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Eur Respir Monogr 2013; 59: 135143. Copyright ERS 2013. DOI: 10.1183/1025448x.10012012 Print ISBN: 978-1-84984-032-3 Online ISBN: 978-1-84984-033-0 Print ISSN: 1025-448x Online ISSN: 2075-6674
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leep has several effects on breathing, including changes in central respiratory control, lung mechanics and muscle contractility. These effects do not have an adverse impact on healthy individuals but may result in significant hypoxaemia and hypercapnia in patients with COPD, particularly during rapid eye movement (REM) sleep [1]. Gas exchange in sleeping normal subjects is largely a consequence of hypoventilation, although ventilation/perfusion abnormalities may also contribute. In COPD patients, hypoventilation is more pronounced, particularly during REM sleep, due to a number of factors: airflow obstruction, hyperinflation, respiratory muscle dysfunction, blunted ventilatory responses to hypercapnia and/or hypoxia, ventilation/perfusion mismatching, and medications such as loop diuretics and oral steroids. Sleep disturbance is also common in COPD [2, 3] and it is likely that it is a consequence of the underlying lung disease,
although adverse effects of drug therapy on sleep quality may also contribute. It is likely that sleep disturbance contributes to the nonspecific daytime symptoms of chronic fatigue and lethargy, and to the overall impairment in quality of life described by these patients [4]. While the relationships between sleep and COPD are separate and distinct from sleep apnoea, there are interactions of sleep and breathing that may influence the relationship between obstructive sleep apnoea syndrome (OSAS) and COPD. In particular, patients with both COPD and OSAS develop more pronounced nocturnal oxygen desaturation than COPD or OSAS alone, which predisposes to pulmonary hypertension and more severe cardiovascular disease [5]. In this chapter, we discuss the clinical syndrome in which COPD and OSAS coexist, commonly referred to as overlap syndrome. The chapter also reviews the epidemiology, pathophysiology, cardiovascular comorbidity and management of this prevalent disorder.
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augmented physiological adaptations that are normally associated with sleep [1]. Respiratory muscle responses to respiratory centre outputs are diminished, particularly during REM sleep and especially those involving the accessory muscles of respiration; this is particularly relevant in COPD where lung hyperinflation may reduce diaphragmatic efficiency, thus necessitating an increased accessory muscle contribution to breathing [15]. Minute ventilation falls during non-REM and more so during REM sleep, even in normal subjects; this is predominantly because of a reduction in tidal volume due to increased upper airway resistance and diminished inspiratory drive, with a slight fall in arterial oxygen saturation (Sa,O2) that is not clinically significant in normal subjects [16]. However, in COPD, this reduction in ventilation is augmented, resulting in greater hypoxaemia during sleep with associated hypercapnia [17]. As many such patients have hypoxaemia while awake, they are especially prone to nocturnal oxygen desaturation as they are on the steep portion of the oxyhaemoglobin dissociation curve. A recent report also indicated that upper airway narrowing without the presence of obstructive apnoea or hypopnoea is significantly related to nocturnal oxygen desaturation in COPD patients [18]. Several pathophysiological factors influence the relationship between COPD and OSAS (table 1). COPD-related factors that may predispose to SDB include rostral shift of peripheral oedema when supine, resulting in fluid accumulation in the neck, and thus contributing to pharyngeal narrowing [19]. While there are no data in COPD, this phenomenon might be particularly expected in patients with cor pulmonale where peripheral oedema is a major feature. BMI and cigarette smoking also affect pathophysiological relationships. Neck obesity contributes to upper airway narrowing, which is key to the pathophysiology of OSAS [20]. Truncal obesity promotes ventilatory disturbances by reducing chest wall compliance and respiratory muscle strength [21]. Furthermore, truncal obesity is associated with reduced functional residual capacity, which contributes to ventilation/perfusion mismatching. However, many patients with advanced COPD have a low BMI, which protects against upper airway obstruction. Cigarette smoking predisposes to upper airway obstruction by increasing upper airway resistance due to local inflammation and oedema [20]. The medication used in COPD may also influence the interaction between COPD and OSAS. Theophyllines [22], inhaled anti-cholinergic agents [23] and inhaled long-acting b-agonists [24] ameliorate nocturnal oxygen desaturation, perhaps due to reductions in both gas trapping and lower airway obstruction. Corticosteroids may predispose to upper airway obstruction by promoting central obesity and fluid retention with associated upper airway narrowing, in addition to myopathy and metabolic alkalosis. In contrast, theophylline therapy has been demonstrated to reduce AHI in patients with OSAS without COPD [25].
