InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Cardiology and Cardiovascular Medicine » "Cardiovascular Risk Factors", book edited by Armen Yuri Gasparyan, ISBN 978-953-51-0240-3, Published: March 14, 2012 under CC BY 3.0 license. © The Author(s).

Chapter 18

Obstructive Sleep Apnoea Syndrome as a Systemic Low-Grade Inflammatory Disorder

By Carlos Zamarrón, Emilio Morete and Felix del Campo Matias
DOI: 10.5772/32376

Article top

Obstructive Sleep Apnoea Syndrome as a Systemic Low-Grade Inflammatory Disorder

Carlos Zamarrón1, Emilio Morete1 and Felix del Campo Matias2

1. Introduction

Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by recurrent upper airway collapse during sleep. A reduction or complete cessation of airflow occurs despite ongoing inspiratory efforts and leads to arousals, sleep fragmentation, and oxyhemoglobin desaturation (Remmers et al., 1978; Young et al., 1993).

Though clinically recognized for more than four decades (Gastaut et al., 1965), general awareness of OSAS has been slow to develop. OSAS has been associated with cardiovascular disease (Marin et al., 2005; Duran-Cantolla et al., 2010; Barbe et al., 2010), automobile accidents (Teran-Santos et al., 1999), chronic obstructive pulmonary disease (Chaouat et al., 1995), heart failure (Oldenburg et al., 2007) and health related quality of life deterioration (Pichel et al., 2004). OSAS often coexists with obesity and has been related to insulin resistance and metabolic syndrome (Choi et al., 2008).

Patients with OSAS experience repetitive episodes of hypoxia and reoxygenation during transient cessation of breathing that may have systemic effects. These patients also present increased levels of biomarkers linked to endocrine-metabolic and cardiovascular alterations (Zamarron et al., 2008). Moreover, OSAS may involve sleep fragmentation, tonic elevation of sympathetic neural activity, oxidative stress, inflammation, hypercoagulability and endothelial dysfunction (Bradley & Floras, 2009; Fava et al., 2011). All of this indicates that OSAS should be considered a systemic disease rather than a local abnormality.

The present review analyses the pathophysiology related to the systemic consequences of OSAS and the mechanisms involved in the association between OSAS and systemic diseases (Figure 1).

2. Sleep fragmentation

Extreme sleep habits can affect health and have been associated with increased inflammation. Significant changes in habitual sleep duration can lead to chronic low-grade systemic inflammation (Meisinger et al., 2005; Patel et al., 2009). Activation of pro-inflammatory pathways may represent a mechanism. In a recent study in pediatric OSAS patients, increased TNF-α levels were primarily driven by sleep fragmentation and body mass index. These levels were closely associated with the degree of sleepiness, as measured by the Multiple Sleep Latency Test. Surgical treatment of OSAS resulted in significant reductions in TNF-α levels with reciprocal prolongations in sleep latency (Gozal et al., 2010).


Figure 1.

A schematic summary of the proponed sequence of events in OSAS starting from episodic hypoxia and ending with systemic consequences.

Sleep fragmentation increases sympathetic nervous activity, which, in turn, results in a higher metabolic rate and elevated catecholamine secretion. Furthermore, severe sleep fragmentation can disturb nocturnal renin and aldosterone secretion profiles, and increase nighttime urine excretion. Moller et al. found that long-term CPAP reduced blood pressure, which was correlated with reductions in plasma renin and angiotensin II levels (Moller et al., 2003).

Although the mechanism of this altered inflammatory status in humans undergoing experimental sleep loss is unknown, it is likely that autonomic activation and metabolic changes play key roles (Mullington et al., 2010).

3. Enhanced sympathetic traffic

In OSAS patients, tonic activation of chemoreflex activity produces enhanced sympathetic traffic (Somers et al., 1988). Cyclic intermittent hypoxia (IH) and hypercapnia provides the causal link between upper airway obstruction during sleep and sympathetic activation during awakening. In a recent study in healthy humans, IH significantly increased sympathetic activity and daytime blood pressure after a single night of exposure. The baroreflex control of sympathetic outflow declined (Tamisier et al., 2011). Surges in sympathetic nervous system activity associated with apneic events have also been related to antifibrinolytic activity reflected by elevations in PAI-1 (von & Dimsdale, 2003). During apneic events, there is an up-regulation of the renin-angiotensin system and down-regulation of nitric oxide synthases (Fletcher et al., 1999; Prabhakar et al., 2001).

The increased sympathetic activity and IH associated with apneic episodes has been proposed as a possible mechanism behind the association between OSAS, systemic inflammation and cardiovascular disease. CPAP reduces sympathetic nerve activity (Maser et al., 2008), increases arterial baroreflex sensitivity (Marrone et al., 2011) and decreases vascular risk (Kohler et al., 2008).

4. Oxidative stress

There is an emerging consensus that OSAS is an oxidative stress disorder. In a recent study involving children with OSAS, Malakasioti found an increase of hydrogen peroxide levels in exhaled breath condensate, which is an indirect index of altered redox status in the respiratory tract (Malakasioti et al., 2011).

Apnea produces a decline in oxygen levels followed by reoxygenation when breathing resumes. The cyclical episodes of hypoxia-reoxygenation, analogous to cardiac ischemia/reoxygenation injury causing ATP depletion and xanthine oxidase activation, and increases the generation of oxygen-derived free radicals. CPAP therapy decreases the levels of oxidative stress in OSAS patients (Chin et al., 2000; Alonso-Fernandez et al., 2009).

Oxidative stress can profoundly regulate the cellular transcriptome through activation of transcription factors, including specificity protein-1, hypoxia-inducible factor-1, c-jun, and possibly nuclear factor-kappaB. Activation of redox-sensitive gene expression is suggested by the increase in some protein products of these genes, including VEGF (Teramoto et al., 2003), EPO (Marrone et al., 2008), endothelin-1 (Belaidi et al., 2009), inflammatory cytokines and adhesion molecules (Ohga et al., 1999; Dyugovskaya et al., 2002; Ohga et al., 2003).

Increased oxidative stress has been associated with development of cardiovascular diseases and can be promoted by the chronic intermittent hypoxia characteristic of OSAS (Park et al., 2007). A variety of studies suggest that oxidative stress is present in OSAS at levels relevant to tissues such as the arterial wall (Grebe et al., 2006; Barcelo et al., 2006). This process enhances lipid uptake into human macrophages and may contribute to atherosclerosis in OSAS patients (Lattimore et al., 2005). Furthermore, OSAS decreases blood antioxidant status in high BMI subjects and may change the relationship between oxidative stress markers (Wysocka et al., 2008). After CPAP, expression of eNOS and phosphorylated eNOS was found to be significantly increased whereas expression of nitrotyrosine and nuclear factor-kappaB significantly decreased (Jelic et al., 2010) but some studies shown that CPAP may not affect antioxidant defense (Alzoghaibi & Bahammam, 2011).

Recently, Nair reported that oxidative stress is mediated, at least in part, by excessive NADPH oxidase activity. This author suggests that pharmacological agents targeting NADPH oxidase may provide a therapeutic strategy in OSAS (Nair et al., 2011).

5. Systemic inflammation

Local and systemic inflammation is present in OSAS. Insofar as local inflammation, bronchial and nasal changes are especially relevant (Devouassoux et al., 2007). In a recent study, patients showed a significant increase in IL-8 and ICAM concentrations in both plasma and exhaled condensate. In addition, they showed a higher neutrophil percentage in induced sputum. These findings were significantly and positively correlated to AHI (Carpagnano et al., 2010), however, CPAP-therapy did have a significant effect (Lacedonia et al., 2011).

Several studies have reported changes in circulating levels of adhesion molecules in OSAS patients (El-Solh et al., 2002; Zamarron-Sanz et al., 2006). Dyugovskaya analysed polymorphonuclear apoptosis and expression of adhesion molecules in vitro in patients with moderate to severe OSAS. Decreased apoptosis and increased expression of adhesion molecules were observed. Although adhesion molecules may facilitate increased polymorphonuclear-endothelium interactions, decreased apoptosis may further augment these interactions and facilitate free radical and proteolytic enzymes (Dyugovskaya et al., 2008).

OSAS patients present increased levels of inflammatory mediators such as TNFα and IL-6 (Imagawa et al., 2004; Bravo et al., 2007) that decrease with CPAP treatment (Arias et al., 2008; Steiropoulos et al., 2009).

Systemic inflammation is increasingly being recognized as a risk factor for a number of complications including atherosclerosis (Ross, 1999) and is a well-established factor in the pathogenesis of cardiovascular disease (Hansson, 2005). Certain acute-phase proteins that have been associated in humans with cardiovascular disease, such as serum amyloid (Svatikova et al., 2003), C-reactive protein (Taheri et al., 2007; Punjabi & Beamer, 2007) which have been associated in humans with cardiovascular disease are elevated in OSAS patients and improve with CPAP treatment (Yokoe et al., 2003; Kuramoto et al., 2009).

