American Journal of Respiratory and Critical Care Medicine

Cardiovascular Effects of Normal Sleep

Cardiovascular Effects of Obstructive Sleep Apnea

 Acute Physiological Effects

 Chronic Physiological Effects

Clinical Cardiovascular Disease and Obstructive Sleep Apnea




 Ischemic Heart Disease

 Congestive Heart Failure

Cheyne–Stokes Respiration and Congestive Heart Failure



 Clinical Significance



Cardiovascular and cerebrovascular diseases are the most common life-threatening and debilitating diseases in the industrialized world. However, the incidence and mortality rates of these diseases have recently begun to decline largely owing to the identification of their underlying pathophysiologies, promotion of preventative behavior, and development of effective therapies. Nevertheless, much remains to be done to reduce the burden of these diseases further. An examination of the potential role of sleep apnea in the pathogenesis of these disorders holds promise to further this end. Over the past decade, the concerted efforts of many investigators throughout the world have transformed our understanding of the many mechanisms by which sleep apnea may contribute to the pathophysiology and complications of cardiovascular diseases. The primary objectives of this article, therefore, are to critically review the possible adverse physiological consequences of sleep apnea on the cardiovascular system, and to assess whether such adverse effects constitute a risk for the development of chronic cardiovascular and cerebrovascular diseases. However, we will not consider pulmonary hypertension, as this has been reviewed in detail elsewhere (1, 2). Similarly, owing to a lack of experimental data, cardiac arrythmias will not be covered. Although the effects of treating sleep apnea on cardiovascular outcomes will be discussed, this discussion will of necessity be brief owing to the paucity of well-conducted clinical trials in this area. Finally, we wish to highlight gaps in knowledge and important controversies in need of resolution that could direct future research.

The transition from wakefulness to non-rapid eye movement (NREM) sleep is accompanied by marked alterations in respiratory and cardiovascular regulation. Normally, there is a sudden withdrawal of the nonchemical wakefulness drive to breathe resulting in a slight but abrupt decrease in minute ventilation and increase in PaCO2 (3, 4). Subsequently, there is a further progressive reduction in central respiratory drive accompanied by a decrease in minute ventilation, an increase in PaCO2 , and a decrease in PaO2 from stages 1 through 4 NREM sleep (4). In the deeper stages of NREM sleep, respiration is under predominantly metabolic control, resulting in a very regular pattern of breathing (4, 5). Alterations in cardiovascular autonomic regulation mirror these changes in respiratory control. As the metabolic rate declines from wakefulness to a relatively constant lower level during stages 1 to 4 NREM sleep, parasympathetic nervous system tone increases, and sympathetic nervous system activity (SNA), heart rate (HR), blood pressure (BP), stroke volume, cardiac output, and systemic vascular resistance decrease (6-12). As a result, the cardiovascular system is in a state of hemodynamic and autonomic quiescence during which myocardial workload is reduced. Parallel declines in central respiratory and sympathetic nervous outflow related to the transition from wakefulness to sleep may be related, in part, to central connections between the respiratory-related and central cardiovascular sympathetic neurons in the brainstem (13). Increases in parasympathetic activity and decreases in SNA contribute to an increase in baroreflex sensitivity during NREM sleep compared with wakefulness (14, 15).

Although NREM sleep is characterized by relative stability of the respiratory, cardiovascular, and autonomic systems, K complexes and spontaneous arousals from sleep intermittently punctuate this quiescent tableau (9). Arousals are associated with abrupt increases in chemosensitivity and reinstitution of the wakefulness drive to breathe. However, they are also accompanied by augmented ventilation, which exceeds that expected for the ambient PaCO2 and reinstitution of the wakefulness drive. Abrupt increases in BP and HR, due to sudden increases in SNA and withdrawal of cardiac vagal activity, also exceed waking levels (16). It appears that increases in BP and HR from NREM sleep to relaxed wakefulness involve augmented SNA, but not parasympathetic withdrawal. This indicates that arousal is a distinct transient state of heightened respiratory and cardiovascular activity (17, 18).

During the transition from NREM to rapid eye movement (REM) sleep there are further, but to some extent divergent alterations in respiratory and cardiovascular activity. Breathing becomes less dependent on metabolic drive and more so on behavioral factors (4, 19). The combination of an increase in the threshold for a ventilatory response, a further reduction in ventilatory responsiveness to chemostimulation, and skeletal muscle atonia affecting the nondiaphragmatic respiratory muscles leads to decreases in ventilation and increases in PaCO2 (20, 21). This is accompanied by an irregular pattern of breathing, particularly during phasic REM sleep, that is probably related to dream content. In contrast to ventilation during REM sleep, SNA, BP, and HR increase to levels similar to relaxed wakefulness (7, 9). Like ventilation, there are irregular surges in SNA, HR, and BP linked to phasic REM sleep events (22). The cause of the dissociation between central respiratory drive and sympathetic outflow during REM sleep is not yet clear. One possibility is that the sympathetic nervous system is not subject to any functional equivalent of the postsynaptic inhibition of skeletal muscle that affects the respiratory system. In any case, because adults spend 85% of their total sleep time in NREM sleep, sleep is generally a time of cardiovascular relaxation. However, sleep apnea disrupts this state of cardiovascular quiescence.

Acute Physiological Effects

As a consequence of repetitive obstructive apneas, hemodynamic variables and cardiovascular autonomic activity oscillate between the apneic and ventilatory phases. Surges in HR and BP typically occur 5–7 s after apnea termination (23, 24), coincident with arousal from sleep, peak ventilation, and the nadir of SaO2 . These repetitive surges counteract the usual fall in HR and BP that accompany normal sleep and are thought to contribute to the adverse cardiovascular consequences of obstructive sleep apnea (OSA). Three key pathophyiological features of OSA give rise to these abnormal cardiovascular oscillations: generation of exaggerated negative intrathoracic pressure against the occluded pharynx, hypoxia, and arousals from sleep.

Negative intrathoracic pressure.

Ineffective inspiratory efforts are a hallmark of obstructive apneas. The resulting exaggerated negative intrathoracic pressure swings increase left ventricular (LV) transmural pressure by increasing the difference between extracardiac and intracardiac pressures, and hence afterload, but without increasing BP (25-27). It also increases venous return to the right ventricle, leading to its distension. The resulting leftward shift of the interventricular septum can impede LV diastolic filling (28). There is also evidence that exaggerated negative intrathoracic pressure during apnea can impair LV relaxation, which could further impede LV filling (29). The combination of increased LV afterload and reduced LV preload leads to a reduction in stroke volume during obstructive apneas that is proportional to the negative intrathoracic pressure generated (1, 30-33). However, it appears that exaggerated negative intrathoracic pressure does not acutely impair LV contractility when underlying LV function is normal (34). Following release of obstructive apneas, stroke volume abruptly increases (1, 33, 34).

Vagal afferent feedback from lung inflation inhibits sympathetic outflow, whereas apnea disinhibits it (35). Thus, during a breath hold, sympathetic vasoconstrictor outflow to muscle (MSNA) increases progressively from its onset until its termination owing to progressive hypoxic stimulation (36). However, during the initial phase of an obstructive apnea or Mueller maneuver, MSNA is suppressed (36, 37). This is due to the effects of obstructive apneas on baroreceptor activity. Negative intrathoracic pressure causes transmural intrathoracic aortic pressure to increase, which activates aortic baroreceptors and inhibits sympathetic outflow (36, 37). On the other hand, there is a simultaneous fall in BP due to the reduction in stroke volume, which suppresses carotid sinus baroreceptor activity and tends to reflexively augment sympathetic outflow. Because the influence of the aortic baroreceptors predominates, the net effect is suppression of MSNA. Toward the end of these events, however, MSNA rises in response to hypoxia. Depending on the strength of the hypoxic stimulus and the sympathetic vasoconstrictor response, BP can, but does not invariably increase toward the end of apneas (24, 26, 34, 38).


During obstructive apneas, the sympathoexcitatory effect of hypoxia is amplified by apnea and CO2 retention. This results in increased sympathetic vasoconstrictor tone (39). However, as discussed above, these sympathoexcitatory effects are not engaged until several seconds into the apnea. Owing to the circulatory delay between the lung and the peripheral chemoreceptors, the sensing of nadir SaO2 that occurs in the lungs at the end of apnea is not detected at the carotid bodies until several seconds later (40). As a result, the maximum vasoconstrictor and chronotropic effects of apnea-related hypoxia occur during the postapneic ventilatory phase and are associated with surges in BP and HR (41) (Figure 1). These effects increase the metabolic demands of the myocardium in the face of reduced O2 supply. Moreover, intermittent hypoxia during obstructive apneas may directly depress cardiac contractility (42), or reduce cardiac performance indirectly by causing pulmonary vasoconstriction and increasing pulmonary arterial pressure (33). The degree of desaturation during each obstructive apnea has been directly related to the magnitude of the increase in BP following the apnea (8, 43). Although these effects can be partly inhibited by administration of O2 during voluntary Mueller maneuvers (36), supplemental O2 has little effect on BP surges following apneas in patients with OSA (24, 44). This observation indicates that factors other than hypoxia, such as hypercapnia and arousals from sleep, must also be contributing to surges in postapneic BP (16, 18, 39).

