No abstract

The L-type Ca current (I Ca,L ), essential for normal cardiac function, also regulates dynamic action potential (AP) properties that promote ventricular fibrillation. Blocking I Ca,L can prevent ventricular fibrillation, but only at levels suppressing contractility. We speculated that, instead of blocking I Ca,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 (CaM 1234 ) in rabbit ventricular myocytes to inhibit Ca-dependent I Ca,L inactivation, combined with the ATP-sensitive K current agonist pinacidil or I Ca,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 I Ca,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/Ca i transient alternans but maintained a normal Ca i transient. In simulated two-dimensional cardiac tissue, these changes prevented the arrhythmogenic spatially discordant APD/Ca i transient alternans and spiral wave breakup. These findings provide a proof-of-concept test that I Ca,L can be targeted to increase dynamic wave stability without depressing contractility, which may have promise as an antifibrillatory strategy.