The mechanisms by which inflammation contributes to OSAS-induced vascular dysfunction are not known. Reoxygenation after a brief period of hypoxia as experienced repetitively and systematically by OSAS patients may predispose to cell stress. It has been suggested that such events favor the activation of a proinflammatory response as mediated through the nuclear transcription factor nuclear factor-kappaB, a master regulator of inflammatory gene expression.

Inflammation may be an important link between increased sympathetic nervous system activity and vascular dysfunction in OSAS. Chronically elevated sympathetic activity produced an inflammatory response in several organs and vascular beds (Yu et al., 2005).

Some authors point to the role of the T-lymphocyte. This cell is known to play an important role in ANG II-induced hypertension and endothelial dysfunction via NADPH oxidase-induced superoxide production (Guzik et al., 2007).

Increased expression of inflammatory cytokines may contribute to endothelial dysfunction and subsequent cardiovascular complications (Ryan et al., 2005; Foster et al., 2007). Currently, some studies suggest that pentraxin 3, an acute phase response protein, is rapidly produced and released by several cell types, in particular by mononuclear phagocytes, and endothelial cells in response to primary inflammatory signals, may play a significant role in OSAS-associated vascular damage (Kasai et al., 2011). Arnaud report that some inhibition of molecules such as RANTES/CCL5, a cytokine that is a a selective attractant for memory T lymphocytes and monocytes may play a significant role in athesroscletoric remodeling OSAS-associated vascular damage (Arnaud et al., 2011)

However, mesenchymal stem cells triggered an early anti-inflammatory response in rats subjected to recurrent obstructive apneas, suggesting that these stem cells could play a role in the physiological response to counterbalance inflammation in OSAS (Carreras et al., 2010).

In a recent study on healthy human males, Querido et al. analysed the effect over 10 days of nightly IH in the following systemic inflammatory markers: serum granulocyte macrophage colony-stimulating factor, interferon-gamma, interleukin-1 β, interleukin-6, interleukin-8, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1. There was no significant change in any of the markers. These findings suggest that a more substantial or a different pattern of hypoxemia might be necessary to activate systemic inflammation, that the system may need to be primed before hypoxic exposure, or that increases in inflammatory markers OSAS patients may be more related to other factors such as obesity or nocturnal arousal (Querido et al., 2011).

6. Hypercoagulability

Hypercoagulability resulting from increased coagulation or inhibited fibrinolysis is associated with an increased risk for cardiovascular disease (Zouaoui et al., 2006). This is another factor implicated in the association between this disease and OSAS (Peled et al., 2008).

A variety of findings support the existence of a relation between hypercoagulability, OSAS and cardiovascular disease. Firstly, patients with OSAS present higher plasma levels of several procoagulant factors such as fibrinogen (Reinhart et al., 2002; Tkacova et al., 2008), activated clotting factor FVII, FXIIa and thrombin/antithrombin III complexes (von et al., 2005) and the fibrinolysis-inhibiting enzyme plasminogen activator inihibitor (PAI-1) (von et al., 2006; Zamarron et al., 2008). Secondly, increased D-dimer levels in untreated OSAS have been correlated with severity of nocturnal hypoxemia, characteristic of OSAS (Shitrit et al., 2005). Thirdly, sleep fragmentation and sleep efficiency data have been associated with increased levels of von Willebrand factor and soluble tissue factor, two markers of a prothrombotic state (von et al., 2007).

OSAS is associated with platelet activation (Akinnusi et al., 2009). Platelet activation is a link in the pathophysiology of diseases prone to thrombosis and inflammation (Gasparyan et al., 2011). In these patients, platelet activation is associated with greater levels of oxygen desaturation (Oga et al., 2009;Rahangdale et al., 2011) that decreases after CPAP treatment (Varol et al., 2011).

In a current article, thromboelastography, a simple test of hemostasis, has been proposed for evaluating the risk of future cardiovascular disease in patients with OSAS (Othman et al., 2010).

7. Endothelial dysfunction

Endothelial dysfunction is an early marker of vascular abnormality preceding clinically overt cardiovascular disease (Giannotti & Landmesser, 2007; Halcox et al., 2009).

The intact endothelium regulates vascular tone and repair capacity, maintaining proinflammatory, anti-inflammatory, and coagulation homeostasis. Alteration of these homeostatic pathways results in endothelial dysfunction before structural changes in the vasculature. The hypoxia, hypercapnia, and pressor surges accompanying obstructive apneic events may serve as potent stimuli for the release of vasoactive substances and for impairment of endothelial function.

In OSAS, endothelial dysfunction could be caused by both hypoxia-reoxygenation cycles and chronic sleep fragmentation produced by repetitive arousals. A causal relationship between OSAS and endothelial dysfunction was demonstrated by a study in which flow-mediated dilation in the forearm was improved by CPAP treatment (Ip et al., 2004; Trzepizur et al., 2009). Levels of nitric oxide, a major vasodilator substance released by the endothelium, have been found to be decreased in OSAS patients, and these levels normalize with CPAP therapy (Haight & Djupesland, 2003).

A number of studies with OSAS patients indicate an associated endothelial dysfunction (Nieto et al., 2004). In patients with OSAS, increased production of superoxide by neutrophils (Schulz et al., 2000), increased biomarkers of lipid peroxidation (Lavie et al., 2004), and increased levels of 8-isoprostanes (Alonso Fernandez 2009; Carpagnano et al., 2003) have been observed.

Among the most important vasoconstrictive substances is endothelin-1, a peptide hormone secreted under the influence of hypoxia (Kanagy et al., 2001). Several studies have reported higher endothelin-1 levels in OSAS patients (Phillips et al 1999; Saarelainen & Hasan, 2000) however, Grimpen reports conflicting findings (Grimpen et al., 2000). This divergence might be explained by differences in study design. The groups studied by Phillips (Phillips et al., 1999) and Saarelainen (Saarelainen & Hasan, 2000) had more severe disease and, thus, underwent more severe oxygen desaturations that acted as a trigger for endothelin-1 secretion. Gjorup showed that hypertensive OSAS patients had greater nocturnal and diurnal endothelin-1 plasma levels than healthy controls, suggesting that OSAS does not affect plasma endothelin-1 levels in the absence of coexistent cardiovascular diseases (Gjorup et al., 2007).

The inconsistency of the above endothelin-1 levels likely reflects the predominantly abluminal release of endothelin. Using rat models of arterial hypertension, several authors have reported elevated vascular production of endothelin-1, while circulating levels remained similar to controls (Pohl & Busse, 1989; Rossi & Pitter, 2006). This demonstrates that circulating levels of endothelin-1 do not exclude elevated vascular production in OSAS.

In recent years, endothelial progenitor cells have gained a central role in vascular regeneration and endothelial repair capacity through angiogenesis and restoring endothelial function of injured blood vessels. Endothelial progenitor cells are decreased in patients with endothelial dysfunction and underlie an increased risk for cardiovascular morbidity in OSAS. Endothelial progenitor cells may have a potential role in the pathogenesis of vascular diseases that is pertinent to OSAS (Berger & Lavie, 2011).

It has recently been reported that OSAS patients presented increased oxidant production in the microcirculation and endothelial dysfunction, both of which improved with treatment (Patt et al., 2010)

8. OSAS and endocrine-metabolic consequences

Even though OSAS is generally less prevalent in women than men, differences diminish after the onset of menopause. This may be the result of declining estrogen and progesterone (Resta et al., 2004; Anttalainen et al., 2006). Accordingly, estrogen replacement therapy in menopausal women lessens the prevalence of OSAS (Shahar et al., 2003; Wesstrom et al., 2005).

On the other hand, men diagnosed with OSAS may manifest decreased libido and a decline in morning serum testosterone levels (Teloken et al., 2006; Hoekema et al., 2006). At first, this was thought to reflect an associated dysfunction of the pituitary-gonadal axis related to sleep fragmentation and hypoxia (Meston et al., 2003). However, the correction of hypoxia and sleep fragmentation in OSAS patients treated with CPAP does not lead to complete recovery, suggesting that existence of other underlying causes. In a recent study, with the exception of prolactine, CPAP therapy produced no significant changes the serum level of sexual hormones including FSH and LH (Macrea et al., 2010). Some authors claim that obesity is the major contributing factor to the reduced pituitary gonadal function in OSAS (Luboshitzky et al., 2005).

