The goal of this Program Project is to develop novel antiarrhythmic approaches based on improved understanding of the arrhythmia mechanisms causing sudden cardiac death. Project 4 will combine biological experiments and mathematical modeling to study how the interaction between the L-type Ca curret (l{Ca,L}), the Ca{i} transient and other Ca-sensitive currents lead to early afterdepolarizations (EADs) in normal and failing ventricular myocytes (Aim 1). This analysis will then be used to guide development of therapeutic strategies to suppress EADs and EAD-mediated arrhythmias by modifying I{Ca,L} properties (Aim 2). We will utilize the dynamic patch clamp approach which permits virtual currents to be added and interact bidirectionally with the endogenous currents of a live myocyte. EADs will be induced with various interventions, and then suppressed by the Ca channel blocker nifedepine. In stages, the dynamic clamp will add back a virtual I{Ca,L} virtual Ca;transient, and other Ca-sensitive currents to determine the necessary interactions required to reconstitute EADs. Given the critical importance of the I{Ca,L} window current in EAD formation, we will use the dynamic clamp approach to explore how the kinetic and/or voltage dependent properties of I{Ca,L} can be modified to suppress """"""""reconstituted"""""""" EADs in isolated myocytes. The normal I{Ca,L} in the dynamic clamp will be replaced with an appropriately modified virtual I{Ca,L} to identify which modifications eliminate EADs while preserving a normal Ca{i} transient (Aim 2a). Using this information, we will explore genetic modifications of I{Ca,L} in rabbit ventricular myocytes to identify interventions which suppress EADs without adversely affecting E-C coupling, using two strategies: i) genetic overexpression of ancillary Ca channel subunits to replace the corresponding native Ca channel subunits. ii) downregulation of native Ca channel subunits in the adult rabbit ventricular myocytes using appropriate viral vectors. These hybrid modeling/experimental studies promise to both advance our understanding of the mechanisms of EAD formation and identify novel antiarrhythmic strategies. Project 4 will be complemented by the modeling studies in Project 1, cellular level studies in P2, and tissue level studies in Project 3.

Public Health Relevance

Every year in the United States, 300,000 men and women succumb to sudden cardiac death due to ventricular arrhythmias. The research proposed will investigate the underlying mechanisms of these lethal arrhythmias and search for hovel therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-PPG-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Kung, Geoffrey L; Vaseghi, Marmar; Gahm, Jin K et al. (2018) Microstructural Infarct Border Zone Remodeling in the Post-infarct Swine Heart Measured by Diffusion Tensor MRI. Front Physiol 9:826
Jiang, Zhaolei; Zhao, Ye; Tsai, Wei-Chung et al. (2018) Effects of Vagal Nerve Stimulation on Ganglionated Plexi Nerve Activity and Ventricular Rate in Ambulatory Dogs With Persistent Atrial Fibrillation. JACC Clin Electrophysiol 4:1106-1114
Yin, Dechun; Chen, Mu; Yang, Na et al. (2018) Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits. Heart Rhythm 15:761-769
Chen, Mu; Xu, Dong-Zhu; Wu, Adonis Z et al. (2018) Concomitant SK current activation and sodium current inhibition cause J wave syndrome. JCI Insight 3:
Yuan, Yuan; Jiang, Zhaolei; Zhao, Ye et al. (2018) Long-term intermittent high-amplitude subcutaneous nerve stimulation reduces sympathetic tone in ambulatory dogs. Heart Rhythm 15:451-459
Shelton, Richard S; Ogawa, Masahiro; Lin, Hongbo et al. (2018) Effects of Stellate Ganglion Cryoablation on Subcutaneous Nerve Activity and Atrial Tachyarrhythmias in a Canine Model of Pacing-Induced Heart Failure. JACC Clin Electrophysiol 4:686-695
Zhao, Ye; Yuan, Yuan; Tsai, Wei-Chung et al. (2018) Antiarrhythmic effects of stimulating the left dorsal branch of the thoracic nerve in a canine model of paroxysmal atrial tachyarrhythmias. Heart Rhythm 15:1242-1251
Pezhouman, Arash; Cao, Hong; Fishbein, Michael C et al. (2018) Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade. J Heart Health 4:
Ponnaluri, A V S; Perotti, L E; Ennis, D B et al. (2017) A viscoactive constitutive modeling framework with variational updates for the myocardium. Comput Methods Appl Mech Eng 314:85-101
Uradu, Andrea; Wan, Juyi; Doytchinova, Anisiia et al. (2017) Skin sympathetic nerve activity precedes the onset and termination of paroxysmal atrial tachycardia and fibrillation. Heart Rhythm 14:964-971

Showing the most recent 10 out of 275 publications