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Published Online: 11 February 2009

In Vitro Electrophysiological Drug Testing Using Human Embryonic Stem Cell Derived Cardiomyocytes

Publication: Stem Cells and Development
Volume 18, Issue Number 1

Abstract

Pro-arrhythmia (development of cardiac arrhythmias as a pharmacological side effect) has become the single most common cause of the withdrawal or restrictions of previously marketed drugs. The development of new medications, free from these side effects, is hampered by the lack of an in vitro assay for human cardiac tissue. We hypothesized that human embryonic stem cell–derived cardiomyocytes (hESC-CMs) assessed with a combination of single cell electrophysiology and microelectrode array (MEA) mapping can serve as a novel model for electrophysiological drug screening. Current-clamp studies revealed that E-4031 and Sotalol (IKr blockers) significantly increased hESC-CM’s action potential duration and also induced after-depolarizations (the in vitro correlates of increased arrhythmogenic potential). Multicellular aggregates of hESC-CMs were then analyzed with the MEA technique. Application of class I (Quinidine, Procaineamide) and class III (Sotalol) antiarrhythmic agents, E-4031, and Cisapride (a noncardiogenic agent known to lengthen QT) resulted in dose-dependent prolongation of the corrected field potential duration (cFPD). We next utilized the MEA technique to also assess pharmacological effects on conduction. Activation maps demonstrated significant conduction slowing following administration of Na channel blockers (Quinidine and Propafenone) and of the gap junction blocker (1-heptanol). While most attention has been focused on the prospects of using hESC-derived cardiomyocytes for regenerative medicine, this study highlights the possible utilization of these unique cells also for cardiac electrophysiological studies, drug screening, and target validation.

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Published In

cover image Stem Cells and Development
Stem Cells and Development
Volume 18Issue Number 1January/February 2009
Pages: 161 - 172
PubMed: 18510453

History

Published online: 11 February 2009
Published ahead of print: 13 January 2009
Published in print: January/February 2009
Published ahead of production: 29 May 2008

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Oren Caspi
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Ilanit Itzhaki
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Izhak Kehat
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Cardiology Department, Rambam Medical Center, Haifa, Israel.
Amira Gepstein
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Gil Arbel
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Irit Huber
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Jonathan Satin
Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
Lior Gepstein
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Cardiology Department, Rambam Medical Center, Haifa, Israel.

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