A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms

Jonathan D. Moreno, Z. Iris Zhu, Pei Chi Yang, John R. Bankston, Mao Tsuen Jeng, Chaoyi Kang, Lianguo Wang, Jason D. Bayer, David J. Christini, Natalia A. Trayanova, Crystal M Ripplinger, Robert S. Kass, Colleen E Clancy

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

A long-sought, and thus far elusive, goal has been to develop drugs to manage diseases of excitability. One such disease that affects millions each year is cardiac arrhythmia, which occurs when electrical impulses in the heart become disordered, sometimes causing sudden death. Pharmacological management of cardiac arrhythmia has failed because it is not possible to predict how drugs that target cardiac ion channels, and have intrinsically complex dynamic interactions with ion channels, will alter the emergent electrical behavior generated in the heart. Here, we applied a computational model, which was informed and validated by experimental data, that defined key measurable parameters necessary to simulate the interaction kinetics of the anti-arrhythmic drugs flecainide and lidocaine with cardiac sodium channels. We then used the model to predict the effects of these drugs on normal human ventricular cellular and tissue electrical activity in the setting of a common arrhythmia trigger, spontaneous ventricular ectopy. The model forecasts the clinically relevant concentrations at which flecainide and lidocaine exacerbate, rather than ameliorate, arrhythmia. Experiments in rabbit hearts and simulations in human ventricles based on magnetic resonance images validated the model predictions. This computational framework initiates the first steps toward development of a virtual drug-screening system that models drug-channel interactions and predicts the effects of drugs on emergent electrical activity in the heart.

Original languageEnglish (US)
Article number98ra83
JournalScience Translational Medicine
Volume3
Issue number98
DOIs
StatePublished - Aug 31 2011

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Anti-Arrhythmia Agents
Cardiac Arrhythmias
Flecainide
Pharmaceutical Preparations
Lidocaine
Ion Channels
Preclinical Drug Evaluations
Sodium Channels
Sudden Death
Drug Interactions
Magnetic Resonance Spectroscopy
Pharmacology
Rabbits

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms. / Moreno, Jonathan D.; Zhu, Z. Iris; Yang, Pei Chi; Bankston, John R.; Jeng, Mao Tsuen; Kang, Chaoyi; Wang, Lianguo; Bayer, Jason D.; Christini, David J.; Trayanova, Natalia A.; Ripplinger, Crystal M; Kass, Robert S.; Clancy, Colleen E.

In: Science Translational Medicine, Vol. 3, No. 98, 98ra83, 31.08.2011.

Research output: Contribution to journalArticle

Moreno, JD, Zhu, ZI, Yang, PC, Bankston, JR, Jeng, MT, Kang, C, Wang, L, Bayer, JD, Christini, DJ, Trayanova, NA, Ripplinger, CM, Kass, RS & Clancy, CE 2011, 'A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms', Science Translational Medicine, vol. 3, no. 98, 98ra83. https://doi.org/10.1126/scitranslmed.3002588
Moreno, Jonathan D. ; Zhu, Z. Iris ; Yang, Pei Chi ; Bankston, John R. ; Jeng, Mao Tsuen ; Kang, Chaoyi ; Wang, Lianguo ; Bayer, Jason D. ; Christini, David J. ; Trayanova, Natalia A. ; Ripplinger, Crystal M ; Kass, Robert S. ; Clancy, Colleen E. / A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms. In: Science Translational Medicine. 2011 ; Vol. 3, No. 98.
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