Soluble ST2 in Ventricular Dysfunction

CHAPTER FOUR

Soluble ST2 in Ventricular Dysfunction Silvia Lupu*,†, Lucia Agoston-Coldea*,†,1 *Department of Cardiovascular Disease and Transplant Institute, University of Medicine and Pharmacy of Targu Mures, Targu Mures, Romania † Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania 1 Corresponding author: e-mail address: [email protected]

Contents 1. 2. 3. 4.

Introduction Biological Background and Function of ST2 sST2 in Experimental Observations ST2 in Clinical Studies 4.1 Diagnostic utility of ST2 and correlations to other markers of myocardial dysfunction 4.2 Prognostic utility of sST2 in cardiovascular disease 4.3 sST2 for monitoring response to therapy 4.4 sST2 in noncardiovascular disease 5. Future Perspectives 6. Conclusion References

140 141 142 144 145 147 149 149 152 153 153

Abstract Heart failure is a commonly encountered condition associated with increased morbidity, mortality, and healthcare cost. For years, its management has been strongly influenced by the use of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide biomarkers. In some cases, this approach does not always identify patients with heart failure accurately and may not provide the best prognostic assessment, particularly in the presence of comorbidities. Biomarkers that help refine diagnosis and risk stratification are needed. Soluble ST2, a peptide belonging to the interleukin-1 receptor family, is secreted when cardiomyocytes and cardiac fibroblasts are subjected to mechanical strain. Although preliminary results on this novel biomarker are encouraging, additional and more comprehensive studies are clearly needed to establish its role in the management of patients with heart failure. The purpose of this chapter is to provide an overview of data currently available.

Advances in Clinical Chemistry, Volume 69 ISSN 0065-2423 http://dx.doi.org/10.1016/bs.acc.2014.12.005

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2015 Elsevier Inc. All rights reserved.

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ABBREVIATIONS AP-1 activator protein 1 BNP B-type natriuretic peptide CLARITY-TIMI 28 Clopidogrel as Adjunctive Reperfusion Therapy - Thrombolysis In Myocardial Infarction 28 ENTIRE-TIMI 23 Enoxaparin and TNK-tPA with or Without GPIIb/IIIa Inhibitor as Reperfusion - Thrombolysis In Myocardial Infarction 23 ERK extracellular signal-regulated kinase GRACE-RS Global Registry of Acute Coronary Events Risk Scoring IKK inhibitor of kappa-B kinase IL-1 RAcP interleukin-1 receptor accessory protein IL-1 interleukin-1 IL-33 interleukin 33 IRAK-1/4 interleukin-1 receptor associated kinase LV left ventricle MAL My88 adaptor-like MERLIN-TIMI 36 Metabolic Efficiency with Ranolazine for Less Ischemia in Non-STElevation Acute Coronary Syndrome - Thrombolysis In Myocardial Infarction 36 MOCA multinational observational cohort on acute heart failure mRNA messenger ribonucleic acid MUSIC MUerte Subita en Insuficiencia Cardiaca MyD88 myeloid differentiation primary response gene 88 NF-kB nuclear factor kappa-light-chain enhancer of activated B cells Non-STEMI non-ST segment elevation myocardial infarction NT-proBNP N-terminal pro-B-type natriuretic peptide PHFS Penn Heart Failure Study PRAISE-2 Prospective Randomized Amlodipine Survival Evaluation-2 PRIDE Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department RV right ventricle sST2 soluble interleukin-1 receptor family member ST2L transmembrane isoform interleukin-1 receptor family member STEMI ST segment elevation myocardial infarction

1. INTRODUCTION Heart failure is a disabling condition reaching an estimated prevalence of 1–2% and is the main cause of morbidity and mortality in industrialized countries, significantly increasing healthcare costs across the Western world [1,2]. Even in developing countries, the incidence of heart failure is rising, affecting quality of life and survival rates [3]. Clinical symptoms of heart failure and cardiovascular events emerge as a consequence of cardiac remodeling [4,5], which involves alterations in heart cells and the extracellular matrix [6-9],

