Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes
Toxicological Sciences, vol. 176, pp. 103–123
Abstract
Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHTs). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-noise ratio, reduce spontaneous beat rate to ≤ 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHTs. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHTs. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHTs, these parameters typically served as the primary source of predictivity in 2D. The reliance of these "secondary" parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation.
Authors 22
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University Medical Center Hamburg-Eppendorf · German Centre for Cardiovascular Research
Affiliation as printed
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, 20246 Hamburg, and DZHK (German Center for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZD, Leiden, The Netherlands
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Affiliation as printed
Department of Stem Cell Biology, University of Nottingham, University Park, Nottingham NG7 2RD, UK
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Affiliation as printed
Department of Stem Cell Biology, University of Nottingham, University Park, Nottingham NG7 2RD, UK
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University Medical Center Hamburg-Eppendorf · German Centre for Cardiovascular Research
Affiliation as printed
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, 20246 Hamburg, and DZHK (German Center for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZD, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZD, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZD, Leiden, The Netherlands
Ncardia, 2333 BD, Leiden, The Netherlands
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Affiliation as printed
Ncardia, 2333 BD, Leiden, The Netherlands
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Affiliation as printed
Clyde Biosciences Ltd, Biocity Scotland, Newhouse, Lanarkshire ML1 5HU, UK
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University Medical Center Hamburg-Eppendorf · German Centre for Cardiovascular Research
Affiliation as printed
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, 20246 Hamburg, and DZHK (German Center for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany
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GlaxoSmithKline (United States)
Affiliation as printed
GlaxoSmithKline, Collegeville, Pennsylvania 19426
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National Centre for the Replacement Refinement and Reduction of Animals in Research
Affiliation as printed
NC3Rs, London NW1 2BE, UK
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GlaxoSmithKline (United States)
Affiliation as printed
GlaxoSmithKline, Collegeville, Pennsylvania 19426
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GlaxoSmithKline (United States)
Affiliation as printed
GlaxoSmithKline, Collegeville, Pennsylvania 19426
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Affiliation as printed
Clyde Biosciences Ltd, Biocity Scotland, Newhouse, Lanarkshire ML1 5HU, UK
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK
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Affiliation as printed
Clyde Biosciences Ltd, Biocity Scotland, Newhouse, Lanarkshire ML1 5HU, UK
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK
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GlaxoSmithKline (United Kingdom)
Affiliation as printed
GlaxoSmithKline, David Jack Centre for R&D, Ware, Hertfordshire SG12 0DP, UK
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Leiden University Medical Center · University of Twente
Affiliation as printed
Department Applied Stem Cell Technologies, University of Twente, 7500 EA Enschede, The Netherlands
Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZD, Leiden, The Netherlands
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University Medical Center Hamburg-Eppendorf · German Centre for Cardiovascular Research
Affiliation as printed
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, 20246 Hamburg, and DZHK (German Center for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany
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University Medical Center Hamburg-Eppendorf · German Centre for Cardiovascular Research
Affiliation as printed
Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, 20246 Hamburg, and DZHK (German Center for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany
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Chris N. Denning corresponding
Affiliation as printed
Department of Stem Cell Biology, University of Nottingham, University Park, Nottingham NG7 2RD, UK
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