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Updated: Mar 3, 2026
Automated Contraction Analysis of Human Engineered Heart Tissue for Cardiac Drug Safety Screening
Published on: April 15, 2017
Blinded Contractility Analysis in hiPSC-Cardiomyocytes in Engineered Heart Tissue Format: Comparison With Human
Ingra Mannhardt1,2, Alexandra Eder1,2, Berengere Dumotier3
1Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Insights
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in engineered heart tissue (EHT) show promise for drug testing, accurately detecting most inotropic effects but with limitations in beta-2 adrenergic responses.
Area of Science:
- Cardiovascular Pharmacology
- Stem Cell Biology
- Drug Discovery
Background:
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) offer a human-relevant model for drug testing.
- The validity of hiPSC-CM, particularly in 3D engineered heart tissue (EHT), for assessing inotropic drug effects requires further investigation.
- Comparing hiPSC-EHT to human atrial trabeculae (hAT) provides insights into model-specific drug responses.
Purpose of the Study:
- To evaluate the efficacy of hiPSC-CM-derived EHT as an assay for detecting inotropic drug effects.
- To compare the responses of hiPSC-EHT and hAT to a panel of 10 indicator compounds with known inotropic actions.
- To assess the variability and stability of hiPSC-EHT compared to hAT for drug screening.
Main Methods:
- Blinded analysis of 10 indicator compounds on electrically stimulated (1.5 Hz) hiPSC-EHT and hAT.
- Preparation of EHT from iCell hiPSC-CM and hAT from human atrial tissue.
- Measurement of baseline force variation coefficient, contraction amplitude, and kinetics in both models.
Main Results:
- hiPSC-EHT demonstrated lower intra-batch variation (17%) than hAT (49%) in baseline force measurements.
- hiPSC-EHT accurately detected most positive and negative inotropic effects, including those mediated by cAMP-dependent and -independent pathways.
- Limitations were observed for beta-2 adrenergic and PDE3 effects in hiPSC-EHT, suggesting an immature cardiomyocyte phenotype, while hAT showed variable or non-interpretable results for some compounds.
Conclusions:
- hiPSC-EHT serves as a robust and less variable model for evaluating certain inotropic drug effects in a human context.
- The model shows promise for drug discovery but requires consideration of its limitations, particularly for beta-adrenergic and PDE3-related drug responses.
- Further optimization may enhance the utility of hiPSC-EHT for comprehensive cardiovascular drug testing.
Abstract:
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). 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 (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 both models. 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.
