Multichannel modulation of depolarizing and repolarizing ion currents increases the positive rate‐dependent action potential prolongation

Prolongation of the action potential duration (APD) could prevent reentrant arrhythmias if prolongation occurs at the fast excitation rates of tachycardia with minimal prolongation at slow excitation rates (i.e., if prolongation is positive rate‐dependent). APD prolongation by current anti‐arrhythmic agents is either reverse (larger APD prolongation at slow rates than at fast rates) or neutral (similar APD prolongation at slow and fast rates), which may not result in an effective anti‐arrhythmic action. In this report we show that, in computer models of the human ventricular action potential, the combined modulation of both depolarizing and repolarizing ion currents results in a stronger positive rate‐dependent APD prolongation than modulation of repolarizing potassium currents. A robust positive rate‐dependent APD prolongation correlates with an acceleration of phase 2 repolarization and a deceleration of phase 3 repolarization, which leads to a triangulation of the action potential. A positive rate‐dependent APD prolongation decreases the repolarization reserve with respect to control, which can be managed by interventions that prolong APD at fast excitation rates and shorten APD at slow excitation rates. For both computer models of the action potential, I(CaL) and I(K1) are the most important ion currents to achieve a positive rate‐dependent APD prolongation. In conclusion, multichannel modulation of depolarizing and repolarizing ion currents, with ion channel activators and blockers, results in a robust APD prolongation at fast excitation rates, which should be anti‐arrhythmic, while minimizing APD prolongation at slow heart rates, which should reduce pro‐arrhythmic risks.