Javier Piérola

Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment

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), γ-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 μg·dL−1) and vitamin E levels (1,525±499 versus 1,774±503 μg·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.

Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial

Background: Previous studies have presented contradictory data concerning obstructive sleep apnoea syndrome (OSAS), lipid oxidation and nitric oxide (NO) bioavailability. This study was undertaken to (1) compare the concentration of 8-isoprostane and total nitrate and nitrite (NOx) in plasma of middle-aged men with OSAS and no other known co-morbidity and healthy controls of the same age, gender and body mass index; and (2) test the hypothesis that nasal continuous positive airway pressure (CPAP) therapy attenuates oxidative stress and nitrate deficiency. Methods: A prospective, randomised, placebo controlled, double-blind, crossover study was performed in 31 consecutive middle-aged men with newly diagnosed OSAS and 15 healthy control subjects. Patients with OSAS were randomised to receive sham CPAP or effective CPAP for 12 weeks. Blood pressure, urinary catecholamine levels and plasma 8-isoprostane and NOx concentrations were obtained before and after both treatment modalities. Results: Patients with OSAS had significantly higher 8-isoprostane levels (median (IQR) 42.5 (29.2–78.2) vs 20.0 (12.5–52.5) pg/ml, p = 0.041, Mann-Whitney test) and lower NOx levels (264 (165–650) vs 590 (251–1465) μmol/l, p = 0.022) than healthy subjects. Body mass index, blood pressure and urinary catecholamines were unchanged by CPAP therapy, but 8-isoprostane concentrations decreased (38.5 (24.2–58.7) pg/ml at baseline vs 22.5 (16.2–35.3) pg/ml on CPAP, p = 0.0001) and NOx levels increased (280 (177–707) vs 1373 (981–1517) μmol/l, p = 0.0001) after CPAP. Conclusions: OSAS is associated with an increase in oxidative stress and a decrease in NOx that is normalised by CPAP therapy.

Insulin resistance and daytime sleepiness in patients with sleep apnoea

Background: Excessive daytime sleepiness (EDS), obesity and insulin resistance (IR) occur frequently in patients with obstructive sleep apnoea syndrome (OSAS). We hypothesised that in these patients, EDS is a marker of IR, independent of obesity. Methods: We studied 44 patients with OSAS (22 with and 22 without EDS) matched for age (±5 years), body mass index (BMI ±3 kg/m2) and severity of OSAS (as determined by the apnoea–hypopnoea index (AHI)), and 23 healthy controls. Patients (n = 35) were re-examined after 3 months of effective therapy with continuous positive airway pressure (CPAP). EDS was assessed by both subjective (Epworth Sleepiness Scale) and objective (Multiple Sleep Latency Test) methods. IR was determined by the HOMA index. Serum levels of glucose, triglycerides, cholesterol, cortisol, insulin, thyrotropin, growth hormone and insulin-like growth factor I (IGF-I) were also determined. Results: Despite the fact that age, BMI and AHI were similar, patients with EDS had higher plasma levels of glucose (p<0.05) and insulin (p<0.01), as well as evidence of IR (p<0.01) compared with patients without EDS or healthy controls. CPAP treatment reduced cholesterol, insulin and the HOMA index and increased IGF-1 levels in patients with EDS, but did not modify any of these variables in patients without EDS. Conclusion: EDS in OSAS is associated with IR, independent of obesity. Hence EDS may be a useful clinical marker to identify patients with OSAS at risk of metabolic syndrome.

Endothelial Function and Circulating Endothelial Progenitor Cells in Patients with Sleep Apnea Syndrome

Background: Endothelial dysfunction and cardiovascular diseases are frequent in patients with obstructive sleep apnea (OSA). Circulating endothelial progenitor cells (EPCs) contribute to repair dysfunctional endothelium and have been related to increased cardiovascular risk. Objectives: We tested the hypothesis that the number of circulating EPCs may be altered in OSA patients. Methods: EPCs (CD34+ VEGF-R2+) were isolated and quantified from peripheral blood samples of OSA patients (n = 13) and healthy controls (n = 13) matched for age and sex. All subjects were free of any other known cardiovascular risk factors. The plasma levels of vascular endothelial growth factor (VEGF) were also determined, and the endothelium-dependent and endothelium-independent vascular function was assessed in all subjects. Results: Patients with OSA had lower levels of EPCs (p < 0.05) and higher plasma levels of VEGF (p < 0.05) than controls. Endothelial function was not different between OSA and controls. Conclusions: Patients with OSA free of any other known cardiovascular risk factor show a reduced number of circulating EPCs and an increase in plasma VEGF levels. These alterations may contribute to future endothelial dysfunction in these patients.

