Proarrhythmia risk prediction using human induced pluripotent stem cell-derived cardiomyocytes
| Autor: | Tomohiko Taniguchi, Daiju Yamazaki, Atsuhiro Yamanishi, Norimasa Miyamoto, Yasunari Kanda, Daisuke Saji, Masakazu Ishimura, Yuko Sekino, Yuta Moriyama, Masao Oguchi, Kaori Miyamoto, Sanae Maeda, Kaoru Morimura, Takashi Kitaguchi, Hiroyuki Tashibu, Etsushi Takahashi, Hiroki Ohnaka |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Risk
0301 basic medicine Induced Pluripotent Stem Cells hERG 030204 cardiovascular system & hematology Pharmacology Biomarkers Pharmacological Afterdepolarization 03 medical and health sciences 0302 clinical medicine Risk groups Torsades de Pointes Drug Discovery Humans Medicine Myocytes Cardiac Induced pluripotent stem cell Cells Cultured health care economics and organizations Proarrhythmia Framingham Risk Score biology business.industry lcsh:RM1-950 Arrhythmias Cardiac medicine.disease Long QT Syndrome 030104 developmental biology lcsh:Therapeutics. Pharmacology Drug development Plasma concentration biology.protein Molecular Medicine business Microelectrodes Forecasting |
| Zdroj: | Journal of Pharmacological Sciences, Vol 136, Iss 4, Pp 249-256 (2018) |
| ISSN: | 1347-8613 |
| Popis: | Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to become a useful tool for proarrhythmia risk prediction in the non-clinical drug development phase. Several features including electrophysiological properties, ion channel expression profile and drug responses were investigated using commercially available hiPSC-CMs, such as iCell-CMs and Cor.4U-CMs. Although drug-induced arrhythmia has been extensively examined by microelectrode array (MEA) assays in iCell-CMs, it has not been fully understood an availability of Cor.4U-CMs for proarrhythmia risk. Here, we evaluated the predictivity of proarrhythmia risk using Cor.4U-CMs. MEA assay revealed linear regression between inter-spike interval and field potential duration (FPD). The hERG inhibitor E−4031 induced reverse-use dependent FPD prolongation. We next evaluated the proarrhythmia risk prediction by a two-dimensional map, which we have previously proposed. We determined the relative torsade de pointes risk score, based on the extent of FPD with Fridericia's correction (FPDcF) change and early afterdepolarization occurrence, and calculated the margins normalized to free effective therapeutic plasma concentrations. The drugs were classified into three risk groups using the two-dimensional map. This risk-categorization system showed high concordance with the torsadogenic information obtained by a public database CredibleMeds. Taken together, these results indicate that Cor.4U-CMs can be used for drug-induced proarrhythmia risk prediction. Keywords: Early afterdepolarization, hiPSC-CMs, Microelectrode array, Proarrhythmia, Safety assessment |
| Databáze: | OpenAIRE |
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