Atrial Fibrillation Promotion With Long-Term Repetitive Obstructive Sleep Apnea in a Rat Model

作者：Iwasaki Yu ki; Kato Takeshi; Xiong Feng; Shi Yan Fen; Naud Patrice; Maguy Ange; Mizuno Kyoichi; Tardif Jean Claude; Comtois Philippe; Nattel Stanley^*

来源：Journal of the American College of Cardiology, 2014, 64(19): 2013-2023.

DOI：10.1016/j.jacc.2014.05.077

• atrial fibrosis
• cardiac arrhythmia mechanisms
• diastolic dysfunction
• electrocardiogram
• obstructive sleep apnea

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.
OBJECTIVES 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.

• 出版日期2014-11-11