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

Francesca Margara, Zhinuo Wang, Alfonso Bueno-Orovio, Blanca Rodriguez
University of Oxford


The successful integration of biophysically detailed information on human cardiac (patho-)physiology in computational modelling and simulation frameworks has facilitated and augmented basic science mechanistic investigations of cardiac function and disease. Such tools have been particularly helpful for the evaluation of the cardiac safety and efficacy of new or existing therapeutical interventions through human in-silico drug trials. The prediction of drug-induced cardiotoxicity remains in fact a big challenge for both preclinical and clinical settings, with cardiac adverse outcomes emerging in the clinic even though they did not occur in previous stages of drug development. Among them, the prediction of drug action on cardiac contraction and electrophysiology is especially complex. 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 model the integrated electro-mechanical function of human ventricular cardiomyocytes by coupling state-of-the-art electrophysiology, excitation-contraction coupling, and contractility models. We analyse both pure potassium and calcium channels blockers, given their prevailing use in clinical practice. Slow delayed rectifier potassium conductance was scaled to simulate a 50, 80, 95, and 100% channel block, while L-Type calcium conductance was scaled to simulate a 10, 30, 50, and 80% channel block. The coupled model provides extended capabilities to concurrently investigate and replicate action potential, calcium dynamics and force generation features, in line with experimental data. In-silico trials 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. Calcium block induces action potential duration shortening up to 50 ms for the highest channel block degree. 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.