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Themed Issue Papers |
Departments of 1 Physiology and Biophysics2 Medicine3 Clinical Neurosciences, Faculty of Medicine4 Faculty of Kinesiology, University of Calgary, Heritage Medical Research Building, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1
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(Received 5 September 2006;
accepted after revision 15 November 2006; first published online 23 November 2006)
Corresponding author P. J. Hanly: Department of Medicine, Faculty of Medicine, University of Calgary, Health Sciences Center, Room 1421, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1. Email: phanly{at}ucalgary.ca
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Introduction |
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TopAbstractIntroductionReferences |
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Intermittent hypoxia has been shown to affect the control of breathing (Gozal & Gozal, 2001; Mitchell et al. 2001; Prabhakar, 2001; Mitchell & Johnson, 2003; Morris et al. 2003), the cardiovascular system (Tahawi et al. 2001; Phillips et al. 2004, 2005) and the autonomic nervous system (Morgan et al. 1995; Yasuma & Hayano, 2000; Cutler et al. 2004b). Recent initiatives in OSA research have included the development of experimental animal and human models of acute and chronic intermittent hypoxia to evaluate potential mechanisms for the association between OSA and vascular disease. The objectives of this review are to outline some of these basic mechanisms and to compare the results from studies involving OSA patients with those from experimental models of intermittent hypoxia.
Obstructive sleep apnoea
Obstructive sleep apnoea is a chronic medical condition characterized by repeated episodes of apnoea during sleep (Young et al. 2002). Each apnoea characteristically lasts about 20 s and is terminated by an abrupt restoration of ventilation. Obstructive sleep apnoea occurs in 2% of middle-aged women and 4% of middle-aged men in the general population (Young et al. 1993) and its prevalence is much higher in specific high-risk patient groups, such as those with congestive heart failure (40%; Sin et al. 1999), end-stage kidney disease (50%; Hanly & Pierratos, 2001) and stroke (60%; Yaggi et al. 2005).
Apnoeas occur because of recurrent closure of the upper airway during sleep (Guilleminault et al. 1976). In the majority of patients, the pathogenesis of OSA involves both a structural and a functional abnormality of the pharynx. This has been extensively reviewed elsewhere (Fogel et al. 2004; Ryan & Bradley, 2005; White, 2005) and is not discussed here. However, it is important to stress that each cycle of apnoea and resumption of ventilation is accompanied by arterial oxyhaemoglobin desaturation and resaturation. Since most individuals with OSA typically resaturate their haemoglobin into the normal range, this exposes them to intermittent hypoxia throughout the night. The development of intermittent hypoxia and the physiological responses this evokes are thought to be responsible for the subsequent clinical manifestations of vascular disease (Lavie, 2005).
Obstructive sleep apnoea presents clinically with complaints of excessive daytime sleepiness, fatigue, irritability and deficits in attention and memory, and with nocturnal symptoms which may include a history of snoring, apnoeas, choking and frequent awakenings (Stierer & Punjabi, 2005). The diagnosis and severity of OSA are assessed by overnight, attended polysomnography, which involves the continuous recording of sleep and breathing. Sleep stages are determined from the electroencephalogram, the electro-oculogram and a submental electromyogram. Breathing is assessed by measuring respiratory effort (typically by monitoring movement of the chest and abdomen by inductance plethysmography), nasal airflow and SaO2. Additional monitoring includes snoring, body position and electrocardiography. Figure 1A shows a 2 min excerpt from a polysomnogram of a patient with OSA. There are standardized criteria to score an apnoea and hypopnoea, from which the apnoea/hypopnoea index (AHI) is derived (American Academy of Sleep Medicine, 1999). An apnoea is defined as the absence of airflow for 10 s or more. An hypopnoea is defined as a 50% reduction in airflow for 10 s or more or a marked reduction in airflow associated with an arousal and/or a 4% decrease in SaO2. Apnoeas are classified as obstructive if there is evidence of continued effort to breathe, such as paradoxical movement of the chest wall and abdomen, and central if there is a transient loss or reduction of respiratory effort. The AHI indicates OSA severity and is defined as the number of apnoeas and hypopnoeas per hour of sleep. Obstructive sleep apnoea is typically defined as an AHI of 5 or more per hour (Stierer & Punjabi, 2005) and is further classified as mild (AHI 5–15), moderate (AHI 16–30) and severe (AHI > 30; American Academy of Sleep Medicine, 1999).
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Obstructive sleep apnoea and cardiovascular disease
The demonstration of strong epidemiological associations between OSA and vascular disease has led to the consensus that OSA is a risk factor for the development of hypertension (Morrell et al. 2000; Nieto et al. 2000; Peppard et al. 2000), myocardial infarction (Hung et al. 1990; Shahar et al. 2001) and stroke (Arzt et al. 2005; Yaggi et al. 2005). Data from the Wisconsin Sleep Cohort Study, which investigated a community-based population, was analysed prospectively for the association between OSA and hypertension (Peppard et al. 2000). The investigators found a dose–response relationship between OSA at baseline and the prevalence of hypertension four years later, which was independent of confounding factors such as weight, age, gender, and the consumption of alcohol and nicotine. Obstructive sleep apnoea is also associated with an increased risk for myocardial infarction. In a cross-sectional analysis of the Sleep Heart Health Study, the association between OSA and self-reported myocardial infarction was assessed in 6424 individuals from the general population (Shahar et al. 2001). In this study, the relative odds for heart failure, adjusted for confounding factors, were significantly elevated in patients with OSA (2.38), indicating an elevated risk for myocardial infarction. The odds ratios for coronary heart disease (1.58) and stroke (1.27) were also significantly increased. Finally, in a cross-sectional analysis of 1475 subjects from the general population, those subjects with an AHI greater than 20 had increased odds for stroke compared with those without OSA after adjustment for known confounding factors (Arzt et al. 2005). Yaggi et al. (2005) found similar results in a group of 1022 patients referred to a sleep clinic for assessment of sleep apnoea (697 had OSA). Obstructive sleep apnoea significantly increased the risk of stroke independently of other risk factors, including hypertension.
