Development of Novel Approaches for the Pharmacologic Treatment of Atrial Fibrill

描述（由申请人提供）：我们的提案旨在表征心房和心室心肌固有的电异质性，我们的团队在过去的许多年中对此做出了重大贡献。我们的具体目标是：1)探索从犬心脏分离的心房细胞和心室细胞钠通道和动作电位特征的差异，并评估这些差异如何有助于抑制心房选择性钠通道和抑制心房颤动的受体阻滞剂；2)确定犬右心房发现的电和药理学异质性在多大程度上存在于左心房；3)确定正常犬左右心房与心力衰竭犬（HF）分离的组织和细胞在何种程度上存在电性和药理学异质性；4)评估从心力衰竭犬分离的心房发生心房颤动的倾向，确定心律失常发生的底物和触发因素。5)评估不同类型的钠通道阻滞剂终止和抑制房颤再诱导的有效性，确定这些药物在多大程度上具有心房选择性，以及涉及的机制；6)探讨钠通道阻滞剂对HF犬心房选择性钠通道阻滞的基础；7)评估副交感神经激动剂对正常和心力衰竭犬心房房颤发展的影响。我们建议的主要目标是探讨犬心脏左右心房和心室之间存在的电异质性的程度，并检查这些异质性的放大如何促进正常心脏以及从起搏诱导扩张型心肌病犬分离的结构受损心脏的心房和室性心律失常的发展。拟议的项目是一个临床相关的研究调查，旨在促进我们对心房心律失常的发展和治疗方法的理解。心房选择性调节钠通道可以在不显著改变心室电生理的情况下预防房颤，这一假设的检验是创新和令人兴奋的，并有可能在房颤治疗的药理学方法中产生范式转变，这是我们社会面临的最大的未满足的医疗需求之一。该项目的成功完成还将确定有助于心房选择性的离子和细胞机制，从而为开发可能通往床边的新疗法创造一个独特的平台。

DESCRIPTION (provided by applicant): 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. ventricular cells isolated from the canine heart and assess how these distinctions contribute to atrial-selective sodium 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) assess the influence 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 heterogeneities exist between the right and left atrium and ventricles of the canine heart and examine how amplification 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 significantly altering ventricular electrophysiology is innovative and exciting and has the potential to produce a paradigm 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. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in the clinic, affecting an estimated 2.5 million Americans. Its prevalence is age-related and is increasing sharply with aging of the population, to the point where the term epidemic has been applied. AF is a major complication associated with congestive heart failure (CHF), which affects an estimated 5 million patients in the United States and is a major cause of hospitalization and mortality. Currently available therapeutic options all have intrinsic limitations and new approaches to the pharmacologic management of atrial fibrillation are critically needed. Safe and effective pharmacologic treatment for AF is one of the greatest unmet medical needs facing our society. Successful completion of the studies proposed in this competing renewal will significantly advance this goal and lead to the development of innovative and effective pharmacologic treatments for AF.