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Obstructive sleep apnoea (OSA) upregulates the programmed cell death-1 receptor and its ligand (PD-L1) pathway, potentially compromising immunosurveillance. We compared circulating levels of soluble PD-L1 (sPD-L1) in patients with cutaneous melanoma according to the presence and severity of OSA, and evaluated relationships with tumour aggressiveness and invasiveness.In a multicentre observational study, 360 patients with cutaneous melanoma underwent sleep studies, and serum sPD-L1 levels were assayed using ELISA. Cutaneous melanoma aggressiveness indices included mitotic rate, Breslow index, tumour ulceration, Clark level and tumour stage, and sentinel lymph node (SLN) metastasis was recorded as a marker of invasiveness.sPD-L1 levels were higher in severe OSA compared to mild OSA or non-OSA patients. In OSA patients, sPD-L1 levels correlated with Breslow index and were higher in patients with tumour ulceration, advanced primary tumour stages or with locoregional disease. The incorporation of sPD-L1 to the classic risk factors to SLN metastasis led to net improvements in the classification of 27.3%.Thus, sPD-L1 levels are increased in melanoma patients with severe OSA, and, in addition, might serve as a potential biomarker of cutaneous melanoma aggressiveness and invasiveness in this group of subjects., Competing Interests: Conflict of interest: C. Cubillos-Zapata has nothing to disclose. Conflict of interest: M.Á. Martínez-García has nothing to disclose. Conflict of interest: F. Campos-Rodríguez has nothing to disclose. Conflict of interest: M. Sánchez de la Torre has nothing to disclose. Conflict of interest: E. Nagore has nothing to disclose. Conflict of interest: A. Martorell-Calatayud has nothing to disclose. Conflict of interest: L. Hernández Blasco has nothing to disclose. Conflict of interest: E. Chiner Vives has nothing to disclose. Conflict of interest: J. Abad-Capa has nothing to disclose. Conflict of interest: J.M. Montserrat has nothing to disclose. Conflict of interest: V. Cabriada-Nuño has nothing to disclose. Conflict of interest: I. Cano-Pumarega has nothing to disclose. Conflict of interest: J. Corral-Peñafiel has nothing to disclose. Conflict of interest: T. Diaz-Cambriles has nothing to disclose. Conflict of interest: O. Mediano has nothing to disclose. Conflict of interest: M. Somoza-González has nothing to disclose. Conflict of interest: J. Dalmau-Arias has nothing to disclose. Conflict of interest: I. Almendros has nothing to disclose. Conflict of interest: R. Farré has nothing to disclose. Conflict of interest: E. López-Collazo has nothing to disclose. Conflict of interest: D. Gozal has nothing to disclose. Conflict of interest: F. García-Río has nothing to disclose., (Copyright ©ERS 2019.)

Obstructive sleep apnoea (OSA) has been inconsistently associated with insulin resistance and adverse metabolic states. We aimed to assess independent contributions of OSA to insulin resistance and dyslipidaemia in a large paediatric cohort.Habitually snoring children underwent overnight polysomnography, anthropometric measurements and fasting laboratory evaluations. Primary outcome measures included insulin, glucose, homeostasis model of insulin resistance, lipoproteins and sleep disturbance measures.Among 459 children aged 5-12 years, obesity was the primary driver of most associations between OSA and metabolic measures, but sleep duration was inversely associated with glucose levels, with N3 and rapid eye movement (REM) sleep being negatively associated and sleep fragmentation positively associated with insulin resistance measures. In children with mild OSA, the presence of obesity increased the odds for insulin resistance, while higher apnoea/hypopnoea index values emerged among obese children who were more insulin-resistant.The exclusive presence of interactions between OSA and obesity in the degree of insulin resistance is coupled with synergistic contributions by sleep fragmentation to insulin resistance in the context of obesity. Insufficient N3 or REM sleep may also contribute to higher glycaemia independently of obesity. Studies are needed to better delineate the roles of puberty and sleep fragmentation in insulin resistance and the metabolic syndrome., (Copyright ©ERS 2016.)

There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress.59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) >20 events·h(-1)) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using samples from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. "Treatment" effects (sham CPAP versus CPAP) were calculated via linear regression.Sham CPAP provoked moderate-to-severe OSA (mean ODI 46 events·h(-1)), but blood markers of oxidative stress did not change significantly (MDA "treatment" effect (95% CI) -0.02 (-0.23 to +0.19) μmol·L(-1)). Urinary F2-isoprostane fell significantly by ~30% (-0.26 (-0.42 to -0.10) ng·mL(-1)) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng·mL(-1)).We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress., (Copyright ©ERS 2015.)

Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Dyslipidaemia has been implicated as a mechanism linking OSA with atherosclerosis, but no consistent associations with lipids exist for OSA or positive airway pressure treatment. We assessed the relationships between fasting lipid levels and obesity and OSA severity, and explored the impact of positive airway pressure treatment on 2-year fasting lipid level changes. Analyses included moderate-to-severe OSA patients from the Icelandic Sleep Apnoea Cohort. Fasting morning lipids were analysed in 613 untreated participants not on lipid-lowering medications at baseline. Patients were then initiated on positive airway pressure and followed for 2 years. Sub-classification using propensity score quintiles, which aimed to replicate covariate balance associated with randomised trials and, therefore, minimise selection bias and allow causal inference, was used to design the treatment group comparisons. 199 positive airway pressure adherent patients and 118 non-users were identified. At baseline, obesity was positively correlated with triglycerides and negatively correlated with total cholesterol, and low-density and high-density lipoprotein cholesterol. A small correlation was observed between the apnoea/hypopnoea index and high-density lipoprotein cholesterol. No effect of positive airway pressure adherence on 2-year fasting lipid changes was observed. Results do not support the concept of changes in fasting lipids as a primary mechanism for the increased risk of atherosclerotic cardiovascular disease in OSA., (©ERS 2014.)

There is increasing evidence that intermittent hypoxia resulting from obstructive sleep apnoea (OSA) is independently associated with dyslipidaemia. Currently, no data exist on potential links between OSA-related dyslipidaemia and susceptibility genes for dyslipidaemia in such patients. Our aim was to study the effects of the apolipoprotein E (APOE) genotype and sleep apnoea severity on atherogenic dyslipidaemia in patients with OSA. 519 clinically stable subjects prospectively recruited at a tertiary referral teaching hospital underwent full polysomnography. APOE gene polymorphisms were assessed using real-time PCR. In all APOE genotype groups, serum triglycerides increased while high-density lipoprotein (HDL) cholesterol was reduced with increasing severity of OSA in each APOE genotype group, whereas the deleterious effects of OSA on serum apolipoprotein (Apo)B levels were observed in ε2 carriers and the ε3/ε3 genotype only. Nevertheless, the ε4 allele carriers had ApoB levels within the risk range, irrespective of nocturnal hypoxia. In addition, among patients with the high-risk ε4 genotype, those with the most severe nocturnal hypoxia had significantly higher triglyceride and lower HDL cholesterol levels compared with nonhypoxic ε4 subjects. APOE genotype and the oxygen desaturation index were both independent predictors of serum triglyceride levels (p=0.009 and p<0.001, respectively; R(2)=0.148) and ApoB levels (p=0.001 and p=0.003, respectively; R(2)=0.104). Our findings suggest that OSA has adverse effects on several lipid parameters over and above the effects carried by APOE genotype. Further st1udies are needed to analyse the effects of high-risk genotypes on metabolic and cardiovascular outcomes in patients with OSA.

Plasma von Willebrand factor (VWF), produced in and released from vascular endothelial cells by various stimuli including hypoxia, induces platelet aggregation under high shear stress and plays dual pivotal roles in haemostasis and thrombosis within arterioles, which are regulated by the size of vWF multimers (VWFMs). Patients with obstructive sleep apnoea (OSA) have increased risk of thrombotic cardiovascular events, but the pathogenesis is unclear. We examined the relationship between VWF and OSA by measuring VWF antigen (VWF:Ag), VWFMs, VWF collagen binding activity (VWF:CB) and a disintegrin-like, metalloproteinase, and thrombospiondin type 1 motifs 13. A total of 58 OSA patients were enrolled. Blood samples were collected before sleep, after sleep, and after one night of nasal continuous positive airway pressure therapy. Based on VWFM analysis, OSA patients were classified into three groups; consistently normal VWFMs (group 1, n=29), increased high molecular weight (HMW)-VWFMs at 06:00 h (group 2, n=18), and decreased or absent HMW-VWFMs at 06:00 h (group 3, n=11). Patients in group 3 had significantly worse apnoea/hypopnoea index; VWF:CB followed a similar pattern. We observed a significant decrease in platelet count between 21:00 h and 06:00 h in OSA patients, potentially associated with reduced larger VWFMs together with decreased VWF:Ag levels. Severe OSA may contribute to an arterial pro-thrombotic state.

