REVIEW URRENT C OPINION
Emerging biomarkers for acute heart conditions Vlad C. Vasile a,b and Allan S. Jaffe a,b
Purpose of review Acute cardiac conditions such as acute myocardial infarction and heart failure are associated with significant morbidity and mortality. Rapid diagnosis allows risk stratification and initiation of treatment in a timely manner. Numerous novel biomarkers have been identified to predict outcomes. These may assist in tailoring of appropriate therapy to high-risk patients. Recent findings This study reviews several novel biomarkers – galectin-3, ST2 and copeptin. The scope of this review is to identify and underline the clinical aspects of these emerging biomarkers. Summary Galectin-3 is an active biomarker found in inflammatory and fibrotic processes, and is a marker of mortality. ST2 is released by stressed cardiac myocytes and also predicts mortality in heart failure and myocardial infarction. Copeptin is a stable arginine vasopressin precursor associated with increased risk of heart failure. It may also be useful to exclude acute myocardial infarction. Keywords acute coronary syndromes, copeptin, galectin-3, heart failure, ST2
INTRODUCTION Despite a modest decrease in the prevalence of coronary artery disease (CAD) in the last decade, cardiovascular disease still accounts for as much as 15% of deaths [1]. Biomarkers and imaging have improved the diagnosis and treatment of patients with acute ischemic heart disease and heart failure [2–4,5 ,6 ,7]. A variety of novel biomarkers have recently been introduced [8–17]. They may improve identification of patients with heart failure and lowrisk patients who can leave the emergency department expeditiously, reducing overcrowding [18]. Currently, cardiac troponin (cTn) is accepted universally as the biomarker of choice for the diagnosis of myocardial infarction (MI) [2–4]. The recent introduction of high-sensitivity troponin (hscTn) assays will improve the early diagnosis and triage of patients with chest pain presenting acutely [19]. The new assays detect low cTn concentrations in significantly more individuals than in general population without cardiovascular disease [20–22]. However, there is still controversy regarding the optimal reference values to use with hscTn assays. Even values below the 99th percentile upper reference limit, which is the cutoff value used to diagnose acute MI (AMI), may still be indicative of cardiovascular comorbidities [20,23,24], including heart failure [25]. In fact, most patients with acute heart &
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failure will have elevations of hscTn. It is conceivable that eventually a combination of hscTn and natriuretic peptides will be used to define acute heart failure [26]. There is a need for novel biomarkers to aid in the more rapid diagnosis and management of patients with acute coronary syndromes (ACS), and to augment the use of hscTn and natriuretic peptides in the development and prediction of outcomes in patients with heart failure. The purpose of this review is to evaluate the current evidence regarding a few of these emerging biomarkers for cardiovascular disease, with a focus on ACS and heart failure. We will discuss galectin-3, ST2 and copeptin as novel candidates. Intrinsic to this evaluation are the proposed criteria from the American Heart Association for the use of new techniques [27] (Table 1).
a
Division of Cardiovascular Diseases, Department of Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA b
Correspondence to Allan S. Jaffe, MD, Cardiovascular Division, Gonda 5, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 507 284 3680; fax: +1 507 266 0228; e-mail: [email protected] Curr Opin Cardiol 2014, 29:312–318 DOI:10.1097/HCO.0000000000000077 Volume 29 Number 4 July 2014
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Emerging biomarkers for acute heart conditions Vasile and Jaffe
KEY POINTS Galectin-3 is associated with both inflammation and fibrosis processes, and is a biomarker of cardiovascular mortality. ST2 is a marker of stress, and it has shown utility in predicting mortality in patients with heart failure and myocardial infarction. Copeptin is a stable arginine vasopressin precursor and is associated with mortality and events in heart failure. There is controversy about its role in the early triage of patients with chest pain in the emergency department.
GALECTIN-3 Galectins belong to the lectin family. Lectins bind to b-galactosides through evolutionary conserved sequences and contain carbohydrate recognition domains. Galectin-3 contains proline-rich and glycine-rich N-terminal domains which make it able to oligomerize, that is, combine with other molecules. Galectin-3 is ubiquitously expressed and it is present both in the cytoplasm, nucleus and outside cells. It is thought that galectin-3 stimulates collagen production and hypertrophy as appropriate responses to injury. Galectin-3 also mediates cell–cell and cell–extracellular matrix adhesion, cell growth and differentiation, cell cycle regulation, apoptosis, angiogenesis, tumor genesis, tumor growth, metastasis and immune reactions [28–30]. Galectin-3 is implicated in cardiac remodeling which occurs in response to acute insults such as AMI and cardiomyopathies, and can lead to chronic heart failure [31]. This process involves dilatation of the heart that leads to increased wall stress, which reduces subendocardial blood flow; the process can
cycle on itself leading to heart failure [32]. Fibroblasts and myofibroblasts are recruited to remove the damaged tissue and to initiate the deposition of collagen precursors into the extracellular matrix to heal the area. This leads to myocardial fibrosis, which is thought to require the release of galectin-3 from macrophages. Galectin-3 is upregulated in all situations in which macrophages are activated in response to cardiac injury [33], such as in murine models of heart failure, interferon-6-induced active myocarditis, cardiomyopathy and hypertension. An early increase in galectin-3 expression is associated with the hypertrophic response [34]. In patients with aortic stenosis undergoing valve replacement, those with a depressed ejection fraction have increased galectin-3 expression compared with those who remain compensated [33]. Experimental infusion of galectin-3 in the pericardium of normal rats leads to excessive fibrosis [33,35]. Fibrosis can have detrimental effects on cardiac performance by increasing myocardial stiffness and reducing the normal hypertrophic response. Elevated galectin-3 may identify individuals who are prone to an excessive response and adverse outcomes. This response may be systemic and not simply local, such that cardiac fibrosis may lead to renal fibrosis and vice versa. In healthy individuals, galectin-3 has a normal distribution with a reference interval of 3.8–21.0 ng/ml [36]. Statistically significant differences occur with age, sex, diabetes, hypertension, hypercholesterolemia, increased BMI, renal dysfunction and smoking status [37]. The reference change variation and index of individuality is 39% (hourly) and 61% (weekly) and 1.0 (hourly and weekly) [38]. Galectin-3 values do not change markedly over time. The Prevention of Renal and Vascular Endstage Disease Intervention (PREVEND) study of post-MI patients supports this supposition
Table 1. American Heart Association recommendations for reporting novel risk biomarkers 1.
