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.
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.
|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 Î±2Î´-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|
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