Modifying L-type calcium current kinetics: consequences for cardiac excitation and arrhythmia dynamics.
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.
Mahajan
Aman
A
UCLA Cardiovascular Research Laboratory, Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Sato
Daisuke
D
Shiferaw
Yohannes
Y
Baher
Ali
A
Xie
Lai-Hua
LH
Peralta
Robert
R
Olcese
Riccardo
R
Garfinkel
Alan
A
Qu
Zhilin
Z
Weiss
James N
JN
D000200:Action Potentials; D000256:Adenoviridae; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology; D011817:Rabbits
D020746:Calcium Channels, L-Type; D002147:Calmodulin; D050505:Mutant Proteins; D049452:Green Fluorescent Proteins