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including cell hypertrophy [10], myocyte apoptosis and necrosis [11-17], fibroblast proliferation and activation [18], ultimately leading to extensive fibrosis and myocardial dysfunction. For that reason, during the past two decades, the clinical management of heart failure has been greatly influenced by the use of stretch-induced biomarkers. Until recently, the B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NTproBNP) have been recognized as the only reliable markers for diagnostic and prognostic purposes in heart failure of various etiologies, although a plethora of potential biomarkers have also been identified [19-26]. Current heart failure guidelines recommend the use of BNP or NT-proBNP in clinical practice for diagnostic and prognostic purposes [2]. However, the concentrations of BNP and NT-proBNP can be influenced by individual factors such as age and sex [27-29], as well as by renal function [30,31], body mass index [32], thyroid function [33], and anemia [31], which implies that other biomarkers are required in order to correctly identify patients with heart failure. Among possible contenders that may become heart failure biomarkers, soluble interleukin-1 receptor family member (sST2) has become a hot topic and has been studied in both experimental [34-36] and clinical settings [37-39], providing interesting results. sST2 is a multifunctional biomarker, involved in ventricular mechanical stress [40,41] and ventricular remodeling which contributes to ventricle fibrosis, hypertrophy [34], inflammation [42], and eventually, to ventricular dysfunction. sST2 is secreted by cardiomyocytes and myocardial fibroblasts as a response to ventricular wall stretch and was shown to elevate in a number of cardiovascular conditions, such as acute and chronic heart failure [43-48], pulmonary artery hypertension [49-52], or ischemic heart disease [53-55]. This chapter summarizes current data regarding sST2 as a marker of ventricular dysfunction. In addition, most relevant information available about sST2 biology, generated by both in vivo and in vitro research, is discussed in the context of heart failure.

2. BIOLOGICAL BACKGROUND AND FUNCTION OF ST2 ST2 is a peptide belonging to the interleukin-1 (IL-1) receptor family [56], which is secreted when cardiomyocytes and cardiac fibroblasts are subjected to mechanical strain [41] under three main primary isoforms, a transmembrane isoform (ST2L) [34,57], a secreted soluble (sST2) form [57], and a variant form interleukin-1 receptor family member, which is expressed in the gastrointestinal tract (stomach, small intestine, and colon) [58], each regulated by different promoters that induce differential

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messenger ribonucleic acid (mRNA) expression [57]. The transmembrane isoform is membrane-bound, having three extracellular immunoglobulin G domains, one transmembrane, and an intracellular SIR domain resembling toll-like receptors and other interleukin-1 receptors [34,57]. The transmembrane isoform is mostly expressed by cardiomyocytes and cardiac fibroblasts, as well as by some type 2 T helper lymphocytes and mast cells [41,57,59,60]. sST2 lacks the transmembrane and the intracellular domains, but closely resembles the extracellular region of ST2L [57], only having nine additional amino acids on the C terminus of the molecule [61]. sST2 travels freely in the blood stream, acting as a decoy receptor for interleukin 33 (IL-33) and preventing it from binding to ST2L [34,62]. The three isoforms are produced by 30 splicing of the primary transcript of the ST2 gene [63], which is placed on chromosome 2q11.2, as part of the IL-1 gene cluster [64]. The transcription of both isoforms in response to mechanical strain in cardiomyocytes and cardiac fibroblasts [41] mediates myocyte hypertrophy and cardiac fibrosis [34], a process that involves ST2L, sST2, and their ligand—IL-33 [34,35]. IL-33 is a member of the IL-1 family which also includes IL-1α, IL-1β, and interleukin 18 [35]. IL-33 mARN is expressed by several types of cells such as smooth muscle cells, epithelial cells, fibroblasts, keratinocytes, dendritic cells, and activated macrophages, which makes it available in a broad range of tissues, including the myocardium [35]. IL-33 is produced as pro-IL-33, which is already biologically active [36] and increases its potency 10-fold after being cleaved by elastase and cathepsin G [65]. By contrast, cleavage by caspase-1 dampens the effects of IL-33 [36] although it was initially thought to be an activating factor [66,67]. The activity of the IL-33/ST2L complex also requires the binding of a coreceptor—IL-1 Receptor Accessory Protein (IL-1 RAcP) [68-70], further regulating inflammation via the nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) pathway [71,72]. Experimental evidence showed, however, that IL-33 was more likely to dampen inflammation rather than favor it, and, consequently, exerted a protective role [71,72]. Figure 1 provides a graphical representation of the IL-33 and ST2L interaction.

