The novel collagen matrikine, endotrophin, is associated with mortality and cardiovascular events in patients with atherosclerosis

BACKGROUND: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO‐C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention. OBJECTIVE: In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO‐C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. METHODS: Sections from the stenotic human carotid plaques were stained with the PRO‐C6 antibody. PRO‐C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro‐ and macrovascular hard end‐points for innovative diabetes tools (IMI‐SUMMIT, validation cohort, n = 1,378). Median follow‐up was 43 months. Kaplan–Meier curves and log‐rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. RESULTS: PRO‐C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO‐C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 −1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 −1.241], p = 0.04) and all‐cause death (HR 1.087 [95% CI 1.008 −1.172], p = 0.03). In the validation cohort, PRO‐C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 −1.117], p = 0.017). CONCLUSION: PRO‐C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all‐cause mortality in two large prospective cohorts.