Immunometabolic regulation of cardiac macrophages in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome driven by comorbidities, chronic low-grade inflammation, and cardiac remodeling. Cardiac resident macrophages (CRMs) and monocyte-derived macrophages (MDMs) play central roles in linking immunometabolism to HFpEF pathogenesis. Resident CCR2^- macrophages maintain homeostasis and tissue repair, whereas monocyte-derived CCR2⁺ macrophages drive inflammation, fibrosis, and diastolic dysfunction. In HFpEF, comorbidity-induced metabolic shifts promote pro-inflammatory macrophage polarization, while metabolites like fatty acids, lactate, and succinate modulate these responses through metabolic and epigenetic pathways. Targeting specific macrophage subsets offers promising therapeutic avenues, though challenges like off-target effects and clinical translation remain. This review summarizes cardiac macrophage heterogeneity, immunometabolic crosstalk, and regulatory mechanisms in HFpEF, highlighting emerging subset-specific therapeutic strategies.