Report basic study design and outcomes.
2.
Report level of standard of risk factors and the result of risk model using established factors.
3.
Evaluate the novel marker in the population and report the following: relative risk, odds ratio or hazard ratio conveyed by the novel marker alone, and after statistical adjustment for established risk factors, with associated confidence intervals and P value, as well as the P value for addition of the novel biomarker to a model that contains the standard risk markers.
4.
Report the discrimination of the new marker: C index and its confidence interval for model with established risk factors and including the novel marker, as well as integrated discrimination index, discrimination slope or R2 for the model with and without the novel biomarker.
5.
Report of accuracy for the new biomarker: display observed versus expected event rates across the range of predicted risk for models with and without the novel risk biomarker, as well as the number of subjects reclassified and the event rate in the reclassified category using generally recognized risk thresholds.
Adapted with permission from [27]. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
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and demonstrates that patients in the highest quintile of galectin-3 (median 15.6 ng/ml) had a 15% 10-year mortality rate compared with a 5% rate for those in the lowest quartile (median 7.7 ng/ml) [39 ]. In the Framingham Offspring Cohort of 3353 participants, galectin-3 was not significant for increased left ventricular mass after multivariate analysis [37]. Nonetheless, galectin-3 was associated with an increased risk of incident heart failure [hazard ratio 1.28 per 1 SD increase in log galectin-3, 95% confidence interval (CI) 1.14– 1.43; P < 0.0001], which remained significant after adjustment for clinical variables including B-type natriuretic peptide (BNP; hazard ratio 1.23, 95% CI 1.04–1.47; P ¼ 0.02). Galectin-3 was also associated with risk of all-cause mortality (multivariableadjusted hazard ratio 1.15, 95% CI 1.04–1.28; P ¼ 0.01). In the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 (PROVEIT-TIMI 22) trial, patients who developed heart failure after ACS had higher baseline galectin-3 concentrations (median 16.7 ng/l [25th–75th percentile 14.0–20.6] versus 14.6 ng/l [12.0–17.6]; P ¼ 0.004) [40]. Patients with a baseline galectin-3 concentration above the median had an odds ratio (OR) of 2.1 (95% CI 1.2–3.6) for heart failure (P ¼ 0.010). Galectin-3 values showed a graded relationship with the risk of heart failure. These patients were more likely to have hypertension, diabetes, prior MI and prior heart failure, but galectin-3 remained significant even after adjustment (adjusted OR 1.4, 95% CI 1.1–1.9; P ¼ 0.020). Galectin-3 median and interquartile ranges were 9.2 (7.4–12.1) in patients with heart failure and 6.9 (5.2–8.7) in patients without. Compared with N-terminal prohormone of BNP (NT-proBNP) and all clinical data available in those studies, the elevated concentration of galectin-3 was the best independent predictor of 60-day mortality (OR 10.3; P < 0.01) and 60-day death or recurrent heart failure (OR 14.3; P < 0.001) [41]. Galectin-3 was also found to have prognostic value in patients with dyspnea [42]. The Community Outreach and Cardiovascular Health (COACH) study showed higher values were independent predictors of heart failure, rehospitalization and death [43], particularly in patients with preserved ejection fraction. The Deventer–Alkmaar Heart Failure Clinic (DEAL-HF) study showed an increased risk of mortality with high galectin-3 concentration [44], which was also associated with heart failure severity [45 ], all-cause mortality and poor renal function [46]. Modest evidence suggests that galectin-3 might be beneficial for targeting treatment to high-risk patients with heart failure [35,47,48]. Importantly, data from COACH and the N-terminal &
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Pro-BNP Investigation of Dyspnea in the Emergency department (PRIDE) trials suggest the elevated galectin-3 values identify patients at high risk for readmission [43,41]. Changes in galectin-3 of 15% or more identified a particularly high-risk group. This change in galectin-3 is within conjoint analytic and biological variation, and thus is likely to be simply a spontaneous change. Although there appears to be prognostic values to galectin-3 in those with heart failure, the diagnosis of acute heart failure relies on echocardiography and NT-proBNP which are superior [41]. Integration of galectin-3 in the clinical practice of patients with heart failure has been suggested by some authors [49,50] who have argued that given the relationship of galectin-3 to fibrosis, aldosterone antagonists might be uniquely valuable in those with elevated values. Data to support this reasonable speculation are not presently available.
