Gap Junction Remodeling and Arrhythmogenesis in Ischemic Heart

在日本，心源性猝死在心肌梗死后存活的患者中很常见。此外，许多心功能不全的患者发生突发性心律失常死亡的风险很高。但是导致这类患者致死性心律失常的分子机制尚未明确。为了深入了解临界心律失常的作用，我们在小鼠体内建立了一个主要间隙连接蛋白Cx43零等位基因和野生型杂合的缺血模型。采用超声心动图和组织病理学检查心肌梗死（MI）后的结构变化。虽然心肌间隙连接中Cx43表达减少不影响梗死后重构，但与野生型（C×43+/+）相比，C×43-deficient （C×43+/-）小鼠的梗死面积更小。植入式遥测系统显示自发性室性心律失常仅发生在C×43+/-小鼠梗死。采用心律失常诱发法对心肌梗死愈合后的离体心脏进行分析。心肌梗死时Cx43+/和+/+心脏均可诱发室性心动过速，但缺血小鼠C×43+/-in急性期诱发室性心律失常的可能性更高。有趣的是，与形态学伤口愈合相比，电恢复相当快。免疫组织化学观察到Cx43在间隙连接通道中的分布减少了基底偶联。间隙连接重构被认为是缺血性心脏心律失常发生的重要因素。人类心脏手术围手术期患者被认为处于与这些缺血模型相似的状态。对具有明确遗传缺陷的小鼠心肌梗死后心律失常的分析，将揭示这些蛋白在心肌梗死愈合患者或术后患者心源性猝死中的作用。细胞间通讯的改变是对心肌细胞损伤的基本反应，有助于心律失常的发生。基因改造小鼠的人类疾病模型对于了解心源性猝死的机制和从源头上预防它而不是一旦发生致命性心律失常就终止它是非常宝贵的。少

In Japan sudden cardiac death is common in patients who have survived myocardial infarction. Also many patients who have cardiac dysfunction have the high risk of sudden arrhythmic death. But the molecular mechanisms responsible for the lethal arrhythmia in such patients have not defined yet In order to gain insights about the role of critical arrhythmia we created the ischemia model in mice heterozygous for a major gap junction protein Cx43 null allele and wild type. The structural consequences following myocardial infarction (MI) were examined by echocardiography and histopathological study. Although post-infarction remodeling was not affected by diminished Cx43 expression in cardiac gap junctions, infarct size was smaller it C×43-deficient (C×43+/-) mice compared with wild type (C×43+/+). Implanted telemetry system revealed spontaneous ventricular arrhythmias occurred only in C×43+/-mice with infarction. Isolated hearts with healed myocardial infarction were analyzed by the arrhythm … More ia induction study. Ventricular tachycardia was induced in both Cx43+/-and +/+ hearts with MI. But the inducibility of ventricular arrhythmia was higher in C×43+/-in acute phase in mice with ischemia. Interestingly the electrica recovery was rather quick compared with morphological wound healing. Reduced basal coupling was observed as the distribution of Cx43 in gap junction channel which was visualized by immunohistochemical study. Gap junction remodeling was considered as an essential factor of arrhythmogenesis in heart with ischemic injury. Perioperative patients in human cardiac surgery are considered as being in the similar condition of these ischemic model. Analysis of arrhythmias following MI in mouse lines with defined genetic defects will shed light on the roles of these proteins in sudden cardiac death in patients with healed MI or post operative patients. Alterations in cell-cell communication occur as a fundamental response to myocyte injury which contributes to arrhythmogenesis. Human disease models in genetically altered mice are invaluable for mechanistic understanding of sudder cardiac death and to prevent it at its source instead of terminating a lethal arrhythmia once it occurred. Less