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

Abstract

Background: Endotrophin, 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).

Methods: We 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).

Results: Plasma 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).

Conclusions: Circulating 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.).

Figure 1.. Multivariable Cox Proportional-Hazards Models in the TOPCAT trial.

Multivariable Cox proportional-hazards models that include endotrophin, NT-proBNP, and MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score as predictors of (Panel A) the primary end point, (Panel B) death or heart failure–related hospital admission, and (Panel C) death in the Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist trial. Each of the three models included all three predictors.

Figure 2.. Kaplan–Meier Survival Curves in the TOPCAT trial.

Kaplan–Meier survival curves for tertiles of plasma endotrophin (ET) for (Panel A) the primary end point, (Panel B) all-cause death or heart failure–related hospital admission (DHFA), and (Panel C) all-cause death in the Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist trial.

Figure 3.. Forest Plot of Participant-Level Meta-Analysis.

Forest plot of our participant-level (PL) meta-analysis assessing the relationship between (Panels A and B) endotrophin and death and (Panels C and D) death or heart failure–related hospital admission in six heart failure (HF) with preserved ejection fraction cohort studies in unadjusted analyses (Panels A and C) and models adjusted for MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score (Panels B and D). A hazard ratio >1 indicates a higher risk of death with higher endotrophin levels. PEOPLE denotes, Prospective Evaluation of Outcome in Patients with Heart Failure with Preserved Left Ventricular Ejection Fraction; TOPCAT, Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist trial.

Figure 4.. Relationship Between Endotrophin and Outcomes in Heart Failure with Reduced Ejection Fraction (n=1642) in Analysis 4.

Cox proportional-hazards models that include endotrophin (n = 1,642), MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score, and BNP as predictors of death (Panels A and B) and of death or heart failure–related hospitalization (DHFA; Panels C and D). Panels A and C present unadjusted standardized hazard ratios, whereas Panels B and D present multivariable models that include endotrophin, MAGGIC risk score, and BNP. Multivariable models (Panels B and D) are based on participants for whom complete covariate data were available (n = 1337; 761 first DHFA events; 346 deaths).