Impaired circadian variation of platelet activity in patients with sleep apnea.

BACKGROUND: Cardiovascular diseases are frequent in patients with obstructive sleep apnea (OSAS). There is evidence that the day-night pattern of myocardial infarction and sudden cardiac death observed in the general population is altered in patients with OSAS. This study investigates potential abnormalities in the circadian profiles of platelet activity in OSAS. METHODS: We studied 37 patients with OSAS [7 of whom were also studied after 3 months on continuous positive airway pressure (CPAP) treatment] and 11 controls. In each subject, we obtained six different blood samples during 24-h period (2200, 0200, 0600, 1000, 1400, and 1800 hours). Platelet activity was determined by flow cytometry immediately after sampling. RESULTS: We found that nocturnal platelet activity was significantly increased in patients with OSAS (p = 0.043) and that effective treatment with CPAP decreased platelet activity in these patients but differences just failed to reach statistical significance (p = 0.063). CONCLUSIONS: OSAS is associated with increased platelet activity during the night, and that this appears to be improved by chronic use of CPAP. These results may contribute to explain the high prevalence of cardiovascular events during sleep in OSAS.

Non-synonymous polymorphism in the neuropeptide S precursor gene and sleep apnea.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a complex disease with a strong genetic basis. One of the primary molecular domains affected by OSAS is sympathetic activity. Neuropeptide S (NPS) plays an important role in the regulation of the sleep-wakefulness cycle, anxiety states, and daytime sleepiness. It is important to study neuropeptides related to sympathetic activity regulation and how their function could be modified by genetic variants affecting the expression of these molecules. OBJECTIVES: We investigated the association of the non-synonymous polymorphism rs4751440 in the NPS precursor gene with OSAS and certain variables related to OSAS (daytime sleepiness, body mass index (BMI), insulin resistance, and blood pressure). This polymorphism causes an amino acid substitution in exon 3 of the human NPS precursor gene. PATIENTS AND METHODS: We included 253 OSAS patients and 70 healthy subjects. Genotyping was done by polymerase chain reaction using specific flanking primers and agarose gel electrophoresis. Daytime sleepiness, BMI, plasma levels of high-density lipoprotein, glucose, total cholesterol, insulin, triglycerides, and the homeostasis model assessment index were also determined. RESULTS: A similar genotypic and allelic distribution was found in OSAS patients and controls. The risk of OSAS was not associated with the rs4751440 polymorphism. There was no significant interaction between daytime sleepiness or metabolic variables and the rs4751440 polymorphism. CONCLUSION: Genotypic and allelic frequency distribution of the rs4751440 polymorphism was similar in OSAS patients and controls. In this population-based study, we could not show a significant association between rs4751440 polymorphism and susceptibility to OSAS or certain phenotypes related to OSAS (daytime sleepiness, BMI, systolic blood pressure, and insulin resistance) with the exception of diastolic blood pressure.

Nontypeable Haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke.

Nontypeable Haemophilus influenzae (NTHI) is an opportunistic gram-negative pathogen that causes respiratory infections and is associated with progression of respiratory diseases. Cigarette smoke is a main risk factor for development of respiratory infections and chronic respiratory diseases. Glucocorticoids, which are anti-inflammatory drugs, are still the most common therapy for these diseases. Alveolar macrophages are professional phagocytes that reside in the lung and are responsible for clearing infections by the action of their phagolysosomal machinery and promotion of local inflammation. In this study, we dissected the interaction between NTHI and alveolar macrophages and the effect of cigarette smoke on this interaction. We showed that alveolar macrophages clear NTHI infections by adhesion, phagocytosis, and phagolysosomal processing of the pathogen. Bacterial uptake requires host actin polymerization, the integrity of plasma membrane lipid rafts, and activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Parallel to bacterial clearance, macrophages secrete tumor necrosis factor alpha (TNF-alpha) upon NTHI infection. In contrast, exposure to cigarette smoke extract (CSE) impaired alveolar macrophage phagocytosis, although NTHI-induced TNF-alpha secretion was not abrogated. Mechanistically, our data showed that CSE reduced PI3K signaling activation triggered by NTHI. Treatment of CSE-exposed cells with the glucocorticoid dexamethasone reduced the amount of TNF-alpha secreted upon NTHI infection but did not compensate for CSE-dependent phagocytic impairment. The deleterious effect of cigarette smoke was observed in macrophage cell lines and in human alveolar macrophages obtained from smokers and from patients with chronic obstructive pulmonary disease.

A controlled trial of noninvasive ventilation for chronic obstructive pulmonary disease exacerbations.