Hypoxia has varying influences on HR according to the presence or absence of airflow, and the balance of its parasympathetic and sympathetic stimulatory effects. In the absence of airflow, hypoxic stimulation of the carotid body is vagotonic, and causes bradycardia (45, 46). Conversely, in the presence of airflow (e.g., hypoxic rebreathing), hypoxia causes tachycardia because stretching of the lungs inhibits vagal outflow to the heart and permits unopposed cardiac sympathetic discharge. Nevertheless, HR responses to obstructive apneas vary greatly among individuals. This variability in HR responses is probably due to differences in severity of hypoxia, intrinsic hypoxic chemosensitivity, and the relative influence of hypoxia on vagal and sympathetic input to the sinoatrial node (47, 48). Accordingly, where parasympathetic influence predominates, HR may slow, where sympathetic influence predominates, HR may rise, and where vagal and sympathetic influences are relatively equal, HR may remain unchanged (49). However, upon resumption of airflow at termination of apnea, HR invariably rises owing to disengagement of hypoxia-mediated cardiac vagal outflow and unopposed cardiac sympathetic discharge (16, 39, 50). When bradycardia occurs during obstructive apneas, administration of supplemental O2 or atropine attenuates it (51).


Arousal is a critical defense mechanism that activates upper airway dilator muscles and prevents asphyxiation in OSA (21). However, it also contributes to the abrupt surges in HR and BP following termination of apnea (16), but the degree to which it does so remains controversial. O'Donnell and colleagues (26) induced obstructive apneas of similar length in dogs with and without arousal. Apneas terminated prior to arousal caused increases in BP, but termination by an arousal caused a further increase. Similarly, Trinder and coworkers (18) described augmentation in HR and BP during the ventilatory phase of Cheyne–Stokes respiration, both awake and during sleep in the absence of arousals. Arousals caused only a small further increment in HR and BP. One confounding factor is that arousals are accompanied by an abrupt increase in ventilation that precedes increases in HR and BP. This suggests that the increased ventilatory drive at termination of apnea coactivates cardiovascular sympathetic neurons that are closely linked with respiratory neurons in the brainstem (13). Indeed, voluntary periodic breathing during wakefulness causes postapneic surges in HR and BP even in the absence of hypoxia or arousals from sleep (52). Matters are further complicated by the observation that sudden lung inflation at termination of apnea counteracts asphyxia-induced sympathetic activation causing an abrupt decrease in MSNA, which plays a role in the fall in BP prior to the onset of the next apnea (41). Taken together, these observations indicate that although arousals from sleep can contribute, they are not critical to the development of postapneic surges in HR and BP.

Chronic Physiological Effects
Autonomic cardiovascular function.

OSA is associated with chronic abnormalities of cardiovascular autonomic regulation both during sleep and wakefulness. These are characterized by increased SNA, reduced baroreflex sensitivity and HR variability, and increased BP variability (41, 53-56). A number of studies have shown that patients with OSA have higher SNA during sleep and wakefulness than control subjects (41, 53, 54) (Figure 2). Treatment of OSA either by tracheostomy (57) or continuous positive airway pressure (CPAP) leads to a reduction in nocturnal and daytime SNA. The latter effect appears to require several months of CPAP therapy (58-60). This beneficial effect is presumably related to elimination of OSA, nocturnal hypoxia, and arousals from sleep.

Peripheral chemoreceptors and sympathetic nervous system activity.

The mechanisms by which OSA leads to persistent sympathetic activation are incompletely understood. There are several lines of evidence favoring an important role for hypoxia in this phenomenon. Urinary norepinephrine concentrations are inversely proportional to minimal nocturnal SaO2 in patients with OSA (61). In addition, both short-term sustained and intermittent challenges with combined hypoxia and hypercapnia cause elevations in MSNA that persist for at least 20 min following withdrawal of the exposure (62, 63). This prolonged sympathetic effect appears to be due to hypoxia rather than hypercapnia (64).

The carotid bodies may be an important intermediate step in the pathway between exposure to intermittent hypoxia and development of sustained elevations in SNA. For example, it has been reported that patients with OSA have increased peripheral chemoreflex sensitivity (65) and pressor responses to hypoxia (66). A mechanism for this is suggested by the observation that daily short-term exposure to hypoxia increases peripheral hypoxic chemosensitivity (67). However, other investigators have reported either normal (68) or depressed hypoxic ventilatory responses in patients and animals with OSA (69, 70). Nevertheless, carotid body denervation prevents the development of hypertension in rats exposed to intermittent hypoxia (71), and desensitization of the peripheral chemoreceptors by administration of 100% O2 in awake normoxic patients with OSA reduces MSNA, HR, and BP (72). These findings suggest that the peripheral chemoreceptors stimulate cardiovascular sympathetic outflow in patients with OSA even when they are normoxic and awake.


Under normal conditions, activation of the carotid sinus and aortic arch baroreceptors by an increase in BP reflexively inhibits sympathetic outflow, increases cardiac vagal outflow, and reduces HR. A decrease in BP does the opposite. Therefore, depression of baroreceptor sensitivity could contribute to sympathetic activation and parasympathetic withdrawal (73). In patients with OSA, repetitive nocturnal surges in BP may downregulate baroreceptors and blunt their sensitivity. However, studies of baroreflex sensitivity in patients with OSA have yielded inconsistent results; some investigators report that it is depressed (73, 74), and others report that it is normal (75). Brooks and coworkers (76) found that in concert with an increase in BP, induction of OSA in dogs caused a parallel shift of the baroreflex curve to the right, indicating an increase in the set point to a higher BP, but without any change in sensitivity. Thus, the baroreflex appeared no longer capable of counteracting the higher BP, and may have been contributing to it by indirectly maintaining a higher sympathetic outflow (77). However, because dogs are quadrupeds that do not undergo as extreme postural changes as humans, it is unclear what implications these findings have for patients with OSA. On the other hand, Tkacova and colleagues (78) demonstrated that acute elimination of OSA by CPAP in patients with congestive heart failure (CHF) caused both an immediate increase in baroreflex sensitivity and a decrease in the set point in association with a reduction in BP. These findings have two important implications. First, they suggest that OSA may both increase the set point and depress the sensitivity of the baroreflex. Second, such abnormalities are to some extent reversible.

Heart rate variability.

Cardiovascular autonomic function has also been assessed in patients with OSA by examination of daytime heart rate variability using power spectral analysis. Normally, HR varies at high frequency (HF) as a function of respiration. This respiratory sinus arrhythmia is modulated primarily by cardiac vagal activity. Heart rate variability at lower frequencies is thought to be modulated by sympathetic activity, although there is controversy on this point (79). In general, patients with OSA have a decrease in the HF component of HR variability and an increase in the low-frequency component (55, 80, 81). This abnormal pattern is thought to reflect decreased parasympathetic and increased sympathetic modulation of HR. Treatment of OSA with CPAP has been shown to restore these indices toward normal, both acutely (82) and chronically (83).

Circulating hormones.

In addition to catecholamines, levels of other circulating hormones involved in the regulation of BP and fluid volume, such as renin, aldosterone, and vasopressin, have been studied in relation to OSA. All of these hormones have pressor or fluid- and sodium-retaining effects that would predispose to hypertension. However, there is no clear indication what, if any, effect OSA has on the levels of these hormones (84-86).

Results have been more consistent in the case of atrial natriuretic peptide, a vasoactive hormone secreted primarily in response to right atrial distension (87). In patients with OSA, its concentration is elevated in proportion to the degree of hypoxemia-induced increases in pulmonary artery pressure and negative intrathoracic pressure swings (85, 88-90). Atrial natriuretic peptide promotes diuresis, natriuresis, and vasodilation and thereby counteracts the pressor and fluid-retaining effects of the hormones mentioned above (91). Consequently, high nocturnal atrial natriuretic peptide levels probably contribute to nocturia, a common feature of OSA. In uncontrolled studies, abolition of OSA by CPAP was associated with reductions in nocturnal urinary atrial natriuretic peptide and urine excretion (90, 91).

