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

心源性猝死在存活的心肌梗塞(MI)患者中很常见，但相关的分子机制复杂且尚未明确。为了便于建立小鼠模型，以确定心肌梗塞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冠脉阻断创建了MI，主要缝隙连接蛋白Cx43零等位基因和野生型杂合子。为了描述心肌梗塞的结构性后果，我们使用了超声心动图。术后1周和10周，左室舒张末期容量均随梗死面积增加而增加。然而，在野生型和Cx43缺陷型小鼠中，左室舒张末期容量和梗塞面积之间的关系没有发现差异。Cx43表达减弱并不影响梗死后重构与梗塞面积的关系。采用体外刺激诱发室性心动过速(VT)的方法对已治愈的MI患者的心脏进行分析。在两个Cx…中均诱导出VT更多的43颗/和/心脏患有心肌梗死。对脑室切片进行组织学检查。与/鼠相比，Cx43/-鼠的脑梗塞面积较小。对心肌梗死的特殊形态特征进行评估，包括心肌梗死是否是跨壁心肌梗死，有无室壁瘤样扩张，梗死区间质纤维化斑片状，以及心内膜下心肌细胞存活。在可诱发室性心动过速的心脏中，心内膜下可见一层存活的心肌细胞，但这一特征在Cx43/-和//心脏中的发生情况相似。Cx43/-和/或Cx43/-和/或Cx43/-心肌梗死后重构的其他特征与心梗愈合后心律失常和收缩功能障碍的发生频率相同。基础偶联降低本身并不会显著改变心肌梗死愈合或心肌梗死后重构。对有明确遗传缺陷的小鼠心肌梗死后心律失常的分析将有助于阐明这些蛋白在治愈的心肌梗死患者心源性猝死中的作用。较少

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