In the diseased heart, the high risk of Sudden Cardiac Death has traditionally been ascribed to increased tissue heterogeneity associated with disease-related structural and electrical remodeling, which predisposes cardiac tissue to electrical wavebreak and ventricular fibrillation (VF). However, recent studies indicate that dynamic wave instability operates synergistically with pre-existing tissue heterogeneity to promote wavebreak. Dynamic wave stability is regulated by multiple factors, including electrical restitution, intracellular Ca (Cai) cycling, cardiac memory, and electrotonic currents. The goal of this project is to combine mathematical and experimental biology to develop novel therapeutics for VF, based on altering global voltage-Cai dynamics to increase wave stability. To develop this concept, the first goal is to overcome shortcomings of existing action potential (AP) models by incorporating realistic voltage-Cai cycling dynamics into AP models for normal and failing adult rabbit ventricular myocytes and neonatal rat ventricular myocytes, validated experimentally against patch clamp and Cai imaging data.
The second aim i s to explore interactions between voltage-Cai dynamics and tissue heterogeneity experimentally in the simplified 2D geometry of cultured neonatal rat ventricular tissue monolayers, complementing the theoretical studies in Project 2.
The third aim i s to use the developed AP models in combination with biological experiments to develop and evaluate specific molecular targets for suppressing wave instability driven by Vm-Cai cycling dynamics, in collaboration with Projects 2, 3 and 4. Based on preliminary studies showing that the L-type Ca current sits at a critical focal point controlling multiple aspects of dynamic wave stability, we will focus on modification of this current as the initial strategy. We will utilize mathematical modeling, patch clamp studies, optical mapping, and adenoviral gene transfer into cultured neonatal rat ventricular monolayers and, in collaboration with Project 3, intact rabbit hearts as a proof-of-concept strategy for gene therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of California Los Angeles
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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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