In vitro electrophysiological drug testing using human embryonic stem cell derived cardiomyocytes

Area of Science:

• Cardiovascular Pharmacology
• Stem Cell Biology
• Electrophysiology

Background:

• Pro-arrhythmia is a major cause of drug withdrawal.
• Lack of in vitro human cardiac models hinders development of safer drugs.

Purpose of the Study:

• To establish human embryonic stem cell-derived cardiomyocytes (hESC-CMs) as a novel in vitro model for electrophysiological drug screening.
• To assess the utility of hESC-CMs in combination with single-cell electrophysiology and microelectrode array (MEA) mapping for predicting drug-induced arrhythmias.

Main Methods:

• Single-cell electrophysiology (current-clamp) to measure action potential duration and after-depolarizations.
• Microelectrode array (MEA) mapping to assess field potential duration and conduction velocity.
• Application of various ion channel blockers and antiarrhythmic agents to hESC-CMs.

Main Results:

• IKr blockers (E-4031, Sotalol) increased action potential duration and induced after-depolarizations in hESC-CMs.
• MEA analysis showed dose-dependent prolongation of corrected field potential duration (cFPD) with Class I/III antiarrhythmics and QT-prolonging agents.
• Na+ channel and gap junction blockers significantly slowed conduction velocity in hESC-CMs.

Conclusions:

• hESC-CMs combined with electrophysiology and MEA provide a robust in vitro platform for cardiac drug screening.
• This model can predict pro-arrhythmic potential and assess drug effects on cardiac electrophysiology and conduction.
• hESC-CMs hold significant potential for drug discovery and validation beyond regenerative medicine applications.