title: Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model.
abstract: BACKGROUND
  Obstructive sleep apnea (OSA) importantly contributes to the occurrence of atrial fibrillation (AF) in humans, but the mechanisms are poorly understood. Experimental research has provided insights into AF promotion by acute OSA episodes. However, patients with OSA usually have frequent nocturnal episodes for some time before manifesting AF.
  
  
  OBJECTIVE
  The goal of this study was to test the hypothesis that repetitive OSA causes cardiac remodeling that predisposes to AF.
  
  
  METHODS
  We mimicked OSA by using a mechanical ventilator and closing the airway at end-expiration with a 3-way stopcock (OSA rats). Matched control groups included rats with the ventilator stopped but airway left open (open airway rats) and continuously ventilated rats (sham rats). OSA rats were exposed to 20 consecutive 2-min cycles of 40 s of apnea/80 s of ventilation per day, 5 days per week for 4 weeks.
  
  
  RESULTS
  OSA significantly increased the duration of AF from (median [interquartile range]) 2.6 s [1.9 s to 8.9 s] (shams) and 16 s [1.8 s to 93 s] (open airway) to 49s [34 s to 444 s]. AF inducibility increased to 56% (9 of 16) of OSA rats; this is up from 15% (2 of 13) and 13% (2 of 15) in open airway and sham rats, respectively (p < 0.05). OSA rats exhibited substantial atrial conduction slowing on optical mapping, along with connexin-43 down-regulation on both quantitative immunofluorescence (expression reduced by 58% vs sham rats) and Western blot (reduced by 38%), as well as increased atrial fibrous tissue content (by 71%). OSA also caused left ventricular hypertrophy, dilation, and diastolic dysfunction and enhanced AF inducibility during superimposed acute OSA episodes to 82.4% of rats.
  
  
  CONCLUSIONS
  Chronically repeated OSA episodes cause AF-promoting cardiac remodeling, with conduction abnormalities related to connexin dysregulation and fibrosis playing a prominent role. This novel animal model provides mechanistic insights into an important clinical problem and may be useful for further exploration of underlying mechanisms and therapeutic approaches.
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Yu-Ki
authors.initials: YK
authors.lastname: Iwasaki
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology, McGill University, Montreal, Quebec, Canada.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Shi
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Ange
authors.initials: A
authors.lastname: Maguy
authors.affiliation: Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Mizuno
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Department of Physiology, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Comtois
authors.affiliation: Department of Medicine, Montréal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology, McGill University, Montreal, Quebec, Canada. Electronic address: stanley.nattel@icm-mhi.org.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D064752:Atrial Remodeling / Q000502:physiology*; D018031:Connexin 43 / Q000378:metabolism; D003971:Diastole; D004195:Disease Models, Animal; D004452:Echocardiography; D004594:Electrophysiology; D006325:Heart Atria / Q000503:physiopathology; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial; D020181:Sleep Apnea, Obstructive / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat
keywords: atrial fibrosis; cardiac arrhythmia mechanisms; diastolic dysfunction; electrocardiogram; obstructive sleep apnea