Ventricular fibrillation (VF) is the most common cause of sudden death, accounting for over 300,000 deaths annually in the US alone. The objective of this proposed Program Project is to develop a rational approach to the therapy of sudden cardiac death (SCO) through understanding the pathogenesis of VF at the mechanistic level. The proposal represents a continuation of our efforts, which began with our SCOR in Sudden Cardiac Death in 1995, to address this objective by combining mathematical biology with experimental biology to integrate information at the molecular, cellular, tissue and systems levels. The theme of this proposed Program Project is that dynamic wave instability (regulated by electrical restitution, intracellular Cai cycling, cardiac memory and diffusive currents) interacts synergistically with increased electrical and structural tissue heterogeneity in the diseased heart to increase the risk of VF and SCO, and that by developing molecular interventions designed to decrease dynamic wave instability, VF and SCO can be prevented. The four projects and three cores will address this theme using experimental approaches including patch clamping, optical mapping with fluorescent dyes, molecular biology, adenoviral gene transfer, and theoretical approaches including mathematical modeling, computer simulations and nonlinear dynamics. Studies ranging from isolated myocytes to intact normal and diseased ventricles, both in vivo and in silico, will be conducted interactively through this Program Project to evaluate comprehensively dynamic factors controlling wave stability as therapeutic targets for prevention of VF and SCO.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL078931-05
Application #
7652438
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Lathrop, David A
Project Start
2005-08-10
Project End
2011-04-30
Budget Start
2009-07-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2009
Total Cost
$2,075,400
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
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:
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
Ko, Christopher Y; Liu, Michael B; Song, Zhen et al. (2017) Multiscale Determinants of Delayed Afterdepolarization Amplitude in Cardiac Tissue. Biophys J 112:1949-1961

Showing the most recent 10 out of 275 publications