Invited critical reviewSoluble ST2 in heart failure
Introduction
Heart failure (HF) is a complex clinical syndrome that results from structural or functional impairment of ventricular filling or ejection of blood. The main cardinal symptoms of HF are dyspnea and fatigue. There is no single diagnostic test for HF because it is largely a clinical diagnosis based on a careful history and physical examination [1], [2]. Current HF guidelines recommend the measurement of natriuretic peptides for the diagnosis of heart failure. Further, measurement of natriuretic peptides and cardiac troponin is useful for establishing prognosis or disease severity in patients with HF [1], [2]. In addition, other biomarkers are gaining attention for their utility in HF management. Among them, soluble ST2 (sST2) a novel biomarker integrating inflammation, fibrosis, and cardiac stress has been included in the 2013 ACCF/AHA guideline for additive risk stratification of patients with HF [2].
Comprehensive reviews on sST2 in different human diseases have recently been published elsewhere [3], [4], [5], [6], [7]. Blood concentrations of sST2 are increased in inflammatory and in heart diseases and are considered a valuable prognostic marker in both conditions as shown in Table 1 [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153]. In multiple clinical trials, sST2 has emerged as a clinically useful prognostic biomarker in patients with cardiovascular diseases, including myocardial infarction [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], acute dyspnea [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], and heart failure (HF) [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93]. Interestingly, sST2 even provides prognostic information in a low-risk community-based population [148].
In this review, the role of sST2 as a HF biomarker will be discussed, specifically addressing analytical considerations of measuring sST2 as well as the clinical applications of measurement of sST2 for the diagnosis, prognosis and monitoring of acute and chronic HF.
Section snippets
Biology of sST2
In 1989, ST2, an interleukin-1 (IL-1) receptor family member, was first identified by two independent laboratories working on growth stimulated fibroblasts [154], [155]. Located on chromosome 2 the human ST2 gene is known to encode at least three isoforms by alternative promotor splicing — a membrane bound receptor ST2L; a secreted soluble form sST2; and a variant form STV (which is predominantly expressed in the gastrointestinal tract).
Interleukin-33 (IL-33), the functional ligand for ST2L,
Analytical considerations of sST2
The first enzyme-linked immunosorbent assay for the measurement of sST2 in human serum/plasma was constructed in 2000 [158]. Since then, several in-house assays and commercially available assays have been described in the literature. As shown in Table 2, mainly three commercially available assays (ELISAs) have been used to determine circulating sST2 concentrations in published clinical studies; the Presage ST2 assay (Critical Diagnostics, San Diego, CA, USA), the MBL ST2 assay (Medical &
Clinical applications of sST2 measurement in cardiac disease
The use of sST2 as a potential biomarker for cardiac disease was first highlighted in 2002 by the finding that sST2 mRNA was highly induced in cultured rat cardiomyocytes following mechanical strain or treatment with IL-1β, and that sST2 concentrations were transiently increased in the blood of mice following myocardial infarction [48]. Research in animal models of cardiac overload and myocardial infarction has further reported that the IL-33/ST2L signaling axis is a mechanical responsive
sST2 and diagnosis of HF
The diagnostic value of sST2 for HF was first evaluated in the PRIDE study in 593 patients presenting to the emergency department with acute dyspnea [10]. Even though circulating sST2 concentrations were higher in patients with acute HF compared to dyspnea due to non-cardiac causes, sST2 was not a valuable tool for the diagnosis of HF.
In a similar study in 251 patients presenting to an emergency department with acute dyspnea, we examined several biomarkers including sST2 for the diagnosis of HF
sST2 in acute HF
As summarized in Table 3, there are several outcome studies on acute HF patients assessing the prognostic value of sST2 [10], [11], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69].
The results of the studies on acute HF patients demonstrated that sST2 measured on hospital admission is strongly associated with the measures of HF severity and poor outcome [10], [11], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69]. sST2 provided independent and additive prognostic information
sST2 in chronic HF
In chronic HF, elevated concentrations of sST2 are strongly associated with measures of HF severity, increased risk of death or cardiac transplantation, sudden cardiac death, cardiovascular events, as well as cardiac hospitalization as outlined in Table 3 [70], [71], [72], [74], [77], [78], [79], [80], [81], [82], [84], [85], [86], [87], [88], [89], [90], [91], [92].
A large multi-center study on ambulatory chronic patients with increased sST2 at baseline had markedly increased risk of death or
sST2 and monitoring of HF
In Table 2 several studies on serial measurements of sST2 for outcome prediction in HF patients are shown [62], [63], [67], [69], [71], [81], [88], [90]. In the first study on sST2 in chronic HF patients, changes in sST2 over two weeks were an independent predictor of a composite of all-cause mortality and cardiac transplantation, indicating that serial measurements of sST2 might be use full for outcome prediction in HF [71].
Further, it has been demonstrated in hospitalized patients with acute
Conclusions and future perspectives
As summarized in Table 1, sST2 concentrations are increased in various diseases such as inflammatory disease and heart disease [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69],
Financial & competing interests disclosure
Dr. Dieplinger and Dr. Mueller declared no competing interests.
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