title: Ablation of androgen receptor gene triggers right ventricular outflow tract ventricular tachycardia.
abstract: BACKGROUND
  Sex hormones and calcium (Ca(2+)) regulation play roles in the pathophysiology of ventricular tachycardia from right ventricular outflow tract (RVOT). The purpose of this study was to evaluate whether androgen receptor knockout (ARKO) can increase RVOT arrhythmogenesis through modulating RVOT electrophysiology and Ca(2+) homeostasis.
  
  
  METHODS
  Conventional microelectrodes were used to study the action potential (AP) in RVOT tissues prepared from wild type (WT) and ARKO mice (aged 6-10 months) before and after caffeine (1mM), isoproterenol (1 μM), adenosine (10 μM) and flecainide (5 μM) administration. The Fluo-3 fluorescence Ca(2+) imaging with confocal microscopy and western blots were used to investigate intracellular Ca(2+) (Ca(2+)i) transients, Ca(2+) sparks, and the expressions of ionic channel proteins in ARKO and WT RVOT myocytes.
  
  
  RESULTS
  We found that ARKO RVOTs (n = 13) had longer AP duration, faster burst firing (5.4 ± 0.7 vs. 3.4 ± 0.7 Hz, P < 0.05), and higher incidence of early afterdepolarizations (82% vs. 8%, P < 0.001) than WT RVOTs (n = 11). Adenosine and flecainide can suppress caffeine- or isoproterenol-induced spontaneous rates and burst firing in WT RVOTs, but not in ARKO RVOTs. ARKO RVOT myocytes had a higher frequency (7.7 ± 2.8 vs. 1.3 ± 0.4 spark/mm/s, P < 0.05) and incidence (89% vs. 47%, P < 0.05) of Ca(2+) sparks, and greater expressions of Cav1.2, NCX, phosphorylated RyR (s2814), phosphorylated phospholamban (Thr17), CAMKII and GRK2 than WT RVOT myocytes. However, ARKO and WT RVOT myocytes exhibit similar Ca(2+)i transients and SR Ca(2+) content, and less expression of calsequestrin.
  
  
  CONCLUSIONS
  ARKO changes RVOT electrophysiology and Ca(2+) homeostasis with increased ventricular arrhythmogenesis.
authors.affiliation: Division of Cardiology, Tzu-Chi General Hospital, Hualien, Taiwan.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: Division of Cardiology, Sijhih Cathay General Hospital, New Taipei City, Taiwan.
authors.forename: Yen-Yu
authors.initials: YY
authors.lastname: Lu
authors.affiliation: Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Chien-Jung
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.affiliation: Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.affiliation: Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Research Center for Biomedical Devices and Prototyping Production, Taipei Medical University, Taipei, Taiwan; Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: yangly@tmu.edu.tw.
authors.forename: Liang-Yo
authors.initials: LY
authors.lastname: Yang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: a9900112@ms15.hinet.net.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D005424:Flecainide / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011944:Receptors, Androgen / Q000172:deficiency* / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen; D002110:Caffeine; D000241:Adenosine; D005424:Flecainide; D007545:Isoproterenol; D002118:Calcium
keywords: Arrhythmogenicity; Calcium handling; Right ventricular outflow tract; Ventricular arrhythmias