9. Obesity

Central, or visceral, obesity is associated with the greatest risk for OSAS (Shinohara et al., 1997). The mechanism by which obesity can favor the onset of OSAS is not well-known, but it could be that central obesity precipitates or exacerbates OSAS because fat deposits in the upper airway affect distensibility (Isono, 2009). The increased volume of abdominal fat could predispose to hypoventilation during sleep and/or reduce the oxygen reserve, favoring oxygen desaturation during sleep (Schwartz et al., 2008). In addition, the disrupted sleep patterns characteristic of OSAS predispose to metabolic effects and weight gain. Patel investigated the association between self-reported usual sleep duration and subsequent weight gain in the Nurses' Health Study. They showed that a habitual sleep time of less than 7 hours is associated with a modest increase in future weight gain and incident obesity (Patel et al., 2006).

In recent years, much attention has been focused on the interaction between OSAS and products released by adipose tissue such as leptin, adiponectin, resistin and grelin (Ronti et al., 2006).

Leptin is an adipocyte-derived hormone that regulates body weight through control of appetite and energy expenditure (Proulx et al., 2002). Furthermore, leptin is a cytokine and is therefore also involved in the inflammatory process. Several studies have shown increased levels of leptin in OSAS (Phillips et al., 2000; Tokuda et al., 2008), suggesting its role in the disease (Ip et al., 2000). The mechanisms underlying the relation between leptin and OSAS are very diverse, and may involve overnight changes in apnea levels (Patel et al., 2004; Sanner et al., 2004), sleep hypoxemia (Tatsumi et al., 2005), and hypercapnia (Shimura et al., 2005).

A direct relationship between OSAS and leptin is supported by the fact that effective OSAS treatment with CPAP also influences leptin levels (Shimizu et al., 2002; Cuhadaroglu et al., 2009). Although the precise mechanism explaining the effect of CPAP has not yet been elucidated, it can be inferred that reduction in sympathetic activity (Snitker et al., 1997), and improvement in insulin sensitivity play a role (Brooks et al., 1994).

Leptin levels have been proposed as a prognostic marker for OSAS (Ozturk et al., 2003) and have been implicated in the pathogenesis of OSAS-related cardiovascular disease (Kapsimalis et al., 2008; Tokuda et al., 2008; Al et al., 2009).

Leptin can also act as a respiratory stimulant, and impairment of the leptin signaling pathway causes respiratory depression in mice (O'Donnell et al., 2000). This hormone has been associated with obesity hypoventilation syndrome in humans (Phipps et al., 2002) and may reflect a compensatory response to hypoventilation (Makinodan et al., 2008).

OSAS has independently been associated with reduced levels of adiponectin (Masserini et al., 2006; Zhang et al., 2006; Carneiro et al., 2009) which may favour cardiovascular disease development. The recurrent hypoxia-reoxygenation attacks in OSAS patients may activate oxidative stress and lead to low levels of adiponectin (Vatansever et al., 2010).

Some authors have observed that serum adiponectin levels may be independent of the degree of OSAS (Tokuda et al., 2008). Decreased adiponectin may result from increased sympathetic activity (Delporte et al., 2002), and higher levels of cytokines such as IL-6 and TNFα (Fasshauer et al., 2003). In fact, there are conflicting reports as to whether CPAP treatment of OSAS effectively normalizes adiponectin levels (de Lima et al., 2010).

Obesity has been implicated in the relation between OSAS and adiponectin (Makino et al., 2006), In a recent study involving media under hypoxic conditions in an ex-vivo mouse model, adiponectin secretion was measured. In obese mice, hypoxic stress reduced adiponectin in the supernatant of mesenteric fat tissue, but not subcutaneous fat tissue. These findings suggest that abdominal obesity, representing abundant mesenteric fat tissue susceptible to hypoxic stress, partly explains adiponectin levels in OSAS patients, and that reduction of visceral fat accumulation may combat OSAS-related atherosclerotic cardiovascular diseases in abdominal obesity (Nakagawa et al., 2011).

Resistin is a white adipose tissue hormone whose function has yet to be established. In a study of 20 obese OSAS patients, Harsch found that CPAP treatment of OSAS had no significant influence on resistin levels (Harsch et al., 2004). In OSAS patients, hypoxic stress during sleep may enhance resistin production, possibly mediating systemic inflammatory processes. Through its effect on OSAS, CPAP therapy may help control resistin production (Yamamoto et al., 2008).

OSAS may decrease serum resistin levels in subjects with excess body mass and also may contribute to glucose metabolism, but has no influence on leptin levels (Wysocka et al., 2009)

Ghrelin is a hormone that influences appetite and fat accumulation and its physiological effects are opposite to those of leptin. No clear relation has been found between ghrelin and OSAS. In a study of 30 obese OSAS patients, Harsch found that plasma ghrelin levels were significantly higher in OSAS patients than in controls. These elevated ghrelin levels could not be explained by obesity alone, since they rapidly decreased with CPAP therapy (Harsch et al., 2003). In another study of 30 untreated obese patients with moderate-severe OSAS, significantly higher levels of serum leptin were found in OSAS patients than in controls, but ghrelin levels were no different (Ulukavak et al., 2005).

In a recent study of 55 consecutive OSAS patients, the study group presented significantly higher serum ghrelin levels than controls. There was a significant positive correlation between ghrelin and AHI. No significant difference was noted in the levels of leptin, adiponectin, and resistin (Li et al., 2010).

Increased ghrelin levels have been found to support the presence of increased appetite and caloric intake in obese patients with OSAS, which in turn may further promote the severity of the underlying conditions (Spruyt et al., 2010). In obese children, OSAS is associated with daytime sleepiness, elevation of proinflammatory cytokines, increased leptin, and decreased adiponectin (Tsaoussoglou et al., 2010).

10. OSAS and insulin resistance

A variety of studies based on animal models indicate that hypoxia can alter glucose homeostasis (Cheng et al., 1997; Li et al., 2006). Polotsky described that long-term exposure to intermittent hypoxia increased levels of insulin and glucose intolerance in obese, leptin-deficient mice (Polotsky et al., 2003). Humans exposed to hypoxia present worsened glucose tolerance (Braun et al., 2001).

Insulin resistance is a central part of the metabolic syndrome, a condition that is reaching epidemic proportions in Western Society and now emerging in developing countries (Prentice, 2006). Most studies involving OSAS and insulin resistance demonstrate an association between these two diseases, independently of obesity (Tassone et al., 2003; McArdle et al., 2007). In a large population-based study involving normoglycemic hypertensive men, Resnick found that the severity of OSAS was associated with increased insulin resistance (Resnick et al., 2003). The magnitude of these beneficial effects is modulated by the hours of CPAP adherence and the degree of obesity (Tasali et al., 2011).

Insulin resistance is associated to states of inflammation (Reaven, 2005). Monocyte chemoattractant protein-1 levels are elevated in OSAS and may be involved in the pathogenesis of insulin resistance in these patients (Piemonti et al., 2003; Hayashi et al., 2006).

11. Metabolic syndrome and OSAS

Metabolic syndrome is an emerging public health problem that represents a constellation of cardiovascular risk factors (Batsis et al., 2007). The clinical identification of metabolic syndrome is based on measures of abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and glucose intolerance (Executive Summary of the NCEP., 2001).

Although the etiology of this syndrome is largely unknown, it is likely to be comprised of a complex interaction between genetic, metabolic, and environmental factors (Nestel, 2003). Several recent studies suggest that a proinflammatory state may also be an important component (Aso et al., 2005; Gude et al., 2009). The close association between OSAS and metabolic syndrome is called “Syndrome Z”(Wilcox et al., 1998)

The prevalence of metabolic syndrome is markedly higher among OSAS patients. Ambrosetti et al. studied 89 consecutive OSAS patients and found metabolic syndrome in 53% of them (Ambrosetti et al., 2006). Another recent study found a prevalence of 68% (Drager et al., 2009). Obese OSAS patients may have an increased rate of metabolic syndrome and higher levels of serum lipids, fasting glucose, leptin and fibrinogen than obese subjects without OSAS. Thus, clinicians should be encouraged to systematically evaluate the presence of metabolic abnormalities in OSAS and vice versa (Basoglu et al., 2011).

Both clinical and animal studies suggest that an independent relationship may exist between OSAS and hyperlipidemia. Hypoxic stress produced by OSAS potentially increases the risk of hyperlipidemia. In rodent models, hyperlipidemia can result from exposure to intermittent hypoxia (Li et al., 2005). In a sample of nearly 5,000 subjects from the Sleep Heart Health study, there was a positive association between OSAS severity and increased serum total cholesterol and triglycerides, as well as decreased serum HDL, in people under the age of 65 (Newman et al., 2001).

In a population-based sample of four hundred women aged 20-70 years the frequency of metabolic syndrome increased from 10.5% in women with AHI <5 to 57.1% in women with AHI ≥ 30. AHI and minimal saturation level remained significantly associated with metabolic syndrome also when adjusting for the waist-to-hip-ratio (Theorell-Haglow et al., 2011).

