Chronically elevated branched chain amino acid levels are pro-arrhythmic.
Chronically elevated branched chain amino acid levels are pro-arrhythmic.
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DOI：
10.1093/cvr/cvab207
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发表时间：
2022-06-22
影响因子：
10.8
通讯作者：
中科院分区：
文献类型：
--
作者：
心律失常构成主要的健康和经济负担，并且与显著的发病率和死亡率相关，包括心力衰竭、中风和心源性猝死（SCD）。对疾病机制和途径的不完全了解阻碍了有效预防和治疗策略的制定。我们的目的是确定新的机制，潜在的心律失常和SCD使用一个公正的方法。我们采用了表型驱动的N-乙基-N-亚硝基脲诱变筛选，并确定了一个小鼠品系，在没有先前症状的情况下，在年幼时（6-9周）猝死的发生率很高。发现受影响的小鼠在编码支链氨基酸转氨酶2的Bcat 2基因中对于无义突变Bcat2p.Q300*/p.Q300* 是纯合的。在4-5周龄时，Bcat 2 p. Q300 */p. Q300 * 小鼠显示出分支链氨基酸（BCAAs-亮氨酸、异亮氨酸、缬氨酸）的血浆水平的急剧增加，这是由于BCAAs的不完全catering，除了离体诱导的心律失常以及心脏传导和复极障碍之外。与这些结果一致，在德国社区为基础的KORA F4研究中，血浆BCAA水平与心电图传导和复极指数呈正相关。从Bcat2p.Q300*/p.Q300* 小鼠分离的心肌细胞显示动作电位（AP）延长、促心律失常事件（早期和晚期后去极化，触发AP）和钙稳态失调。人多能干细胞衍生的心肌细胞与浓度升高的BCAA孵育诱导了类似的钙调节异常和促凋亡事件，这被雷帕霉素阻止，证明了mTOR通路激活的关键参与。我们的研究结果首次确定了BCAA升高与心律失常之间的因果关系，这对与BCAA代谢失调相关的疾病（如糖尿病，代谢综合征和心力衰竭）的发生有影响。
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. 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. 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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DOI：
10.1016/j.bbadis.2015.12.021
发表时间：
2016-04-01
影响因子：
6.2
作者：
Caioli, Silvia;Candelotti, Elena;Zona, Cristina
通讯作者：
Zona, Cristina
影响因子：
37.8
作者：
Huxley RR;Lopez FL;Folsom AR;Agarwal SK;Loehr LR;Soliman EZ;Maclehose R;Konety S;Alonso A
通讯作者：
Alonso A
影响因子：
6.1
作者：
Priori, Silvia G.;Blomstrom-Lundqvist, Carina;Van Veldhuisen, Dirk J.
通讯作者：
Van Veldhuisen, Dirk J.
影响因子：
4.5
作者：
Lodder EM;Scicluna BP;Milano A;Sun AY;Tang H;Remme CA;Moerland PD;Tanck MW;Pitt GS;Marchuk DA;Bezzina CR
通讯作者：
Bezzina CR
影响因子：
4.5
作者：
Parks, Randi J.;Howlett, Susan E.
通讯作者：
Howlett, Susan E.