ST2 ST2 belongs to the Toll-like and interleukin 1 receptor family characterized by extracellular leucine-rich repeat motifs and represented by the receptors TLR-1–12 [51,52]. Interleukin 33 (IL33) is an ST2 ligand with multiple roles. ST2 is a specific cellular marker which may differentiate Th2 from Th1 cells [53]. The ST2 or IL33 exists in two main isoforms resulting from alternative splicing: ST2L which is a transmembrane component and a circulating isoform sST2. It is thought that IL33 binds to the transmembrane form to downregulate hypertrophy and fibrosis. The soluble sST2 by binding to IL33 in the circulation acts as a decoy-binding receptor, reducing the availability of IL33 to bind to the ligand receptor and enhancing Th2-mediated inflammation, permitting increased fibrosis and hypertrophy. Elevated levels of sST2 are associated with inflammatory conditions [54–57]. Biomechanical strain of cardiomyocytes leads to increased levels of both IL33 and sST2. Increased IL33 may have cardioprotective effects – reduced fibrosis and hypertrophy, preserved ejection fraction and improved survival [58,59]. IL33 expression reduces the degree of hypertrophy and fibrosis in vivo [59]. However, high levels of sST2 blunt this protective response. There are sex differences of ST2 levels in normal individuals, but the biological variation is modest. The initial clinical use of sST2 was part of the PRIDE study; sST2 concentrations were higher in patients with acute decompensated heart failure compared with those with other causes of dyspnea [60]. The marker was less useful for the diagnosis of heart failure when compared to NT-proBNP; Volume 29 Number 4 July 2014
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however, sST2 had more predictive value [61]. ST2 is a strong predictor of mortality in patients with dyspnea, particularly in those with preserved ejection fraction [62]. Elevated sST2 concentrations may predict sudden cardiac death in patients with chronic heart failure and provide complementary information to NT-proBNP levels [63]. Short-term variation of ST2 is correlated with long-term mortality in patients with heart failure [64]. Eplerenone Post-acute myocardial infarction Heart Failure Efficacy and Survival (EPHESUS) trial suggests that elevated ST2 values are a predictor of patients with heart failure who will benefit from aldosterone blockade [65]. Eplerenone attenuates remodeling in patients with a higher baseline values of ST2, implying that ST2 predicts not only outcomes, but also which category of patients are more likely to benefit from intervention [66]. Moreover, sST2 measurement is useful to identify patients with chronic heart failure who may particularly benefit from higher beta-blocker doses [67]. In experimental models of acute MI, sST2 is upregulated [68]. Elevated sST2 levels correlate with increased 30-day mortality after adjusting for risk factors [69]. sST2 levels correlated with impaired epicardial coronary flow and with subsequent risk of cardiovascular death and heart failure [70]. Patients with ST elevation myocardial infarction (STEMI) and a low Thrombolysis In Myocardial Infarction (TIMI)-risk score who were in the highest quartile of sST2 and NTpro-BNP serum levels manifested a 6.6-fold increased risk of cardiovascular death or heart failure at 30-day follow-up. In patients with a high TIMI-risk score, those in the highest quartile of baseline sST2 and NTpro-BNP levels had an approximately 25-fold increased risk [71]. Receiver Operating Characteristics analysis of ST2 in patients with dyspnea showed an area under the curve of 0.74 and a 1-year mortality if ST2 was increased greater than 0.2 ng/ml, independently of the presence of acute heart failure [61]. Further studies have confirmed a correlation of mortality with ST2 [72]. ST2 is also prognostic in patients with non-STEMI [73,74]. ST2 may predict future development of heart failure in community cohorts [75 ]. The proper use of ST2 remains to be defined. The data for this marker are just beyond stage 4 American Heart Association guidelines. Data on how to specifically respond to elevated levels therapeutically remain to be elaborated. &&
COPEPTIN Copeptin is a stable arginine vasopressin (AVP) precursor which is cleaved from the vasopressin-copeptin precursor peptide prior to release from the
hypothalamo-pituitary axis in response to hypovolemia, hyponatremia or low serum osmolality [76,77]. Copeptin is the C-terminal part of the preprohormone and is released in stoichiometric concentrations with AVP. It has actions similar to AVP, but unlike AVP, copeptin is stable at room temperature and easily measurable [78]. Copeptin appears to be useful for many diagnoses such as diabetes insipidus or posterior pituitary disturbances [79], shock, sepsis and heart failure [80–84] because it is an acute-phase reactant. Copeptin has a prominent place in the National Institute of Health Stroke Scale (NIHSS) score [85], and correlates with the severity of traumatic brain injury [86] and hematoma volume in intracerebral hemorrhages [87]. Copeptin is a promising biomarker in cardiovascular disease [88]; a combination of copeptin levels less than 14 pmol/l and cTn levels less than 0.01 mg/l ruled out MI, with a negative predictive value (NPV) of 99.7% and high sensitivity (98.8%) [89]. Several studies have reported a sensitivity and NPV approximating 100% when in combined copeptin and hscTn approach triaging chest pain in the ED [90,91 ]. However, not all studies have been positive [92]. In healthy individuals, the median value of copeptin is 4.2 pmol/l (range 1–13.8 pmol/l) [78]. Copeptin