HUMAN ATRIAL FIBRILLATION--CHANGES IN CHANNEL EXPRESSION

100万美国人患有心房颤动， 常见的慢性心律失常心房颤动是导致 显著不适、发病率和死亡率。的机制 心房颤动的持续存在被认为 包括有效不应期的缩短， 心房，但电生理重构的细节 心房所经历的变化还知之甚少我们建议使用 一种新颖的、高度综合的方法来探索 完整的、分离的、 离体心房肌细胞钾电流和钙电流的分布 心肌细胞特异性钾通道和钙通道的表达 在同一心房组织的膜部分的亚基。的 该建议的具体目标是：1）评估利率依赖 心房波长的调制（动作电位持续时间， 不应期和传导速度 从正常窦性心律或慢性心房颤动患者中获得 纤维性颤动2)为了表征动作电位， 特定的K+成分，和电压门控的Ca 2+的密度 从相同的心房组织中分离的肌细胞中的电流， 目标#1。3）确定土壤的密度和相对分布， K+和CA 2+通道α亚单位负责功能性 在相同的心房组织和肌细胞中测量的电流， 目标#1和#2。4）将生物化学测量值（目的）关联起来， #3）电生理测量（目标#1和#2）， 并与临床测量期间获得的不应性 外科手术微电极，双极和光学 离体人心房肌电活动的测量 K+和Ca 2+的组织穿孔膜片全细胞记录 单个心房肌细胞中的电流，以及Western印迹分析 K+和Ca 2+通道（心房组织中的x-亚基表达， 将使用肌细胞来实现实验目的。 的 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 在人类心房中的表达。需要这些信息， 确定新的、更安全和更有效的战略， 治疗这种致残性心律失常，通过识别逻辑， 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.