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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL078931-07
Application #
8376285
Study Section
Special Emphasis Panel (ZHL1-PPG-S)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
7
Fiscal Year
2012
Total Cost
$306,808
Indirect Cost
$92,878
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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:
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:
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

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