Independent Prognostic Value of Serum Soluble ST2 Measurements in Patients With Heart Failure and a Reduced Ejection Fraction in the PARADIGM-HF Trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure).
O'Meara Eileen,Prescott Margaret F,Claggett Brian,Rouleau Jean L,Chiang Lu-May,Solomon Scott D,Packer Milton,McMurray John J V,Zile Michael R
Circulation. Heart failure
BACKGROUND:Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined. METHODS AND RESULTS:Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes (=0.001, 0.012, and 0.009 for the 3 outcomes, respectively). CONCLUSIONS:Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT01035255.
10.1161/CIRCHEARTFAILURE.117.004446
Establishment of reference intervals for soluble ST2 from a United States population.
Lu Jun,Snider James V,Grenache David G
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:Soluble ST2 (sST2) is a protein in the interleukin-1 receptor family secreted by myocytes in response to mechanical strain. Elevated sST2 is strongly prognostic in patients with heart failure. METHODS:sST2 was measured using the Presage ST2 ELISA. Evaluation included imprecision, linearity, recovery, analytical sensitivity, limit of quantification, stability, and sample type comparisons. Gender-specific reference intervals were established from 245 male and 245 female serum specimens. RESULTS:At sST2 concentrations of 11.6, 26.9, and 88.0 ng/mL, the within-day CV was 7.6, 2.4, and 3.8%, respectively and the total CV was 11.5, 14.0, and 6.3%, respectively. The assay was linear over a concentration range of 2.8-161.1 ng/mL (y=0.95x+2.25; R(2)=0.997; Sy.x=3.03). The limit of quantification was 3.3 ng/mL. sST2 was stable for 2 days at room temperature, 10days at 4 °C, and 30 days at -20 °C. Concentrations of sST2 were significantly higher in males compared to females (24.9 vs. 16.9 ng/mL; p<0.0001) but were not correlated by age in either gender (r=-0.07; p=0.14). Reference intervals for sST2 were determined to be 8.6-49.3 and 7.2-33.5 ng/mL for males and females, respectively. CONCLUSION:The Presage ST2 ELISA had acceptable performance characteristics for quantifying sST2 in serum or plasma. The assay is precise and linear over a wide sST2 concentration range and can measure low sST2 concentrations. Concentrations of sST2 are unaffected by age but are higher in males compared to females.
10.1016/j.cca.2010.07.014
Soluble ST2 serum concentration and renal function in heart failure.
Bayes-Genis Antoni,Zamora Elisabet,de Antonio Marta,Galán Amparo,Vila Joan,Urrutia Agustín,Díez Crisanto,Coll Ramon,Altimir Salvador,Lupón Josep
Journal of cardiac failure
BACKGROUND:Soluble ST2 (sST2) provides important prognostic information in patients with heart failure (HF). How sST2 serum concentration is related to renal function is uncertain. We evaluated the association between sST2 and renal function and compared its prognostic value in HF patients with renal insufficiency. METHODS AND RESULTS:Patients (n = 879; median age 70.4 years; 71.8% men) were divided into 3 subgroups according to estimated glomerular filtration rate (eGFR): ≥60 mL/min/1.73 m(2) (n = 337); 30-59 mL/min/1.73 m(2) (n = 352); and <30 mL/min/1.73 m(2) (n = 190). sST2 (rho = -0.16; P < .001), N-terminal pro-B-type natriuretic peptide (rho = -0.40; P < .001), and high-sensitivity cardiac troponin T (rho = -0.47; P < .001) inversely correlated with eGFR. All-cause mortality was the primary end point. During a median follow-up of 3.46 years, 312 patients (35%) died, 246 of them from the subgroup of 542 patients with eGFR <60 mL/min/1.73 m(2) (45%). Biomarker combination including sST2 showed best discrimination, calibration, and reclassification metrics in renal insufficiency patients (net reclassification improvement 16.6 [95% confidence interval (CI) 8.1-25; P < .001]; integrated discrimination improvement 4.2 [95% CI 2.2-6.2; P < .001]). Improvement in reclassification was higher in these patients than in the total cohort. CONCLUSIONS:The prognostic value of sST2 was not influenced by renal function. On top of other biomarkers, sST2 improved long-term prediction in patients with renal insufficiency even more than in the total cohort.
10.1016/j.cardfail.2013.09.005
The biology of ST2: the International ST2 Consensus Panel.
Pascual-Figal Domingo A,Januzzi James L
The American journal of cardiology
ST2 is a member of the interleukin 1 receptor family with 2 main isoforms: transmembrane or cellular (ST2L) and soluble or circulating (sST2) forms. ST2 is the receptor of the IL-33, which is an IL-1-like cytokine that can be secreted by living cells in response to cell damage. IL-33 exerts its cellular functions by binding a receptor complex composed of ST2L and IL-1R accessory protein. The IL-33/ST2 system is upregulated in cardiomyocytes and fibroblasts as response to mechanical stimulation or injury. The interaction between IL33 and ST2L has been demonstrated to be cardioprotective: in experimental models, this interaction reduces myocardial fibrosis, prevents cardiomyocyte hypertrophy, reduces apoptosis, and improves myocardial function. The beneficial effects of IL-33 are specifically through the ST2L receptor. sST2 avidly binds IL-33 which results in interruption of the interaction between IL-33/ST2L and consequently eliminates the antiremodeling effects; thus, sST2 is viewed as a decoy receptor. In recent years, knowledge about ST2 role in the pathophysiology of cardiovascular diseases has broadly expanded, with strong links to myocardial dysfunction, fibrosis, and remodeling. Beyond its myocardial role, the IL-33/ST2 system could have an additional role in the development and progression of atherosclerosis. In conclusion, IL-33/ST2L signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which may have therapeutic potential for beneficially regulating the myocardial response to overload and injury. In contrast, sST2 acts as a decoy receptor and, by sequestering IL-33, antagonizes the cardioprotective effects of IL-33/ST2L interaction.
