Circulating fragments of collagen I synthesis are associated with heart failure hospitalization and death two years after acute myocardial infarction in elderly patients

Background Quantification of myocardial fibrosis carries important diagnostic and prognostic value. As access to biopsies for gold-standard histological evaluation is limited, and imaging has limited specificity and low accessibility, blood biomarkers reflecting fibrosis are an alternative strategy. Myocardial fibrosis comprises excessive fibrillar collagens, mainly type I, deposited by activated fibroblasts. Procollagen has peptides that are cleaved off by proteases prior to fibril incorporation that can reach the circulation; the type I collagen C-terminal propeptide (PICP) provides a stoichiometric representation of collagen type I production. Aims To assess circulating levels of a collagen I synthesis biomarker in association with patient characteristics, infarct size, and major adverse cardiovascular events (MACE) in elderly patients with a recent acute myocardial infarction (AMI). Methods The OMEMI trial (Omega-3 Fatty acids in Elderly with Myocardial Infarction) was a multicenter, randomized controlled trial of omega-3 supplements vs. placebo recruiting 1027 patients aged 70-82 years with AMI 2-8 weeks before the baseline visit, from 2012-2020. The overall trial was neutral. In this substudy, PICP was measured in serum (n=1022 baseline, n=896 at 2 years) using a commercially available ELISA kit (Microvue). Cox proportional hazards regression was used to analyze time to MACE (comprising stroke, AMI, heart failure, unscheduled revascularization, and death). Results Median (Q1-Q3) CICP levels were 94 (74-122) ng/mL at baseline and 97 (78-121) ng/ml at two-years follow-up. At baseline, higher PICP correlated with higher cardiac troponin T (cTnT, r=0.15, p<0.001) and N-terminal pro-B-type natriuretic peptide (NT-proBNP, r=0.24, p<0.001), but not with creatinine, demographics or comorbidities. Peak cTnT during the index AMI was not associated with PICP. Higher PICP associated with higher risk of MACE in unadjusted models (HR 1.48 [95%CI 1.10-2.00], p=0.009 per log unit increase in PICP), and after adjustment for age, sex, current smoking, BMI, systolic blood pressure, hypertension, diabetes and heart failure (HR 1.38 [1.02-1.86], p=0.034), but was no longer significant after adjustment for creatinine, cTnT and NT-proBNP (HR 1.18 [0.86-1.63], p=0.31). From baseline to two years, there was a small increase in PICP (median +4 [-15 to +23] ng/mL, p<0.001). Greater delta PICP associated with male sex, but not peak cTnT during the index AMI. Baseline PICP ldid not modify the treatment effect of omega-3 on MACE (p-for-interaction=0.89). Conclusion Circulating levels of PICP 2-8 weeks post-AMI are associated with myocardial injury and stress, and patients with higher levels had greater risk of cardiovascular events during two years follow-up. PICP levels remained overall stable from baseline to two years. Our findings warrant further exploration into the use of collagen I fragment biomarkers in patient monitoring.