Interpretation of field potentials measured on a multi electrode array in pharmacological toxicity screening on primary and human pluripotent stem cell-derived cardiomyocytes.
Multi electrode arrays (MEAs) are increasingly used to detect external field potentials in electrically active cells. Recently, in combination with cardiomyocytes derived from human (induced) pluripotent stem cells they have started to become a preferred tool to examine newly developed drugs for potential cardiac toxicity in pre-clinical safety pharmacology. The most important risk parameter is proarrhythmic activity in cardiomyocytes which can cause sudden cardiac death. Whilst MEAs can provide medium- to high- throughput noninvasive assay platform, the translation of a field potential to cardiac action potential (normally measured by low-throughput patch clamp) is complex so that accurate assessment of drug risk to the heart is in practice still challenging. To address this, we used computational simulation to study the theoretical relationship between aspects of the field potential and the underlying cardiac action potential. We then validated the model in both primary mouse- and human pluripotent (embryonic) stem cell-derived cardiomyocytes showing that field potentials measured in MEAs could be converted to action potentials that were essentially identical to those determined directly by electrophysiological patch clamp. The method significantly increased the amount of information that could be extracted from MEA measurements and thus combined the advantages of medium/high throughput with more informative readouts. We believe that this will benefit the analysis of drug toxicity screening of cardiomyocytes using in time and accuracy.
Department Anatomy and Embryology, Leiden University Medical Centre, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. Electronic address: l.g.j.tertoolen@lumc.nl.
L G J
LGJ
Tertoolen
Pluriomics B.V., Biopartner Building 3, Galileiweg 8, 2333 BD, Leiden, The Netherlands. Electronic address: stefan.braam@pluriomics.com.
S R
SR
Braam
Department Anatomy and Embryology, Leiden University Medical Centre, Einthovenweg 20, 2300 RC, Leiden, The Netherlands. Electronic address: b.j.vanmeer@lumc.nl.
B J
BJ
van Meer
Department of Applied Stem Cell Technologies, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands. Electronic address: robert.passier@twente.nl.
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R
Passier
Department Anatomy and Embryology, Leiden University Medical Centre, Einthovenweg 20, 2300 RC, Leiden, The Netherlands; Department of Applied Stem Cell Technologies, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE, Enschede, The Netherlands. Electronic address: c.l.mummery@lumc.nl.
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CL
Mummery
D000200:Action Potentials; D000818:Animals; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D051379:Mice; D008839:Microelectrodes; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000187:drug effects*; D039904:Pluripotent Stem Cells / Q000166:cytology
Action potential; Cardiomyocytes; Cardiotoxicity; Computational simulation; Field potential; Multi electrode array