Procollagen type I carboxy-terminal propeptide predicts outcome in new onset heart failure with preserved ejection fraction in the PREFERS cohort

Background Myocardial fibrosis is considered an important underlying mechanism of heart failure (HF) with preserved ejection fraction (HFpEF). Circulating procollagen type I carboxy-terminal propeptide (PICP) is a marker of collagen synthesis and correlates with histological myocardial fibrosis. Carboxy-terminal telopeptide of collagen type I (CITP) is a product of collagen degradation, and the ratio of CITP to serum matrix metalloproteinase-1 (MMP-1) is inversely correlated to collagen cross-linking (CCL). The prognostic role of PICP and the CITP: MMP-1 ratio in new onset HF is unclear. Aim To evaluate the prognostic value of serum PICP and the CITP: MMP-1 ratio in a cohort of new onset HFpEF. Methods Serum concentration of PICP, CITP and MMP-1 were assessed within two weeks of de novo HF diagnosis and after twelve months in 477 patients (124 HFpEF, 52 HF with mildly reduced EF [HFmrEF] and 301 HF with reduced EF [HFrEF]) from the PREFERS (Preserved and Reduced Ejection Fraction Epidemiological Regional Study) cohort, median age 71 years, 64 % male. Patients were treated according to ESC HF guidelines and followed at HF clinics between 2014 and 2018 (median follow-up 3.8 years). Stratification into high- or low-PICP groups was based on the median value (82.6 ng/mL). High CCL was defined as a CITP: MMP-1 ratio below median (1.8). Time-to-event analysis was performed using Kaplan-Meier estimates with hazard ratios calculated from Cox regression models, adjusted for age and estimated glomerular filtration rate (eGFR). Outcome was measured by composite of time to cardiovascular (CV) mortality or first HF-hospitalization. Results Median PICP at diagnosis did not differ between HFpEF, HFmrEF or HFrEF (p = 0.49). Baseline PICP above median was associated with higher risk of the composite endpoint in HFpEF (adjusted HR 3.98 CI 2.02-7.83 p <0.001), Figure 1. This was not seen for the combined HFrEF and HFmrEF patients (adjusted HR 0.99 CI 0.57-1.74 p = 0.981). At twelve months follow-up, median PICP increased by 16.4 ng/L (22 %) in HFpEF (p <0.001), 3.5 ng/L (5.5 %) in HFmrEF (p = 0.1) and 4.9 ng/L (6.5 %) in HFrEF (p = 0.01). In HFpEF, higher degree of CCL was associated with a larger increase in PICP (27 vs 8 %, p = 0.017), Figure 2. This was not seen for HFmrEF and HFrEF. The CITP: MMP-1 ratio was not associated with risk for the composite endpoint. Conclusion High serum PICP at the time of HFpEF diagnosis was associated with worse prognosis in a cohort of patients with new-onset HF which may reflect higher degree of myocardial fibrosis. The degree of CCL was not associated with outcome but correlated with higher increase in PICP over one year in HFpEF. PICP may be useful in identifying HFpEF patients with worse prognosis and possibly for targeting and monitoring anti-fibrotic treatment.