Antonia Barceló

Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.

CONTEXT Continuous positive airway pressure (CPAP) is the first-line treatment for patients with symptomatic obstructive sleep apnea (OSA). However, its indication for all patients with sleep-disordered breathing, regardless of daytime symptoms, is unclear. OBJECTIVE To evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA. DESIGN, SETTING, AND PATIENTS Multicenter, parallel-group, randomized controlled trial in 14 teaching hospitals in Spain. Between May 2004 and May 2006, 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1) or greater and an Epworth Sleepiness Scale score of 10 or less (scores range from 0-24, with values <10 suggesting no daytime sleepiness). Exclusion criteria were previous cardiovascular event, physical or psychological incapacity, chronic disease, or drug or alcohol addiction. Follow-up ended in May 2009. INTERVENTION Patients were allocated to receive CPAP treatment or no active intervention. All participants received dietary counseling and sleep hygiene advice. MAIN OUTCOME MEASURES Incidence of either systemic hypertension (taking antihypertensive medication or blood pressure greater than 140/90 mm Hg) or cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, heart failure, or cardiovascular death). RESULTS Seven hundred twenty-three patients underwent follow-up for a median of 4 (interquartile range, 2.7-4.4) years (1 patient from each group did not receive allocated treatment); 357 in the CPAP group and 366 in the control group were included in the analysis. In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events (17 unstable angina or arrhythmia, 3 nonfatal stroke, 3 heart failure, 2 nonfatal myocardial infarction, 2 transient ischemic attack, 1 cardiovascular death). In the control group there were 79 patients with new hypertension and 31 cardiovascular events (11 unstable angina or arrhythmia, 8 nonfatal myocardial infarction, 5 transient ischemic attack, 5 heart failure, 2 nonfatal stroke). The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years (95% CI, 7.36-11.04) in the CPAP group and 11.02 per 100 person-years (95% CI, 8.96-13.08) in the control group. The incidence density ratio was 0.83 (95% CI, 0.63-1.1; P = .20). CONCLUSIONS In patients with OSA without daytime sleepiness, the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events. However, the study may have had limited power to detect a significant difference. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00127348.

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.

Daytime sleepiness and polysomnographic variables in sleep apnoea patients

Excessive daytime sleepiness (EDS) is not invariably present in patients with obstructive sleep apnoea syndrome (OSAS). The aim of the present study was to investigate polysomnographic determinants of EDS in patients with OSAS. EDS was assessed using the Epworth Sleepiness Scale (ESS) and the multiple sleep latency test (MSLT). Patients showed EDS whenever the ESS score was >10 and the MSLT score <5 min. Absence of EDS was defined as having an ESS score of <10 and an MSLT score of >10 min. In total, 23 male patients with EDS (mean±sd ESS and MSLT score 17±3 and 4±1 min, respectively) and 17 without EDS (ESS and MSLT score 5±2 and 16±3 min, respectively), were studied. Both groups exhibited a similar apnoea/hypopnoea index (62±18 versus 60±20 events·h−1). Patients with EDS exhibited shorter sleep latency (11±16 versus 18±18 min) and greater sleep efficiency (90±7 versus 82±13%) than those without EDS. Patients with EDS showed lower oxygenation (lowest arterial oxygen saturation 69±12 versus 79±8%; mean arterial oxygen saturation 87±6 versus 90±5%). Sleep stage distribution and arousal index did not differ between the groups. Patients with obstructive sleep apnoea syndrome and excessive daytime sleepiness are characterised by shorter sleep latency, increased sleep efficiency and worse nocturnal oxygenation than those without excessive daytime sleepiness. Nocturnal hypoxaemia can be a major determinant of excessive daytime sleepiness in patients with obstructive sleep apnoea syndrome.

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.

Daytime sleepiness and polysomnography in obstructive sleep apnea patients

BACKGROUND Excessive daytime sleepiness (EDS) is the major complaint in subjects with obstructive sleep apnea syndrome (OSAS). However, EDS is not universally present in all patients with OSAS. The mechanisms explaining why some patients with OSAS complain of EDS whereas others do not are unknown. OBJECTIVE To investigate polysomnographic determinants of excessive daytime sleepiness (EDS) in a large multicenter cohort of patients with obstructive sleep apnea (OSAS). METHODS All consecutive patients with an apnea-hypopnea index greater than 5h(-1) who were evaluated between 2003 and 2005. EDS was assessed using the Epworth Sleepiness Scale (ESS), and patients were considered to have EDS if the ESS was >10. RESULTS A total of 1649 patients with EDS ((mean [+/-SD] Epworth 15+/-3) and 1233 without EDS (Epworth 7+/-3) were studied. Patients with EDS were slightly younger than patients without EDS (51+/-12 vs 54+/-13 years, p<0.0001), had longer total sleep time (p<0.007), shorter sleep latency (p<0001), greater sleep efficiency (p<0.0001) and less NREM sleep in stages 1 and 2 (p<0.007) than those without EDS. Furthermore, patients with EDS had slightly higher AHI (p<0.005) and arousal index (p<0.001) and lower nadir oxygen saturation (p<0.01). CONCLUSIONS Patients with OSAS and EDS are characterized by longer sleep duration and increased slow wave sleep compared to those without EDS. Although patients with EDS showed a mild worsening of respiratory disturbance and sleep fragmentation, these results suggest that sleep apnea and sleep disruption are not the primary determinants of EDS in all of these patients.

Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive sleep apnoea

The metabolic syndrome shows a variable prevalence in obstructive sleep apnoea (OSA), and its association with insulin resistance or excessive daytime sleepiness in OSA is unclear. This study assessed the following in consecutive patients with newly diagnosed OSA: 1) the prevalence of metabolic syndrome; and 2) its association with insulin resistance and daytime sleepiness. Metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III criteria), insulin resistance (Homeostatic Model Assessment (HOMA) index, n=288) and daytime sleepiness (Epworth Sleepiness Scale) were assessed in 529 OSA patients. The prevalence of metabolic syndrome was 51.2%, which increased with OSA severity. Each metabolic syndrome component correlated with apnoea/hypopnoea index, but only blood pressure retained significance after correction for confounders. Both obesity and OSA contributed to metabolic abnormalities, with different sex-related patterns, since diagnosis of metabolic syndrome was significantly associated with neck circumference, age, body mass index and lowest arterial oxygen saturation in males, and with age and arousal index in females. The number of metabolic syndrome components increased with HOMA index (p<0.001). Prevalence of sleepiness was the same in patients with and without metabolic syndrome. The metabolic syndrome occurs in about half of “real-life” OSA patients, irrespective of daytime sleepiness, and is a reliable marker of insulin resistance.

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.

Precision Medicine in Patients With Resistant Hypertension and Obstructive Sleep Apnea: Blood Pressure Response to Continuous Positive Airway Pressure Treatment.

BACKGROUND In patients with resistant hypertension (RH) and obstructive sleep apnea (OSA), the blood pressure response to continuous positive airway pressure (CPAP) treatment is highly variable and could be associated with differential micro-ribonucleic acid (miRNA) profiles. Currently, no available methods exist to identify patients who will respond favorably to CPAP treatment. OBJECTIVES The aim of this study was to identify plasma miRNA profiles that predict blood pressure responses to CPAP treatment. METHODS Cardiovascular system-focused circulating miRNA expression was evaluated in plasma samples using an 84-miRNA array among patients with RH and OSA at baseline and after 3 months of adherent CPAP use. Pathway analysis and miRNA target gene enrichment were performed in silico. Plasma levels of peptides and hormones related to cardiovascular function were also measured. RESULTS The OSA responder group exhibited blood pressure decreases exceeding the observed median (>4.5 mm Hg) after CPAP, which were not present in the nonresponder group (≤4.5 mm Hg) (p < 0.01). Three miRNAs provided a discriminatory predictive model for such a favorable blood pressure response to CPAP (area under the curve: 0.92; p = 0.01). Additionally, CPAP treatment significantly altered a total of 47 plasma miRNAs and decreased aldosterone-to-renin ratios in the responder group (p = 0.016) but not in the nonresponder group. CONCLUSIONS A singular pre-CPAP treatment cluster of 3 plasma miRNAs predicts blood pressure responses to CPAP treatment in patients with RH and OSA. CPAP treatment is accompanied by changes in cardiovascular system-related miRNAs that may potentially influence the risk for cardiovascular disease among patients with OSA and RH. (Effect of Continuous Positive Airway Pressure [CPAP] Treatment in the Control of Refractory Hypertension; NCT00616265).

Angiotensin converting enzyme in patients with sleep apnoea syndrome: plasma activity and gene polymorphisms

The prevalence of several cardiovascular diseases is increased with obstructive sleep apnoea syndrome (OSAS), due to, as yet, unclear reasons. Angiotensin converting enzyme (ACE) abnormalities have been implicated in the pathogenesis of various cardiovascular diseases. In this study, plasma ACE activity and the distribution of an insertion (I)/deletion (D) polymorphism of the ACE gene were determined in OSAS patients and in healthy controls. A total of 63 patients with OSAS (mean+/-SEM 54.5+/-2.5 apnoea/hypopnoeas.h(-1)) and 32 healthy subjects were studied. To avoid potential confounding factors, patients treated with ACE inhibitors or continuous positive airway pressure were excluded, as well as controls in whom a blood sample was not obtained early in the morning. ACE activity was determined spectrophotometrically in 46 OSAS patients and 25 controls. The I/D ACE polymorphism was determined by polymerase chain reaction in 44 patients and 32 controls. ACE activity was higher in OSAS patients (53.9+/-2.5 IU.L(-1)) than in healthy controls (42.4+/-3.1 IU.L(-1), p<0.01). This was independent of the presence of arterial hypertension. The frequency distribution of the DD, II and ID genotypes in OSAS patients (30%, 16%, 54%, respectively) was not significantly different from that seen in healthy subjects (31%, 28%, 41%, respectively, p=0.356). These results indicate that ACE plasma activity is increased in untreated OSAS patients. This increased activity may contribute to the pathogenesis of the cardiovascular disease in these patients.