Journal Article


Chronically elevated branched chain amino acid levels are pro-arrhythmic

Abstract

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.

Attached files

Authors

Portero, Vincent
Nicol, Thomas
Podliesna, Svitlana
Marchal, Gerard A.
Baartscheer, Antonius
Casini, Simona
Tadros, Rafik
Treur, Jorien L.
Tanck, Michael W.T.
Cox, I. Jane
Probert, Fay
Hough, Tertius A.
Falcone, Sara
Beekman, Leander
Müller-Nurasyid, Martina
Kastenmüller, Gabi
Gieger, Christian
Peters, Annette
Kääb, Stefan
Sinner, Moritz F.
Blease, Andrew
Verkerk, Arie O.
Bezzina, Connie R.
Potter, Paul K.
Remme, Carol Ann

Oxford Brookes departments

Department of Biological and Medical Sciences

Dates

Year: 2021


Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 International License


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