Advanced Cardiovascular Toxicity Screening: Integrating Human iPSC-Derived Cardiomyocytes with 2D In Silico Models

The pharmaceutical industry is evolving with the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) for in vitro cardiac safety screening. Traditional reliance on QT-interval prolongation as a main arrhythmogenicity marker is being challenged. In addition, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative recommends using computer modeling and in silico platforms as a more comprehensive approach for arrhythmogenicity testing in conjunction with hiPSC-CM in vitro screening. Our study presents an innovative platform that integrates in vitro hiPSC-CM propagation test with in silico models to assess the potential arrhythmogenic effect of drug-induced impact on ionic currents and electrophysiological intercellular coupling. Utilizing the electrophysiological and morphological characteristics of hiPSC-CM, we offer a thorough evaluation of potential drug-induced cardiac risks by computer modeling. We show, using the examples of lidocaine (100-300 μM) and Cyclophosphamide (639, 852 μM), that with the use of an integrative experimental and computer platform, it is possible to correctly display the clinical manifestations of side effects in advance.