Vascular and endothelial effects, and atherosclerosis . . Abnormalities of vascular responsiveness could contribute to chronic elevations in BP in patients with OSA. However, experiments on vascular responses to hypoxia, and α- and β-adrenergic stimulation in OSA have yielded inconsistent results (66, 68, 92). Studies of the potential role of the potent endogenous vasoconstrictor, endothelin-1, in the pathogenesis of systemic hypertension in patients with OSA have also been inconclusive (93, 94). Similarly, studies of responses to endogenous vasodilators in patients with OSA have yielded conflicting results: some investigators found depressed circulating nitric oxide levels and a selective defect in endothelium-dependent vascular relaxation (95, 96), whereas others did not (97). Taken together, the above findings do not provide persuasive evidence of either a primary vascular lesion or abnormal vascular responsiveness to hypoxia or to endothelially dependent vasoconstrictors or dilators.

It has been hypothesized that intermittent hypoxia with abrupt decreases and increases in cardiac output in association with OSA could provoke elaboration of oxygen free radicals and ischemia–reperfusion injury to the vascular wall (98). Such a process could precipitate or accelerate the formation of atherosclerotic plaques and vascular smooth muscle proliferation (99, 100). A recent study demonstrated increased superoxide anion production in patients with OSA that was markedly diminished following CPAP therapy (101). However, there is no direct evidence that OSA can precipitate or accelerate atherosclerosis.


Platelet aggregability is enhanced by catecholamines and is associated with an increased risk of cardiovascular events (102, 103). Shortly after arising in the morning, there is a surge in plasma catecholamines and a simultaneous increase in platelet aggregability to peak levels, which corresponds to the peak incidence of cardiovascular and cerebrovascular events (103-107). The hypothesis that OSA might predispose to such ischemic events is plausible because the longest REM episode with the most severe apneas generally occurs just before awakening in the morning. Moreover, in contrast to healthy subjects, in patients with OSA, platelet aggregability increases significantly overnight in association with elevated nocturnal catecholamine levels (108-111). Abolition of OSA by CPAP has been reported to reduce platelet aggregability in association with reductions in overnight catecholamine levels (109, 110, 112).

OSA is also associated with laboratory evidence of a predisposition to clot formation. For example, hematocrit is increased, probably due to nocturnal hypoxemia (113). Overnight and daytime fibrinogen levels (114), as well as whole blood viscosity (115), are also elevated. The mechanisms for these associations remain to be determined. Nevertheless, the observations that CPAP therapy can alleviate some of these abnormalities and can reduce Factor VII clotting activity (116) suggest that OSA is contributing to them. However, definitive evidence that OSA predisposes to clot formation awaits further research.

Potential adverse cardiovascular physiological effects of sleep apnea are listed in Table 1.


Acute Effects
 Reduced myocardial oxygen delivery
  Intermittent hypoxia
  Decreased cardiac output
 Increased myocardial oxygen demand
  Arousals from sleep
  Sympathetic nervous system activation
  Increase in left ventricular afterload
   Negative intrathoracic pressure
   Increased blood pressure
  Increased heart rate
 Nocturnal myocardial ischemia
 Nocturnal pulmonary edema
 Cardiac arrhythmias
Chronic Effects
 Autonomic cardiovascular derangements
  Sympathetic nervous system activation
  Reduced heart rate variability
  Impaired baroreflex control of heart rate
  Systemic hypertension—nocturnal and diurnal
 Myocardial effects
  Left ventricular hypertrophy
  Left ventricular dysfunction and failure
 Increased platelet aggregability and blood coagulability
  Increased susceptibility to thrombotic and embolic cardiac and    cerebrovascular events


Despite the large number of cross-sectional or case-controlled epidemiological studies describing associations between OSA and various cardiovascular diseases (CVD), the issue of whether OSA independently increases the risk of CVD has been contentious. However, as the results of well-designed large-scale studies are becoming available, the issue is approaching resolution in favor of a significant relationship.

The difficulty in establishing whether there is a causal link between OSA and CVD is made particularly challenging by at least four factors. First, any associations between OSA and CVD observed in cross-sectional studies must always be interpreted in light of numerous potentially confounding variables, such as obesity. Second, the results of many epidemiological studies may not be comparable because of the use of different techniques to establish the diagnosis and severity of sleep-disordered breathing. Third, it may require many years to decades for any CVD to develop as a result of exposure to OSA. Finally, until recently there has not been a suitable animal model to study the long-term cardiovascular effects of OSA.

Attempts to control for confounding variables may themselves introduce problems, especially if statistical adjustments are made for variables that are part of the causal pathway (117). For instance, some studies investigating the link between OSA and CVD control for preexisting hypertension. However, if OSA leads to CVD through its effects on BP, any statistical adjustment for hypertension will tend to “overcontrol” for this variable, concealing a genuine association. Moreover, current measurements of OSA, such as apnea–hypopnea index, may not accurately reflect the most relevant pathophysiologic aspects of OSA contributing to CVD. Because the frequency of apnea and hypopneas per hour of sleep (apnea–hypopnea index or AHI) is likely a very imperfect reflection of the physiological burden of OSA in a given individual, the resulting extraneous variability will obscure attempts to find associations between this measure of OSA and CVD. Some combination of frequency and duration of apneas, frequency and degree of desaturations, and Pco 2 and frequency of arousals might provide a better overall index of the cardiovascular burden of OSA. For all these reasons, it is critically important that the design of epidemiological studies takes into account these issues, and that it controls for the right potentially confounding independent variables, but that it does not “overcontrol” for other variables that may not be independent of sleep apnea.

With respect to sleep recording techniques, the use of sophisticated instrumentation under well-controlled conditions is the best way to detect, classify, and quantify sleep-disordered breathing, and its influence on respiratory, neurological, and cardiovascular variables. Accordingly, epidemiological studies that employ full polysomnography are more likely to yield reliable results than are those in which only one or a few variables, such as O2 saturation, are recorded.

It is well established that hypertension leads to CVD only after years to decades of exposure (118). The same may be true of OSA. Therefore, the best means of investigating the potential impact of OSA on CVD risk is through large-scale, long-term prospective epidemiological studies. Another approach to determine whether OSA causes CVD is through the use of animal models. Fortunately, a canine model of OSA has been developed (119) that allows chronic exposure of dogs to repetitive upper airway occlusions during sleep.

In view of the above, it is clear that studies that have adhered to the principles of controlling for confounding variables, use of proper instrumentation and prospective designs for epidemiological studies, and exploitation of appropriate animal models of disease are those most likely to yield reliable results. Consequently, in the following discussion, we emphasize the findings of those studies that have employed one or more of the above principles to establish the clearest picture of the extent to which OSA may be a risk factor for various CVDs.


Hypertension, which affects 20% of the adult population, is one of the commonest diseases in North America (118). It is a major risk factor for the development of coronary artery disease, CHF, and strokes. Moreover, effective therapy of hypertension reduces the risk of developing these disorders. However, in only 5–10% of cases of hypertension is an underlying secondary cause identified. It is in this context that the potential importance of OSA as a secondary and possibly treatable cause of hypertension must be viewed.

Methodologically rigorous population-based studies have yielded convincing evidence in favor of a modest, but definite association between OSA and systemic hypertension, independent of age, obesity, or other confounding factors (120-122). The Sleep Heart Health study employed in-home polysomnography (120) in a cross-sectional analysis of 6,132 subjects. A clear independent association between OSA and hypertension was observed in which the prevalence of hypertension increased with increasing AHI. However, the association was quite modest with an adjusted odds ratio for the most severe OSA category, AHI > 30 (versus AHI < 1.5) of only 1.37 (CI 1.03–1.83). Similarly, in a cross-sectional analysis of 1,069 subjects who underwent in-laboratory polysomnography in the Wisconsin Sleep Cohort Study (121) a significant linear increase in daytime BP with increasing AHI was observed. The association between OSA and hypertension was stronger in this study with an adjusted odds ratio for hypertension associated with AHI > 30 (versus < 1) of 3.1 (CI 1.7–5.7). Furthermore, results have recently been reported from prospective follow-up of 893 of those subjects over 4 to 8 yr (122). The odds ratio for the new onset of hypertension at follow-up assessments, associated with the presence of OSA at baseline, was 2.89 (CI 1.46–5.64 for an AHI > 15 versus 0). These are the strongest epidemiological data yet demonstrating an association between OSA and daytime hypertension. Indeed, they support the notion that OSA contributes to the development of hypertension.


