Secreted Frizzled Related Protein 3 in Chronic Heart Failure: Analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)

Abstract

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: http://www.clinicaltrials.gov NCT00206310.

Conflict of interest statement

Competing Interests: John Kjekshus and John J. V. McMurray have received consulting or advisory board fees from AstraZeneca. John Kjekshus, John J. V. McMurray, John G. F. Cleland and Lars Gullestad have received lecture fees from AstraZeneca. John J. V. McMurray has received research grants from AstraZeneca. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Kaplan-Meier curves for the primary end point (panel A), as well as for all-cause (B) and CV (C) mortality according to tertile sFRP3 concentration.

T1, lowest tertile serum sFRP3; T3, highest tertile serum sFRP3. Patients with T2 sFRP3 showed a markedly better outcome than patients in T1 and T2; p<0.001 for the primary end point and all-cause mortality, p<0.002 for CV mortality.

Fig 2. Kaplan Meier plots showing the association between tertiles of sFRP3 and all-cause mortality in the GISSI-HF-HF trial stratified according to age and presence of ischemic heart disease.

A. ischemic HF <70 years of age B. ischemic HF >70 years of age C. non-ischemic HF > 70 years D. all-cause mortality in CORONA using cut-off derived from the GISSI-HF-HF trial.

Fig 3. Possible mechanism linking sFRP3 release during LV wall stress and non-linear association with survival.

Increased wall stress [1] may induce the release of sFRP3 from fibroblasts [2]. Depending on concentration of sFRP3 [3], this may lead to insufficient, balanced or excess inhibition of the Wnt [4] in the presence of inflammation and lead to a non-linear association with survival [5].