Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes

Ching Han Liu, Yao Chang Chen, Yen Yu Lu, Yung Kuo Lin, Satoshi Higa, Shih Ann Chen, Yi Jen Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Lithium intoxication induces Brugada-pattern ECG, ventricular arrhythmia, and sudden death with the predominant preference for the male over the female gender. This study investigated the mechanisms of gender difference in lithium-induced arrhythmogenesis. The ECG parameters were recorded in male and female rabbits before and after the intravenous administration of lithium chloride (LiCl) (1, 3, 10 mmol/kg). Patch clamps were used to study the sodium current (INa) and late sodium current (INa-late) in the isolated single male and female right ventricular outflow tract (RVOT) cardiomyocytes before and after LiCl. Male rabbits (n = 9) were more prone to developing lithium-induced Brugada-pattern ECG changes (incomplete right bundle branch block, ST elevation and QRS widening) with fatal arrhythmia (66.7% vs. 0%, p = 0.002) than in female (n = 7) rabbits at 10 mmol/kg (but not 1 or 3 mmol/kg). Compared to those in the female RVOT cardiomyocytes, LiCl (100 μM) reduced INa to a greater extent and increased INa-late in the male RVOT cardiomyocytes. Moreover, in the presence of ranolazine (the INa-late inhibitor, 3.6 mg/kg iv loading, followed by a second iv bolus 6.0 mg/kg administered 30 min later, n = 5), LiCl (10 mmol/kg) did not induce Brugada-pattern ECG changes (p < 0.005). The male gender is much predisposed to lithium-induced Brugada-pattern ECG changes with a greater impact on INa and INa-late in RVOT cardiomyocytes. Targeting INa-late may be a potential therapeutic strategy for Brugada syndrome-related ventricular tachyarrhythmia.

Original languageEnglish
Article number2727
JournalBiomedicines
Volume10
Issue number11
DOIs
Publication statusPublished - Nov 2022

Keywords

  • Brugada syndrome
  • gender
  • lithium intoxication
  • right ventricular outflow tract
  • sodium current dysregulation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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