柯萨奇病毒和腺病毒受体是心肌缺血情况下心脏传导和心律失常易感性的调节因子。
Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia.
作者信息
Marsman Roos F J, Bezzina Connie R, Freiberg Fabian, Verkerk Arie O, Adriaens Michiel E, Podliesna Svitlana, Chen Chen, Purfürst Bettina, Spallek Bastian, Koopmann Tamara T, Baczko Istvan, Dos Remedios Cristobal G, George Alfred L, Bishopric Nanette H, Lodder Elisabeth M, de Bakker Jacques M T, Fischer Robert, Coronel Ruben, Wilde Arthur A M, Gotthardt Michael, Remme Carol Ann
机构信息
Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
出版信息
J Am Coll Cardiol. 2014 Feb 18;63(6):549-59. doi: 10.1016/j.jacc.2013.10.062. Epub 2013 Nov 27.
OBJECTIVES
The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia.
BACKGROUND
A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks of the cardiomyocyte.
METHODS
The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed using CAR haploinsufficient (CAR⁺/⁻) mice.
RESULTS
In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR⁺/⁻ mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR⁺/⁻ hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR⁺/⁻ myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5.
CONCLUSIONS
CAR is a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease.
目的
本研究旨在探讨柯萨奇病毒和腺病毒受体（CAR）在心肌缺血情况下对心室传导及心律失常易感性的调节作用。
背景
心肌梗死期间心室颤动风险中的遗传因素已得到充分证实。近期一项关于急性心肌梗死期间心室颤动的全基因组关联研究，导致在CXADR基因附近的21号染色体21q21位点（rs2824292）被识别出来。CXADR编码CAR，一种主要位于心肌细胞闰盘处的细胞粘附分子。
方法
在人类左心室样本中研究CAR转录水平与rs2824292基因型之间的相关性。使用CAR单倍体不足（CAR⁺/⁻）小鼠进行电生理研究和分子分析。
结果
在人类左心室样本中，21q21全基因组关联研究位点的风险等位基因与较低的CXADR信使核糖核酸水平相关，表明心脏中CAR水平降低易引发缺血性心室颤动。左前降支结扎后急性心肌缺血早期，CAR⁺/⁻小鼠的心脏除了心律失常发作更早外，还表现出心室传导减慢。连接蛋白43的表达和分布未受影响，但CAR⁺/⁻心脏在药理学电去偶联时心律失常易感性增加。对分离的CAR⁺/⁻心肌细胞进行膜片钳分析显示，特别是在闰盘处钠电流幅度降低。此外，CAR在体外与NaV1.5共沉淀，表明CAR通过与NaV1.5的物理相互作用影响钠通道功能。
结论
CAR是心肌缺血情况下心室传导和心律失常易感性的新型调节因子。心律失常易感性的遗传决定因素（如CAR）可能构成未来对冠心病患者潜在致命性室性心律失常进行风险分层的靶点。
Zotero 插件