levels are influenced by sex and renal function [93]. Copeptin concentrations are higher in AMI than in unstable angina [94]. Copeptin rises more rapidly than cTn. cTn peaks are discernable as early as 2–3 h after the onset of symptoms [32,95]. Copeptin reaches the plateau concentrations by 4–6 h, then it declines slowly but remains detectable for 3–5 days [96,97]. Higher levels of copeptin correlate with ECG changes in patients with chest pain [94]. Copeptin levels correlate with non-STEMI diagnosis and subsequent risk [97], likely because of the worsening of the outcome of the Global Registry of Acute Coronary Events (GRACE) score [98]. The Biomarker in Cardiology-8 (BIC-8) study [99 ] showed that instant early ruleout using both cTn and copeptin in low-to-intermediate risk patients with suspected ACS presenting to the ED was safe for patients to be discharged home. The process was effective as 66% of patients tested for both biomarkers were discharged from the ED compared with only 12% in a single conventional biomarker testing approach. However, 50% of those who had AMI did not manifest elevations of copeptin and were observed in the ED, suggesting that the success of that strategy was related largely to clinical judgment and not to biomarker. In addition, the group chosen for this strategy was a very low-risk group with an event rate of approximately 5%. This
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is common in some EDs but not in many others. The paucity of elevations also suggests that most acutely ill patients were not enrolled. In patients with heart failure following MI, elevations of copeptin are associated with a worse prognosis [100–103]. Copeptin correlates with the heart failure stage as well [104]. Patients with elevated copeptin levels might benefit from early treatment with AVP V2 receptor antagonists – vaptans [105–107]. Vaptans control symptoms but do not reduce mortality in patients with heart failure [81,108]. Copeptin can be used as a predictor of mortality in heart failure populations similarly to other established biomarkers [109,110], although a multibiomarker approach provides more benefit than each marker alone [88,110,111].
CONCLUSION Galectin-3 levels are elevated in patients with chronic heart failure, both with preserved and reduced ejection fraction, as well as in acute heart failure, hypertrophic hearts and aortic stenosis. Galectin-3 has a high predictive value for short-term and long-term mortality, and exhibits additive value to BNP in patients with heart failure. sST2 level in patients presenting to ED with symptoms suggestive of ACS or heart failure provide useful prognostic information. sST2 could potentially be used in a multibiomarker approach along with established biomarkers such as BNP. Copeptin can be used to identify patients at high cardiovascular risk. Copeptin provides diagnostic information in ACS, especially with a multibiomarker approach. At this time, there is controversy over whether it has a role in the evaluation of chest pain patients and particularly in the exclusion of AMI. Acknowledgements None. Conflicts of interest V.C.V. – none; A.S.J. has consulted for most of the major diagnostic companies.
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Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction. Circulation 2008; 117:1936–1944. 72. Rehman SU, Mueller T, Januzzi JL Jr. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol 2008; 52:1458–1465. 73. Eggers KM, Armstrong PW, Califf RM, et al. ST2 and mortality in non-STsegment elevation acute coronary syndrome. Am Heart J 2010; 159:788–794. 74. Kohli P, Bonaca MP, Kakkar R, et al. Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial. Clin Chem 2012; 58:257– 266. 75. Wang TJ, Wollert KC, Larson MG, et al. Prognostic utility of novel biomarkers && of cardiovascular stress: the Framingham Heart Study. Circulation 2012; 126:1596–1604. 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Clinical trials 85. De Marchis GM, Katan M, Weck A, et al. Copeptin and risk stratification in patients with ischemic stroke and transient ischemic attack: the CoRisk study. Int J Stroke 2013; 8:214–218. 86. Kleindienst A, Brabant G, Morgenthaler NG, et al. Following brain trauma, copeptin, a stable peptide derived from the AVP precusor, does not reflect osmoregulation but correlates with injury severity. Acta Neurochir Suppl 2010; 106:221–224. 87. Zweifel C, Katan M, Schuetz P, et al. Copeptin is associated with mortality and outcome in patients with acute intracerebral hemorrhage. BMC Neurol 2010; 10:34. 88. Khan SQ, Dhillon OS, O’Brien RJ, et al. C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study. Circulation 2007; 115:2103–2110. 89. Giannitsis E, Kehayova T, Vafaie M, Katus HA. Combined testing of highsensitivity troponin T and copeptin on presentation at prespecified cutoffs improves rapid rule-out of non-ST-segment elevation myocardial infarction. Clin Chem 2011; 57:1452–1455. 90. Lotze U, Lemm H, Heyer A, Muller K. Combined determination of highly sensitive troponin T and copeptin for early exclusion of acute myocardial infarction: first experience in an emergency department of a general hospital. Vasc Health Risk Manag 2011; 7:509–515. 91. Ray P, Charpentier S, Chenevier-Gobeaux C, et al. Combined copeptin and & troponin to rule out myocardial infarction in patients with chest pain and a history of coronary artery disease. Am J Emerg Med 2012; 30:440–448. For patients with acute chest pain lasting for less than 6 h and a previous history of CAD, the combination of a normal copeptin and normal cTn allows for ruling out AMI, with a negative predictive value greater than 95%. 