3. sST2 IN EXPERIMENTAL OBSERVATIONS Experimental data have shed some light on pathophysiological mechanisms behind cardiac remodeling that involve ST2 and IL-33. The research conducted by Sanada et al. [34] on ST2/ mice whose hearts

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Cardiac fibroblast

Cardiac myocyte sST2

Elastase CathepsinG ST2L

Pro IL33

IL33

MyD88/MAL

AP-1

IL-1RAcP

IRAK -1 & 4 sST2

IL33

ERK TRAF6

Proinflammatory mediators

IKK mRNA Binding of IL-33 by sST2 prevents its interactional with ST2L, leading To cellular hypertrophy, apoptosis, necrosis and fibrosis

NF-kB

Extracellular

Inflammatory gene expression

sST2 increases cardiac remodeling

Figure 1 IL-33 binds to ST2L, reducing myocardial fibrosis and hypertrophy via the NF-kB pathway. The activity of the IL-33/ST2L complex requires the binding of a coreceptor (IL-1 RAcP), which contains a Toll interleukin receptor domain involved in intracellular signaling. The MyD88 adaptor protein is further recruited and NF-kB is activated via IRAK-1 and -4 and TRAF6, leading to the production of inflammatory mediators. sST2 acts as a decoy receptor and prevents IL-33 from binding to ST2L, thus dampening its cardioprotective effects. Abbreviations: sST2, soluble interleukin-1 receptor family member; ST2L, transmembrane isoform interleukin-1 receptor family member; IL-33, interleukin 33; IL-1RAcP, interleukin-1 receptor accessory protein; NF-kB, nuclear factor kappa-light-chain enhancer of activated B cells; MyD88, myeloid differentiation primary response gene 88; MAL, My88 adaptor-like; IRAK, interleukin-1 receptor associated kinase; TRAF6, TNF (tumor necrosis factor) receptor associated factor 6; ERK, extracellular signal-regulated kinase; IKK, inhibitor of kappa-B kinase; AP-1, activator protein 1; mRNA, messenger ribonucleic acid.

were exposed to pressure overload by transverse aortic constriction provided tantalizing evidence of the complex role of IL-33 and ST2 in heart disease. The authors showed that, despite the fact that IL-33 activated NF-kB in both cardiac myocytes and fibroblasts, it dampened the direct effect of angiotensin II and phenylephrine on NF-kB activation, an effect which was more obvious in cardiac myocytes and only transitory in cardiac fibroblasts. Moreover, the activation of NF-kB via IL-33 was quite mild and overrun by the inhibiting effect of IL-33 on other NF-kB activators, thus limiting inflammation and cardiac hypertrophy as a response to

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pressure overload. Accordingly, unlike their wild-type littermates, ST2/ mice had more marked ventricular hypertrophy and poorer systolic function and failed to respond to therapy with purified recombinant IL-33. Interestingly, the induction of sST2 secretion limited the protective effect of IL-33/ST2L signaling, leading to the conclusion that sST2 acts as a decoy receptor [34] and has deleterious effects on cardiovascular functions. Other researchers reported similar results. For instance, Miller et al. [73] conducted a study on apo-E/ mice which were fed a high-fat diet, showing that the development of aortic atherosclerotic plaques was significantly diminished after treatment with IL-33 and increased when sST2 was administered. Also, in another study, IL-33 was shown to exert a protective role on the endothelium through nitric oxide production, thus inducing angiogenesis and increased vascular permeability [74]. Moreover, other researchers provided evidence that IL-33 exerted its antiinflammatory effect in genetically obese mice which lost significant amounts of weight after being treated with IL-33 [75]. In another study, the cardioprotective effects of IL-33/ST2L were studied in myocardial ischemia, both in vitro, on cultured myocardial cells, and in vivo, after coronary artery ligation in mice, showing positive results [76]. In vitro, IL-33 was shown to reduce apoptosis in cardiac myocytes, an effect which was dampened by administering sST2. In vivo, wild-type mice recovered better after myocardial infarction when treated with IL-33, while their ST2/ littermates failed to respond to therapy [76]. In conclusion, experimental data have led to several valid facts, particularly that the IL-33/ST2L signaling system has a protective role, limiting cardiac remodeling, and that sST2 acts as a decoy receptor that binds IL-33 and prevents it from exerting beneficial effects after binding on ST2L. Evidence from clinical studies seems to concur with these findings.

