Irregularities of the heartbeat due to cardiac electrical dysfunction are one of the most frequent causes of mortality and morbidity in the human population. Major advances have been made recently in studying the molecular processes of cardiac electrical excitation. Despite this important progress, the mechanisms that underlie arrhythmogenic activity in patients remain only partially understood. Consequently, treatment (by drugs or non-pharmacological interventions) remains largely empirical with unpredictable outcomes in many cases. The overall objective of this project is to further our understanding of mechanisms that underlie cardiac excitation and arrhythmias, and of principles behind interventions that lead to arrhythmia termination and prevention. It is our premise that understanding of mechanisms is imperative to the development of effective treatment of arrhythmia (including new approaches such as molecular and gene therapy) and prevention of sudden death. Our approach is to study these phenomena through the use of detailed mathematical, computer models in close conjunction with experimental observations. Using computational biology, we will integrate processes from the molecular level (ion-channel structure/function) to the whole-cell, and to the multicellular cardiac tissue. The focus of this application is on action potential (AP) repolarization and its rate dependence.
Specific aims are: (1)To develop the computational biology methodology for relating the molecular structure of ion channels and its dynamic conformational changes during gating to the channel kinetic properties and functioning as current carrier in the whole-cell. (2)To use the above approach to study the effects of mutations that alter the channel protein structure on whole cell electrophysiological function and rate-dependent repolarization of the AP. (3) To develop a quantitatively accurate model of the human cardiac ventricular AP based on extensive data from the normal human heart, and to study rate dependent properties of the human AP. (4) To study the properties and repolarization-dependent mechanisms of arrhythmias in the remodeled myocardium post myocardial infarction. The proposal has an important translational element, as understanding the molecular basis of channel gating and arrhythmia will assist in design of new therapies (pharmacological and molecular). Given the large interspecies differences, the development of an accurate human myocyte model based on consistent human data is essential for simulating human arrhythmias and evaluating possible therapies. Finally, myocardial infarction is a major cause of cardiac arrhythmias and sudden death, which gives this proposal a very important clinical significance.

Public Health Relevance

An estimated 400,000 Americans die each year from erratic heart rhythms and many more are severely disabled (estimated annual fatalities worldwide is seven million). The proposed research is aimed at understanding the disease processes that cause cardiac rhythm disorders so that mechanism-based diagnosis, prevention and treatment can be developed and applied.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049054-18
Application #
7789585
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
1993-02-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
18
Fiscal Year
2010
Total Cost
$380,000
Indirect Cost
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Rudy, Yoram (2017) Noninvasive ECG imaging (ECGI): Mapping the arrhythmic substrate of the human heart. Int J Cardiol 237:13-14
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:
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
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
Vijayakumar, Ramya; Vasireddi, Sunil K; Cuculich, Phillip S et al. (2016) Methodology Considerations in Phase Mapping of Human Cardiac Arrhythmias. Circ Arrhythm Electrophysiol 9:
Rudy, Yoram; Lindsay, Bruce D (2015) Electrocardiographic imaging of heart rhythm disorders: from bench to bedside. Card Electrophysiol Clin 7:17-35
Rudy, Yoram (2015) The forward problem of electrocardiography revisited. Circ Arrhythm Electrophysiol 8:526-8
Varma, Niraj; Ploux, Sylvain; Ritter, Philippe et al. (2015) Noninvasive mapping of electrical dyssynchrony in heart failure and cardiac resynchronization therapy. Card Electrophysiol Clin 7:125-34

Showing the most recent 10 out of 129 publications