The strong relationship between OSA and cardiovascular disease has important clinical and public health relevance. The increased prevalence of hypertension, myocardial infarction and stroke increases both cardiovascular morbidity and mortality and the demand on healthcare resources. Observational cohort studies indicate that untreated patients with OSA have an increased risk of fatal and non-fatal cardiovascular events (Marin et al. 2005), a heightened risk of sudden cardiac death during the sleeping hours (Gami et al. 2005), and an increased risk of stroke or death from any cause (Yaggi et al. 2005). Effective treatment of OSA with CPAP may reduce this risk of cardiovascular disease (Marin et al. 2005).
Experimental models of intermittent hypoxia
Models of intermittent hypoxia have been developed to mimic the pattern of hypoxaemia experienced by patients with OSA. A model of intermittent hypoxia that seeks to mimic OSA must emulate its characteristics. These were briefly described above and are described here in further detail. Patients with OSA have repeated apnoeas throughout the night, with each apnoea lasting a minimum of 10 s. However, the average duration of apnoea in a large sleep clinic population is about 20 s (O'Connor et al. 2000). Patients with moderate-to-severe OSA have an AHI greater than 30 events per hour of sleep (American Academy of Sleep Medicine, 1999). The degree of associated hypoxia varies considerably between patients, but each apnoea is associated with arterial oxyhaemoglobin desaturation of at least 4% followed by resaturation to normal levels (American Academy of Sleep Medicine, 1999). The different models of intermittent hypoxia that have been used in animals and humans are discussed below. The considerable variation between them is summarized in Table 1.
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Human models. Models of intermittent hypoxia in healthy human subjects can be separated into short-term and chronic. Short-term intermittent hypoxia models generally use 30 s periods of hypoxia or voluntary apnoeas interspersed with normoxia for 20–60 min (Xie et al. 2000; Cutler et al. 2004a; Tamisier et al. 2005). Models of chronic intermittent hypoxia have exposed individuals to an hour of intermittent hypoxia (5 min hypoxia alternating with 5 min normoxia) daily for 2 weeks (Foster et al. 2005). In addition, some studies control the level of carbon dioxide (Foster et al. 2005), whereas others do not (Tamisier et al. 2005).
Comparison of animal and human models of intermittent hypoxia. Animal models of intermittent hypoxia generally mimic OSA better than human models for several reasons. Since the animals studied are smaller than humans, changes in SaO2 are more rapid and of greater magnitude. Healthy humans require longer periods of hypoxia to induce arterial oxyhaemoglobin desaturation and thus require longer cycling time. Animals can be safely exposed to chronic intermittent hypoxia without much supervision, while exposing humans to chronic intermittent hypoxia is much more labour intensive. Although data from experimental models of intermittent hypoxia appear to demonstrate similar physiological responses to those seen in OSA patients, these models are limited by the fact that many do not incorporate monitoring of sleep, are not accompanied by apnoea or sleep fragmentation, and do not include exposure to hypercapnia. Exposure to hypercapnia during intermittent hypoxia may not be critical, because the effect of intermittent hypoxia on diurnal blood pressure in rats is similar regardless of whether the level of carbon dioxide is increased or not (Fletcher et al. 1995). However, hypercapnic hypoxia does lead to greater sympathetic activation than hypocapnic hypoxia (Tamisier et al. 2004). Despite these limitations, intermittent hypoxia models are a useful tool for studying the progression of cardiovascular disease in OSA.
Intermittent hypoxia and vasomotor function
Intermittent hypoxia alters vasomotor function. Specifically, chronic exposure to intermittent hypoxia attenuates vasodilator function and, in most cases (but not all), vasoconstrictor function is enhanced. The response to short-term intermittent hypoxia has not been studied in detail. The balance between vasodilatation and vasoconstriction is physiologically important because it determines blood flow to metabolically active tissues, which has implications for the pathogenesis of hypertension and ischaemia of the heart and brain.
Vasoconstrictor function and the sympathetic nervous system
Intermittent hypoxia is hypothesized to stimulate chemoreceptor activity, increasing sympathetic nervous system activity, which leads to vasoconstriction and, potentially, systemic hypertension. Figure 2 shows a theoretical schematic diagram that outlines the pathways by which intermittent hypoxia may lead to hypertension and should be viewed as a supplement to this section. Since sympathetic nervous system activity remains elevated after removal of hypoxia (Xie et al. 2001), it has been hypothesized that intermittent hypoxia ‘ramps up’ sympathetic activity and increases sympathetic responsiveness to subsequent bouts of hypoxia (Greenberg et al. 1999; Cutler et al. 2004b). Elevated sympathetic nervous system activity results in activation of vascular smooth muscle, leading to vasoconstriction and elevated systemic blood pressure (Fletcher et al. 2002). Furthermore, elevated sympathetic nervous system activity is thought to upregulate the production of angiotensin II by stimulating the production of renin in the kidney (Fletcher et al. 2002). Angiotensin II is a potent vasoconstrictor which is important in the regulation of systemic blood pressure. Other possibilities leading to altered vasoconstrictor function and systemic hypertension include baroreflex impairment (Cortelli et al. 1994; Lai et al. 2006) and increased production of the vasoconstrictor endothelin-1 (Phillips et al. 1999).
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- and ß2-adrenergic vascular responses (Grote et al. 2000), thus suggesting a functional downregulation of vascular sympathoadrenergic receptors. The renin–angiotensin system is highly involved in controlling systemic blood pressure. Renin is produced in the kidneys and converts angiotensinogen to angiotensin I, which is then converted to the vasoactive mediator angiotensin II by angiotensin-converting enzyme (Perazella & Setaro, 2003). Circulating angiotensin II has two effects: (a) it causes vasoconstriction; and (b) it stimulates the adrenal cortex to secrete aldosterone (Perazella & Setaro, 2003). Aldosterone decreases sodium excretion, causing water retention, and is therefore important in the control of blood volume and blood pressure (Perazella & Setaro, 2003). The vasoconstrictor response to angiotensin II is increased in patients with OSA (Fig. 2) and is likely to contribute to the secondary hypertension observed in approximately 50% of OSA patients (Millman et al. 1991; Kraiczi et al. 2000).
