In vitro electrophysiological drug testing using human embryonic stem cell derived cardiomyocytes.
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.
Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Department of Biophysics and Physiology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel.
Oren
O
Caspi
Ilanit
I
Itzhaki
Izhak
I
Kehat
Amira
A
Gepstein
Gil
G
Arbel
Irit
I
Huber
Jonathan
J
Satin
Lior
L
Gepstein
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D020117:Cisapride / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology / Q000379:methods*; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011342:Procainamide / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D017366:Serotonin Receptor Agonists; D012313:RNA; D013015:Sotalol; D011802:Quinidine; D011342:Procainamide; D020117:Cisapride