Modifying L-Type Calcium Current Kinetics: Consequences for Cardiac Excitation and Arrhythmia Dynamics

The L-type Ca current (ICa,L), essential for normal cardiac function, also regulates dynamic action potential (AP) properties that promote ventricular fibrillation. Blocking ICa,L can prevent ventricular fibrillation, but only at levels suppressing contractility. We speculated that, instead of blocking ICa,L, modifying its shape by altering kinetic features could produce equivalent anti-fibrillatory effects without depressing contractility. To test this concept experimentally, we overexpressed a mutant Ca-insensitive calmodulin (CaM1234) in rabbit ventricular myocytes to inhibit Ca-dependent ICa,L inactivation, combined with the ATP-sensitive K current agonist pinacidil or ICa,L blocker verapamil to maintain AP duration (APD) near control levels. Cell shortening was enhanced in pinacidil-treated myocytes, but depressed in verapamil-treated myocytes. Both combinations flattened APD restitution slope and prevented APD alternans, similar to ICa,L blockade. To predict the arrhythmogenic consequences, we simulated the cellular effects using a new AP model, which reproduced flattening of APD restitution slope and prevention of APD/Cai transient alternans but maintained a normal Cai transient. In simulated two-dimensional cardiac tissue, these changes prevented the arrhythmogenic spatially discordant APD/Cai transient alternans and spiral wave breakup. These findings provide a proof-of-concept test that ICa,L can be targeted to increase dynamic wave stability without depressing contractility, which may have promise as an antifibrillatory strategy.