The most compelling experimental evidence that OSA can cause hypertension comes from studies in animals. Brooks and coworkers (119) demonstrated that exposure of dogs to obstructive apneas during sleep for 1–3 mo caused chronic elevations in BP both during sleep and wakefulness. In addition, reversal of OSA caused nocturnal and daytime BP to fall back to baseline levels within 1–4 wk. However, exposure of the same dogs to acoustic stimuli during sleep, which provoked arousals and acute BP elevations equal to those observed during OSA, did not lead to diurnal hypertension. Similar results have been described in rats (123). These findings indicated that arousals from sleep were insufficient to cause diurnal hypertension, but that additional stimuli related to OSA were necessary for its development.

The mechanisms through which OSA promotes hypertension have not been fully elucidated. However, converging evidence from physiological studies in humans and animals points toward intermittent hypoxia and sympathetic nervous system activation playing central roles. As described above, elevated sympathetic vasoconstrictor nerve traffic in OSA appears to be sustained into wakefulness through chronic alterations in chemoreflex sensitivity and baroreflex set point. Together, these may promote upregulation of sympathetic vasoconstrictor tone. Conversely, when OSA is eliminated by CPAP, sympathetic vasoconstrictor activity falls both acutely at night (41) and chronically during wakefulness (58, 59) in association with reductions in BP.

Consistent with these observations, Fletcher and colleagues demonstrated that intermittent exposure of rats to hypoxia for 8 h/d over 35 d induced sustained arterial hypertension (124). Elevations in BP were prevented by both carotid body and sympathetic nervous system denervation (125, 126). These observations indicated that episodic hypoxia exerted its long-term effects on BP through stimulation of the peripheral chemoreceptors, which are potent stimulators of brainstem sympathetic vasoconstrictor outflow. Additional studies demonstrated that exposure of rats to intermittent hypoxia provoked increased activity of the adrenal glands, renal sympathetic nerves, and the renin angiotensin system, all of which could promote increases in BP (127, 128). Recent work also suggests that patients with OSA have an increased pressor response to hypoxia (66). However, although abnormal vascular endothelial-mediated vasodilatory and constrictor responsiveness has been postulated as contributing to hypertension in OSA, data on these points are inconclusive (66, 68, 93-97).

Another interesting observation arising from these experiments was that sustained elevations in BP in response to intermittent hypoxia occurred only in certain spontaneously hypertensive strains of rats. These observations therefore suggest that vascular responses to intermittent hypoxia are at least partially under genetic control. They further imply that there may be a subset of humans and animals with a genetic predisposition to the development of systemic hypertension in response to OSA. If so, this might explain why, among patients with OSA of equal severity, some develop hypertension and others do not.

In summary, animal models of OSA strongly support the notion that sustained diurnal hypertension can arise from chronic exposure to recurrent obstructive apneas. However, findings from these experiments in animals must be interpreted with a few caveats. First, there may be important differences in response to apneas between species. Second, OSA in humans probably evolves over many years, which could allow for the development of compensatory protective mechanisms. Findings derived from animal models in which severe sleep apnea is rapidly introduced may not be generalizable to the human disease state. Notwithstanding these reservations, animal models have provided powerful evidence for a direct causative link between OSA and daytime hypertension.

Clinical significance.

In the controversy about whether OSA can lead to daytime hypertension, one point that is frequently overlooked is that OSA undoubtedly causes elevations in BP during sleep. Considering that humans typically spend one-third of their lives sleeping, it is necessary to consider the possibility that these nocturnal increases in BP might in themselves contribute to hypertensive cardiovascular complications (129-132).

The normal nocturnal decrease in BP averages about 15% below daytime levels and is generally preserved in patients with essential hypertension (i.e., “dippers”). In contrast, many OSA patients are “nondippers” because they have an attenuated or absent fall in nocturnal BP (133-135). It is therefore possible that many patients with essential hypertension who have a “nondipping” pattern of nocturnal BP have undiagnosed OSA. For example, Portaluppi and coworkers (135) reported the presence of unsuspected OSA in 10 of 11 “nondipping” patients with hypertension but in none of 10 “dipping” patients with hypertension. These results imply that the “nondipping” condition is probably related to sleep apnea in many cases of essential hypertension. Because “nondipping” is associated with a higher risk of cardiovascular complications independent of daytime BP levels (129-132), the debate about whether OSA leads to daytime hypertension may be less important than previously supposed.


A number of studies have suggested that hypertension in patients with OSA is more difficult to control by conventional means than is hypertension in nonapneic patients (136). Conversely, OSA is common in patients with difficult to control hypertension (137). Furthermore, it has been recently reported that in patients whose hypertension was refractory to maximal medical therapy, 87% had OSA (138). Taken together, these findings suggest that hypertensive patients with OSA may be relatively resistant to the antihypertensive medications.

Among the commonly prescribed antihypertensive agents, β-blockers have been reported to be the most effective in lowering daytime BP in hypertensive patients with OSA (139). This observation is in keeping with the hypothesis that sympathetic overactivity is involved in the pathogenesis of OSA-induced hypertension. However, antihypertensive medications have little effect on nocturnal BP in OSA, possibly because they do not alleviate OSA (139, 140).

A number of uncontrolled studies have reported that reversal of OSA by tracheostomy or CPAP in patients who were normotensive while awake was associated with a reduction in BP and MSNA during sleep (41, 57). Similar results have been reported in patients with heart failure with OSA who were on BP lowering medications (38).

Several randomized (141-143) and nonrandomized (144– 147) clinical trials have addressed the effects of CPAP on daytime BP in patients with OSA. However, these studies suffered from a serious flaw in design; the great majority of patients studied were normotensive while awake. Not surprisingly, the effects of CPAP on diurnal BP were trivial or nonexistent. Only one nonrandomized trial has examined the effects of CPAP in patients with OSA all of whom were hypertensive while awake despite aggressive antihypertensive therapy. Logan and coworkers (148) found that treatment of these patients with CPAP over a 2-mo period led to clinically significant reductions in both nocturnal and daytime BP. Although not definitive, these results do emphasize the need for well-designed randomized trials to ascertain with certainty whether treating OSA will lower daytime BP in patients with hypertension. The findings of such studies will be very important because OSA may well prove to be the commonest, potentially treatable secondary cause of hypertension.


In North America, stroke is the third leading cause of death and the leading cause of long-term disability (149, 150). The first large-scale population-based study to examine the potential relationship between sleep apnea and stroke was in 6,424 subjects in the Sleep Heart Health Study. The presence of OSA was associated with a clear, but modestly increased prevalence of stroke; the odds ratio for the highest AHI quartile (AHI > 11) was 1.58 times (CI 1.02–2.46) that of the lowest quartile (AHI < 1.4) (151).

Among subjects who have suffered a stroke, sleep apnea is extremely common and is reported to occur in 43–91% of patients (152-156). These prevalences are significantly higher than in control subjects without stroke. In all these studies, OSA predominated, whereas central sleep apnea (CSA) was observed in only a small minority of patients (less than 10%). It remains unclear, however, to what extent sleep apnea detected following a stroke might be a consequence of the stroke, rather than a preexisting condition. Bassetti and Aldrich (154) argued that OSA most likely preceded stroke, based on the observation that the frequency and severity of sleep apnea did not differ between patients with stroke and those with transient ischemic attacks. In addition, Parra and colleagues (156) found that the frequency of obstructive apneas did not decline between the period immediately after the stroke to 3 mo later. However, there was a decline in frequency of central apneas. These data suggested that acute stroke predisposed to development of CSA, but that OSA was more likely already present at the time of the stroke.


A number of mechanisms through which OSA could predispose to cerebrovascular events are discussed above. These include systemic hypertension, increased platelet aggregability, and blood coagulability (109, 110, 112). In addition, during obstructive apneas there is a significant decline in cerebral blood flow due mainly to a reduction in cardiac output (157, 158). The decline in cerebral perfusion is also tightly linked with reductions in BP, which could predispose to cerebrovascular accidents in subjects with flow-limiting lesions of the carotid or vertebral circulations. This would be of particular relevance during REM sleep when cerebral blood flow and oxygen demands are normally highest, but when apneas are accompanied by the greatest degrees of hypoxia (159). Such an imbalance could put the cerebral circulation at risk, especially during the early morning hours during, or immediately following, the longest episode of REM sleep (106, 153, 160). In addition, abrupt and marked alterations in blood flow velocity associated with alternating obstructive apneas and hyperpneas could lead to abrupt alterations in vascular shear forces, and acceleration of atherosclerosis (159, 161, 162).

Central apneas have been reported, in a number of older studies, to be associated with bilateral hemispheric and brainstem infarctions (163-167). However, in all except one of these studies (167), sleep monitoring was not performed and potential behavioral influences related to wakefulness could not be ruled out. More recent data have not detected an association between stroke location and apnea type (156). The observation that central apneas dissipate over time following stroke suggests that strokes may promote central apneas in the immediate poststroke period, but as brain inflammation and edema resolve, so do central apneas. However, there are as yet insufficient physiological data to determine the type (hypercapnic or nonhypercapnic) or etiology of central apneas in the poststroke period (168).

