Chronic Obstructive Pulmonary Disease and ... - ATS Journals

Pulmonary Perspective Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea Overlaps in Pathophysiology, Systemic Inflammation, and Cardiovascular Disease Walter T. McNicholas1 1

Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome represent two of the most prevalent chronic respiratory disorders in clinical practice, and cardiovascular diseases represent a major comorbidity in each disorder. The two disorders coexist (overlap syndrome) in approximately 1% of adults but asymptomatic lower airway obstruction together with sleep-disordered breathing is more prevalent. Although obstructive sleep apnea syndrome has similar prevalence in COPD as the general population, and vice versa, factors such as body mass index and smoking influence relationships. Nocturnal oxygen desaturation develops in COPD, independent of apnea/hypopnea, and is more severe in the overlap syndrome, thus predisposing to pulmonary hypertension. Furthermore, upper airway flow limitation contributes to nocturnal desaturation in COPD without apnea/hypopnea. Evidence of systemic inflammation in COPD and sleep apnea, involving C-reactive protein and IL-6, in addition to nuclear factor-kB–dependent pathways involving tumor necrosis factor-a and IL-8, provides insight into potential basic interactions between both disorders. Furthermore, oxidative stress develops in each disorder, in addition to activation and/or dysfunction of circulating leukocytes. These findings are clinically relevant because systemic inflammation may contribute to the pathogenesis of cardiovascular diseases and the cell/molecular pathways involved are similar to those identified in COPD and sleep apnea. However, the pathophysiological and clinical significance of systemic inflammation in COPD and sleep apnea is not proven, and thus, studies of patients with the overlap syndrome should provide insight into the mechanisms of systemic inflammation in COPD and sleep apnea, in addition to potential relationships with cardiovascular disease. Keywords: chronic obstructive pulmonary disease; obstructive sleep apnea; hypoxia; systemic inflammation; cardiovascular disease

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSAS) represent two of the most prevalent chronic respiratory disorders in clinical practice, and the term ‘‘overlap syndrome’’ is commonly used to describe the two disorders, when coexisting. Epidemiological studies (1, 2) indicate a prevalence of approximately 1% for the overlap syndrome in adult males, but the coexistence of asymptomatic lower airway obstruction with sleep-disordered breathing is con-

(Received in original form March 5, 2009; accepted in final form July 23, 2009) Correspondence and requests for reprints should be addressed to Walter T. McNicholas, M.D., Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. E-mail: [email protected] Am J Respir Crit Care Med Vol 180. pp 692–700, 2009 Originally Published in Press as DOI: 10.1164/rccm.200903-0347PP on July 23, 2009 Internet address: www.atsjournals.org

siderably higher. Overlap patients develop more pronounced nocturnal oxygen desaturation (NOD) than COPD or OSAS alone, which predisposes to pulmonary hypertension (3). The possible coexistence of COPD with OSAS is important because systemic inflammation develops in each disorder (4, 5) and may contribute to the pathogenesis of associated comorbidities, particularly cardiovascular. Inflammation plays an important role in atherosclerosis and cardiovascular disease (6), which represent the principal comorbidity in COPD (7) and OSAS (8, 9). However, putative causative links between OSASor COPD-induced systemic inflammation and cardiovascular disease remain unproven. Furthermore, no study has evaluated potential interactions between these disorders in the development of systemic inflammation or cardiovascular disease. The objectives of this Pulmonary Perspective are, first, to review the relationships of COPD and OSAS with cardiovascular disease from the perspective of systemic inflammation and hypoxia; second, to review the epidemiology of the overlap syndrome and related factors that may influence prevalence; third, to review pathophysiological interactions between COPD, sleep, and OSAS; fourth, to review the evidence for shared systemic inflammatory pathways in COPD and OSAS; and finally, to propose future research directions, particularly where studies of overlap patients may provide insight into systemic manifestations of COPD and OSAS, in addition to potential relationships with cardiovascular disease.