Moller et al. (2003) measured 24 h blood pressure and the plasma concentrations of angiotensin II and aldosterone in a group of patients with OSA and in healthy controls. Patients with OSA had elevated diurnal and nocturnal blood pressure and also elevated plasma levels of angiotensin II and aldosterone. Therapy with CPAP reduced blood pressure and was associated with a decrease in the activity of the renin–angiotensin system. However, the results from this study should be interpreted with caution because control subjects were not carefully matched for body mass index and obesity. Since obesity is a risk factor for hypertension, this could have confounded interpretation of the results. In addition, increased angiotensin II concentration in OSA patients could have resulted from comorbid hypertension rather than OSA. As indicated above, interestingly, vasoconstrictor sensitivity to angiotensin II is enhanced in patients with OSA (Kraiczi et al. 2000). During infusion of angiotensin II, mean forearm conductance was 40% lower in OSA patients than in the control subjects (Kraiczi et al. 2000).
Another possible mechanism leading to altered vasoconstrictor function, which is shown in Fig. 2, involves endothelin-1, a vasoconstrictive neuropeptide which is produced by endothelin-converting enzyme from the precursor peptide, big endothelin-1 (Greenberg et al. 1992). Endothelin-1 is produced in vascular endothelial cells in response to hypoxia and sheer stress, and the cleavage of endothelin-1 from big endothelin is inhibited by NO (Greenberg et al. 1992; Marasciulo et al. 2006). Since intermittent hypoxia increases sheer stress and reduces NO bioavailability, this may be responsible for increased endothelin-1 production. However, it is not fully understood how production of endothelin-1 is upregulated (Phillips et al. 1999). Subsequent studies suggest that plasma endothelin-1 is not elevated in OSA patients but that big endothelin-1 is elevated, and that it is reduced following CPAP therapy (Grimpen et al. 2000; Jordan et al. 2005). Further study is required to clarify these inconsistencies.
Human models.
Healthy human models of chronic intermittent hypoxia have not yet been used to investigate the effects of intermittent hypoxia on MSNA, plasma catecholamines, or - and ß2-adrenergic vascular responses, nor have they been used to investigate the effects of intermittent hypoxia on the renin–angiotensin system or on endothelin-1-mediated vasoconstriction. However, changes in MSNA following short-term intermittent hypoxia and acute hypoxia have been extensively studied.
Twenty minutes of sustained hypoxia and hypercapnia [SaO2, 80% and end-tidal partial pressure of CO2 (PET,CO2), +5 mmHg] in healthy, awake humans caused a 220% increase in MSNA, which persisted following removal of the stimulus (Morgan et al. 1995). This important finding has implications for the pathogenesis of chronically elevated sympathetic nervous system activity that accompanies OSA and has provided the basis for subsequent studies. Xie et al. (2000) determined that intermittent hypoxia and hypercapnia had a similar effect. Twenty minutes of intermittent hypoxia–hypercapnia [20 s hypoxia–hypercapnia (SaO2, 80% and PET,CO2, +5 mmHg) alternating with 40 s of normoxia) led to a 175% increase in MSNA, which remained 150% above baseline 20 min following the end of the intermittent hypoxia–hypercapnia protocol. In order to determine the relative contributions of hypoxia and hypercapnia to the development of persistent sympathoexcitation, an additional study was done in which healthy humans were exposed to 20 min of sustained hypoxia and hypercapnia separately (Xie et al. 2001). Hypoxia elicited prolonged sympathetic activation even after removal of the stimulus, but hypercapnia did not.
Cutler et al. (2004a,b) used a model of intermittent hypoxia, which was induced by voluntary apnoea (1 x 30 s apnoea per minute, for 20 min), to determine whether the cessation of breathing is important in prolonged sympathetic activation. Their results indicated that MSNA was significantly elevated for up to 180 min following the end of intermittent hypoxia. This was found for exposure to 20 min of hypercapnic hypoxia and isocapnic hypoxia (no apnoeas), and suggests that hypoxia is the primary mediator of this response. Leuenberger et al. (2005) also found sustained sympathetic activation and a transient elevation of blood pressure following 30 min of voluntary end-expiratory apnoeas that were primed with a hypoxic gas mixture and lasted for 20 s out of each minute.
To determine whether the pattern and intensity of the hypoxic exposure was important in determining sympathoexcitation, Tamisier et al. (2005) compared a 2 h continuous hypoxic protocol with a 2 h intermittent hypoxia protocol. Their results show persistent sympathoexcitation following continuous hypoxia but not following cyclic hypoxia. This contrasts with the other studies discussed previously, possibly because the hypoxic protocols were hypocapnic, and hypocapnic hypoxia does not lead to a significant post-stimulus sympathoexcitation (Tamisier et al. 2004).
Animal models. Animal models have been used to demonstrate that chronic intermittent hypoxia alters adrenergic vascular responses. Phillips et al. (2005) used video microscopy to measure the diameter of the isolated gracilis muscle resistance arteries before and during exposure to noradrenaline at various intraluminal pressures in rats exposed to 14 days of chronic intermittent hypoxia (60 s period of FIO2 = 10% every 4 min for 12 h day–1). They found that resting tone, myogenic activation and vasoconstrictor responses to noradrenaline were reduced in these animals. Interestingly, treatment of the rats' drinking water with a superoxide scavenger restored myogenic responses and noradrenaline-induced constriction, suggesting a role for superoxide production in the attenuated vasoconstrictor responsiveness to noradrenaline in intermittent hypoxia.
