L-Type Calcium Channel Inhibition Contributes to the Proarrhythmic Effects of Aconitine in Human Cardiomyocytes

Area of Science:

• Cardiology
• Electrophysiology
• Pharmacology

Background:

• Aconitine (ACO) is known to cause lethal ventricular tachyarrhythmias.
• The cellular effects and mechanisms of ACO in human cardiomyocytes were previously unexplored.

Purpose of the Study:

• To assess the proarrhythmic effects of ACO in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
• To elucidate the cellular mechanisms underlying ACO-induced proarrhythmia in human cardiac cells.

Main Methods:

• Utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for cellular and electrophysiological studies.
• Employed laser-scanning confocal calcium imaging, automated voltage-clamp assays, and microelectrode array assays.
• Investigated effects on action potential duration, calcium transients, ion channel currents (LTCC, INa, IKr), and field potentials.

Main Results:

• ACO concentration-dependently shortened action potential durations (>40%) and induced delayed after-depolarizations in hiPSC-CMs.
• ACO decreased [Ca2+]i transient duration/amplitude, increased beating frequencies (>60%), and reduced L-type calcium channel (LTCC) currents (ICa,L).
• ACO inhibited ICa,L, moderately suppressed IKr, and did not alter peak/late Na+ currents (INa) in hiPSC-CMs, unlike in animal models.

Conclusions:

• L-type calcium channel inhibition plays a primary role in the proarrhythmic action of ACO in human cardiomyocytes.
• Findings highlight the importance of human iPSC-derived models for understanding drug effects on cardiac electrophysiology.