Obesity and metabolic syndrome (MS) occur frequently in patients with obstructive sleep apnoea syndrome (OSAS). We hypothesised that circulating free fatty acids (FFAs) are elevated in OSAS patients independently of obesity. This elevation may contribute to the development of MS in these patients. We studied 119 OSAS patients and 119 controls. Participants were recruited and studied at sleep unit of our institution (Hospital Universitari Son Dureta, Palma de Mallorca, Spain) and were matched for sex, age and body mass index (BMI). The occurrence of MS was analysed by clinical criteria. Serum levels of FFAs, glucose, triglycerides, cholesterol, high-density lipoprotein-cholesterol, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, C-reactive protein and 8-isoprostanes were determined. Prevalence of MS was higher in OSAS than in the control group (38 versus 21%; p=0.006). OSAS patients had higher FFAs levels than controls (mean±sd 12.2±4.9 versus 10.5±5.0 mg·dL(-1); p=0.015). Among subjects without MS, OSAS patients (OSAS+ MS-) showed higher levels of FFAs than controls (OSAS- MS-) (11.6±4.7 versus 10.0±4.4 mg·dL(-1); p=0.04). In a multiple regression model, after adjustment for age, sex, BMI and the presence of MS, FFAs were significantly associated with apnoea/hypopnoea index (p=0.04). This study shows that FFAs are elevated in OSAS and could be one of the mechanisms involved in the metabolic complications of OSAS.

Obstructive sleep apnoea (OSA) is common in children and leads to multiple end-organ morbidities. Myeloid-related protein (MRP) 8/14 plays an important pathophysiological role in atherosclerosis, and plasma levels correlate with endothelial cell dysfunction. We hypothesised that MRP8/14 levels would be altered in children with OSA. 255 children (aged 7.6+/-1.5 yrs) were included after a sleep study and a morning blood sample. MRP8/14 and interleukin-6 plasma levels were assayed using ELISA and C-reactive protein by immunoturbidometry. Endothelial function was assessed as the hyperaemic response after occlusion of the brachial artery. Plasma log MRP8/14 levels showed apnoea/hypopnoea index (AHI) dose-dependent increases regardless of obesity. Moreover, log MRP8/14 levels correlated with log AHI (r = 0.340, p<0.001) after controlling for age and body mass index Z-score, and with endothelial function. Children with the highest MRP levels (>1.34 ug x mL(-1)) had 2.4- and 5.4-fold increased odds of mild OSA and moderate-to-severe OSA, respectively, after adjusting for confounding variables. Plasma MRP8/14 levels are associated with paediatric OSA and may reflect increased risk for cardiovascular morbidity. The short- and long-term consequences of elevated MRP8/14 on cardiovascular function in the context of paediatric OSA remain to be defined.

In obstructive sleep apnoea (OSA), oxidative stress contributes to endothelial dysfunction in the peripheral circulation. In the lung, oxidative stress can lead to alveolar injury. The present authors hypothesised that patients with OSA would have biomarker evidence of increased alveolar wall permeability. Sleep characteristics, brachial artery flow-mediated dilation and plasma KL-6 levels were observed in 11 otherwise healthy patients with OSA and 10 controls. Median (interquartile range) plasma KL-6 levels were higher in patients with OSA compared with controls: 317 (232-506) U.mL(-1) versus 226 (179-257) U.mL(-1), respectively. Higher plasma KL-6 levels were associated with greater time spent asleep with an oxyhaemoglobin saturation <90%, lower nadir saturation, more frequent desaturation of >4% during sleep and lower brachial artery flow-mediated dilation. Adjustment for nadir saturation or flow-mediated dilation attenuated the association between plasma KL-6 levels and OSA. Circulating KL-6 levels are elevated in some patients with obstructive sleep apnoea, possibly reflecting increased alveolar wall permeability.

