DECREASING TRANSMURAL DISPERSION OF VENTRICULAR ACTION POTENTIAL REPOLARIZATION WITH MULTICHANNEL PHARMACOLOGY

Abstract

Dispersion of repolarization results from a non-homogeneous recovery of excitability in cardiac tissue, and it is an important factor in arrhythmogenesis because it could lead to the initiation and maintenance of a variety of arrhythmias. Antiarrhythmic agents that prolong APD by selectively blocking specific ion channels (like IKr) often increase dispersion of repolarization, which could result in a pro-arrhythmic risk. In this report, using computer models of the action potential of human epicardial and mid-myocardial myocytes, we have identified two strategies to prolong APD while reducing transmural dispersion of repolarization. The first strategy, which involves blocking several depolarizing and repolarizing ion channels (INaL, ICaL, IKr and INaCa), can reduce the transmural APD dispersion by about 20%. The second strategy, which involves the use of a combination of ion channel blockers and activators, results in a stronger reduction in transmural dispersion of repolarization than using only ion channel blockers. Enhancing IKs and blocking IKr can reduce transmural APD dispersion by about 70%. Our results suggest that a multichannel pharmacology strategy (as opposed to a single channel strategy), possibly using ion channel blockers and activators, can be effective at increasing APD while minimizing dispersion of repolarization.