Silke Ryan

Selective Activation of Inflammatory Pathways by Intermittent Hypoxia in Obstructive Sleep Apnea Syndrome

Background— Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/reoxygenation (IHR), is an independent risk factor for cardiovascular disease. We investigated the underlying molecular mechanisms of this association in a translational study. Methods and Results— In a novel in vitro model of IHR, we used HeLa cells transfected with reporter constructs and DNA binding assays for the master transcriptional regulators of the inflammatory and adaptive pathways (NF&kgr;B and HIF-1, respectively) to investigate underlying transcriptional events initiated by repeated cell exposure to IHR. Furthermore, we prospectively studied 19 male OSAS patients (median apnea-hypopnea frequency, 48.5 episodes per hour; interquartile range [IQR], 28.5 to 72.9) and 17 matched normal control subjects. Circulating levels of the proinflammatory cytokine tumor necrosis factor-&agr; and the adaptive factor erythropoietin were assayed in all subjects at baseline and again after 6 weeks of continuous positive airway pressure therapy in patients. Full blood count was measured as part of a detailed baseline evaluation. HeLa cells exposed to IHR demonstrated selective activation of the proinflammatory transcription factor NF&kgr;B (P<0.001 by ANOVA), whereas the adaptive regulator HIF-1 was not activated, as demonstrated by luciferase reporter assays and DNA binding studies. Circulating tumor necrosis factor-&agr; levels were higher in OSAS patients (2.56 pg/mL; IQR, 2.01 to 3.42 pg/mL) than in control subjects (1.25 pg/mL; IQR, 0.94 to 1.87; P<0.001) but normalized with continuous positive airway pressure therapy (1.24 pg/mL; IQR, 0.78 to 2.35 pg/mL; P=0.002). In contrast, erythropoietin levels were similar throughout. Furthermore, circulating neutrophil levels were higher in OSAS patients than in control subjects, whereas the hematocrit was unaltered. Conclusions— These data demonstrate selective activation of inflammatory over adaptive pathways in IHR and OSAS, which may be an important molecular mechanism of cardiovascular disease.

Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome?

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent disease and is recognised as a major public health burden. Large-scale epidemiological studies have demonstrated an independent relationship between OSAS and various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood but a multifactorial aetiology is likely. Inflammatory processes have emerged as critical in the pathogenesis of atherosclerosis at all stages of atheroma formation. Increased levels of various circulating markers of inflammation including tumour necrosis factor α (TNFα), interleukin 6 (IL6), IL-8 and C-reactive protein (CRP) have been reported as associated with future cardiovascular risk. There is increasing evidence of elevated inflammatory markers in OSAS with a significant fall after effective treatment with continuous positive airway pressure. This evidence is particularly strong for TNFα, whereas studies on IL6 and CRP have yielded conflicting results possibly due to the confounding effects of obesity. Cell culture and animal studies have significantly contributed to our understanding of the underlying mechanisms of the association between OSAS and inflammation. Intermittent hypoxia, the hallmark of OSAS, results in activation of pro-inflammatory transcription factors such as nuclear factor kappa B (NF-κB) and activator protein (AP)-1. These promote activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro-inflammatory mediators that may lead to endothelial dysfunction. This review provides a critical analysis of the current evidence for an association between OSAS, inflammation and cardiovascular disease, discusses basic mechanisms that may be responsible for this association and proposes future research possibilities.Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent disease and is recognised as a major public health burden. Large-scale epidemiological studies have demonstrated an independent relationship between OSAS and various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood but a multifactorial aetiology is likely. Inflammatory processes have emerged as critical in the pathogenesis of atherosclerosis at all stages of atheroma formation. Increased levels of various circulating markers of inflammation including tumour necrosis factor alpha (TNFalpha), interleukin 6 (IL6), IL-8 and C-reactive protein (CRP) have been reported as associated with future cardiovascular risk. There is increasing evidence of elevated inflammatory markers in OSAS with a significant fall after effective treatment with continuous positive airway pressure. This evidence is particularly strong for TNFalpha, whereas studies on IL6 and CRP have yielded conflicting results possibly due to the confounding effects of obesity. Cell culture and animal studies have significantly contributed to our understanding of the underlying mechanisms of the association between OSAS and inflammation. Intermittent hypoxia, the hallmark of OSAS, results in activation of pro-inflammatory transcription factors such as nuclear factor kappa B (NF-kappaB) and activator protein (AP)-1. These promote activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro-inflammatory mediators that may lead to endothelial dysfunction. This review provides a critical analysis of the current evidence for an association between OSAS, inflammation and cardiovascular disease, discusses basic mechanisms that may be responsible for this association and proposes future research possibilities.

Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity

Background: High C-reactive protein (CRP) and homocysteine levels are risk factors for cardiovascular disease. Some, but not all, previous studies have reported increased levels of CRP and homocysteine in patients with obstructive sleep apnoea syndrome (OSAS). A study was undertaken to investigate the levels of these factors in carefully selected patients with OSAS and matched normal controls. Methods: CRP and homocysteine levels were measured in 110 subjects following polysomnography (PSG). Non-OSAS patients (group 1) were compared with two patient groups (mild/moderate OSAS (group 2) and severe OSAS (group 3)) group-matched for body mass index (BMI), and a fourth group of patients with severe OSAS who were more obese (group 4). All were free of other disease and similar in age, smoking habits and cholesterol levels. 50 suitable patients were commenced on continuous positive airway pressure (CPAP) treatment after PSG and 49 were reassessed 6 weeks later. Results: CRP levels were similar in groups 1, 2 and 3 (median (interquartile range (IQR)) 1.11 (0.76–2.11) mg/l vs 1.82 (1.20–3.71) mg/l vs 2.20 (1.16–3.59) mg/l; p = 0.727, Kruskal-Wallis test), but were significantly higher in group 4 than in the other groups (5.36 (2.42–9.17) mg/l, p<0.05 by individual group comparisons). In multivariate analysis of all subjects, BMI was an independent predictor for CRP levels (β = 0.221; p = 0.006) but apnoea-hypopnoea index and other measures of OSAS were not. There was no difference in homocysteine levels between all four groups (p = 0.1). CPAP did not alter CRP (2.29 (1.32–4.10) vs 2.84 (1.13–5.40) mg/l; p = 0.145) or homocysteine levels (8.49 (3.66) vs 9.90 (4.72) μmol/l; p = 0.381). Conclusion: CRP and homocysteine levels are not associated with OSAS severity in men but CRP is independently associated with obesity.

Diabetes Mellitus Prevalence and Control in Sleep-Disordered Breathing: The European Sleep Apnea Cohort (ESADA) Study

BACKGROUND OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population. METHODS We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects. RESULTS T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) (P < .001), respectively, for prevalent T2DM. Diabetic subjects with more severe OSA had worse glycemic control, with adjusted mean HbA1c levels 0.72% higher in patients with severe OSA than in those without sleep-disordered breathing (analysis of covariance, P < .001). CONCLUSIONS Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM.

Sleep apnoea and the heart

Sleep apnoea is associated with significant daytime functioning impairment and marked cardiovascular morbidities, leading to a significant increase in mortality. Sympathetic activation, oxidative stress and systemic inflammation have been shown to be the main intermediary mechanisms associated with sleep apnoea and intermittent hypoxia. There are now convincing data regarding the association between hypertension, arrhythmias, coronary heart disease, heart failure, increased cardiovascular mortality and sleep apnoea. This has been evidenced in sleep apnoea patients and is supported by experimental data obtained in intermittent hypoxia. Whether treating sleep apnoea enables chronic cardiovascular consequences to be reversed is not fully established as regard coronary heart disease, arrhythmias and heart failure. In this late condition, complex bidirectional relationships occur, with obstructive sleep apnoea being a risk factor for heart failure whilst central sleep apnoea mainly appears as a consequence of heart failure. It remains to be established in adequately designed studies, i.e. large randomised controlled trials, whether treating sleep apnoea can improve heart failure morbidity and mortality.

Obstructive sleep apnea and inflammation: relationship to cardiovascular co-morbidity.

