ELECTROPHYSIOLOGY OF CARDIAC DYSSYNCHRONY AND CRT

心脏不同步的电生理学和 CRT

• 批准号: 6951261
• 负责人: Gordon Frank Tomaselli
• 金额: $ 25.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951261
• 关键词: action potentials; arrhythmia; autonomic nervous system; disease /disorder model; dogs; electronic pacemaker; electrophysiology; gap junctions; gene expression; gene expression profiling; heart conduction system; heart contraction; heart disorder; heart electrical activity; heart failure; ion transport; mechanical stress; membrane channels; membrane transport proteins; messenger RNA; perfusion; proteomics; sarcolemma; tissue /cell preparation

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.

在具有脱位收缩的心脏失败的心脏中，在最高区域壁应力下的晚期激活区域（外侧心内膜）表现出降低的关键兴奋性和钙处理蛋白质和间隙连接通道蛋白的表达降低。即使没有心力衰竭（HF），左束分支块引起的持续脱节也会改变区域组织电生理学。我们的初步数据表明，相对于传导速度和难治性，前/隔膜（低负载）和侧（高负载）壁之间的差异是差异，这在心内膜下特别明显。我们假设异质性的心脏异质机械负载夸张 仅HF产生的区域传导和磨性的区域分散。此外，早期和晚期激活的心室室中的区域和晚期激活区域之间存在离子电流功能表达的显着区域和透壁差异。这些差异通过同时发生的HF有效加剧，导致心律不齐的敏感性增强，并通过收缩同步恢复而逆转。为了检验这些假设，我们将：1。表征区域电生理底物以及对灌注和光学映射的灌注心肌楔子中同步收缩的失败和非触发性心脏和非触发性心脏的易感性； 2。表征急性拉伸的影响和改变自主语调对 电生理底物和对室性心律不齐的易感性失败和非触发心脏与同步收缩失败和控制心脏的敏感性； 3。表征伴随着失败心脏的异议障碍的区域细胞电生理学。 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.