PURPOSE: This prospective, multicenter, double-blind, placebo-controlled study tested the hypothesis that noninvasive positive pressure ventilation reduces the need for endotracheal intubation in patients hospitalized in a pulmonary ward because of acute exacerbation of chronic obstructive pulmonary disease. MATERIALS AND METHODS: Seventy-five consecutive patients with exacerbation (pH, 7.31 +/- 0.02; Pao(2), 45 +/- 9 mm Hg; Paco(2), 69 +/- 13 mm Hg) were randomly assigned to receive noninvasive ventilation or sham noninvasive ventilation during the first 3 days of hospitalization on top of standard medical treatment. RESULTS: The need for intubation (according to predefined criteria) was lower in the noninvasive ventilation group (13.5% vs 34%, P < .01); in 31 patients with pH not exceeding 7.30, these percentages were 22% and 77%, respectively (P < .001). Arterial pH and Paco(2) improved in both groups, but changes were enhanced by noninvasive ventilation. Length of stay was lower in the noninvasive ventilation group (10 +/- 5 vs 12 +/- 6 days, P = .06). In-hospital mortality was similar in both groups. CONCLUSIONS: These results demonstrate that noninvasive positive pressure ventilation, in a pulmonary ward, reduces the need for endotracheal intubation, particularly in the more severe patients, and leads to a faster recovery in patients with acute exacerbation of chronic obstructive pulmonary disease.

Prediction of risk of COPD exacerbations by the BODE index.

OBJECTIVES: This study assesses the power of the BODE index, a multidimensional grading system that predicts mortality, to predict subsequent exacerbations in patients with COPD. DESIGN: Prospective cohort study. PATIENTS AND INTERVENTIONS: A total of 275 COPD patients were followed every 6 months up to 8 years (median of 5.1 years). Baseline clinical variables were recorded and the BODE index was calculated. We investigated the prognostic value of BODE quartiles (scores 0-2, 3-4, 5-6 and 7-10) for both the number and severity of exacerbations requiring ambulatory treatment, emergency room visit, or hospitalization. RESULTS: The annual rate of COPD exacerbations was 1.95 (95% CI, 0.90-2.1). The mean time to a first exacerbation was inversely proportional to the worsening of the BODE quartiles (7.9 yrs, 5.7 yrs, 3.4 yrs and 1.3 yrs for BODE scores of 0-2, 3-4, 5-6 and 7-10, respectively). Similarly, the mean time to a first COPD emergency room visit was 6.7 yrs, 3.6 yrs, 2.0 yrs and 0.8 yrs for BODE quartiles (all p<0.05). Using ROC curves, the BODE index was a better predictor of exacerbation than the FEV(1) alone (p<0.01). CONCLUSIONS: The BODE index is a better predictor of the number and severity of exacerbations in COPD than FEV(1) alone.

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.

Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease.

RATIONALE: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families. OBJECTIVES: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD. METHODS: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema. MEASUREMENTS AND MAIN RESULTS: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD. CONCLUSIONS: Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes.

Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease.

OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients. PATIENTS AND METHODS: To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV1] 29 +/- 2.5% ref) and in 8 healthy sedentary subjects (FEV1 98 +/- 5% ref). RESULTS: We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD. CONCLUSIONS: This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1beta, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise.

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.

Pulmonary and systemic hepatocyte and keratinocyte growth factors in patients with chronic obstructive pulmonary disease.

BACKGROUND: The potential role of growth factors in chronic obstructive pulmonary disease (COPD) has begun to be addressed only recently and is still poorly understood. For this study, we investigated potential abnormalities of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) in patients with COPD. METHODS: To this end, we compared the levels of HGF and KGF, measured by enzyme-linked immunosorbent assay (ELISA), in bronchoalveolar lavage (BAL) fluid and in serum in 18 patients with COPD (62 +/- 9 yrs, forced expiratory volume in one second [FEV1] 57 +/- 12% ref, X +/- standard deviation of mean), 18 smokers with normal lung function (58 +/- 8 yrs, FEV1 90 +/- 6% ref) and 8 never smokers (67 +/- 9 yrs, 94 +/- 14% ref). RESULTS: We found that in BAL, HGF levels were higher in patients with COPD than in the other two groups whereas, in serum, HGF concentration was highest in smokers with normal lung function (p < 0.01). KGF levels were not significantly different between groups, neither in blood nor in BAL (most values were below the detection limit). CONCLUSIONS: These results highlight a different response of HGF in BAL and serum in smokers with and without COPD that may be relevant for tissue repair in COPD.