Chronically elevated branched chain amino acid levels are pro-arrhythmic

Area of Science:

• Cardiovascular Research
• Metabolic Disorders
• Genetics

Background:

• Cardiac arrhythmias pose a significant health burden, contributing to heart failure, stroke, and sudden cardiac death (SCD).
• Current understanding of arrhythmia mechanisms is incomplete, hindering the development of effective preventive and therapeutic strategies.

Purpose of the Study:

• To identify novel mechanisms underlying cardiac arrhythmias and SCD using an unbiased genetic approach.
• To investigate the role of branched-chain amino acid (BCAA) metabolism in arrhythmogenesis.

Main Methods:

• A phenotype-driven mutagenesis screen identified a mouse line with high incidence of sudden death.
• Genetic analysis revealed a nonsense mutation in the Bcat2 gene, leading to BCAA accumulation.
• Electrophysiological studies and calcium imaging were performed on isolated cardiomyocytes and human stem cell-derived cardiomyocytes.

Main Results:

• Mice with the Bcat2 mutation exhibited elevated plasma BCAAs and developed inducible arrhythmias, conduction disturbances, and repolarization abnormalities.
• Elevated BCAAs impaired cardiomyocyte function, causing action potential prolongation, pro-arrhythmic events, and calcium dysregulation.
• Human cardiomyocytes exposed to high BCAAs showed similar calcium dysregulation and pro-arrhythmic events, preventable by rapamycin, indicating mTOR pathway involvement.

Conclusions:

• A causative link between elevated BCAAs and cardiac arrhythmias has been established.
• BCAA metabolism dysregulation is implicated in arrhythmogenesis, with relevance to conditions such as diabetes, metabolic syndrome, and heart failure.
• Targeting the mTOR pathway may offer a therapeutic strategy for BCAA-related cardiac dysfunction.