What has become clear, however, is that Cheyne–Stokes respiration is decidedly uncommon following stroke. Thus the attribution of Cheyne–Stokes respiration to cerebral damage in the older literature (169) must be reevaluated in light of more recent findings. Because Cheyne–Stokes respiration is essentially periodic breathing with a long cycle length, and because cycle length is inversely proportional to cardiac output (40), it is possible that this breathing disorder is a sign of underlying cardiac dysfunction (see below). In fact, coronary artery disease is present in approximately one-third of patients with stroke and, over the long term, cardiac events are the leading cause of death following stroke (170). It is therefore possible that in the older studies of Cheyne–Stokes respiration in poststroke patients, underlying cardiac dysfunction may have been present, but undetected (165, 166, 169). Consequently, the pathophysiology and clinical significance of CSA following stroke remain to be elucidated.

Clinical significance.

When sleep apnea is present following a stroke, it could further compromise cognitive and physical functioning. For example, OSA is associated with excessive daytime sleepiness and impaired cognitive function, reaction times, and simulated driving performance (171, 172). In addition, apnea-related hypoxia can lead to the elaboration of neuroinhibitory peptides, such as γ-aminobutyric acid, which could also further compromise cerebral function (173). Indeed, following a stroke, patients with OSA have worse functional capacity than patients without OSA. This difference could not be attributed to differences in the severity of the stroke (152, 153).


Well-designed randomized clinical trials in which the effects of treating sleep apnea on neurological outcomes in patients with strokes have yet to be performed. Such studies need to be undertaken, for they will provide the evidence upon which a rational approach to the diagnosis and treatment of sleep apnea in patients with strokes will be based.

Ischemic Heart Disease

In a cross-sectional analysis of the Sleep Heart Health Study cohort, OSA was found to be an independent risk factor for coronary artery disease (CAD) (151). However, the association was modest; the odds ratio for CAD of the highest AHI quartile (AHI > 11) was 1.27 times (CI 0.99–1.62) that of the lowest quartile (AHI < 1.4). Prospective follow-up of the cohort should provide additional insights into the relationship between OSA and CAD. Because it has been established that OSA increases the risk for hypertension, it seems likely that it would also increase the risk for disorders, such as CAD, that are associated with hypertension.


As described above, OSA exerts several acute physiological effects that could predispose to myocardial ischemia during sleep. In dogs with experimentally induced coronary artery stenosis, obstructive apneas can lead to myocardial ischemia even in the absence of hypoxia (174, 175). However, in the absence of a coronary stenosis, myocardial ischemia was not observed. Others have reported that electrocardiographic signs of ischemia in patients with OSA with CAD were more closely linked to increases in HR and BP related to apneas than to O2 desaturation. These observations suggested that the main trigger of ischemia was an increase in O2 demand rather than a reduction in supply (176). In another study, Mueller maneuvers, which simulated the effects of obstructive apneas, caused more pronounced reductions in LV ejection fraction (LVEF) in humans with, than in those without CAD (177). These findings emphasize that the diseased myocardium is more susceptible to the adverse effects of obstructive apneas than is the normal myocardium.

Clinical significance.

Nocturnal ST-segment changes consistent with myocardial ischemia are quite common among patients with OSA and coexisting CAD. Various studies have reported prevalences of such ischemic changes ranging from 20 to 100% (176, 178-182). ST-segment depressions are more frequent in those with more severe OSA or prior complaints of nocturnal angina (179, 180). Ischemic episodes have been related both to O2 desaturation and to the postapneic surges in HR and BP (176, 179, 180), and can provoke awakening with complaints of angina (179-181) (Figure 3). Myocardial ischemia during sleep in patients with OSA may also be asymptomatic (i.e., silent). However, to date, there are no reports of the prevalence of OSA among patients with CAD with silent nocturnal ischemia.

Studies in patients with OSA without coexisting CAD have been less consistent. In some, no evidence of nocturnal ischemic episodes in such patients was reported (176, 183, 184), whereas in another, ST-segment depressions during the night occurred in 30% of patients (185). Acute application of CPAP to these patients significantly reduced the total duration of ST-segment depression. The reason for discrepancies between these studies remains unclear. Accordingly, there is uncertainty as to whether OSA causes nocturnal myocardial ischemia in the absence of CAD.

In patients with CAD, OSA may be a poor prognostic indicator. Among 62 patients with CAD followed prospectively for 5 yr, Peker and coworkers (186) found that those with OSA had a significantly higher mortality rate (38%) than those without OSA (9%, p = 0.018), even after controlling for potentially confounding factors.


There are no published randomized trials on the effects of treating OSA on nocturnal myocardial ischemia and angina. However, in uncontrolled studies, treatment of OSA with CPAP in patients with nocturnal angina was associated acutely with reduced frequency of ST-segment depression and chronically with relief of nocturnal angina (176, 179, 180). Nevertheless, larger, longer term randomized trials are required to more clearly delineate the role of diagnosing and treating OSA in patients with CAD.

Congestive Heart Failure

Observations from epidemiological studies indicate an association between OSA and CHF. In the Sleep Heart Health Study, the presence of OSA (i.e., AHI ⩾ 11) was associated with a 2.38 relative odds for CHF independent of other known risk factors (151). This risk exceeded that for all other cardiovascular diseases examined including hypertension, CAD, and stroke. In the two largest series of patients with CHF with systolic dysfunction evaluated for sleep-disordered breathing, 11% of 81 patients (187) and 37% of 450 patients (188) had OSA. This prevalence exceeds the approximate 5–10% prevalence of OSA reported in otherwise healthy adults (189). Risk factors for OSA among patients with CHF differed by sex: among men only increasing body mass index, and among women only increasing age were significant (188).

In addition, as many as one-third of patients with clinical CHF have normal systolic function, but are thought to have diastolic dysfunction (190). Diastolic dysfunction results from inadequate diastolic filling due to reduced LV compliance. There has been only one study examining the prevalence of sleep-disordered breathing in diastolic heart failure. Chan and coworkers (191) found that 55% of 20 patients with this condition had an AHI > 10. Of these, approximately two-thirds had predominantly obstructive apneas, suggesting that OSA may play a role in the development of diastolic dysfunction. Taken together, these epidemiological data raise the possibility that OSA can contribute to the development of both systolic and diastolic LV dysfunction.

On the other hand, there remains the possibility that CHF itself can contribute to the development of OSA. Two lines of evidence support this view. First, it has long been hypothesized that an underlying tendency to periodic breathing could destabilize the upper airway and predispose to collapse. Patients with CHF are predisposed to periodic breathing because of increased chemosensitivity, hyperventilation, and, possibly, prolonged circulation time (192-194). According to this view, as respiratory drive declines during the waning phase of periodic breathing, drive to the pharyngeal dilator muscles declines as well (195, 196). Should the relative reduction in pharyngeal dilator muscle tone exceed that of the diaphragm, upper airway collapse could ensue. Indeed, in contrast to the abrupt rise and rapid fall in tidal volume that characterizes OSA in patients with normal cardiac function, in patients with CHF with OSA, tidal volumes during hyperpneas often have a waxing–waning appearance typical of Cheyne–Stokes respiration (38). This suggests the presence of an underlying periodic breathing disorder. Second, since patients with CHF suffer from fluid retention and dependent edema, it is possible that upon reclining, accumulation of edema in the soft tissues of the neck and pharynx could narrow the upper airway and make it more collapsible (197). Nevertheless, regardless of the underlying cause of upper airway collapse in patients with CHF with OSA, it is rapidly reversed by acute application of CPAP (38, 198).


As discussed above, and illustrated in Figure 4, OSA exposes the left ventricle to several factors that could impair its function. It is conceivable that over months to years, these factors could have cumulative adverse effects on LV structure and diastolic and systolic function in some individuals.

There are several case reports of patients presenting with acute nocturnal pulmonary edema who were subsequently found to have OSA, but normal LV systolic function (199, 200). Treatment of OSA with CPAP was associated with a reduction in episodes of pulmonary edema. These cases suggest that the adverse effects of OSA can be sufficient to cause acute LV failure during sleep in susceptible individuals.