4. ST2 IN CLINICAL STUDIES sST2-related clinical studies were conducted on patients with acute or chronic heart failure, ischemic heart disease, or pulmonary hypertension and attempted to explore the diagnostic and prognostic ability of this biomarker by resorting to comparisons with previously acknowledged biomarkers of myocardial stretch or damage. Also, some researchers studied correlations to imaging parameters as well as possible confounders.

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4.1 Diagnostic utility of ST2 and correlations to other markers of myocardial dysfunction Currently, data regarding the diagnostic utility of ST2 are quite scarce, and research is hindered by the presence of possible confounders yet to be identified and the lack of standardized reference values in the normal population. 4.1.1 ST2 in normal populations Until now, Dieplinger et al. reported reference intervals of 4–31 ng/mL in males and 2–21 ng/mL in females in an Austrian population of healthy individuals [77], while higher values of 8.6–49.3 ng/mL in males and 7.2–33.5 ng/mL in females were determined in an American population, despite using the same assay for analysis [78]. The American authors attributed these differences to possibly unidentified heart disease in their cohort of asymptomatic patients, acknowledging the fact that they did not determine the concentrations of other biomarkers such as BNP, calcitonin, C-reactive protein, or interleukin 6 when selecting individuals for their study, unlike the Austrian authors. Interestingly, in their study, ST2 concentrations did not show any significant variation according to age [78]. 4.1.2 Correlations to clinical factors and other biomarkers Regarding patients with heart disease, the diagnostic ability of ST2 remains to be established. Results from the Pro-Brain natriuretic Peptide Investigation of Dyspnea in the Emergency Department (PRIDE) study showed that sST2 concentrations were considerably higher in patients with acute heart failure than in healthy subjects, but NT-proBNP was superior in term of diagnostic abilities [44]. One recent study explored the utility of sST2 in 59 patients with idiopathic or heritable pulmonary artery hypertension who were under 16 years of age when diagnosed. In these patients, sST2 concentrations correlated well with heart failure symptoms severity as assessed by the New York Heart Association class and provided prognostic significance, as further discussed in this chapter [50]. Interesting results have been published regarding patients with coronary artery disease. In a study on 373 patients presenting with either ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (non-STEMI), or stable angina, the highest concentrations of sST2 were observed in patients with STEMI, while patients with non-STEMI had significantly higher values than patients with stable angina and normal controls. Interestingly, IL-33 concentrations were not different between the

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four groups but were considerably higher in women and nonsmokers. A positive significant correlation was observed between sST2 concentrations and serum creatinine, although other cardiovascular risk factors did not seem to be correlated with increased sST2 concentrations [79]. By contrast, in a group of patients with non-STEMI, patients with higher sST2 concentrations were more likely to be male, elderly (75 years of age), and have associated conditions such as diabetes mellitus or dyslipidemia. They were also more likely to have impaired renal function, as assessed by the glomerular filtration rate [55]. In this latter study, sST2 was only moderately correlated to troponin and BNP. This finding is consistent with results from other studies. In fact, in most studies on patients with acute heart failure or acute coronary syndromes, sST2 concentrations were only modestly correlated to BNP or NT-proBNP [43,44,80] in patients with both preserved and diminished ejection fraction [80,81]. 4.1.3 Correlations to imaging parameters Some researchers attempted to establish correlations between sST2 concentrations and imaging parameters. For instance, Shah et al. conducted a study on patients presenting with acute dyspnea, 66% of which had dyspnea due to cardiac causes and established correlations between sST2 concentrations and echocardiographic indices of left and right heart dysfunction. Accordingly, sST2 concentrations were shown to correlate directly with higher left ventricle (LV) end-systolic area and volume and higher right ventricle (RV) systolic pressure, more severe tricuspid regurgitation, and a higher frequency of RV hypokinesis, and inversely correlated to LV ejection fraction and RV fractional area change [82]. A significant negative, although weak, correlation to LV ejection fraction, as assessed by echocardiography, was also reported in another research [43]. Similar findings were reported by Manzano-Fernandez et al. who reported slightly higher values of sST2 in patients with systolic heart failure versus patients with preserved ejection fraction [81]. By contrast, Pascual-Figal et al. did not find any statistically significant correlation between sST2 and LV ejection fraction in patients with acutely decompensated heart failure [80]. A cardiac magnetic resonance imaging-based study on patients with acute myocardial infarction and depressed LV ejection fraction (<40%) provided some interesting results, showing that sST2 concentrations increased significantly with infarct size, as assessed by the infarct volume index, correlated with the endomyocardial extent of the infarction and were higher in case of greater infarct

