Obstructive Sleep Apnoea, Cigarette Smoking and Plasma Orexin-A in a Sleep Clinic Cohort

The Journal of International Medical Research 2009; 37: 331 – 340 Obstructive Sleep Apnoea, Cigarette Smoking and Plasma Orexin-A in a Sleep Clinic Cohort K AKSU1, S FIRAT GÜVEN1, F AKSU1, B CIFTCI1, T ULUKAVAK CIFTCI2, S AKSARAY3, T ŞIPIT1 AND Y PEKER4 1 Sleep Disorders Centre, Department of Pulmonology, Atatürk Chest Diseases and Chest Surgery Education and Research Hospital, Ankara, Turkey; 2Department of Pulmonology, Gazi University, Faculty of Medicine, Ankara, Turkey; 3Department of Biochemistry, Numune Training and Education Hospital, Ankara, Turkey; 4Sleep Medicine Unit, Department of Neurology and Rehabilitation Medicine, Skoevde, Sweden Orexin-A is a neuropeptide involved in the regulation of food intake and the sleep–wake cycle. This study investigated plasma orexin-A levels in a sleep clinic cohort, adjusting for smoking habits, in 76 participants comprising 41 with obstructive sleep apnoea (OSA) (apnoea–hypopnoea index [AHI] 44.1 ± 19.1 events/h) and 35 without OSA (AHI 6.3 ± 4.7 events/h). Plasma orexin-A levels were significantly lower in OSA patients (15.0 ± 4.6 ng/ml) compared with those without OSA (31.4 ± 6.5 ng/ml). In non-OSA subjects, there was no significant difference between never smokers and ex/current smokers in plasma orexin-A levels (32.9 ± 9.5 versus 29.7 ± 8.9 ng/ml, respectively) whereas, in the OSA sub-group, orexin-A levels were significantly lower in never smokers than in ex/current smokers (4.0 ± 1.2 versus 21.4 ± 7.0 ng/ml). A significant inverse relationship was found between plasma orexin-A levels and AHI amongst never smokers, but there was no significant relationship amongst ex/current smokers. These results confirm previous studies demonstrating lower levels of plasma orexin-A in OSA patients and indicate that smoking may affect orexin-A levels and AHI. KEY WORDS: OBSTRUCTIVE SLEEP APNOEA; OREXIN-A; CIGARETTE SMOKING; APNOEA–HYPOPNOEA INDEX Introduction Obstructive sleep apnoea (OSA) is a common disorder with a diversity of symptoms1 and increased cardiovascular morbidity2 Underlying mechanisms regarding the pathogenesis as well as the severity of the disease still remain unclear. A neuropeptide, orexin-A (also known as hypocretin-1), has been reported to be involved in the regulation of food intake and the sleep–wake cycle,3,4 and some authors have demonstrated low levels of plasma orexin-A in OSA patients,5 – 7 while others have found the opposite.8 There are also conflicting data regarding the relationship between plasma orexin-A levels and the severity of OSA in 331 K Aksu, S Firat Güven, F Aksu et al. Obstructive sleep apnoea, smoking and plasma orexin-A terms of the apnoea–hypopnoea index (AHI)6 – 8 as well as the impact of alleviation of OSA by continuous positive airway pressure (CPAP) treatment.7,9 Results from human trials have suggested that plasma orexin-A levels are negatively correlated with body mass index (BMI)10 and positively correlated with age.11 Cigarette smoking, which is common in clinic populations, has been suggested to be an independent risk factor for OSA by some authors,12,13 whereas others do not support this.14,15 Some beneficial effects of nicotine, including protection against OSA, were discussed in the early 1990s,16 however, overnight transdermal nicotine administration was shown adversely to affect sleep and respiratory parameters in non-smokers17 and a recent study has revealed that smoking interacts with OSA to increase cardiovascular risk.18 The role of nicotine on orexin-A levels has been previously studied in rats, demonstrating suppressed slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and increased wakefulness in a dosedependent manner.19 To our knowledge, however, there are no data on the impact of cigarette smoking on plasma orexin-A levels in OSA patients. The aim of the current study was to address the relationship between levels of plasma orexin-A and OSA, whilst considering cigarette smoking as a confounding factor, in a sleep clinic population. Patients and methods STUDY POPULATION All participants were recruited from subjects who were being investigated in the Sleep Disorders Centre of the Atatürk Chest Diseases and Chest Surgery Education and Research Hospital, Ankara, Turkey, between 1 January 2005 and 31 July 2006, following concerns of snoring or clinical suspicion of OSA. Subjects were eligible if they were willing to participate in the study, if they did not have cardiovascular disease, diabetes mellitus, renal failure, chronic obstructive pulmonary disease (COPD), asthma or malignancy, if they had not previously been diagnosed or treated for OSA, if they had no history of episodes of cataplexy, and if they were free from hypnotic drugs. Subjects with total sleep time < 240 min and those with signs of central sleep apnoea on polysomnography recordings were excluded. The study protocol was approved by the ethics committee of the Atatürk Chest Diseases and Chest Surgery Education and Research Hospital and both written and verbal informed consent were obtained from each participant prior to study entry. SMOKING HISTORY AND STUDY ASSESSMENTS Current smokers were defined as subjects who were smokers at the time of admission to the Sleep Disorders Centre as well as those who had stopped smoking for < 6 months prior to admission. Subjects who had ceased smoking ≥ 6 months prior to admission were defined as ex-smokers. Both current smokers and exsmokers were questioned about the number of cigarettes that they smoked daily as well as the number of years that they smoked. Assuming that a pack contains 20 cigarettes, pack-years were estimated using the following formula: (cigarettes per day/20) × years smoked. Current smokers and ex-smokers were grouped together in the statistical analysis so as to provide sufficient statistical power to evaluate the effect of smoking behaviour on plasma orexin-A levels; subjects who never smoked were grouped separately as non-smokers. 332 K Aksu, S Firat Güven, F Aksu et al. Obstructive sleep apnoea, smoking and plasma orexin-A All subjects underwent pulmonary function tests (Vmax 229; SensorMedics® Corp., Yorba Linda, CA, USA), and forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) values and FEV1/FVC ratios were recorded. Subjects with FEV1/FVC < 70% were excluded as they were regarded as having COPD. Body weight and height measurements were assessed and BMI (kg/m2) was computed as the ratio between body weight (kg) and squared height (m). Excessive daytime sleepiness was reported using the Epworth Sleepiness Scale (ESS).20 OVERNIGHT SLEEP STUDIES All participants underwent full-night polysomnography, using the Compumedics® Voyager Digital Imaging E-series system (Compumedics®, Melbourne, Australia). They were advised not to sleep during the daytime, and not to consume caffeinecontaining beverages, food, alcohol, and any medication that might affect their sleep pattern within 12 h prior to the fu (...truncated)