Hypertension is the single most important predisposing factor for the development of LV hypertrophy and systolic and diastolic LV failure (201, 202). Accordingly, the most obvious mechanism through which OSA could lead to the development or progression of LV failure is systemic hypertension. However, ischemia and reduced contractility due to hypoxia (42), as well as cardiac myocyte injury or necrosis due to increased catecholamine stimulation (203), could also contribute. Regardless of the precise mechanisms involved, there is now direct experimental evidence that OSA can lead to interstitial pulmonary edema as well as LV hypertrophy and dysfunction. In anesthetized dogs, Fletcher and colleagues (204) demonstrated the development of subtle degrees of interstitial pulmonary edema after 8 h of exposure to recurrent obstructive apneas. In addition, Parker and coworkers (34) showed that exposure of dogs to experimental obstructive apneas during sleep for several weeks to months led to the development of increased LV mass and reduced ejection fraction in association with systemic hypertension. However, it is not clear whether OSA can lead to LV hypertrophy in humans. Whereas one study reported greater LV wall thickness in normotensive OSA patients than in normotensive control subjects (205), another did not (206).

Clinical significance.

Because the diseased left ventricle is more susceptible to the negative hemodynamic effects of increases in afterload than the normal left ventricle (207), OSA may have particularly deleterious effects in patients with coexisting heart disease. For example, when humans with CHF are exposed to exaggerated negative intrathoracic pressure during Mueller maneuvers, they experience greater reductions in stroke volume and cardiac output that persist longer into the postapneic period than in subjects with normal ventricular function (208). In addition, survival in CHF is inversely proportional to cardiac noradrenergic drive (209). Therefore, elevated SNA associated with OSA (41, 53, 54) would have particularly adverse prognostic implications in patients with coexisting heart failure.


Only one study has examined the effects of treating OSA on LV systolic function in patients with CHF. Malone and colleagues (198) demonstrated, in eight patients with idiopathic dilated cardiomyopathy, that treatment of coexisting OSA by CPAP for 1 mo caused dramatic improvements in LVEF (from 37% to 49%) and cardiac functional status. Although these data are encouraging, larger randomized trials will be required to determine whether treatment of OSA in patients with systolic and diastolic heart failure improves cardiac function and other cardiovascular outcomes. The findings of the above mentioned study also suggested that OSA can contribute to the development of LV systolic dysfunction in patients with CHF of otherwise unknown etiology.


Cheyne–Stokes respiration with central sleep apnea (CSR–CSA) is a form of periodic breathing in which apneas and hypopneas alternate with ventilatory periods having a waxing–waning pattern of tidal volume (Figure 5). CSR–CSA is common among patients with CHF, being present in 30–40% in the largest reported series (187, 188). Growing evidence indicates that CSR–CSA is part of a vicious pathophysiological cycle involving the cardiovascular, pulmonary, and autonomic nervous systems that contributes to the progression of CHF (210-212). However, although CSR–CSA is common in men, it is seldom seen in women with CHF for reasons that remain to be fully elucidated (188). This observation may help to account for the higher mortality rate for men than for women following the onset of CHF (213).


Figure 6 provides a schematic representation of the pathophysiology of CSR–CSA. The key pathophysiological mechanism leading to CSR–CSA is a fluctuation of PaCO2 below and above the apneic threshold. When PaCO2 is periodically driven below threshold by intervening episodes of hyperventilation, central neural outflow to the respiratory muscles is temporarily suppressed and central apneas ensue. A number of factors can contribute to respiratory control system instability and predispose to fluctuations in PaCO2 .


Patients with CHF with CSR–CSA have lower PaCO2 both during wakefulness and sleep than those without CSR–CSA (194, 214, 215). Moreover, episodes of CSR–CSA are usually triggered by abrupt increases in ventilation and reductions in PaCO2 below the apneic threshold (194). Inhalation of a CO2-enriched gas mixture sufficient to raise PaCO2 by just 1–3 mm Hg eliminates central apneas and hypopneas both in patients with CSR–CSA and idiopathic CSA (216, 217). These findings also emphasize that the prevailing PCO2 in patients with CSR–CSA is closer to their sleeping apneic threshold (i.e., within 1–3 mm Hg) than it is in healthy subjects whose prevailing PaCO2 is 3–5 mm Hg above the sleeping apneic threshold (218). Under this condition, even a modest increase in ventilation can drive PaCO2 below the apneic threshold (194, 219).

The mechanisms responsible for chronic hypocapnia in patients with CSR–CSA have not been fully elucidated. One possible explanation is hypoxia. However, both awake and mean nocturnal SaO2 in patients with CHF with CSR–CSA are usually within normal limits and do not differ from those in patients with CHF without CSR–CSA (194, 214, 220). Another possibility is that hyperventilation arises from stimulation of pulmonary vagal irritant receptors by increased LV volumes, filling pressures, and pulmonary congestion (220-222). In favor of this hypothesis, Solin and coworkers (223) demonstrated significantly higher pulmonary capillary wedge pressures and lower PaCO2 in patients with CHF than in those without CSR– CSA. Others have demonstrated an inverse relationship between PaCO2 and LV filling pressure in patients with CHF (224). Accordingly, CSR–CSA may be a respiratory manifestation of elevated LV filling pressure (220).

Increased chemoreceptor responsiveness.

Elevated chemoreceptor responsiveness (gain) could destabilize the respiratory control system, both by decreasing the prevailing PaCO2 and by increasing the tendency to hyperventilate, thus precipitating ventilatory overshoot (193, 225, 226). Several studies have demonstrated higher central (227, 228) and peripheral chemoresponsiveness (229, 230) in patients with CHF with either periodic breathing while awake or CSR–CSA than among those either with OSA or without any sleep apnea. It remains to be determined whether such increases in central and peripheral chemoresponsiveness predates or is a consequence of the development of CHF (231). Evidence for the latter hypothesis comes from experiments in rabbits in whom induction of CHF led to increased peripheral but not central chemosensitivity (193). These results support the notion that CHF itself can sensitize the peripheral chemoreceptors, possibly by impairing the ventilatory inhibitory effect of carotid body nitric oxide production (193).


The role of hypoxia in the pathogenesis of CSR– CSA in heart failure is uncertain. Studies of patients with CHF and CSR–CSA have consistently shown them to be normoxic while awake (194, 214). Nevertheless, hypoxic dips during apneas may propagate CSR–CSA by provoking arousals and amplifying the ventilatory response to CO2 at the termination of central apneas (225). A number of studies have investigated the effects of supplemental O2 in patients with CHF and CSR– CSA, with varying results. In general, where O2 was administered at high flow rates, the frequency of central respiratory events was significantly reduced (232-234). In one study, reductions in central apneas were associated with increases in PCO2 (235). This observation suggested that increases in PaO2 suppressed respiratory drive allowing PaCO2 to rise above the apnea threshold (235). In contrast, during studies in which O2 was administered to patients with CSR–CSA at lower flow rates just sufficient to raise SaO2 into the normoxic range, little or no effect was observed on the frequency of central events or on PCO2 (216, 236). It is therefore likely that where supplemental O2 reduces the severity of CSR–CSA, it does so partly by raising PaCO2 .

State changes and arousals.

Shifts in the state of consciousness are likely to destabilize breathing. With the transition from wakefulness to NREM sleep, the waking neural drive to breathe is lost, and the threshold for a ventilatory response to CO2 is increased (4). Therefore, if the ambient PaCO2 during wakefulness is below this higher sleeping threshold, the transition to NREM sleep will be accompanied by a transient loss of respiratory drive resulting in a central apnea. During the apnea, PaCO2 rises until it reaches the new higher threshold level and initiates breathing. If sleep becomes firmly established, regular breathing resumes (237). However, if an arousal should occur, the increased PaCO2 level associated with sleep now represents a state of relative hypercapnia for wakefulness and will stimulate hyperpnea. In addition, other studies have demonstrated that arousals cause ventilation to rise above the waking level independent of PaCO2 (17). Accordingly, arousal contributes independently to ventilatory control system instability.

The role of arousal in CSR–CSA contrasts with its role in OSA where it is a critical defense mechanism that terminates apneas by triggering opening of the upper airway. In CSR– CSA, however, arousals often occur after airflow has resumed. It therefore appears that resumption of airflow following central apneas is not always dependent on an arousal (194, 214, 219). Paradoxically, arousals actually trigger and propagate central apneas and therefore contribute to their genesis. Indeed, the critical role of arousals in sustaining ventilatory overshoot during periodic breathing has been demonstrated both in patients with CSR–CSA and those with idiopathic CSA, a disorder that shares many features of CSR–CSA (194, 237, 238).