Moderate-severe obstructive sleep apnoea (OSA) has been associated with several pro-atherogenic mechanisms and increased cardiovascular risk, but it is not known if minimally symptomatic OSA has similar effects. Circulating cell-derived microparticles have been shown to have pro-inflammatory, pro-coagulant and endothelial function-impairing effects, as well as to predict subclinical atherosclerosis and cardiovascular risk. In 57 patients with minimally symptomatic OSA, and 15 closely matched control subjects without OSA, AnnexinV-positive, platelet-, leukocyte- and endothelial cell-derived microparticles were measured by flow cytometry. In patients with OSA, median (interquartile range) levels of AnnexinV-positive microparticles were significantly elevated compared with control subjects: 2,586 (1,566-3,964) microL(-1) versus 1,206 (474-2,501) microL(-1), respectively. Levels of platelet-derived and leukocyte-derived microparticles were also significantly higher in patients with OSA (2,267 (1,102-3,592) microL(-1) and 20 (14-31) microL(-1), respectively) compared with control subjects (925 (328-2,068) microL(-1) and 15 (5-23) microL(-1), respectively). Endothelial cell-derived microparticle levels were similar in patients with OSA compared with control subjects (13 (8-25) microL(-1) versus 11 (6-17) microL(-1)). In patients with minimally symptomatic obstructive sleep apnoea, levels of AnnexinV-positive, platelet- and leukocyte-derived microparticles are elevated when compared with closely matched control subjects without obstructive sleep apnoea. These findings suggest that these patients may be at increased cardiovascular risk, despite being minimally symptomatic.

Obstructive sleep apnoea (OSA) is associated with insulin resistance and metabolic syndrome. There is evidence that adipocyte-fatty acid binding protein (A-FABP) may be involved in the development of cardiometabolic dysfunction. The present authors hypothesise that A-FABP is upregulated in OSA. A total of 124 males without hypertension, diabetes mellitus, hyperlipidaemia or cardiovascular disease were recruited and underwent polysomnography. Serum A-FABP levels showed significant positive correlations with duration of oxygen desaturation and minimal oxygen saturation, fasting insulin and insulin resistance index by homeostasis model assessment. When subjects were divided into tertiles according to apnoea/hypopnoea index (AHI), serum A-FABP levels were significantly higher in the group with AHI >/=34.4 events.h(-1) than the groups with AHI 13.2-34.4 events.h(-1) or with AHI <13.2 events.h(-1). Serum A-FABP levels were significantly higher in the AHI >/=34.4 group than obesity-matched subjects with AHI <34.4 events.h(-1). Serum adipocyte-fatty acid binding protein levels correlated with obstructive sleep apnoea and insulin resistance, independently of obesity, and were significantly higher in severe obstructive sleep apnoea. Adipocyte-fatty acid binding protein may play a role in obstructive sleep apnoea and metabolic dysfunction.

There is increasing evidence that inflammation plays an important role in the development of cardiovascular complications in patients with obstructive sleep apnoea (OSA). No previous works have studied levels of soluble tumour necrosis factor-alpha receptor (sTNFR)-1 in patients with OSA. The aims of the present study were to examine serum levels of sTNFR-1 and the effect of nasal continuous positive airway pressure (CPAP) in patients with OSA. A prospective, randomised, placebo-controlled crossover study was performed. In total, 30 consecutive newly diagnosed OSA patients (apnoea/hypopnoea index 43.8+/-27.0 events x h(-1)) and 15 healthy obese patients were selected. Urinary levels of norepinephrine and epinephrine, as well as plasma sTNFR-1, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and leukotriene (LT)B(4) levels were obtained at baseline and after 3 months of CPAP or sham CPAP. Nocturnal urinary levels of norepinephrine, epinephrine and sTNFR-1 (1,053+/-269 versus 820+/-166 pg x mL(-1)) were significantly higher in OSA patients. There were no significant differences in plasma levels of IL-6, LTB(4), or TNF-alpha between the two study groups. There were no significant differences in blood pressure, urinary catecholamine levels, or plasma IL-6, LTB(4) and TNF-alpha levels after both treatment modalities. However, after 3 months of effective CPAP usage, sTNFR-1 levels were significantly reduced (1,053+/-269 versus 899+/-254 pg x mL(-1)). Obstructive sleep apnoea patients have higher levels of soluble tumour necrosis factor-alpha receptor 1 than individuals without OSA; soluble tumour necrosis factor-alpha receptor 1 levels are lowered by continuous positive airway pressure therapy. These findings further corroborate a potential role of inflammation in the natural history of obstructive sleep apnoea.