Both OSAS and metabolic syndrome may exert negative synergistic effects on the cardiovascular system through multiple mechanisms (Bonsignore & Zito, 2008; Levy et al., 2009).

Intermittent hypoxia, the hallmark feature of OSAS, leads to a preferential activation of inflammatory pathways. Oxidative stress, cardiovascular inflammation, endothelial dysfunction, and metabolic abnormalities in OSAS could accelerate atherogenesis (Quercioli et al., 2010). 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 (Kent et al., 2011)

12. Conclusions

OSAS patients experience hypoxia–reoxygenation episodes, hypercapnia and arousal from sleep with modifications in the autonomic nervous system, oxidative stress and inflammation. OSAS is frequently associated to endocrine metabolic alterations and obesity.

Inflammatory processes play an important role in the pathogenesis of atherosclerosis and circulating levels of several inflammation markers have been associated with future cardiovascular risk. OSAS plays a mediating role between obesity and cardiovascular disease. Clinical and experimental data suggest a relationship between OSAS and adipose tissue pathophysiology which appears biologically plausible, however, further research is still needed. Multiple factors have been proposed to activate proinflammatory pathways in obesity, including generation of reactive oxygen species, and release of inflammatory cytokines potentially activated by OSAS-related hypoxic stress. All of this indicates that, more than a local abnormality, OSAS should be considered a systemic disease.