In contrast to OSA, CSR–CSA is more pronounced during NREM sleep, where chemical–metabolic factors are the predominant influence on ventilatory control, than during REM sleep where behavioral nonmetabolic factors predominate (21, 194, 219). In addition, during REM sleep arousability to respiratory stimuli is diminished compared with the lighter stages of NREM sleep. As a result, the tendency to ventilatory overshoot and hypocapnia is diminished in REM sleep, which dampens CSR–CSA. Similarly, in the deeper (i.e., slow wave) stages of NREM sleep where arousability is also decreased, CSR–CSA tends to dissipate (194). Although Cheyne–Stokes respiration can be observed in wakefulness (18, 219), it is much less common here than in NREM sleep probably because of nonmetabolic and behavioral influences.

Upper airway instability.

Upper airway obstruction has been described at the onset and at the end of central apneas in some patients with CHF (195) and could promote ventilatory overshoot upon the abrupt decrease in upper airways resistance at the termination of apneas (196). It is also possible that upper airway collapse itself can reflexively precipitate central apneas (239). A more likely possibility in the setting of CHF, however, is that adverse effects of OSA on cardiac function can predispose to central apneas. In patients with CHF having approximately equal numbers of obstructive and central apneas, obstructive apneas predominate at the beginning of the night, whereas central apneas predominate at the end. The shift from obstructive to central events occurred in association with a decrease in Pco 2 and prolongation of circulation time (240). Thus, obstructive events likely converted to central events as Pco 2 fell below the apneic threshold due to an overnight deterioration in cardiac function. Such deterioration probably arose from the combined effects of OSA and of increasing venous return in the recumbent position that raised LV filling pressure and lowered Pco 2 (240, 241). These observations raise the question as to whether OSA could, over time, predispose to CSR–CSA after the onset of cardiac failure.

Prolonged circulation time.

Prolonged circulation time causing delays in transmitting changes in arterial blood gas tensions within the lungs to the chemoreceptors could theoretically destabilize the respiratory control system. It could do so by changing a negative feedback into a positive feedback system (226). In support of this theory, Guyton (242) induced periodic breathing in dogs by inserting a length of tubing between the heart and cerebral circulation to prolong transit time between the lungs and the chemoreceptors. However, CSR–CSA could be generated only when the circulatory delay was a few minutes in duration, far exceeding that seen in patients with CHF. In humans, lung to peripheral chemoreceptor circulation time is inversely proportional to stroke volume and cardiac output (40). Mortara and coworkers (243) found, in patients with CHF, that prolonged circulation time was a major determinant of the presence of CSR–CSA. In contrast, other investigators have found no significant differences in LVEF, circulation time, or cardiac output between patients with CHF with and without CSR–CSA (194, 210, 223). Taken together, these data suggest that prolonged circulatory delay is probably not the critical factor predisposing to central apneas in CHF. However, circulatory delay influences periodic breathing cycle length such that cycle length is proportional to lung to carotid body circulation time (40). This accounts for the greater length of the periodic breathing cycle in patients with CHF than in subjects with idiopathic CSA whose cardiac function is normal.

Clinical Significance

CSR–CSA shares several pathophysiological features of OSA including episodic hypoxia and arousals from sleep. However, unlike OSA, generation of exaggerated negative intrathoracic pressure is not a feature of CSR–CSA. Therefore, the overall burden of CSR–CSA may not be as great as that of OSA. Nevertheless, several studies indicate that this burden is clinically significant.

Frequent arousals in association with CSR–CSA contribute to sleep fragmentation and excessive daytime sleepiness in patients with CHF (244, 245). More importantly, CSR–CSA contributes to higher rates of death and cardiac transplantation in patients with CHF in proportion to the frequency of central events, independently of other risk factors (210-212) (Figure 7).

CSR–CSA provokes oscillations in HR and BP, similar to those seen during OSA: peaks occur during hyperpnea and troughs during apnea. However, increases in HR and BP progress to peak levels more gradually, paralleling gradual increases in ventilation (18). This probably reflects the gradual progression of hypoxia and sympathetic activation due to prolonged circulatory delay. The mechanisms mediating these oscillations are not completely understood. They could be related to the same mechanisms that have been implicated in OSA (see above), including hypoxia and arousals from sleep. However, in cases of CSR–CSA in which central apneas continue despite abolition of apnea-related hypoxia by supplemental O2, periodic oscillations in HR and BP persist (236). This observation indicates that mechanisms other than hypoxia are involved.

Arousals may contribute to oscillations in BP during CSR– CSA. However, Trinder and colleagues (18) found that the major contribution to BP oscillations during CSR–CSA in NREM sleep were ventilatory oscillations. Arousals caused small, but significant further increases in BP, but these were proportional to the accompanying increase in ventilation. In addition, among those patients with CHF who had Cheyne–Stokes respiration while awake, periodic oscillations in BP, related to oscillations in ventilation, persisted in the absence of arousals. Similarly, voluntary periodic breathing in awake healthy subjects, under normoxic conditions, causes oscillations in HR and BP proportional to the augmentation of ventilation during the ventilatory phase (52). Accordingly, periodic breathing itself may entrain oscillations in HR and BP (18, 246).

Entrainment of HR and BP by periodic breathing may be due to phase linking of central sympathetic neuronal output to central respiratory drive (247). Regardless of their exact causes, when these HR and BP oscillations are analyzed by frequency spectral analysis, they occur at very low frequency (VLF, < 0.05 Hz). Indeed, HR and BP variability of patients with CHF is often dominated by variability within the VLF range in association with markedly decreased variability in the low-frequency (LF, 0.05–0.15 Hz) and high-frequency (HF, > 0.15 Hz) ranges. This abnormal HR variability in patients with CHF is a sign of autonomic derangement characterized by sympathetic nervous activation and cardiac vagal withdrawal (248, 249). It is also a marker of increased risk of death (229).

However, the potential importance of CSR–CSA in generating such VLF oscillations has only recently been recognized through the convergence of two observations. First, in patients with CHF, VLF oscillations in HR are associated with increased peripheral chemosensitivity (229). Second, CSR–CSA is also associated with augmented central and peripheral chemosensitivity (228, 230). Because augmented chemosensitivity plays an important role in generating CSR–CSA, it became obvious that the relationship between augmented peripheral chemosensitivity and VLF oscillations in HR variability was through the intermediate step of CSR–CSA (52, 192, 216, 246, 250).

CSR–CSA in patients with CHF is associated with increased SNA (251). In one study, norepinephrine concentrations were proportional to the frequency of arousals from sleep and degree of apnea-related hypoxia (252). These data strongly suggest that sympathetic activation in these patients is not simply a compensatory response to low cardiac output, but is directly related to the presence of CSR–CSA. This excessive and pathological sympathoexcitation is likely one factor that contributes to the increased risk of death in patients with CSR–CSA (210-212).

Because of hypoxic dips, arousals from sleep, sympathetic activation, and elevations in HR and BP, CSR–CSA may facilitate ventricular arrhythmias. Javaheri and Corbett (215) found that patients with CHF with hypocapnia (PaCO2 < 35) had both a higher prevalence of central apneas and a higher rate of ventricular ectopy than eucapnic patients. Because one-third of the patients with CHF die suddenly (253), the potential relationship of CSR–CSA with ventricular arrhythmias warrants further investigation.


Because CSR–CSA is associated with a poor prognosis, it should be considered a therapeutic target in CHF (254). However, a detailed discussion of the treatment of CSR–CSA in patients with CHF is beyond the scope of this review. Readers wishing an in depth discussion of this subject are referred to two recent articles (255, 256). The therapeutic approach to CSR–CSA must take into account that CSR–CSA arises from CHF. Accordingly, the first consideration is to optimize anti-heart failure drug therapy (257). Should CSR–CSA persist, a number of other therapeutic options that specifically target CSR–CSA are available.

Various forms of positive airway pressure including CPAP, bilevel, and adaptive pressure support servo-ventilation have been shown to reduce the frequency of central events in patients with CHF (244, 258, 259). The most extensively tested of these over clinically relevant time periods is CPAP. Short-term application of CPAP to patients with stable chronic CHF has been shown to reduce LV afterload (260), augment stroke volume in those with elevated LV filling pressure (261), and reduce cardiac SNA (262). Long-term nightly use of CPAP over 1 to 3 mo has been shown to alleviate CSR–CSA (244, 258) (Figure 8), increase LVEF (263) and inspiratory muscle strength (264), and reduce mitral regurgitation, atrial natriuretic peptide (265), and SNA (252). It has also been shown to improve quality of life (263).

The largest and longest randomized-controlled clinical trial of CPAP for CHF involved 66 patients, 29 with and 37 without CSR–CSA (212). Over a follow-up period of up to 5 yr, patients in the CSR–CSA group who complied with CPAP experienced a significant reduction in the combined rate of mortality and cardiac transplantation (Figure 8). In contrast, among patients with CHF without CSR–CSA those randomized to CPAP did not experience any significant decrease in the mortality–cardiac transplantation rate. However, these results cannot be considered definitive because of the small number of patients involved. Nevertheless, they do indicate the need for a larger long-term multicenter trial involving patients with CHF with CSR–CSA. Such a trial, the Canadian Continuous Positive Airway Pressure Trial for Congestive Heart Failure (CANPAP), is presently underway (266).