Fletcher and colleagues have intensively studied the effects of intermittent hypoxia on the development of hypertension and the role of the sympathetic nervous system, peripheral chemoreceptors and the renin–angiotensin system in this response (Fletcher et al. 1992a, 1999, 2000, 2002). They first determined that intermittent hypoxia (2 x 12 s periods of FIO2 = 2–3% per minute, 8 h day–1 for 35 days) led to a 13 mmHg increase in mean arterial blood pressure (MAP; Fletcher et al. 1992c), and subsequently prevented the increase in MAP by carotid body denervation (Fletcher et al. 1992a), chemical sympathectomy (Fletcher et al. 1992b), adrenal demedullation (Bao et al. 1997) and renal artery denervation (Bao et al. 1997). In addition, they demonstrated that intermittent eucapnic and hypercarbic hypoxia had no additional effects on diurnal blood pressure compared with hypocapnic intermittent hypoxia (Fletcher et al. 1995). Using this model of intermittent hypoxia, they have shown that blockade of the angiotensin-1 receptor with losartan prevented the rise in blood pressure following chronic intermittent hypoxia (Fletcher et al. 1999) and that suppression of the renin–angiotensin system (by salt loading) prevented the increase in MAP (Fletcher et al. 2002). This work has generated the hypothesis that secondary hypertension in OSA is a result of adrenergic and renin–angiotensin system overactivity, as outlined in Fig. 2.
Interestingly, rats exposed to intermittent hypoxia 8 h day–1 for 11 days (90 s period of 5% O2–5% CO2 every 90 s) increased plasma endothelin-1, as measured by radioimmunoassay (Kanagy et al. 2001). These rats also demonstrated a significant increase in MAP (Kanagy et al. 2001). Using a 35 day chronic intermittent hypoxia protocol (1 x 40 s period of FIO2 = 5% per minute for 8 h day–1), Lefebvre et al. (2006) reported a 17% increase in carotid artery contraction in response to endothelin-1, and cyclo-oxygenase inhibition by indomethacin reduced contraction of the carotid artery by 24%. Allahdadi et al. (2005) subjected rats to chronic intermittent hypoxia–hypercapnia (20 cycles of 5% O2–5% CO2 per hour; 7 h day–1 for 14 days) and measured the diameter and vessel wall calcium concentration simultaneously in mesenteric arteries with endothelial function disabled. The intermittent hypoxia–hypercapnia protocol led to increased constrictor sensitivity to endothelin-1 and increased calcium sensitivity compared with control animals. They also reported an increase in endothelin-A receptor expression. This suggests that intermittent hypoxia alters signalling components unique to endothelin-1 at the receptor and post-receptor level that increase calcium sensitivity during endothelin-A receptor activation (Allahdadi et al. 2005).
Vasodilator function
Intermittent hypoxia provokes a cascade of events that ultimately lead to endothelial dysfunction, inflammation and atherosclerosis. Figure 3 is a schematic diagram outlining this hypothetical pathway and should be used throughout this section as a supplement to the text. It is hypothesized that intermittent hypoxia leads to the formation of free radicals or reactive oxygen species (ROS; Jordan et al. 2006) which react with nitric oxide (NO), an important vasodilator, to produce peroxynitrite (Lavie, 2003). This reaction can diminish the bioavailability of NO and thereby attenuate NO-dependent vasodilatation (Cohen, 1995). Oxidative stress is also capable of increasing transcription factor production and adhesion molecule expression and is discussed in the following section.
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Plasma levels of NO derivatives are decreased in OSA patients and increase following CPAP therapy, thus supporting the hypothesis that NO bioavailability is reduced in OSA (Ip et al. 2000; Schulz et al. 2000b). In addition, basal NO production is increased in OSA patients following CPAP therapy, reflected by a significantly greater reduction in forearm blood flow by NO synthase blockade with NG-monomethyl-L-arginine (L-NMMA; Lattimore et al. 2006). However, other studies do not support the notion that NO-mediated oxidative/nitrosative stress occurs in patients with OSA (Svatikova et al. 2004). Since superoxide-mediated scavenging of NO generates peroxynitrite, which can nitrosylate membrane proteins and oxidize lipids, Svatikova et al. (2004) measured circulating nitrotyrosine as an indicator of peroxynitrite formation. Their results showed no difference in nitrotyrosine levels between control and OSA groups and suggest that peroxynitrite formation does not occur in OSA. Instead, it has been proposed that an endogenous competitive inhibitor of NO synthase reduces NO production (Suzuki et al. 2006). Further studies are required to clarify these conflicting results.
Cerebrovascular reactivity to carbon dioxide is reduced in patients with OSA (Diomedi et al. 1998; Placidi et al. 1998; Xie et al. 2005). Two reports have measured cerebrovascular reactivity to hypercapnia in OSA patients by means of transcranial Doppler ultrasonography of the middle cerebral artery during breath-holds (Diomedi et al. 1998; Placidi et al. 1998). Both studies measured the breath-hold index (BHI), which is calculated by dividing the increase in middle cerebral artery blood flow velocity during a breath-hold by the duration of the breath-hold. These studies report a 60% reduction in breath-hold index in OSA patients compared with control subjects during wakefulness (Diomedi et al. 1998; Placidi et al. 1998). Following CPAP therapy, the BHI increased in OSA patients to values comparable to controls (Diomedi et al. 1998).
Human models. A single study (Foster et al. 2005) has assessed ‘the cerebral vascular’ response to chronic intermittent hypoxia in humans. Foster et al. (2005) assessed cerebral tissue oxygenation using two protocols of intermittent hypoxia. Subjects were exposed to either 30 min of hypoxia [12% O2; long duration intermittent hypoxia (LDIH)] per day or to a 5 min hypoxia (12% O2) to 5 min normoxia cycle [short duration intermittent hypoxia (SDIH)] for an hour per day for 12 days. Throughout both protocols, cerebral tissue oxygenation was assessed using near-infrared spectroscopy during a progressive hypoxic challenge. The change in cerebral tissue oxygenation indexed to the change in SaO2 during the hypoxic challenge was used as a measure of the sensitivity of cerebral oxygen saturation to hypoxia. Regardless of the protocol used, the authors observed an initial increase in cerebral oxygen saturation sensitivity on day 3, followed by a subsequent decline, which was evident by the 12th day (Fig. 4A). Although both protocols demonstrated similar findings, SDIH had a greater effect than LDIH (Fig. 4B and C). These findings suggest that the vascular processes required to maintain homeostasis of cerebral blood flow and tissue oxygenation are altered by intermittent hypoxia and that this effect is greater following exposure to short cycles of desaturation–resaturation.
