Abstract
Background and Objectives: Cardiotoxicity represents a significant challenge in drug development, with adverse cardiac events potentially causing late-stage project terminations or drug withdrawals. Traditional animal-based assays often fall short in predicting human cardiac safety reliably. Recent advances, such as using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in combination with multi-electrode arrays (MEA), provide a more physiologically relevant and sensitive approach to evaluate drug-induced cardiac effects and detect potential cardiotoxicity at an early stage (1). 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 (Ncardia) were seeded in 24-well MEA plates and exposed to a single dose (1µM) of Prestwick’s phytochemicals, which includes 320 well-known and novel plant-based compounds. MEA recordings were taken at multiple time points: 30min, 2hrs (acute phase), 24hrs and 48hrs (chronic phase). Various electrophysiological, contractility and viability parameters were measured using the Maestro Edge MEA system (Axion BioSystems). The Toxicological Prioritization Index application was then employed to rank the screened compounds for overall cardiotoxicity (2). Results: The hiPSC-CMs MEA assay effectively identified a range of phytochemical-induced cardiotoxicities, including rhythmic abnormalities (112 compounds), alterations in field potential duration (56 compounds), as well as changes in contractility (29 compounds) and viability parameters (12 compounds). Remarkably, well-known pro-arrhythmic drugs such as quinidine and E-4031, whether included in the library or used as positive controls, consistently achieved high scores in their respective categories, underscoring the assay's accuracy. Discussion and Conclusion: This study highlights the hiPSC-CM-MEA assay's capacity to precisely detect cardiotoxic effects in preclinical studies, encompassing both established cardioactive drugs and novel compounds. The assay is ideally suited for initial high-throughput screening, allowing us to pinpoint the most intriguing compounds for an in-depth analysis utilizing the 3D engineered heart tissue model.