title: In vitro model for assessing arrhythmogenic properties of drugs based on high-resolution impedance measurements.
abstract: OBJECTIVE
  Cardiac dysfunction is one of the main cause of drug candidate failures in the preclinical and/or clinical studies and responsible for the retraction of large number of drugs from the market. The prediction of arrhythmic risk based on preclinical trials during drug development remains limited despite intensive and costly investigation. Moreover, methods for analyzing beating behavior of cardiomyocytes (CMs) in culture to diagnose arrhythmias are not well developed.
  
  
  METHODS
  In this study, we combined two emerging technologies, induced pluripotent stem (iPS) cell-derived CMs and impedance-based real-time (xCELLigence RTCA Cardio Instrument) monitoring of CM electrical activity, to assess the effect of drugs known affect cardiac activity such as isoproterenol, carbachol, terfenadine, sotalol and doxorubicin. Cells were exposed to a drug in a single dose or repeated dose scenarios and data were analyzed using RTCA Cardio software, Poincaré plot and detrended fluctuation analysis.
  
  
  RESULTS
  The results revealed significant changes in beating parameters of iPS-CMs induced by reference compounds. Heptanol, gap junction blocker, completely disrupted the synchronous beating pattern of iPS-CMs. Decrease of beating rate, amplitude and beat-to-beat signal variations of iPS-CMs monolayer observed in the presence of doxorubicin revealed severe abnormality detected by the system. Additionally, the irregular beating rhythms recorded in the presence of Terfenadine and Sotalol at high concentration, reflect abnormalities in cell contraction and/or relaxation which may lead to arrhythmia.
  
  
  CONCLUSIONS
  All these results indicated that xCELLigence RTCA Cardio system combined with iPS cells, has the potential to be an attractive high-throughput tool for studying CMs during prolonged culture times and to screen potential drugs for cardiotoxic side effects.
authors.affiliation: Institute of Neurophysiology, University of Cologne, Cologne, Germany. filo.nguemo@uni-koeln.de
authors.forename: Filomain
authors.initials: F
authors.lastname: Nguemo
authors.forename: Tomo
authors.initials: T
authors.lastname: Šarić
authors.forename: Kurt
authors.initials: K
authors.lastname: Pfannkuche
authors.forename: Manfred
authors.initials: M
authors.lastname: Watzele
authors.forename: Michael
authors.initials: M
authors.lastname: Reppel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004566:Electrodes; D006321:Heart / Q000187:drug effects*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008962:Models, Theoretical; D018408:Patch-Clamp Techniques; D013015:Sotalol / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D016593:Terfenadine; D004317:Doxorubicin; D002217:Carbachol; D013015:Sotalol; D007545:Isoproterenol