Endotrophin, a Collagen VI Formation–Derived Peptide, in Heart Failure

Abstract

BackgroundEndotrophin, a collagen type VI–derived peptide, mediates metabolic dysregulation, inflammation, and fibrosis in animal models, but has not been studied in human heart failure (HF).MethodsWe examined the association between circulating endotrophin and outcomes in participants suffering from HF with preserved ejection fraction (HFpEF) enrolled in the TOPCAT trial (n=205). Associations were validated in a participant-level meta-analysis (n=810) that included participants with HFpEF from the PHFS study (United States; n=174), PEOPLE cohort (New Zealand; n=168), a randomized trial of vasodilator therapy (United States; n=45), a cohort from Donostia University Hospital and University of Navarra (Spain; n=171), and the TRAINING-HF trial (Spain; n=47). We also assessed associations in HF with reduced ejection fraction in PHFS (n=1,642).ResultsPlasma endotrophin levels at baseline were associated with risk of future death (standardized hazard ratio [HR]=1.74; 95% confidence interval [CI]=1.36–2.24; P<0.001) and death or HF-related hospital admission (DHFA; standardized HR=2.11; 95% CI=1.67–2.67; P<0.001) in TOPCAT. Endotrophin improved reclassification and discrimination for these outcomes beyond the MAGGIC risk score and NT-proBNP (N-terminal pro b-type natriuretic peptide). Findings were confirmed in the participant-level meta-analysis. In participants with HF with reduced ejection fraction in PHFS, endotrophin levels were associated with death (standardized HR=1.82; 95% CI=1.66–2.00; P<0.001) and DHFA (standardized HR=1.40; 95% CI=1.31–1.50; P<0.001), but the strength of the latter association was substantially lower than for the MAGGIC risk score (standardized HR=1.93; 95% CI=1.76–2.12) and BNP (standardized HR=1.78; 95% CI=1.66–1.92).ConclusionsCirculating endotrophin levels are independently associated with future poor outcomes in patients with HF, particularly in HFpEF. (Funded by Bristol Myers Squibb; Instituto de Salud Carlos III [Spain] and European Regional Development Fund; European Commission CRUCIAL project; and the U.S. National Institutes of Health National Heart, Lung, and Blood Institute.)