Serotonin reuptake inhibitors attenuate cardiac fibrosis in HFpEF by inhibiting the SERT-Hic5 pathway

Abstract HFpEF lacks therapies that directly reverse cardiac fibrosis. We used cMAP screening to identify SSRIs as candidate agents to reverse cardiac remodeling. In two independent clinical cohorts, SSRI exposure was associated with improved diastolic function, attenuated remodeling and reduced multiorgan dysfunction. Human myocardial biopsies linked SERT-Hic5 signaling to HFpEF severity. In a murine HFpEF model, fluvoxamine ameliorated diastolic dysfunction, hypertrophy and fibrosis by inhibiting fibroblast SERT. Our findings highlight the therapeutic potential of repurposing SSRIs targeting this fibroblast-specific pathogenic cascade for HFpEF and support further prospective investigation.