk-factor scores.

Primary prevention of cardiovascular disease • hsTn predicts cardiovascular risk in asymptomatic individuals with excellent diagnostic accuracy. • Whether population-based screening will be a cost-effective approach to primary prevention of cardiovascular disease remains unclear.

Secondary prevention of cardiovascular disease • hsTn values provide important prognostic value in patients with existing cardiovascular disease and may play a role in the selection of therapy for these patients.

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High-sensitivity troponin: where are we now & where do we go from here? 

lar and non-AMI conditions. Gender-specific reference levels for hsTn provide an exciting opportunity to correct the current disparities that exist in the diagnosis and p­rediction of cardiovascular risk in men and women.

AS Jaffe acknowledges that he has or does consult for most of the major diagnostic companies, including many that

produce high-sensitivity cardiac troponin assays. FK Korley has consulted for Abbott Laboratories. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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death in end-stage renal disease. Circulation 106(23), 2941–2945 (2002).



Important review paper that provides guidance on how high-sensitivity troponin assays should be used clinically.

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Than M, Aldous S, Lord SJ et al. A 2-hour diagnostic protocol for possible cardiac chest pain in the emergency department: a randomized clinical trial. JAMA Intern. Med. 174(1), 51–58 (2014).

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Kavsak PA, MacRae AR. Letter by Kavsak and MacRae regarding article, “Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction”. Circulation 125(6), e358; author reply e359 (2012).

Bandstein N, Ljung R, Johansson M, Holzmann MJ. Undetectable high sensitivity cardiac troponin T level in the emergency department and risk of myocardial infarction. J. Am. Coll. Cardiol. doi:10.1016/j.jacc.2014.03.017 (2014) (Epub ahead of print).  



Study of more than 14,000 patients that reports on the negative predictive value of undetectable high-sensitivity troponin T for ruling out acute coronary syndrome.

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Jaffe AS, Apple FS. High-sensitivity cardiac troponin assays: isn’t it time for equality? Clin. Chem. 60(1), 7–9 (2014).

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Wiviott SD, Cannon CP, Morrow DA et al. Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction 18) substudy. Circulation 109(5), 580–586 (2004).

•• Review paper that discusses high-sensitivity troponins and provides a summary of challenges associated with clinical use of these assays. 26

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Giannitsis E, Becker M, Kurz K, Hess G, Zdunek D, Katus HA. High-sensitivity cardiac troponin T for early prediction of evolving non-ST-segment elevation myocardial infarction in patients with suspected acute coronary syndrome and negative troponin results on admission. Clin. Chem. 56(4), 642–650 (2010). 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. 58(1), 209–218 (2012). Study that examined the discriminative ability of absolute versus relative changes in high-sensitivity troponin for discriminating between acute coronary syndrome and nonacute coronary syndrome presentations.

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Wildi K, Reichlin T, Twerenbold R et al. Serial changes in high-sensitivity cardiac troponin I in the early diagnosis of acute myocardial infarction. Int. J. Cardiol. 168(4), 4103–4110 (2013).

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Cullen L, Parsonage WA, Greenslade J et al. Delta troponin for the early diagnosis of AMI in emergency patients with chest pain. Int. J. Cardiol. 168(3), 2602–2608 (2013).

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Koerbin G, Abhayaratna WP, Potter JM et al. Effect of population selection on 99th percentile values for a high sensitivity cardiac troponin I and T assays. Clin. Biochem. 46(16–17), 1636–1643 (2013).

Kagen L, Scheidt S, Butt A. Serum myoglobin in myocardial infarction: the “staccato phenomenon.” Is acute myocardial infarction in man an intermittent event? Am. J. Med. 62(1), 86–92 (1977).

Bjurman C, Larsson M, Johanson P et al. Small changes in troponin T levels are common in patients with non-ST-segment elevation myocardial infarction and are linked to higher mortality. J. Am. Coll. Cardiol. 62(14), 1231–1238 (2013).

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Irfan A, Reichlin T, Twerenbold R et al. Early diagnosis of myocardial infarction using absolute and relative changes in cardiac troponin concentrations. Am. J. Med. 126(9), 781–788 (2013).

