716 Review in depth
Significance of measurable cardiac troponin by high-sensitivity assays in patients with chronic stable heart failure Roberto Latini and Serge Masson Biological markers released into the bloodstream by the injured cardiac myocytes have contributed over the years to the diagnosis of acute myocardial infarction. Recent evidence suggests that the measurement of even minute amounts of circulating cardiac contractile proteins may be useful in the clinical assessment of patients with heart failure. Here, we briefly discuss the clinical significance of troponin measurement in chronic heart failure, in light of the availability of a new generation of highly sensitive immunoassays that are changing our understanding and interpretation
c 2013 of this syndrome. Coron Artery Dis 24:716–719 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Pathophysiology of cardiac troponin release in chronic heart failure
skeletal muscle (myopathy), possibly after the re-expression of skeletal muscle troponin isoforms detected by the antibodies used for troponin T assay [12]. Finally, the neuroendocrine systems and inflammatory processes that are chronically activated in patients with HF might contribute per se to myocyte injury and cell death and thereby to troponin release. Experimental investigations using well-characterized animal models of cardiac damage (myocardial infarction, cardiac overload, diabetes, renal dysfunction, neuroendocrine activation, exposition to chemotherapeutic drugs) and/or cultured isolated myocytes (hypoxia, hyperglycemia, hormonal stimulation) will probably help in deciphering the biological complexity behind the simple measurement of a cardiac contractile protein in the blood of patients with HF.
Cardiac myocyte cell death occurs at a very low but continuous rate during physiologic aging, and contributes to the onset of myocardial dysfunction in the elderly [1,2]. Apparently healthy men lose B1 g of myocardial tissue per year, corresponding to 64 million cells. However, the precise mechanism (apoptotic or necrotic cell death) remains unclear [2]. For instance, it is unknown whether and to what extent apoptosis contributes toward cardiac troponin elevation in chronic heart failure (HF) [3]. Cardiomyocyte death has been observed in animal models of postmyocardial infarction left ventricular dysfunction [4] and in patients with chronic HF [5,6]. Stretching of cardiac myocytes might trigger the leakage of the cytosolic pool of troponins by transient loss of cellmembrane integrity. Reversible damage caused by limited ischemia and reoxygenation can trigger the formation and release into the extracellular space of membranous blebs containing large cytoplasmic molecules, including troponins [7]. There are, however, many alternative causes, when acute myocardial infarction is excluded, for elevation of circulating cardiac troponin [8–11]. An exhaustive list of all these reasons is beyond the scope of the present brief overview, but conditions such as strenuous exercise, sepsis, exposure to chemotherapeutic agents, and decreased renal or respiratory functions are associated with troponin elevation. Concomitant diseases, often present in patients with HF (chronic pulmonary obstructive disease, diabetes, hypertension, renal dysfunction), may also concur with high levels of troponins in the blood. For instance, decreased renal clearance contributes toward elevated circulating levels of cardiac troponins in patients with chronic HF and kidney disease [11]. Circulating cardiac troponin levels may also be elevated in diseased c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
Coronary Artery Disease 2013, 24:716–719 Keywords: anticancer therapy, cardiac troponin, heart failure, natriuretic peptides, prognosis, toxicity Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Correspondence to Roberto Latini, MD, Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Privata Giuseppe La Masa 19, 20156 Milan, Italy Tel: + 39 023 901 4454; fax: + 39 023 320 0049; e-mail: [email protected]
Troponin T versus troponin I The contractile system of the cardiac myocyte contains three troponins (C, I, and T) but only troponins I and T are cardiac-specific, whereas the two isoforms of cardiac and skeletal muscle troponin C are indistinguishable. Although the criteria for defining high sensitivity are debated [13], there are some differences in the analytical characteristics of contemporary cardiac troponin assays with very low detection limits [14]. To our knowledge, no compelling, head-to-head comparisons of the clinical value of cardiac troponin I and T measured with highsensitivity assays have been published to date in chronic HF. Indeed, some comparisons either involved reagents of different generations (a conventional, sensitivity troponin T vs. a new generation high-sensitivity troponin I assay) [15], or two conventional (low sensitivity) assays [16]. In contrast, the superiority of high sensitivity over conventional assays has been documented in stable patients with chronic HF [15,17,18] or coronary artery DOI: 10.1097/MCA.0000000000000051
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Troponins and heart failure Latini and Masson 717
disease [19]. In conclusion, high-sensitivity cardiac troponin I and T may be considered superior to conventional reagents and equivalent in HF, in the absence of more definitive data.
