Ventricular fibrillation (VF) is the nnost common cause of sudden cardiac death (SCD), and accounts for over 300,000 deaths per year in the United States alone. However, despite 50 years of molecular and cellular research, no biological therapy has yet emerged with comparable efficacy to the implantable cardioverterdefibrillator. The objective of this proposed Program Project is to develop rational novel therapies to prevent SCD through a better understanding of the pathogenesis of VF at the mechanistic level. The proposal continues our efforts, which began with our SCOR in Sudden Cardiac Death (1995-2004) and has continued in the current Program Project (2005-2010), to address this objective by integrating information at the molecular, cellular, tissue and organism levels using a systems approach combining experimental and mathematical biology. Continuing along these lines, this Program Project will focus on trigger-substrate interactions, with the central theme related to how early (EADs) and delayed (DADs) afterdepolarizations, classically considered as arrhythmia triggers, simultaneously enhance the vulnerability ofthe tissue substrate to create the milieu leading to VF and SCD. We will analyze the synergism between dynamic factors and pre-existing tissue heterogeneities in this process. Project 1 (Multi-scale Modeling of Arrhythmias) wiil develop the theoretical framework, complemented by the experimental analysis at the molecular/cellular level in Project 2 (Cellular Mechanisms of Arrhythmias), the tissue level in Project 3 (Arrhythmias and Antiarrhythmic Targets in Failing Hearts), and therapeutic development in Project 4 (Molecular Approaches to Arrhythmia Therapy), facilitated by 3 cores (Computer and Math Core A, Biology and Bioengineering Core B, and Administrative Core C). Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease.

Public Health Relevance

The proposed Program Project will study the mechanisms of sudden cardiac death due to ventricular arrhythmias, which prematurely takes the lives of more than 300,000 U.S. citizens each year. The goal is to use this information to develop novel therapies to prevent this deadly manifestation of heart disease.

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 (F1))
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
Landaw, Julian; Garfinkel, Alan; Weiss, James N et al. (2017) Memory-Induced Chaos in Cardiac Excitation. Phys Rev Lett 118:138101
Yin, Dechun; Hsieh, Yu-Cheng; Tsai, Wei-Chung et al. (2017) Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts. Circ Arrhythm Electrophysiol 10:e004434
Everett 4th, Thomas H; Doytchinova, Anisiia; Cha, Yong-Mei et al. (2017) Recording sympathetic nerve activity from the skin. Trends Cardiovasc Med 27:463-472
Perotti, Luigi E; Ponnaluri, Aditya V S; Krishnamoorthi, Shankarjee et al. (2017) Method for the unique identification of hyperelastic material properties using full-field measures. Application to the passive myocardium material response. Int J Numer Method Biomed Eng 33:
Choi, Eue-Keun; Zhao, Ye; Everett 4th, Thomas H et al. (2017) Ganglionated plexi as neuromodulation targets for atrial fibrillation. J Cardiovasc Electrophysiol 28:1485-1491
Tsai, Wei-Chung; Chan, Yi-Hsin; Chinda, Kroekkiat et al. (2017) Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs. Heart Rhythm 14:255-262
Yuan, Yuan; Hassel, Jonathan L; Doytchinova, Anisiia et al. (2017) Left cervical vagal nerve stimulation reduces skin sympathetic nerve activity in patients with drug resistant epilepsy. Heart Rhythm 14:1771-1778
Shen, Mark J; Coffey, Arthur C; Straka, Susan et al. (2017) Simultaneous recordings of intrinsic cardiac nerve activity and skin sympathetic nerve activity from human patients during the postoperative period. Heart Rhythm 14:1587-1593
Weiss, James N; Qu, Zhilin; Shivkumar, Kalyanam (2017) Electrophysiology of Hypokalemia and Hyperkalemia. Circ Arrhythm Electrophysiol 10:
Karagueuzian, Hrayr S; Pezhouman, Arash; Angelini, Marina et al. (2017) Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets. Front Pharmacol 8:36

Showing the most recent 10 out of 267 publications