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Thygesen K, Mair J, Giannitsis E et al. How to use highsensitivity cardiac troponins in acute cardiac care. Eur. Heart J. 33(18), 2252–2257 (2012).

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High-sensitivity troponin: where are we now & where do we go from here? 

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Blomkalns AL, Chen AY, Hochman JS et al. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative. J. Am. Coll. Cardiol. 45(6), 832–837 (2005).

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McKie PM, Heublein DM, Scott CG et al. Defining high-sensitivity cardiac troponin concentrations in the community. Clin. Chem. 59(7), 1099–110 (2013).

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Bohula May EA, Bonaca MP, Jarolim P et al. Prognostic performance of a high-sensitivity cardiac troponin I assay in patients with non-ST-elevation acute coronary syndrome. Clin. Chem. 60(1), 158–164 (2014).

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Mills NL, Shah AS, Griffiths M, Swahn E. High-STEACS. High-sensitivity cardiac troponin and the under diagnosis of myocardial infarction in women. Eur. Soc. Cardiol. Congr. (2013). Although in abstract only format, this study describes potential underdiagnosis of acute coronary syndrome in women, revealed only with the use of a high-sensitivity troponin assay.

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Alpert JS, Thygesen KA, White HD, Jaffe AS. Diagnostic and therapeutic implications of type 2 myocardial infarction: review and commentary. Am. J. Med. 127(2), 105–108 (2014).

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Saaby L, Poulsen TS, Hosbond S et al. Classification of myocardial infarction: frequency and features of type 2 myocardial infarction. Am. J. Med. 126(9), 789–797 (2013).



Important study that includes a strategy for distinguishing between type 1 and type 2 myocardial infarction.

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Giannitsis E, Steen H, Kurz K et al. Cardiac magnetic resonance imaging study for quantification of infarct size comparing directly serial versus single time-point measurements of cardiac troponin T. J. Am. Coll. Cardiol. 51(3), 307–314 (2008).

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Vasile VC, Babuin L, Giannitsis E, Katus HA, Jaffe AS. Relationship of MRI-determined infarct size and cTnI measurements in patients with ST-elevation myocardial infarction. Clin. Chem. 54(3), 617–619 (2008). Misumida N, Fox J, Kanei Y. CRT-111 impact of high left ventricular mass index on peak troponin level after STelevation myocardial infarction. J. Am. Coll. Cardiol. Intv. 7(2_S), S10–S10 (2014).

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Saaby L, Poulsen TS, Diederichsen AC et al. Mortality rate in type 2 myocardial infarction: observations from an unselected hospital cohort. Am. J. Med. 127(4), 295–302 (2014). 



One of the first publications that used a systematic method for classifying type 1 versus type 2 myocardial infarction.

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Anderson JL, Adams CD, Antman EM et al. 2012 ACCF/ AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 61(23), e179–e347 (2013).

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Parissis JT, Papadakis J, Kadoglou NP et al. Prognostic value of high sensitivity troponin T in patients with acutely decompensated heart failure and non-detectable conventional troponin T levels. Int. J. Cardiol. 168(4), 3609–3612 (2013).

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de Antonio M, Lupon J, Galan A et al. Head-to-head comparison of high-sensitivity troponin T and sensitivecontemporary troponin I regarding heart failure risk stratification. Clin. Chim. Acta 426, 18–24 (2013).

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Masson S, Anand I, Favero C et al. Serial measurement of cardiac troponin T using a highly sensitive assay in patients with chronic heart failure: data from 2 large randomized clinical trials. Circulation 125(2), 280–288 (2012).

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Metra M, Cotter G, Davison BA et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J. Am. Coll. Cardiol. 61(2), 196–206 (2013).

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Hijazi Z, Wallentin L, Siegbahn A et al. High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J. Am. Coll. Cardiol. 63(1), 52–61 (2014).

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Hijazi Z, Siegbahn A, Andersson U et al. High-sensitivity troponin I for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 129(6), 625–634 (2014).



Examines the use of high-sensitivity troponin to predict adverse outcomes in atrial fibrillation.

