Multichannel Modulation of Depolarizing and Repolarizing Ion Currents Increases the Positive Rate Dependence of Action Potential Prolongation

Abstract

ABSTRACTA pharmacological approach to prevent reentrant tachycardias is to prolong the action potential duration (APD) of the myocytes that provide the substrate for the arrhythmia. For such an anti-arrhythmic approach to be effective, APD prolongation should be positive rate dependent, that is, it should maximize APD prolongation at the fast excitation rates of tachycardia and minimize APD prolongation at slow excitation rates. 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 (INaL, ICaL, IKs, IKrand IK1) results in a stronger positive rate dependent APD prolongation than modulation of just repolarizing potassium currents (IKs, IKrand IK1); modulation of a single repolarizing current (IKr) results in reverse rate dependence. 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 shape. A positive rate dependent APD prolongation decreases the repolarization reserve with respect to control at slow excitation rates, which can be managed by interventions that prolong APD at fast excitation rates and shorten APD at slow excitation rates. Feature importance analysis shows that, for both computer models of the action potential, ICaLand IK1are 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 potential pro-arrhythmic risks.