Carotid intima media thickness in patients with obstructive sleep apnea: comparison with a community-based cohort.

BACKGROUND: The impact of obstructive sleep apnea (OSA) on the development of atherosclerotic cardiovascular disease (CVD) in the absence of overt CVD or risk factors is unclear. Our purpose was to assess whether patients with OSA without overt CVD or risk factors have subclinical atherosclerosis as evaluated by carotid intima medial thickness (CIMT) compared to matched controls. METHODS: We measured CIMT in patients >40 years old, who underwent polysomnography for suspected OSA and did not have a history of CVD or risk factors (smoking, hypertension, diabetes, hyperlipidemia). OSA severity was classified according to apnea-hypopnea index. Serum levels of high-sensitivity C-reactive protein, fibrinogen, and lipids were assessed and relationships with OSA severity explored. CIMT measurements from patients with OSA were compared those of to age-, gender-, and BMI-matched controls from a community-based cohort without known CVD or OSA. RESULTS: Fifty-one patients were studied. Of these, patients with severe OSA had an increased CIMT compared to patients without OSA, but the relationship was not significant after controlling for age (p = 0.10). However, 37 patients had OSA and were matched to 105 controls. CIMT was significantly increased in OSA patients versus controls (0.77 vs. 0.68 mm, p = 0.03). The difference between patients and controls was greater for patients with severe OSA (0.83 vs. 0.71 mm) than for patients with mild-to-moderate OSA (0.71 vs. 0.67 mm). CONCLUSIONS: Patients with OSA but without a history of or risk factors for CVD have increased CIMT compared to a BMI-, age-, and gender-matched cohort. This provides evidence that OSA is an independent risk factor for the development of CVD.

Effects of 10 days of modest intermittent hypoxia on circulating measures of inflammation in healthy humans.

PURPOSE: Obstructive sleep apnea (OSA) is a common disease which is associated with elevated inflammatory markers and adhesion molecules, possibly due to nightly intermittent hypoxia (IH). The purpose of this study was to test the hypothesis that IH would increase systemic inflammatory markers in healthy human males. METHODS: Healthy, young male subjects (n = 9; 24 ± 2 years) were exposed to a single daily isocapnic hypoxia exposure (oxyhemoglobin saturation = 80%, 1 h/day) for 10 consecutive days. Serum granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1ß, interleukin-6, interleukin-8, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1 were measured before and following the 10 days of IH using Luminex. RESULTS: Nine subjects completed the study (24 ± 2 years; 24 ± 2 kg/m(2)). The mean oxyhemoglobin saturation was 80.8 ± 1.6% during the hypoxia exposures. There was no significant change in any of the markers of inflammation (paired t test, P > 0.2 all cytokines). CONCLUSIONS: These findings suggest that (1) a more substantial or a different pattern of hypoxemia might be necessary to activate systemic inflammation, (2) the system may need to be primed before hypoxic exposure, or (3) increases in inflammatory markers in patients with OSA may be more related to other factors such as obesity or nocturnal arousal.

Pro-atherogenic cytokine profile of patients with suspected obstructive sleep apnea.

PURPOSE: Systemic inflammation is important in the pathogenesis of cardiovascular disease (CVD). We sought to characterize the systemic inflammatory profile associated with obstructive sleep apnea (OSA). METHODS: Adult patients referred for suspected OSA at the University of British Columbia Hospital Sleep Disorders Program were recruited for our study. Patients using HMG CoA inhibitors or a history of CVD were excluded. Fasting serum samples were obtained the morning after their diagnostic polysomnograms. Samples were tested for the following circulating inflammatory mediators: interferon gamma; interleukins 1B, 6, and 8; intercellular and vascular cell adhesion molecules (sICAM-1 and sVCAM-1); and leptin using a multiplex Luminex System. RESULTS: There were 176 patients; 68% were male, mean age = 50 +/- (SD) 11 years, mean apnea/hyponea index (AHI) = 22.9 +/- 22/h, mean desaturation (i.e. % of sleep time spent below an oxyhemoglobin saturation of 90%) = 5.4% +/- 15, and mean body mass index (BMI) = 32.2 +/- 8 kg/m(2). In univariate analyses, only leptin, sVCAM-1, and sICAM-1 were significantly associated with indices of OSA severity (i.e. AHI and/or desaturation). In multivariate linear regression analyses that controlled for BMI, gender, age, and current smoking; desaturation persisted as a significant independent predictor for elevated sVCAM-1 and leptin. CONCLUSIONS: We did not find significant associations between OSA and markers of activated innate immunity (IL-1B, 6, and 8). However, OSA severity was independently associated with serum levels of sVCAM-1 and leptin; these may represent mechanisms involved in the pathogenesis of OSA-related CVD.