92. Karakas M, Januzzi JL Jr, Meyer J, et al. Copeptin does not add diagnostic information to high-sensitivity troponin T in low- to intermediate-risk patients with acute chest pain: results from the rule out myocardial infarction by computed tomography (ROMICAT) study. Clin Chem 2011; 57:1137– 1145. 93. Bhandari SS, Loke I, Davies JE, et al. Gender and renal function influence plasma levels of copeptin in healthy individuals. Clin Sci (Lond) 2009; 116:257–263. 94. Reichlin T, Hochholzer W, Stelzig C, et al. Incremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Coll Cardiol 2009; 54:60– 68. 95. Melanson SE, Morrow DA, Jarolim P. Earlier detection of myocardial injury in a preliminary evaluation using a new troponin I assay with improved sensitivity. Am J Clin Pathol 2007; 128:282–286. 96. Peacock WF. Will SCUBE1 solve the ischemia marker deficit? J Am Coll Cardiol 2008; 51:2181–2183. 97. Gu YL, Voors AA, Zijlstra F, et al. Comparison of the temporal release pattern of copeptin with conventional biomarkers in acute myocardial infarction. Clin Res Cardiol 2011; 100:1069–1076.
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Volume 29 Number 4 July 2014
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Emerging biomarkers for acute heart conditions Vlad C. Vasile a,b and Allan S. Jaffe a,b
Purpose of review Acute cardiac conditions such as acute myocardial infarction and heart failure are associated with significant morbidity and mortality. Rapid diagnosis allows risk stratification and initiation of treatment in a timely manner. Numerous novel biomarkers have been identified to predict outcomes. These may assist in tailoring of appropriate therapy to high-risk patients. Recent findings This study reviews several novel biomarkers – galectin-3, ST2 and copeptin. The scope of this review is to identify and underline the clinical aspects of these emerging biomarkers. Summary Galectin-3 is an active biomarker found in inflammatory and fibrotic processes, and is a marker of mortality. ST2 is released by stressed cardiac myocytes and also predicts mortality in heart failure and myocardial infarction. Copeptin is a stable arginine vasopressin precursor associated with increased risk of heart failure. It may also be useful to exclude acute myocardial infarction. Keywords acute coronary syndromes, copeptin, galectin-3, heart failure, ST2
INTRODUCTION Despite a modest decrease in the prevalence of coronary artery disease (CAD) in the last decade, cardiovascular disease still accounts for as much as 15% of deaths [1]. Biomarkers and imaging have improved the diagnosis and treatment of patients with acute ischemic heart disease and heart failure [2–4,5 ,6 ,7]. A variety of novel biomarkers have recently been introduced [8–17]. They may improve identification of patients with heart failure and lowrisk patients who can leave the emergency department expeditiously, reducing overcrowding [18]. Currently, cardiac troponin (cTn) is accepted universally as the biomarker of choice for the diagnosis of myocardial infarction (MI) [2–4]. The recent introduction of high-sensitivity troponin (hscTn) assays will improve the early diagnosis and triage of patients with chest pain presenting acutely [19]. The new assays detect low cTn concentrations in significantly more individuals than in general population without cardiovascular disease [20–22]. However, there is still controversy regarding the optimal reference values to use with hscTn assays. Even values below the 99th percentile upper reference limit, which is the cutoff value used to diagnose acute MI (AMI), may still be indicative of cardiovascular comorbidities [20,23,24], including heart failure [25]. In fact, most patients with acute heart &
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failure will have elevations of hscTn. It is conceivable that eventually a combination of hscTn and natriuretic peptides will be used to define acute heart failure [26]. There is a need for novel biomarkers to aid in the more rapid diagnosis and management of patients with acute coronary syndromes (ACS), and to augment the use of hscTn and natriuretic peptides in the development and prediction of outcomes in patients with heart failure. The purpose of this review is to evaluate the current evidence regarding a few of these emerging biomarkers for cardiovascular disease, with a focus on ACS and heart failure. We will discuss galectin-3, ST2 and copeptin as novel candidates. Intrinsic to this evaluation are the proposed criteria from the American Heart Association for the use of new techniques [27] (Table 1).
a
Division of Cardiovascular Diseases, Department of Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA b
Correspondence to Allan S. Jaffe, MD, Cardiovascular Division, Gonda 5, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 507 284 3680; fax: +1 507 266 0228; e-mail: [email protected] Curr Opin Cardiol 2014, 29:312–318 DOI:10.1097/HCO.0000000000000077 Volume 29 Number 4 July 2014
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Emerging biomarkers for acute heart conditions Vasile and Jaffe
KEY POINTS Galectin-3 is associated with both inflammation and fibrosis processes, and is a biomarker of cardiovascular mortality. ST2 is a marker of stress, and it has shown utility in predicting mortality in patients with heart failure and myocardial infarction. Copeptin is a stable arginine vasopressin precursor and is associated with mortality and events in heart failure. There is controversy about its role in the early triage of patients with chest pain in the emergency department.