ROLE OF SYSTEMIC INFLAMMATION IN CARDIOVASCULAR DISEASE AND RELATIONSHIPS WITH COPD, OSAS, AND HYPOXIA Inflammation plays a key role in atherosclerotic plaque formation, from initiation of the fatty streak to the later stages of plaque rupture (6). In brief summary, endothelial dysfunction develops at an early stage in response to oxidized lipids, inflammatory cytokines such as tumor necrosis factor (TNF)-a, IL-1 and IL-6, and other factors including reactive oxygen species (ROS). This process leads to up-regulation 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 oxidized lipids to form foam cells. These cells accumulate to form a lipid pool, which is a central component of the early atherosclerotic plaque. As the plaque develops, a fibrous cap forms that separates the plaque from the vascular lumen. The ongoing inflammatory response, matrix degradation, and cell apoptosis lead to thinning of the fibrous cap and enlargement of the lipid core, ultimately resulting in plaque rupture.

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Inflammatory mediators participate in all stages of atherosclerosis and the detailed mechanisms are reviewed elsewhere (6, 10). However, there is no current evidence that targeted antiinflammatory therapy such as TNF-a antagonists ameliorate this process. Both COPD and OSAS are associated with increased activation of many inflammatory cell and molecular mechanisms associated with atherosclerosis (8, 11), which provide basic mechanisms to support the clinical and epidemiological data demonstrating COPD and OSAS as independent risk factors for cardiovascular disease (7–9). Hypoxia plays an important role in the progression of atherosclerosis by stimulating angiogenesis within the atherosclerotic plaque (12), principally via activation of the adaptive hypoxia-responsive transcription factor, hypoxia-inducible factor (HIF)-1. Inflammation within the plaque is a key factor in generating hypoxia by increasing metabolic demand. Intraplaque microvessels facilitate plaque progression and ultimate rupture by providing an entry point for inflammatory cells, red blood cells, and lipoproteins (12). Furthermore, important interactions occur between lipids and hypoxia in the development of atherosclerosis. In particular, chronic intermittent hypoxia together with a high-fat diet promotes atherosclerosis in male C57BL/6 mice, whereas hypoxia or a high-fat diet alone does not (13). These findings suggest that the greater hypoxia in the overlap syndrome might predispose to atherosclerosis more than COPD or OSAS alone, but this possibility is unproven. Hypercapnia also modulates inflammatory responses in a variety of settings including sepsis and ischemia–reperfusion. Hypercapnic acidosis has been demonstrated to have antiinflammatory effects through inhibition of the proinflammatory transcription factor nuclear factor (NF)-kB in an in vitro model using endothelial cells (14), and hypercapnia was associated with reduced TNF-a levels in an in vivo animal model of ischemia–reperfusion (15). Furthermore, hypercapnia depresses both pro- and antiinflammatory cytokine production in endotoxin-stimulated whole blood cultures taken from normal human subjects (16). These findings underline the complexity of potential interactions between hypoxia and hypercapnia in the inflammatory response.

CARDIOVASCULAR DISEASE IN COPD, OSAS, AND OVERLAP SYNDROME The mechanisms of cardiovascular disease in COPD and OSAS are multifactorial, but both disorders involve systemic inflam-

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mation. Whether systemic inflammation is an independent entity or largely a spillover of pulmonary inflammation in COPD (5), or upper airway inflammation in OSAS (17), is unclear. However, circulating levels of cytokines such as TNF-a and IL-8 correlate poorly with sputum levels in COPD, which argues against a simple spillover effect (18). Intermediate factors are also important because smoking (19) and obesity (20) are associated with increased systemic inflammatory markers such as IL-6, TNF-a, and ROS. COPD

