Repeated exposure to transient obstructive sleep apnea related conditions causes an atrial fibrillation substrate in a chronic rat model.

Abstract Background High night-to-night variability of obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways. Objective We elucidated the effect of repeated exposure to transient OSA-conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF-substrate. Methods INAP (48 events/4h, Apnea-Hypopnea-Index (AHI)=12/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as controls (CTR). In an acute-test-series (ATS), rats were either sacrificed immediately (n=9/group) or after 24h of recovery (ATS-REC n=5/group). To simulate high night-to-night variability in OSA, INAP-applications (n=10; 24 events/4h, AHI=6/h) were repeated every second day for three weeks in a chronic-test-series (CTS). Results INAP increased atrial oxidative stress acutely, represented in decreases of reduced (GSH) to oxidized (GSSG) glutathione-ratio (ATS: INAP 0.33±0.05 vs. CTR 1±0.26; p=0.016), which was reversible after 24h (ATS-REC: INAP vs. CTR; p=n.s.). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin43 expression and increased interstitial fibrosis formation (CTS: INAP 7.0±0.5% vs. CTR 5.1±0.3%; p=0.013), which were associated with longer inducible AF-episodes (CTS: INAP 11.65±4.43 seconds vs. CTR 0.7±0.33 seconds; p=0.033). Conclusions Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF-substrates and was associated with increased AF-susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development.