Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford OX1 3QD, UK.
Philos Trans A Math Phys Eng Sci. 2010 Jun 28;368(1921):3001-25. doi: 10.1098/rsta.2010.0083.
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.
在本文中，我们展示了如何使用先进的计算建模和模拟来研究药物对心脏电生理学和特定致心律失常风险生物标志物的影响。为此，我们首先对从离子到心电图水平的拟议心律失常风险生物标志物进行了全面的文献综述。该综述强调了拟议生物标志物的多样性、药物致心律失常的机制的复杂性以及药物对心脏电生理学的影响在不同动物物种之间存在显著差异。仅使用实验来预测药物致心律失常的风险在临床前和临床上都是具有挑战性的，正如新化合物推向市场的成本上升所证明的那样。在过去的 40 年里，计算建模和模拟极大地促进了对心脏电生理学和心律失常的理解。在本文的第二部分，我们展示了如何使用最先进的开源计算建模和模拟工具来模拟不同动物物种的心室电生理学中药物诱导的离子通道阻断的多尺度效应，包括细胞、组织和整个心室水平。我们相信，将计算建模和模拟与实验技术结合使用可能是评估药物安全性药理学的有力工具。
