Abstract
Background: Cardiotoxicity remains a major challenge in drug development, as adverse cardiac events can lead to severe health consequences, late-stage project terminations or even market withdrawals of drugs. Traditional animal-based assays often struggle to predict human cardiac safety reliably. To address this, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in combination with advanced screening platforms, like multi-electrode arrays (MEA), have emerged recently as valuable tools for preclinical drug screenings. This innovative approach offers a more physiologically relevant and sensitive platform for evaluating compound-induced cardiac effects and detecting potential cardiotoxic effects at an early stage. Here, we assess the effectiveness of the hiPSC-CMs-MEA assay in detecting both acute and chronic electrophysiological, cardiotoxic, and proarrhythmic effects caused by Prestwick’s phytochemicals. Material and Methods: Commercial hiPSC-CMs were seeded in 24-well MEA plates and exposed to a single dose (1µM) of Prestwick’s phytochemicals, comprising 320 well-known and novel plant-based compounds. MEA recordings were conducted at multiple time points: 30min, 2hrs (acute phase), 24hrs and 48hrs (chronic phase). Several parameters related to electrophysiology, contractility and viability were measured using the Maestro Edge MEA. The screened compounds were ranked for overall cardiotoxicity by integrating the measured parameters into the Toxicological Prioritization Index application. Results and Conclusion: The hiPSC-CMs MEA assay successfully detected various phytochemical-induced cardiotoxicities, including arrhythmic events (EADs, ectopic beats, TdP-like arrhythmia) and changes in field potential (56 compounds), contractility (29 compounds), and viability parameters (12 compounds). Of note, classic pro-arrhythmic drugs (e.g., quinidine, E-4031), whether already present in the library or employed as positive controls, consistently received high scores in the expected categories, indicating high accuracy of the assay. This study showcases the hiPSC-CM-MEA assay's ability to accurately identify cardiotoxic effects in preclinical studies not only of approved cardioactive drugs but also of novel compounds. Funding Sources: This research was funded by the ITAT1047-InCardio-Interreg Project.