GALECTIN-3 Galectins belong to the lectin family. Lectins bind to b-galactosides through evolutionary conserved sequences and contain carbohydrate recognition domains. Galectin-3 contains proline-rich and glycine-rich N-terminal domains which make it able to oligomerize, that is, combine with other molecules. Galectin-3 is ubiquitously expressed and it is present both in the cytoplasm, nucleus and outside cells. It is thought that galectin-3 stimulates collagen production and hypertrophy as appropriate responses to injury. Galectin-3 also mediates cell–cell and cell–extracellular matrix adhesion, cell growth and differentiation, cell cycle regulation, apoptosis, angiogenesis, tumor genesis, tumor growth, metastasis and immune reactions [28–30]. Galectin-3 is implicated in cardiac remodeling which occurs in response to acute insults such as AMI and cardiomyopathies, and can lead to chronic heart failure [31]. This process involves dilatation of the heart that leads to increased wall stress, which reduces subendocardial blood flow; the process can
cycle on itself leading to heart failure [32]. Fibroblasts and myofibroblasts are recruited to remove the damaged tissue and to initiate the deposition of collagen precursors into the extracellular matrix to heal the area. This leads to myocardial fibrosis, which is thought to require the release of galectin-3 from macrophages. Galectin-3 is upregulated in all situations in which macrophages are activated in response to cardiac injury [33], such as in murine models of heart failure, interferon-6-induced active myocarditis, cardiomyopathy and hypertension. An early increase in galectin-3 expression is associated with the hypertrophic response [34]. In patients with aortic stenosis undergoing valve replacement, those with a depressed ejection fraction have increased galectin-3 expression compared with those who remain compensated [33]. Experimental infusion of galectin-3 in the pericardium of normal rats leads to excessive fibrosis [33,35]. Fibrosis can have detrimental effects on cardiac performance by increasing myocardial stiffness and reducing the normal hypertrophic response. Elevated galectin-3 may identify individuals who are prone to an excessive response and adverse outcomes. This response may be systemic and not simply local, such that cardiac fibrosis may lead to renal fibrosis and vice versa. In healthy individuals, galectin-3 has a normal distribution with a reference interval of 3.8–21.0 ng/ml [36]. Statistically significant differences occur with age, sex, diabetes, hypertension, hypercholesterolemia, increased BMI, renal dysfunction and smoking status [37]. The reference change variation and index of individuality is 39% (hourly) and 61% (weekly) and 1.0 (hourly and weekly) [38]. Galectin-3 values do not change markedly over time. The Prevention of Renal and Vascular Endstage Disease Intervention (PREVEND) study of post-MI patients supports this supposition
Table 1. American Heart Association recommendations for reporting novel risk biomarkers 1.
Report basic study design and outcomes.
2.
Report level of standard of risk factors and the result of risk model using established factors.
3.
Evaluate the novel marker in the population and report the following: relative risk, odds ratio or hazard ratio conveyed by the novel marker alone, and after statistical adjustment for established risk factors, with associated confidence intervals and P value, as well as the P value for addition of the novel biomarker to a model that contains the standard risk markers.
4.
Report the discrimination of the new marker: C index and its confidence interval for model with established risk factors and including the novel marker, as well as integrated discrimination index, discrimination slope or R2 for the model with and without the novel biomarker.
5.
Report of accuracy for the new biomarker: display observed versus expected event rates across the range of predicted risk for models with and without the novel risk biomarker, as well as the number of subjects reclassified and the event rate in the reclassified category using generally recognized risk thresholds.
