title: Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs.
abstract: BACKGROUND
  The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF.
  
  
  METHODS
  We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG.
  
  
  RESULTS
  We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV·s (95% confidence interval [CI] 3.08-6.60 mV·s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV·s (95% CI 2.27-5.20 mV·s; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF-time and to 4.07 mV·s (95% CI 2.42-5.72 mV·s; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG.
  
  
  CONCLUSIONS
  VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF.
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
authors.forename: Kroekkiat
authors.initials: K
authors.lastname: Chinda
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Division of Cardiology, The First Department of Medicine, Chang-Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Chan
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Andrew Y-T
authors.initials: AY
authors.lastname: Lin
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Jheel
authors.initials: J
authors.lastname: Patel
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiac Surgery, The First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Cardiology, Hunter Holmes McGuire VA Medical Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Tan
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shen
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine and the Fairbanks School of Public Health, Indianapolis, Indiana.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine and the Fairbanks School of Public Health, Indianapolis, Indiana.
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.affiliation: Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Nipon
authors.initials: N
authors.lastname: Chattipakorn
authors.affiliation: Department of Pediatrics, Riley Heart Research Center, Indianapolis, Indiana.
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart-von der Lohe
authors.affiliation: The Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Lan S
authors.initials: LS
authors.lastname: Chen
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan.
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: chenpp@iu.edu.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D002304:Cardiac Pacing, Artificial / Q000379:methods*; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D006325:Heart Atria / Q000294:innervation / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D013233:Stellate Ganglion / Q000502:physiology*; D055536:Vagus Nerve Stimulation / Q000379:methods*
keywords: Atrial fibrillation; Excitotoxicity; Vagal nerve stimulation