High-throughput multiparametric cardiotoxicity screening using optical electrophysiology in hiPSC-CM spheroids

Abstract

Cardiotoxicity continues to be a leading cause of drug attrition, underscoring the need for predictive, human-relevant preclinical assays. Human iPSC-derived cardiomyocytes (hiPSC-CMs) offer an improved platform over traditional hERG assays by capturing the integrated electrophysiological response of the heart. In this study, we established a 3D hiPSC-CM spheroid model compatible with ultra-high-throughput screening to assess cardiac drug liability using concurrent optical voltage and calcium recordings. Using nifedipine and E-4031 as reference compounds, we evaluated acute, chronic, and recovery responses. Multiparametric metrics such as action potential duration, beat interval, calcium transient duration, amplitude, and triangulation were quantified. The assay revealed distinct, physiologically relevant drug effects and recovery patterns. Together, these findings demonstrate that our 3D optical electrophysiology platform enables scalable, multiparametric cardiac safety testing, aligning with FDA Modernization Act 2.0 initiatives to enhance predictivity and reduce reliance on animal models.