All-optical electrophysiology refines populations of in silico human iPS-CMs for drug evaluation

Abstract

High-throughput in vitro drug assays have been impacted by recent advances in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) technology and by contact-free all-optical systems simultaneously measuring action potential (AP) and Ca2+ transient (CaTr). Parallel computational advances have shown that in silico models can predict drug effects with high accuracy. In this work, we combine these in vitro and in silico technologies and demonstrate the utility of high-throughput experimental data to refine in silico hiPS-CM populations, and to predict and explain drug action mechanisms. Optically-obtained hiPS-CM AP and CaTr were used from spontaneous activity and under pacing in control and drug conditions at multiple doses. An updated version of the Paci2018 model was developed to refine the description of hiPS-CM spontaneous electrical activity; a population of in silico hiPS-CMs was constructed and calibrated using the optically-recorded AP and CaTr. We tested five drugs (astemizole, dofetilide, ibutilide, bepridil and diltiazem), and compared simulations against in vitro optical recordings. Our simulations showed that physiologically-accurate population of models can be obtained by integrating AP and CaTr control records. Thus constructed population of models predicted correctly the drug effects and occurrence of adverse episodes, even though the population was optimized only based on control data and in vitro drug testing data were not deployed during its calibration. Furthermore, the in silico investigation yielded mechanistic insights, e.g. through simulations, bepridils more pro-arrhythmic action in adult cardiomyocytes compared to hiPS-CMs could be traced to the different expression of ion currents in the two. Therefore, our work: i) supports the utility of all-optical electrophysiology in providing high-content data to refine experimentally-calibrated populations of in silico hiPS-CMs, ii) offers insights into certain limitations when translating results obtained in hiPS-CMs to humans and shows the strength of combining high-throughput in vitro and population in silico approaches. SignificanceWe demonstrate the integration of human in silico drug trials and optically-recorded simultaneous action potential and calcium transient data from human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) for prediction and mechanistic investigations of drug action. We propose a population of in silico models i) based on a new hiPS-CM model recapitulating the mechanisms underlying hiPS-CM automaticity and ii) calibrated with all-optical measurements. We used our in silico population to predict and evaluate the effects of 5 drugs and the underlying biophysical mechanisms, obtaining results in agreement with our experiments and one independent dataset. This work supports the use of high-content, high-quality all-optical electrophysiology data to develop, calibrate and validate computer models of hiPS-CM for in silico drug trials.