1 - Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) 2001 JAMA, 285 2486 2497 .
2 - M. E. Akinnusi, L. L. Paasch, K. R. Szarpa, P. K. Wallace, A. A. El Solh, 2009 Impact of nasal continuous positive airway pressure therapy on markers of platelet activation in patients with obstructive sleep apnea. Respiration, 77 25 31 .
3 - L. N. Al, A. Mulgrew, R. Cheema, S. Vaneeden, A. Butt, J. Fleetham, et al. 2009 Pro-atherogenic cytokine profile of patients with suspected obstructive sleep apnea. Sleep Breath., 13 391 5
4 - A. Alonso-Fernandez, F. Garcia-Rio, M. A. Arias, A. Hernanz, P. M. de la , J. Pierola, et al. 2009 Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial. Thorax, 64 581 586 .
5 - M. A. Alzoghaibi, A. S. Bahammam, 2011 The effect of one night of continuous positive airway pressure therapy on oxidative stress and antioxidant defense in hypertensive patients with severe obstructive sleep apnea. Sleep Breath, 13 391 5 May 13. [Epub ahead of print]
6 - M. Ambrosetti, A. M. Lucioni, S. Conti, R. F. Pedretti, M. Neri, 2006 Metabolic syndrome in obstructive sleep apnea and related cardiovascular risk. J.Cardiovasc.Med. (Hagerstown.), 7 826 829 .
7 - U. Anttalainen, T. Saaresranta, J. Aittokallio, N. Kalleinen, T. Vahlberg, I. Virtanen, et al. 2006 Impact of menopause on the manifestation and severity of sleep-disordered breathing. Acta Obstet.Gynecol.Scand., 85 1381 1388 .
8 - M. A. Arias, F. Garcia-Rio, A. Alonso-Fernandez, A. Hernanz, R. Hidalgo, V. Martinez-Mateo, et al. 2008 CPAP decreases plasma levels of soluble tumour necrosis factor-alpha receptor 1 in obstructive sleep apnoea. Eur.Respir.J., 32 1009 1015 .
9 - C. Arnaud, P. C. Beguin, S. Lantuejoul, J. L. Pepin, C. Guillermet, G. Pelli, et al. 2011 The Inflammatory Pre-Atherosclerotic Remodeling Induced by Intermittent Hypoxia is Attenuated by RANTES/CCL5 Inhibition. Am.J.Respir.Crit. Care. Med., Jun 16. [Epub ahead of print]
10 - Y. Aso, S. Wakabayashi, R. Yamamoto, R. Matsutomo, K. Takebayashi, T. Inukai, 2005 Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care, 28 2211 2216 .
11 - F. Barbe, J. Duran-Cantolla, F. Capote, P. M. de la , E. Chiner, J. F. Masa, et al. 2010 Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am.J.Respir.Crit Care Med., 181 718 726 .
12 - A. Barcelo, F. Barbe, P. M. de la , M. Vila, G. Perez, J. Pierola, et al. 2006 Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment. Eur.Respir.J., 27 756 760 .
13 - O. K. Basoglu, F. Sarac, S. Sarac, H. Uluer, C. Yilmaz, 2011 Metabolic syndrome, insulin resistance, fibrinogen, homocysteine, leptin, and C-reactive protein in obese patients with obstructive sleep apnea syndrome. Ann.Thorac.Med., 6 120 125 .
14 - J. A. Batsis, R. E. Nieto-Martinez, F. Lopez-Jimenez, 2007 Metabolic syndrome: from global epidemiology to individualized medicine. Clin.Pharmacol.Ther., 82 509 524 .
15 - E. Belaidi, M. Joyeux-Faure, C. Ribuot, S. H. Launois, P. Levy, D. Godin-Ribuot, 2009 Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea. J.Am.Coll.Cardiol., 53 1309 1317 .
16 - S. Berger, L. Lavie, 2011 Endothelial progenitor cells in cardiovascular disease and hypoxia-potential implications to obstructive sleep apnea. Transl.Res., 158 1 13 .
17 - M. R. Bonsignore, A. Zito, 2008 Metabolic effects of the obstructive sleep apnea syndrome and cardiovascular risk. Arch.Physiol. Biochem., 114 255 260 .
18 - T. D. Bradley, J. S. Floras, 2009 Obstructive sleep apnoea and its cardiovascular consequences. Lancet, 373 82 93 .
19 - B. Braun, P. B. Rock, S. Zamudio, G. E. Wolfel, R. S. Mazzeo, S. R. Muza, et al. 2001 Women at altitude: short-term exposure to hypoxia and/or alpha(1)-adrenergic blockade reduces insulin sensitivity. J.Appl.Physiol, 91 623 631 .
20 - M. D. Bravo, L. D. Serpero, A. Barcelo, F. Barbe, A. Agusti, D. Gozal, 2007 Inflammatory proteins in patients with obstructive sleep apnea with and without daytime sleepiness. Sleep Breath, 11 177 85 .
21 - B. Brooks, P. A. Cistulli, M. Borkman, G. Ross, S. McGhee, R. R. Grunstein, et al. 1994 Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: effect of continuous positive airway pressure treatment on insulin responsiveness. J.Clin.Endocrinol.Metab, 79 1681 1685 .
22 - G. Carneiro, S. M. Togeiro, F. F. Ribeiro-Filho, E. Truksinas, A. B. Ribeiro, M. T. Zanella, et al. 2009 Continuous Positive Airway Pressure Therapy Improves Hypoadiponectinemia in Severe Obese Men with Obstructive Sleep Apnea without Changes in Insulin Resistance. Metab Syndr.Relat. Disord., 7 537 42
23 - G. E. Carpagnano, S. A. Kharitonov, O. Resta, M. P. Foschino-Barbaro, E. Gramiccioni, P. J. Barnes, 2003 8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy. Chest, 124 1386 1392 .
24 - G. E. Carpagnano, A. Spanevello, R. Sabato, A. Depalo, G. P. Palladino, L. Bergantino, et al. 2010 Systemic and airway inflammation in sleep apnea and obesity: the role of ICAM-1 and IL-8. Transl.Res., 155 35 43 .
25 - A. Carreras, I. Almendros, J. M. Montserrat, D. Navajas, R. Farre, 2010 Mesenchymal stem cells reduce inflammation in a rat model of obstructive sleep apnea. Respir.Physiol. Neurobiol., 172 210 212 .
26 - A. Chaouat, E. Weitzenblum, J. Krieger, T. Ifoundza, M. Oswald, R. Kessler, 1995 Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am.J.Respir.Crit Care Med., 151 82 86 .
27 - N. Cheng, W. Cai, M. Jiang, S. Wu, 1997 Effect of hypoxia on blood glucose, hormones, and insulin receptor functions in newborn calves. Pediatr.Res., 41 852 856 .
28 - K. Chin, T. Nakamura, K. Shimizu, M. Mishima, T. Nakamura, M. Miyasaka, et al. 2000 Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am.J.Med., 109 562 567 .
29 - K. M. Choi, J. S. Lee, H. S. Park, S. H. Baik, D. S. Choi, S. M. Kim, 2008 Relationship between sleep duration and the metabolic syndrome: Korean National Health and Nutrition Survey 2001. Int.J.Obes. (Lond), 32 1091 1097 .
30 - C. Cuhadaroglu, A. Utkusavas, L. Ozturk, S. Salman, T. Ece, 2009 Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea. Lung, 187 75 81 .
31 - A. M. De Lima, C. M. Franco, C. M. de Castro, A. A. Bezerra, L. Jr. Ataide, A. Halpern, 2010 Effects of nasal continuous positive airway pressure treatment on oxidative stress and adiponectin levels in obese patients with obstructive sleep apnea. Respiration, 79 370 376 .
32 - M. L. Delporte, T. Funahashi, M. Takahashi, Y. Matsuzawa, S. M. Brichard, 2002 Pre- and post-translational negative effect of beta-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies. Biochem.J., 367 677 685 .
33 - G. Devouassoux, P. Levy, E. Rossini, I. Pin, M. Fior-Gozlan, M. Henry, et al. 2007 Sleep apnea is associated with bronchial inflammation and continuous positive airway pressure-induced airway hyperresponsiveness. J.Allergy. Clin.Immunol., 119 597 603 .
34 - L. F. Drager, E. L. Queiroz, H. F. Lopes, P. R. Genta, E. M. Krieger, G. Lorenzi-Filho, 2009 Obstructive sleep apnea is highly prevalent and correlates with impaired glycemic control in consecutive patients with the metabolic syndrome. J.Cardiometab.Syndr., 4 89 95 .
35 - J. Duran-Cantolla, F. Aizpuru, J. M. Montserrat, E. Ballester, J. Teran-Santos, J. I. Aguirregomoscorta, et al. 2010 Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ, 341, c5991.
36 - L. Dyugovskaya, P. Lavie, L. Lavie, 2002 Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am.J.Respir.Crit Care Med., 165 934 939 .
37 - L. Dyugovskaya, A. Polyakov, P. Lavie, L. Lavie, 2008 Delayed neutrophil apoptosis in patients with sleep apnea. Am.J.Respir.Crit Care Med., 177 544 554 .
38 - A. A. El-Solh, M. J. Mador, P. Sikka, R. S. Dhillon, D. Amsterdam, B. J. Grant, 2002 Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea. Chest, 121 1541 1547 .
39 - M. Fasshauer, S. Kralisch, M. Klier, U. Lossner, M. Bluher, J. Klein, et al. 2003 Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem.Biophys.Res.Commun., 301 1045 1050 .
40 - C. Fava, M. Montagnana, E. J. Favaloro, G. C. Guidi, G. Lippi, 2011 Obstructive sleep apnea syndrome and cardiovascular diseases. Semin.Thromb.Hemost., 37 280 297 .
41 - E. C. Fletcher, G. Bao, R. Li, 1999 Renin activity and blood pressure in response to chronic episodic hypoxia. Hypertension, 34 309 314 .
42 - G. E. Foster, M. J. Poulin, P. J. Hanly, 2007 Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea. Exp.Physiol, 92 51 65 .
43 - A. Y. Gasparyan, L. Ayvazyan, D. P. Mikhailidis, G. D. Kitas, 2011 Mean platelet volume: a link between thrombosis and inflammation? Curr.Pharm.Des, 17 47 58 .
