title: Influence of field potential duration on spontaneous beating rate of human induced pluripotent stem cell-derived cardiomyocytes: Implications for data analysis and test system selection.
abstract: BACKGROUND
  Field potential duration in human pluripotent stem cell (hiPSC)-derived cardiomyocytes is discussed as parameter for the assessment of drug-induced delayed repolarization. In spontaneously beating hiPSC-derived cardiomyocytes field potential duration varies depending on beating rate but beating rate can also be influenced by field potential duration. This interdependence is not fully understood and therefore mandates careful data analysis and cautious interpretation of the results.
  
  
  METHODS
  We analysed data from several types of hiPSC-derived cardiomyocytes and, for comparison, primary embryonic chick cardiomyocytes using reference compounds to study the relationship between spontaneous rate and field potential duration. Based on such data we developed a method based on a regression model of drug-induced changes in the inter-beat interval versus changes in the field potential duration to distinguish primary rate from repolarisation effects.
  
  
  RESULTS
  We demonstrate the application of this approach with reference and research compounds. Cells from different sources differed with regard to the direct or indirect effects of reference compounds on spontaneous beating. All cell types showed an adaptation of field potential duration upon rate changes induced by reference compounds, however, the adaptation of the spontaneous rate after compound-induced changes in field potential duration varied considerably between cell types.
  
  
  CONCLUSIONS
  As shown by comparison with data from guinea pig papillary muscle, an ex vivo model with a fixed stimulation rate, this approach is more appropriate than the application of correction algorithms routinely used for in vivo data since such algorithms do not account for a dependence of rate on field potential duration.
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Support, Birkendorfer Straße 65, 88397 Biberach, Germany. Electronic address: Georg.Rast@boehringer-ingelheim.com.
authors: Georg
authors: G
authors: Rast
authors: Natural and Medical Sciences Institute at the University of Tübingen, Electrophysiology, Markwiesenstraße 55, 72770 Reutlingen, Germany.
authors: Udo
authors: U
authors: Kraushaar
authors: Natural and Medical Sciences Institute at the University of Tübingen, Electrophysiology, Markwiesenstraße 55, 72770 Reutlingen, Germany.
authors: Sandra
authors: S
authors: Buckenmaier
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Clinical Statistics, Birkendorfer Straße 65, 88397 Biberach, Germany.
authors: Carina
authors: C
authors: Ittrich
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Drug Discovery Support, Birkendorfer Straße 65, 88397 Biberach, Germany.
authors: Brian D
authors: BD
authors: Guth
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D023401:Animal Use Alternatives; D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002642:Chick Embryo; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
keywords: Cardiomyocyte; Delayed repolarization; Drug safety; Induced pluripotent stem cell; Methods; Proarrhythmic risk; Rate correction algorithm