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，我们的团队在过去多年中对此做出了重大贡献。我们的具体目标是：1）探测从犬心脏分离的心房与心室细胞的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心房选择性钠通道抑制和通过INa阻断剂抑制心房纤颤; 2）确定犬右心房中发现的电和药理学异质性在多大程度上存在于左心房中; 3）确定在正常狗的犬右心房和左心房中发现的电和药理学异质性与从心力衰竭狗（HF）分离的相应组织和细胞的电和药理学异质性的不同程度; 4）评估在从心力衰竭狗分离的心房中发生心房纤颤的倾向，并定义作为纤颤发生基础的底物和触发因素。5)评估不同类型的钠通道阻滞剂在终止和抑制AF再诱导方面的有效性，确定这些药物在多大程度上是心房选择性的，以及所涉及的机制; 6）探索在HF犬中负责钠通道阻滞剂抗AF作用的心房选择性钠通道阻滞的基础;和7）评估副交感神经激动剂对从正常和心力衰竭狗分离的心房中AF发展的影响。我们的建议的主要目标是探讨在何种程度上存在的电异质性之间的右，左心房和心室的犬心脏，并研究如何放大这些异质性有助于房性和室性心律失常的发展，在正常的心脏，以及在结构受损的心脏与起搏诱导的扩张型心肌病的狗隔离。该项目是一个临床相关的研究调查，旨在提高我们对房性心律失常的发展和治疗方法的理解。中心焦点涉及对钠通道的心房选择性调节可以在不显著改变心室电生理学的情况下预防AF的假设的测试，这是创新和令人兴奋的，并且有可能在AF的药理学治疗方法中产生范式转变，AF是我们社会面临的最大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，从而为开发新疗法创造一个独特的平台，这些疗法可能会进入临床。 公共卫生相关性：心房颤动（AF）是临床上最常见的持续性心律失常，影响约250万美国人。它的流行与年龄有关，随着人口老龄化而急剧增加，达到了流行病一词的程度。AF是与充血性心力衰竭（CHF）相关的主要并发症，在美国影响约500万患者，是住院和死亡的主要原因。目前可用的治疗方案都有内在的局限性，迫切需要新的方法来药物管理房颤。安全有效的房颤药物治疗是我们社会面临的最大未满足的医疗需求之一。成功完成本次竞争性更新中提出的研究将显著推进这一目标，并导致开发创新和有效的AF药物治疗。

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.