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

João Pedro Ferreira (Lead / Corresponding author), Wouter Ouwerkerk, Bernadet T. Santema, Dirk J. van Veldhuisen, Chim C. Lang, Leong L. Ng, Stefan D. Anker, Kenneth Dickstein, Marco Metra, John G. F. Cleland, Nilesh J. Samani, Gerasimos S. Filippatos, Joseph-Pierre Aboumallem, Rudolf A. de Boer, Sylwia Figarska, Iziah E. Sama, Adriaan A. Voors, Faiez Zannad

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Pages (from-to)2228-2236
Number of pages9
JournalCardiovascular Research
Issue number10
Publication statusPublished - 1 Oct 2020


  • aging
  • chronological age
  • biological age
  • biomarkers
  • heart failure with reduced ejection fraction


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