Abstract
Heart Failure with Preserved Ejection Fraction (HFpEF) is a complex and heterogeneous syndrome characterized by diastolic dysfunction, systemic comorbidities, and metabolic remodeling. This study investigates cardiac metabolism, mitochondrial lipid remodeling, and contractile energetics in three murine HFpEF models LDLR/P407, Alport, and HF/L-NAME with and without dietary supplementation of α-ketoglutarate (αKG), a central tricarboxylic acid (TCA) cycle metabolite. Using multimodal approaches including ¹⁸F-FDG PET imaging, targeted metabolomics, cardiolipin profiling, echocardiography, and myosin energetic state assays, we observed enhanced cardiac glucose uptake, accumulation of TCA intermediates (NADH, αKG, succinyl-CoA), and increased levels of branched-chain amino acids (BCAAs), notably leucine, across models. αKG supplementation exacerbated diastolic dysfunction and increased sudden death in LDLR/P407 mice, suggesting maladaptive metabolic overload. Altered cardiolipin remodeling was also observed with αKG, implicating mitochondrial lipid dysregulation in functional decline. Additionally, myosin SRX:DRX ratio analysis revealed energetic dysregulation linked to contractile dysfunction. Our findings identify distinct metabolic endotypes within HFpEF and highlight the context-dependent role of αKG, which may act as either a metabolic modulator or a stressor. These results underscore the need for precision strategies targeting cardiac bioenergetics and mitochondrial remodeling in HFpEF treatment.