Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Heart Rhythm. 2012 Apr;9(4):600-7. doi: 10.1016/j.hrthm.2011.11.025. Epub 2011 Nov 16.
Reduced expression of connexin43 (Cx43) and sodium channel (Nav1.5) and increased expression of collagen (fibrosis) are important determinants of impulse conduction in the heart.
To study the importance and interaction of these factors at very low Cx43 expression, inducible Cx43 knockout mice with and without inducible ventricular tachycardia (VT) were compared through electrophysiology and immunohistochemistry.
Cx43(CreER(T)/fl) mice were induced with tamoxifen and killed after 2 weeks. Epicardial activation mapping was performed on Langendorff-perfused hearts, and arrhythmia vulnerability was tested. Mice were divided into arrhythmogenic (VT+; n = 13) and nonarrhythmogenic (VT-; n = 10) animals, and heart tissue was analyzed for Cx43, Nav1.5, and fibrosis.
VT+ mice had decreased Cx43 expression with increased global, but not local, heterogeneity of Cx43 than did VT- mice. Nav1.5-immunoreactive protein expression was lower in VT+ than in VT- mice, specifically at sites devoid of Cx43. Levels of fibrosis were similar between VT- and VT+ mice. QRS duration was increased and epicardial activation was more dispersed in VT+ mice than in VT- mice. The effective refractory period was similar between the 2 groups. Premature stimulation resulted in a more severe conduction slowing in VT+ than in VT- hearts in the right ventricle. Separate patch-clamp experiments in isolated rat ventricular myocytes confirmed that the loss of Cx43 expression correlated with the decreased sodium current amplitude.
Global heterogeneity in Cx43 expression and concomitant heterogeneous downregulation of sodium-channel protein expression and sodium current leads to slowed and dispersed conduction, which sensitizes the heart for ventricular arrhythmias.
连接蛋白 43（Cx43）和钠通道（Nav1.5）表达减少以及胶原蛋白（纤维化）表达增加是心脏冲动传导的重要决定因素。
在 Cx43 低表达的情况下，研究这些因素的重要性及其相互作用，通过电生理学和免疫组织化学比较诱导型 Cx43 敲除小鼠和诱导型室性心动过速（VT）的 Cx43 敲除小鼠。
用他莫昔芬诱导 Cx43（CreER（T）/fl）小鼠，2 周后处死。对 Langendorff 灌流心脏进行心外膜激活映射，并进行心律失常易感性测试。将小鼠分为致心律失常（VT+；n=13）和非致心律失常（VT-；n=10）两组，分析心脏组织的 Cx43、Nav1.5 和纤维化。
VT+小鼠的 Cx43 表达减少，与 VT-小鼠相比，Cx43 表达的整体异质性增加，局部异质性不变。Nav1.5 免疫反应性蛋白在 VT+小鼠中的表达低于 VT-小鼠，特别是在没有 Cx43 的部位。VT-和 VT+小鼠之间的纤维化水平相似。与 VT-小鼠相比，VT+小鼠的 QRS 持续时间延长，心外膜激活更分散。2 组的有效不应期相似。在右心室中，VT+小鼠的过早刺激导致传导速度减慢比 VT-小鼠更严重。在分离的大鼠心室肌细胞的单独贴附斑实验中证实，Cx43 表达的丧失与钠电流幅度减少的钠通道蛋白表达的异质性下调相关。
Cx43 表达的整体异质性以及钠通道蛋白表达和钠电流的异质性下调导致传导减慢和分散，使心脏容易发生室性心律失常。