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13.8% O2) for five consecutive nights and found that the cerebral blood flow sensitivity to hypoxia, which was assessed during a stepwise reduction in end-tidal oxygen pressure (PET,O2), was increased by 116% compared with baseline values. This model of sustained hypoxia stimulates an adaptive process that increases cerebral vasodilatation in response to hypoxia.
Animal models.
Data from animal models of intermittent hypoxia have provided further insight into how vascular function may be altered in patients with OSA. Tahawi et al. (2001) exposed rats to 35 days of intermittent hypoxia (2 x 12 s periods of FIO22–3% per minute, 8 h day–1) and measured in vivo arteriolar reactivity in the cremaster muscle by video microscopy. They found a 16 mmHg increase in MAP and an attenuated response to acetylcholine-induced, arteriolar vasodilatation. In addition, the vasoconstrictor response to NO blockade by NG-nitro-L-arginine methyl ester (L-NAME) was reduced by 83% in arterioles of rats exposed to intermittent hypoxia, implying lower basal release of NO. More recently, Phillips et al. (2004) exposed rats to a different pattern of intermittent hypoxia (1 x 60 s period of FIO2
= 10% every 4 min, 12 h day–1 for 14 days). They studied vascular reactivity ex vivo in the resistance vessel of the gracilis muscle and the middle cerebral artery by video microscopy. Acetylcholine-induced dilatation of the gracilis artery and middle cerebral artery was severely attenuated, while the responses to sodium nitroprusside (a NO donor) and to calcium-free physiological saline solution were similar between rats exposed to intermittent hypoxia and control animals. Furthermore, dilatation of both the gracilis artery and the middle cerebral artery in response to hypoxia was virtually abolished in intermittently hypoxic animals. Taken together, these data imply that exposure to intermittent hypoxia reduces the bioavailability of NO in resistance vessels of the cerebral and skeletal muscle circulation and severely blunts the vasodilator response to acute hypoxia. While the evidence seems strong, these conclusions are not shared by all studies. For example, acetylcholine-induced relaxation of vascular smooth muscle in the aorta, carotid artery and mesenteric vascular bed was not altered following 35 days of chronic intermittent hypoxia (1 x 40 s period of FIO2
= 5% per minute, 8 h day–1; Lefebvre et al. 2006). These findings may indicate that conductance vessels and resistance vessels react differently to chronic intermittent hypoxia.
Vessel inflammation and atherosclerosis
Intermittent hypoxia is thought to cause vessel inflammation and lead to the progression of atherosclerosis (Lavie, 2005). It is hypothesized to upregulate transcription factor production and adhesion molecule expression, which can aid in the production of ROS and exacerbate endothelial dysfunction, as illustrated in Fig. 3.
Patients with OSA.
Leukocyte accumulation and adhesion to the endothelium with cell surface receptors and the initiation of leucocyte–endothelial cell interactions can critically impair endothelial cell function and promote the atherogenic process (Fig. 3; Dyugovskaya et al. 2002). Dyugovskaya et al. (2002) determined that OSA was associated with increased expression of adhesion molecules CD15 and CD11c on monocytes, increased adherence of monocytes in culture to human endothelial cells, and increased intracellular ROS production and upregulation of CD15 expression due to hypoxia in vitro in monocytes of control subjects. Further studies implicate cytokine production of CD4 and CD8 T cells of OSA patients in atherogenesis and plaque development (Dyugovskaya et al. 2005). Apparently, CD4 and CD8 T cells undergo phenotypic and functional changes, resulting in a shift towards type-2 cytokine dominance with increased interleukin (IL)-4 and decreased IL-10 expression (Dyugovskaya et al. 2005). In addition, CD8 T cells of OSA patients exhibit a fourfold increase in tumour necrosis factor- and CD40 ligand (Dyugovskaya et al. 2005). Serum levels of IL-6 and IL-18 are also elevated in OSA patients and are significantly correlated with duration of OSA-related hypoxia and severity of OSA (Minoguchi et al. 2005).
Biomarkers of oxidative stress (plasma malondialdehyde and urinary o,o'-ditryosine) are elevated in OSA and correlate well with the severity of hypoxaemia (Jordan et al. 2006). Increased oxidative stress and immune cell activation in OSA lead to increased ROS production in monocytes and polymorphonuclear neutrophils, overexpression of adhesion molecules and cytotoxicity of monocytes (Schulz et al. 2000a; Dyugovskaya et al. 2002, 2005). This further reduces NO bioavailability and increases monocyte and platelet adhesion, thus aiding in the progression of atherosclerosis and vascular dysfunction (Fig. 3). Middle-aged patients with OSA who are free of clinically overt cardiovascular diseases have early signs of atherosclerosis (Drager et al. 2005). For example, patients with OSA have a significantly increased pulse wave velocity, increased intima–media thickness and decreased carotid diameter compared with matched controls (Altin et al. 2005; Drager et al. 2005; Saletu et al. 2006). In addition, serum inflammatory markers are elevated in OSA patients; these have been proposed as significant predictors of atherosclerosis and its complications (Hackam & Anand, 2003).
Intermittent hypoxia may also stimulate the production of vascular endothelial growth factor (VEGF), a potent angiogenic cytokine which, because of its ability to stimulate smooth muscle proliferation, is implicated in the progression of atherosclerosis. Serum levels of VEGF are elevated in patients with OSA and correlate strongly with the degree of nocturnal hypoxaemia (Lavie et al. 2002; Schulz et al. 2002). Levels of VEGF decrease in patients successfully treated with CPAP (Schulz et al. 2002). In addition to increased levels of VEGF, OSA patients have increased fibrinogen levels, platelet coagulation, blood viscosity and C-reactive protein (Fig. 3; Wessendorf et al. 2000; Minoguchi et al. 2005; Saletu et al. 2006). The increases in C-reactive protein and fibrinogen levels are strongly correlated with indices of OSA severity (Wessendorf et al. 2000; Minoguchi et al. 2005; Saletu et al. 2006).
Human models. Healthy human models of intermittent hypoxia have not been used to assess the relationship between hypoxia and vessel inflammation and atherosclerosis. Future research in this area of study will undoubtedly be useful.
