Please use this identifier to cite or link to this item: http://hdl.handle.net/10662/24073
Title: Comprehensive translational assessment of human-induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias
Authors: Blinova, Ksenia
Stohlman, Jayna
Vicente, José
Chan, Dulciana
Johannesen, Lars
Hortigón Vinagre, Maria Pura
Zamora Rodríguez, Víctor
Smith, Godfrey L.
Crumb, William J.
Pang, Li
Lyn-Cook, Beverly
Ross, James
Brock, Mathew
Chvatal, Stacie
Millard, Daniel
Galeotti, Loriano
Stockbridge, Norman
Strauss, David G.
Keywords: Arritmias inducidas por fármacos;Cadiomiocitos humanos derivados de células madres inducidas pluripotentes;Sondas sensibles al voltaje;Drug-induced arritmias;Human induced pluripotent stem cells derived cardiomyocytes;Voltage sensitive dye;Arritmia cardíaca;Cardiac arrhythmia;Cardiomiocitos;Cardiac myocytes;Combinaciones de drogas;Drug combinations;Canales iónicos;Ion channels;Canal de potasio;Potassium channel;Sodio;Sodium;Células madre pluripotentes;Pluripotent stem cells
Issue Date: 2016
Publisher: Oxford University Press
Abstract: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSCCMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.
Description: iPSC-CMs for this study were obtained via material transfer agreement from Cellular Dynamics International and Axiogenesis AG. All iPSC-CM experiments were performed at FDA under research collaboration agreements with Clyde Biosciences and Axion Biosystems. Patch clamp experiments were performed at Zenas Technologies. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the U.S. Department of Health and Human Services.
URI: http://hdl.handle.net/10662/24073
ISSN: 1096-6080
DOI: 10.1093/toxsci/kfw200
Appears in Collections:DBYBM - Artículos
DIMEM - Artículos

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