Human Ventricular Modelling and Simulation of Drug Action on Electrophysiology and Contraction

Abstract

Drug safety and efficacy assessment remains as one of the biggest challenges in both preclinical and clinical drug development. Cardiac adverse outcomes may emerge even though they did not occur in early stages of drug development. Among them, the prediction of drug action on cardiac contraction and electrophysiology is especially complex. Human in-silico drug trials constitute a powerful methodology for their investigation and can integrate and augment biophysically detailed experimental information. In this study, we present an integrated modelling and simulation framework for the simultaneous assessment of electrophysiological and contractile effects of drug action in human cardiac function. We analyse both pure potassium and calcium channels blockers, given their prevailing use in clinical practice. Simulation results demonstrate the positive inotropic effect of potassium blockers, with the potential occurrence of contractile abnormalities triggered by repolarisation abnormalities, and the dose-dependent negative inotropic effect of calcium blockers. This study demonstrates the translational and preclinical potential of human-based in-silico drug trials to investigate drug-induced effects on human cardiac electromechanical function.