Adapted with permission from [27]. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
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Clinical trials
and demonstrates that patients in the highest quintile of galectin-3 (median 15.6 ng/ml) had a 15% 10-year mortality rate compared with a 5% rate for those in the lowest quartile (median 7.7 ng/ml) [39 ]. In the Framingham Offspring Cohort of 3353 participants, galectin-3 was not significant for increased left ventricular mass after multivariate analysis [37]. Nonetheless, galectin-3 was associated with an increased risk of incident heart failure [hazard ratio 1.28 per 1 SD increase in log galectin-3, 95% confidence interval (CI) 1.14– 1.43; P < 0.0001], which remained significant after adjustment for clinical variables including B-type natriuretic peptide (BNP; hazard ratio 1.23, 95% CI 1.04–1.47; P ¼ 0.02). Galectin-3 was also associated with risk of all-cause mortality (multivariableadjusted hazard ratio 1.15, 95% CI 1.04–1.28; P ¼ 0.01). In the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 (PROVEIT-TIMI 22) trial, patients who developed heart failure after ACS had higher baseline galectin-3 concentrations (median 16.7 ng/l [25th–75th percentile 14.0–20.6] versus 14.6 ng/l [12.0–17.6]; P ¼ 0.004) [40]. Patients with a baseline galectin-3 concentration above the median had an odds ratio (OR) of 2.1 (95% CI 1.2–3.6) for heart failure (P ¼ 0.010). Galectin-3 values showed a graded relationship with the risk of heart failure. These patients were more likely to have hypertension, diabetes, prior MI and prior heart failure, but galectin-3 remained significant even after adjustment (adjusted OR 1.4, 95% CI 1.1–1.9; P ¼ 0.020). Galectin-3 median and interquartile ranges were 9.2 (7.4–12.1) in patients with heart failure and 6.9 (5.2–8.7) in patients without. Compared with N-terminal prohormone of BNP (NT-proBNP) and all clinical data available in those studies, the elevated concentration of galectin-3 was the best independent predictor of 60-day mortality (OR 10.3; P < 0.01) and 60-day death or recurrent heart failure (OR 14.3; P < 0.001) [41]. Galectin-3 was also found to have prognostic value in patients with dyspnea [42]. The Community Outreach and Cardiovascular Health (COACH) study showed higher values were independent predictors of heart failure, rehospitalization and death [43], particularly in patients with preserved ejection fraction. The Deventer–Alkmaar Heart Failure Clinic (DEAL-HF) study showed an increased risk of mortality with high galectin-3 concentration [44], which was also associated with heart failure severity [45 ], all-cause mortality and poor renal function [46]. Modest evidence suggests that galectin-3 might be beneficial for targeting treatment to high-risk patients with heart failure [35,47,48]. Importantly, data from COACH and the N-terminal &
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Pro-BNP Investigation of Dyspnea in the Emergency department (PRIDE) trials suggest the elevated galectin-3 values identify patients at high risk for readmission [43,41]. Changes in galectin-3 of 15% or more identified a particularly high-risk group. This change in galectin-3 is within conjoint analytic and biological variation, and thus is likely to be simply a spontaneous change. Although there appears to be prognostic values to galectin-3 in those with heart failure, the diagnosis of acute heart failure relies on echocardiography and NT-proBNP which are superior [41]. Integration of galectin-3 in the clinical practice of patients with heart failure has been suggested by some authors [49,50] who have argued that given the relationship of galectin-3 to fibrosis, aldosterone antagonists might be uniquely valuable in those with elevated values. Data to support this reasonable speculation are not presently available.
ST2 ST2 belongs to the Toll-like and interleukin 1 receptor family characterized by extracellular leucine-rich repeat motifs and represented by the receptors TLR-1–12 [51,52]. Interleukin 33 (IL33) is an ST2 ligand with multiple roles. ST2 is a specific cellular marker which may differentiate Th2 from Th1 cells [53]. The ST2 or IL33 exists in two main isoforms resulting from alternative splicing: ST2L which is a transmembrane component and a circulating isoform sST2. It is thought that IL33 binds to the transmembrane form to downregulate hypertrophy and fibrosis. The soluble sST2 by binding to IL33 in the circulation acts as a decoy-binding receptor, reducing the availability of IL33 to bind to the ligand receptor and enhancing Th2-mediated inflammation, permitting increased fibrosis and hypertrophy. Elevated levels of sST2 are associated with inflammatory conditions [54–57]. Biomechanical strain of cardiomyocytes leads to increased levels of both IL33 and sST2. Increased IL33 may have cardioprotective effects – reduced fibrosis and hypertrophy, preserved ejection fraction and improved survival [58,59]. IL33 expression reduces the degree of hypertrophy and fibrosis in vivo [59]. However, high levels of sST2 blunt this protective response. There are sex differences of ST2 levels in normal individuals, but the biological variation is modest. The initial clinical use of sST2 was part of the PRIDE study; sST2 concentrations were higher in patients with acute decompensated heart failure compared with those with other causes of dyspnea [60]. The marker was less useful for the diagnosis of heart failure when compared to NT-proBNP; Volume 29 Number 4 July 2014
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Emerging biomarkers for acute heart conditions Vasile and Jaffe
