Advanced cardiotoxicity profiling using field potential imaging with UHD-CMOS-MEA in human iPSC-derived...

Area of Science:

• Cardiovascular research
• Drug safety assessment
• Stem cell biology

Background:

• Current in vitro cardiotoxicity assays primarily assess QT interval prolongation and arrhythmia risk.
• Existing methods often fail to capture complex ion channel interactions or early chronic cardiotoxicity.
• Predicting drug mechanisms of action in vitro remains a significant challenge.

Purpose of the Study:

• To develop and validate a high-resolution field potential imaging system for comprehensive cardiotoxicity profiling.
• To extend analytical capabilities beyond conventional microelectrode arrays (MEAs) for enhanced electrophysiological endpoint extraction.
• To establish a mechanism-aware framework for improved preclinical drug safety evaluation.

Main Methods:

• Utilized an ultra-high-density complementary metal-oxide-semiconductor microelectrode array (MEA) with 236,880 electrodes for near single-cell resolution.
• Acquired high-resolution electrophysiological data, including excitation origins, conduction velocity, and propagation area.
• Performed pharmacological testing with known agents (Isoproterenol, mexiletine, E-4031) and chronic doxorubicin exposure.

Main Results:

• The system visualized compound-specific effects with unprecedented spatiotemporal resolution, reflecting mechanisms of action.
• Accurate classification of acute drug mechanisms was achieved through multivariate analysis of novel and conventional endpoints.
• Early detection of chronic cardiotoxicity from low-dose doxorubicin was achieved within 24 hours, preceding previous reports.

Conclusions:

• The developed high-resolution MEA platform provides a mechanism-aware framework for in vitro cardiotoxicity profiling.
• This approach enhances predictive accuracy by capturing multi-ion channel interactions and spatial conduction abnormalities.
• The system offers sensitive detection of early chronic cardiotoxicity, improving long-term cardiac safety evaluations.