HUMAN ATRIAL FIBRILLATION--CHANGES IN CHANNEL EXPRESSION

点击翻译按钮获取中文摘要

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.