Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes
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 an...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/10/11/2727 |
| _version_ | 1797468970130866176 |
|---|---|
| author | Ching-Han Liu Yao-Chang Chen Yen-Yu Lu Yung-Kuo Lin Satoshi Higa Shih-Ann Chen Yi-Jen Chen |
| author_facet | Ching-Han Liu Yao-Chang Chen Yen-Yu Lu Yung-Kuo Lin Satoshi Higa Shih-Ann Chen Yi-Jen Chen |
| author_sort | Ching-Han Liu |
| collection | DOAJ |
| description | 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 (I<sub>Na</sub>) and late sodium current (I<sub>Na-late</sub>) in the isolated single male and female right ventricular outflow tract (RVOT) cardiomyocytes before and after LiCl. Male rabbits (<i>n</i> = 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%, <i>p</i> = 0.002) than in female (<i>n</i> = 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 I<sub>Na</sub> to a greater extent and increased I<sub>Na-late</sub> in the male RVOT cardiomyocytes. Moreover, in the presence of ranolazine (the I<sub>Na-late</sub> inhibitor, 3.6 mg/kg iv loading, followed by a second iv bolus 6.0 mg/kg administered 30 min later, <i>n</i> = 5), LiCl (10 mmol/kg) did not induce Brugada-pattern ECG changes (<i>p</i> < 0.005). The male gender is much predisposed to lithium-induced Brugada-pattern ECG changes with a greater impact on I<sub>Na</sub> and I<sub>Na-late</sub> in RVOT cardiomyocytes. Targeting I<sub>Na-late</sub> may be a potential therapeutic strategy for Brugada syndrome-related ventricular tachyarrhythmia. |
| first_indexed | 2024-03-09T19:14:52Z |
| format | Article |
| id | doaj.art-19755402101d46eeac3020aa4bb9fe16 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T19:14:52Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-19755402101d46eeac3020aa4bb9fe162023-11-24T03:49:47ZengMDPI AGBiomedicines2227-90592022-10-011011272710.3390/biomedicines10112727Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract CardiomyocytesChing-Han Liu0Yao-Chang Chen1Yen-Yu Lu2Yung-Kuo Lin3Satoshi Higa4Shih-Ann Chen5Yi-Jen Chen6Division of Cardiology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, TaiwanDepartment of Biomedical Engineering, National Defense Medical Center, Taipei 11490, TaiwanDivision of Cardiology, Sijhih Cathay General Hospital, Sijhih, New Taipei City 22174, TaiwanCardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, TaiwanCardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Urasoe 901-2131, Okinawa, JapanHeart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, TaiwanCardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, TaiwanLithium 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 (I<sub>Na</sub>) and late sodium current (I<sub>Na-late</sub>) in the isolated single male and female right ventricular outflow tract (RVOT) cardiomyocytes before and after LiCl. Male rabbits (<i>n</i> = 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%, <i>p</i> = 0.002) than in female (<i>n</i> = 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 I<sub>Na</sub> to a greater extent and increased I<sub>Na-late</sub> in the male RVOT cardiomyocytes. Moreover, in the presence of ranolazine (the I<sub>Na-late</sub> inhibitor, 3.6 mg/kg iv loading, followed by a second iv bolus 6.0 mg/kg administered 30 min later, <i>n</i> = 5), LiCl (10 mmol/kg) did not induce Brugada-pattern ECG changes (<i>p</i> < 0.005). The male gender is much predisposed to lithium-induced Brugada-pattern ECG changes with a greater impact on I<sub>Na</sub> and I<sub>Na-late</sub> in RVOT cardiomyocytes. Targeting I<sub>Na-late</sub> may be a potential therapeutic strategy for Brugada syndrome-related ventricular tachyarrhythmia.https://www.mdpi.com/2227-9059/10/11/2727Brugada syndromegenderlithium intoxicationsodium current dysregulationright ventricular outflow tract |
| spellingShingle | Ching-Han Liu Yao-Chang Chen Yen-Yu Lu Yung-Kuo Lin Satoshi Higa Shih-Ann Chen Yi-Jen Chen Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes Biomedicines Brugada syndrome gender lithium intoxication sodium current dysregulation right ventricular outflow tract |
| title | Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes |
| title_full | Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes |
| title_fullStr | Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes |
| title_full_unstemmed | Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes |
| title_short | Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes |
| title_sort | gender difference in lithium induced sodium current dysregulation and ventricular arrhythmogenesis in right ventricular outflow tract cardiomyocytes |
| topic | Brugada syndrome gender lithium intoxication sodium current dysregulation right ventricular outflow tract |
| url | https://www.mdpi.com/2227-9059/10/11/2727 |
| work_keys_str_mv | AT chinghanliu genderdifferenceinlithiuminducedsodiumcurrentdysregulationandventriculararrhythmogenesisinrightventricularoutflowtractcardiomyocytes AT yaochangchen genderdifferenceinlithiuminducedsodiumcurrentdysregulationandventriculararrhythmogenesisinrightventricularoutflowtractcardiomyocytes AT yenyulu genderdifferenceinlithiuminducedsodiumcurrentdysregulationandventriculararrhythmogenesisinrightventricularoutflowtractcardiomyocytes AT yungkuolin genderdifferenceinlithiuminducedsodiumcurrentdysregulationandventriculararrhythmogenesisinrightventricularoutflowtractcardiomyocytes AT satoshihiga genderdifferenceinlithiuminducedsodiumcurrentdysregulationandventriculararrhythmogenesisinrightventricularoutflowtractcardiomyocytes AT shihannchen genderdifferenceinlithiuminducedsodiumcurrentdysregulationandventriculararrhythmogenesisinrightventricularoutflowtractcardiomyocytes AT yijenchen genderdifferenceinlithiuminducedsodiumcurrentdysregulationandventriculararrhythmogenesisinrightventricularoutflowtractcardiomyocytes |