Animal models. Intermittent hypoxia in animal models also leads to oxidative stress and inflammation. Rats exposed to 5 weeks of chronic intermittent hypoxia (1 x 60 s period of FIO2 = 4–5% every 2 min, 8 h day–1 for 5 days week–1) have greater myocardial lipid peroxides and lower levels of myocardial superoxide dismutase (Chen et al. 2005). This suggests that intermittent hypoxia, in addition to increasing ROS production, decreases a major antioxidant system. In a model of chronic intermittent hypoxia–hypercapnia (2 x 15 s periods of FIO2 = 6–8% and CO2 = 10–14% per minute; 8 h day–1 for 3 weeks), platelet reactivity was significantly elevated, as were platelet adhesion and aggregation (Dunleavy et al. 2005).
Altay et al. (2004) undertook a novel study using knockout mice to determine the role of nitric oxide in the inflammatory response to intermittent hypoxia. Animals were mechanically ventilated and subjected to 12 cycles of intermittent hypoxia by turning the ventilator off for 30 s every 5 min, over 1 h. The mice were wild type, neuronal NO synthase (nNOS) knockouts, or endothelial NO synthase (eNOS) knockouts. Following intermittent hypoxia, leucocyte–endothelial cell adherence in the cortical venular microcirculation was measured by using epifluorescence videomicroscopy, and hippocampal CA1 pyramidal cell injury was evaluated by light microscopy by counting viable pyramidal cells present in the CA1 sector. They found that this brief exposure to intermittent hypoxia was sufficient to trigger a rapid and prolonged inflammatory response in the cerebral microcirculation. Leucocytes became adherent to cortical venular endothelium within 4 h. Neuronally derived NOS modulated leucocyte–endothelial cell interactions because leucocyte–endothelial cell adherence was absent in nNOS knockout mice. Cerebrovascular inflammation was accentuated in eNOS knockout mice, which suggests that NO produced by eNOS is important in limiting cerebrovascular inflammation and prevents injury/death to hippocampal pyramidal cells.
Together, these results suggest that OSA is indeed a disorder of oxidative stress, leads to inflammation and may accelerate the progression of atherosclerosis.
Conclusion
This review has highlighted the association between OSA and vascular disease, outlined some potential basic mechanisms for this association, and compared the results from studies on OSA patients with those from experimental human and animal models of intermittent hypoxia. It is clear that intermittent hypoxia leads to hypertension and that sympathetic overactivity and the renin–angiotensin system are important in this response. In addition, altered vascular function and baroreceptor function could be involved. Intermittent hypoxia leads to a systemic inflammatory response which may contribute to the progression of atherosclerosis and decreased vascular function, which are highly important responses relating to an increased risk of stroke and myocardial infarction in patients with OSA. To date, the small number of studies on experimental human models of intermittent hypoxia have demonstrated sustained sympathetic activation and altered cerebral oxygenation. Animal studies have provided the bulk of our knowledge regarding basic mechanisms responsible for the development of hypertension following chronic intermittent hypoxia, and are beginning to provide valuable data regarding the role of intermittent hypoxia and vascular dysfunction. Despite these advances, further research is required to determine the basic mechanisms that link OSA and vascular disease. We propose that advances will be led by collaborative clinical and basic science research on patients with OSA and experimental models of intermittent hypoxia. It is anticipated that such studies will provide an improved understanding of this important clinical problem and form the basis for effective therapeutic strategies.
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References |
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TopAbstractIntroductionReferences |
|---|
Altay T, Gonzales ER, Park TS & Gidday JM (2004). Cerebrovascular inflammation after brief episodic hypoxia: modulation by neuronal and endothelial nitric oxide synthase. J Appl Physiol 96, 1223–1230.
Altin R, Ozdemir H, Mahmutyazicioglu K, Kart L, Uzun L, Ozer T, Savranlar A & Aydin M (2005). Evaluation of carotid artery wall thickness with high-resolution sonography in obstructive sleep apnea syndrome. J Clin Ultrasound 33, 80–86.[CrossRef][Medline]
American Academy of Sleep Medicine Task Force (1999). Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 22, 667–689.[Medline]
Arzt M, Young T, Finn L, Skatrud JB & Bradley TD (2005). Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 172, 1447–1451.
Bao G, Metreveli N, Li R, Taylor A & Fletcher EC (1997). Blood pressure response to chronic episodic hypoxia: role of the sympathetic nervous system. J Appl Physiol 83, 95–101.
Carlson JT, Rangemark C & Hedner JA (1996). Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. J Hypertens 14, 577–584.[CrossRef][Medline]
Chen L, Einbinder E, Zhang Q, Hasday J, Balke CW & Scharf SM (2005). Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med 172, 915–920.
Cohen RA (1995). The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog Cardiovasc Dis 38, 105–128.[CrossRef][Medline]
Cortelli P, Parchi P, Sforza E, Contin M, Pierangeli G, Barletta G & Lugaresi E (1994). Cardiovascular autonomic dysfunction in normotensive awake subjects with obstructive sleep apnoea syndrome. Clin Auton Res 4, 57–62.[CrossRef][Medline]
Cutler MJ, Swift NM, Keller DM, Wasmund WL, Burk JR & Smith ML (2004a). Periods of intermittent hypoxic apnea can alter chemoreflex control of sympathetic nerve activity in humans. Am J Physiol Heart Circ Physiol 287, H2054–H2060.
Cutler MJ, Swift NM, Keller DM, Wasmund WL & Smith ML (2004b). Hypoxia-mediated prolonged elevation of sympathetic nerve activity after periods of intermittent hypoxic apnea. J Appl Physiol 96, 754–761.
Diomedi M, Placidi F, Cupini LM, Bernardi G & Silvestrini M (1998). Cerebral hemodynamic changes in sleep apnea syndrome and effect of continuous positive airway pressure treatment. Neurology 51, 1051–1056.
Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM & Lorenzi-Filho G (2005). Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 172, 613–618.
Dunleavy M, Dooley M, Cox D & Bradford A (2005). Chronic intermittent asphyxia increases platelet reactivity in rats. Exp Physiol 90, 411–416.
