Editorial 625
High-sensitive cardiac troponin assays: more information, more challenges Stephen L. Seliger and Christopher R. deFilippi Coronary Artery Disease 2013, 24:625–627 Keywords: acute coronary syndrome, chronic kidney disease, diagnosis, heart failure, prognosis
Correspondence to Stephen L. Seliger, MD, MS, 22 S. Greene Street, N3W143, Baltimore, MD 21201, USA Tel: + 1 410 328 5720; fax: + 1 410 328 5685; e-mail: [email protected]
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
More than 6 years ago, national guidelines committees called for dramatic improvements in the commercially available cardiac troponin-I (cTnI) and cardiac troponin-T (cTnT) assays to allow for accurate quantification of low-level concentrations, with the goal of improving the early diagnosis of myocardial infarction [1]. In response, assay manufacturers have developed and introduced markedly more sensitive assays for cardiac troponins, often terming such assays ‘highsensitive’. Although different definitions of ‘high-sensitive’ have been considered and no one definition is universally accepted, one widely referenced definition states that concentrations of cardiac troponins can be reliably quantified using such assays in at least 50% of a healthy general population [2]. This is, however, in contrast to contemporary assays, which typically detect circulating cardiac troponins in 1–20% of the general population [3,4]. Table 1 provides proposed nomenclature for troponin assays, although many authors use the term ‘high-sensitive’ to incorporate all assays detecting levels in at least 50% of a general population. The introduction of increasingly sensitive assays for cardiac troponins has not been completely embraced by the clinical community. Several years ago, an editorialist for the Journal of the American College of Cardiology famously wrote: ‘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’ [5]. Several years after the introduction of these high-sensitive assays, what changes have occurred in the application of cTnI and cTnT measurements for diagnosis and risk stratification? In the intervening period, much of the world outside the USA (where no high-sensitive assay has been approved as of this writing) has gained extensive clinical experience using these high-sensitive assays. A revised universal definition of myocardial infarction has been introduced, in a large part focusing on cTnI and/or cTnT interpretation, and its pitfalls, as the crux of the diagnosis [6]. A guidance document on the use of sensitive and high-sensitive assays has also been published by the American College of Cardiology [7]. Most importantly, there is a growing body of research identifying the potential role of a high-sensitive assay for earlier detection and improved risk stratification of patients with possible acute coronary syndromes. In fact, the greater c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
frequency of low-level elevations of cardiac troponins using these assays has led to unstable angina becoming a diagnosis on the ‘verge of extinction’. The introduction of these assays has also highlighted a future role for measuring cardiac troponins in a variety of disease states, cardiac or otherwise, to stratify ‘at-risk’ populations for potential cardiovascular complications and perhaps (one day) do much the same for the general population. In this Review in depth, we have assembled a group of authors who are all considered leaders in the field of cardiac biomarkers. As a result of their efforts, we are able to provide a comprehensive and cutting-edge review of the analytical and clinical issues that surround the present and potential future application of the high-sensitive cTnI and cTnT assays. First, Robert Christenson, a leader in the field of clinical chemistry, reviews the analytical differences between conventional and the new high-sensitive cardiac assays. He discusses the often-confusing nomenclature employed by assay manufacturers, with terms such as ‘highly-sensitive’, ‘ultra-sensitive’, and like terminology used to describe different newer generation assays. He summarizes the performance characteristics of the nearly 30 commercially available assays, and considers the analytical challenges and pitfalls of measuring troponin concentrations often 10-fold lower than the current generation of ‘sensitive’ assays. Finally, he discusses the ongoing and critically important efforts at assay harmonization and standardization – especially for cTnI – that will permit greater comparison of results obtained from different assays. Next, Dr Christian Mueller, author of several seminal papers on high-sensitive cardiac troponins for the diagnosis of myocardial infarction, describes the diagnostic accuracy of this newest generation assay. He highlights an important consequence of the greater low-level quantification of cardiac troponins with high-sensitive assays: the potential for more rapid and accurate rule out of myocardial infarction. He reviews some of his ground-breaking research on novel algorithms for accelerating a rule-out/rule-in protocol to less than several hours among emergency department patients presenting with chest pain. James McCord, a leader in urgent acute coronary syndrome care in the emergency department DOI: 10.1097/MCA.0000000000000045
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
626 Coronary Artery Disease 2013, Vol 24 No 8
Table 1 Proposed nomenclature and current and potential future applications of cardiac troponin assays on the basis of sensitivity and limit of detection Application
Conventional troponin Contemporary-sensitive troponin High-sensitive troponin Super-sensitive troponin
Assay criterion
Diagnosis Myocardial infarction
Risk stratification Secondary prevention
Risk stratification Primary prevention
10% CV r 99th percentile Detectable in Z 50% of the general population Detectable in Z 95% of the general population
+ ++ ++ ?
