Ventricular fibrillation (VF) is the most 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 cardioverter- defibrillator. 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 of the 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) will 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))
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Qu, Zhilin; Weiss, James N (2015) Mechanisms of ventricular arrhythmias: from molecular fluctuations to electrical turbulence. Annu Rev Physiol 77:29-55
Nivala, Michael; Song, Zhen; Weiss, James N et al. (2015) T-tubule disruption promotes calcium alternans in failing ventricular myocytes: mechanistic insights from computational modeling. J Mol Cell Cardiol 79:32-41
Doytchinova, Anisiia; Patel, Jheel; Zhou, Shengmei et al. (2015) Subcutaneous nerve activity and spontaneous ventricular arrhythmias in ambulatory dogs. Heart Rhythm 12:612-20
Robinson, Eric A; Rhee, Kyoung-Suk; Doytchinova, Anisiia et al. (2015) Estimating sympathetic tone by recording subcutaneous nerve activity in ambulatory dogs. J Cardiovasc Electrophysiol 26:70-8
Qu, Zhilin; Hu, Gang; Garfinkel, Alan et al. (2014) Nonlinear and Stochastic Dynamics in the Heart. Phys Rep 543:61-162
Hoang, Allen; Shen, Changyu; Zheng, James et al. (2014) Utilization rates of implantable cardioverter-defibrillators for primary prevention of sudden cardiac death: a 2012 calculation for a midwestern health referral region. Heart Rhythm 11:849-55
Pezhouman, Arash; Madahian, Sepideh; Stepanyan, Hayk et al. (2014) Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts. Heart Rhythm 11:492-501
Hellyer, Jessica; George Akingba, A; Rhee, Kyoung-Suk et al. (2014) Autonomic nerve activity and blood pressure in ambulatory dogs. Heart Rhythm 11:307-13
Yu, Chih-Chieh; Ai, Tomohiko; Weiss, James N et al. (2014) Apamin does not inhibit human cardiac Na+ current, L-type Ca2+ current or other major K+ currents. PLoS One 9:e96691
Chen, Peng-Sheng; Chen, Lan S; Fishbein, Michael C et al. (2014) Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res 114:1500-15

Showing the most recent 10 out of 184 publications