title: Chronic drug-induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell-derived cardiomyocytes.
abstract: OBJECTIVE
  In the pharmaceutical industry risk assessments of chronic cardiac safety liabilities are mostly performed during late stages of preclinical drug development using in vivo animal models. Here, we explored the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to detect chronic cardiac risks such as drug-induced cardiomyocyte toxicity.
  
  
  METHODS
  Video microscopy-based motion field imaging was applied to evaluate the chronic effect (over 72 h) of cardiotoxic drugs on the contractile motion of hiPS-CMs. In parallel, the release of cardiac troponin I (cTnI), heart fatty acid binding protein (FABP3) and N-terminal pro-brain natriuretic peptide (NT-proBNP) was analysed from cell medium, and transcriptional profiling of hiPS-CMs was done at the end of the experiment.
  
  
  RESULTS
  Different cardiotoxic drugs altered the contractile motion properties of hiPS-CMs together with increasing the release of cardiac biomarkers. FABP3 and cTnI were shown to be potential surrogates to predict cardiotoxicity in hiPS-CMs, whereas NT-proBNP seemed to be a less valuable biomarker. Furthermore, drug-induced cardiotoxicity produced by chronic exposure of hiPS-CMs to arsenic trioxide, doxorubicin or panobinostat was associated with different profiles of changes in contractile parameters, biomarker release and transcriptional expression.
  
  
  CONCLUSIONS
  We have shown that a parallel assessment of motion field imaging-derived contractile properties, release of biomarkers and transcriptional changes can detect diverse mechanisms of chronic drug-induced cardiac liabilities in hiPS-CMs. Hence, hiPS-CMs could potentially improve and accelerate cardiovascular de-risking of compounds at earlier stages of drug discovery.
  
  
  BACKGROUND
  This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.
authors.affiliation: Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kopljar
authors.affiliation: Computational Sciences, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: De Bondt
authors.affiliation: Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Vinken
authors.affiliation: Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Ard
authors.initials: A
authors.lastname: Teisman
authors.affiliation: Preclinical Safety and Development, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Spring House, PA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Damiano
authors.affiliation: Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Nick
authors.initials: N
authors.lastname: Goeminne
authors.affiliation: Computational Sciences, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Van den Wyngaert
authors.affiliation: Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: Preclinical Development and Safety, Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Hua Rong
authors.initials: HR
authors.lastname: Lu
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D015415:Biomarkers / Q000378:metabolism; D066126:Cardiotoxicity / Q000209:etiology* / Q000503:physiopathology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity; D007211:Indoles / Q000633:toxicity; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D018715:Microscopy, Video; D009119:Muscle Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D010087:Oxides / Q000633:toxicity; D000077767:Panobinostat
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D015415:Biomarkers; D006877:Hydroxamic Acids; D007211:Indoles; D010087:Oxides; D004317:Doxorubicin; D000077767:Panobinostat; D000077237:Arsenic Trioxide