10.1016/j.amjcard.2015.01.034
Prognostic Value of Soluble Suppression of Tumorigenicity-2 in Chronic Heart Failure: A Meta-Analysis.
Aimo Alberto,Vergaro Giuseppe,Passino Claudio,Ripoli Andrea,Ky Bonnie,Miller Wayne L,Bayes-Genis Antoni,Anand Inder,Januzzi James L,Emdin Michele
JACC. Heart failure
OBJECTIVES:The purpose of this study was to perform the first meta-analysis of currently available data. BACKGROUND:Soluble suppression of tumorigenesis 2 (sST2) plasma concentration is elevated in chronic heart failure (CHF) and helps to predict prognosis in this setting, although the evidence is limited. METHODS:Three databases (Medline, Cochrane Library, and Scopus) were searched. Inclusion criteria were: follow-up studies; papers published in English; enrollment of CHF outpatients; available data on hazard ratio (HR) for the log ST2 (so that the reported HRs represent the risk per doubling of sST2) and 95% confidence interval (CI) for all-cause death, and possibly also for cardiovascular (CV) death; and use of standardized sST2 assay. Exclusion criteria were: sST2 considered only as an element of a prognostic score, and studies on patients with end-stage HF. RESULTS:Seven studies were finally included for all-cause death, with a global population of 6,372 patients; data on CV death were available for 5 studies, totaling 5,051 patients. The HR was 1.75 (95% CI: 1.37 to 2.22) for all-cause death and 1.79 (95% CI: 1.22 to 2.63) for CV death (both p < 0.001). Significant heterogeneity among studies was detected in the quantification of sST2 predictive value, attributable to marked differences in pharmacological treatment among trials. The predictive power of sST2 was greater when patients were managed according to present guideline-recommended medical treatment. CONCLUSIONS:sST2 is a predictor of both all-cause and CV death in CHF outpatients. The present meta-analysis supports the use of sST2 for risk stratification in patients with stable CHF.
10.1016/j.jchf.2016.09.010
Meta-Analysis of Soluble Suppression of Tumorigenicity-2 and Prognosis in Acute Heart Failure.
Aimo Alberto,Vergaro Giuseppe,Ripoli Andrea,Bayes-Genis Antoni,Pascual Figal Domingo A,de Boer Rudolf A,Lassus Johan,Mebazaa Alexandre,Gayat Etienne,Breidthardt Tobias,Sabti Zaid,Mueller Christian,Brunner-La Rocca Hans-Peter,Tang W H Wilson,Grodin Justin L,Zhang Yuhui,Bettencourt Paulo,Maisel Alan S,Passino Claudio,Januzzi James L,Emdin Michele
JACC. Heart failure
OBJECTIVES:The aim of this study was to perform a meta-analysis of currently available data regarding the prognostic significance of soluble suppression of tumorigenecity-2 (sST2) concentration in acute heart failure (AHF). BACKGROUND:Concentration of sST2 may have prognostic value in AHF. A comprehensive assessment of all available studies regarding sST2 in AHF is lacking. METHODS:Three databases (MEDLINE, Cochrane Library, and Scopus) were searched. Inclusion criteria were follow-up studies, papers published in English, enrollment of patients with AHF, and availability of median hazard ratios for all-cause death and other outcome measures, when available. RESULTS:Ten studies were included, with a global population of 4,835 patients and a median follow-up duration of 13.5 months. The following global hazard ratios calculated for log(sST2) were admission sST2 and all-cause death, 2.46 (95% confidence interval [CI]: 1.80 to 3.37; p < 0.001); discharge sST2 and all-cause death, 2.06 (95% CI: 1.37 to 3.11; p < 0.001); admission sST2 and cardiovascular death, 2.29 (95% CI: 1.41 to 3.73; p < 0.001); discharge sST2 and cardiovascular death, 2.20 (95% CI: 1.48 to 3.25; p < 0.001); admission sST2 and heart failure (HF) hospitalization, 1.21 (95% CI: 0.96 to 1.52; p = 0.060); discharge sST2 and HF hospitalization, 1.54 (95% CI: 1.03 to 2.32; p = 0.007); admission sST2 and all-cause death or HF hospitalization, 1.74 (95% CI: 1.24 to 2.45; p < 0.001); and discharge sST2 and all-cause death or HF hospitalization, 1.63 (95% CI: 1.14 to 2.33; p < 0.001). CONCLUSIONS:Plasma sST2 has prognostic value with respect to all-cause and cardiovascular death as well as the composite outcome of all-cause death or HF hospitalization, with both admission and discharge values having prognostic efficacy. Discharge sST2, but not admission sST2, is predictive of HF rehospitalization during follow-up.
10.1016/j.jchf.2016.12.016