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 I_Kr) 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 (I_NaL, I_CaL, I_Kr, and I_NaCa), 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.