Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy
Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy
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DOI：
10.1161/01.res.0000144125.61927.1c
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发表时间：
2004-10-01
影响因子：
20.1
通讯作者：
Tomaselli, GF
中科院分区：
文献类型：
--
作者：
Akar, FG;Spragg, DD;Tomaselli, GF
心力衰竭（HF）与室性快速性心律失常引起的猝死风险增加相关。最近的研究表明，在非缺血性扩张型心肌病犬模型中，复极异常，特别是跨壁复极的不均一性在多形性室性心动过速的发生中有夸大的作用。在该模型中，传导异常的存在和程度在胚胎发生中起作用尚不确定。通过快速RV起搏3至4周在犬中产生HF。从正常和衰竭犬的LV和RV分离的动脉灌注犬楔形制剂的心外膜和内膜表面记录高分辨率光学动作电位。采用膜片钳记录、Western印迹分析和免疫细胞化学研究了传导的细胞和分子决定因素。HF与容量传导心电图的QRS持续时间显著延长（33%）以及LV和RV的心外膜和心内膜传导速度（CV）显著减慢（>20%）相关。Cx43表达在LV的心外膜和内膜层中减少>40%，但在衰竭心脏的RV中没有变化。尽管心外膜Cx43表达高于心内膜Cx43表达，但心外膜CV始终较慢（P < 0.01）。免疫细胞化学分析显示，占主导地位的Cx43与N-钙粘蛋白在正常与失败的样品共定位，因为Cx43被重新分配从闰盘的细胞边缘在失败的组织。此外，在衰竭心脏的LV和RV中检测到低磷酸化的Cx 43显著增加（P < 0.05）。正常和衰竭心脏的离体心室肌细胞动作电位上行速度没有差异（P = 0.8，不显著），Masson三色染色显示HF中纤维化含量没有显著变化。非缺血性扩张型心肌病与CV显著减慢相关，而CV显著减慢与Cx43表达减少无直接关系。Cx43磷酸化和定位的变化可能导致HF中的间隙连接功能障碍、CV减慢和心律失常。
Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias. Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain. HF was produced in dogs by rapid RV-pacing for 3 to 4 weeks. High-resolution optical action potentials were recorded from epicardial and endocardial surfaces of arterially perfused canine wedge preparations isolated from LV and RV of normal and failing dogs. Cellular and molecular determinants of conduction were investigated using patch-clamp recordings, Western blot analysis, and immunocytochemistry. HF was associated with marked prolongation (by 33%) of the QRS duration of the volume conducted electrocardiogram and significant (>20%) slowing of epicardial and endocardial conduction velocities (CV) in both LV and RV. Cx43 expression was reduced by >40% in epicardial and endocardial layers of the LV, but was unchanged in the RV of failing hearts. Despite greater epicardial than endocardial Cx43 expression, epicardial CV was consistently slower (P < 0.01). Immunocytochemical analysis revealed predominant colocalization of Cx43 with N-cadherin in normal versus failing samples, because Cx43 was redistributed from the intercalated disk to lateral cell borders in failing tissue. Moreover, a significant (P < 0.05) increase in hypophosphorylated Cx43 was detected in the LV and RV of failing hearts. Action potential upstroke velocities in isolated ventricular myocytes from normal and failing hearts were not different (P = 0.8, not significant), and Masson trichrome staining revealed no significant change in fibrosis content in HF. Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression. Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF.