Memory, Remodeling and Ventricular Arrhythmias

描述（来自应用程序的逐字）：准确预测和预防 室性快速性心律失常的发生率会对 在美国每年约有30万人。然而， 这一领域是这样的，进一步努力识别，理解和 新方法的应用是必要的。因此， 建议的研究是寻求新的方向，了解基本的 心肌的可塑性，这样我们就可以故意诱导治疗 有益的重塑我们的假设是我们可以重塑离子 通道和缝隙连接，以防止发生潜在的致命 心律不齐我们的方法集中在心脏记忆的调制， 心室起搏可诱导的非病理性重塑 或心律失常，并与复极改变有关， 耐火度和间隙连接密度和分布。我们的协议专注于 论三追求的基本机制与临床表现的结合 目的：探讨（1）心脏记忆诱导的机制 正常人心室局部复极改变和不应性 与抗心律失常药物的相互作用; (2)缝隙连接重构的电生理意义 与正常和梗死、缺血心脏的心脏记忆有关; (3)电生理变化的离子和分子决定因素， 表征心脏记忆。该模型是长期仪器犬 有或无梗死，进行3周心脏起搏以诱导 记忆，并在临床替代品（有意识的狗）中进行研究， 心电图和心向量图技术。我们用心脏标测 以确定心室激动和复极特征， 有和无梗死的记忆设置，微电极技术， 确定细胞机制的变化，看到在 完整的动物研究，生物物理和分子技术，以了解 伴随着肌膜离子通道和缝隙连接的变化， 识别负责记忆的亚细胞机制， 与心律失常的相互作用。提案中还包括 实验旨在了解负责的机制， 抗癫痫药物作用的不可预测性，这可能是 药物记忆相互作用总体方法是还原论（要求 关于亚细胞水平机制的问题）和整合。我们认为 它将使我们能够理解和调节记忆和心律失常， 在临床环境中可预测和可再现地基于 信息导出。

DESCRIPTION (Verbatim from the application): Accurate prediction and prevention of ventricular tachyarrhythmias would have a major impact on the survival of approximately 300,000 persons/year in the US. Yet, the current status of the field is such that further efforts at identification, comprehension and application of novel approaches are warranted. Therefore, the goal of the proposed studies is to seek new directions for understanding the fundamental plasticity of myocardium such that we can deliberately induce therapeutically beneficial remodeling. Our general hypothesis is that we can remodel ion channels and gap junctions to prevent the occurrence of potentially lethal arrhythmias. Our approach focuses on the modulation of cardiac memory, a non-pathological form of remodeling that can be induced by ventricular pacing or arrhythmias and that is associated with altered repolarization, refractoriness and gap junctional density and distribution. Our protocols focus on integration of basic mechanism and clinical expression in pursuing three aims: to determine (1) the mechanisms underlying cardiac memory-induced regional ventricular alterations in repolarization and refractoriness in normal and arrhythmic infarcted hearts and the interaction with antiarrhythmic drugs; (2) the electrophysiological significance of the remodeling of gap junctions associated with cardiac memory in normal and infarcted, arrhythmic hearts; and (3) the ionic and molecular determinants of the electrophysiologic changes that characterize cardiac memory. The model is the chronically instrumented canine with or without infarction which undergoes 3 weeks of cardiac pacing to induce memory, and is studied in a clinical surrogate (the conscious dog) using electrocardiographic and vectorcardiographic techniques. We use cardiac mapping to determine ventricular activation and repolarization characteristics in the setting of memory with and without infarction, microelectrode techniques to determine the cellular mechanisms responsible for the changes seen in the intact animal studies, and biophysical and molecular techniques to understand accompanying sarcolemmal ion channel and gap junctional changes with the intent of identifying the subcellular mechanisms responsible for memory and its interaction with arrhythmias. Incorporated in the proposal as well are experiments aimed at understanding the mechanisms responsible for the unpredictability of antiarrhythmic drug actions, which may be a consequence of drug-memory interactions. The overall approach is both reductionist (asking questions about mechanism at the subcellular level) and integrative. We believe it will permit us to understand and to modulate memory and arrhythmias predictably and reproducibly in a clinical setting based on the mechanistic information derived.