Severity of oxygen desaturation is predictive of early atherosclerosis in obstructive sleep apnoea (OSA). Leukotriene (LT)B(4) is a lipid mediator involved in atherogenesis. In 40 non-obese OSA patients, free of a cardiovascular history, and 20 healthy volunteers, the following were evaluated: 1) LTB(4) production by polymorphonuclear leukocytes (PMNs) stimulated with A23187; and 2) the relationships between LTB(4) production and both OSA severity and infraclinical atherosclerosis markers. The effect of continuous positive airway pressure (CPAP) on LTB(4) production was also studied. An overnight sleep study was followed by first-morning blood sampling. Isolated PMNs were stimulated with A23187 in order to induce LTB(4) production, which was measured by liquid chromatography-tandem mass spectrometry. Carotid intima-media thickness (IMT) and luminal diameter were measured in subset groups of 28 OSA patients and 11 controls. LTB(4) production was increased in OSA patients compared with controls. LTB(4) levels correlated with the mean and minimal arterial oxygen saturation (S(a,O(2))). LTB(4) production correlated with luminal diameter data in patients with a mean S(a,O(2)) of < or = 94% but not with IMT. Lastly, CPAP significantly reduced LTB(4) production by 50%. Leukotriene B(4) production is increased in obstructive sleep apnoea in relation to oxygen desaturation. Leukotriene B(4) could promote early vascular remodelling in moderate-to-severe hypoxic obstructive sleep apnoea patients.

Antioxidant counteraction of oxidative stress has been poorly explored in obstructive sleep apnoea (OSA). Serum albumin is a major antioxidant agent and structural modifications induced by glucose or free radicals impair its antioxidant properties. The aim of the present study was to compare antioxidant capacities and structural changes of albumin in nonobese OSA patients and healthy volunteers. Albumin structural changes were studied by quenching of fluorescence in the presence of acrylamide. Albumin thiols and fructosamines, reflecting oxidation- and glycation-induced changes in serum albumin, respectively, were assessed. Albumin structural changes were demonstrated by a significant decrease in quenching of fluorescence in OSA patients. Oxidation, resulting in a significant decrease in thiol groups (3.7+/-0.7 versus 2.3+/-0.4 micromol x g(-1) protein), and glycation, associated with a significant increase in fructosamines (226.6+/-27 versus 286+/-44.4 micromol x L(-1)), were found when comparing healthy volunteers with OSA patients. There was a significant relationship between both parameters and sleep apnoea severity. After continuous positive airway pressure intervention, albumin thiol groups were reassessed in seven of the 16 OSA patients and increased significantly from 2.25+/-0.39 to 2.79+/-0.31 micromol x g(-1) protein. Obstructive sleep apnoea patients demonstrated a reduction in serum albumin antioxidant properties that may aggravate oxidative stress and, thus, contribute to cardiovascular and metabolic morbidities.

Melatonin is a pineal hormone that regulates the human cycle of sleep and wakefulness. Plasma melatonin levels were investigated in patients with obstructive sleep apnoea syndrome (OSAS). In total, 20 patients with OSAS and 11 healthy controls were studied. OSAS patients were tested twice: on the night of diagnostic polysomnography and the night of continuous positive airway pressure (CPAP) titration. Controls were tested on one occasion. Plasma melatonin levels were determined at 23:00 h (light period), at 02:00 h (dark period) and at 06:00 h (light period) in patients and control subjects using the radioimmunoassay method. The control subjects showed a nocturnal melatonin peak value at 02:00 h (70.6+/-14 pg.mL(-1)). However, this nocturnal melatonin peak was absent in the OSAS patients. The highest melatonin value was found in OSAS patients on the night of diagnosis, at 06:00 h (49.3+/-36.8 pg.mL(-1)). It was found that the melatonin level in OSAS patients at 06:00 h was significantly lower in the night of titration (35.6+/-37.9 pg.mL(-1)) than in the diagnosis night. However, the melatonin levels at either 23:00 h or 02:00 h in OSAS patients did not differ significantly when comparing levels in the night of diagnostic polysomnography (23:00 h: 31.6+/-29.8 pg.mL(-1); 02:00 h: 47.4+/-33.8 pg.mL(-1)) with levels in the night of CPAP titration (23:00 h: 20.2+/-10.3 pg.mL(-1); 02:00 h: 37.7+/-27.5 pg.mL(-1)). Patients with obstructive sleep apnoea syndrome have an abnormal melatonin secretion pattern. The absence of a nocturnal serum melatonin peak could be partially related to the difficulty that these patients have in achieving a normal sleep-wakefulness pattern.

