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Background: We have previously demonstrated an association between increased sFRP3 expression and adverse outcome in a population of HF irrespective of cause and left ventricular ejection fraction. In this study we evaluated the prognostic value of sFRP3 in older patients with chronic systolic HF of ischemic origin. Methods: We evaluated sFRP3, by tertiles, as a risk factor for the primary endpoint (cardiovascular [CV] mortality, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV mortality, death from worsening HF (WHF), any coronary event, including sudden death, as well as hospitalizations for CV causes and WHF in 1444 patients from the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo. Results: Kaplan-Meier curves for the primary endpoint, as well as all-cause- and CV mortality revealed a markedly better survival for patients with sFRP3 levels in the middle tertile of compared to the 1st and 3rd tertile. In multivariable Cox-regression, after full adjustment including high-sensitive CRP and NT-proBNP, a lower event rate for the primary end point, all cause and CV mortality was observed for patients with tertile 2 sFRP3 levels (HR 0.57 [0.44–0.74], 0.55 [0.44–0.74] and 0.52 [0.39–0.69]; p<0.001), as well as for the number of coronary events (HR 0.62 [0.47–0.82], p = 0.001) and sudden death (HR 0.55 [0.37–0.82], p = 0.002). Applying sFRP3 values to the fully adjusted regression model resulted in highly significant continuous net reclassification improvements for the primary endpoint, all cause and CV mortality, coronary events and sudden death (range 0.24–0.31; p≤0.002 for all). Conclusions: Intermediate serum sFRP3 levels are associated with better survival and fewer CV events than low or high sFRP3 levels, independently of conventional risk factors, in older patients with chronic systolic HF of ischemic origin. Our study suggests that balanced Wnt activity might confer protective effects in a clinical HF setting. Trial Registration: [ABSTRACT FROM AUTHOR]