Connexin43 as a determinant of arrhythmia inducibility in cardiac gap junction of infarct heart

心源性猝死在心肌梗死（MI）存活患者中很常见，但其分子机制复杂且不明确。为了促进小鼠模型的发展，以确定心肌梗死后致死性心律失常的关键基因产物，我们在C57BL/6J小鼠中通过LAD冠状动脉闭塞建立了心肌梗死，C57BL/6J小鼠的主要间隙连接蛋白Cx43零等位基因和野生型杂合。为了描述心肌梗死的结构性后果，我们使用了超声心动图。手术后1周和10周，左室舒张末期容积随梗死面积增加。然而，在野生型和cx43缺陷小鼠中，左心室舒张末期容积和梗死面积之间的关系没有差异。梗死后重构作为梗死面积的功能不受Cx43表达减少的影响。对心肌梗死愈合的离体心脏采用外刺激法诱发室性心动过速（VT）进行分析。心肌梗死43例+/和+/+心脏均可诱发室速。与+/+小鼠相比，Cx43+/-小鼠的梗死面积较小。评估特定形态学特征，包括梗死是否为跨壁性或非跨壁性，是否存在心室动脉瘤扩张，梗死边界区斑块性间质纤维化，以及存活的心内膜下肌细胞。存活的心内膜下肌细胞层在可诱导室速的心脏中更为常见，但这一特征在Cx43+/和+/+心脏中也相似。梗死后重构的其他特征与心肌梗死愈合后心律失常和收缩功能障碍的发展有关，在Cx43 +/和+/+心脏中也以相同的频率观察到。减少基底偶联本身并不显著改变梗死愈合或心肌梗死后重构。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心源性猝死中的作用

Sudden cardiac death is common in patients who have survived myocardial infarction (MI), but the molecular mechanisms responsible are complex and poorly defined. To facilitate development of a mouse model to define gene products critical in lethal arrhythmia following MI, we created MI by LAD coronary occlusion in C57BL/6J mice heterozygous for a major gap junction protein Cx43 null allele and wildtype. To characterize structural consequences in MI, we used echocardiography. Left ventricular end-diastolic volume was increased as a function of infarct size at both 1 and 10 weeks after surgery. However, no differences in the relationship between left ventricular end-diastolic volume and infarct size were seen in wildtype and Cx43-deficient mice. Post-infarction remodeling as a function of infarct size was not affected by diminished Cx43 expression. Isolated hearts with healed MI were analyzed with extrastimulus protocol for inducing ventricular tachycardia (VT). VT was induced in both Cx … More 43+/-and +/+ hearts with MI. Ventricular sections were examined histologically. Infarct size was smaller in Cx43+/-mice compared with +/+ mice. Specific morphological features were evaluated including whether infarcts were transmural or non-transmural, and the presence or absence of ventricular aneurysmal dilatation, patchy interstitial fibrosis at infarct border zones, and surviving subendocardial myocytes. A layer of surviving subendocardial myocytes was seen more frequently in hearts in which VT could be induced but the occurrence of this feature was similar in Cx43+/-and +/+ hearts. The other features of post-infarct remodeling pertinent to development of arrhythmias and contractile dysfunction in hearts with healed infarcts were also observed with equal frequency in Cx43 +/-and +/+ hearts. Reduced basal coupling does not by itself significantly alter infarct healing or post-MI remodeling. 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. Less