44 - H. Gastaut, C. A. Tassinari, B. Duron, 1965 [Polygraphic study of diurnal and nocturnal (hypnic and respiratory) episodal manifestations of Pickwick syndrome]. Rev.Neurol. (Paris), 112 568 579 .
45 - G. Giannotti, U. Landmesser, 2007 Endothelial dysfunction as an early sign of atherosclerosis. Herz, 32 568 572 .
46 - P. H. Gjorup, L. Sadauskiene, J. Wessels, O. Nyvad, B. Strunge, E. B. Pedersen, 2007 Abnormally increased endothelin-1 in plasma during the night in obstructive sleep apnea: relation to blood pressure and severity of disease. Am.J.Hypertens., 20 44 52 .
47 - D. Gozal, L. D. Serpero, L. Kheirandish-Gozal, O. S. Capdevila, A. Khalyfa, R. Tauman, 2010 Sleep measures and morning plasma TNF-alpha levels in children with Sleep-disordered breathing. Sleep, 33 319 325 .
48 - M. Grebe, H. J. Eisele, N. Weissmann, C. Schaefer, H. Tillmanns, W. Seeger, et al. 2006 Antioxidant vitamin C improves endothelial function in obstructive sleep apnea. Am.J.Respir.Crit Care Med., 173 897 901 .
49 - F. Grimpen, P. Kanne, E. Schulz, G. Hagenah, G. Hasenfuss, S. Andreas, 2000 Endothelin-1 plasma levels are not elevated in patients with obstructive sleep apnoea. Eur.Respir.J., 15 320 325 .
50 - F. Gude, J. Rey-Garcia, C. Fernandez-Merino, L. Meijide, L. Garcia-Ortiz, C. Zamarron, et al. 2009 Serum levels of gamma-glutamyl transferase are associated with markers of nocturnal hypoxemia in a general adult population. Clin.Chim.Acta. 407 67 71
51 - T. J. Guzik, N. E. Hoch, K. A. Brown, L. A. McCann, A. Rahman, S. Dikalov, et al. 2007 Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J.Exp.Med., 204 2449 2460 .
52 - J. S. Haight, P. G. Djupesland, 2003 Nitric oxide (NO) and obstructive sleep apnea (OSA). Sleep Breath., 7 53 62 .
53 - J. P. Halcox, A. E. Donald, E. Ellins, D. R. Witte, M. J. Shipley, E. J. Brunner, et al. 2009 Endothelial function predicts progression of carotid intima-media thickness. Circulation, 119 1005 1012 .
54 - G. K. Hansson, 2005 Inflammation, atherosclerosis, and coronary artery disease. N.Engl.J.Med., 352 1685 1695 .
55 - I. A. Harsch, C. Koebnick, H. Wallaschofski, S. P. Schahin, E. G. Hahn, J. H. Ficker, et al. 2004 Resistin levels in patients with obstructive sleep apnoea syndrome--the link to subclinical inflammation? Med.Sci.Monit., 10, CR510 -CR515.
56 - I. A. Harsch, P. C. Konturek, C. Koebnick, P. P. Kuehnlein, F. S. Fuchs, S. S. Pour, et al. 2003 Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment. Eur.Respir.J., 22 251 257 .
57 - M. Hayashi, K. Fujimoto, K. Urushibata, A. Takamizawa, O. Kinoshita, K. Kubo, 2006 Hypoxia-sensitive molecules may modulate the development of atherosclerosis in sleep apnoea syndrome. Respirology., 11 24 31 .
58 - A. Hoekema, A. L. Stel, B. Stegenga, J. H. van der Hoeven, P. J. Wijkstra, M. F. van Driel, et al. 2006 Sexual Function and Obstructive Sleep Apnea-Hypopnea: A Randomized Clinical Trial Evaluating the Effects of Oral-Appliance and Continuous Positive Airway Pressure Therapy. J.Sex Med., 4 Pt 2):1153 62
59 - S. Imagawa, Y. Yamaguchi, K. Ogawa, N. Obara, N. Suzuki, M. Yamamoto, et al. 2004 Interleukin-6 and tumor necrosis factor-alpha in patients with obstructive sleep apnea-hypopnea syndrome. Respiration, 71 24 29 .
60 - M. S. Ip, K. S. Lam, C. Ho, K. W. Tsang, W. Lam, 2000 Serum leptin and vascular risk factors in obstructive sleep apnea. Chest, 118 580 586 .
61 - M. S. Ip, H. F. Tse, B. Lam, K. W. Tsang, W. K. Lam, 2004 Endothelial function in obstructive sleep apnea and response to treatment. Am.J.Respir.Crit. Care. Med., 169 348 353 .
62 - S. Isono, 2009 Obstructive sleep apnea of obese adults: pathophysiology and perioperative airway management. Anesthesiology, 110 908 921 .
63 - S. Jelic, D. J. Lederer, T. Adams, M. Padeletti, P. C. Colombo, P. H. Factor, et al. 2010 Vascular inflammation in obesity and sleep apnea. Circulation, 121 1014 1021 .
64 - N. L. Kanagy, B. R. Walker, L. D. Nelin, 2001 Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension, 37 511 515 .
65 - F. Kapsimalis, G. Varouchakis, A. Manousaki, S. Daskas, D. Nikita, M. Kryger, et al. 2008 Association of sleep apnea severity and obesity with insulin resistance, C-reactive protein, and leptin levels in male patients with obstructive sleep apnea. Lung, 186 209 217 .
66 - T. Kasai, K. Inoue, T. Kumagai, M. Kato, F. Kawana, M. Sagara, et al. 2011 Plasma pentraxin3 and arterial stiffness in men with obstructive sleep apnea. Am.J.Hypertens., 24 401 407 .
67 - B. D. Kent, S. Ryan, W. T. Mc Nicholas, 2011 Obstructive sleep apnea and inflammation: Relationship to cardiovascular co-morbidity. Respir.Physiol Neurobiol., 178 475 81 .
68 - M. Kohler, J. C. Pepperell, B. Casadei, S. Craig, N. Crosthwaite, J. R. Stradling, et al. 2008 CPAP and measures of cardiovascular risk in males with OSAS. Eur.Respir.J., 32 1488 1496 .
69 - E. Kuramoto, S. Kinami, Y. Ishida, H. Shiotani, Y. Nishimura, 2009 Continuous positive nasal airway pressure decreases levels of serum amyloid A and improves autonomic function in obstructive sleep apnea syndrome. Int.J.Cardiol., 135 338 345 .
70 - D. Lacedonia, F. G. Salerno, G. E. Carpagnano, R. Sabato, A. Depalo, M. P. Foschino-Barbaro, 2011 Effect of CPAP-therapy on bronchial and nasal inflammation in patients affected by obstructive sleep apnea syndrome. Rhinology, 49 232 237 .
71 - J. D. Lattimore, I. Wilcox, S. Nakhla, M. Langenfeld, W. Jessup, D. S. Celermajer, 2005 Repetitive hypoxia increases lipid loading in human macrophages-a potentially atherogenic effect. Atherosclerosis, 179 255 259 .
72 - L. Lavie, A. Vishnevsky, P. Lavie, 2004 Evidence for lipid peroxidation in obstructive sleep apnea. Sleep, 27 123 128 .
73 - P. Levy, J. L. Pepin, C. Arnaud, J. P. Baguet, M. Dematteis, F. Mach, 2009 Obstructive sleep apnea and atherosclerosis. Prog.Cardiovasc.Dis., 51 400 410 .
74 - A. M. Li, C. Ng, S. K. Ng, M. M. Chan, H. K. So, I. Chan, et al. 2010 Adipokines in children with obstructive sleep apnea and the effects of treatment. Chest, 137 529 535 .
75 - J. Li, M. Bosch-Marce, A. Nanayakkara, V. Savransky, S. K. Fried, G. L. Semenza, et al. 2006 Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1alpha. Physiol. Genomics, 25 450 457 .
76 - J. Li, L. N. Thorne, N. M. Punjabi, C. K. Sun, A. R. Schwartz, P. L. Smith, et al. 2005 Intermittent hypoxia induces hyperlipidemia in lean mice. Circ.Res., 97 698 706 .
77 - R. Luboshitzky, L. Lavie, Z. Shen-Orr, P. Herer, 2005 Altered luteinizing hormone and testosterone secretion in middle-aged obese men with obstructive sleep apnea. Obes.Res., 13 780 786 .
78 - M. M. Macrea, T. J. Martin, L. Zagrean, 2010 Infertility and obstructive sleep apnea: the effect of continuous positive airway pressure therapy on serum prolactin levels. Sleep Breath., 14 253 257 .
79 - S. Makino, H. Handa, K. Suzukawa, M. Fujiwara, M. Nakamura, S. Muraoka, et al. 2006 Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance. Clin.Endocrinol. (Oxf), 64 12 19 .
80 - K. Makinodan, M. Yoshikawa, A. Fukuoka, S. Tamaki, N. Koyama, M. Yamauchi, et al. 2008 Effect of serum leptin levels on hypercapnic ventilatory response in obstructive sleep apnea. Respiration, 75 257 264 .
81 - G. Malakasioti, E. Alexopoulos, C. Befani, K. Tanou, V. Varlami, D. Ziogas, et al. 2011 Oxidative stress and inflammatory markers in the exhaled breath condensate of children with OSA. Sleep Breath..
82 - J. M. Marin, S. J. Carrizo, E. Vicente, A. G. Agusti, 2005 Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet, 365 1046 1053 .
83 - O. Marrone, A. Salvaggio, A. L. Bue, A. Bonanno, L. Riccobono, G. Insalaco, et al. 2011 Blood Pressure Changes After Automatic and Fixed CPAP in Obstructive Sleep Apnea: Relationship with Nocturnal Sympathetic Activity. Clin.Exp.Hypertens., 33 373 80 .
84 - O. Marrone, A. Salvaggio, M. Gioia, A. Bonanno, M. Profita, L. Riccobono, et al. 2008 Reticulocytes in untreated obstructive sleep apnoea. Monaldi Arch.Chest, Dis., 69 107 113 .
85 - R. E. Maser, M. J. Lenhard, A. A. Rizzo, A. A. Vasile, 2008 Continuous positive airway pressure therapy improves cardiovascular autonomic function for persons with sleep-disordered breathing. Chest, 133 86 91 .
86 - B. Masserini, P. S. Morpurgo, F. Donadio, C. Baldessari, R. Bossi, P. Beck-Peccoz, et al. 2006 Reduced levels of adiponectin in sleep apnea syndrome. J.Endocrinol.Invest, 29 700 705 .
87 - N. McArdle, D. Hillman, L. Beilin, G. Watts, 2007 Metabolic risk factors for vascular disease in obstructive sleep apnea: a matched controlled study. Am.J.Respir.Crit. Care. Med., 175 190 195 .
