Multiscale modelling and simulation investigation of variability and abnormalities in repolarization: Application to drug cardiotoxicity

Abnormalities in cardiac repolarization have been implicated in cardiac arrhythmogenesis caused by disease, mutations and drugs. Of particular concern for regulatory agencies, pharmaceutical industry and society is the fact that certain drugs, in particular those not designed to affect the heart, can exhibit cardio-toxicity (i.e.unwanted side effects), which can put patients at risk of developing lethal arrhythmias. Drug cardiotoxicity is often related to abnormalities in repolarization caused by drug-induced alterations at the ionic level. Given the limitations of in vitro and in vivo testing in preclinical prediction of drug cardiotoxicity, there is increasing interest in computational methods to complement experimental findings. The paper describes how state-of-the-art computational cardiac electrophysiology is being used to investigate the mechanisms of drug cardiotoxicity and the role of biological variability in its many forms in determining proarrythmic responses to drugs. The work described here is being conducted under the umbrella of the European funded grant preDiCT. The main aim is to unravel the mechanisms of drug-induced arrhythmic risk in the context of high inter-subject electrophysiological variability, and to propose novel arrhythmic risk biomarkers based on this research.