Obstructive sleep apnoea (OSA) is associated with oxygen desaturation to a varying degree. A patent foramen ovale (PFO) may allow interatrial right-to-left shunting. The hypothesis of the current study was that oxygen desaturation will occur more often, in proportion to the frequency of respiratory disturbances, in OSA subjects with PFO than in those without. In a group of 209 subjects diagnosed with OSA, the proportion of desaturation to respiratory events was calculated as the ratio of oxygen desaturation index (ODI)/apnoea-hypopnoea index (AHI). A total of 15 cases with high proportional desaturation (ODI/AHI >or=0.66) were individually matched with 15 controls with low proportional desaturation (ODI/AHI or=20 bubbles passed over from the right to the left atrium after a single injection. The prevalence of large PFO was nine out of 15 (60%) in the high proportional desaturation group versus two out of 15 (13%) in the low proportional desaturation group. The median number of passing bubbles was positively correlated to minimum oxygen saturation among those with PFO. In conclusion, oxygen desaturation occurs more often, in proportion to the frequency of respiratory disturbances, in obstructive sleep apnoea subjects with a patent foramen ovale than in those without.

In the present study, the authors examined the relationship between lipid peroxidation and inflammation in patients with obstructive sleep apnoea (OSA). A total of 40 obese patients with OSA were studied, along with 18 obese and 12 lean subjects without OSA. Overnight excretion of 8-isoprostane in urine and serum levels of high-sensitivity C-reactive protein (hsCRP) were measured. In addition, the effects of 3 months' treatment with nasal continuous positive airway pressure (nCPAP) were studied in 20 obese patients with moderate-to-severe OSA. Overnight urinary excretion of 8-isoprostane and serum levels of hsCRP were significantly higher in patients with moderate-to-severe OSA compared with patients with mild OSA and obese or lean subjects without OSA. Overnight urinary excretion of 8-isoprostane significantly correlated with apnoea-hypopnoea index, duration of hypoxia during sleep, body mass index, and serum levels of hsCRP in patients with OSA. The severity of OSA was an independent factor predicting the urinary excretion of 8-isoprostane. nCPAP significantly decreased urinary excretion of 8-isoprostane and serum levels of hsCRP. In conclusion, these results suggest that both obstructive sleep apnoea severity and obesity can independently contribute to elevations in urinary excretion of 8-isoprostane. Therefore, obstructive sleep apnoea may increase the risks of cardiovascular morbidity in obese patients.

The episodes of hypoxia/re-oxygenation associated with the respiratory disturbances observed in patients with obstructive sleep apnoea syndrome (OSAS) may induce the generation of oxygen free radicals. Indeed, several studies suggest that OSAS is associated with oxidative stress. The present study tested the hypothesis that patients with OSAS have an alteration in antioxidant defences. The plasma levels of total antioxidant status (TAS), glutathione peroxidase (GPX), gamma-glutamyltransferase (GGT), vitamins A, E, B12 and folate, and homocysteine were determined in 47 patients with OSAS and 37 healthy subjects. Of these, 27 patients who used continuous positive airway pressure (CPAP) for >4 h.night-1 were re-examined 12 months later. Patients with OSAS had lower TAS (1.4+/-0.16 versus 1.50+/-0.10 mmol.L-1), vitamin A (64+/-19 versus 74+/-17 microg.dL-1) and vitamin E levels (1,525+/-499 versus 1,774+/-503 microg.dL-1), and increased values of GGT (42+/-22 versus 32+/-16 U.L-1) than controls. There was no difference between groups in GPX, homocysteine, vitamin B12 and folate plasma levels. CPAP treatment normalised the levels of TAS (1.50+/-0.13 mmol.L-1) and the activity of GGT (30+/-14 U.L-1) without any influence on vitamins levels. In conclusion, the results indicate that patients with obstructive sleep apnoea syndrome have a decreased antioxidant capacity that is partially reversed by continuous positive airway pressure treatment.

Recent studies suggest an association of obstructive sleep apnoea (OSA) with cardiovascular risk factors, such as dyslipidaemia. The present study analyses the effects of OSA and its therapy on serum lipid concentrations in 470 OSA patients in a single centre study. Multivariate regression showed a significant association between the apnoea-hypopnoea index and high-density lipoprotein cholesterol (HDL-C) serum levels (n = 366), independent of age, sex, body mass index, diabetes and lipid lowering medication. There were no independent associations with total cholesterol, triglyceride and low-density lipoprotein cholesterol serum levels. During follow-up (6 months) with effective bilevel or continuous positive airway pressure therapy in 127 patients (lipoproteins: n = 86) without change in their lipid lowering therapy, the mean HDL-C serum level increased significantly by 5.8% from 46.9+/-15.8 to 49.6+/-15.3 mg x dL(-1) (mean+/-SD). An independent relationship was found between the change of apnoea-hypopnoea index and the change of high-density lipoprotein cholesterol or triglycerides, respectively. All patients with abnormal serum lipid/lipoprotein levels improved significantly under bilevel or continuous positive airway pressure therapy. This study demonstrates an influence of obstructive sleep apnoea and its therapy on high-density lipoprotein cholesterol levels.

