Key result
Elevated plasma valine is linked to prolonged PR and QTc intervals, signaling pro-arrhythmic potential.
Why the study?
Development of effective preventive and therapeutic strategies for cardiac arrhythmias is hampered by incomplete knowledge of underlying disease mechanisms.
Do elevated branched chain amino acid levels induce arrhythmias and alter cardiac electrophysiology?
Do elevated branched chain amino acid levels induce arrhythmias and alter cardiac electrophysiology?
Answers are grounded in this paper and cite their sources.
Chronically elevated BCAA levels are directly pro-arrhythmic via mTOR pathway activation, suggesting a novel mechanism for arrhythmias in metabolic disorders.
AIMS: Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. METHODS AND RESULTS: We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs-leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. CONCLUSIONS: Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.
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Portero et al. (2021) studied General population (n=2,304). Elevated branched chain amino acid (BCAA) levels vs. Lower BCAA levels was evaluated on PR interval (beta 0.0335 ms/µmol/L, p=<0.001). Elevated fasting plasma valine levels were significantly associated with prolonged PR interval (beta 0.0335 ms/µmol/L, p<0.001) and QTc interval (p=0.002) in the general population, supporting preclinical findings that elevated BCAAs are pro-arrhythmic.
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