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transmurality, and when microvascular obstruction was present; also, sST2 concentrations correlated inversely with LV ejection fraction. These correlations were obvious at the baseline and persisted after 24 weeks of followup [83]. Other imaging-based studies reported correlations between right chamber parameters and sST2 concentrations. In a study on patients with secondary pulmonary hypertension due to chronic obstructive pulmonary disease, sST2 concentrations were significantly correlated to pulmonary artery pressure and showed an inverse relationship with RV fractional area change, RV ejection fraction, and tricuspid annular plane systolic excursion [84]. Correlations to right chambers’ dimensions also emerged from another study in which patients with increased sST2 concentrations were more likely to have enlarged right (and not left) chambers and higher RV systolic pressures, but that particular population included patients randomly referred for echocardiography, for various reasons [85]. Therefore, these latter results should be interpreted with caution.

4.2 Prognostic utility of sST2 in cardiovascular disease Most sST2-related studies explored the prognostic utility of this biomarker, often comparing it or using it in combination with other biomarkers, particularly the already acknowledged BNP and NT-proBNP. Therefore, data regarding patients with various conditions, such as acute and chronic heart failure, acute myocardial infarction, and pulmonary hypertension, are already beginning to pool. 4.2.1 Short-term outcomes In a cohort of 295 acute heart failure patients, sST2 failed to show a satisfactory predictive value, when used individually to predict mortality at 5–30 days and did not add prognostic utility to NT-proBNP [86]. Results regarding short-term outcomes in acute coronary syndromes are, however, more promising. Data from the Enoxaparin and TNK-tPA with or Without GPIIb/IIIa Inhibitor as Reperfusion-Thrombolysis In Myocardial Infarction 23 (ENTIRE-TIMI 23) trials showed that sST2 was increased early and rose within the first day after acute myocardial infarction, reaching a maximum at 12 h. Increased baseline sST2 concentrations predicted worse outcome due to death or new onset of heart failure in the first 30 days [87]. Kohli et al. also confirmed that increased sST2 concentrations were associated with higher risk of heart failure within 30 days after a non-STEMI, despite having found weak correlations between sST2 and other biomarkers of acute injury and myocardial stress; the increased risk for heart failure

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persisted at 1 year [55], which is consistent with the results reported by Eggers et al. [54]. In another study focused on patients with ST segment elevation myocardial infarction recruited from the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28) trial, increased sST2 concentrations were also associated with higher 30-days cardiovascular mortality and risk of heart failure, independently of baseline characteristics. Predictive power was significantly improved when taking into account both sST2 and NT-proBNP [37]. 4.2.2 Long-term outcomes In the long run, sST2 concentrations assessment has proven more useful, particularly if used in combination with other biomarkers. In the PRIDE study, higher sST2 concentrations strongly predicted 1-year mortality in patients with all-cause dyspnea and in acute heart failure patients. Moreover, the combined use of both sST2 and NT-proBNP identified patients with the highest risk of death [23]. Similar results were derived from MUSIC (MUerte Subita en Insuficiencia Cardiaca) registry data, supporting the combined use of NT-proBNP and sST2 for assessing the risk of sudden cardiac death in patients with heart failure [80]. Although both sST2 and NT-proBNP showed rather low sensitivity and specificity (83% vs. 72% and 51% vs. 73%, respectively) when used separately, risk stratification was considerably improved when both biomarkers were taken into account. Consequently, 71% of the patients in whom both biomarkers were over the established cut-off values experienced sudden cardiac death within the 3 years of follow-up, while only 4% of the patients who had low values of both biomarkers died. These findings are consistent with results from other studies [43]. For instance, Ky et al. demonstrated a considerably higher risk of death and transplantation in chronic heart failure patients with very increased sST2 concentrations (>36.3 ng/mL), particularly if NT-proBNP was also increased [38]. In addition to that, Daniels et al. assessed mortality at 1 year in outpatients referring for an echocardiogram. In their study, when a single marker was increased, the risk of death was 2.6 times greater than in individuals with normal values and increased to 5.5 times if both biomarkers were increased [85]. Moreover, Rehman et al. proved that sST2 had a 96% negative predictive value for 1-year mortality in patients with acute heart failure [43]. Interestingly, in a series of patients with acute dyspnea and preserved LV ejection fraction, sST2 concentrations predicted 1-year mortality independently after multivariate analysis, while NT-proBNP did not [88]. Also, increased sST2 concentrations were shown to predict

