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Abstract
High-throughput in vitro drug assays have been impacted by recent advances in human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) technology and by contact-free all-optical systems simultaneously measuring action potentials (APs) and Ca2+ transients (CaTrs). Parallel computational advances have shown that in silico simulations can predict drug effects with high accuracy. We combine these in vitro and in silico technologies and demonstrate the utility of high-throughput experimental data to refine in silico hiPSC-CM populations and to predict and explain drug action mechanisms. Optically obtained hiPSC-CM APs and CaTrs were used from spontaneous activity and under optical pacing in control and drug conditions at multiple doses. An updated version of the Paci2018 model was developed to refine the description of hiPSC-CM spontaneous electrical activity; a population of in silico hiPSC-CMs was constructed and calibrated using simultaneously recorded APs and CaTrs. We tested in silico five drugs (astemizole, dofetilide, ibutilide, bepridil, and diltiazem) and compared the outcomes to 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 correctly predicted 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, bepridil’s more proarrhythmic action in adult cardiomyocytes compared to hiPSC-CMs could be traced to the different expression of ion currents in the two. Therefore, our work 1) supports the utility of all-optical electrophysiology in providing high-content data to refine experimentally calibrated populations of in silico hiPSC-CMs, 2) offers insights into certain limitations when translating results obtained in hiPSC-CMs to humans, and 3) shows the strength of combining high-throughput in vitro and population in silico approaches.
Highlights
Both new in silico methods and the use of human induced pluripotent stem cell-derived cardiomyocytes have become increasingly important in tackling the challenge of assessment and prediction of drug effects and their potential cardiotoxicity, as supported by the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative [1,2,3]
We demonstrate the integration of human in silico drug trials and optically recorded simultaneous action potential and calcium transient data from syncytia of human induced pluripotent stem cell-derived cardiomyocytes for prediction and mechanistic investigations of drug action
1) we present an improved version of the Paci2018 hiPSC-CM model [16], providing improved simulation of the Naþ/Ca2þ exchanger (INCX) role in sustaining the automaticity of action potential (AP). 2) We use high-throughput optical measurements of APs and Ca2þ transients (CaTrs) alone and both to calibrate an in silico population of hiPSC-CMs models
Summary
Both new in silico methods and the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become increasingly important in tackling the challenge of assessment and prediction of drug effects and their potential cardiotoxicity, as supported by the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative [1,2,3]. The potential of hiPSC-CMs for drug-induced proarrhythmia predictions in vitro has been shown in experimental studies [10,11] despite certain outstanding limitations. Concerns lie with their high interlab and interbatch variability and level of maturity compared to adult cardiomyocytes [12], e.g., spontaneous beating, cell morphology, disorganization of their contractile elements [13], and different ion channel expression [14]. The robustness of in silico models depends on the amount and the quality of the experimental data used in their calibration and validation Such data have been acquired from a limited number of isolated cells (outside of their multicellular environment) through time-demanding and tedious manual patch-clamp techniques
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