+ + ++ ?
– – + ?
?, unknown, insufficient data to support the role for either application; CV, coefficient of variation. Reproduced with permission [2].
Fig. 1
Myocardial injury with cell death marked by cardiac troponin elevation
Cardiac procedure
Myocardial injury
Noncardiac major procedure
Clinical evidence of acute myocardial ischemia with rise and/or fall of cardiac troponin
Myocardial infarction
Tachyarrhythmia/brady arrhythmia
Heart failure
Renal failure
This illustration shows various clinical entities that can be associated with myocardial injury along with cell death, marked by cardiac troponin elevation including renal failure, heart failure, tachyarrhythmia or bradyarrhythmia, and cardiac or noncardiac procedures. However, these entities can also be associated with myocardial infarction in the setting of clinical evidence of acute myocardial ischemia with the rise and/or fall of cardiac troponin. Reproduced with permission [6].
setting, reviews the prognostic and diagnostic implications of using cardiac troponins measured using highsensitive assays versus contemporary tests. He suggests that such high-sensitive assays will lead to greater identification and potentially improved outcomes of high-risk patients with chest pain, while highlighting the importance of additional and more rigorous research (including cost-effectiveness analyses) on these effects. One consequence of the greater sensitivity of measurement of cardiac troponins for the diagnosis of acute coronary syndromes is a decreased specificity, with pathophysiological processes other than acute myocardial infarction contributing to low-level elevations (Fig. 1). Thus, the remaining reviews
focus on the measurement of high-sensitive cTnI and cTnT in common chronic cardiac (heart failure) and noncardiac conditions [chronic kidney disease (CKD)], as well as measures in the general population. Roberto Latini and Serge Masson, leading heart failure trialists, review the potential mechanisms to explain cardiac troponin release in chronic heart failure. Although previously attributed exclusively to myocardial necrosis, other potential mechanisms for low-level elevation of cardiac troponins including apoptosis, reversible ischemic injury with reoxygenation, and neuroendocrine activation are considered. They further discuss the prognostic implications of detectable cardiac troponins in the blood of chronic heart failure patients and what this means with respect to the overall prognosis,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
High-sensitive cardiac troponin assays Seliger and deFilippi 627
following therapy with serial levels, and to potentially identifying patients who will progress to symptomatic disease when receiving cardiotoxic chemotherapy. Next, we review the anticipated prevalence, associated cardiac pathology, and prognosis associated with low-level elevation of cardiac troponins in patients with CKD, perhaps the most common noncardiac condition associated with chronic elevation. We discuss the potential mechanisms responsible for such elevations, including the relative contributions of decreased renal clearance of cardiac troponins in CKD versus increased cardiac release. We also discuss the clinical challenges of biomarker-based diagnosis of acute myocardial infarction in CKD patients with chest pain when using high-sensitivity cardiac troponin assays. Finally, James de Lemos, one of the lead investigators of the Dallas Heart Study, evaluates the prevalence, cardiovascular associations, and prognosis associated with measurable cardiac troponins with a highsensitive assay in general population cohorts. Perhaps this test, still synonymous with the diagnosis of acute myocardial infarction, could one day be used to identify ‘at-risk’ asymptomatic individuals in an effort to modify the lifestyle and risk factors to reduce cardiac morbidity and mortality.
Diagnostics. Dr Christopher R. deFilippi has received research funding from Roche Diagnostics and Singulex, speaking fees from Roche Diagnostics, and has served as consultant and advisory board member for Roche Diagnostics.