Serial measurements of circulating troponin The threshold for detecting myocyte injury has been lowered and a new generation of highly sensitive troponin assays with a very low detection limit (in the range of few ng/l or lower) and good precision are now commercially available. A continuous release of minute amounts of cardiac troponins into the bloodstream is detectable with recent high-sensitivity reagents in almost all patients with stable chronic HF [15,17]. Elevation of circulating troponin levels relates to outcome in these patients, even within a range of concentrations not measurable previously with conventional assays. In two large and multicenter clinical trials (Val-HeFT and GISSI-HF), baseline concentration of troponin predicted adverse outcome (all-cause mortality or hospital admission for HF) in patients with stable HF with reduced left ventricular systolic function (Fig. 1) [17,20]. The prognostic value of troponin was independent of demographic and clinical variables, and showed an incremental prognostic accuracy even in the presence of the best current biomarker in HF, the natriuretic peptides [17]. There are only few data on the role of troponin in patients with chronic HF and preserved ejection fraction [21]. In summary, a single measurement of circulating troponin at any time during the natural progression of HF provides robust, independent prognostic information, irrespective of the clinical presentation (acute or chronic), etiology (ischemic or nonischemic), troponin form (I or T), and generation of reagents (traditional or high sensitivity). Patients with chronic HF manifest progression of disease over time. A simple circulating biomarker that could monitor this evolution would be highly desirable to help in their clinical management in and out of the hospital. For this reason, numerous studies have assessed the value of repeated measurements of troponin levels over time in community-dwelling older adults [22], in ambulatory patients with chronic HF [20,23,24], acute HF [25,26], or chest pain [27]. Although the analysis and interpretation of serial measurements and changes over time of biomarker concentrations are challenging and not easily comparable, most studies suggest that even small changes in troponin have prognostic significance and may help to identify patients at risk. However, the added value of serial measurements of troponin over a single determination (in particular the last available) or over other cardiac biomarkers (in particular natriuretic peptides) seems to be quite limited in several clinical contexts. The evidence available so far does not support serial measurement of troponins for risk stratification of patients with chronic HF until a full understanding of its implementation in clinical routine will be gained [28].
Natriuretic peptides and troponins: two cardiac markers with the same potential in chronic heart failure? High-sensitivity troponins and natriuretic peptides are independent and almost equipotent risk predictors in chronic HF when compared head to head [17,29–31]. Several studies have attempted to evaluate the added value of combining these two markers to improve their prognostic accuracy. In Val-HeFT, baseline high-sensitivity cardiac troponin T (hs-cTnT) showed a modest but significant incremental prognostic accuracy compared with brain natriuretic peptide (BNP) as estimated by increases in the likelihood ratio or C-index, two statistical metrics of discrimination [17]. In addition, changes over time of hs-cTnT concentration in Val-HeFT and in GISSIHF (respectively, 4000 and 1200 patients with both markers assayed) marginally improved patients’ reclassification (net reclassification improvement, an intuitive and meaningful measurement of the usefulness of new biomarkers) in models that included demographic and clinical variables, in addition to NT-proBNP [20]. Few investigators have evaluated the potential of combining the two cardiac markers in relevant cohorts of patients with chronic HF. The take-home message is that patients with both markers elevated have worse outcome than those with either one marker elevated [30,32]. In summary, for historical reasons, natriuretic peptides are still the benchmark biomarkers for risk prediction in chronic HF. High-sensitivity cardiac troponins are noninferior, and the combination of both markers does not provide remarkable improvements, although statistically significant. The choice of either marker is therefore influenced by other considerations, including technical and economical reasons.
