title: Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations.
abstract: 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.
authors.affiliation: Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford OX1 3QD, UK.
authors.forename: A
authors.initials: A
authors.lastname: Corrias
authors.forename: X
authors.initials: X
authors.lastname: Jie
authors.forename: L
authors.initials: L
authors.lastname: Romero
authors.forename: M J
authors.initials: MJ
authors.lastname: Bishop
authors.forename: M
authors.initials: M
authors.lastname: Bernabeu
authors.forename: E
authors.initials: E
authors.lastname: Pueyo
authors.forename: B
authors.initials: B
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D012306:Risk
chemical_list: D015415:Biomarkers