Human embryonic stem cell-derived cardiomyocytes demonstrated dose-dependent prolongation of field potential duration and conduction slowing in response to known arrhythmogenic drugs.
Can human embryonic stem cell-derived cardiomyocytes serve as a valid in vitro model for electrophysiological drug screening and detecting pro-arrhythmic effects?
Human embryonic stem cell-derived cardiomyocytes combined with microelectrode array mapping provide a viable in vitro model for screening drugs for pro-arrhythmic side effects.
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.
Caspi et al. (Thu,) conducted a other in Pro-arrhythmia. Arrhythmogenic and antiarrhythmic drugs (e.g., E-4031, Sotalol, Quinidine, Cisapride) was evaluated on Action potential duration, after-depolarizations, corrected field potential duration (cFPD), and conduction slowing. Human embryonic stem cell-derived cardiomyocytes demonstrated dose-dependent prolongation of field potential duration and conduction slowing in response to known arrhythmogenic drugs.
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