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1-year mortality in acute destabilized heart failure, independently of several confounding factors such as advanced age, renal dysfunction, impaired LV ejection fraction, or NYHA class [89]. In a subseries of patients with NYHA III/IV heart failure from the Prospective Randomized Amlodipine Survival Evaluation-2 (PRAISE-2) study, the change in sST2 concentrations predicted subsequent mortality or transplantation independently of other biomarkers such as BNP and proatrial natriuretic peptide [90]. Moreover, in another study on young patients with idiopathic or heritable pulmonary artery hypertension which were followed up for a median period of 23 months, increased sST2 (cut-off value 11.1 ng/mL) had a significantly good relation to mortality (AUC ¼ 0.803), overrunning other markers of myocardial stress or damage such as NT-proBNP, human heart fatty acid-binding protein, or high-sensitivity troponin T; as in the previously mentioned conditions, the prognosis was particularly grim if both sST2 and NT-proBNP were above cut-off values [50]. An overview on the current research on sST2 as a prognostic factor is presented in Table 1.

4.3 sST2 for monitoring response to therapy The ability of sST2 for monitoring response to therapy is still open for debate, as evidence regarding this particular subject is inconclusive. In the study by Weir et al. eplerenone had no significant impact on sST2 concentrations over time [83]. Also, neither treatment with ranolazine in patients recruited in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 36 (MERLIN-TIMI 36) trial [55] nor the administration of amlodipine in the PRAISE-2 study [90] did not influence sST2 concentrations.

4.4 sST2 in noncardiovascular disease Although the results of previously mentioned studies support the use of sST2 in the management of cardiovascular disease, particularly for prognostic purposes, sST2 was also shown to be significantly increased in other diseases, such as acute asthma [95] rheumatoid arthritis [96], lupus erythematosus [97], inflammatory bowel disease [98], other autoimmune diseases [99], or sepsis [100]; in the latter condition, increased sST2 concentrations predicted higher mortality rates [100,101]. Interestingly, Dieplinger et al. also reported modest increases in sST2 concentrations in patients with heart failure, while

Table 1 Clinical studies assessing the prognosis ability of sST2 Number of Study Population patients Study focus

Endpoints

Follow-up

References

ENTIRETIMI 23

Acute myocardial infarction

810

Short-term prognosis

Death; death/heart failure combined

30 days

Shimpo et al. [87]

CLARITYTIMI 28

Acute myocardial infarction

1239

Short-term prognosis

Cardiovascular death; heart failure

30 days

Sabatine et al. [37]

MERLINTIMI 36

Acute myocardial infarction

4426

Short- (30 days) and long-term prognosis (1 year)

Cardiovascular death/heart failure combined; cardiovascular death; allcause death; sudden cardiac death; heart failure—individually

1 year

Kohli et al. [55]

GRACE-RS Acute myocardial infarction

577

Long-term prognosis

Major cardiac events (death, heart failure readmission, and reinfarction combined)

532 days

Dhillon et al. [91]

Not applicable

1345 Stable coronary artery disease

Long-term prognosis

All-cause mortality

9.8 years

Dieplinger et al. [53]

PRIDE

Acute heart failure

593

Long-term prognosis

Mortality

1 year

Januzzi et al. [44]

MOCA

Acute heart failure

728

Short- (30 days) and long- (1 year) term prognosis

Mortality

1 year

Lassus et al. [92]

STRATIFY

Acute heart failure

295

Short-term prognosis

Readmissions for heart failure

30 days

HenryOkafor et al. [86]

Veteran Affairs Med

Acute heart failure

150

Medium-term prognosis

Mortality

90 days

Boisot et al. [93]

PRIDE

Acute dyspnoea

134

Long-term prognosis

Mortality

4 years

Shah et al. [82]

Not applicable

Acute heart failure

346

Long-term prognosis

Mortality

1 year

Rehman et al. [43]

Not applicable

Acute heart failure

447

Long-term prognosis

Mortality

1 year

ManzanoFerna´ndez et al. [81]

MUSIC

Chronic systolic heart failure

36

Long-term prognosis

Sudden cardiac death

3 years

Pascual-Figal et al. [80]

