Development of Novel Approaches for the Pharmacologic Treatment of Atrial Fibrill

7.项目摘要摘要 我们的建议是为了描述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对此做出了重大贡献。我们的特定 目的：1)探讨心房和心室肌钠离子通道和动作电位特征的差异。 从犬心脏分离出肌细胞，并评估这些差异是如何促进心房选择性SO-2的。 钠通道抑制和INA阻滞剂对心房颤动的抑制；2)确定 犬右心房存在电和药理异质性，左心房存在电和药理异质性； 确定犬左侧和右侧电学和药理学异质性的程度 正常犬的心房不同于心衰犬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，以及 明确心律失常发生的基础和触发因素。5)评估不同方案的有效性 钠通道阻滞剂在终止和抑制房颤再诱导中的作用 这些药物对心房选择性的程度及其作用机制；6)探讨心房选择性的基础 钠通道阻滞剂对心力衰竭犬的抗房颤作用；以及7)AS- 副交感神经激动剂对正常及正常成人心房颤动发生的影响 心力衰竭的狗。我们建议的主要目标是探索电子异质结在多大程度上 犬心脏的左、右心房和左心室之间存在遗传，并研究如何- 这些异质性的放大有助于房性和室性心律失常的发生。 起搏诱导犬的正常心脏和结构受损的心脏 扩张型心肌病。拟议的项目是一项与临床相关的研究调查，旨在推动 我们对房性心律失常发展的认识和治疗方法。中心关注点涉及 心房选择性钠通道调变可预防房颤的假说检验 改变心室电生理学是创新和令人兴奋的，并有可能产生一种新的 房颤最大的未得到满足的医疗需求之一--治疗房颤的药理学方法的放射学转变 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 这有助于心房的选择性，从而为开发新的疗法创造了一个独特的平台 可能会找到他们躺在床边的方法。

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.