Strategies for prolonging ventricular action potential duration without increasing transmural dispersion of repolarization

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 action potential duration (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, mid-myocardial, and endocardial myocytes, we have identified strategies to prolong APD without increasing transmural dispersion of repolarization. The first strategy, which involves blocking several depolarizing and repolarizing ion channels (INaL, ICaL, IKr, and INaCa), can prolong APD while decreasing transmural APD dispersion by about 20%–60%, depending on the model. The second strategy, which involves the use of a combination of ion channel blockers and activators, can prolong APD while decreasing transmural APD dispersion by about 70%, a stronger reduction in transmural dispersion of repolarization than using only ion channel blockers. 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.