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Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae

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Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae. / Mannhardt, Ingra; Eder, Alexandra; Dumotier, Berengere; Prondzynski, Maksymilian; Krämer, Elisabeth; Traebert, Martin; Söhren, Klaus-Dieter; Flenner, Frederik; Stathopoulou, Konstantina; Lemoine, Marc D; Carrier, Lucie; Christ, Torsten; Eschenhagen, Thomas; Hansen, Arne.

In: TOXICOL SCI, Vol. 158, No. 1, 01.07.2017, p. 164-175.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Mannhardt, I, Eder, A, Dumotier, B, Prondzynski, M, Krämer, E, Traebert, M, Söhren, K-D, Flenner, F, Stathopoulou, K, Lemoine, MD, Carrier, L, Christ, T, Eschenhagen, T & Hansen, A 2017, 'Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae', TOXICOL SCI, vol. 158, no. 1, pp. 164-175. https://doi.org/10.1093/toxsci/kfx081

APA

Mannhardt, I., Eder, A., Dumotier, B., Prondzynski, M., Krämer, E., Traebert, M., Söhren, K-D., Flenner, F., Stathopoulou, K., Lemoine, M. D., Carrier, L., Christ, T., Eschenhagen, T., & Hansen, A. (2017). Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae. TOXICOL SCI, 158(1), 164-175. https://doi.org/10.1093/toxsci/kfx081

Vancouver

Mannhardt I, Eder A, Dumotier B, Prondzynski M, Krämer E, Traebert M et al. Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae. TOXICOL SCI. 2017 Jul 1;158(1):164-175. https://doi.org/10.1093/toxsci/kfx081

Bibtex

@article{3f8d2042efbb4504a321aa9293dc8b25,
title = "Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae",
abstract = "Objective: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) may serve as a new assay for drug testing in a human context, but their validity particularly for the evaluation of inotropic drug effects remains unclear. In this blinded analysis, we compared the effects of 10 indicator compounds with known inotropic effects in electrically stimulated (1.5 Hz) hiPSC-CM-derived 3 dimensional engineered heart tissue (EHT) and human atrial trabeculae (hAT).Methods and results: Human EHTs were prepared from iCell{\textregistered} hiPSC-CM, hAT obtained at routine heart surgery. Mean intra-batch variation coefficient in baseline force measurement was 17% for EHT and 49% for hAT. The PDE-inhibitor milrinone did not affect EHT contraction force, but increased force in hAT. Citalopram (SSRI), nifedipine (LTCC-blocker) and lidocaine (Na + channel-blocker) had negative inotropic effects on EHT and hAT. Formoterol (beta-2 agonist) had positive lusitropic but no inotropic effect in EHT, and positive clinotropic, lusitropic and inotropic effects in hAT. Tacrolimus (calcineurin-inhibitor) had a negative inotropic effect in EHTs, but no effect in hAT. Digoxin (Na + -K + -ATPase-inhibitor) showed a positive inotropic effect only in EHTs, but no effect in hAT probably due to short incubation time. Ryanodine (ryanodine receptor-inhibitor) reduced contraction force in both models. Rolipram and acetylsalicylic acid showed non-interpretable results in hAT.Conclusions: Contraction amplitude and kinetics were more stable over time and less variable in hiPSC-EHTs than hAT. HiPSC-EHT faithfully detected cAMP-dependent and independent positive and negative inotropic effects, but limited beta-2 adrenergic or PDE3 effects, compatible with an immature CM phenotype.",
keywords = "Journal Article",
author = "Ingra Mannhardt and Alexandra Eder and Berengere Dumotier and Maksymilian Prondzynski and Elisabeth Kr{\"a}mer and Martin Traebert and Klaus-Dieter S{\"o}hren and Frederik Flenner and Konstantina Stathopoulou and Lemoine, {Marc D} and Lucie Carrier and Torsten Christ and Thomas Eschenhagen and Arne Hansen",
year = "2017",
month = jul,
day = "1",
doi = "10.1093/toxsci/kfx081",
language = "English",
volume = "158",
pages = "164--175",
journal = "TOXICOL SCI",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "1",

