Abstract Body: Background:
Heart failure with preserved ejection fraction (HFpEF) is a growing clinical challenge characterized by complex metabolic dysfunction and limited therapeutic options. While metabolic alterations have been widely reported, the role of branched-chain amino acid BCAA metabolism in HFpEF, particularly in the context of aging, remains incompletely understood.
Methods and Results:
To investigate the role of BCAA metabolism in HFpEF, we established two murine models with distinct etiologies. In young mice, HFpEF was induced by L-NAME combined with high-fat diet HFD, whereas in aging mice, HFD alone was sufficient to induce HFpEF. Notably, both models exhibited significant accumulation of BCAA at systemic and cardiac levels, indicating impaired BCAA catabolism as a shared metabolic feature. Importantly, the requirement of dual stressors in young mice but only HFD in aging mice highlights aging as an independent driver that predisposes to BCAA accumulation and metabolic dysfunction. Mechanistically, genetic inactivation of BCKDK enhanced BCAA oxidation, reduced BCAA accumulation, and significantly improved diastolic function, cardiac hypertrophy, and myocardial remodeling in both models.
Conclusion:
These findings identify BCAA accumulation as a conserved metabolic hallmark of HFpEF across distinct etiologies and establish aging as a critical independent risk factor that lowers the threshold for disease development. Targeting BCAA metabolism may therefore represent a promising therapeutic strategy for HFpEF.