HUMAN ATRIAL FIBRILLATION--CHANGES IN CHANNEL EXPRESSION

100万美国人患有房颤，最多的是 常见的慢性心律失常。房颤是导致 严重的不适、发病率和死亡率。其作用机制 被认为与房颤的持续性有关 包括缩短药物的有效不应期 中庭，但电生理重建的细节 我们对心房所经历的情况知之甚少。我们建议使用 一种新的、高度整合的方法来探索这种关系 在完整的、隔离的 心房组织中钾电流和钙电流的分布 心肌细胞与特异性K和CA2通道的表达 同一心房组织膜组分中的亚单位。这个 该提案的具体目标是：1)评估依赖于利率的 心房波长的调制(动作电位时程， 不应期和传导速度)。 来自正常窦性心律或慢性心房节律的患者 纤颤。2)为了表征动作电位，密度 和电压门控钙离子的密度 从相同的心房组织分离的心肌细胞的电流- 目的#1.3)确定水母的密度和相对分布 K和CA2通道α亚基负责功能 在相同的心房组织和心肌细胞中测量的电流 目标#1和#2.4)来关联生化测量(目标 #3)电生理测量(目标#1和#2)， 并在临床上获得耐热的测量结果 外科手术。双极和光学微电极 人离体心房电活动的测量 组织，穿孔-贴片全细胞钾和钙记录 单个心房肌细胞电流及Western印迹分析 钾和钙通道(x-亚基在心房组织和 肌细胞将被用来完成实验目标。这个 拟议的实验将提供新的和基本的信息 慢性心房颤动对离子通道的影响 在人的心房中表达。需要此信息才能 确定新的、更安全、更有效的战略 治疗这种致残心律失常，通过识别符合逻辑的， 未来治疗干预的特定分子靶点。

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.