title: The electrophysiological effects of cardiac glycosides in human iPSC-derived cardiomyocytes and in guinea pig isolated hearts.
abstract: OBJECTIVE
  Monitoring changes in the field potential (FP) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) following compound administration has been proposed as a novel screening tool to evaluate cardiac ion channel interactions and QT liability. Here we extended the use of FP to evaluate the pharmacological and toxicological properties of cardiac glycosides.
  
  
  METHODS
  FPs were recorded using microelectrode arrays (MEAs) in spontaneously beating hiPSC-CMs. The in vitro effects of ouabain and digoxin on FPs were compared with data generated on hemodynamic and ECG parameters in guinea pig Langendorff hearts.
  
  
  RESULTS
  In hiPSC-CMs, ouabain and digoxin reduced Na(+)-spike amplitude, shortened FP duration (FPD), increased Ca(2+)-wave amplitude, and dose-dependently induced arrhythmic beats. The ouabain-induced changes observed in hiPSC-CMs correlated well with the effects seen in isolated hearts which revealed QT shortening, enhancement of contractility, and arrhythmogenesis. Nifedipine, an L-type Ca(2+) channel blocker, reduced Ca(2+)-wave amplitude and FPD in hiPSC-CMs, and led to parallel effects of decreased ventricular contractility and shortened QT interval in isolated hearts. Further, nifedipine attenuated the Ca(2+)-peak amplitude and proarrhythmic effect of both glycosides. These results suggested that FPD and Ca(2+)-wave amplitude are comparable surrogates of QT interval and contractility of intact hearts, respectively.
  
  
  CONCLUSIONS
  hiPSC-CMs reflect similar cardiac pharmacology as seen in isolated cardiac preparations and thus are a suitable model in study of the pharmacology and toxicology of cardioactive ion channel and transporter modulators.
authors.affiliation: Global Early & Investigative Safety, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Qian
authors.forename: Rory
authors.initials: R
authors.lastname: Abrams
authors.forename: Hai-Ming
authors.initials: HM
authors.lastname: Tang
authors.forename: Thomas
authors.initials: T
authors.lastname: Weiser
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sanders
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Kolaja
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004077:Digoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics; D006801:Humans; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009924:Organ Culture Techniques; D010042:Ouabain / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002301:Cardiac Glycosides; D010042:Ouabain; D004077:Digoxin; D009543:Nifedipine; D002118:Calcium