Dyugovskaya L, Lavie P & Lavie L (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.
Dyugovskaya L, Lavie P & Lavie L (2005). Lymphocyte activation as a possible measure of atherosclerotic risk in patients with sleep apnea. Ann N Y Acad Sci 1051, 340–350.
Faraci FM & Brian JE Jr (1994). Nitric oxide and the cerebral circulation. Stroke 25, 692–703.[Abstract]
Fletcher EC (2000). Effect of episodic hypoxia on sympathetic activity and blood pressure. Respir Physiol 119, 189–197.[CrossRef][Medline]
Fletcher EC (2001). Invited review: Physiological consequences of intermittent hypoxia: systemic blood pressure. J Appl Physiol 90, 1600–1605.
Fletcher EC, Bao G & Li R (1999). Renin activity and blood pressure in response to chronic episodic hypoxia. Hypertension 34, 309–314.
Fletcher EC, Bao G & Miller CC 3rd (1995). Effect of recurrent episodic hypocapnic, eucapnic, and hypercapnic hypoxia on systemic blood pressure. J Appl Physiol 78, 1516–1521.
Fletcher EC, Lesske J, Behm R, Miller CC 3rd, Stauss H & Unger T (1992a). Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 72, 1978–1984.
Fletcher EC, Lesske J, Culman J, Miller CC & Unger T (1992b). Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension 20, 612–619.
Fletcher EC, Lesske J, Qian W, Miller CC 3rd & Unger T (1992c). Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 19, 555–561.
Fletcher EC, Orolinova N & Bader M (2002). Blood pressure response to chronic episodic hypoxia: the renin-angiotensin system. J Appl Physiol 92, 627–633.
Fogel RB, Malhotra A & White DP (2004). Sleep. 2: pathophysiology of obstructive sleep apnoea/hypopnoea syndrome. Thorax 59, 159–163.
Foster GE, McKenzie DC, Milsom WK & Sheel AW (2005). Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia. J Physiol 567, 689–699.
Gami AS, Howard DE, Olson EJ & Somers VK (2005). Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 352, 1206–1214.
Gozal E & Gozal D (2001). Respiratory plasticity following intermittent hypoxia: developmental interactions. J Appl Physiol 90, 1995–1999.
Greenberg DA, Chan J & Sampson HA (1992). Endothelins and the nervous system. Neurology 42, 25–31.
Greenberg HE, Sica A, Batson D & Scharf SM (1999). Chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. J Appl Physiol 86, 298–305.
Grimpen F, Kanne P, Schulz E, Hagenah G, Hasenfuss G & Andreas S (2000). Endothelin-1 plasma levels are not elevated in patients with obstructive sleep apnoea. Eur Respir J 15, 320–325.[Abstract]
Grote L, Kraiczi H & Hedner J (2000). Reduced - and ß2-adrenergic vascular response in patients with obstructive sleep apnea. Am J Respir Crit Care Med 162, 1480–1487.
Guilleminault C, Tilkian A & Dement WC (1976). The sleep apnea syndromes. Annu Rev Med 27, 465–484.[CrossRef][Medline]
Hackam DG & Anand SS (2003). Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA 290, 932–940.
Hanly PJ & Pierratos A (2001). Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med 344, 102–107.
Hirshkowitz M & Sharafkhaneh A (2005). Positive airway pressure therapy of OSA. Semin Respir Crit Care Med 26, 68–79.[CrossRef][Medline]
Hung J, Whitford EG, Parsons RW & Hillman DR (1990). Association of sleep apnoea with myocardial infarction in men. Lancet 336, 261–264.[CrossRef][Medline]
Imadojemu VA, Gleeson K, Quraishi SA, Kunselman AR, Sinoway LI & Leuenberger UA (2002). Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy. Am J Respir Crit Care Med 165, 950–953.
Ip MS, Lam B, Chan LY, Zheng L, Tsang KW, Fung PC & Lam WK (2000). Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 162, 2166–2171.
Jordan W, Cohrs S, Degner D, Meier A, Rodenbeck A, Mayer G, Pilz J, Ruther E, Kornhuber J & Bleich S (2006). Evaluation of oxidative stress measurements in obstructive sleep apnea syndrome. J Neural Transm 113, 239–254.[CrossRef][Medline]
Jordan W, Reinbacher A, Cohrs S, Grunewald RW, Mayer G, Ruther E & Rodenbeck A (2005). Obstructive sleep apnea: plasma endothelin-1 precursor but not endothelin-1 levels are elevated and decline with nasal continuous positive airway pressure. Peptides 26, 1654–1660.[CrossRef][Medline]
Julien C, Bayat S & Levy P (2003). Vascular reactivity to norepinephrine and acetylcholine after chronic intermittent hypoxia in mice. Respir Physiol Neurobiol 139, 21–32.[CrossRef][Medline]
Kanagy NL, Walker BR & Nelin LD (2001). Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension 37, 511–515.
Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V & Somers VK (2000). Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102, 2607–2610.
Kolb JC, Ainslie PN, Ide K & Poulin MJ (2004). Effects of five consecutive nocturnal hypoxic exposures on the cerebrovascular responses to acute hypoxia and hypercapnia in humans. J Appl Physiol 96, 1745–1754.
Kraiczi H, Hedner J, Peker Y & Carlson J (2000). Increased vasoconstrictor sensitivity in obstructive sleep apnea. J Appl Physiol 89, 493–498.
Lai CJ, Yang CC, Hsu YY, Lin YN & Kuo TB (2006). Enhanced sympathetic outflow and decreased baroreflex sensitivity are associated with intermittent hypoxia-induced systemic hypertension in conscious rats. J Appl Physiol 100, 1974–1982.
Lattimore JL, Wilcox I, Skilton M, Langenfeld M & Celermajer DS (2006). Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation. Thorax 61, 491–495.
