ROLE OF POTASSIUM CHANNELS IN FRIBRILLATORY CONDUCTION

Upstate Medical University, Syracuse NY

Investigators

Linked publications & trials

Abstract

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