Liu Ching-Han, Chen Yao-Chang, Lu Yen-Yu, Lin Yung-Kuo, Higa Satoshi, Chen Shih-Ann, Chen Yi-Jen
Division of Cardiology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
Biomedicines. 2022 Oct 28;10(11):2727. doi: 10.3390/biomedicines10112727.
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.
锂中毒可诱发Brugada波型心电图、室性心律失常和猝死，男性比女性更易发生。本研究探讨了锂诱导心律失常发生过程中性别差异的机制。在静脉注射氯化锂（LiCl）（1、3、10 mmol/kg）前后，记录雄性和雌性兔的心电图参数。采用膜片钳技术研究LiCl处理前后分离的单个雄性和雌性右心室流出道（RVOT）心肌细胞的钠电流（INa）和晚钠电流（INa-late）。在10 mmol/kg（而非1或3 mmol/kg）时，雄性兔（n = 9）比雌性兔（n = 7）更易出现锂诱导的Brugada波型心电图改变（不完全性右束支传导阻滞、ST段抬高和QRS波增宽）并伴有致命性心律失常（66.7% 对0%，p = 0.002）。与雌性RVOT心肌细胞相比，LiCl（100 μM）在雄性RVOT心肌细胞中更大程度地降低了INa并增加了INa-late。此外，在存在雷诺嗪（INa-late抑制剂，静脉注射负荷剂量3.6 mg/kg，随后在30分钟后静脉注射第二次推注剂量6.0 mg/kg，n = 5）的情况下，LiCl（10 mmol/kg）未诱发Brugada波型心电图改变（p < 0.005）。男性更容易出现锂诱导的Brugada波型心电图改变，对RVOT心肌细胞中的INa和INa-late影响更大。针对INa-late可能是治疗Brugada综合征相关室性快速心律失常的一种潜在策略。