Lavie L (2003). Obstructive sleep apnoea syndrome – an oxidative stress disorder. Sleep Med Rev 7, 35–51.[CrossRef][Medline]
Lavie L (2005). Sleep-disordered breathing and cerebrovascular disease: a mechanistic approach. Neurol Clin 23, 1059–1075.[CrossRef][Medline]
Lavie L, Kraiczi H, Hefetz A, Ghandour H, Perelman A, Hedner J & Lavie P (2002). Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. Am J Respir Crit Care Med 165, 1624–1628.
Lefebvre B, Godin-Ribuot D, Joyeux-Faure M, Caron F, Bessard G, Levy P & Stanke-Labesque F (2006). Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat. Respir Physiol Neurobiol 150, 278–286.[CrossRef][Medline]
Leuenberger UA, Brubaker D, Quraishi S, Hogeman CS, Imadojemu VA & Gray KS (2005). Effects of intermittent hypoxia on sympathetic activity and blood pressure in humans. Auton Neurosci 121, 87–93.[CrossRef][Medline]
Li KK (2003). Surgical management of obstructive sleep apnea. Clin Chest Med 24, 365–370.[CrossRef][Medline]
Marasciulo FL, Montagnani M & Potenza MA (2006). Endothelin-1: the yin and yang on vascular function. Curr Med Chem 13, 1655–1665.[CrossRef][Medline]
Marin JM, Carrizo SJ, Vicente E & Agusti AG (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.[Medline]
Millman RP, Redline S, Carlisle CC, Assaf AR & Levinson PD (1991). Daytime hypertension in obstructive sleep apnea. Prevalence and contributing risk factors. Chest 99, 861–866.[Medline]
Mills PJ, Kennedy BP, Loredo JS, Dimsdale JE & Ziegler MG (2006). Effects of nasal continuous positive airway pressure and oxygen supplementation on norepinephrine kinetics and cardiovascular responses in obstructive sleep apnea. J Appl Physiol 100, 343–348.
Minoguchi K, Yokoe T, Tazaki T, Minoguchi H, Tanaka A, Oda N, Okada S, Ohta S, Naito H & Adachi M (2005). Increased carotid intima-media thickness and serum inflammatory markers in obstructive sleep apnea. Am J Respir Crit Care Med 172, 625–630.
Mitchell GS, Baker TL, Nanda SA, Fuller DD, Zabka AG, Hodgeman BA, Bavis RW, Mack KJ & Olson EB Jr (2001). Invited review: Intermittent hypoxia and respiratory plasticity. J Appl Physiol 90, 2466–2475.
Mitchell GS & Johnson SM (2003). Neuroplasticity in respiratory motor control. J Appl Physiol 94, 358–374.
Moller DS, Lind P, Strunge B & Pedersen EB (2003). Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnea. Am J Hypertens 16, 274–280.[CrossRef][Medline]
Morgan BJ, Crabtree DC, Palta M & Skatrud JB (1995). Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol 79, 205–213.
Morrell MJ, Finn L, Kim H, Peppard PE, Badr MS & Young T (2000). Sleep fragmentation, awake blood pressure, and sleep-disordered breathing in a population-based study. Am J Respir Crit Care Med 162, 2091–2096.
Morris KF, Baekey DM, Nuding SC, Dick TE, Shannon R & Lindsey BG (2003). Invited review: Neural network plasticity in respiratory control. J Appl Physiol 94, 1242–1252.
Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG & Somers VK (1998). Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation 97, 943–945.
Narkiewicz K, van de Borne PJ, Pesek CA, Dyken ME, Montano N & Somers VK (1999). Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 99, 1183–1189.
Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD & Pickering TG (2000). Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283, 1829–1836.
O'Connor C, Thornley KS & Hanly PJ (2000). Gender differences in the polysomnographic features of obstructive sleep apnea. Am J Respir Crit Care Med 161, 1465–1472.
Olson EJ, Park JG & Morgenthaler TI (2005). Obstructive sleep apnea–hypopnea syndrome. Prim Care 32, 329–359.[Medline]
Peng Y-J & Prabhakar NR (2004). Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity. J Appl Physiol 96, 1236–1242.
Peppard PE, Young T, Palta M & Skatrud J (2000). Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342, 1378–1384.
Perazella MA & Setaro JF (2003). Renin-angiotensin aldosterone system: fundamental aspects and clinical implications in renal and cardiovascular disorders. J Nucl Cardiol 10, 184–196.[CrossRef][Medline]
Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME & Somers VK (1999). Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 17, 61–66.[Medline]
Phillips SA, Olson EB, Lombard JH & Morgan BJ (2005). Chronic intermittent hypoxia alters norepinephrine reactivity and mechanics of skeletal muscle resistance arteries. J Appl Physiol 100, 1117–1123.[CrossRef][Medline]
Phillips SA, Olson EB, Morgan BJ & Lombard JH (2004). Chronic intermittent hypoxia impairs endothelium-dependent dilation in rat cerebral and skeletal muscle resistance arteries. Am J Physiol Heart Circ Physiol 286, H388–H393.
Placidi F, Diomedi M, Cupini LM, Bernardi G & Silvestrini M (1998). Impairment of daytime cerebrovascular reactivity in patients with obstructive sleep apnoea syndrome. J Sleep Res 7, 288–292.[CrossRef][Medline]
Prabhakar NR (2001). Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 90, 1986–1994.
Ryan CM & Bradley TD (2005). Pathogenesis of obstructive sleep apnea. J Appl Physiol 99, 2440–2450.
Saletu M, Nosiska D, Kapfhammer G, Lalouschek W, Saletu B, Benesch T & Zeitlhofer J (2006). Structural and serum surrogate markers of cerebrovascular disease in obstructive sleep apnea (OSA): association of mild OSA with early atherosclerosis. J Neurol 253, 746–752.[CrossRef][Medline]
Schulz R, Hummel C, Heinemann S, Seeger W & Grimminger F (2002). Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med 165, 67–70.
Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, Seeger W & Grimminger F (2000a). 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.
Schulz R, Schmidt D, Blum A, Lopes-Ribeiro X, Lucke C, Mayer K, Olschewski H, Seeger W & Grimminger F (2000b). Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy. Thorax 55, 1046–1051.
Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O'Connor GT, Boland LL, Schwartz JE & Samet JM (2001). Sleep-disordered breathing and cardiovascular disease: cross-sectional re
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