Sudden cardiac death (SCD) takes the lives of 300,000 U.S. citizens each year, the majority due to ventricular fibrillation (VF). The overall objective of this Program Project is to achieve a better understanding of the underlying mechanisms to guide the development of novel therapies. Project 3 will involve experiments at the tissue and whole organ levels exploring the roles of intracellular Ca (Ca{I}) cycling dynamics, early (EAD) and delayed (DAD) afterdepolarizations in the generation and maintenance of VF, and the reinitiation of VF after unsuccessful defibrillation in failing hearts. In collaboration with the mathematical modeling studies in Project 1, cellular studies in Project 2, and therapeutic development in Project 4, we will use whole heart optical mapping studies to address two Specific Aims.
Aim 1 will investigate the mechanisms of phase-2 and phase-3 EADs and their relationship to arrhythmias in failing rabbit ventricles. Our preliminary results show that phase-3 EADs arising from boundary areas of prolonged and normal repolarization play a critical role in generating triggered activity (TA) initiating VT and VF. We hypothesize that due to electrophysiological remodeling, this mechanism becomes important in ventricular arrhythmogenesis in failing ventricles. The experimental findings will also be complemented by computer simulations by the Project 1 investigator team.
Aim 2 will test the hypothesis that postshock action potential duration (APD) shortening, spontaneous sarcoplasmic reticulum (SR) Ca release and increased Ca{i}-Vm coupling gain (defined as the sensitivity of membrane voltage Vm to elevations in Ca{i}) synergistically promote VF reinitiation and electrical storm by promoting afterdepolarizations in failing ventricles.
Aim 2 a will test the hypothesis that inhibition of spontaneous SR Ca release is an effective antiarrhythmic strategy to suppress postshock DADs, TA and recurrent VF in failing ventricles.
The Aim 2 b will test the hypothesis that apamin-sensitive small-conductance Ca-activated potassium current (I{KAS}) facilitates spontaneous postshock VF recurrences by shortening APD, and that I{KAS} inhibition can prevent recurrent VF in failing ventricles. Successful completion of these research projects will provide new insights into the mechanisms of phase 3 EADs, and help develop new approaches to preventing recurrent VF during electrical storm in failing ventricles.

Public Health Relevance

The proposed research 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 #
5P01HL078931-09
Application #
8680307
Study Section
Special Emphasis Panel (ZHL1-PPG-S)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$360,787
Indirect Cost
$112,100
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shivkumar, Kalyanam; Ajijola, Olujimi A; Anand, Inder et al. (2016) Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol 594:3911-54
Zhao, Ye; Jiang, Zhaolei; Tsai, Wei-Chung et al. (2016) Ganglionated plexi and ligament of Marshall ablation reduces atrial vulnerability and causes stellate ganglion remodeling in ambulatory dogs. Heart Rhythm 13:2083-90
Tsai, Wei-Chung; Chan, Yi-Hsin; Hsueh, Chia-Hsiang et al. (2016) Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells. Heart Rhythm 13:1527-35
Karagueuzian, H S (2016) Synergism between Enhanced Late Inward Currents and Tissue Fibrosis in the Initiation of Spontaneous Ventricular Tachyarrhythmias. J Heart Health 2:
Chinda, Kroekkiat; Tsai, Wei-Chung; Chan, Yi-Hsin et al. (2016) Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs. Heart Rhythm 13:771-80
Qu, Zhilin; Liu, Michael B; Nivala, Michael (2016) A unified theory of calcium alternans in ventricular myocytes. Sci Rep 6:35625
Song, Zhen; Karma, Alain; Weiss, James N et al. (2016) Long-Lasting Sparks: Multi-Metastability and Release Competition in the Calcium Release Unit Network. PLoS Comput Biol 12:e1004671
Savalli, Nicoletta; Pantazis, Antonios; Sigg, Daniel et al. (2016) The α2δ-1 subunit remodels CaV1.2 voltage sensors and allows Ca2+ influx at physiological membrane potentials. J Gen Physiol 148:147-59
Yu, Chih-Chieh; Ko, Jum-Suk; Ai, Tomohiko et al. (2016) Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current. Heart Rhythm 13:1716-23
Weiss, James N; Qu, Zhilin; Shivkumar, Kalyanam (2016) Ablating atrial fibrillation: A translational science perspective for clinicians. Heart Rhythm 13:1868-77

Showing the most recent 10 out of 242 publications