Journal
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES
Volume 368, Issue 1921, Pages 3001-3025Publisher
ROYAL SOC
DOI: 10.1098/rsta.2010.0083
Keywords
cardiac electrophysiology; biomarkers; modelling; electrocardiogram
Categories
Funding
- European Commission [DG-INFSO-224381]
- UK Medical Research Council
- Royal Society
- Caja de Ahorros de la Inmaculada, Spain
- Ministerio de Ciencia e Innovacin, Spain [TEC-2007-68076-C02-02]
- Wellcome Trust
- MRC [G0700278] Funding Source: UKRI
- Medical Research Council [G0700278] Funding Source: researchfish
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In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.
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