Mechanistic insights into heart failure progression and therapeutic target discovery through plasma microRNA profiling: Findings from HOMAGE

Background Identifying early pathobiological mechanisms associated with the onset and progression of heart failure (HF) could guide development of preventive strategies. Objective To elucidate molecular pathways driving HF pathogenesis and identify potential therapeutic targets by profiling plasma microRNAs (miRNAs). Methods Multicenter study including 799 elderly patients from HOMAGE. Incident HF was defined as the first hospitalization for HF. A panel of miRNAs implicated in HF was analyzed using RT-qPCR. Two machine learning-based feature selection methods were employed to identify contributors for HF onset. Associations between miRNA targets and HF were explored using publicly available datasets. Bioinformatic analyses were performed using the intersected targets, including functional and single-cell enrichment analyses and drug–gene interaction assessment. Results After adjusting for confounders, four miRNAs (miR-21–5p, miR-24–3p, miR-132–3p, miR-221–3p) were significantly associated with incident HF in univariate analyses (FDR < 0.05). The feature selection process identified miR-21–5p, miR-24–3p and miR-221–3p as the most informative miRNAs linked to HF onset. The predicted targetome of these miRNAs encompassed 1293 transcripts, of which 32 demonstrated cardiac expression and differential levels between HF cases and controls across six different datasets. Pathway enrichment analysis revealed five key biological processes associated with HF progression: i) calcium homeostasis and signaling; ii) cell proliferation; iii) stress response and remodeling; iv) metabolic dysregulation; and v) neurohormonal activation. Drug–gene interaction analysis identified five FDA-approved agonists of the target GABBR2. Conclusions The identified miRNAs provide a rationale for future longitudinal and mechanistic studies and potentially inform the development of novel strategies for HF prevention.