Diagnosis and initial management of obstructive sleep apnea without polysomnography: a randomized validation study.

BACKGROUND: Polysomnography (PSG), despite limited availability and high cost, is currently recommended for diagnosis of obstructive sleep apnea and titration of effective continuous positive airway pressure (CPAP). OBJECTIVE: To test the utility of a diagnostic algorithm in conjunction with ambulatory CPAP titration in initial management of obstructive sleep apnea. DESIGN: A randomized, controlled, open-label trial that compared standard PSG with ambulatory CPAP titration in high-risk patients identified by a diagnostic algorithm. SETTING: A tertiary referral sleep disorders program in Vancouver, British Columbia, Canada. PATIENTS: 68 patients with a high pretest probability of moderate to severe obstructive sleep apnea (apnea-hypopnea index [AHI] >15 episodes/h) identified by sequential application of the Epworth Sleepiness Scale (ESS) score, Sleep Apnea Clinical Score, and overnight oximetry. INTERVENTION: Patients were randomly assigned to PSG or ambulatory titration by using a combination of auto-CPAP and overnight oximetry. They were observed for 3 months. MEASUREMENTS: Apnea-hypopnea index on CPAP, ESS score, quality of life, and CPAP adherence. RESULTS: The PSG and ambulatory groups had similar median BMI (38 kg/m2), age (55 years), ESS score (14 points), and respiratory disturbance index (31 episodes of respiratory disturbance/h). Each episode is determined by a computer algorithm based on analysis of oxygen saturation measured by pulse oximetry. After 3 months, there were no differences in the primary outcome, AHI on CPAP (median, 3.2 vs. 2.5; difference, 0.8/h [95% CI, -0.9 to 2.3]) (P = 0.31), between the PSG and ambulatory groups, or in the secondary outcomes, ESS score, Sleep Apnea Quality of Life Index, and CPAP. Adherence to CPAP therapy was better in the ambulatory group than in the PSG group (median, 5.4 vs. 6.0; difference, -1.12 h/night [CI, -2.0 to 0.2]) (P = 0.021). CONCLUSIONS: In the initial management of patients with a high probability of obstructive sleep apnea, PSG confers no advantage over the ambulatory approach in terms of diagnosis and CPAP titration. The ambulatory approach may improve adherence to treatment. When access to PSG is inadequate, the ambulatory approach can be used to expedite management of patients most in need of treatment.

Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant.

BACKGROUND: Alpha1-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, A1AT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs. METHODS AND RESULTS: In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT. CONCLUSIONS: Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.

Mandibular advancement splint as short-term alternative treatment in patients with obstructive sleep apnea already effectively treated with continuous positive airway pressure.

STUDY OBJECTIVES: CPAP is used as the first-line treatment for patients with severe OSA, but this machine is not always feasible to use on the long term. We performed a clinical trial to determine whether patients with OSA could use a mandibular advancement splint (MAS) as a short-term treatment alternative to CPAP. METHODS: Twenty-two patients adherent with CPAP therapy were recruited to the study. Each patient used the MAS for approximately 4 months. The transition between CPAP to MAS was gradual, and patients were asked to start using MAS together with CPAP during the MAS titration until subjective improvement or maximum mandibular advancement was achieved. Sleepiness (ESS), quality of life (SAQLI), and polysomnography were recorded prior to and after MAS titration. Patients recorded CPAP or MAS usage for the following 3 months. RESULTS: Seven women and 12 men with a mean age of 53.8 (± 12.1) years and mean body mass index of 28.1 (± 4.8) kg/m² completed the clinical trial. Prior to MAS, CPAP adherence was 5.8 h/night. AHI decreased significantly with MAS use compared to baseline (30.7 ± 23.1 vs 13.2 ± 11; p < 0.01). Fourteen patients (74%) had > 50% decrease in their AHI, while 2 patients had an increase in their AHI. There were no significant differences in SAQLI between MAS and CPAP treatment, while ESS decreased significantly on MAS. MAS self-reported usage was correlated with treatment efficacy (r = 0.52; p < 0.05). Seventy-five percent of the patients reported being sufficiently satisfied with MAS to continue to use it as an alternative short-term therapy. CONCLUSIONS: MAS partially or completely reduced sleep disordered breathing in the majority of selected, successfully CPAP-treated severe OSA patients. Many patients can probably effectively use MAS as a short-term treatment alternative to CPAP.

