PRO-C6 and endotrophin are associated with cardiac remodelling and adverse outcomes in HFpEF: data from the prospective NETDiamond cohort

Background Heart failure with preserved ejection fraction (HFpEF) is characterized by extracellular matrix (ECM) remodelling and fibrosis, but clinically useful circulating biomarkers reflecting these processes remain limited. Purpose To assess whether circulating ECM-derived biomarkers (PRO-C3, PRO-C6 and endotrophin) are associated with HFpEF, key clinical HF features, and adverse outcomes. Methods In this prospective single-centre NETDiamond cohort analysis, plasma PRO-C3, PRO-C6 and endotrophin were measured using specific enzyme-linked immunosorbent assays (Nordic Bioscience) in controls (n=15) and patients with HFpEF (n=78). Biomarker levels were compared between groups, and in HFpEF their associations with clinical, laboratory and echocardiographic variables, as well as a composite HF endpoint (cardiovascular death, HF hospitalization, or acute HF episode), were evaluated using Cox regression with adjusted models including age, sex, creatinine and BNP. Results Circulating endotrophin was higher in HFpEF versus controls (p=0.0046; exact p=0.0040), whereas PRO-C3 and PRO-C6 were not significantly different. In HFpEF, higher PRO-C6 and endotrophin tertiles were associated with a more adverse clinical profile, including higher high-sensitivity troponin I, worse renal function, and adverse remodelling/diastolic dysfunction indices (including higher LVMI and E/e′); PRO-C6 tertiles were also associated with lower LVEF and higher LAVI, while endotrophin tertiles were associated with higher pulse wave velocity. During follow-up in HFpEF (n=78), 28 HF composite endpoint events occurred. PRO-C6 and endotrophin were associated with higher event risk. In adjusted models, PRO-C6 (HR 3.41, 95% CI 1.22 to 9.53; p=0.019) and endotrophin (HR 2.74, 95% CI 1.20 to 6.22; p=0.016) remained significantly associated with the composite endpoint. Tertile analyses were concordant, with progressively higher risk across PRO-C6 and endotrophin tertiles. Conclusions In this prospective single-centre HFpEF cohort, PRO-C6 and endotrophin identified a higher-risk HFpEF phenotype characterized by myocardial injury and adverse remodelling, and were independently associated with adverse outcomes. These findings support the type VI collagen/endotrophin axis as a promising pathway for HFpEF risk stratification and may also help identify biologically relevant, potentially targetable mechanisms of disease.