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system overactivity and vascular dysfunction. COPD also increases elastolytic activity and accentuates connective tissue degradation, the latter resulting in arterial stiffening [48]. In OSAS, mechanisms of cardiovascular disease include increased sympathetic nervous system activity [49], systemic inflammation [32, 50], oxidative stress [51], endothelial dysfunction [52] and metabolic dysregulation, with the latter involving insulin resistance and disordered lipid metabolism [36, 53]. The mechanisms of OSAS are summarised in figure 1. Intermittent hypoxia is a key feature in systemic inflammation and oxidative stress in OSAS because of the associated intermittent re-oxygenation [51], which has been compared with reperfusion injury, and activates the inflammatory transcription factor nuclear factor (NF)-kB with increased production of related cytokines, including TNF-a and IL-8 [54]. Inflammation plays a key role in atherosclerotic plaque formation, from initiation of the fatty streak to the later stages of plaque rupture [55]. Endothelial dysfunction develops at an early stage in response to oxidised lipids, inflammatory cytokines, such as TNF-a, IL-1 and IL-6, and other factors, including reactive oxygen species. This process leads to upregulation of intercellular adhesion molecules, which promote rolling and adherence of leukocytes to the endothelium. Monocytes and T-cells penetrate the vascular wall where monocytes transform into macrophages, which ingest oxidised lipids to form foam cells. These cells accumulate to form a lipid pool, which is a central component of the early atherosclerotic plaque. Both COPD and OSAS are associated with increased activation of many inflammatory cell and molecular mechanisms associated with atherosclerosis [36, 48]. Hypoxia plays an important role in the progression of atherosclerosis by stimulating angiogenesis within the atherosclerotic plaque [56], principally via activation of the adaptive hypoxia responsive transcription factor, hypoxia inducible factor (HIF)-1. Furthermore, important interactions occur between lipids and hypoxia in the development of atherosclerosis [57]. These findings suggest that greater hypoxaemia in overlap syndrome might be more likely predispose to atherosclerosis than in COPD or OSAS alone; this, however, is unproven. Hypercapnia also OSAS modulates inflammatory responses in a variety of settings, including sepsis and ischaemiareperfusion, Intermittent hypoxaemia and there is evidence of an antiinflammatory effect in both in vitro Systemic Oxidative and in vivo models [58]. These inflammation stress findings underline the complexity of potential interactions between hypoxia and hypercapnia in the Sympathetic Metabolic inflammatory response. excitation dysregulation: While systemic inflammation and cardiovascular disease develop in both COPD and OSAS, there is limited evidence of the possible interactions between the disorders in these developments. Nocturnal oxygen desaturation is greater in patients with overlap syndrome than in those with COPD or OSAS alone [5], and apnoea-associated desaturation is more pronounced. Daytime hypercapnia is also more common in overlap patients [59]. This more pronounced hypoxaemia and hypercapnia might result in greater cardiovascular
Endothelial dysfunction Insulin resistance dyslipidaemia
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Figure 1. Mechanisms associated with intermittent hypoxia in obstructive sleep apnoea syndrome (OSAS) contributing to cardiovascular diseases. The intermittent hypoxia and sleep fragmentation associated with OSAS result in a variety of responses, including increased sympathetic nervous system activity, systemic inflammation, oxidative stress and metabolic dysregulation, the latter involving insulin resistance and disordered lipid metabolism. Inflammation and oxidative stress produce endothelial dysfunction, and the various mechanisms combine to promote the development of atherosclerosis and cardiovascular disease.
morbidity and mortality, and there is some limited evidence to support this possibility [5, 60]. To date, no study has investigated the possible basic interactions between COPD and OSAS, although systemic inflammation does develop in both disorders and systemic hypoxaemia is more pronounced in overlap syndrome than in each disorder alone. However, a recent report by SHIINA et al. [61] involving 524 males with OSAS indicated that overlap patients demonstrated greater arterial stiffness, as measured by brachialankle pulse wave velocity, than patients with OSAS alone. Thus, it seems likely that overlap syndrome is associated with greater cardiovascular morbidity and mortality than each disorder alone; further studies are required to confirm this. Basic interactions between COPD and OSAS that may contribute to the development of cardiovascular disease are summarised in figure 2.
Cardiovascular disease
Figure 2. Overlapping molecular mechanisms of systemic inflammation in COPD and obstructive sleep apnoea syndrome (OSAS). The overlapping molecular pathways of systemic inflammation in COPD and OSAS identify areas in which an evidence base exists for inflammatory pathways common to each disorder (the thickness of the arrows is representative of the weight of evidence in favour). Both COPD and OSAS are associated with elevated levels of Creactive protein (CRP) and interleukin (IL)-6, in addition to tumour necrosis factor (TNF)-a and IL-8, and are also associated with oxidative stress. However, cigarette smoking and obesity are confounding variables in these associations. Hypoxia is a key factor in elevated TNF-a production in OSAS, which is particularly relevant to overlap syndrome. Each inflammatory pathway has been associated with atherogenesis and subsequent cardiovascular disease. Reproduced and modified from [6] with permission from the publisher.
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syndrome to mortality and first-time hospitalisation due to COPD exacerbation, and also examined the impact of CPAP therapy on these major outcomes. The authors reported that patients with overlap syndrome who were not treated with CPAP had a significantly higher mortality rate (relative risk 1.79) and were also more likely to suffer a severe COPD exacerbation leading to hospitalisation (relative risk 1.70) compared with the patient group with COPD alone. The authors concluded that CPAP therapy in overlap syndrome patients is associated with improved survival and decreased hospitalisation rate. MACHADO et al. [63] evaluated the impact of OSAS treatment with CPAP on the survival of hypoxaemic COPD patients and reported that CPAP therapy was associated with higher survival in patients with both moderate-to-severe OSAS and hypoxaemic COPD. Of the 603 hypoxaemic COPD patients receiving long-term oxygen therapy, 95 were diagnosed with moderate-to-severe OSAS. Of this OSAS group, 61 (64%) patients accepted and were adherent to CPAP treatment, and 34 (36%) did not accept or were not adherent and were considered not treated. The 5-year survival rate was significantly higher in the CPAP-treated group (71%) compared with the nontreated group (26%). After adjusting for several potential confounding factors, patients treated with CPAP continued to have a significantly lower risk of death.
Statement of Interest
None declared.
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