In COPD, mechanisms of cardiovascular disease include hypoxia, systemic inflammation, and oxidative stress, together with sympathetic nervous system overactivity and vascular dysfunction (11), and are summarized in Figure 1. Vascular dysfunction in COPD relates to inflammatory cytokines such as IL-6, endothelial dysfunction, and connective tissue degradation, the latter involving increased elastolytic activity and collagen deposition. Genetic factors, lung hyperinflation, and skeletal muscles (19, 21) also contribute to systemic inflammation. COPD is a major, but underrecognized, risk factor for cardiovascular morbidity and mortality, even after adjustment for confounding risk factors such as age, smoking, and body mass index (BMI) (7, 11). Several population studies have demonstrated that cardiovascular morbidity and mortality progressively increase with declining FEV1/FVC ratio, and this relationship is present even in nonsmokers. Other prospective cohort studies indicate that cardiovascular disease represents the leading cause of mortality in patients with COPD (7). Apart from the well-recognized cor pulmonale, cardiovascular diseases independently associated with COPD include coronary artery disease, congestive heart failure, and arrhythmias (11). Nocturnal hypoxemia and hypercapnia in COPD predispose to pulmonary hypertension and sleep-related cardiac arrhythmias (22), in addition to nocturnal death during exacerbations (23). OSAS

In OSAS, mechanisms of cardiovascular disease include increased sympathetic and reduced parasympathetic nervous system activity, systemic inflammation, oxidative stress, endothelial dysfunction, and metabolic dysregulation, the latter involving insulin resistance and disordered lipid metabolism. Intermittent hypoxia is a key feature in systemic inflammation and oxidative stress in OSAS because of the associated intermittent reoxygenation (24), which has been compared with

Figure 1. Mechanisms associated with chronic obstructive pulmonary disease (COPD) contributing to cardiovascular diseases. COPD is associated with the development of systemic inflammation and oxidative stress, both directly and in response to hypoxia. These mechanisms result in endothelial dysfunction and promote atherosclerosis. COPD is also associated with sympathetic nervous system activation and connective tissue degradation, the latter partly due to increased elastolytic activity, which results in arterial stiffening. These mechanisms combine to promote the development of cardiovascular disease.

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reperfusion injury, and activates the inflammatory transcription factor NF-kB with increased production of related cytokines including TNF-a and IL-8 (25). The repetitive generation of negative intrathoracic pressure during obstructive apneas may also adversely affect cardiac function (26). The putative mechanisms of cardiovascular disease associated with intermittent hypoxia and/or sleep fragmentation in OSAS are outlined in Figure 2. OSAS is independently associated with systemic hypertension, and there is growing evidence of independent associations with coronary artery disease, congestive heart failure, arrhythmia, and stroke (8, 9). Pulmonary hypertension may also develop in patients with severe OSAS and/or gross obesity, in whom oxygen desaturation is most pronounced, and such patients may also develop daytime hypercapnia, particularly if there is associated lower airway obstruction (27). Data from the Wisconsin Sleep Cohort Study indicate a higher all-cause and cardiovascular mortality among patients with severe OSAS (28) and observational long-term follow-up studies indicate a lower cardiovascular morbidity and mortality among patients with OSAS treated with continuous positive airway pressure (CPAP) compared with those untreated (29, 30). Overlap Syndrome

Although systemic inflammation develops in both COPD (5, 31) and OSAS (4, 24), no study has investigated possible interactions between the disorders in these developments. Furthermore, few data exist concerning morbidity and mortality in patients with the overlap syndrome. NOD is greater in patients with the overlap syndrome than with COPD or OSAS alone (3) and apnea-associated desaturation is more pronounced. Daytime hypercapnia is also more common in overlap patients (27). This more pronounced hypoxemia and hypercapnia might result in greater cardiovascular morbidity and mortality, and there is

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some evidence to support this possibility. Pulmonary hypertension is more prevalent in overlap patients (3) and a preliminary report indicates that overlap patients have a higher mortality than those with COPD alone (32).

EPIDEMIOLOGICAL CONSIDERATIONS IN OVERLAP SYNDROME The prevalence of OSAS and COPD is reviewed elsewhere (33, 34); this review discusses the prevalence of the overlap syndrome, in addition to factors that influence prevalence such as definitions, obesity, and cigarette smoking. For clarity, the term OSAS refers to the clinical syndrome, whereas OAH refers to obstructive apneas/hypopneas alone without reference to symptoms. Influence of Definitions on the Prevalence of Overlap Syndrome

