Drug-induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias.

ABSTRACT

BACKGROUND AND PURPOSE: Early identification of drug-induced cardiac adverse events is key in drug development. Human-based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug-induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro-arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human-based computer models. EXPERIMENTAL APPROACH: In silico drug trials for 40 reference compounds were performed, testing up to 100-fold the therapeutic concentrations (EFTPCmax ) and using a control population of human ventricular action potential (AP) models, optimised to capture pro-arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+ transient durations at 90%. Drug-induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified. KEY RESULTS: Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration-dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10× EFTPCmax , whereas RA-based predictions required 100× EFTPCmax to reach the same accuracy. As it is dependent on Ca2+ transient, the EMw was also more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current. CONCLUSION AND IMPLICATIONS The EMw is an effective biomarker for in silico predictions of drug-induced clinical pro-arrhythmic risk, particularly for compounds with multichannel blocking action.