Obstructive sleep apnoea syndrome (OSAS) is a common disorder in obesity. Leptin, an adipocyte-derived signalling factor, plays an important role in metabolic control. There is growing evidence that leptin regulation is altered in OSAS. Therefore, the aim of this study was to test the hypothesis that effective treatment will influence leptin levels in OSAS patients. Serum leptin levels were determined in 86 consecutive patients (aged 57.5 +/- 11.0 yrs) with polysomnographically verified OSAS. In addition, leptin levels were reassessed and treatment efficacy was evaluated by polysomnography after 6 months of therapy. Patients were treated with continuous or bilevel positive airway pressure, a mandibular advancement device or conservatively, depending on the clinical symptoms. Mean serum leptin levels did not change with treatment in the whole study group (7.3 +/- 5.0 versus 7.5 +/- 4.8 ng.mL-1), however, leptin levels decreased in effectively treated patients (8.5 +/- 5.0 versus 7.4 +/- 5.1 ng.mL-1) while they increased in ineffectively treated patients (5.0 +/- 4.0 versus 7.7 +/- 4.1 ng.mL-1). Furthermore, not only was there a significant and independent correlation between the change in leptin levels with treatment and the change in body mass index, but also with the change in apnoea/hypopnoea index. Effective treatment of sleep-disordered breathing may have significant effects on leptin levels in obstructive sleep apnoea syndrome patients. Changes in leptin levels are related to changes in apnoea/hypopnoea index in obstructive sleep apnoea syndrome patients.

Serum leptin and ghrelin levels were investigated in patients with obstructive sleep apnoea (OSA) syndrome before and during continuous positive airways pressure (CPAP) treatment and compared with body mass index (BMI)-matched controls without OSA. Male patients (n=30) with OSA (apnoea/hypopnoea index=58+/-16, BMI=32.6+/-5.3 kg x m(-2)) underwent CPAP treatment. Fasting leptin and ghrelin were measured at baseline and 2 days, and in the case of leptin 2 months after initiation of treatment. Baseline plasma ghrelin levels were significantly higher in OSA patients than in controls. After 2 days of CPAP treatment, plasma ghrelin decreased in almost all OSA patients (n=9) to levels that were only slightly higher than those of controls (n=9). Leptin levels did not change significantly from baseline after 2 days of CPAP treatment, but were higher than in the control group. After 8 weeks, leptin levels decreased significantly, although the BMI of the patients showed no change. The decrease in leptin levels was more pronounced in patients with a BMI <30 kg x m(-2). These data indicate that the elevated leptin and ghrelin levels are not determined by obesity alone, since they rapidly decreased during continuous positive airways pressure therapy.

Sleep disruption and daytime sleepiness in obstructive sleep apnoea/hypopnoea syndrome (OSAHS) patients result from recurrent apnoeas/hypopnoeas and arousals from sleep. Around 30% of apnoeas/hypopnoeas are not terminated by visible cortical arousals. The current authors tested the hypotheses that arousal induction is linked to sleep stage, oxygen desaturation, event type, event duration and time of occurrence during the night. Fifteen patients with OSAHS of varying severity were studied and all their apnoeas/hypopnoeas were evaluated. Eight of 15 patients had apnoeas/hypopnoeas in all sleep stages, and all their 610 apnoeas/hypopnoeas were analysed in the between stages comparison; data from all 15 patients were included in other comparisons. Thirty-four per cent of apnoeas/hypopnoeas during slow wave sleep (SWS) were associated with arousal, significantly less than the 77% during nonrapid eye movement (NREM) 1 and 2 and 62% during rapid eye movement (REM) sleep. Arousal induction was not affected by oxygen desaturation, event type, duration or time of the night. The apnoeal/hypopnoea index was 39 x h(-1) in REM 1 and 2, significantly higher compared to 17 x h(-1) in REM or to 11 x h(-1) in SWS sleep. In conclusion, apnoeas/hypopnoeas in slow wave sleep are associated with fewer cortically apparent, visually detected arousals.