Although COPD and OSAS are prevalent, the reported prevalence is influenced by definitions. In the National Health and Nutrition Examination Survey (NHANES III), involving 9,838 normal subjects (35), COPD prevalence ranged from 7.7% for GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage IIa (FEV1/FVC ratio ,70% with FEV1 ,80% and .50% predicted) to 16.8% for GOLD stage I (FEV1/FVC ratio ,70% and FEV1 .80%). The prevalence of obstructive sleep apnea is also influenced by definitions. In the Wisconsin Sleep Cohort Study of 602 middle-aged working adults (36), 4% of males and 2% of females had an apnea–hypopnea frequency (AHI) of at least 5/hour together with daytime sleepiness, which are the minimal criteria for the clinical syndrome (37). However, an AHI of at least 5/hour alone without daytime symptoms occurred in 24% of males and 9% of females. The widely accepted definition of OSAS by an international task force (37) requires obstructed breathing events and compatible daytime symptoms for diagnosis. Thus, the lower prevalence in the Wisconsin Sleep Cohort Study refers to OSAS. However, pathophysiological interactions between COPD and OSAS relate more to sleep-disordered breathing than daytime symptoms; thus, the higher prevalence figures previously cited for OAH alone may be more relevant in this context. Thus, a prevalence for subclinical forms of the overlap of 4% in males could be speculated from a simple calculation based on the prevalence of 16.8% for GOLD stage I in the NHANES Study and 24% among males for an AHI of at least 5/hour in the Wisconsin Sleep Cohort Study. Although the clinical relevance of an isolated AHI of at least 5/hour is uncertain, this finding has been independently associated with hypertension in the Wisconsin Sleep Cohort Study (34). Prevalence of Overlap Syndrome

Figure 2. Mechanisms associated with intermittent hypoxia/sleep fragmentation in obstructive sleep apnea contributing to cardiovascular diseases. The intermittent hypoxia and sleep fragmentation associated with obstructive sleep apnea syndrome (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.

Several reports have assessed the epidemiological relationships between COPD and OSAS (3) (1–3, 38), and details are presented in Table 1. Overall, the data support a similar prevalence of OSAS in patients with COPD as in an equivalent general population. Data from the Sleep Heart Health Study (1) indicate that the respiratory disturbance index (RDI) was less in subjects with lower airway obstruction, largely as a consequence of lower BMI, because RDI values were similar when stratified for BMI. In the World Health Organization (Geneva, Switzerland)-sponsored MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) II project (2), OSAS prevalence was relatively high at 11.3%, but lower airway obstruction did not predispose to OSAS, or OSAS to lower airway obstruction. The overlap syndrome occurred in 1% of subjects, but an AHI of at least 5/hour alone with FEV1/ FVC less than 70% occurred in 3%, which approximates the


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TABLE 1. PREVALENCE OF OVERLAP SYNDROME Author (Ref. No.)

Study Details

Findings

Sanders et al. (1)

Prospective community sample of 5,964 adults >40 yr undergoing spirometry and polysomnography; sample enriched for cardiovascular risk factors including smoking

19% had FEV1/FVC ratio ,70%; 3.8% had FEV1/FVC ratio 60%. This group had lower AHI, largely as a consequence of lower BMI

Bednarek et al. (2)

Prospective community sample of 356 adult males and 320 females aged 41–72 yr

11.3% had AHI >5 with sleepiness; 31.8% had AHI >5 alone; 10.7% had FEV1/FVC ratio ,70%. Overlap syndrome in 1% but FEV1/FVC ,70% and AHI >5 alone in 3%

Chaouat et al. (3)

265 sleep clinic patients with established OSAS (AHI >20/h)

11% had FEV1/FVC ratio ,60%; this group was all male, had lower PaO2, higher PaCO2, and pulmonary artery pressures

Larsson et al. (37)

471 adults with chronic bronchitis and 108 without; 52 subjects had home-based limited sleep studies (type 3 monitor)

7.4% of patients with bronchitis and 3.1% of control subjects had OSAS (AHI .5 with sleepiness); difference not statistically significant

Definition of abbreviations: AHI 5 apnea–hypopnea index; BMI 5 body mass index; OSAS 5 obstructive sleep apnea syndrome.

