Cardiac arrhythmias are a major cause of death and disability, and yet their underlying mechanisms remain incompletely understood. In addition, treatment of arrhythmias by drugs and by non-pharmacological interventions (e.g. pacing, defibrillation) remains largely empiric and the efficiency is unpredictable. The long term objective of the proposed studies is to elucidate, at the cellular and tissue levels, the mechanisms that underlie cardiac excitation and arrhythmogenesis and the mechanisms of interventions (pharmacological and electrical) that lead to termination of arrhythmias. Our premise is that better understanding of the mechanisms is necessary for the development of better therapeutic interventions. Our approach is to study these phenomena through the use of theoretical, computer models in close conjunction with experimental observations.
The specific aims are: 1) To complete the development of a dynamic model of the ventricular action potential based on recent data from single cell and single channel preparations and on experimental measurements of subcellular processes such as calcium fluxes in the sarcoplasmic reticulum. 2) To study, using this model, the mechanisms of arrhythmogenic activity of the single cell including afterdepolarizations (early and delayed) and triggered activity and the effects of various pharmacological interventions on these activities. 3) To study, using the action potential model in conjunction with models of propagation in cardiac tissue, the mechanisms of propagation through a segment of depressed (e.g. ischemic) myocardium and related arrhythmogenic phenomena (slow conduction, conduction block, reflected reentry). 4) To elucidate the mechanisms of termination of circus-movement reentry including spontaneous termination, and termination by electrical and pharmacological interventions. 5) To examine the relative importance of myocardial structure (anisotropy) and nonuniformities of repolarization in the initiation and sustenance of reentry in the setting of chronic infarction, and to elucidate the nature of conduction at the center of the reentrant circuit in relation to these factors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049054-03
Application #
2225144
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1993-02-01
Project End
1998-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ramasubramanian, Smiruthi; Rudy, Yoram (2018) The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations. Biophys J 114:2584-2594
Xu, Jiajing; Rudy, Yoram (2018) Effects of ?-subunit on gating of a potassium ion channel: Molecular simulations of cardiac IKs activation. J Mol Cell Cardiol 124:35-44
Zhang, Junjie; Hocini, Mélèze; Strom, Maria et al. (2017) The Electrophysiological Substrate of Early Repolarization Syndrome: Noninvasive Mapping in Patients. JACC Clin Electrophysiol 3:894-904
Andrews, Christopher M; Srinivasan, Neil T; Rosmini, Stefania et al. (2017) Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging. Circ Arrhythm Electrophysiol 10:
Rudy, Yoram (2017) Noninvasive ECG imaging (ECGI): Mapping the arrhythmic substrate of the human heart. Int J Cardiol 237:13-14
Lee, Hsiang-Chun; Rudy, Yoram; Liang, Hongwu et al. (2017) Pro-arrhythmogenic Effects of the V141M KCNQ1 Mutation in Short QT Syndrome and Its Potential Therapeutic Targets: Insights from Modeling. J Med Biol Eng 37:780-789
Nekouzadeh, Ali; Rudy, Yoram (2016) Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1. Prog Biophys Mol Biol 120:18-27
Vijayakumar, Ramya; Vasireddi, Sunil K; Cuculich, Phillip S et al. (2016) Methodology Considerations in Phase Mapping of Human Cardiac Arrhythmias. Circ Arrhythm Electrophysiol 9:
Zhang, Junjie; Cooper, Daniel H; Desouza, Kavit A et al. (2016) Electrophysiologic Scar Substrate in Relation to VT: Noninvasive High-Resolution Mapping and Risk Assessment with ECGI. Pacing Clin Electrophysiol 39:781-91
Rudy, Yoram; Lindsay, Bruce D (2015) Electrocardiographic imaging of heart rhythm disorders: from bench to bedside. Card Electrophysiol Clin 7:17-35

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