Residual sleep apnea on polysomnography after 3 months of CPAP therapy: clinical implications, predictors and patterns.

OBJECTIVE: We sought to determine the clinical implications, predictors and patterns of residual sleep apnea on continuous positive airway pressure (CPAP) treatment in patients with moderate-to-severe obstructive sleep apnea (OSA). METHODS: We performed a post hoc secondary analysis of data from a previously reported randomized trial. Sleepy patients with a high risk of moderate-to-severe OSA identified by a diagnostic algorithm were randomly assigned to standard CPAP titration during polysomnography (PSG) or ambulatory titration using auto-CPAP and home sleep testing. We observed them for 3 months and measured apnea-hypopnea index (AHI) on CPAP, Epworth sleepiness scale (ESS), sleep apnea quality of life index (SAQLI), CPAP pressure and objective CPAP compliance. RESULTS: Sixty-one patients were randomized, 30 to the PSG group and 31 to the ambulatory group. Fifteen patients (25%) had residual sleep apnea (AHI > 10/h on CPAP) with similar proportions in the PSG (7/30) and ambulatory (8/31) groups. Baseline variables including age, body mass index (BMI), ESS, SAQLI, respiratory disturbance index (RDI) and CPAP pressure did not differ between the groups. Outcomes including compliance were worse in patients with residual sleep apnea. Periodic breathing was prevalent among patients with residual sleep apnea. CONCLUSIONS: Residual sleep apnea is common in patients with moderate-to-severe OSA, despite careful CPAP titration, and is associated with worse outcomes.

Depression and sleep-related symptoms in an adult, indigenous, North American population.

STUDY OBJECTIVES: Symptoms related to sleep disorders are common and may have substantial adverse impacts on mental health. Indigenous North Americans (American Indian) are a medically vulnerable population with reduced access to healthcare services. The purposes of this study were to assess (1) the prevalence of sleep symptoms and (2) the relationships between symptoms and depression in this population. METHODS: We performed a community-based, door-to-door, cross-sectional survey of 3 indigenous North American groups (Gitxsan, Nisga'a and Tsimshian) living in the northwestern part of British Columbia. Between May and September of 2006, subjects completed a comprehensive questionnaire that included questions about sleep habits, medical history, subjective sleepiness (Epworth Sleepiness Scale), and depression (Personal Health Questionnaire [PHQ-9]). Weights and heights were also measured. RESULTS: Four hundred thirty adults participated in the study (response rate = 42%). Their mean age was 43.2 years. Three hundred ninety-three agreed to have heights and weights measured. Their mean body mass index (BMI) was 31.0 +/- 9.2 kg/m2; 45% of them (177/393) were obese (BMI > 30 kg/m2), and 11% (43/393) were morbidly obese (BMI > 40 kg/m2). The prevalence of sleep complaints was high; insomnia symptoms was reported by 17.2%, symptoms of restless legs syndrome (RLS) by 17.7%, and frequent witnessed apneas reported (i.e., being told they stopped breathing at least 3 nights per week) by 7.6%. Of the 76 patients who had RLS symptoms, only 3 (3.9%) reported having received a diagnosis of RLS from a physician. Thirty-three subjects reported having frequent witnessed apneas, but only 5 of them (15.1%) reported having received a diagnosis of OSA from a physician. The mean PHQ9 score was 4.86 +/- 5.13 (reported by 389 subjects). Twenty-eight subjects (7.20%) had moderate to severe depression, with a PHQ-9 score of 15 or greater. In multivariable linear regression analysis, insomnia symptoms, witnessed apneas, and RLS symptoms were independently associated with an increase in PHQ9 score; frequent witnessed apneas were associated with an increase in PHQ9 by 2.46 (95% confidence interval: 0.47-4.46), insomnia symptoms by 4.49 (95% confidence interval: 3.14-5.83), and RLS symptoms by 1.82, (95% confidence interval: 0.53-3.12). CONCLUSIONS: Sleep symptoms and depression are common in the indigenous North American population of northern British Columbia. Sleep-related symptoms (insomnia symptoms, witnessed nocturnal apneas, and RLS symptoms) are independently associated with depression scores. Improving access to sleep-related diagnostic and therapeutic services may substantially improve mental health in this vulnerable patient population.