prevalence speculated previously. Overlap patients had lower nocturnal SaO2 levels than those with COPD or OSAS. Although Larsson and coworkers (38) reported a higher OSAS prevalence in subjects with chronic bronchitis than in control subjects, data were from only 52 subjects undergoing homebased studies without sleep staging. Influence of Body Mass Index, Smoking, and Age on Prevalence

Several confounding factors may influence relationships between COPD and OSAS, particularly BMI and smoking. Obesity is a key factor in OSAS (26), yet low BMI is common in COPD, especially in patients with advanced disease (39). This feature may protect against OAH, and is supported by the finding of a lower RDI in subjects with airflow obstruction, relating to lower BMI (1). On the other hand, many other patients with COPD have elevated BMI, thus predisposing to OAH, and the finding of a higher RDI in overweight patients with airflow obstruction supports this possibility (1). Smoking is a risk factor for COPD and OSAS, and several reports found a higher AHI in smokers than nonsmokers (34). A report based on the Wisconsin Sleep Cohort including 811 adults (40) found that an AHI of at least 5/hour was three times more likely in current smokers than in never-smokers. Heavy smokers (>40 cigarettes/d) had an odds ratio of 6.74 for AHI of at least 5/hour. OSAS and COPD are more common in the elderly (41, 42) and Chaouat and coauthors (3) reported that overlap patients in their sleep clinic cohort were older than patients with OSAS alone.

PATHOPHYSIOLOGY OF SLEEP-RELATED DISTURBANCES IN OVERLAP SYNDROME This perspective focuses on interactions of COPD, sleep, and upper airway obstruction in the pathophysiology of sleeprelated breathing disturbances. Sleep-related Effects in COPD

Sleep quality is impaired in COPD (43), with sleep fragmentation and, as a result, diminished slow-wave and REM sleep. Sleep disturbance is largely a consequence of COPD, not coexisting OAH (22), although cigarette smoking also impairs sleep quality (44). This reduction in REM sleep protects against OAH in COPD, because apneas are more pronounced in OSAS

during REM sleep (26). The effects of chronic sleep disturbance on pulmonary function in COPD are unknown, but an early report found lower FVC and FEV1 (5 and 6%, respectively) in the morning after one night’s sleep deprivation in 15 adult males with stable COPD when compared with measurements after a night of normal sleep (45). However, the mechanisms of this effect were unclear. The principal basis for disturbances in ventilation and gas exchange during sleep in COPD, independent of OAH, relates to augmented physiological adaptations (22). Respiratory center responses to chemical and other inputs are diminished during sleep (46) and respiratory muscle responses to respiratory center outputs are diminished, particularly during REM sleep, and especially involving accessory muscles of respiration. Minute ventilation falls during non-REM and more so during REM sleep, even in normal subjects, predominantly because of a reduction in tidal volume due to increased upper airway resistance and diminished inspiratory drive, with a slight fall in SaO2 that is not clinically significant in normal subjects (47). In COPD, this reduction in ventilation is augmented, resulting in greater falls in SaO2 during sleep with associated hypercapnia. Because many such patients have awake hypoxemia, they are especially prone to nocturnal oxygen desaturation (NOD) by being on the steep portion of the oxyhemoglobin dissociation curve. Furthermore, SaO2 falls more during sleep in COPD patients without OAH than during maximal exercise (48). The ribcage contribution to breathing is reduced, particularly during REM sleep, because of reduced accessory muscle contraction, which particularly affects the intercostal muscles, whereas diaphragmatic contraction is spared. This reduction is important in COPD, where lung hyperinflation may reduce diaphragmatic efficiency (49), thus necessitating an increased accessory muscle contribution to breathing. Skeletal muscle atrophy and dysfunction is common in advanced COPD (39), which may further compromise the contribution made by accessory muscles. A small reduction in FRC occurs during sleep, principally because of a reduction in tonic muscle activity, which may augment ventilation–perfusion mismatching. Pathophysiological Interactions of COPD and OSAS

Several pathophysiological factors influence the relationship between COPD and OSAS (Figure 3). COPD-related factors that may predispose to OAH include rostral shift of peripheral edema when supine, resulting in fluid accumulation in the neck, thus contributing to pharyngeal narrowing (50). Although there

