title: Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes.
abstract: 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 One unmet need is an early screen for cardiotoxicity, which accounts for about one third of safety-based withdrawn pharmaceuticals.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.
authors.affiliation: Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, Nutley, New Jersey 07110, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Rory M C
authors.initials: RM
authors.lastname: Abrams
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Babiarz
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Cohen
authors.forename: Sei
authors.initials: S
authors.lastname: Kameoka
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sanders
authors.forename: Eric
authors.initials: E
authors.lastname: Chiao
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Kolaja
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000009:adverse effects*; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects*; D004364:Pharmaceutical Preparations; D039904:Pluripotent Stem Cells / Q000187:drug effects*
chemical_list: D004364:Pharmaceutical Preparations