Human stem cell-derived cardiomyocytes detect drug-mediated changes in action potentials and ion currents

Area of Science:

• Cardiovascular Pharmacology
• Stem Cell Biology
• Electrophysiology

Background:

• Proarrhythmia assessment is crucial for drug safety pharmacology.
• Human pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) offer a promising model for evaluating drug effects on cardiac electrophysiology.
• Assessing drug-induced changes in cardiac electrophysiology requires reliable and predictive models.

Purpose of the Study:

• To evaluate the utility of hiPSC-CM in measuring drug-induced alterations in cardiac action potentials (AP) and ion currents.
• To assess the proarrhythmic potential of various compounds using hiPSC-CM.
• To compare the efficacy of hiPSC-CM in detecting ion channel interactions versus traditional single ion channel assays.

Main Methods:

• hiPSC-CM were subjected to pacing at 1Hz.
• Increasing concentrations of test compounds were administered, and AP parameters (APD60, APD90, etc.) were measured.
• Voltage clamp experiments were performed to assess specific ion channel currents (e.g., hERG/IKr, calcium currents).

Main Results:

• E-4031 dose-dependently prolonged AP and blocked hERG/IKr current (IC50=17nM).
• Dofetilide, astemizole, terfenadine, and flecainide demonstrated dose-dependent effects on AP duration.
• Nifedipine blocked calcium current (IC50=0.039μM) and shortened APD, while verapamil showed complex effects.
• Chronic pentamidine exposure induced AP prolongation and early afterdepolarizations (EADs).

Conclusions:

• hiPSC-CM action potential recordings can effectively identify drug interactions with multiple ion channels.
• This model overcomes limitations associated with using single ion channel assays in non-cardiac tissues.
• hiPSC-CM provide a valuable platform for comprehensive safety pharmacology testing, particularly for proarrhythmia assessment.