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Figure 3. Pathophysiological interactions between chronic obstructive pulmonary disease (COPD), sleep, and obstructive sleep apnea syndrome (OSAS). Shown are interactions of COPD, sleep, and OSAS, highlighting factors relating to COPD that may promote or inhibit the development of obstructive apnea and hypopnea (OAH). BMI 5 body mass index.

are no data for COPD, this phenomenon might be particularly expected in patients with cor pulmonale, among whom peripheral edema is a major feature. Body mass and cigarette smoking also affect pathophysiological relationships. Neck obesity contributes to upper airway narrowing, which is of key importance in OAH pathophysiology (26), and a preliminary report found that such narrowing predisposes to NOD in COPD, independent of OAH (51). Truncal obesity promotes ventilatory disturbances by reduced chest wall compliance and respiratory muscle strength (52). Furthermore, truncal obesity is associated with reduced FRC, which contributes to ventilation–perfusion mismatching. However, many patients with advanced COPD have low BMI, which protects against OSA. Cigarette smoking predisposes to OAH by increasing upper airway resistance due to local inflammation and edema (26). Medications used in COPD may influence interactions between COPD and OSAS. Theophyllines (53), inhaled anticholinergic agents (54), and inhaled long-acting b-agonists (55) ameliorate NOD, likely because of reductions in both gas trapping and lower airway obstruction. Corticosteroids may predispose to OAH by promoting central obesity and fluid retention with associated upper airway narrowing, in addition to myopathy and metabolic alkalosis.

OVERLAPPING MECHANISMS OF SYSTEMIC INFLAMMATION IN COPD AND OSAS The mechanisms of systemic inflammation in COPD and OSAS are reviewed elsewhere (4, 5, 8, 39, 56); this perspective concentrates on overlapping mechanisms, thus highlighting possible interactions, as outlined in Figure 4. C-reactive Protein and IL-6

The acute-phase inflammatory protein CRP (C-reactive protein) is produced by the liver in response to IL-6 and contributes to atherosclerosis by promoting adhesion molecule expression. CRP levels correlate with future cardiovascular events (57, 58), although conventional cardiovascular risk factors such as obesity may be largely responsible for this association (59). In OSAS, CRP levels are elevated (60, 61), but obesity is an important confounding factor in this relationship (62). The Wisconsin Sleep Cohort Study of 907 adults failed to detect an independent association between CRP and OSAS after adjustment for BMI (63), and a randomized control trial found no difference in CRP and IL-6 levels between therapeutic and sham CPAP after 4 weeks of therapy (64). In COPD, CRP

levels are elevated in patients with stable disease (31) and correlate with pulmonary artery pressures (65). The NHANES III study of 6,629 subjects reported a correlation of CRP with airflow obstruction and myocardial ischemia (66). CRP was an independent predictor of future outcomes in some (67) but not other studies (68, 69), and appears to be a sensitive biomarker of exacerbations (70). IL-6 levels predict future cardiovascular disease (58) and adipose tissue is a major site of production. In OSAS, early studies found increased IL-6 levels (61), but more recent reports of patients with OSAS and matched control subjects found no differences (71), and CPAP therapy had no effect on IL-6 levels (64, 71). Furthermore, the Cleveland Family Study of 385 adults found no association between circulating IL-6 levels and OSAS after adjustment for BMI (72), although an independent association was found between OSAS and soluble IL-6 receptor levels. In COPD, IL-6 levels are increased (69), particularly during exacerbations (73), and IL-6 levels parallel CRP. Thus, there is evidence of increased circulating CRP and IL-6 levels in COPD whereas in OSAS obesity is a major confounding variable and the evidence of an independent relationship between OSAS and CRP/IL-6 levels is less clear. Furthermore, the precise role of CRP and IL-6 in the pathogenesis of cardiovascular disease in these disorders is not fully established. NF-kB and Related Cytokines

