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by claude@2026-07, 2026-07-04
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The study developed field potential imaging (FPI) using an ultra-high-density CMOS microelectrode array (236,880 electrodes) to record beat propagation in human iPSC-derived cardiomyocyte monolayers and to generate new electrophysiological endpoints. Across pharmacological testing, isoproterenol increased excitation origins, mexiletine reduced conduction velocity, and E-4031 decreased propagation area while inducing early afterdepolarizations, and multivariate analysis of 13 compounds across 17 endpoints distinguished conduction velocity and propagation patterns by mechanism of action. After 24 hours exposure to 0.1 μM doxorubicin, conduction velocity and propagation area were reduced, enabling early detection of chronic cardiotoxicity. The paper does not explicitly discuss limitations, and its focus is cardiac safety/tissue electrophysiology endpoints rather than any direct disease biology. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Evaluation using beat propagation analysis of human iPS cardiomyocytes is an effective approach for assessing human cardiac safety in drug development. However, current applications are primarily focused on detecting QT prolongation and arrhythmia risk, while its ability to comprehensively detect cardiotoxicity remains insufficient. Additionally, predicting the mechanism of action, which is crucial in drug development, remains challenging. In this study, we employed field potential imaging (FPI) using an ultra-high-density (UHD) CMOS microelectrode array (MEA) comprising 236,880 electrodes with high spatiotemporal resolution, capable of recording the activity of a monolayer of cardiomyocytes with tens of electrodes per cell. This method enabled the establishment of novel electrophysiological endpoints, including the number of excitation origins, fluctuations in origin positions, conduction velocity, and propagation area. Pharmacological characterization revealed drug-specific effects: isoproterenol increased excitation origins, mexiletine reduced conduction velocity, and E-4031 decreased propagation area while inducing early afterdepolarizations. Multivariate analysis of 13 compounds across 17 electrophysiological endpoints distinguished conduction velocity and propagation patterns based on their mechanisms of action. Additionally, 0.1 μM doxorubicin exposure for 24 hours significantly reduced conduction velocity and propagation area, allowing early detection of chronic cardiotoxicity. These findings suggest that UHD-CMOS-MEA-based FPI enhances cardiotoxicity detection at low concentrations and precisely characterizes ion channel activity across different drug concentrations. The integration of novel electrophysiological endpoints derived from UHD-CMOS-MEA-based FPI, including excitation origin analysis, conduction velocity, and propagation area, along with multivariate analysis, is anticipated to establish a next-generation in vitro platform for comprehensive cardiotoxicity risk assessment and mechanism-based prediction of drug candidates.
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Abstract
Evaluation using beat propagation analysis of human iPS cardiomyocytes is an effective approach for assessing human cardiac safety in drug development. However, current applications are primarily focused on detecting QT prolongation and arrhythmia risk, while its ability to comprehensively detect cardiotoxicity remains insufficient. Additionally, predicting the mechanism of action, which is crucial in drug development, remains challenging. In this study, we employed field potential imaging (FPI) using an ultra-high-density (UHD) CMOS microelectrode array (MEA) comprising 236,880 electrodes with high spatiotemporal resolution, capable of recording the activity of a monolayer of cardiomyocytes with tens of electrodes per cell. This method enabled the establishment of novel electrophysiological endpoints, including the number of excitation origins, fluctuations in origin positions, conduction velocity, and propagation area. Pharmacological characterization revealed drug-specific effects: isoproterenol increased excitation origins, mexiletine reduced conduction velocity, and E-4031 decreased propagation area while inducing early afterdepolarizations. Multivariate analysis of 13 compounds across 17 electrophysiological endpoints distinguished conduction velocity and propagation patterns based on their mechanisms of action. Additionally, 0.1 μM doxorubicin exposure for 24 hours significantly reduced conduction velocity and propagation area, allowing early detection of chronic cardiotoxicity. These findings suggest that UHD-CMOS-MEA-based FPI enhances cardiotoxicity detection at low concentrations and precisely characterizes ion channel activity across different drug concentrations. The integration of novel electrophysiological endpoints derived from UHD-CMOS-MEA-based FPI, including excitation origin analysis, conduction velocity, and propagation area, along with multivariate analysis, is anticipated to establish a next-generation in vitro platform for comprehensive cardiotoxicity risk assessment and mechanism-based prediction of drug candidates.
Competing Interest Statement
The authors have declared no competing interest.
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