Electromechanical In Silico Testing Alters Predicted Drug-Induced Risk to Develop Torsade de Pointes

Torsade de Pointes (TdP) is a type of ventricular tachycardia that can occur as a side effect of several medications. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel testing paradigm that utilizes single cell electrophysiological simulations to predict TdP risk for drugs that could potentially be used clinically. However, the effects on mechanical performance and mechano-electrical feedback are neglected. Here, we demonstrate that including electromechanical simulations in CiPA testing can provide additional insights into the predicted drug-induced TdP risk. In this work, we analyzed six drugs, namely flecainide, ibutilide, metronidazole, mexiletine, quinidine and ranolazine. We compared previously classified risks (low, intermediate, high) with our fully coupled electromechanical simulation results based upon the action potential, the electromechanical window, and the maximum active tension [1]. For ranolazine and metronidazole the predicted risk changed from low to intermediate and intermediate to high, respectively. For the latter, while electrophysiological markers indicated a low risk, the active tension decreased by 58% which can result in a loss of heart function. Therefore, adding mechanics to CiPA testing results in an altered prediction of drug-related TdP risk.