Abstract
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/Ca i 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 411-423 |
| Number of pages | 13 |
| Journal | Biophysical Journal |
| Volume | 94 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 15 2008 |
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ASJC Scopus subject areas
- Biophysics
Cite this
Modifying L-type calcium current kinetics : Consequences for cardiac excitation and arrhythmia dynamics. / Mahajan, Aman; Sato, Daisuke; Shiferaw, Yohannes; Baher, Ali; Xie, Lai Hua; Peralta, Robert; Olcese, Riccardo; Garfinkel, Alan; Qu, Zhilin; Weiss, James N.
In: Biophysical Journal, Vol. 94, No. 2, 15.01.2008, p. 411-423.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Modifying L-type calcium current kinetics
T2 - Consequences for cardiac excitation and arrhythmia dynamics
AU - Mahajan, Aman
AU - Sato, Daisuke
AU - Shiferaw, Yohannes
AU - Baher, Ali
AU - Xie, Lai Hua
AU - Peralta, Robert
AU - Olcese, Riccardo
AU - Garfinkel, Alan
AU - Qu, Zhilin
AU - Weiss, James N.
PY - 2008/1/15
Y1 - 2008/1/15
N2 - 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/Ca i 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.
AB - 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/Ca i 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.
UR - http://www.scopus.com/inward/record.url?scp=38349042115&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38349042115&partnerID=8YFLogxK
U2 - 10.1529/biophysj.106.98590
DO - 10.1529/biophysj.106.98590
M3 - Article
C2 - 18160661
AN - SCOPUS:38349042115
VL - 94
SP - 411
EP - 423
JO - Biophysical Journal
JF - Biophysical Journal
SN - 0006-3495
IS - 2
ER -