Cellular mechanisms for trazodone-induced cardiotoxicity.

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Second-generation antidepressants like SARIs generally have fewer cardiovascular risks.
• However, trazodone has been linked to QT prolongation, cardiac arrhythmias, and ventricular tachycardia in case reports.
• The precise cellular mechanisms of trazodone-induced cardiotoxicity beyond hERG channel effects are not fully understood.

Purpose of the Study:

• To investigate the cellular mechanisms underlying trazodone's adverse cardiac effects.
• To examine trazodone's impact on cardiac action potentials and ion channel function.

Main Methods:

• Utilized whole-cell patch clamp techniques.
• Studied effects in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
• Examined effects on HEK293 cells expressing cardiac ion channels.

Main Results:

• Trazodone dose-dependently reduced maximum upstroke velocity (Vmax) and prolonged action potential duration (APD).
• Observed early afterdepolarizations and triggered ventricular arrhythmias in hiPSC-CMs at 3 and 10 μM.
• Trazodone inhibited major cardiac ion channels (IKr, IKs, INa, ICa), with potent inhibition of hERG.

Conclusions:

• Trazodone-induced APD prolongation and decreased Vmax are primarily due to hERG and sodium channel inhibition.
• Trazodone's inhibitory effects on cardiac ion channels are demonstrable in hiPSC-CMs.
• These findings elucidate the cellular basis for trazodone's cardiotoxicity.