CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes -assessment of inter-facility and cells lot-to-lot-variability-

Nozaki, Yumiko; Honda, Yayoi; Watanabe, Hitoshi; Saiki, Shota; Koyabu, Kiyotaka; Itoh, Tetsuji; Nagasawa, Chiho; Nakamori, Chiaki; Nakayama, Chiaki; Iwasaki, Hiroshi; Suzuki, Shinobu; Washio, Ikumi; Takahashi, Etsushi; Miyamoto, Katsuhiro; Yamanishi, Atsuhiro; Endo, Hideki; Shinozaki, Junko; Nogawa, Hisashi; Kunimatsu, Takeshi

doi:10.1016/j.yrtph.2016.02.007

Cited by 32 publications

(20 citation statements)

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“…mia-like waveforms appear at 0.003-0.01, 30-300, 1-3, and 0.03-0.3 μM of E-4031, moxifl oxacin, fl ecainide and terfenadine, respectively (Nozaki et al, 2016). This indicates that in terms of detection of arrhythmogenic potential, the discrepancy between this calcium transient assay and MEA assay for each concentration is within 10-folds at most.…”

Section: A B a Bmentioning

confidence: 80%

“…Especially, combination of mechanical instrument devices and hiP-SC-CMs is now an actively investigated approach. Example of devices includes fluorescence imaging (Dempsey et al, 2016), multi-electrode array (MEA) (Nozaki et al, 2016;Kitaguchi et al, 2016), cellular impedance (Scott et al, 2014;Guo et al, 2011), and cell motion imaging using high-speed video microscopy (Hayakawa et al, 2014). One of the recently explored approaches for assessing compounds' cardiotoxicity is monitoring hiP-SC-CMs calcium transient used with a fast kinetic fluorescent imaging detection system (Sirenko et al, 2013b;Lu et al, 2015;Pointon et al, 2015;Zeng et al, 2016;Abi-Gerges et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes

et al. 2017

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Monitoring dramatic changes in intracellular calcium ion levels during cardiac contraction and relaxation, known as calcium transient, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be an attractive strategy for assessing compounds on cardiac contractility. In addition, as arrhythmogenic compounds are known to induce characteristic waveform changes in hiPSC-CMs, it is expected that calcium transient would allow evaluation of not only compound-induced effects on cardiac contractility, but also compound arrhythmogenic potential. Using a combination of calcium transient in hiPSC-CMs and a fast kinetic fluorescence imaging detection system, we examined in this study changes in calcium transient waveforms induced by a series of 17 compounds that include positive/negative inotropic agents as well as cardiac ion channel activators/inhibitors. We found that all positive inotropic compounds induced an increase in peak frequency and/or peak amplitude. The effects of a negative inotropic compound could clearly be detected in the presence of a β-adrenergic receptor agonist. Furthermore, most arrhythmogenic compounds raised the ratio of peak decay time to peak rise time (D/R ratio) in calcium transient waveforms. Compound concentrations at which these parameters exceeded cutoff values correlated well with systemic exposure levels at which arrhythmias were reported to be evoked. In conclusion, we believe that peak analysis of calcium transient and determination of D/R ratio are reliable methods for assessing compounds' cardiac contractility and arrhythmogenic potential, respectively. Using these approaches would allow selection of compounds with low cardiotoxic potential at the early stage of drug discovery.

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Section: A B a Bmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes

et al. 2017

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“…Two different laboratory device platforms are being studied: multielectrode arrays and voltage‐sensitive optical technologies. While that analysis is ongoing, multiple preliminary studies have demonstrated the potential of these technologies . The exact role of the iPSC‐cardiomyocytes under CiPA will be guided by the results of these validation efforts.…”

Section: Rationale and Components Of Cipamentioning

confidence: 98%

Mechanistic Model‐Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study

Vicente

Zusterzeel

Johannesen

et al. 2017

Clin Pharma and Therapeutics

109

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The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic‐based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell‐derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J‐Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

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“…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%

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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CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes -assessment of inter-facility and cells lot-to-lot-variability-

Cited by 32 publications

References 30 publications

Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes

Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes

Mechanistic Model‐Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study

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

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