Acknowledgements
7
Conflicts of interest
Dr Stephen L. Seliger has received research funding from Roche Diagnostics and Singulex and consulted for Roche
References 1
2 3
4
5
6
Apple FS, Jesse RL, Newby LK, Wu AH, Christenson RH. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes. Circulation 2007; 115:e352–e355. Keller T, Mu¨nzel T, Blankenberg S. Making it more sensitive: the new era of troponin use. Circulation 2011; 123:1361–1363. Eggers KM, Lind L, Ahlstro¨m H, Bjerner T, Ebeling Barbier C, Larsson A, et al. Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects. Eur Heart J 2008; 29:2252–2258. Wallace TW, Abdullah SM, Drazner MH, Das SR, Khera A, McGuire DK, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation 2006; 113:1958–1965. Jesse RL. On the relative value of an assay versus that of a test: a history of troponin for the diagnosis of myocardial infarction. J Am Coll Cardiol 2010; 55:2125–2128. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60:1581–1598. Newby LK, Jesse RL, Babb JD, Christenson RH, De Fer TM, Diamond GA, et al. ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2012; 60:2427–2463.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
High-sensitive cardiac troponin assays: more information, more challenges Stephen L. Seliger and Christopher R. deFilippi Coronary Artery Disease 2013, 24:625–627 Keywords: acute coronary syndrome, chronic kidney disease, diagnosis, heart failure, prognosis
Correspondence to Stephen L. Seliger, MD, MS, 22 S. Greene Street, N3W143, Baltimore, MD 21201, USA Tel: + 1 410 328 5720; fax: + 1 410 328 5685; e-mail: [email protected]
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
More than 6 years ago, national guidelines committees called for dramatic improvements in the commercially available cardiac troponin-I (cTnI) and cardiac troponin-T (cTnT) assays to allow for accurate quantification of low-level concentrations, with the goal of improving the early diagnosis of myocardial infarction [1]. In response, assay manufacturers have developed and introduced markedly more sensitive assays for cardiac troponins, often terming such assays ‘highsensitive’. Although different definitions of ‘high-sensitive’ have been considered and no one definition is universally accepted, one widely referenced definition states that concentrations of cardiac troponins can be reliably quantified using such assays in at least 50% of a healthy general population [2]. This is, however, in contrast to contemporary assays, which typically detect circulating cardiac troponins in 1–20% of the general population [3,4]. Table 1 provides proposed nomenclature for troponin assays, although many authors use the term ‘high-sensitive’ to incorporate all assays detecting levels in at least 50% of a general population. The introduction of increasingly sensitive assays for cardiac troponins has not been completely embraced by the clinical community. Several years ago, an editorialist for the Journal of the American College of Cardiology famously wrote: ‘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’ [5]. Several years after the introduction of these high-sensitive assays, what changes have occurred in the application of cTnI and cTnT measurements for diagnosis and risk stratification? In the intervening period, much of the world outside the USA (where no high-sensitive assay has been approved as of this writing) has gained extensive clinical experience using these high-sensitive assays. A revised universal definition of myocardial infarction has been introduced, in a large part focusing on cTnI and/or cTnT interpretation, and its pitfalls, as the crux of the diagnosis [6]. A guidance document on the use of sensitive and high-sensitive assays has also been published by the American College of Cardiology [7]. Most importantly, there is a growing body of research identifying the potential role of a high-sensitive assay for earlier detection and improved risk stratification of patients with possible acute coronary syndromes. In fact, the greater c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
frequency of low-level elevations of cardiac troponins using these assays has led to unstable angina becoming a diagnosis on the ‘verge of extinction’. The introduction of these assays has also highlighted a future role for measuring cardiac troponins in a variety of disease states, cardiac or otherwise, to stratify ‘at-risk’ populations for potential cardiovascular complications and perhaps (one day) do much the same for the general population. In this Review in depth, we have assembled a group of authors who are all considered leaders in the field of cardiac biomarkers. As a result of their efforts, we are able to provide a comprehensive and cutting-edge review of the analytical and clinical issues that surround the present and potential future application of the high-sensitive cTnI and cTnT assays. First, Robert Christenson, a leader in the field of clinical chemistry, reviews the analytical differences between conventional and the new high-sensitive cardiac assays. He discusses the often-confusing nomenclature employed by assay manufacturers, with terms such as ‘highly-sensitive’, ‘ultra-sensitive’, and like terminology used to describe different newer generation assays. He summarizes the performance characteristics of the nearly 30 commercially available assays, and considers the analytical challenges and pitfalls of measuring troponin concentrations often 10-fold lower than the current generation of ‘sensitive’ assays. Finally, he discusses the ongoing and critically important efforts at assay harmonization and standardization – especially for cTnI – that will permit greater comparison of results obtained from different assays. Next, Dr Christian Mueller, author of several seminal papers on high-sensitive cardiac troponins for the diagnosis of myocardial infarction, describes the diagnostic accuracy of this newest generation assay. He highlights an important consequence of the greater low-level quantification of cardiac troponins with high-sensitive assays: the potential for more rapid and accurate rule out of myocardial infarction. He reviews some of his ground-breaking research on novel algorithms for accelerating a rule-out/rule-in protocol to less than several hours among emergency department patients presenting with chest pain. James McCord, a leader in urgent acute coronary syndrome care in the emergency department DOI: 10.1097/MCA.0000000000000045
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
626 Coronary Artery Disease 2013, Vol 24 No 8
Table 1 Proposed nomenclature and current and potential future applications of cardiac troponin assays on the basis of sensitivity and limit of detection Application
Conventional troponin Contemporary-sensitive troponin High-sensitive troponin Super-sensitive troponin
Assay criterion
Diagnosis Myocardial infarction
Risk stratification Secondary prevention
Risk stratification Primary prevention
10% CV r 99th percentile Detectable in Z 50% of the general population Detectable in Z 95% of the general population
+ ++ ++ ?
