Abnormalities of the cardiac excitation process that result in cardiac arrhythmias continue to be a major cause of death and disability. In spite of important recent advances in understanding this process (notably, at the molecular level of membrane ion-channels), the mechanisms that underlie arrhythmogenic activity remain incompletely understood. Consequently, treatment (by drugs or non-pharmacological interventions) remains largely empirical with unpredictable outcome in many cases. The overall objective of this project is to further the understanding of mechanisms that underlie cardiac excitation and arrhythmias, and of principles behind interventions that lead to arrhythmia termination and prevention. It is the premise that understanding of mechanisms is imperative to the development of better treatment and prevention of sudden death. As in the previous period of support, the approach is to study these phenomena through the use of theoretical, computer models in close conjunction with experimental observations.
Specific aims are: (1) To develop a model of the cardiac ventricular action potential based on kinetic description of single ion channels. (2) To characterize, using this model, the cellular electrophysiologic consequences of channel-function alteration associated with the Long QT Syndrome. (3) To study the ionic basis of myocardial cellular heterogeneity and its electrophysiologic consequences. (4) To study the effects of regional tissue inhomogeneties (in membrane excitability or tissue architecture) on action potential propagation. (5) To characterize the properties of reentrant propagation and the processes of initiation and termination of reentry in the anisotropic myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049054-10
Application #
6498903
Study Section
Special Emphasis Panel (ZRG4-CVB (02))
Program Officer
Lathrop, David A
Project Start
1993-02-01
Project End
2003-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
10
Fiscal Year
2002
Total Cost
$316,571
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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