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent disease and associated with cardiovascular morbidity and mortality. The pathogenesis of cardiovascular complications in OSAS is incompletely understood but a multifactorial etiology is likely. There is emerging evidence that inflammatory processes leading to endothelial dysfunction play a pivotal role. Various studies have demonstrated elevated inflammatory markers in OSAS patients in comparison to matched control subjects with a significant fall after effective treatment with continuous positive airway pressure. Cell culture and animal studies have significantly enhanced our understanding of the mechanisms of inflammation in OSAS. Intermittent hypoxia, the hallmark feature of OSAS, leads to a preferential activation of inflammatory pathways with the downstream consequence of expression of pro-inflammatory cytokines, chemokines and adhesion molecules that may contribute to endothelial dysfunction. Further studies are required to determine the precise role of inflammation in the cardiovascular pathogenesis of OSAS, particularly its interaction with oxidative stress, obesity and metabolic dysfunction.

Intermittent hypoxia and activation of inflammatory molecular pathways in OSAS

Abstract Obstructive sleep apnoea syndrome (OSAS) represents a highly prevalent disease and is recognized as a risk factor for the development of various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood, but the unique form of hypoxia with repetitive short cycles of desaturation followed by rapid reoxygenation termed intermittent hypoxia (IH) is likely to play a significant role. There is increasing evidence that IH leads to a preferential activation of inflammatory over adaptive pathways. This promotes activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro-inflammatory cytokines, chemokines and adhesion molecules that may contribute to endothelial dysfunction. This review provides a critical analysis of the current evidence of inflammatory mechanisms initiated by IH that may contribute to the cardiovascular pathogenesis in OSAS.

Sleep quality in chronic obstructive pulmonary disease

Background and objective:  Previous reports have shown that patients with chronic obstructive pulmonary disease (COPD) sleep poorly, but the underlying basis remains speculative. The aim of this retrospective study was to determine potential predictors of poor sleep quality in COPD patients.

Obstructive sleep apnoea syndrome: Translating science to clinical practice

Abstract:  OSA syndrome is characterized by recurring episodes of upper airway (UA) obstruction during sleep. The UA is subjected to collapse when the negative airway pressure generated by inspiratory activity of the diaphragm and intercostal muscles exceeds the force produced by the UA dilating muscles. Factors that reduce UA calibre lead to increased UA resistance with the generation of a more negative pharyngeal pressure during inspiration, and thereby predispose to UA occlusion during sleep. As a consequence, UA dilating muscles must contract more forcefully to maintain a patent UA, which may predispose to fatigue. Nasal CPAP counteracts these collapsing forces and is associated with resting of the UA muscles. The more recent development of auto‐adjusting CPAP (APAP) is a reflection of the understanding that the pressure required to prevent UA collapse fluctuates throughout the night and results in a lower mean pressure that may be more comfortable for some patients. The predominant morbidity of the OSA syndrome is cardiovascular and there is growing understanding of the basic mechanisms involved. Intermittent hypoxia appears to play a central role by activating transcription factors that predispose to atherogenesis, particularly NFκB. Sympathetic overactivity also appears to play an important role but the mechanisms involved are unclear.

Effects of salmeterol on sleeping oxygen saturation in chronic obstructive pulmonary disease.

Background: Sleep is associated with important adverse effects in patients with chronic obstructive pulmonary disease (COPD), such as disturbed sleep quality and gas exchange, including hypoxemia and hypercapnia. The effects of inhaled long-acting β2-agonist therapy (LABA) on these disturbances are unclear. Objectives: The aim of the study was to assess the effect of inhaled salmeterol on nocturnal sleeping arterial oxygen saturation (SaO2) and sleep quality. Methods: In a randomized, double-blind, placebo-controlled, crossover study of moderate/severe stable COPD patients, we compared the effects of 4 weeks of treatment with salmeterol 50 µg b.d. and matching placebo on sleeping SaO2 and sleep quality. Overnight polysomnography (PSG) was performed at baseline, and after 4 and 8 weeks in addition to detailed pulmonary function testing. Of 15 patients included, 12 completed the trial (median age 69 years, forced expiratory volume in 1 s, FEV1: 39%). Results: Both mean SaO2 [salmeterol vs. placebo: 92.9% (91.2, 94.7) vs. 91.0% (88.9, 94.8); p = 0.016] and the percentage of sleep spent below 90% of SaO2 [1.8% (0.0, 10.8) vs. 25.6% (0.5, 53.5); p = 0.005] improved significantly with salmeterol. Sleep quality was similar with both salmeterol and placebo on PSG. Static lung volumes, particularly trapped gas volume, tended to improve with salmeterol. Conclusion: We conclude that inhaled LABA therapy improves sleeping SaO2 without significant change in sleep quality.