Development of Novel Approaches for the Pharmacologic Treatment of Atrial Fibrill

7.项目摘要 我们的建议旨在表征心房和心室固有的电异质性 心肌，我们的团队在过去的许多年里做出了巨大的贡献。我们的具体 目的是：1）探讨心房与心室钠通道和动作电位特性的差异， 从犬心脏分离的cular细胞，并评估这些差异如何有助于心房选择性so- 通过INa阻断剂抑制dium通道和抑制房颤; 2）确定在何种程度上 在犬右心房中发现的电和药理学异质性存在于左心房中; 3） 确定在犬右侧和左侧中发现的电气和药理学异质性的程度 正常犬的心房不同于从心力衰竭犬（HF）分离的相应组织和细胞的心房; 4)评估从心力衰竭犬分离的心房中发生房颤的倾向， 定义了肿瘤发生的基质和触发因素。5)评估不同的有效性 钠通道阻滞剂在终止和抑制AF再诱导中的类别，确定 这些药物是心房选择性的程度，以及所涉及的机制; 6）探索心房选择性的基础 钠通道阻滞剂在HF犬中的抗AF作用;和7）作为- 探讨副交感神经激动剂对离体正常心房房颤发生的影响， 心力衰竭的狗我们的建议的主要目标是探讨在何种程度上，电气异质- 基因之间存在的右和左心房和心室的狗的心脏，并检查如何， 这些不均一性的扩大有助于房性和室性心律失常的发展， 正常心脏以及从起搏诱导的狗中分离的结构受损的心脏 扩张型心肌病拟议的项目是一个临床相关的研究调查，旨在推进 我们对房性心律失常的发展和治疗方法的理解。中心焦点涉及 心房选择性调节钠通道可以预防AF，而不需要显著的 巧妙地改变心室电生理学是创新和令人兴奋的，并有可能产生一个pa- AF药物治疗方法的根本性转变，这是最大的未满足医疗需求之一 面对我们的社会。该项目的成功完成还将确定离子和细胞机制 有助于心房选择性，从而为开发新疗法创造了独特的平台 可能会被送到医院

7. Project Summary Abstract Our proposal is designed to characterize the electrical heterogeneity intrinsic to the atrial and ventricular myocardium, to which our group has contributed significantly over the past many years. Our specific aims are to: 1) probe differences in sodium channel and action potential characteristics of atrial vs. ventri- cular cells isolated from the canine heart and assess how these distinctions contribute to atrial-selective so- dium channel inhibition and suppression of atrial fibrillation by INa blockers; 2) determine to what extent the electrical and pharmacologic heterogeneities uncovered in the canine right atrium exist in the left atrium; 3) determine to what extent electrical and pharmacologic heterogeneities uncovered in canine right and left atria of normal dogs differ from those of respective tissues and cells isolated from heart failure dogs (HF); 4) assess the propensity for the development of atrial fibrillation in atria isolated from heart failure dogs and define the substrate and triggers that underlie arrhythmogenesis. 5) assess the effectiveness of different classes of sodium channel blockers in terminating and suppressing re-induction of AF, determine to what extent these agents are atrial-selective, and the mechanisms involved; 6) probe the basis for atrial-selective sodium channel block responsible for the anti-AF effects of sodium channel blockers in HF dogs; and 7) as- sess the influencee of parasympathetic agonists on the development of AF in atria isolated from normal and heart failure dogs. The principal goals of our proposal are to probe the extent to which electrical hetero- geneities exist between the right and left atrium and ventricles of the canine heart and examine how am- plification of these heterogeneities contributes to the development of atrial and ventricular arrhythmias in the normal heart as well as in structurally compromised hearts isolated from dogs with pacing-induced dilated cardiomyopathy. The proposed project is a clinically relevant research inquiry designed to advance our understanding of atrial arrhythmia development and approach to therapy. The central focus involving a test of the hypothesis that atrial-selective modulation of the sodium channel can prevent AF without signifi- cantly altering ventricular electrophysiology is innovative and exciting and has the potential to produce a pa- radigm shift in the pharmacologic approach to therapy of AF, one of the greatest unmet medical needs facing our society. Successful completion of the project will also identify the ionic and cellular mechanisms that contribute to atrial selectivity, thus creating a unique platform for the development of novel therapies that could potentially find their way to the bedside.