HUMAN ATRIAL FIBRILLATION--CHANGES IN CHANNEL EXPRESSION

一百万美国人患有心房颤动，这是最严重的 常见的慢性心律失常。心房颤动的原因是 显着的不适、发病率和死亡率。机制 据认为，参与心房颤动的持续存在 包括缩短有效不应期 心房，而是电生理重塑的细节 人们对心房所经历的情况知之甚少。我们建议使用 一种新颖的、高度集成的方法来探索这种关系 完整的、孤立的电生理特性之间 心房组织中 K 和 Ca2 电流的分布 肌细胞以及特定 K 和 ca2 通道的表达 同一心房组织的膜部分中的亚单位。的 该提案的具体目标是： 1）评估利率依赖 心房波长的调制（动作电位持续时间， 心房组织中的不应期和传导速度） 从正常窦性心律或慢性心房患者获得 颤动。 2) 表征动作电位、密度 特定 K 成分和电压门控 Ca2 的密度 从用于以下的相同心房组织中分离出的肌细胞中的电流： 目标#1。 3）确定密度和相对分布 K 和 CA2 通道 α 亚基负责功能 在相同的心房组织和肌细胞中测量的电流 目标#1 和#2。 4）关联生化测量（目标 #3）通过电生理学测量（目标#1和#2）， 以及在期间获得的不应期的临床测量 外科手术。微电极，双极和光学 离体人体心房电活动的测量 组织、穿孔补片全细胞记录 K 和 Ca2 单个心房肌细胞的电流和蛋白质印迹分析 K 和 Ca2 通道（心房组织中 x 亚基的表达和 肌细胞将用于实现实验目的。 的 拟议的实验将提供新颖和基本的信息 慢性心房颤动对离子通道的影响 在人类心房中表达。需要此信息 确定新颖、更安全、更有效的策略 通过识别逻辑来治疗这种致残性心律失常， 未来治疗干预的具体分子靶点。

One million Americans suffer from atrial fibrillation, the most common chronic arrhythmia. Atrial fibrillation is responsible for significant discomfort, morbidity and mortality. The mechanisms involved in the perpetuation of atrial fibrillation are thought to include a shortening of the effective refractory period of the atrium, but the details of the electrophysiological remodeling which the atria undergoes are poorly understood. We propose to use a novel, highly integrated approach to explore the relationship between the electrophysiological properties of the intact, isolated atrial tissue, the distribution of K+ and Ca2+ currents in isolated myocytes, and the expression of specific K+ and ca2+ channel subunits in the membrane fractions of the same atrial tissue. The specific aims of the proposal are: 1)To evaluate the rate-dependent modulation of atrial wavelength (action potential duration, refractory period, and conduction velocity) in atrial tissue obtained from patients in normal sinus rhythm or in chronic atrial fibrillation. 2) To characterize the action potentials, the density of specific K+ components, and the density of voltage-gated Ca2+ current in myocytes isolated from the same atrial tissue used in - aim #1. 3)To determine the density and relative distribution of the K+ and CA2+ channel alpha subunits responsible for the functional currents measured in the same atrial tissue and myocytes used in aims #1 and #2. 4)To correlate the biochemical measurements (aim #3) with the electrophysiological measurements (aims #1 and #2), and with clinical measures of refractoriness obtained during surgical procedures. Microelectrode, bipolar and optical measurements of electrical activity in isolated human atrial tissue, perforated-patch whole cell recording of K+ and Ca2+ currents in individual atrial myocytes, and Western blot analysis of K+ and Ca2+ channel (x-subunits expression in atrial tissue and myocytes will be used to accomplish the experimental aims. The proposed experiments will provide novel and fundamental information on the impact of chronic atrial fibrillation on ion channel expression in the human atrium. This information is needed to identify novel, safer and more effective strategies for the treatment of this disabling arrhythmia, by identifying logical, specific molecular targets for future therapeutic interventions.