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Kinetic Image Cytometry for Predicting Arrhythmias Using Human Stem Cell-Derived Cardiomyocytes

  • Emily R. Pfeiffer
  • Ross Whittaker
  • Raquel Vega
  • Fabio Cerignoli
  • Patrick M. McDonoughEmail author
  • Jeffrey H. Price
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Kinetic Image Cytometry™ (KIC™), in which living cells are cultured in multi-well dishes and imaged for electrophysiological transients (such as intracellular calcium or membrane potential) using automated digital microscopy/image analysis, represents an advance in the field of high content analysis. KIC methods, coupled with the use of human stem cell-derived cardiomyocytes (hSC-CMs), are potentially very useful for identifying proarrhythmia activity of test compounds, relevant to cardiosafety. In the present study, a panel of 40 compounds was tested with KIC to quantify the effects of the chemicals on the calcium transients associated with contraction in hSC-CMs, and the results compared to the effects of these compounds on the QT-interval from human electrocardiograms. The kinetics of the calcium transients quantified with KIC identified the chemicals that prolong (commonly associated with proarrhythmic activity) or shorten the QT interval with 100 % specificity and 94 % sensitivity. These data, along with data obtained in previous studies utilizing KIC and hSC-CMs, demonstrate that this assay platform represents the current “state-of-the-art” in vitro method for testing drug candidates for proarrhythmic tendencies.

Key words

Arrhythmia Induced pluripotent stem cells Long QT Action potential Calcium transient hERG Cardiomyocytes Potassium channel Sodium channel Calcium channel Torsades de Pointes 

Notes

Acknowledgements

We would like to gratefully acknowledge Axiogenesis for contribution of the hES-CMs used in this study. Development of KIC instrumentation and methods and CyteSeer™ has been supported by several grants including the following: NIH/NHLBI FastTrack STTR R42HL086076 “Live cell and HCS assays to quantify production of cardiomyocytes from stem cells”; CIRM RT1-01143 “Optimization in the Identification, Selection and Induction of Maturation of Subtypes of Cardiomyocytes derived from Human Embryonic Stem Cells”; and NIH/NHLBI STTR R42HL112521 “Optogenetic Multiparametric Assay for HT Cardiotoxicity Testing.”

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Emily R. Pfeiffer
    • 1
  • Ross Whittaker
    • 1
  • Raquel Vega
    • 1
  • Fabio Cerignoli
    • 1
  • Patrick M. McDonough
    • 1
    Email author
  • Jeffrey H. Price
    • 1
  1. 1.Vala SciencesSan DiegoUSA

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