Eicosapentaenoic Acid Attenuates Heart Failure with Preserved Ejection Fraction Via Promoting TREM2-Dependent Efferocytosis

Background Heart failure with preserved ejection fraction (HFpEF) constitutes over 50% of heart failure cases but lacks disease-modifying therapies. The pathophysiological role of eicosapentaenoic acid (EPA) in HFpEF remains undefined. Methods Integrated lipidomics was conducted across HFpEF discovery and validation cohorts. "Two-hit" murine HFpEF model combining high-fat diet (HFD) and 0.5g/L L-NAME​was established to recapitulate human metabolic-inflammatory pathology. EPA’s efficacy was evaluated through prophylactic/therapeutic interventions (160/320 mg/kg/day, human-equivalent 2/4 g/day). Mechanistic studies integrated transcriptomics, molecular docking, triggering receptor expressed on myeloid cells 2 (TREM2) knockout, and siRNA silencing. Results Plasma EPA deficiency correlated with diastolic dysfunction severity and conferred incremental diagnostic value. High-dose EPA (4 g/day equivalent) prevented/reversed diastolic impairment and apoptosis in HFpEF mice. EPA rescued impaired efferocytosis through dual modulation of TREM2, concurrently enhancing functional transmembrane receptor expression while suppressing pathological ectodomain shedding. TREM2 ablation attenuated EPA-mediated benefits on diastolic function and efferocytosis. Conclusion Our work identifies plasma EPA depletion as a potential biomarker for risk stratification and delineates the EPA-TREM2-efferocytosis axis as a putative therapeutic mechanism for HFpEF, suggesting the potential of EPA as a theranostic candidate.