title: Bridging Functional and Structural Cardiotoxicity Assays Using Human Embryonic Stem Cell-Derived Cardiomyocytes for a More Comprehensive Risk Assessment.
abstract: More relevant and reliable preclinical cardiotoxicity tests are required to improve drug safety and reduce the cost of drug development. Current in vitro testing strategies predominantly take the form of functional assays to predict the potential for drug-induced ECG abnormalities in vivo. Cardiotoxicity can also be structural in nature, so a full and efficient assessment of cardiac liabilities for new chemical entities should account for both these phenomena. As well as providing a more appropriate nonclinical model for in vitro cardiotoxicity testing, human stem cell-derived cardiomyocytes offer an integrated system to study drug impact on cardiomyocyte structure as well as function. Employing human embryonic stem cell-derived cardiacmyocytes (hESC-CMs) on 3 assay platforms with complementary insights into cardiac biology (multielectrode array assay, electrophysiology; impedance assay, cell movement/beating; and high content analysis assay, subcellular structure) we profiled a panel of 13 drugs with well characterized cardiac liabilities (Amiodarone, Aspirin, Astemizole, Axitinib, AZT, Bepridil, Doxorubicin, E-4031, Mexiletine, Rosiglitazone, Sunitinib, Sibutramine, and Verapamil). Our data show good correlations with previous studies and reported clinical observations. Using multiparameter phenotypic profiling techniques we demonstrate the dynamic relationship that exists between functional and structural toxicity, and the benefits of this more holistic approach to risk assessment. We conclude by showing for the first time how the advent of transparent MEA plate technology enables functional and structural cardiotoxic responses to be recorded from the same cell population. This approach more directly links changes in morphology of the hESC-CMs with recorded electrophysiology signatures, offering even greater insight into the wide range of potential drug impacts on cardiac physiology, with a throughput that is more amenable to early drug discovery.
authors.affiliation: GE Healthcare Life Sciences, Maynard Centre, Forest Farm, Whitchurch, Cardiff CF14 7YT, UK michael.clements@ge.com mike_clements@live.co.uk.
authors.forename: Mike
authors.initials: M
authors.lastname: Clements
authors.affiliation: GE Healthcare Life Sciences, Maynard Centre, Forest Farm, Whitchurch, Cardiff CF14 7YT, UK.
authors.forename: Val
authors.initials: V
authors.lastname: Millar
authors.affiliation: GE Healthcare Life Sciences, Maynard Centre, Forest Farm, Whitchurch, Cardiff CF14 7YT, UK.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Williams
authors.affiliation: GE Healthcare Life Sciences, Maynard Centre, Forest Farm, Whitchurch, Cardiff CF14 7YT, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Kalinka
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects; D054715:Cardiotoxins / Q000009:adverse effects* / Q000737:chemistry; D002465:Cell Movement / Q000187:drug effects; D053145:Cell Nucleus Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015925:Cryopreservation; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000737:chemistry; D017097:Electric Impedance; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D057166:High-Throughput Screening Assays; D000066449:Human Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008856:Microscopy, Fluorescence; D063154:Mitochondrial Dynamics / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D018570:Risk Assessment / Q000379:methods; D056737:Safety-Based Drug Withdrawals; D046888:Tissue Array Analysis
chemical_list: D054715:Cardiotoxins; D015507:Drugs, Investigational; D005456:Fluorescent Dyes
keywords: cardiomyocyte; cardiotoxicity; drug discovery and development; hESC-CM; in vitro; stem cells