Abstract

Arrhythmogenicity of drugs involves multi-scale events taking place at molecular, cellular, tissue and organ levels. In order to understand the mechanism behind this complex phenomena, we developed a multi-scale 3D heart simulator, with which we can evaluate the arrhythmogenicity of drugs based on their inhibitory actions on multiple ionic currents. Recently, we extended this approach to create a hazard map of drug-induced arrhythmia identifying the region at risk in a multi-dimensional space, each co-ordinate of which represents the inhibition of specific ionic current. This hazard map can also be used to assess the two major uncertainties we encounter in the evaluation of arrhythmogenic risk. One is the uncertainty in experimentally determining the inhibitory action of drugs on ionic currents. The other is the individual variability in the sensitivity to drugs possibly caused by the polymorphism in genes coding ion channels or enzymes responsible for the drug metabolism. These uncertainties can also be identified by a region of drug effects in this hazard map and the distance from its border to the region at risk can be taken to indicate the safety margin.