title: Fluconazole-induced long QT syndrome via impaired human ether-a-go-go-related gene (hERG) protein trafficking in rabbits.
abstract: OBJECTIVE
  hERG protein trafficking deficiency has long been known in drug-induced long QT syndrome (LQTS). However, validated evidence from in vivo data kept scanty. Our goal was to investigate the proarrhythmic action of fluconazole and its underlying mechanism in an animal model.
  
  
  RESULTS
  Twenty female Japanese long-eared white rabbits were randomly distributed into a control group and a fluconazole group for a chronic 2-week treatment. The control group was treated with 0.5% sodium carboxymethylcellulose (CMCNa), and the fluconazole group was treated with fluconazole. Electrocardiograms (ECGs) were recorded during the experimental period. Isolated arterially perfused left ventricular wedge preparations from the rabbits were made 2 weeks after treatment, and the arrhythmia events, the transmural ECG, and action potential from both the endocardium and epicardium were recorded. The changes in hERG protein expression were measured by western blot. The fluconazole group showed a longer QT interval 1 week after treatment (P < 0.05) and a higher arrhythmia occurrence 2 weeks after treatment (P < 0.05) than the control group. The fluconazole group also showed a longer transmural dispersion of repolarization and a higher occurrence of life-threatening torsades de pointes in arterially perfused left ventricular preparations. Furthermore, western blot analysis showed that the density of mature hERG protein was lower in the fluconazole group than that in the control group.
  
  
  CONCLUSIONS
  Fluconazole can prolong the QT interval and possess proarrhythmic activity due to its inhibition of hERG protein trafficking in our experimental model. These findings may impact the clinical potential of fluconazole in humans.
authors.affiliation: Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.
authors.forename: Jinli
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Quan
authors.affiliation: Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ruan
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Rd, Beijing 100029, P.R. China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Rd, Beijing 100029, P.R. China.
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.
authors.forename: Cuntai
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Rd, Beijing 100029, P.R. China.|Texas Cardiac Arrhythmia Institute at St David's Medical Center, Austin, TX, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Bai
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel / Q000378:metabolism*; D004562:Electrocardiography; D005260:Female; D015725:Fluconazole; D006339:Heart Rate; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D021381:Protein Transport; D011817:Rabbits; D013997:Time Factors
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D015725:Fluconazole
keywords: Arrhythmia; Drug-induced long QT syndrome; Fluconazole; QT interval; hERG