The transcription factor NF-kB is a master regulator of inflammatory gene expression and regulates cytokines such as TNF-a and IL-8 that contribute to atherosclerosis by inducing adhesion molecule expression (6). Hypoxia induces NF-kB activation and also activation of the adaptive transcription factor HIF-1, which regulates many genes that promote tissue perfusion and oxygenation (74). NF-kB and HIF-1 pathways also interact in the hypoxic response (75). We demonstrated in an in vitro model of hypoxia a preferential activation of NF-kB over HIF-1 pathways during intermittent hypoxia, whereas sustained hypoxia resulted in preferential activation of HIF-1 (Figure 5) (25). These findings imply that intermittent hypoxia preferentially up-regulates inflammatory pathways, which particularly applies to the hypoxic pattern in OAH but may also apply to patients with COPD during sleep and exercise. The findings also suggest that disorders associated with chronic sustained hypoxia, such as hypoventilation syndromes or COPD patients with chronic hypoxemia, may invoke an HIF-1–mediated response more so than OSAS, in which intermittent hypoxemia is the dominant pattern, although persistent hypoxemia may also


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Figure 4. Overlapping molecular mechanisms of systemic inflammation in chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSAS). Overlapping molecular pathways of systemic inflammation in COPD and OSAS identify areas where an evidence base exists for inflammatory pathways common to each disorder. Both COPD and OSAS are associated with elevated levels of C-reactive protein (CRP) and IL-6, in addition to tumor 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 the overlap syndrome. Each inflammatory pathway has been associated with atherogenesis and subsequent cardiovascular disease.

occur in OSAS especially in severely obese patients. In COPD, there is NF-kB activation in skeletal muscles (76), which may contribute to skeletal muscle wasting. Tumor Necrosis Factor-a and IL-8

Circulating TNF-a and IL-8 levels correlate with early atherosclerosis, and are predictive of coronary heart disease and congestive heart failure (77). In COPD, TNF-a and IL-8 levels are elevated compared with control subjects (31, 78) and TNF-a elevation is associated with muscle wasting, likely relating to TNF-a accumulation in muscle tissue (79). Systemic hypoxemia contributes to TNF-a elevation in COPD (80), which is particularly relevant in the overlap syndrome where hypoxemia is more

pronounced. Furthermore, circulating TNF-a levels are higher in COPD patients with pulmonary hypertension, who are also more hypoxemic (65). In OSAS, circulating TNF-a and IL-8 levels are elevated in patients compared with control subjects, independent of obesity, and fall with CPAP therapy (71). The oxygen desaturation index is the strongest predictor of TNF-a and IL-8 levels in OSAS, and T cells and monocytes are potential sources of TNF-a (81). Unlike COPD, TNF-a elevation does not appear to be associated with muscle wasting in OSAS. Overall, the data indicate activation of TNF-a in COPD and OSAS with hypoxemia being a key factor. Thus, TNF-a and related cytokine levels should be particularly elevated in

Figure 5. Inflammatory and adaptive transcription factor responses to intermittent and sustained hypoxia. Shown is the increase in luciferase activity, comparing HeLa cells treated with normoxia; after exposure to 2, 4, 8, or 16 cycles of intermittent hypoxia (IH); or to 24-hour sustained hypoxia (SH) in constructs under the control of nuclear factor (NF)-kB (left) or hypoxia-inducible factor (HIF)-1 (right). Reprinted by permission from Reference 25.

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patients with the overlap syndrome, and studies of this pathway in overlap patients may provide insight into the role of NF-kB– dependent pathways in cardiovascular disease. Oxidative Stress

