Abstract
AimsCardiac 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 resultsWe 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.ConclusionsOur 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.
Highlights
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)
No heterozygous Bcat2C1121T or wild-type mice succumbed to sudden death before the age of eight weeks and no homozygous mice lived beyond this age
Since cellular branched chain amino acids (BCAAs) metabolism is reflected by CVR-2021-0172-R1 BCAA plasma levels, the latter may serve as a circulating prognostic biomarker of arrhythmia and SCD risk
Summary
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). SCD remains a leading cause of mortality in the Western world, accounting for up to 20% of all natural deaths, and up to 50% of all cardiovascular deaths.[1] Arrhythmias typically occur in the setting of an underlying pathology, including myocardial ischemia, structural derangements, and co-morbidities such as hypertension.[1,2] patients suffering from metabolic disorders (diabetes, obesity) and heart failure are at increased risk for arrhythmias and SCD.[3,4,5,6,7,8] Despite decades of research, few anti-arrhythmic therapeutic options exist due to the complexity of underlying pathologies. Development of efficient preventive and therapeutic strategies is essential but is as yet hampered by incomplete knowledge of disease mechanisms
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