Measurement of cerebral tissue saturation during obstructive sleep apnoea (OSA) may provide additional information to conventional peripheral oxygen saturation. Thirteen subjects with OSA (mean apnoea/hypopnoea index 65.7+/-27.9) were monitored using full polysomnography and monitoring of near-infrared cerebral tissue oxygenation index (TOI). One-thousand and thirty-six apnoeas and hypopnoeas were analysed, in terms of duration, sleep stage, arterial oxygen saturation (Sa,O2) dip, minimum Sa,O2, TOI dip and minimum TOI. Cerebral TOI is a measure of cerebral tissue saturation of haemoglobin with oxygen, calculated using near-infrared spatially resolved spectroscopy, which has been shown to have a high specificity for intracranial changes. Decreases in cerebral oxygenation were observed during apnoeas and hypopnoeas. Baseline TOI ranged from 50.1-73.0% and mean apnoea/hypopnoea related TOI dips ranged from 1.43-6.85%. Mean Sa,O2 dips varied from 3.8-21.7%. In regression analysis, factors significantly predicting the magnitude of the TOI dip were Sa,O2 dip, minimum Sa,O2, apnoea duration and rapid eye movement sleep stage. The effect of apnoea duration and sleep stage remained significant after Sa,O2 was included in the regression equation. Near-infrared spectroscopy provides a noninvasive technique for monitoring cerebral tissue saturation during obstructive sleep apnoea.

Sleep apnoea syndrome (SAS) is a known risk factor for vascular diseases and stroke. Structural brain damage, manifesting as an overt neurological deficit or more subtly as cognitive dysfunction, is a frequent symptom in SAS. The presence of a biochemical marker of cerebral injury would be of great benefit in SAS to screen for even small brain damage and to monitor efficiacy of therapy. Therefore, in 10 patients with mild SAS (age 50.8+/-9.9 yrs, respiratory disturbance index (RDI) 18+/-3.6, lowest arterial oxygen saturation (min Sa,O2) 80.5+/-4.06%) and nine patients with severe SAS (age 50.3+/-11.5 yrs, RDI 75.4+/-21.7, min Sa,O2 56.56+/-14.58%), serum concentrations of neuron-specific enolase (NSE), S-100beta protein, and beta-trace were measured just before and after sleep using commercially available assays. Only serum levels in the normal range could be found, independent of when the blood was taken or the degree of SAS. Structural cerebral injury caused by sleep apnoea syndrome in patients without neurological symptoms or previous cerebrovascular events may be too small to produce a measurable increase in S-100beta, neuron-specific enolase and beta-trace serum concentrations or subclinical cerebral damage may be outside the lower detection limits of the analytical methods which were used. There is a need for biochemical markers and more sensitive methods for detecting small cerebral injury in sleep apnoea syndrome.

Cardiovascular disorders are common in patients with obstructive sleep apnoea syndrome (OSAS) but there is debate as to whether OSAS is an independent risk factor for their development, since OSAS may be associated with other disorders and risk factors that predispose to cardiovascular disease. In an effort to quantify the risk of OSAS patients for cardiovascular disease arising from these other factors, the authors assessed the future risk for cardiovascular disease among a group of 114 consecutive patients with established OSAS prior to nasal continuous positive airway pressure therapy, using an established method of risk prediction employed in the Framingham studies. Patients were 100 males, aged (mean+/-SD) 52+/-9.0 yrs, and 14 females, aged 51+/-10.4 yrs, with an apnoea/hypopnoea index of 45+/-22 x h(-1). Based on either a prior diagnosis, or a mean of three resting blood pressure recordings >140 mmHg systolic and/or 90 diastolic, 68% of patients were hypertensive. Only 18% were current smokers, while 16% had either diabetes mellitus or impaired glucose tolerance, and 63% had elevated fasting cholesterol and/or triglyceride levels. The estimated 10-yr risk of a coronary heart disease (CHD) event in males was (mean+/-SEM) 13.9+/-0.9%, 95% confidence interval (95% CI) 12.1-16.0, and for a stroke was 12.3+/-1.4%; 95% CI 9.4-15.1, with a combined 10 yr risk for stroke and CHD events of 32.9+/-2.7%; 95% CI 27.8-38.5 in males aged >53 yrs. These findings indicate that obstructive sleep apnoea syndrome patients are at high risk of future cardiovascular disease from factors other than obstructive sleep apnoea syndrome, and may help explain the difficulties in identifying a potential independent risk from obstructive sleep apnoea syndrome.