Development of Novel Approaches for the Pharmacologic Treatment of Atrial Fibrill

心房颤动药物治疗新方法的开发

• 批准号: 8204914
• 负责人: Charles Antzelevitch
• 金额: $ 43.75万
• 依托单位: MASONIC MEDICAL RESEARCH LABORATORY, INC
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204914
• 关键词: Action Potentials; Affect; Aging; Agonist; American; Arrhythmia; Atrial Fibrillation; Calcium; Canis familiaris; Cells; Characteristics; Clinic; Complication; Congestive Heart Failure; Development; Dilated Cardiomyopathy; Drug Combinations; Effectiveness; Electrophysiology (science); Epidemic; Goals; Heart; Heart Atrium; Heart failure; Heterogeneity; Homeostasis; Hospitalization; Laboratories; Lead; Left; Left atrial structure; Medical; Medication Management; Myocardium; Patients; Pharmacology; Phase; Play; Population; Preparation; Prevalence; Pulmonary veins; Research; Research Design; Right atrial structure; Role; Societies; Sodium Channel; Sodium Channel Blockers; Staging; Testing; Therapeutic; Tissues; United States; Ventricular; Ventricular Arrhythmia; Ventricular Function; abstracting; age related; base; clinically relevant; design; innovation; mortality; novel; novel strategies; prevent

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.

7. 项目概要摘要 我们的建议旨在描述心房和心室固有的电不均匀性 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) 探究心房与心室钠通道和动作电位特征的差异 从犬心脏中分离出的细胞，并评估这些区别如何促进心房选择性 INa 阻滞剂对钠通道的抑制和心房颤动的抑制； 2）确定到什么程度 在犬右心房中发现的电学和药理学异质性也存在于左心房中； 3） 确定犬左右两侧电学和药理异质性的程度 正常犬的心房与从心力衰竭犬（HF）中分离出的相应组织和细胞不同； 4) 评估从心力衰竭犬中分离出的心房发生房颤的倾向， 定义心律失常发生的底物和触发因素。 5）评估不同方法的有效性 钠通道阻滞剂在终止和抑制房颤再诱发方面的类别，确定 这些药物的心房选择性程度以及所涉及的机制； 6) 探查心房选择性的基础 钠通道阻滞剂负责钠通道阻滞剂对心衰犬的抗房颤作用； 7) 作为- 评估副交感神经激动剂对正常心房和心房房颤发生的影响 心力衰竭的狗。我们提案的主要目标是探讨电异质性的程度 犬心脏的左右心房和心室之间存在遗传性，并检查它们是如何- 这些异质性的扩大导致房性和室性心律失常的发生 正常心脏以及从起搏引起的狗中分离出的结构受损的心脏 扩张型心肌病。拟议的项目是一项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 检验以下假设：钠通道的心房选择性调节可以预防 AF，但没有显着性 巧妙地改变心室电生理学是创新的、令人兴奋的，并且有潜力产生一种 房颤治疗的药理学方法发生彻底转变，房颤是最大的未满足的医疗需求之一 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独特的平台 这可能会进入床边。