Alpha-1-antitrypsin deficiency: current concepts.

Since the condition was first described four decades ago, alpha-1-antitrypsin (A1AT) deficiency has served as a model for other disease processes. A1AT is the archetypal serpin designed to ensnare proteases, a process that involves significant conformational change within the molecule. Mutations in the A1AT gene lead to misfolding of the protein and accumulation within the endoplasmic reticulum of hepatocytes resulting in two different pathologic processes. First, the accumulation of mutant A1AT protein has a directly toxic effect on the liver, resulting in hepatitis and cirrhosis. Second, the resultant decrease in circulating A1AT results in protease-antiprotease imbalance at the lung surface and emphysema ensues. A1AT deficiency therefore can be seen as two distinct disease processes: a conformational disease of the liver and a protease-antiprotease imbalance of the lung. This two-stage model of disease in A1AT deficiency is elegant in its simplicity and goes a long way to explaining the clinical manifestations that occur in patients with the condition. However, some aspects of the disease are not readily explained. Recent findings suggest that there is more to the lung damage in A1AT deficiency than simple proteolytic insult and that the presence of the mutant protein itself is proinflammatory and may indeed cause chronic injury to the cells that produce it. This review discusses some of the emerging concepts in alpha-1-antitrypsin research and outlines the implications these new ideas may have for treatment of this condition.

Prevalence, risk factors and impact on daytime sleepiness and hypertension of periodic leg movements with arousals in patients with obstructive sleep apnea.

STUDY OBJECTIVE: To determine the prevalence, risk factors, and impact on daytime sleepiness and hypertension of periodic leg movements of sleep (PLMS) with associated arousals in patients with obstructive sleep apnea (OSA). METHODS: A single-center retrospective case series of 798 consecutive patients who underwent diagnostic overnight polysomnography for suspected OSA. We performed discriminant function analysis using clinical and polysomnographic variables to examine the relationship between PLMS (periodic leg movement arousal index > or =5 per hour) and potential risk factors, including OSA. RESULTS: Mean +/- SD age was 50 +/- 12 years, body mass index 32 +/- 8 kg/m2, Epworth Sleepiness Scale (ESS) score 11 +/- 5, and apnea-hypopnea index 31 +/- 26 per hour. Sixty-eight percent were men, 30% had systemic hypertension, and 19% were smokers. Ninety-two percent had OSA (apnea-hypopnea index +/- 5); 47% had PLMS; 44% had both OSA and PLMS; and among patients with OSA, 48% had PLMS. Significant predictors of PLMS, in order of importance, were number of predisposing medical conditions, age, number of predisposing medications, obesity, and OSA. Medical conditions that significantly predicted PLMS were depression, fibromyalgia, and diabetes mellitus. The ESS score and hypertension status were no different between those with both OSA and PLMS and those with OSA alone. CONCLUSIONS: One in 2 patients investigated for OSA has PLMS. Risk factors for PLMS include preexisting medical conditions-particularly depression, fibromyalgia, and diabetes mellitus-increasing age, predisposing medications, obesity, and OSA. The combination of OSA and PLMS results in no greater subjective daytime sleepiness or prevalence of hypertension than OSA alone.

Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z alpha 1-antitrypsin deficiency.

Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z alpha1-antitrypsin (A1AT) deficiency is a genetic disease associated with accumulation of misfolded A1AT in the endoplasmic reticulum (ER) of hepatocytes. We sought to identify intracellular events involved in the molecular pathogenesis of Z A1AT-induced liver disease using an in vitro model system of Z A1AT ER accumulation. We investigated ER stress signals induced by Z A1AT and demonstrated that both the ER overload response and the unfolded protein response were activated by mutant Z A1AT, but not wild-type M A1AT. Interestingly, activation of the unfolded protein response pathway required an additional insult, whereas NF-kappa B activation, a hallmark of the ER overload response, was constitutive. These findings have important implications for the design of future therapeutics for Z A1AT liver disease and may also impact on drug design for other conformational diseases.