Differences in biomarkers and molecular pathways according to age for patients with HFrEF.

AIMS: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable population. METHODS AND RESULTS: From a panel of 363 cardiovascular biomarkers available in 1,611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged > 75yr versus <65yr. Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly versus younger patients. After adjustment, multiple test correction (FDR 1%), and cross-validation, 27/363 biomarkers were associated with older age, 22 positively, and 5 negatively. The biomarkers that were positively associated with older age were associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumorigenesis. Among the 27 biomarkers, WFDC2 (WAP Four-Disulfide-Core-Domain-2) - that broadly functions as a protease inhibitor - was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed. CONCLUSIONS: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumor cell regulation were activated, while pathways associated with tumor proliferation functions were down-regulated. These findings may help in a better understanding of the aging processes in HFrEF and identify potential therapeutic targets. TRANSLATIONAL PERSPECTIVE: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. Using a large set of circulating proteins, elderly patients had higher concentrations of proteins associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas pathways that may point to cell proliferation and tumorigenesis were down-regulated. WAP Four-Disulfide-Core-Domain-2 was associated with older age and had the strongest association with an increased risk of all outcomes. Understanding the underlying pathophysiological processes associated with aging in HFrEF may potentially lead to targeted therapies in this vulnerable population.