A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes

Ando, Hiroyuki; Yoshinaga, Takashi; Yamamoto, Wataru; Asakura, Kiyoshi; Uda, Takaaki; Taniguchi, Tomohiko; Ojima, Atsuko; Shinkyo, Raku; Kikuchi, K.; Osada, Tomoharu; Hayashi, Seiji; Kasai, Chieko; Miyamoto, Naokazu; Tashibu, Hiroyuki; Yamazaki, Daiju; Sugiyama, Atsushi; Kanda, Yasunari; Sawada, Kohei; Sekino, Yuko

doi:10.1016/j.vascn.2016.12.003

Cited by 156 publications

(111 citation statements)

References 61 publications

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“…1 (B)). Recently, it was demonstrated that drugs could be categorized into three TdP risks based on the effect of the drugs on extracellular field potential with MEA (Ando et al, 2017). According to that report, astemizole and bepridil were classified as intermediate risk, which was slightly different from our study.…”

Section: Resultscontrasting

confidence: 93%

“…These assays detect changes in electrical activity of cardiomyocytes upon drug treatment for a short period (several minutes to several hours). The Consortium for Safety Assessment using Human iPS Cells (CSAHi) initiated an effort to establish standard protocols by MEA systems for risk assessment of arrhythmia and QT prolongation using various reference drugs (Ando et al, 2017;Asakura et al, 2015;Nozaki et al, 2016Nozaki et al, , 2017Yamamoto et al, 2016). In those experimental processes, Nozaki et al (2017) investigated gene expression profiles using hiPS-CMs that were cultured in three different facilities to assess the equivalency of the data among laboratories; there was no difference among the gene expression profiles in the three facilities.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis

et al. 2017

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-In recent years, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) have been widely used to develop evaluation systems for drug cardiotoxicity, including the arrhythmia caused by QT prolongation. To accurately assess the arrhythmogenic potential of drugs, associated with QT prolongation, we developed an evaluation system using hiPS-CMs and gene expression analysis. hiPS-CMs were treated with 8 arrhythmogenic and 17 non-arrhythmogenic drugs at several concentrations for 24 hr to comprehensively analyze gene expression. The results showed that 19 genes were upregulated in the arrhythmogenic drug-treated cells compared with their expression levels in the nontreated and non-arrhythmogenic drug-treated cells. The arrhythmogenic risks of the drugs were evaluated by scoring gene expression levels. The results indicated that arrhythmogenic risks could be inferred when cells were treated at a concentration 100 times higher than the maximum blood concentration of the drug. Thus, we succeeded in developing a system for evaluation of the arrhythmogenic potential of drugs using gene expression analysis.

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Section: Resultscontrasting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis

et al. 2017

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“…TdP, associated with the substance [24,25]. Few studies show the effect of arrhythmogenic drugs on arrhythmic beating, changes in beat rate [2] and FPD [14] using monolayers of human iPSC-derived cardiomyocytes (iCell®). Shaheen et al ArcLight for evaluation of conduction slowing and APD prolongation under chemical compounds [15].…”

Section: Discussionmentioning

confidence: 99%

The Use of iPSC-Derived Cardiomyocytes and Optical Mapping for Erythromycin Arrhythmogenicity Testing

Podgurskaya

Tsvelaya

Slotvitsky

et al. 2019

Preprint

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AbbreviationsI Kr -rapid delayed rectifying potassium current; I Ks -slow delayed rectifying potassium current; I K1 -inward rectifying potassium current; iPSC -induced pluripotent stem cell; hERG -human ether-a-go-go-related gene;FPD -field potential duration; NRVM -neonatal rat ventricular myocyte; CV -conduction velocity; MCRmaximum capture rate; TdP -Torsade de Pointes AbstractErythromycin is an antibiotic that prolongs the QT-interval and causes Torsade de Pointes (TdP) by blocking the rapid delayed rectifying potassium current (I Kr ) without affecting either the slow delayed rectifying potassium current (I Ks ) or inward rectifying potassium current (I K1 ). Erythromycin exerts this effect in the range of 1.5 µM-100 μ M. However, the mechanism of action underlying its cardiotoxic effect and its role in the induction of arrhythmias, especially in multicellular cardiac experimental models, remain unclear. In this study the re-entry formation, conduction velocity, and maximum capture rate were investigated in a monolayer of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a healthy donor and in a neonatal rat ventricular myocyte (NRVM) monolayer using the optical mapping method under erythromycin concentrations of 15, 30, and 45 μ M. In the monolayer of human iPSC-derived cardiomyocytes, the conduction velocity (CV) varied up to 12±9% at concentrations of 15-45 μ M as compared with that of the control, whereas the maximum capture rate (MCR) declined substantially up to 28±12% (p < 0.05). In contrast, the tests on the NRVM monolayer showed no significant effect on the MCR. The results of the arrhythmogenicity test provided evidence for a "window" of concentrations of the drug (15 to 30 μ M) at which the probability of re-entry increased. AcknowledgmentsThis study was funded by the Russian Ministry of Education and Science of the Russian Federation grant (state task) 6.9906.2017/BCh.

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“…Cell chips in which cells are arranged on a microarray have recently been developed. Assays using such chips can simultaneously evaluate multiple items using a small amount of cells and samples, and are useful for rapid and easy high‐throughput screening (Ando et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…amount of cells and samples, and are useful for rapid and easy highthroughput screening (Ando et al, 2017).…”

mentioning

confidence: 99%

Three‐dimensional bioprinting human cardiac tissue chips of using a painting needle method

Chikae

Kubota

Nakamura

et al. 2019

Biotech & Bioengineering

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Three‐dimensional (3D) printers are attracting attention as a method for arranging and building cells in three dimensions. Bioprinting technology has potential in tissue engineering for the fabrication of scaffolds, cells, and tissues. However, these various printing technologies have limitations with respect to print resolution and due to the characteristics of bioink such as viscosity. We report a method for constructing of 3D tissues with a “microscopic painting device using a painting needle method” that, when used with the layer‐by‐layer (LbL) cell coating technique, replaces conventional methods. This method is a technique of attaching the high viscosity bioink to the painting needle tip and arranging it on a substrate, and can construct 3D tissues without damage to cells. Cell viability is the same before and after painting. We used this biofabrication device to construct 3D cardiac tissue (LbL‐3D Heart) using human‐induced pluripotent stem cell–derived cardiomyocytes. The constructed LbL‐3D Heart chips had multiple layers with a thickness of 60 µm, a diameter of 1.1 mm, and showed synchronous beating (50–60 beats per min). The aforementioned device and method of 3D tissue construction can be applied to various kinds of tissue models and would be a useful tool for pharmaceutical applications.

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A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes

Cited by 156 publications

References 61 publications

Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis

Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis

The Use of iPSC-Derived Cardiomyocytes and Optical Mapping for Erythromycin Arrhythmogenicity Testing

Three‐dimensional bioprinting human cardiac tissue chips of using a painting needle method

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