}

RIS

TY - JOUR

T1 - Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae

AU - Mannhardt, Ingra

AU - Eder, Alexandra

AU - Dumotier, Berengere

AU - Prondzynski, Maksymilian

AU - Krämer, Elisabeth

AU - Traebert, Martin

AU - Söhren, Klaus-Dieter

AU - Flenner, Frederik

AU - Stathopoulou, Konstantina

AU - Lemoine, Marc D

AU - Carrier, Lucie

AU - Christ, Torsten

AU - Eschenhagen, Thomas

AU - Hansen, Arne

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Objective: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) may serve as a new assay for drug testing in a human context, but their validity particularly for the evaluation of inotropic drug effects remains unclear. In this blinded analysis, we compared the effects of 10 indicator compounds with known inotropic effects in electrically stimulated (1.5 Hz) hiPSC-CM-derived 3 dimensional engineered heart tissue (EHT) and human atrial trabeculae (hAT).Methods and results: Human EHTs were prepared from iCell® hiPSC-CM, hAT obtained at routine heart surgery. Mean intra-batch variation coefficient in baseline force measurement was 17% for EHT and 49% for hAT. The PDE-inhibitor milrinone did not affect EHT contraction force, but increased force in hAT. Citalopram (SSRI), nifedipine (LTCC-blocker) and lidocaine (Na + channel-blocker) had negative inotropic effects on EHT and hAT. Formoterol (beta-2 agonist) had positive lusitropic but no inotropic effect in EHT, and positive clinotropic, lusitropic and inotropic effects in hAT. Tacrolimus (calcineurin-inhibitor) had a negative inotropic effect in EHTs, but no effect in hAT. Digoxin (Na + -K + -ATPase-inhibitor) showed a positive inotropic effect only in EHTs, but no effect in hAT probably due to short incubation time. Ryanodine (ryanodine receptor-inhibitor) reduced contraction force in both models. Rolipram and acetylsalicylic acid showed non-interpretable results in hAT.Conclusions: Contraction amplitude and kinetics were more stable over time and less variable in hiPSC-EHTs than hAT. HiPSC-EHT faithfully detected cAMP-dependent and independent positive and negative inotropic effects, but limited beta-2 adrenergic or PDE3 effects, compatible with an immature CM phenotype.

AB - Objective: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) may serve as a new assay for drug testing in a human context, but their validity particularly for the evaluation of inotropic drug effects remains unclear. In this blinded analysis, we compared the effects of 10 indicator compounds with known inotropic effects in electrically stimulated (1.5 Hz) hiPSC-CM-derived 3 dimensional engineered heart tissue (EHT) and human atrial trabeculae (hAT).Methods and results: Human EHTs were prepared from iCell® hiPSC-CM, hAT obtained at routine heart surgery. Mean intra-batch variation coefficient in baseline force measurement was 17% for EHT and 49% for hAT. The PDE-inhibitor milrinone did not affect EHT contraction force, but increased force in hAT. Citalopram (SSRI), nifedipine (LTCC-blocker) and lidocaine (Na + channel-blocker) had negative inotropic effects on EHT and hAT. Formoterol (beta-2 agonist) had positive lusitropic but no inotropic effect in EHT, and positive clinotropic, lusitropic and inotropic effects in hAT. Tacrolimus (calcineurin-inhibitor) had a negative inotropic effect in EHTs, but no effect in hAT. Digoxin (Na + -K + -ATPase-inhibitor) showed a positive inotropic effect only in EHTs, but no effect in hAT probably due to short incubation time. Ryanodine (ryanodine receptor-inhibitor) reduced contraction force in both models. Rolipram and acetylsalicylic acid showed non-interpretable results in hAT.Conclusions: Contraction amplitude and kinetics were more stable over time and less variable in hiPSC-EHTs than hAT. HiPSC-EHT faithfully detected cAMP-dependent and independent positive and negative inotropic effects, but limited beta-2 adrenergic or PDE3 effects, compatible with an immature CM phenotype.

KW - Journal Article

U2 - 10.1093/toxsci/kfx081

DO - 10.1093/toxsci/kfx081

M3 - SCORING: Journal article

C2 - 28453742

VL - 158

SP - 164

EP - 175

JO - TOXICOL SCI

JF - TOXICOL SCI

SN - 1096-6080

IS - 1

ER -