Background-We identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes and hypothesized that ST2 participates in the acute myocardial response to stress and injury. Methods and Results-ST2 mRNA was induced in cardiac myocytes by mechanical strain (4.7Ϯ0.9-fold) and interleukin-1␤ (2.0Ϯ0.2-fold). Promoter analysis revealed that the proximal and not the distal promoter of ST2 is responsible for transcriptional activation in cardiac myocytes by strain and interleukin-1␤. In mice subjected to coronary artery ligation, serum ST2 was transiently increased compared with unoperated controls (20.8Ϯ4.4 versus 0.8Ϯ0.8 ng/mL, PϽ0.05). Soluble ST2 levels were increased in the serum of human patients (Nϭ69) 1 day after myocardial infarction and correlated positively with creatine kinase (rϭ0.41, PϽ0.001) and negatively with ejection fraction (Pϭ0.02). Conclusions-These data identify ST2 release in response to myocardial infarction and suggest a role for this innate immune receptor in myocardial injury.

Background-Using genomic technology, we previously identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes. The soluble receptor form of ST2 is secreted and detectable in human serum. This study tested the hypothesis that soluble ST2 levels in the serum of patients with severe chronic heart failure are increased in patients with neurohormonal activation. Methods and Results-Serum samples, clinical variables, and neurohormone levels from the PRAISE-2 heart failure trial (NYHA functional class III-IV; end point, mortality or transplantation) were analyzed. ST2 serum measurements were performed with ELISA on samples from 161 patients obtained at trial enrollment and from 139 of the same patients obtained 2 weeks after trial enrollment. Baseline ST2 levels were correlated with baseline B-type natriuretic peptide (BNP) levels (rϭ0.36, PϽ0.0001), baseline proatrial natriuretic peptide (ProANP) levels (rϭ0.36, PϽ0.0001), and baseline norepinephrine levels (rϭ0.39, PϽ0.0001). The change in ST2 was significant as a univariate predictor of subsequent mortality or transplantation (Pϭ0.048), as was baseline BNP (PϽ0.0001) and baseline ProANP (PϽ0.0001). In multivariate models including BNP and ProANP, the change in ST2 remained significant as a predictor of mortality or transplantation independent of BNP and ProANP. Conclusions-Serum soluble ST2 is a novel biomarker for neurohormonal activation in patients with heart failure. In patients with severe chronic NYHA class III to IV heart failure, the change in ST2 levels is an independent predictor of subsequent mortality or transplantation.

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