+ + ++ ?
– – + ?
?, unknown, insufficient data to support the role for either application; CV, coefficient of variation. Reproduced with permission [2].
Fig. 1
Myocardial injury with cell death marked by cardiac troponin elevation
Cardiac procedure
Myocardial injury
Noncardiac major procedure
Clinical evidence of acute myocardial ischemia with rise and/or fall of cardiac troponin
Myocardial infarction
Tachyarrhythmia/brady arrhythmia
Heart failure
Renal failure
This illustration shows various clinical entities that can be associated with myocardial injury along with cell death, marked by cardiac troponin elevation including renal failure, heart failure, tachyarrhythmia or bradyarrhythmia, and cardiac or noncardiac procedures. However, these entities can also be associated with myocardial infarction in the setting of clinical evidence of acute myocardial ischemia with the rise and/or fall of cardiac troponin. Reproduced with permission [6].
setting, reviews the prognostic and diagnostic implications of using cardiac troponins measured using highsensitive assays versus contemporary tests. He suggests that such high-sensitive assays will lead to greater identification and potentially improved outcomes of high-risk patients with chest pain, while highlighting the importance of additional and more rigorous research (including cost-effectiveness analyses) on these effects. One consequence of the greater sensitivity of measurement of cardiac troponins for the diagnosis of acute coronary syndromes is a decreased specificity, with pathophysiological processes other than acute myocardial infarction contributing to low-level elevations (Fig. 1). Thus, the remaining reviews
focus on the measurement of high-sensitive cTnI and cTnT in common chronic cardiac (heart failure) and noncardiac conditions [chronic kidney disease (CKD)], as well as measures in the general population. Roberto Latini and Serge Masson, leading heart failure trialists, review the potential mechanisms to explain cardiac troponin release in chronic heart failure. Although previously attributed exclusively to myocardial necrosis, other potential mechanisms for low-level elevation of cardiac troponins including apoptosis, reversible ischemic injury with reoxygenation, and neuroendocrine activation are considered. They further discuss the prognostic implications of detectable cardiac troponins in the blood of chronic heart failure patients and what this means with respect to the overall prognosis,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
High-sensitive cardiac troponin assays Seliger and deFilippi 627
following therapy with serial levels, and to potentially identifying patients who will progress to symptomatic disease when receiving cardiotoxic chemotherapy. Next, we review the anticipated prevalence, associated cardiac pathology, and prognosis associated with low-level elevation of cardiac troponins in patients with CKD, perhaps the most common noncardiac condition associated with chronic elevation. We discuss the potential mechanisms responsible for such elevations, including the relative contributions of decreased renal clearance of cardiac troponins in CKD versus increased cardiac release. We also discuss the clinical challenges of biomarker-based diagnosis of acute myocardial infarction in CKD patients with chest pain when using high-sensitivity cardiac troponin assays. Finally, James de Lemos, one of the lead investigators of the Dallas Heart Study, evaluates the prevalence, cardiovascular associations, and prognosis associated with measurable cardiac troponins with a highsensitive assay in general population cohorts. Perhaps this test, still synonymous with the diagnosis of acute myocardial infarction, could one day be used to identify ‘at-risk’ asymptomatic individuals in an effort to modify the lifestyle and risk factors to reduce cardiac morbidity and mortality.
Diagnostics. Dr Christopher R. deFilippi has received research funding from Roche Diagnostics and Singulex, speaking fees from Roche Diagnostics, and has served as consultant and advisory board member for Roche Diagnostics.
Acknowledgements
7
Conflicts of interest
Dr Stephen L. Seliger has received research funding from Roche Diagnostics and Singulex and consulted for Roche
References 1
2 3
4
5
6
Apple FS, Jesse RL, Newby LK, Wu AH, Christenson RH. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes. Circulation 2007; 115:e352–e355. Keller T, Mu¨nzel T, Blankenberg S. Making it more sensitive: the new era of troponin use. Circulation 2011; 123:1361–1363. Eggers KM, Lind L, Ahlstro¨m H, Bjerner T, Ebeling Barbier C, Larsson A, et al. Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects. Eur Heart J 2008; 29:2252–2258. Wallace TW, Abdullah SM, Drazner MH, Das SR, Khera A, McGuire DK, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation 2006; 113:1958–1965. Jesse RL. On the relative value of an assay versus that of a test: a history of troponin for the diagnosis of myocardial infarction. J Am Coll Cardiol 2010; 55:2125–2128. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60:1581–1598. Newby LK, Jesse RL, Babb JD, Christenson RH, De Fer TM, Diamond GA, et al. ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2012; 60:2427–2463.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
