Estimating the Risk of Drug-Induced Proarrhythmia Using Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes
| Autor: | Joshua E. Babiarz, Jennifer D. Cohen, Martin Sanders, Liang Guo, Eric Chiao, Sei Kameoka, Rory Abrams, Kyle L. Kolaja |
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| Rok vydání: | 2011 |
| Předmět: |
Pluripotent Stem Cells
Proarrhythmia Cardiac function curve Cardiotoxicity Drug discovery Cardiac myocyte Drug Evaluation Preclinical Cardiac arrhythmia Arrhythmias Cardiac Cell Differentiation Pharmacology Toxicology medicine.disease Pharmaceutical Preparations Drug Discovery medicine Humans Myocyte Myocytes Cardiac Induced pluripotent stem cell Cells Cultured |
| Zdroj: | Toxicological Sciences. 123:281-289 |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | Improved in vitro systems for predicting drug-induced toxicity are needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition. One unmet need is an early screen for cardiotoxicity, which accounts for about one third of safety-based withdrawn pharmaceuticals. Herein, the first published report of a high-throughput functional assay employing a monolayer of beating human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is described, detailing a model that accurately detects drug-induced cardiac abnormalities. Using 96-well plates with interdigitated electrode arrays that assess impedance, the rhythmic, synchronous contractions of the iPSC-CMs were detected. Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in compound-specific changes in the beat rate and/or the amplitude of the impedance measurement. Changes in impedance for the compounds tested were comparable with the results from a related technology, electric field potential assessment obtained from microelectrode arrays. Using the results from the set of compounds, an index of drug-induced arrhythmias was calculated, enabling the determination of a drug's proarrhythmic potential. This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology. |
| Databáze: | OpenAIRE |
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