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- Creator:
- Mahajan, Aman, Weiss, James N., Sato, Daisuke, Peralta, Robert Jonathan, Garfinkel, Alan J., Baher, Ali, Shiferaw, Yohannes, Xie, Lai-Hua, Qu, Zhilin, and Olcese, Riccardo
- Description:
- 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.
- Resource Type:
- Article
- Identifier:
- 0006-3495
- Campus Tesim:
- Northridge
- Creator:
- Siegerman, Carin L., Shivkumar, Kalyanam, Garfinkel, Alan J., Baher, Ali, and Shiferaw, Yohannes
- Description:
- It is well documented that parasympathetic stimulation leads to atrial arrhythmias. Because acetylcholine abolishes the dome portion of an action potential (AP), phase 2 reentry (P2R), reentry due to propagation of the dome of an AP from areas with this dome to areas without it, may be the responsible mechanism. However, how exactly this happens remains unclear.
- Resource Type:
- Article
- Identifier:
- 1547-5271
- Campus Tesim:
- Northridge
- Creator:
- Yang, Ming-Jim, Karma, Alain, Mahajan, Aman, Chen, Peng-Sheng, Weiss, James N., Sato, Daisuke, Restrepo, Juan G., Baher, Ali, Shiferaw, Yohannes, Xie, Lai-Hua, Qu, Zhilin, Garfinkel, Alan J., and Olcese, Riccardo
- Description:
- Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Cai) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using an existing rabbit ventricular action potential model, we modified the L-type calcium (Ca) current (ICa,L) and Cai cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35–37°C. Incorporating a minimal seven-state Markovian model of ICa,L that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Cai cycling model, the new model replicates experimentally observed action potential duration and Cai transient alternans at rapid heart rates, and accurately reproduces experimental action potential duration restitution curves obtained by either dynamic or S1S2 pacing.
- Resource Type:
- Article
- Identifier:
- 0006-3495
- Campus Tesim:
- Northridge
- Creator:
- Lynch, Adam, Mahajan, Aman, Weiss, James N., Dave, Amish S., Valderrabano, Miguel, Baher, Ali, Shiferaw, Yohannes, Xie, Lai-Hua, Qu, Zhilin, Diego, Carlos De, and Olcese, Riccardo
- Description:
- In homogenous tissue, conduction velocity restitution (CVR) is required for the development of spatially discordant alternans (SDA) except after an ectopic beat. We hypothesized that global capture of monolayers would eliminate CV gradients and SDA would arise from calcium (Ca) dynamics in the absence of CVR involvement.
- Resource Type:
- Article
- Identifier:
- 1547-5271
- Campus Tesim:
- Northridge
- Creator:
- Snoussi, Mehdi, Abasi, Lannah, Prokopzuk, Federico, Mahajan, Aman, Taheri-Argahi, Sattar, Ha, Bae-Yeun, Peralta, Robert Jonathan, Del Rosario, Nathan-Alexander, Baher, Ali, Shiferaw, Yohannes, Xie, Lai-Hua, Qu, Zhilin, Talledo, Paul, and Weiss, James N.
- Description:
- Ventricular fibrillation (VF) is characterized by multiple reentrant waves promoted by both dynamical instabilities and anatomical heterogeneities. Decreasing dynamic wave instability by flattening action potential duration restitution (APDR) slope with drugs which block the L-type calcium current, such as verapamil and D600, has been shown to convert VF to VT. However, the doses required also severely depress contractility. We hypothesized that blocking Ca-induced inactivation of the L-type Ca current, while maintaining a normal APD, will flatten APDR slope without severely depressing the intracellular Ca transient and contractility.
- Resource Type:
- Article
- Identifier:
- 1547-5271
- Campus Tesim:
- Northridge
- Creator:
- Mahajan, Aman, Weiss, James N., Baher, Ali, Shiferaw, Yohannes, Xie, Lai-Hua, Qu, Zhilin, and Olcese, Riccardo
- Description:
- Ventricular fibrillation (VF), a leading cause of sudden cardiac death, is due multiple re-entrant waves created as a result of spiral wave break-up. Dynamic wave instabilities can cause spontaneous wavebreak, leading to a fibrillation like state even in completely homogenous tissue. L-type calcium current (ICa,L) modulates two major determinants of dynamic wave stability, APD (action potential duration) restitution and calcium cycling, and hence, can serve as a potential therapeutic target. The essential aims of this study are to 1) develop a new model of rabbit ventricular myocyte ICa,Lbased on experimental data acquired under physiological conditions 2) develop a computationally tractable ventricular AP model that incorporates the new ICa,Lformulation and quantitatively reproduces the nonlinear aspects of the experimentally observed cardiac dynamics at rapid heart rates.
- Resource Type:
- Article
- Identifier:
- 1547-5271
- Campus Tesim:
- Northridge
- Creator:
- Garfinkel, Alan J., Baher, Ali, Shiferaw, Yohannes, Hayat-Davoudi, Ashkan, and Qu, Zhilin
- Description:
- The mechanism of initiation of ventricular fibrillation (VF) in normal and diseased heart is poorly understood. It has been shown that VF starts with a simple reentry, or ventricular tachycardia (VT), which then degenerates into the multiple meandering wavelets that characterize VF. Although a steeply-sloped action potential duration restitution (APDR) curve promotes the transition of VT to VF, its role in the initiation of reentry is less clear. We performed a comprehensive study using a detailed anatomic model of the canine heart to investigate the role of APDR in initiating reentry by a single extrastimulus (S2).
- Resource Type:
- Article
- Identifier:
- 1547-5271
- Campus Tesim:
- Northridge