Abstract
High night-to-night variability in 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. 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. INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS). INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033). 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.
Highlights
Obstructive sleep apnea (OSA) is prevalent in up to 70% of all patients with atrial fibrillation (AF) and affects the efficacy of pharmacological and catheter-based strategies for rhythm control.[1,2,3] In nonrandomized observational clinical trials, treatment of severe OSA improved AF catheter ablation outcomes.[1,2] Most clinical and preclinical research mainly focused on the role of severe OSA
Left ventricular expression of brain natriuretic peptide Four hours of repetitively applied intermittent negative upper airway pressure (INAP) resulted in an enhanced expression of brain natriuretic peptide (BNP) messenger RNA, a marker for increased cardiac volume and pressure overload, in the left ventricular (LV) of INAP-acute test series (ATS) compared with CTR-ATS (1.72 6 0.16 vs 1.10 6 0.14 relative gene expression/glyceraldehyde 3-phosphate dehydrogenase, respectively; P 5 .009)
Mild-to-moderate OSA with high night-to-night variability simulated by repeated exposure to these transient biological responses related to OSA for 3 weeks resulted in an arrhythmogenic substrate for AF
Summary
Obstructive sleep apnea (OSA) is prevalent in up to 70% of all patients with atrial fibrillation (AF) and affects the efficacy of pharmacological and catheter-based strategies for rhythm control.[1,2,3] In nonrandomized observational clinical trials, treatment of severe OSA improved AF catheter ablation outcomes.[1,2] Most clinical and preclinical research mainly focused on the role of severe OSA. OSA episodes are characterized by high-frequency desaturation-reoxygenation, and intrathoracic pressure swings occur during ineffective inspiration against the occluded upper airways, which increases transmural pressure gradients and may expose the thin-walled atria to increased stretch.[4,5] despite the described high prevalence of OSA in patients with AF, longitudinal assessment of sleep apnea severity in patients with AF and cardiovascular implantable electronic devices in the VARIOSA-AF study (Variability of Sleep Apnea Severity and Risk of Atrial Fibrillation) indicated that most patients with AF do not demonstrate severe sleep apnea every day, but rather mild or moderate sleep apnea and considerable intraindividual night-to-night variability.[6,7,8] This creates a scenario of transient exposure to OSA-related conditions, characterized by intermittent hypoxia and intrathoracic pressure swings. Obstructive apneas are characterized by intermittent deoxygenationreoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways
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