Effect of therapy on troponin level, guided therapy, and stability of troponin in stable heart failure patients There are no published data on the use of cardiac troponin levels to guide patients’ treatment in HF, such as has been done with natriuretic peptides. The reason may be the lack of data on the effects of drug therapy of HF on circulating cardiac troponin levels, whereas several studies have documented such effects on natriuretic peptides. This is possibly an area of future research. In Val-HeFT, valsartan markedly decreased BNP and NT-proBNP, but it did not affect hs-cTnT concentrations over time (Roberto Latini and Serge Masson, unpublished data); this finding suggests that troponins may be less than optimal candidates for therapeutic guidance.
Prevention and monitoring of cardiac toxicity of anticancer agents The survival rate of cancer patients has increased significantly because of the considerable progresses of modern cancer therapy. However, a high price has been
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
718 Coronary Artery Disease 2013, Vol 24 No 8
must be highlighted. First, not all patients treated with chemotherapy require cardiac function monitoring as frequently as suggested by the guidelines; second, the value of this monitoring on the basis of serial evaluation of left ventricular ejection fraction seems to be neither sensitive nor specific enough to predict late declines in cardiac function.
Fig. 1
(a)
Val-HeFT
Hazard ratio (95% CI)
50
10 5
1 1
2
3
Hs-cTnT range (ng/l)
38
Although anthracyclines are among the most widely used chemotherapeutic agents associated with cardiac toxicity, other newer agents such as herceptin and trastuzumab also have cardiotoxic potential.
GISSI-HF
50 Hazard ratio (95% CI)
4
10 5
1 1
2
Hs-cTnT range (ng/l)
44
Crude hazard ratios and 95% confidence intervals (95% CI) for all-cause mortality by deciles of high-sensitivity cardiac troponin T (hs-cTnT) concentration at baseline in the Val-HeFT and GISSI-HF trials. The concentration range, absolute number of deaths, and death rate (%) are reported for each decile of hs-cTnT. Hazard ratios and 95% CIs are reported on a logarithmic scale. Number of patients per decile: B400 for Val-HeFT, and 120 for GISSI-HF. Interval of normality for hs-cTnT is
Significance of measurable cardiac troponin by high-sensitivity assays in patients with chronic stable heart failure Roberto Latini and Serge Masson Biological markers released into the bloodstream by the injured cardiac myocytes have contributed over the years to the diagnosis of acute myocardial infarction. Recent evidence suggests that the measurement of even minute amounts of circulating cardiac contractile proteins may be useful in the clinical assessment of patients with heart failure. Here, we briefly discuss the clinical significance of troponin measurement in chronic heart failure, in light of the availability of a new generation of highly sensitive immunoassays that are changing our understanding and interpretation
c 2013 of this syndrome. Coron Artery Dis 24:716–719 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Pathophysiology of cardiac troponin release in chronic heart failure
skeletal muscle (myopathy), possibly after the re-expression of skeletal muscle troponin isoforms detected by the antibodies used for troponin T assay [12]. Finally, the neuroendocrine systems and inflammatory processes that are chronically activated in patients with HF might contribute per se to myocyte injury and cell death and thereby to troponin release. Experimental investigations using well-characterized animal models of cardiac damage (myocardial infarction, cardiac overload, diabetes, renal dysfunction, neuroendocrine activation, exposition to chemotherapeutic drugs) and/or cultured isolated myocytes (hypoxia, hyperglycemia, hormonal stimulation) will probably help in deciphering the biological complexity behind the simple measurement of a cardiac contractile protein in the blood of patients with HF.
