Memory, Remodeling and Ventricular Arrhythmias

描述(来自应用程序的逐字)：准确的预测和预防 室性快速性心律失常会对患者的存活率产生重大影响 在美国，每年大约有30万人。然而，目前的状况是 领域是这样的，即进一步努力识别、理解和 新方法的应用是有必要的。因此，我们的目标是 提出的研究是为了寻求理解基本的新方向 心肌的可塑性，以至于我们可以通过治疗来刻意诱导 有益的重塑。我们的普遍假设是，我们可以对离子进行重新建模 渠道和缝隙连接，以防止发生潜在的致命 心律不齐。我们的方法侧重于心脏记忆的调节，一种 可由心脏起搏引起的非病理形式的重构 或心律不齐，并与改变的复极相关， 耐火度和缝隙结密度及分布。我们的协议重点是 论追求三个统一的基本机制与临床表现 目的：确定(1)心脏记忆诱导的机制 正常人复极和不应期的局部室壁改变 心律失常、心肌梗死及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 与正常和梗死性心律失常心脏的心脏记忆有关；以及 (3)电生理改变的离子和分子决定因素 以心脏记忆为特征。模型是慢性仪器化犬科动物 伴或不伴心肌梗死3周心脏起搏诱导 记忆，并在临床代用品(清醒的狗)中使用 心电图和心电向量图技术。我们使用心脏标测 目的：测定心肌梗死患者的心室激活和复极特征 在有和没有梗塞的情况下设置记忆，微电极技术 确定导致这些变化的细胞机制 完整的动物研究，以及生物物理和分子技术 伴随的肌膜离子通道和缝隙连接随意图的变化 识别负责记忆和记忆的亚细胞机制 与心律失常的相互作用。提案中还包括 实验的目的是了解导致这种现象的机制。 抗心律失常药物作用的不可预测性，这可能是 药物与记忆的相互作用。总体方法既是简化主义的(询问 关于亚细胞水平的机制的问题)和综合性。我们相信 它将允许我们理解和调节记忆和心律失常 在基于机理的临床环境中可预测且可重现 派生的信息。

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.