88 - C. Meisinger, M. Heier, H. Loewel, 2005 Sleep disturbance as a predictor of type 2 diabetes mellitus in men and women from the general population. Diabetologia, 48 235 241 .
89 - N. Meston, R. J. Davies, R. Mullins, C. Jenkinson, J. A. Wass, J. R. Stradling, 2003 Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea. J.Intern.Med., 254 447 454 .
90 - D. S. Moller, P. Lind, B. Strunge, E. B. Pedersen, 2003 Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnea. Am.J.Hypertens., 16 274 280 .
91 - J. M. Mullington, N. S. Simpson, H. K. Meier-Ewert, M. Haack, 2010 Sleep loss and inflammation. Best.Pract.Res.Clin.Endocrinol.Metab, 24 775 784 .
92 - D. Nair, E. A. Dayyat, S. X. Zhang, Y. Wang, D. Gozal, 2011 Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS.One., 6, e19847 .
93 - Y. Nakagawa, K. Kishida, S. Kihara, R. Yoshida, T. Funahashi, I. Shimomura, 2011 Nocturnal falls of adiponectin levels in sleep apnea with abdominal obesity and impact of hypoxia-induced dysregulated adiponectin production in obese murine mesenteric adipose tissue. J.Atheroscler.Thromb., 18 240 247 .
94 - P. Nestel, 2003 Metabolic syndrome: multiple candidate genes, multiple environmental factors--multiple syndromes? Int.J.Clin.Pract.Suppl, 3 9 .
95 - A. B. Newman, F. J. Nieto, U. Guidry, B. K. Lind, S. Redline, T. G. Pickering, et al. 2001 Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am.J.Epidemiol., 154 50 59 .
96 - F. J. Nieto, D. M. Herrington, S. Redline, E. J. Benjamin, J. A. Robbins, 2004 Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. Am.J.Respir.Crit Care Med., 169 354 360 .
97 - C. P. O’Donnell, C. G. Tankersley, V. P. Polotsky, A. R. Schwartz, P. L. Smith, 2000 Leptin, obesity, and respiratory function. Respir.Physiol, 119 163 170 .
98 - T. Oga, K. Chin, A. Tabuchi, M. Kawato, T. Morimoto, K. Takahashi, et al. 2009 Effects of obstructive sleep apnea with intermittent hypoxia on platelet aggregability. J.Atheroscler.Thromb., 16 862 869 .
99 - E. Ohga, T. Nagase, T. Tomita, S. Teramoto, T. Matsuse, H. Katayama, et al. 1999 Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J.Appl.Physiol, 87 10 14 .
100 - E. Ohga, T. Tomita, H. Wada, H. Yamamoto, T. Nagase, Y. Ouchi, 2003 Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J.Appl.Physiol, 94 179 184 .
101 - O. Oldenburg, B. Lamp, L. Faber, H. Teschler, D. Horstkotte, V. Topfer, 2007 Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur.J.Heart Fail., 9 251 257 .
102 - M. Othman, S. P. Gordon, S. Iscoe, 2010 Repeated inspiratory occlusions in anesthetized rats acutely increase blood coagulability as assessed by thromboelastography. Respir.Physiol, Neurobiol., 171 61 66 .
103 - L. Ozturk, M. Unal, L. Tamer, F. Celikoglu, 2003 The association of the severity of obstructive sleep apnea with plasma leptin levels. Arch.Otolaryngol.Head Neck Surg., 129 538 540 .
104 - A. M. Park, H. Nagase, S. V. Kumar, Y. J. Suzuki, 2007 Effects of intermittent hypoxia on the heart. Antioxid.Redox.Signal., 9 723 729 .
105 - S. R. Patel, A. Malhotra, D. P. White, D. J. Gottlieb, F. B. Hu, 2006 Association between reduced sleep and weight gain in women. Am.J.Epidemiol., 164 947 954 .
106 - S. R. Patel, L. J. Palmer, E. K. Larkin, N. S. Jenny, D. P. White, S. Redline, 2004 Relationship between obstructive sleep apnea and diurnal leptin rhythms. Sleep, 27 235 239 .
107 - S. R. Patel, X. Zhu, A. Storfer-Isser, R. Mehra, N. S. Jenny, R. Tracy, et al. 2009 Sleep duration and biomarkers of inflammation. Sleep, 32 200 204 .
108 - B. T. Patt, D. Jarjoura, D. N. Haddad, C. K. Sen, S. Roy, N. A. Flavahan, et al. 2010 Endothelial dysfunction in the microcirculation of patients with obstructive sleep apnea. Am.J.Respir.Crit. Care. Med., 182 1540 1545 .
109 - N. Peled, M. Kassirer, M. R. Kramer, O. Rogowski, D. Shlomi, B. Fox, et al. 2008 Increased erythrocyte adhesiveness and aggregation in obstructive sleep apnea syndrome. Thromb.Res., 121 631 636 .
110 - B. G. Phillips, M. Kato, K. Narkiewicz, I. Choe, V. K. Somers, 2000 Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am.J.Physiol. Heart. Circ.Physiol., 279, H234 -H237.
111 - B. G. Phillips, K. Narkiewicz, C. A. Pesek, W. G. Haynes, M. E. Dyken, V. K. Somers, 1999 Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J.Hypertens., 17 61 66 .
112 - P. R. Phipps, E. Starritt, I. Caterson, R. R. Grunstein, 2002 Association of serum leptin with hypoventilation in human obesity. Thorax, 57 75 76 .
113 - F. Pichel, C. Zamarron, F. Magan, C. F. del , R. Alvarez-Sala, J. R. Suarez, 2004 Health-related quality of life in patients with obstructive sleep apnea: effects of long-term positive airway pressure treatment. Respir.Med., 98 968 976 .
114 - L. Piemonti, G. Calori, A. Mercalli, G. Lattuada, P. Monti, M. P. Garancini, et al. 2003 Fasting plasma leptin, tumor necrosis factor-alpha receptor 2, and monocyte chemoattracting protein 1 concentration in a population of glucose-tolerant and glucose-intolerant women: impact on cardiovascular mortality. Diabetes Care, 26 2883 2889 .
115 - U. Pohl, R. Busse, 1989 Differential vascular sensitivity to luminally and adventitially applied endothelin-1. J.Cardiovasc.Pharmacol., 13 Suppl 5, S188 -S190.
116 - V. Y. Polotsky, J. Li, N. M. Punjabi, A. E. Rubin, P. L. Smith, A. R. Schwartz, et al. 2003 Intermittent hypoxia increases insulin resistance in genetically obese mice. J.Physiol, 552 253 264 .
117 - N. R. Prabhakar, R. D. Fields, T. Baker, E. C. Fletcher, 2001 Intermittent hypoxia: cell to system. Am.J.Physiol. Lung. Cell. Mol.Physiol., 281, L524 -L528.
118 - A. M. Prentice, 2006 The emerging epidemic of obesity in developing countries. Int.J.Epidemiol., 35 93 99 .
119 - K. Proulx, D. Richard, C. D. Walker, 2002 Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. Endocrinology, 143 4683 4692 .
120 - N. M. Punjabi, B. A. Beamer, 2007 C-reactive protein is associated with sleep disordered breathing independent of adiposity. Sleep, 30 29 34 .
121 - J. S. Querido, A. W. Sheel, R. Cheema, E. S. Van , A. T. Mulgrew, N. T. Ayas, 2011 Effects of 10 days of modest intermittent hypoxia on circulating measures of inflammation in healthy humans. Sleep Breath. Jul 9. [Epub ahead of print]
122 - A. Quercioli, F. Mach, F. Montecucco, 2010 Inflammation accelerates atherosclerotic processes in obstructive sleep apnea syndrome (OSAS). Sleep Breath., 14 261 269 .
123 - S. Rahangdale, S. Y. Yeh, V. Novack, K. Stevenson, M. R. Barnard, M. I. Furman, et al. 2011 The influence of intermittent hypoxemia on platelet activation in obese patients with obstructive sleep apnea. J Clin Sleep Med., 15;7 172 8
124 - G. M. Reaven, 2005 Insulin resistance, the insulin resistance syndrome, and cardiovascular disease. Panminerva Med., 47 201 210 .
125 - W. H. Reinhart, J. Oswald, R. Walter, M. Kuhn, 2002 Blood viscosity and platelet function in patients with obstructive sleep apnea syndrome treated with nasal continuous positive airway pressure. Clin.Hemorheol.Microcirc., 27 201 207 .
126 - J. E. Remmers, W. J. de Groot, E. K. Sauerland, A. M. Anch, 1978 Pathogenesis of upper airway occlusion during sleep. J.Appl.Physiol, 44 931 938 .
127 - H. E. Resnick, K. Jones, G. Ruotolo, A. K. Jain, J. Henderson, W. Lu, et al. 2003 Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic american indians: the Strong Heart Study. Diabetes Care, 26 861 867 .
128 - O. Resta, P. Bonfitto, R. Sabato, P. G. De, M. P. Barbaro, 2004 Prevalence of obstructive sleep apnoea in a sample of obese women: effect of menopause. Diabetes Nutr.Metab., 17 296 303 .
129 - T. Ronti, G. Lupattelli, E. Mannarino, 2006 The endocrine function of adipose tissue: an update. Clin.Endocrinol. (Oxf), 64 355 365 .
130 - R. Ross, 1999 Atherosclerosis--an inflammatory disease. N.Engl.J.Med., 340 115 126 .
131 - G. P. Rossi, G. Pitter, 2006 Genetic variation in the endothelin system: do polymorphisms affect the therapeutic strategies? Ann.N.Y.Acad.Sci., 1069 34 50 .
132 - S. Ryan, C. T. Taylor, W. T. Mc Nicholas, 2005 Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation, 112 2660 2667 .
133 - S. Saarelainen, J. Hasan, 2000 Circulating endothelin-1 and obstructive sleep apnoea. Eur.Respir.J., 16 794 795 .
134 - B. M. Sanner, P. Kollhosser, N. Buechner, W. Zidek, M. Tepel, 2004 Influence of treatment on leptin levels in patients with obstructive sleep apnoea. Eur.Respir.J., 23 601 604 .
135 - R. Schulz, S. Mahmoudi, K. Hattar, U. Sibelius, H. Olschewski, K. Mayer, et al. 2000 Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am.J.Respir.Crit. Care. Med., 162 566 570 .