Cardiac myocyte cell death occurs at a very low but continuous rate during physiologic aging, and contributes to the onset of myocardial dysfunction in the elderly [1,2]. Apparently healthy men lose B1 g of myocardial tissue per year, corresponding to 64 million cells. However, the precise mechanism (apoptotic or necrotic cell death) remains unclear [2]. For instance, it is unknown whether and to what extent apoptosis contributes toward cardiac troponin elevation in chronic heart failure (HF) [3]. Cardiomyocyte death has been observed in animal models of postmyocardial infarction left ventricular dysfunction [4] and in patients with chronic HF [5,6]. Stretching of cardiac myocytes might trigger the leakage of the cytosolic pool of troponins by transient loss of cellmembrane integrity. Reversible damage caused by limited ischemia and reoxygenation can trigger the formation and release into the extracellular space of membranous blebs containing large cytoplasmic molecules, including troponins [7]. There are, however, many alternative causes, when acute myocardial infarction is excluded, for elevation of circulating cardiac troponin [8–11]. An exhaustive list of all these reasons is beyond the scope of the present brief overview, but conditions such as strenuous exercise, sepsis, exposure to chemotherapeutic agents, and decreased renal or respiratory functions are associated with troponin elevation. Concomitant diseases, often present in patients with HF (chronic pulmonary obstructive disease, diabetes, hypertension, renal dysfunction), may also concur with high levels of troponins in the blood. For instance, decreased renal clearance contributes toward elevated circulating levels of cardiac troponins in patients with chronic HF and kidney disease [11]. Circulating cardiac troponin levels may also be elevated in diseased c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
Coronary Artery Disease 2013, 24:716–719 Keywords: anticancer therapy, cardiac troponin, heart failure, natriuretic peptides, prognosis, toxicity Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy Correspondence to Roberto Latini, MD, Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Privata Giuseppe La Masa 19, 20156 Milan, Italy Tel: + 39 023 901 4454; fax: + 39 023 320 0049; e-mail: [email protected]
Troponin T versus troponin I The contractile system of the cardiac myocyte contains three troponins (C, I, and T) but only troponins I and T are cardiac-specific, whereas the two isoforms of cardiac and skeletal muscle troponin C are indistinguishable. Although the criteria for defining high sensitivity are debated [13], there are some differences in the analytical characteristics of contemporary cardiac troponin assays with very low detection limits [14]. To our knowledge, no compelling, head-to-head comparisons of the clinical value of cardiac troponin I and T measured with highsensitivity assays have been published to date in chronic HF. Indeed, some comparisons either involved reagents of different generations (a conventional, sensitivity troponin T vs. a new generation high-sensitivity troponin I assay) [15], or two conventional (low sensitivity) assays [16]. In contrast, the superiority of high sensitivity over conventional assays has been documented in stable patients with chronic HF [15,17,18] or coronary artery DOI: 10.1097/MCA.0000000000000051
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Troponins and heart failure Latini and Masson 717
disease [19]. In conclusion, high-sensitivity cardiac troponin I and T may be considered superior to conventional reagents and equivalent in HF, in the absence of more definitive data.
Serial measurements of circulating troponin The threshold for detecting myocyte injury has been lowered and a new generation of highly sensitive troponin assays with a very low detection limit (in the range of few ng/l or lower) and good precision are now commercially available. A continuous release of minute amounts of cardiac troponins into the bloodstream is detectable with recent high-sensitivity reagents in almost all patients with stable chronic HF [15,17]. Elevation of circulating troponin levels relates to outcome in these patients, even within a range of concentrations not measurable previously with conventional assays. In two large and multicenter clinical trials (Val-HeFT and GISSI-HF), baseline concentration of troponin predicted adverse outcome (all-cause mortality or hospital admission for HF) in patients with stable HF with reduced left ventricular systolic function (Fig. 1) [17,20]. The prognostic value of troponin was independent of demographic and clinical variables, and showed an incremental prognostic accuracy even in the presence of the best current biomarker in HF, the natriuretic peptides [17]. There are only few data on the role of troponin in patients with chronic HF and preserved ejection fraction [21]. In summary, a single measurement of circulating troponin at any time during the natural progression of HF provides robust, independent prognostic information, irrespective of the clinical presentation (acute or chronic), etiology (ischemic or nonischemic), troponin form (I or T), and generation of reagents (traditional or high sensitivity). Patients with chronic HF manifest progression of disease over time. A simple circulating biomarker that could monitor this evolution would be highly desirable to help in their clinical management in and out of the hospital. For this reason, numerous studies have assessed the value of repeated measurements of troponin levels over time in community-dwelling older adults [22], in ambulatory patients with chronic HF [20,23,24], acute HF [25,26], or chest pain [27]. Although the analysis and interpretation of serial measurements and changes over time of biomarker concentrations are challenging and not easily comparable, most studies suggest that even small changes in troponin have prognostic significance and may help to identify patients at risk. However, the added value of serial measurements of troponin over a single determination (in particular the last available) or over other cardiac biomarkers (in particular natriuretic peptides) seems to be quite limited in several clinical contexts. The evidence available so far does not support serial measurement of troponins for risk stratification of patients with chronic HF until a full understanding of its implementation in clinical routine will be gained [28].
