%0 Journal Article %1 Mannhardt2017 %A Mannhardt, Ingra %A Eder, Alexandra %A Dumotier, Berengere %A Prondzynski, Maksymilian %A Kr amer, Elisabeth %A Traebert, Martin %A Flenner, Frederik %A Stathopoulou, Konstantina %A Lemoine, Marc D. %A Carrier, Lucie %A Christ, Torsten %A Eschenhagen, Thomas %A Hansen, Arne %D 2017 %J Toxicological Sciences %K Blinded_drug_screening Cardiotoxicity Engineered_heart_tissue IPS Safety_pharmacology %R 10.1093/toxsci/kfx081 %T Blinded contractility analysis in hipsc-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae %X © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. 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 (1.5Hz) hiPSC-CM-derived 3-dimensional engineered heart tissue (EHT) and human atrial trabeculae (hAT). Human EHTs were prepared from iCell hiPSCCM, hAT obtained at routine heart surgery. Mean intra-batch variation coefficient in baseline forcemeasurement was 17\% for EHT and 49\% for hAT. The PDE-inhibitormilrinone did not affect EHT contraction force, but increased force in hAT. Citalopram (selective serotonin reuptake inhibitor), 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 bothmodels. Rolipram and acetylsalicylic acid showed noninterpretable results in hAT. 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.

@article{Mannhardt2017, abstract = {{\textcopyright} The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. 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 (1.5Hz) hiPSC-CM-derived 3-dimensional engineered heart tissue (EHT) and human atrial trabeculae (hAT). Human EHTs were prepared from iCell hiPSCCM, hAT obtained at routine heart surgery. Mean intra-batch variation coefficient in baseline forcemeasurement was 17{\%} for EHT and 49{\%} for hAT. The PDE-inhibitormilrinone did not affect EHT contraction force, but increased force in hAT. Citalopram (selective serotonin reuptake inhibitor), 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 bothmodels. Rolipram and acetylsalicylic acid showed noninterpretable results in hAT. 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.}, added-at = {2019-06-17T23:34:05.000+0200}, author = {Mannhardt, Ingra and Eder, Alexandra and Dumotier, Berengere and Prondzynski, Maksymilian and Kr amer, Elisabeth and Traebert, Martin and Flenner, Frederik and Stathopoulou, Konstantina and Lemoine, Marc D. and Carrier, Lucie and Christ, Torsten and Eschenhagen, Thomas and Hansen, Arne}, biburl = {https://www.bibsonomy.org/bibtex/245486370221f47064bf3524fc2abb5ce/fcdi}, doi = {10.1093/toxsci/kfx081}, interhash = {1f3a6abe53eb3c36429994dd418a34d1}, intrahash = {45486370221f47064bf3524fc2abb5ce}, issn = {10960929}, journal = {Toxicological Sciences}, keywords = {Blinded_drug_screening Cardiotoxicity Engineered_heart_tissue IPS Safety_pharmacology}, timestamp = {2019-06-18T22:58:44.000+0200}, title = {{Blinded contractility analysis in hipsc-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae}}, year = 2017 }