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

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Abstract

Erythromycin is an antibiotic that prolongs the QT-interval and causes Torsade de Pointes (TdP) by blocking the rapid delayed rectifying potassium current (IKr) without affecting either the slow delayed rectifying potassium current (IKs) or inward rectifying potassium current (IK1). Erythromycin exerts this effect in the range of 1.5–100 μM. 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 μM. In the monolayer of human iPSC-derived cardiomyocytes, the conduction velocity (CV) varied up to 12 ± 9% at concentrations of 15–45 μM as compared with that of the control, whereas the maximum capture rate (MCR) declined substantially up to 28 ± 12% (p < 0.01). 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 (15–30 μM) at which the probability of re-entry increased.

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Abbreviations

I 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

MCR:

Maximum capture rate

TdP:

Torsade de Pointes

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Acknowledgements

This 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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Authors and Affiliations

  1. Moscow Institute of Physics and Technology, Moscow, Russia

    A. D. Podgurskaya, V. A. Tsvelaya, M. M. Slotvitsky & K. I. Agladze

  2. Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia

    E. V. Dementyeva & K. R. Valetdinova

  3. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia

    E. V. Dementyeva & K. R. Valetdinova

  4. Meshalkin National Medical Research Center, Ministry of Health of Russian Federation, Novosibirsk, Russia

    E. V. Dementyeva & K. R. Valetdinova

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  1. A. D. Podgurskaya
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  3. M. M. Slotvitsky
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  4. E. V. Dementyeva
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Correspondence to K. I. Agladze.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Podgurskaya, A.D., Tsvelaya, V.A., Slotvitsky, M.M. et al. The Use of iPSC-Derived Cardiomyocytes and Optical Mapping for Erythromycin Arrhythmogenicity Testing. Cardiovasc Toxicol 19, 518–528 (2019). https://doi.org/10.1007/s12012-019-09532-x

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