ELECTROPHYSIOLOGY OF CARDIAC DYSSYNCHRONY AND CRT

在不协调收缩的衰竭心脏中，处于最高区域壁应力（心内膜外侧）下的晚激活区域表现出关键兴奋性、钙处理蛋白和间隙连接通道蛋白的表达减少。即使没有心力衰竭（HF），左束分支阻滞引起的持续协调失调也会改变局部组织电生理。我们的初步数据表明，前/间隔（低负荷）和侧壁（高负荷）在传导速度和耐火度方面存在显著差异，这在心内膜下尤为明显。我们假设不同步收缩心脏的异质机械负荷会夸大

In failing hearts with discoordinate contraction, the late-activated territory, which is under highest regional wall stress (lateral endocardium), exhibits reduced expression of key excitability and calcium handling proteins and gap junction channel proteins. Even without heart failure (HF), sustained discoordination induced by left-bundle branch block alters regional tissue electrophysiology. Our preliminary data demonstrates marked disparities between the anterior/septal (low load) and lateral (high load) walls with respect to conduction velocity and refractoriness, which are particularly pronounced in the subendocardium. We hypothesize that heterogeneous mechanical load in dyssynchronously contracting hearts exaggerates regional dispersion of conduction and refractoriness beyond that produced by HF alone. Further, significant regional and transmural differences in the functional expression of ionic currents exist between early and late-activated regions of dyssynchronously contracting ventricles. These differences are potently exacerbated by concurrent HF resulting in enhanced arrhythmia susceptibility, and are reversed by restoration of contractile synchrony. In order to test these hypotheses we will: 1. Characterize the regional electrophysiological substrate and susceptibility to ventricular arrhythmias in synchronously and dyssynchronously contracting failing and non-failing hearts in perfused myocardial wedges using electrical and optical mapping; 2. Characterize the effect of acute stretch and altered autonomic tone on the electrophysiological substrate and susceptibility to ventricular arrhythmias in dyssynchronously contracting failing and non-failing hearts versus synchronously contraction failing and control hearts; 3. Characterize regional cellular electrophysiology accompanying dyssynchrony in failing hearts. We will contrast APs and ionic currents (Na, Ca, K, Na-Ca exchanger) in myocytes isolated from inner versus outer layers of the lateral and antero-septal walls in normal and failing hearts with or without dyssynchrony, and relate changes to corresponding mRNA and protein expression, expression profiling and analysis of the sarcolemma subproteome as well as optical APs and CaT described in Aim #1.