Oxidative stress occurs in COPD (82) and OSAS (24) and is associated with increased ROS production, principally from leukocytes. Although ROS serve important physiological roles in signal transduction and as second messengers in signaling pathways, excessive production may damage cellular components and biomolecules including lipids, proteins, and DNA (83) and contribute to vascular endothelial dysfunction. In COPD, oxidative stress occurs in the lungs and systemically (82) with increased ROS production from both intrapulmonary and circulating leukocytes, particularly during exacerbations. Oxidative stress in COPD may also result from reduced antioxidant capacity and mechanisms include reduced levels of the transcription factor nuclear factor erythroid 2-related factor 2 in lung tissue, which is a master regulator of antioxidant gene production. In patients with OSAS, ROS production by circulating leukocytes is increased and reduced after CPAP therapy (84), and is also increased in rodents exposed to intermittent hypoxia (85). Patients with OSAS also demonstrate oxidation of macromolecules, particularly lipid peroxidation (86). Intermittent hypoxia may particularly promote oxidative stress because the associated intermittent reoxygenation has been compared with reperfusion injury where increased ROS production is evident (24). However, confounding factors such as cigarette smoking and obesity also promote oxidative stress (19, 87). Furthermore, interactions of oxidative stress with pathways of systemic inflammation in response to hypoxia, such as those involving NF-kB, are complex and not fully elucidated. Evidence supporting a causal association include reports that ROS upregulates mitogen-activated protein kinase pathways, which then activate inflammatory transcription factors such as NFkB; and by reports that TNF-a stimulation results in increased intracellular ROS production (83). However, NF-kB can also be activated in an ROS-independent fashion and several signal cascades activate NF-kB without ROS involvement (88). Circulating Inflammatory Cells

There is evidence of activation/dysfunction of circulating leukocytes in COPD and OSAS, which has particular relevance because leukocyte accumulation and adhesion to the endothelium are of key importance to atherosclerotic plaque formation (6). In OSAS, circulating neutrophil numbers are elevated compared with matched control subjects (25) and impaired neutrophil apoptosis occurs together with increased adhesion molecule expression (89). Recurrent obstructive apneas in rats lead to increased leukocyte–endothelial cell interactions such as leukocyte rolling and adhesion (90). Cytotoxic T-cell lymphocytes in patients with OSAS acquire an activated phenotype resulting in cytotoxicity against endothelial cells (91). Furthermore, monocytes from patients with OSAS adhere more firmly to endothelial cells than do those from control subjects, which is decreased by CPAP therapy (92). In stable COPD, circulating neutrophil numbers are elevated (31). Abnormalities of circulating neutrophils have been reported in patients with COPD that facilitate recruitment into the lungs, such as increased expression of the surface adhesion molecule CD11b and elevated circulating levels of intercellular adhesion molecule-1 (93). Increased surface expression of CD11b/CD18 has also been demonstrated on circulating neutrophils during apoptosis in patients with stable COPD (94). Lymphocyte abnormalities reported in COPD include higher

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numbers of circulating cytotoxic CD81 lymphocytes and higher cytochrome oxidase activity in circulating lymphocytes of patients with COPD than in control subjects (95). However, cigarette smoking may be an important confounding variable in these changes (39).

FUTURE RESEARCH DIRECTIONS Despite the high prevalence of overlap syndrome, few data are available on its pathophysiological and clinical consequences. Most information relates to cross-sectional analysis of selected clinic cohorts and there are no long-term follow-up studies. The finding that NOD in COPD relates mainly to upper airway narrowing without OAH requires confirmation. The association of systemic inflammation with COPD and OSAS indicates that the possibility of an overlap is relevant to protocols evaluating pathophysiological mechanisms in each disorder. Because polysomnography may pose difficulties in COPD-related studies, ambulatory monitoring systems are available that record cardiorespiratory variables suited to evaluating sleep-related breathing disturbances (96). Although there is evidence in COPD and OSAS of overlapping mechanisms relating to inflammation, oxidative stress, and leukocyte dysfunction, there may be differences in the magnitude and consequences of these responses. Furthermore, the role of inflammatory markers in the prediction of cardiovascular morbidity in OSAS and COPD is unclear and long-term prospective studies are lacking. Data are particularly lacking on these responses in the overlap syndrome, and the potential relationships to cardiovascular disease. If systemic inflammation is important in COPD and OSAS, studies in overlap patients should provide insight regarding the nature and significance of these responses. Because hypoxia is greater in the overlap syndrome, evaluating the role of hypoxia in systemic inflammation among overlap patients may provide additional insights into the mechanisms involved in each disorder. Conflict of Interest Statement: The author does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Acknowledgment: The author acknowledges with thanks the critical feedback from several expert colleagues in the preparation of this manuscript, namely William MacNee (Edinburgh), John Stradling (Oxford), Michael P. Keane (Dublin), and Peter Calverley (Liverpool).

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