Chronically elevated branched chain amino acid levels are pro-arrhythmic

作者：Vincent Portero, T. NICOL, Svitlana Podliesna, Gerard A. Marchal, Antonius Baartscheer, Simona Casini, Rafik Tadros, Jorien L. Treur, Michael W.T. Tanck, I. Jane Cox, Fay Probert, Tertius Hough, Sara Falcone, Leander Beekman, Martina Müller‐Nurasyid, Gabi Kastenmüller, Christian Gieger, Annette Peters, Stefan Kääb, Moritz F. Sinner, Andrew Blease, Arie O. Verkerk, Connie R. Bezzina, Paul Potter, Carol Ann Remme · 发表于：Cardiovascular Research · 年份：2021 · DOI：10.1093/cvr/cvab207 · 被引用次数：76 · 研究领域：Cardiac electrophysiology and arrhythmias、Cardiovascular Effects of Exercise、Congenital heart defects research

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 ...