however, sST2 had more predictive value [61]. ST2 is a strong predictor of mortality in patients with dyspnea, particularly in those with preserved ejection fraction [62]. Elevated sST2 concentrations may predict sudden cardiac death in patients with chronic heart failure and provide complementary information to NT-proBNP levels [63]. Short-term variation of ST2 is correlated with long-term mortality in patients with heart failure [64]. Eplerenone Post-acute myocardial infarction Heart Failure Efficacy and Survival (EPHESUS) trial suggests that elevated ST2 values are a predictor of patients with heart failure who will benefit from aldosterone blockade [65]. Eplerenone attenuates remodeling in patients with a higher baseline values of ST2, implying that ST2 predicts not only outcomes, but also which category of patients are more likely to benefit from intervention [66]. Moreover, sST2 measurement is useful to identify patients with chronic heart failure who may particularly benefit from higher beta-blocker doses [67]. In experimental models of acute MI, sST2 is upregulated [68]. Elevated sST2 levels correlate with increased 30-day mortality after adjusting for risk factors [69]. sST2 levels correlated with impaired epicardial coronary flow and with subsequent risk of cardiovascular death and heart failure [70]. Patients with ST elevation myocardial infarction (STEMI) and a low Thrombolysis In Myocardial Infarction (TIMI)-risk score who were in the highest quartile of sST2 and NTpro-BNP serum levels manifested a 6.6-fold increased risk of cardiovascular death or heart failure at 30-day follow-up. In patients with a high TIMI-risk score, those in the highest quartile of baseline sST2 and NTpro-BNP levels had an approximately 25-fold increased risk [71]. Receiver Operating Characteristics analysis of ST2 in patients with dyspnea showed an area under the curve of 0.74 and a 1-year mortality if ST2 was increased greater than 0.2 ng/ml, independently of the presence of acute heart failure [61]. Further studies have confirmed a correlation of mortality with ST2 [72]. ST2 is also prognostic in patients with non-STEMI [73,74]. ST2 may predict future development of heart failure in community cohorts [75 ]. The proper use of ST2 remains to be defined. The data for this marker are just beyond stage 4 American Heart Association guidelines. Data on how to specifically respond to elevated levels therapeutically remain to be elaborated. &&
COPEPTIN Copeptin is a stable arginine vasopressin (AVP) precursor which is cleaved from the vasopressin-copeptin precursor peptide prior to release from the
hypothalamo-pituitary axis in response to hypovolemia, hyponatremia or low serum osmolality [76,77]. Copeptin is the C-terminal part of the preprohormone and is released in stoichiometric concentrations with AVP. It has actions similar to AVP, but unlike AVP, copeptin is stable at room temperature and easily measurable [78]. Copeptin appears to be useful for many diagnoses such as diabetes insipidus or posterior pituitary disturbances [79], shock, sepsis and heart failure [80–84] because it is an acute-phase reactant. Copeptin has a prominent place in the National Institute of Health Stroke Scale (NIHSS) score [85], and correlates with the severity of traumatic brain injury [86] and hematoma volume in intracerebral hemorrhages [87]. Copeptin is a promising biomarker in cardiovascular disease [88]; a combination of copeptin levels less than 14 pmol/l and cTn levels less than 0.01 mg/l ruled out MI, with a negative predictive value (NPV) of 99.7% and high sensitivity (98.8%) [89]. Several studies have reported a sensitivity and NPV approximating 100% when in combined copeptin and hscTn approach triaging chest pain in the ED [90,91 ]. However, not all studies have been positive [92]. In healthy individuals, the median value of copeptin is 4.2 pmol/l (range 1–13.8 pmol/l) [78]. Copeptin levels are influenced by sex and renal function [93]. Copeptin concentrations are higher in AMI than in unstable angina [94]. Copeptin rises more rapidly than cTn. cTn peaks are discernable as early as 2–3 h after the onset of symptoms [32,95]. Copeptin reaches the plateau concentrations by 4–6 h, then it declines slowly but remains detectable for 3–5 days [96,97]. Higher levels of copeptin correlate with ECG changes in patients with chest pain [94]. Copeptin levels correlate with non-STEMI diagnosis and subsequent risk [97], likely because of the worsening of the outcome of the Global Registry of Acute Coronary Events (GRACE) score [98]. The Biomarker in Cardiology-8 (BIC-8) study [99 ] showed that instant early ruleout using both cTn and copeptin in low-to-intermediate risk patients with suspected ACS presenting to the ED was safe for patients to be discharged home. The process was effective as 66% of patients tested for both biomarkers were discharged from the ED compared with only 12% in a single conventional biomarker testing approach. However, 50% of those who had AMI did not manifest elevations of copeptin and were observed in the ED, suggesting that the success of that strategy was related largely to clinical judgment and not to biomarker. In addition, the group chosen for this strategy was a very low-risk group with an event rate of approximately 5%. This
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is common in some EDs but not in many others. The paucity of elevations also suggests that most acutely ill patients were not enrolled. In patients with heart failure following MI, elevations of copeptin are associated with a worse prognosis [100–103]. Copeptin correlates with the heart failure stage as well [104]. Patients with elevated copeptin levels might benefit from early treatment with AVP V2 receptor antagonists – vaptans [105–107]. Vaptans control symptoms but do not reduce mortality in patients with heart failure [81,108]. Copeptin can be used as a predictor of mortality in heart failure populations similarly to other established biomarkers [109,110], although a multibiomarker approach provides more benefit than each marker alone [88,110,111].
CONCLUSION Galectin-3 levels are elevated in patients with chronic heart failure, both with preserved and reduced ejection fraction, as well as in acute heart failure, hypertrophic hearts and aortic stenosis. Galectin-3 has a high predictive value for short-term and long-term mortality, and exhibits additive value to BNP in patients with heart failure. sST2 level in patients presenting to ED with symptoms suggestive of ACS or heart failure provide useful prognostic information. sST2 could potentially be used in a multibiomarker approach along with established biomarkers such as BNP. Copeptin can be used to identify patients at high cardiovascular risk. Copeptin provides diagnostic information in ACS, especially with a multibiomarker approach. At this time, there is controversy over whether it has a role in the evaluation of chest pain patients and particularly in the exclusion of AMI. Acknowledgements None. Conflicts of interest V.C.V. – none; A.S.J. has consulted for most of the major diagnostic companies.
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