BCAA catabolism targeted therapy for heart failure with preserved ejection fraction

Area of Science:

• Cardiovascular Medicine
• Metabolic Disorders
• Biochemistry

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a significant unmet medical need.
• Metabolic dysfunction, particularly in glucose and fatty acid metabolism, is implicated in HFpEF pathogenesis.
• The role of other metabolic pathways, such as branched-chain amino acid (BCAA) metabolism, in HFpEF remains under-investigated.

Purpose of the Study:

• To investigate the role of BCAA metabolism in HFpEF.
• To explore whether enhancing BCAA catabolic flux can serve as a therapeutic strategy for HFpEF.

Main Methods:

• System-based metabolomics and targeted mass spectrometry were used on human HFpEF patient samples.
• A preclinical HFpEF mouse model was established using a high-fat diet (HFD) and L-NAME.
• BCAA catabolic activity was modulated by genetic inactivation or pharmacological inhibition of BCKDK (branched-chain ketoacid-dehydrogenase kinase).

Main Results:

• Abnormal circulating BCAA levels and impaired cardiac BCAA catabolism were observed in HFpEF patients and the mouse model.
• Inactivation of BCKDK in mice improved cardiac function, reduced cardiac hypertrophy and remodeling, and enhanced myocardial insulin signaling.
• Pharmacological inhibition of BCKDK reversed HFpEF-associated diastolic dysfunction and cardiac hypertrophy in mice.

Conclusions:

• Global catabolic impairment of BCAAs is a key pathogenic factor and metabolic signature in HFpEF.
• Restoring BCAA catabolic flux represents a potential therapeutic strategy for HFpEF.