P798Application of intermittent negative upper airway pressure as a novel rat model for obstructive sleep apnea and atrial fibrillation

Abstract

Background: Obstructive sleep apnea (OSA) is associated with increased occurrence of atrial fibrillation (AF). Obstructive respiratory events lead to intermittent hypoxia (IH) and ineffective inspiration against the occluded upper airways result in intrathoracic pressure changes and increasing cardiac transmural pressure gradients. Animal models mimicking intrathoracic pressure changes on top of IH are not available. Method: In spontaneously breathing sedated rats (2% isoflurane), IH (n= 9) was applied by intermittent increase in the respiratory dead volume. Reproducible and standardized obstructive respiratory events were induced by defined intermittent negative upper airway pressure (INAP = inverse CPAP) applied via a customized mask which was connected to a negative pressure device (n= 9). One minute of IH or INAP was followed by a rest period of nine minutes for four hours every second day. Blood pressure was measured by telemetry. Rats with comparable anesthesia were used as controls (CTR). After three weeks, left ventricular pressure was measured invasively and inducible AF-duration by atrial burst stimulation was determined before sacrifice. Left (LA) and ventricular (LV) tissue was processed for histological and biochemical analyses. Results: Blood pressure and end-diastolic left ventricular pressure were not affected by IH or INAP. Intermittent desaturation ( 77% O2) and post-apneic hyperventilation was comparable in INAP-and IH-rats, but INAP-rats showed significantly higher breathing efforts during apnea compared to IH-rats (IH: 3.4460.13 Vs. INAP: 4.4760.14 mbar p<0.01). LA interstitial fibrosis formation (LA: +135% vs. CTR, p=0.01) and LA-myocyte diameters (LA: +107%, p=0.03 vs. CTR) were increased in INAP-rats, but unchanged in IH-rats. This was associated with longer inducible AFdurations in INAP-rats (p=0.02 vs. CTR INAP: 11.65 seconds CTR: 0.98 seconds) but not in IH-rats (p=0.31 vs. CTR IH: 1.28 seconds). Conclusion: Application of INAP in rats mimics important components of OSA beyond IH and allows the study of the progressive arrhythmogenic substrate in the atrium independent of the development of hypertension or overt diastolic dysfunction.