CORONA

Chronic heart failure

1449

Medium-term prognosis

Death due to worsening heart failure; 3 months hospitalization due to worsening heart failure; hospitalization due to any cardiovascular cause

Broch et al. [94]

PHFS

Chronic heart failure

1141

Long-term prognosis

Death and cardiac transplantation combined

Ky et al. [38]

2.8 years

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patients with pneumonia and chronic obstructive pulmonary disease had moderately increased concentrations of sST2; sST2 concentrations were particularly high in patients with sepsis [77]. Accordingly, when other inflammatory states are suspected, sST2 concentrations should be interpreted with caution and not attributed to cardiovascular disease alone.

5. FUTURE PERSPECTIVES The National Institutes of Health defined the term biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological process, pathogenic process, or pharmacological response to a therapeutic intervention” [102]. Accordingly, biomarkers should be useful for diagnostic purposes, as well as for clinical decision making, monitoring response to therapy, or predicting patient outcomes, provided that sensitivity and specificity are high enough and the means for accurate measurements are available. Although the management of heart failure has been greatly influenced by the measurement of BNP and NT-proBNP, these biomarkers are not infallible and have been shown to be altered by other conditions than heart failure [27-31]. Also, among patients with heart failure, the evolution of the disease and the response to treatment are variable, leading to very different outcomes, which may be influenced by the pathological cause of heart failure, pathophysiological characteristics (e.g., systolic vs. diastolic ventricular dysfunction), and the acuity and severity of heart failure. Under these circumstances, a multimarker strategy may be useful in refining risk stratification among patients with heart failure. As mentioned previously, data regarding the use of sST2 in clinical settings are beginning to pool and research in this field is now facilitated by the fact that accurate immunoassay techniques are available for measurement and have obtained regulatory approval for clinical use [77]. In this context, the potential utility of sST2 is increasing, as clinical studies provide results that endorse the role of this biomarker for diagnosis and outcome assessment in a broader demographic of patients. Interestingly, in a population of healthy subjects [103], increased concentrations of sST2 predicted future heart failure, even when adjusted for other novel and established biomarkers and clinical variables. Moreover, in the study by Bayes-Genis et al. sST2 was proved to be superior to galectin-3 for risk stratification in patients with chronic heart failure [104]. Also, in another study on patients with chronic heart failure, sST2 added independent prognostic information to clinical

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variables and NT-proBNP, while growth differentiation factor-15 and highly sensitive troponin T did not [46]. Moreover, preliminary data suggest that sST2 measurement may help to guide antiventricular remodeling therapy in order to prevent heart failure complications [83]. In addition to that, the analysis of data from large trials such as CLARITY-TIMI 28 [37], MERLIN-TIMI 36 [55], the PRIDE study [23], or MUSIC registry [80] supports the combined use of sST2 and BNP or NT-proBNP for risk stratification. Even in randomly selected patients presenting for echocardiographic assessment, patients with increased concentrations of both sST2 and NT-proBNP carried a 2.6-fold higher risk of 1-year mortality compared to patients in which a single marker was increased, and a 5.5-fold higher risk compared to patients with neither marker increased [85]. Based on the currently available research, the 2013 ACC/AHA Guideline for the Management of Heart Failure [105] states that sST2 is “not only predictive of hospitalization and death in patients with heart failure but also additive to natriuretic peptide concentrations in [its] prognostic value.” This recommendation is given the highest level of evidence (A).

6. CONCLUSION Research on sST2 shows promising results regarding its clinical use in providing prognostic information in patients with heart failure, particularly if used in a multimarker approach, together with BNP and NT-proBNP. Regarding the ability of sST2 to diagnose heart failure, results are conflicting and hindered by the fact that sST2 is increased in other proinflammatory states such as autoimmune disease or sepsis. Moreover, normal value intervals have not yet been established. In addition to that, research on the value of sST2 for monitoring the response to therapy is necessary and currently scarce. If future research covers the current gaps in evidence, sST2 may become an acknowledged biomarker of heart failure and help improve patient management.

REFERENCES [1] A. Mosterd, A.W. Hoes, Clinical epidemiology of heart failure, Heart 93 (2007) 1137–1146. [2] J.J. McMurray, S. Adamopoulos, S.D. Anker, et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur. Heart J. 33 (2012) 1787–1847.

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