(W1267) DEVELOPMENT OF AN HD-CMOS–MEA–BASED METHOD FOR CARDIOTOXICITY DETECTION AND MECHANISM-OF-ACTION PREDICTION IN HUMAN IPSC-DERIVED CARDIOMYOCYTES USING BEAT PROPAGATION PATTERNS
Abstract: In new drug development, cardiotoxicity—particularly QT prolongation—often leads to clinical trial termination or market withdrawal. Although the ICH S7B guideline focuses on hERG blockade, it is insufficient for multi-ion channel mechanisms. The CiPA initiative aims for more comprehensive analyses, but challenges remain with complex compounds. In this study, we employed an HD-CMOS-MEA platform equipped with 240,000 densely arranged microelectrodes to measure human iPSC-derived cardiomyocytes. For the pharmacological tests, we selected compounds and concentrations whose toxicity could not be fully captured by conventional MEA, as well as negative compounds—14 in total—and recorded their extracellular field potentials. The high resolution of the HD-CMOS-MEA system allows tens of electrodes to record the activity of a single cell, enabling us to construct 17 parameters from the acquired data, including the number of initiation sites, variability of initiation site positions, conduction velocity, and propagation area. In the case of isoproterenol, a β1-adrenergic receptor agonist, we detected a specific increase in the number of initiation sites. Mexiletine, a Na⁺ channel inhibitor, led to a marked decrease in conduction velocity, whereas the hERG channel blocker E4031 caused a reduction in propagation area. Furthermore, we identified distinct conduction velocities and propagation patterns according to the mechanism of action of each compound, suggesting that HD-CMOS-MEA–based cardiotoxicity assessment may sensitively capture channel-specific activities at different concentrations, even in compounds with multiple modes of action. Additionally, when human iPSC-derived cardiomyocytes were exposed to doxorubicin at 0.1 µM—a concentration known to exhibit chronic cardiotoxicity—both propagation area and conduction velocity were found to decrease 24 hours post-exposure. Compared with conventional toxicity tests, the HD-CMOS-MEA system demonstrated the ability to detect cardiotoxicity at lower concentrations and over shorter chronic exposure periods. These findings highlight an enhanced level of precision in cardiotoxicity evaluation for drug development and offer a new platform to elucidate complex interactions among multiple ion channels.
Funding Source: the grant of collaborative project with Sony semiconductor solutions Inc. Japan Agency for Medical Research and Development (AMED)