Natriuretic peptides and troponins: two cardiac markers with the same potential in chronic heart failure? High-sensitivity troponins and natriuretic peptides are independent and almost equipotent risk predictors in chronic HF when compared head to head [17,29–31]. Several studies have attempted to evaluate the added value of combining these two markers to improve their prognostic accuracy. In Val-HeFT, baseline high-sensitivity cardiac troponin T (hs-cTnT) showed a modest but significant incremental prognostic accuracy compared with brain natriuretic peptide (BNP) as estimated by increases in the likelihood ratio or C-index, two statistical metrics of discrimination [17]. In addition, changes over time of hs-cTnT concentration in Val-HeFT and in GISSIHF (respectively, 4000 and 1200 patients with both markers assayed) marginally improved patients’ reclassification (net reclassification improvement, an intuitive and meaningful measurement of the usefulness of new biomarkers) in models that included demographic and clinical variables, in addition to NT-proBNP [20]. Few investigators have evaluated the potential of combining the two cardiac markers in relevant cohorts of patients with chronic HF. The take-home message is that patients with both markers elevated have worse outcome than those with either one marker elevated [30,32]. In summary, for historical reasons, natriuretic peptides are still the benchmark biomarkers for risk prediction in chronic HF. High-sensitivity cardiac troponins are noninferior, and the combination of both markers does not provide remarkable improvements, although statistically significant. The choice of either marker is therefore influenced by other considerations, including technical and economical reasons.
Effect of therapy on troponin level, guided therapy, and stability of troponin in stable heart failure patients There are no published data on the use of cardiac troponin levels to guide patients’ treatment in HF, such as has been done with natriuretic peptides. The reason may be the lack of data on the effects of drug therapy of HF on circulating cardiac troponin levels, whereas several studies have documented such effects on natriuretic peptides. This is possibly an area of future research. In Val-HeFT, valsartan markedly decreased BNP and NT-proBNP, but it did not affect hs-cTnT concentrations over time (Roberto Latini and Serge Masson, unpublished data); this finding suggests that troponins may be less than optimal candidates for therapeutic guidance.
Prevention and monitoring of cardiac toxicity of anticancer agents The survival rate of cancer patients has increased significantly because of the considerable progresses of modern cancer therapy. However, a high price has been
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
718 Coronary Artery Disease 2013, Vol 24 No 8
must be highlighted. First, not all patients treated with chemotherapy require cardiac function monitoring as frequently as suggested by the guidelines; second, the value of this monitoring on the basis of serial evaluation of left ventricular ejection fraction seems to be neither sensitive nor specific enough to predict late declines in cardiac function.
Fig. 1
(a)
Val-HeFT
Hazard ratio (95% CI)
50
10 5
1 1
2
3
Hs-cTnT range (ng/l)
38
Although anthracyclines are among the most widely used chemotherapeutic agents associated with cardiac toxicity, other newer agents such as herceptin and trastuzumab also have cardiotoxic potential.
GISSI-HF
50 Hazard ratio (95% CI)
4
10 5
1 1
2
Hs-cTnT range (ng/l)
44
Crude hazard ratios and 95% confidence intervals (95% CI) for all-cause mortality by deciles of high-sensitivity cardiac troponin T (hs-cTnT) concentration at baseline in the Val-HeFT and GISSI-HF trials. The concentration range, absolute number of deaths, and death rate (%) are reported for each decile of hs-cTnT. Hazard ratios and 95% CIs are reported on a logarithmic scale. Number of patients per decile: B400 for Val-HeFT, and 120 for GISSI-HF. Interval of normality for hs-cTnT is