Telomere shortening in sleep apnea syndrome

BACKGROUND Telomere length (TL) in circulating leukocytes relates to the chronological age of the individual but it is believed to reflect also the cumulative burden of oxidative stress and inflammation over the life-time. Shortening of TL has been reported in several chronic conditions characterized by oxidative stress and inflammation, such as diabetes and atherosclerosis. Because these conditions also occur in patients with Obstructive Sleep Apnea Syndrome (OSAS), we hypothesized that TL would be reduced in patients with OSAS. METHODS We compared TL in 256 patients with OSAS and 148 controls without OSAS. We also investigated if TL was related to the severity of OSAS, the presence of metabolic disorders and/or cardiovascular risk factors in these patients. RESULTS TL was significantly shorter in patients with OSAS than in controls (p<0.001). This difference persisted after adjustment for age, body mass index, cholesterol, triglycerides, glucose, and uric acid levels, smoking status and the presence of arterial hypertension (p=0.018). TL was not related to the severity of OSAS as assessed by the apnea-hypopnea index, nocturnal oxygen saturation and daytime sleepiness. CONCLUSIONS TL in circulating leukocytes is shorter in patients with OSAS than subjects without OSAS. The mechanism of this observation is unresolved since it appears independent of chronological age, the severity of OSAS and/or the presence of cardiovascular or metabolic alterations but the potential utility of TL as a biomarker of increased cardiovascular risk in these patients justifies further studies.

Free fatty acids and the metabolic syndrome in patients with obstructive sleep apnoea

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, &ggr;-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.

Increased plasma levels of asymmetric dimethylarginine and soluble CD40 ligand in patients with sleep apnea.

Background: Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS). Objectives: In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure). Methods: We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23). Results: Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied. Conclusions: OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

Day–night variations in endothelial dysfunction markers and haemostatic factors in sleep apnoea

Patients with sleep apnoea have a significant alteration in the day–night pattern of myocardial infarction and sudden cardiac death observed in the general population. The aim of this study was to investigate the influence of sleep apnoea on the diurnal variations in various haemostatic parameters (factor VII, von Willebrand factor and plasminogen activator inhibitor (PAI)-1) and markers of endothelial dysfunction (asymmetric dimethylarginine (ADMA) and soluble CD40 ligand (sCD40L)). We studied 26 male patients with obstructive sleep apnoea syndrome (OSAS; 13 patients with severe OSAS (apnoea/hypopnoea index (AHI) >30 events·h−1) and 13 patients with mild-to-moderate OSAS (AHI <30 events·h−1)) and 12 controls of similar body mass index (BMI) and waist circumference. In each subject, six different samples were obtained over 24 h. Although all the markers values tended to be higher in patients with severe OSAS, differences did not reach statistical significance at any time. PAI-1 levels were significantly related to BMI (p<0.001), mean (p<0.001) and minimal (p=0.047) nocturnal oxygenation saturation. ADMA levels were significantly related to arousal index (p=0.046). The results of this study suggest that day–night variations in factor VII:antigen (Ag), von Willebrand factor:Ag, PAI-1, sCD40L and ADMA levels may be dependent on either the obesity index or metabolic dysfunction rather than on sleep apnoea alone.

Relationship between aldosterone and the metabolic syndrome in patients with obstructive sleep apnea hypopnea syndrome: effect of continuous positive airway pressure treatment

Background Metabolic syndrome (MS) occurs frequently in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We hypothesized that aldosterone levels are elevated in OSAHS and associated with the presence of MS. Methods We studied 66 patients with OSAHS (33 with MS and 33 without MS) and 35 controls. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) clinical criteria. Measurements of plasma renin activity (PRA), aldosterone, aldosterone:PRA ratio, creatinine, glucose, triglycerides, cholesterol and HDL cholesterol were obtained at baseline and after CPAP treatment. Results Aldosterone levels were associated with the severity of OSAHS and higher than controls (p = 0.046). Significant differences in aldosterone levels were detected between OSAHS patients with and without MS (p = 0.041). A significant reduction was observed in the aldosterone levels in patients under CPAP treatment (p = 0.012). Conclusion This study shows that aldosterone levels are elevated in OSAHS in comparison to controls, and that CPAP therapy reduces aldosterone levels. It also shows that aldosterone levels are associated with the presence of metabolic syndrome, suggesting that aldosterone excess might predispose or aggravate the metabolic and cardiovascular complications of OSAHS. Trial registration The study is not a randomized controlled trial and was not registered.

β3-Adrenergic receptor Trp64Arg polymorphism and increased body mass index in sleep apnoea

Obesity is an important risk factor for obstructive sleep apnoea syndrome (OSAS), insulin resistance and cardiovascular disease. The substitution of tryptophan 64 with arginine (Trp64Arg) polymorphism (Arg variant) of the β3-adrenergic receptor (ADRB3) has been associated with obesity. In this study, the prevalence of the Trp64Arg ADRB3 polymorphism in a large group of patients with OSAS and its association with body mass index (BMI), insulin resistance and hypertension were evaluated. ADRB3 genotype was determined in 387 patients with OSAS and 137 healthy subjects recruited from three Spanish tertiary hospitals. The distributions of the ADRB3 genotypes were similar in OSAS and controls, and, in a multivariate model, the risk of OSAS was not associated with the presence of the Arg variant of the ADRB3 gene. However, BMI was higher in those patients with OSAS who carried this genetic variant than in those with the Trp variant. Furthermore, a linear trend for higher BMI was found in those with the Arg variant (56, 75 and 100% for Trp/Trp, Trp/Arg and Arg/Arg, respectively). Insulin resistance, blood pressures and serum levels of lipids and glucose were not associated with the presence of the Arg variant of the ADRB3 gene. The presence of the arginine 64 allele of the β3-adrenergic receptor gene does not increase the risk of obstructive sleep apnoea syndrome, but is associated with the development of obesity in those patients who suffer obstructive sleep apnoea syndrome.