CSAHi study: Detection of drug-induced ion channel/receptor responses, QT prolongation, and arrhythmia using multi-electrode arrays in combination with human induced pluripotent stem cell-derived cardiomyocytes

The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combin...

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Vydáno v:	Journal of pharmacological and toxicological methods Ročník 85; s. 73 - 81
Hlavní autoři:	Kitaguchi, Takashi, Moriyama, Yuta, Taniguchi, Tomohiko, Maeda, Sanae, Ando, Hiroyuki, Uda, Takaaki, Otabe, Koji, Oguchi, Masao, Shimizu, Shigekazu, Saito, Hiroyuki, Toratani, Atsushi, Asayama, Mahoko, Yamamoto, Wataru, Matsumoto, Emi, Saji, Daisuke, Ohnaka, Hiroki, Miyamoto, Norimasa
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 01.05.2017
Témata:	action potentials arrhythmia Arrhythmias, Cardiac - chemically induced Arrhythmias, Cardiac - physiopathology calcium cardiomyocytes Cardiotonic Agents - pharmacology cardiotoxicity Cardiotoxins - pharmacology Cells, Cultured CSAHi Dose-Response Relationship, Drug Drug Evaluation, Preclinical - methods Field potential fluoxetine guinea pigs Heart Rate - drug effects Heart Rate - physiology Human induced pluripotent stem cell-derived cardiomyocytes Humans Induced Pluripotent Stem Cells - drug effects Induced Pluripotent Stem Cells - physiology ion channels Ion Channels - agonists Ion Channels - antagonists & inhibitors Ion Channels - physiology isoproterenols Methods Multi-electrode array muscles Myocytes, Cardiac - drug effects Myocytes, Cardiac - physiology ouabain pimozide Proarrhythmia QT prolongation quinidine Torsade de pointes toxicology TdP DMSO Ito ZD7288 (PubChem CID: 123983) FPDc FP Proarrhythmia hCQT IK1 IKs IKr Levcromakalim (PubChem CID: 93504) hESC-CMs hCTdP INa Torsade de pointes hERG Isoproterenol hydrochloride (PubChem CID: 5807) CSAHi (±)-Bay K8644 (PubChem CID: 2303) Ouabain octahydrate (PubChem CID: 122130920) MCEAD/TA MEA EAD IS TA BaCl2 dihydrate (PubChem CID: 5284346) Multi-electrode array Human induced pluripotent stem cell-derived cardiomyocytes ICH hCmax NS1643 (PubChem CID: 10177784) FPDc10 gpAPD Mibefradil dihydrochloride (PubChem CID: 60662) QT prolongation hiPSC-CMs Field potential FPD IKATP Methods BaCl dihydrate (PubChem CID: 5284346)
ISSN:	1056-8719, 1873-488X, 1873-488X
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Popis
Shrnutí:	The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combination with hiPSC-CMs could provide a generalizable platform by using 7 reference drugs at 10 testing facilities. Using this approach, we evaluated responses to reference drugs that modulate a range of cardiac ion currents and have a range of arrhythmogenic effects. We used the MEA system (MED64) and commercially available hiPSC-CMs (iCell cardiomyocytes) to evaluate drug effects on the beat rate, field potential duration (FPD), FPD corrected by Fridericia's formula (FPDc), and the incidence of arrhythmia-like waveforms. This assay detected the repolarization effects of Bay K8644, mibefradil, NS1643, levcromakalim, and ouabain; and the chronotropic effects of isoproterenol, ZD7288, and BaCl2. Chronotropy was also affected by K+ and Ca2+ current modulation. This system detected repolarization delays and the arrhythmogenic effects of quinidine, cisapride, thioridazine, astemizole, bepridil, and pimozide more sensitively than the established guinea pig papillary muscle action potential assay. It also predicted clinical QT prolongation by drugs with multiple ion channel effects (fluoxetine, amiodarone, tolterodine, vanoxerine, alfuzosin, and ranolazine). MEA in combination with hiPSC-CMs may provide a powerful method to detect various cardiac electrophysiological effects, QT prolongation, and arrhythmia during drug discovery. However, the data require careful interpretation to predict chronotropic effects and arrhythmogenic effects of candidate drugs with multiple ion channel effects.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1056-8719 1873-488X 1873-488X
DOI:	10.1016/j.vascn.2017.02.001