title: Dynamic monitoring of beating periodicity of stem cell-derived cardiomyocytes as a predictive tool for preclinical safety assessment.
abstract: OBJECTIVE
  Cardiac toxicity is a major concern in drug development and it is imperative that clinical candidates are thoroughly tested for adverse effects earlier in the drug discovery process. In this report, we investigate the utility of an impedance-based microelectronic detection system in conjunction with mouse embryonic stem cell-derived cardiomyocytes for assessment of compound risk in the drug discovery process.
  
  
  METHODS
  Beating of cardiomyocytes was measured by a recently developed microelectronic-based system using impedance readouts. We used mouse stem cell-derived cardiomyocytes to obtain dose-response profiles for over 60 compounds, including ion channel modulators, chronotropic/ionotropic agents, hERG trafficking inhibitors and drugs known to induce Torsades de Pointes arrhythmias.
  
  
  RESULTS
  This system sensitively and quantitatively detected effects of modulators of cardiac function, including some compounds missed by electrophysiology. Pro-arrhythmic compounds produced characteristic profiles reflecting arrhythmia, which can be used for identification of other pro-arrhythmic compounds. The time series data can be used to identify compounds that induce arrhythmia by complex mechanisms such as inhibition of hERG channels trafficking. Furthermore, the time resolution allows for assessment of compounds that simultaneously affect both beating and viability of cardiomyocytes.
  
  
  CONCLUSIONS
  Microelectronic monitoring of stem cell-derived cardiomyocyte beating provides a high throughput, quantitative and predictive assay system that can be used for assessment of cardiac liability earlier in the drug discovery process. The convergence of stem cell technology with microelectronic monitoring should facilitate cardiac safety assessment.
authors.affiliation: ACEA Biosciences Inc., San Diego, California, USA. yabassi@aceabio.com
authors.forename: Yama A
authors.initials: YA
authors.lastname: Abassi
authors.forename: Biao
authors.initials: B
authors.lastname: Xi
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Ouyang
authors.forename: Alexander
authors.initials: A
authors.lastname: Seiler
authors.forename: Manfred
authors.initials: M
authors.lastname: Watzele
authors.forename: Ralf
authors.initials: R
authors.lastname: Kettenhofen
authors.forename: Heribert
authors.initials: H
authors.lastname: Bohlen
authors.forename: Andreas
authors.initials: A
authors.lastname: Ehlich
authors.forename: Eugen
authors.initials: E
authors.lastname: Kolossov
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D017097:Electric Impedance; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D016171:Torsades de Pointes / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
chemical_list: D015220:Calcium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D015221:Potassium Channels; D015222:Sodium Channels