This project is aimed at increasing the understanding of the role of potassium channels in the control of frequency dependent cardiac excitation, intermittent wave propagation and fibril latory conduction. We propose a multi-disciplinary approach to investigate the individual and cooperative roles in normal and abnormal excitability played by the strong inward rectifier Kir2.1 (KCNJ2) channel that is responsible for IK1 and the delayed rectifiers HERG (KCNH2) and KvLQT1(KCNQ1;/minK(KCNE1) forming the channels that carry IKr and IKs, respectively. Our main focus is the manner in which the degree of inward rectification of lK1 and the gating kinetics of IKrand IKs alone or in combination, modify the ability of cardiac electrical waves to propagate when interacting with anatomical or functional obstacles in their path. Our general hypothesis is that changes in the density of IK1, lKr and/or lK have sharp consequences on excitability and conduction, and thus on the dynamics of spatially distributed, intermittent wavelets that propagate through atrial and ventricular muscle during fibrillation. Our approaches span three different levels of integration: the cell, the two-dimensional myocyte monolayer and the three-dimensional heart. At the cellular level (Specific Aim 1), we take advantage of the tools of molecular biology, viral transfer and patch clamping to test unambiguously the idea that, in the presence of unchanged excitatory sodium and/or calcium currents, post-repolarization refractoriness and rate-dependent excitation are controlled by both the degree IK1 rectification and the kinetics of IKr and/or IKs gating. At the two-dimensional level (Specific Aim 2), we investigate and quantify the individual roles of these three different currents in wavebreak formation and the phenomenon of """"""""vortex shedding"""""""". Finally, at the level of the whole heart (Specific Aim 3), we use a transgenic approach and optical mapping to investigate the electrophysiological consequences of genetic mutations in Kir channels leading to greater outward IK1 density;and the effects of introducing IKs into the mouse genome on the dynamics of rotors and VF and their modification by autonomic input. Successful achievement of our objectives should help clarify the molecular mechanisms of wavebreak in cardiac fibrillation. The work proposed is directly relevant to the understanding of the pro-arrhythmic effects of gain-of-function changes in specific potassium channels that have been shown to occur in certain clinically conditions, including persistent AF, the short QT syndrome and idiopathic VF.
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