title: Functional and Transcriptional Characterization of Histone Deacetylase Inhibitor-Mediated Cardiac Adverse Effects in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
abstract: Histone deacetylase (HDAC) inhibitors possess therapeutic potential to reverse aberrant epigenetic changes associated with cancers, neurological diseases, and immune disorders. Unfortunately, clinical studies with some HDAC inhibitors displayed delayed cardiac adverse effects, such as atrial fibrillation and ventricular tachycardia. However, the underlying molecular mechanism(s) of HDAC inhibitor-mediated cardiotoxicity remains poorly understood and is difficult to detect in the early stages of preclinical drug development because of a delayed onset of effects. In the present study, we show for the first time in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) that HDAC inhibitors (dacinostat, panobinostat, vorinostat, entinostat, and tubastatin-a) induce delayed dose-related cardiac dysfunction at therapeutic concentrations associated with cardiac adverse effects in humans. HDAC inhibitor-mediated delayed effects on the beating properties of hiPS-CMs developed after 12 hours by decreasing the beat rate, shortening the field potential duration, and inducing arrhythmic behavior under form of sustained contractions and fibrillation-like patterns. Transcriptional changes that are common between the cardiotoxic HDAC inhibitors but different from noncardiotoxic treatments identified cardiac-specific genes and pathways related to structural and functional changes in cardiomyocytes. Combining the functional data with epigenetic changes in hiPS-CMs allowed us to identify molecular targets that might explain HDAC inhibitor-mediated cardiac adverse effects in humans. Therefore, hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and support identification of better HDAC inhibitors with an improved benefit-risk profile.
  
  
  CONCLUSIONS
  Histone deacetylase (HDAC) inhibitors are a promising class of drugs to treat certain cancers, autoimmune, and neurodegenerative diseases. However, treated patients can experience various cardiac adverse events such as hearth rhythm disorders. This study found that human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) can predict cardiac adverse events in patients caused by HDAC inhibitors. Furthermore, transcriptional changes at the level of gene expression supported the effects on the beating properties of hiPS-CMs and highlight targets that might cause these cardiac adverse effects. hiPS-CMs represent a valuable translational model to assess HDAC inhibitor-mediated cardiotoxicity and to support development of safer HDAC inhibitors.
authors.affiliation: Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica, Beerse, Belgium ikopljar@its.jnj.com.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kopljar
authors.affiliation: Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: De Bondt
authors.affiliation: Open Analytics, Antwerpen, Belgium.
authors.forename: Laure
authors.initials: L
authors.lastname: Cougnaud
authors.affiliation: Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Eddy
authors.initials: E
authors.lastname: Vlaminckx
authors.affiliation: Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Van den Wyngaert
authors.affiliation: Discovery Sciences, Janssen Research and Development, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: Hua Rong
authors.initials: HR
authors.lastname: Lu
mesh_terms: D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005838:Genotype; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000633:toxicity*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D018570:Risk Assessment; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D056572:Histone Deacetylase Inhibitors
keywords: Arrhythmia; Cardiotoxicity; Histone deacetylase inhibitor; Human-induced stem cell-derived cardiomyocytes; Impedance