Akar Fadi G, Spragg David D, Tunin Richard S, Kass David A, Tomaselli Gordon F
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md 21205, USA.
Circ Res. 2004 Oct 1;95(7):717-25. doi: 10.1161/01.RES.0000144125.61927.1c. Epub 2004 Sep 2.
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.
心力衰竭（HF）与室性快速性心律失常导致的猝死风险增加相关。最近的研究表明复极异常，尤其是跨壁复极的过度不均一性，在非缺血性扩张型心肌病犬模型的多形性室性心动过速发生中起作用。在该模型中，传导异常在心律失常发生中所起的作用及其程度尚不确定。通过快速右心室起搏3至4周在犬身上诱发HF。从正常和衰竭犬的左心室和右心室分离出的动脉灌注犬楔形标本的心外膜和心内膜表面记录高分辨率光学动作电位。使用膜片钳记录、蛋白质印迹分析和免疫细胞化学研究传导的细胞和分子决定因素。HF与容积传导心电图的QRS时限显著延长（延长33%）以及左心室和右心室的心外膜和心内膜传导速度（CV）显著减慢（>20%）相关。左心室心外膜和心内膜层的Cx43表达降低>40%，但衰竭心脏的右心室中Cx43表达未改变。尽管心外膜Cx43表达高于心内膜，但心外膜CV始终较慢（P<0.01）。免疫细胞化学分析显示，在正常与衰竭样本中，Cx43与N-钙黏蛋白主要共定位，因为在衰竭组织中Cx43从闰盘重新分布到细胞侧边界。此外，在衰竭心脏的左心室和右心室中检测到低磷酸化Cx43显著（P<0.05）增加。正常和衰竭心脏分离的心室肌细胞的动作电位上升速度无差异（P=0.8，无显著性），Masson三色染色显示HF中纤维化含量无显著变化。非缺血性扩张型心肌病与CV显著减慢相关，这与Cx43表达降低无直接关系。Cx43磷酸化和定位的变化可能导致HF中的缝隙连接功能障碍、CV减慢和心律失常。
