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Multi ‐ Parameter in vitro Assessment of Compound Effe cts on Cardiomyocyte Physiology Using Induced Pluripotent Stem Cells (iPSC)

Oksana Sirenko, Jayne Hesley, Emile Nuwaysir,1 Ivan Rusyn,2 and Evan F Cromwell Molecular Devices, LLC, 1311 Orleans Drive, Sunnyvale, CA 94089,
1Cellular Dynamics International, 525 Science Drive, Madison WI 53711,
2Univeristy of North Carolina, Chapel Hill NC 27599

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Introduction

Highly predictive in vitro assays suitable for high throughput screening (HTS) for potential cardiotoxicity are critical to drug safety testing. Adult human stem cell derived cardiomyocytes show promise for screening compounds during early drug development. We developed methods for measuring the impact of drug candidates on the beating rate of human iPSC derived cardiomyocytes using fast kinetic fluorescence imaging. Cardiomyocyte contraction rate and pattern are characterized by monitoring changes in intracellular Ca2+ measured using calcium sensitive dyes. The assay was optimized for HTS and allows characterization of beating profiles by using multi‐parameter analysis outputs such as beating rate, peak frequency and width, or waveform irregularities. The assay is suitable for assessment of short‐term (minutes) and delayed (days) effects. We tested known cardiotoxic compounds including alpha and beta blockers, hERG inhibitors, ion channel blockers, etc., as well as control drugs. IC50 values showed a significant rank correlation with published values determined by other cardiotoxicity models as well as good concordance with reported human plasma Cmax values. The assay was further tested using commercially available cardiotoxicity library representing different classes of compounds including receptor antagonists, ion channel blockers, anti‐cancer and anti‐inflammatory drugs, and kinase inhibitors. The estimated balanced prediction accuracy of the assay was greater than 80%, and multi‐parameter characterization of beating profiles allowed identification of specific patterns defining hERG or Na+ channel blockers. We conclude that this assay shows utility for screening compounds that have potential to cause arrhythmic and non‐arrhythmic cardiotoxicity

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