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Hijazi Z, Oldgren J, Andersson U et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation 125(13), 1605–1616 (2012).

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de Lemos JA, Drazner MH, Omland T et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 304(22), 2503–2512 (2010).

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Zeller T, Tunstall-Pedoe H, Saarela O et al. High population prevalence of cardiac troponin I measured by a highsensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort. Eur. Heart J. 35(5), 271–281 (2014).

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Hussein AA, Gottdiener JS, Bartz TM et al. Cardiomyocyte injury assessed by a highly sensitive troponin assay and sudden cardiac death in the community: the Cardiovascular Health Study. J. Am. Coll. Cardiol. 62(22), 2112–2120 (2013).

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Saunders JT, Nambi V, de Lemos JA et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the atherosclerosis risk in communities study. Circulation 123(13), 1367–1376 (2011).

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Chambless LE, Folsom AR, Sharrett AR et al. Coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC) study. J. Clin. Epidemiol. 56(9), 880–890 (2003).

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deFilippi CR, de Lemos JA, Christenson RH et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA 304(22), 2494–2502 (2010).

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deFilippi CR, de Lemos JA, Tkaczuk AT et al. Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults. J. Am. Coll. Cardiol. 60(24), 2539–2547 (2012).

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Widera C, Pencina MJ, Bobadilla M et al. Incremental prognostic value of biomarkers beyond the GR ACE (Global Registry of Acute Coronary Events) score and high-sensitivity cardiac troponin T in non-ST-elevation acute coronary syndrome. Clin. Chem. 59(10), 1497–1505 (2013).

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Lindahl B, Venge P, James S. The new high-sensitivity cardiac troponin T assay improves risk assessment in acute coronary syndromes. Am. Heart J. 160(2), 224–229 (2010).

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Wallentin L, Lindholm D, Siegbahn A et al. Biomarkers in relation to the effects of ticagrelor in comparison with Clopidogrel in non-ST-elevation acute coronary syndrome patients managed with or without in-hospital revascularization: a substudy from the prospective randomized Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 129(3), 293–303 (2014).

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Woodward M, Brindle P, Tunstall-Pedoe H. Adding social deprivation and family history to cardiovascular risk assessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC). Heart 93(2), 172–176 (2007).

Bohula May EA, Bonaca MP, Jarolim P et al. Prognostic performance of a high-sensitivity cardiac troponin I assay in

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patients with non-ST-elevation acute coronary syndrome. Clin. Chem. 60(1), 158–164 (2014). 78

Laufer EM, Mingels AM, Winkens MH et al. The extent of coronary atherosclerosis is associated with increasing circulating levels of high sensitive cardiac troponin T. Arterioscler. Thromb. Vasc. Biol. 30(6), 1269–75 (2010).

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Omland T, Pfeffer MA, Solomon SD et al. Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease. J. Am. Coll. Cardiol. 61(12), 1240–1249 (2013).

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Beatty AL, Ku IA, Christenson RH, DeFilippi CR, Schiller NB, Whooley MA. High-sensitivity cardiac troponin T levels and secondary events in outpatients with coronary heart disease from the Heart and Soul Study. JAMA Intern. Med. 173(9), 763–769 (2013).

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Kavsak PA, Xu L, Yusuf S, McQueen MJ. High-sensitivity cardiac troponin I measurement for risk stratification in a stable high-risk population. Clin. Chem. 57(8), 1146–1153 (2011).

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Lindahl B, Eggers KM, Venge P, James S. Evaluation of four sensitive troponin assays for risk assessment in acute coronary syndromes using a new clinically oriented approach for comparison of assays. Clin. Chem. Lab. Med. 51(9), 1859–1864 (2013).

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Haaf P, Reichlin T, Twerenbold R et al. Risk stratification in patients with acute chest pain using three high-sensitivity cardiac troponin assays. Eur. Heart J. 35(6), 365–375 (2014).

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Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard. Clin. Chem. 55(7), 1303–1306 (2009).

future science group

High-sensitivity troponin: where are we now and where do we go from here?

High-sensitivity troponin (hsTn) assays are used clinically in most parts of the world and are expected to be approved by the US FDA for clinical use ...
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