136 - A. R. Schwartz, S. P. Patil, A. M. Laffan, V. Polotsky, H. Schneider, P. L. Smith, 2008 Obesity and obstructive sleep apnea: pathogenic mechanisms and therapeutic approaches. Proc.Am.Thorac.Soc., 5 185 192 .
137 - E. Shahar, S. Redline, T. Young, L. L. Boland, C. M. Baldwin, F. J. Nieto, et al. 2003 Hormone replacement therapy and sleep-disordered breathing. Am.J.Respir.Crit. Care. Med., 167 1186 1192 .
138 - K. Shimizu, K. Chin, T. Nakamura, H. Masuzaki, Y. Ogawa, R. Hosokawa, et al. 2002 Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome. Thorax, 57 429 434 .
139 - R. Shimura, K. Tatsumi, A. Nakamura, Y. Kasahara, N. Tanabe, Y. Takiguchi, et al. 2005 Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome. Chest, 127 543 549 .
140 - E. Shinohara, S. Kihara, S. Yamashita, M. Yamane, M. Nishida, T. Arai, et al. 1997 Visceral fat accumulation as an important risk factor for obstructive sleep apnoea syndrome in obese subjects. J.Intern.Med., 241 11 18 .
141 - D. Shitrit, N. Peled, A. B. Shitrit, S. Meidan, D. Bendayan, G. Sahar, et al. 2005 An association between oxygen desaturation and D-dimer in patients with obstructive sleep apnea syndrome. Thromb.Haemost., 94 544 547 .
142 - S. Snitker, R. E. Pratley, M. Nicolson, P. A. Tataranni, E. Ravussin, 1997 Relationship between muscle sympathetic nerve activity and plasma leptin concentration. Obes.Res., 5 338 340 .
143 - V. K. Somers, A. L. Mark, F. M. Abboud, 1988 Sympathetic activation by hypoxia and hypercapnia--implications for sleep apnea. Clin.Exp.Hypertens.A, 10 Suppl 1 413 422 .
144 - K. Spruyt, C. O. Sans, L. D. Serpero, L. Kheirandish-Gozal, D. Gozal, 2010 Dietary and physical activity patterns in children with obstructive sleep apnea. J.Pediatr., 156 724 30 .
145 - P. Steiropoulos, I. Kotsianidis, E. Nena, V. Tsara, E. Gounari, O. Hatzizisi, et al. 2009 Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. Sleep, 32 537 543 .
146 - A. Svatikova, R. Wolk, A. S. Shamsuzzaman, T. Kara, E. J. Olson, V. K. Somers, 2003 Serum amyloid a in obstructive sleep apnea. Circulation, 108 1451 1454 .
147 - S. Taheri, D. Austin, L. Lin, F. J. Nieto, T. Young, E. Mignot, 2007 Correlates of serum C-reactive protein (CRP)--no association with sleep duration or sleep disordered breathing. Sleep, 30 991 996 .
148 - R. Tamisier, J. L. Pepin, J. Remy, J. P. Baguet, J. A. Taylor, J. W. Weiss, et al. 2011 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur.Respir.J., 37 119 128 .
149 - E. Tasali, F. Chapotot, R. Leproult, H. Whitmore, D. A. Ehrmann, 2011 Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome. J.Clin.Endocrinol.Metab, 96 365 374 .
150 - F. Tassone, F. Lanfranco, L. Gianotti, S. Pivetti, F. Navone, R. Rossetto, et al. 2003 Obstructive sleep apnoea syndrome impairs insulin sensitivity independently of anthropometric variables. Clin.Endocrinol. (Oxf), 59 374 379 .
151 - K. Tatsumi, Y. Kasahara, K. Kurosu, N. Tanabe, Y. Takiguchi, T. Kuriyama, 2005 Sleep oxygen desaturation and circulating leptin in obstructive sleep apnea-hypopnea syndrome. Chest, 127 716 721 .
152 - P. E. Teloken, E. B. Smith, C. Lodowsky, T. Freedom, J. P. Mulhall, 2006 Defining association between sleep apnea syndrome and erectile dysfunction. Urology, 67 1033 1037 .
153 - J. Theorell-Haglow, C. Berne, C. Janson, E. Lindberg, 2011 The role of obstructive sleep apnea in metabolic syndrome: a population-based study in women. Sleep Med., 12 329 334 .
154 - S. Teramoto, H. Kume, H. Yamamoto, T. Ishii, A. Miyashita, T. Matsuse, et al. 2003 Effects of oxygen administration on the circulating vascular endothelial growth factor (VEGF) levels in patients with obstructive sleep apnea syndrome. Intern.Med., 42 681 685 .
155 - J. Teran-Santos, A. Jimenez-Gomez, J. Cordero-Guevara, 1999 The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N.Engl.J.Med., 340 847 851 .
156 - R. Tkacova, Z. Dorkova, A. Molcanyiova, Z. Radikova, I. Klimes, I. Tkac, 2008 Cardiovascular risk and insulin resistance in patients with obstructive sleep apnea. Med.Sci.Monit., 14, CR438 -CR444.
157 - F. Tokuda, Y. Sando, H. Matsui, H. Koike, T. Yokoyama, 2008 Serum levels of adipocytokines, adiponectin and leptin, in patients with obstructive sleep apnea syndrome. Intern.Med., 47 1843 1849 .
158 - W. Trzepizur, F. Gagnadoux, P. Abraham, P. Rousseau, N. Meslier, J. L. Saumet, et al. 2009 Microvascular endothelial function in obstructive sleep apnea: Impact of continuous positive airway pressure and mandibular advancement. Sleep Med., 10 746 752 .
159 - M. Tsaoussoglou, E. O. Bixler, S. Calhoun, G. P. Chrousos, K. Sauder, A. N. Vgontzas, 2010 Sleep-disordered breathing in obese children is associated with prevalent excessive daytime sleepiness, inflammation, and metabolic abnormalities. J.Clin.Endocrinol.Metab, 95 143 150 .
160 - C. T. Ulukavak, O. Kokturk, N. Bukan, A. Bilgihan, 2005 Leptin and ghrelin levels in patients with obstructive sleep apnea syndrome. Respiration, 72 395 401 .
161 - E. Varol, O. Ozturk, H. Yucel, T. Gonca, M. Has, A. Dogan, et al. 2011 The effects of continuous positive airway pressure therapy on mean platelet volume in patients with obstructive sleep apnea. Platelets. 22 552 6
162 - E. Vatansever, E. Surmen-Gur, A. Ursavas, M. Karadag, 2010 Obstructive sleep apnea causes oxidative damage to plasma lipids and proteins and decreases adiponectin levels. Sleep Breath. 15 275 82
163 - K. R. von, J. E. Dimsdale, 2003 Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease. Chest, 124 1956 1967 .
164 - K. R. von, J. S. Loredo, S. Ancoli-Israel, J. E. Dimsdale, 2006 Association between sleep apnea severity and blood coagulability: Treatment effects of nasal continuous positive airway pressure. Sleep Breath., 10 139 146 .
165 - K. R. von, J. S. Loredo, S. Ancoli-Israel, P. J. Mills, L. Natarajan, J. E. Dimsdale, 2007 Association between polysomnographic measures of disrupted sleep and prothrombotic factors. Chest, 131 733 739 .
166 - K. R. von, J. S. Loredo, F. L. Powell, K. A. Adler, J. E. Dimsdale, 2005 Short-term isocapnic hypoxia and coagulation activation in patients with sleep apnea. Clin.Hemorheol.Microcirc., 33 369 377 .
167 - J. Wesstrom, J. Ulfberg, S. Nilsson, 2005 Sleep apnea and hormone replacement therapy: a pilot study and a literature review. Acta Obstet.Gynecol.Scand., 84 54 57 .
168 - I. Wilcox, S. G. McNamara, F. L. Collins, R. R. Grunstein, C. E. Sullivan, 1998 "Syndrome Z": the interaction of sleep apnoea, vascular risk factors and heart disease. Thorax, 53 Suppl 3, S25 -S28.
169 - E. Wysocka, S. Cofta, M. Cymerys, J. Gozdzik, L. Torlinski, H. Batura-Gabryel, 2008 The impact of the sleep apnea syndrome on oxidant-antioxidant balance in the blood of overweight and obese patients. J.Physiol Pharmacol., 59 Suppl 6 761 769 .
170 - E. Wysocka, S. Cofta, S. Dziegielewska, J. Gozdzik, L. Torlinski, H. Batura-Gabryel, 2009 Adipocytokines in sleep apnea syndrome. Eur.J.Med.Res., 14 Suppl 4 255 258 .
171 - Y. Yamamoto, S. Fujiuchi, M. Hiramatsu, Y. Nishigaki, A. Takeda, Y. Fujita, et al. 2008 Resistin is closely related to systemic inflammation in obstructive sleep apnea. Respiration, 76 377 385 .
172 - T. Yokoe, K. Minoguchi, H. Matsuo, N. Oda, H. Minoguchi, G. Yoshino, et al. 2003 Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation, 107 1129 1134 .
173 - T. Young, M. Palta, J. Dempsey, J. Skatrud, S. Weber, S. Badr, 1993 The occurrence of sleep-disordered breathing among middle-aged adults. N.Engl.J.Med., 328 1230 1235 .
174 - H. J. Yu, B. R. Lin, H. S. Lee, C. T. Shun, C. C. Yang, T. Y. Lai, et al. 2005 Sympathetic vesicovascular reflex induced by acute urinary retention evokes proinflammatory and proapoptotic injury in rat liver. Am.J.Physiol Renal Physiol, 288, F1005 -F1014.
175 - C. Zamarron, P. V. Garcia, A. Riveiro, 2008a Obstructive sleep apnea syndrome is a systemic disease. Current evidence. Eur.J.Intern.Med., 19 390 398 .
176 - C. Zamarron, J. Ricoy, A. Riveiro, F. Gude, 2008b Plasminogen activator inhibitor-1 in obstructive sleep apnea patients with and without hypertension. Lung, 186 151 156 .
177 - C. Zamarron-Sanz, J. Ricoy-Galbaldon, F. Gude-Sampedro, A. Riveiro-Riveiro, 2006 Plasma levels of vascular endothelial markers in obstructive sleep apnea. Arch.Med.Res., 37 552 555 .
178 - X. L. Zhang, K. S. Yin, H. Wang, S. Su, 2006 Serum adiponectin levels in adult male patients with obstructive sleep apnea hypopnea syndrome. Respiration, 73 73 77 .
179 - B. K. Zouaoui, M. Guillaume, C. Henuzet, P. Delree, P. Cauchie, C. Remacle, et al. 2006 Fibrinolysis and cardiovascular risk factors: association with fibrinogen, lipids, and monocyte count. Eur.J.Intern.Med., 17 102 108 .