Mannhardt, Ingra , Eder, Alexandra, Dumotier, Berengere, Traebert, Martin, Soehren, Klaus-Dieter, Christ, Torsten, Eschenhagen, Thomas and Hansen, Arne (2017) Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae. Toxicological sciences, 158 (1). pp. 164-175.

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 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) as reference. Methods and results: Human EHTs were prepared from iCell® hiPSC-CM, hAT obtained at routine heart surgery. Variation coefficient in force measurement was 17% for EHT and 49% for hAT. The PDE-inhibitors milrinone and rolipram did not have any effect on EHT contractility, but a positive inotropic effect in hAT for milrinone and decrease in force for rolipram due to run-down phenomena. Citalopram (SSRI), nifedipine (LTCC-blocker) and lidocaine (Na+ channel-blocker) had negative inotropic effects on EHT and hAT. Formoterol (beta-2-agonist) had no effect in EHT, but positive inotropic effects in hAT. Tacrolimus (calcineurin-inhibitor) had a negative inotropic effect in EHTs and hAT. Digoxin (Na+-K+-ATPase-inhibitor) showed a positive inotropic effect only in EHTs, but no effect in hAT due to short incubation time. Acetylsalicylic acid (COX-inhibitor) had no effect in EHT, but hAT force decreased due to run-down. Ryanodine (ryanodine receptor-inhibitor) reduced contraction force in both models. Conclusions: hiPSC-EHTs were more stable over time and less variable than hAT. They faithfully detected cAMP-dependent and independent positive and negative inotropic effects, but no beta-2 adrenergic or PDE3 effects, compatible with an immature CM phenotype.

Item Type:	Article
Date Deposited:	25 Jul 2017 00:45
Last Modified:	25 Jul 2017 00:45
URI:	https://oak.novartis.com/id/eprint/31766