The effects of nocturnal supplemental O2 on CSR–CSA in patients with CHF have been examined over periods of one night to 4 wk, a time period of little therapeutic consequence in CHF (232, 235, 236, 267). Reductions in the severity of CSR– CSA, a decrease in overnight urinary norepinephrine levels, and an increase in peak O2 consumption during graded exercise with nightly use were reported (233, 234). However, O2 has not been shown to improve direct measures of cardiac function or quality of life. Finally, theophylline has been shown to reduce the severity of CSR–CSA over 5 d, but has not been shown to improve cardiac function, neurohormonal activity, or quality of life (268). Larger, longer-term randomized trials are required to determine which, if any, of these interventions are clinically effective in the management of patients with CHF with CSR–CSA.

Most research in sleep apnea has focused on the pathophysiology of upper airway occlusion in OSA, and the influence of sleep disruption and intermittent hypoxemia on neurobehavioral consequences such as excessive daytime sleepiness, alertness, and cognitive function. This research bore its first tangible fruits with the landmark introduction of nasal CPAP, the most effective and widely used intervention yet developed for OSA (269). With the advent of an effective noninvasive therapy, a number of well-designed randomized clinical trials have established that treatment of OSA by nasal CPAP improves neurobehavioral outcomes (270, 271). However, as reviewed above, an even larger and perhaps more challenging problem has emerged: what is the role of both OSA and CSA in the causation and progression of cardiovascular diseases, and what are the effects of treating sleep-related breathing disorders on cardiovascular end points? Although improvements in neurobehavioral outcomes through the treatment of sleep apnea are important, it can be argued that any beneficial effect of treating OSA and CSA on cardiovascular outcomes could have even greater medical and public health impact. Accordingly, we believe that research in sleep-related breathing disorders is moving into a new and exciting era.

However, advances in this area will require the development of sophisticated animal models to explore pathophysiological mechanisms, and the collaboration of respiratory, cardiovascular, epidemiological, and clinical trials experts to examine the clinical consequences of diagnosing and treating sleep apnea. Clearly, one of the most important challenges now facing the sleep research community is to develop large-scale randomized trials to determine whether treating sleep-related breathing disorders improves cardiovascular outcomes. The challenge becomes even more daunting when population studies indicate that the majority of patients with OSA identified on polysomnography are asymptomatic (189). Hence, many patients with cardiovascular diseases probably have asymptomatic OSA (272). Moreover, treatment of asymptomatic patients with OSA by CPAP has been reported not to improve subjective well being (273). This should not, however, deter further research in this area, because clinical trials have established that the diagnosis and treatment of other asymptomatic diseases, most notably hypertension and hypercholesterolemia, can lead to significant reductions in cardiovascular events (118, 274). Armed with this knowledge, investigators are now in a position to test the possibility that the diagnosis and treatment of sleep-related breathing disorders can improve health outcomes in patients suffering from or at risk for cardiovascular disease.

This work was supported by the Canadian Institutes of Health Research (Grants MOT 11607 and UI 14909). R.S.T. Leung is the recipient of a Canadian Institutes of Health Research Clinician Scientist Phase I Award, and T.D. Bradley is supported by a Canadian Institutes of Health Research Senior Scientist Award.

1. Bradley TDRight and left ventricular functional impairment and sleep apnea. Clin Chest Med131992459479
2. Bradley TD. Breathing during sleep in cardiac disease. In: Saunders NA, Sullivan CE, editors. Sleep and breathing. New York: Marcel Dekker; 1993. p. 787–821.
3. Trinder J. Respiratory and cardiac activity during sleep onset. In: Bradley TD, Floras JS, editors. Sleep apnea: implications in cardiovascular and cerebrovascular disease. New York: Marcel Dekker; 2000. p. 337–354.
4. Phillipson EAControl of breathing during sleep. Am Rev Respir Dis1181978909939
5. Orem J, Osorio I, Brooks E, Dick TActivity of respiratory neurons during NREM sleep. J Neurophysiol54198511441156
6. White DP, Weil JV, Zwillich CWMetabolic rate and breathing during sleep. J Appl Physiol591985384391
7. Somers VK, Dyken ME, Mark AL, Abboud FMSympathetic-nerve activity during sleep in normal subjects. N Engl J Med3281993303307
8. Shepard JWGas exchange and hemodynamics during sleep. Med Clin North Am69198512431264
9. Hornyak M, Cejnar M, Elam M, Matousek M, Wallin BGSympathetic muscle nerve activity during sleep in man. Brain114199112811295
10. Okada H, Iwase S, Mano T, Sugiyama Y, Watanabe TChanges in muscle sympathetic nerve activity during sleep in humans. Neurology41199119611966
11. Mancia GAutonomic modulation of the cardiovascular system during sleep. N Engl J Med3281993347349
12. Khatri IM, Freis EDHemodynamic changes during sleep. J Appl Physiol221967867873
13. Guyenet PG. Lower brainstem mechanisms of respiratory integration. In: Bradley TD, Floras JS, editors. Sleep apnea: implications in cardiovascular and cerebrovascular disease. New York: Marcel Dekker; 2000. p. 61–98.
14. Conway J, Boon N, Jones JV, Sleight PInvolvement of the baroreceptor reflexes in the changes in blood pressure with sleep and mental arousal. Hypertension51983746748
15. Van de Borne P, Nguyen H, Biston P, Linkowski P, Degaute JPEffects of wake and sleep stages on the 24-h autonomic control of blood pressure and heart rate in recumbent men. Am J Physiol2661994H548H554
16. Horner RL, Brooks D, Kozar LF, Tse S, Phillipson EAImmediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs. J Appl Physiol791995151162
17. Horner RL, Rivera MP, Kozar LF, Phillipson EAThe ventilatory response to arousal from sleep is not fully explained by differences in CO(2) levels between sleep and wakefulness. J Physiol5342001881890
18. Trinder J, Merson R, Rosenberg JI, Fitzgerald F, Kleiman J, Bradley TDPathophysiological interactions of ventilation, arousals, and blood pressure oscillations during Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med1622000808813
19. Orem JNeuronal mechanisms of respiration in REM sleep. Sleep31980251267
20. Chandler SH, Chase MH, Nakamura YIntracellular analysis of synaptic mechanisms controlling trigeminal motoneuron activity during sleep and wakefulness. J Neurophysiol441980359371
21. Phillipson EA, Bowes G. Control of breathing during sleep. In: Cherniack NS, and Widdicombe JG, editors. Handbook of physiology: Vol. 2, Control of breathing. Bethesda, MD: Williams & Wilkins; 1986. p. 649–689.
22. Snyder F, Hobson JA, Morrison DF, Goldfrank FChanges in respiration, heart rate, and systolic blood pressure in human sleep. J Appl Physiol191964417422
23. Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Dement WCHemodynamics in sleep-induced apnea. Studies during wakefulness and sleep. Ann Intern Med851976714719
24. Ringler J, Basner RC, Shannon R, Schwartzstein R, Manning H, Weinberger SE, Weiss JWHypoxemia alone does not explain blood pressure elevations after obstructive apneas. J Appl Physiol69199021432148
25. White SG, Fletcher EC, Miller CCAcute systemic blood pressure elevation in obstructive and nonobstructive breath hold in primates. J Appl Physiol791995324330
26. O'Donnell CP, Ayuse T, King ED, Schwartz AR, Smith PL, Robotham JLAirway obstruction during sleep increases blood pressure without arousal. J Appl Physiol801996773781
27. Chen L, Scharf SMComparative hemodynamic effects of periodic obstructive and simulated central apneas in sedated pigs. J Appl Physiol831997485494
28. Brinker JA, Weiss JL, Lappe DL, Rabson JL, Summer WR, Permutt S, Weisfeldt MLLeftward septal displacement during right ventricular loading in man. Circulation611980626633
29. Virolainen J, Ventila M, Turto H, Kupari MEffect of negative intrathoracic pressure on left ventricular pressure dynamics and relaxation. J Appl Physiol791995455460
30. Hall MJ, Ando S, Floras JS, Bradley TDMagnitude and time course of hemodynamic responses to Mueller maneuvers in patients with congestive heart failure. J Appl Physiol85199814761484
31. Guilleminault C, Motta J, Mihm F, Melvin KObstructive sleep apnea and cardiac index. Chest891986331334
32. Tolle FA, Judy WV, Yu PL, Markand ONReduced stroke volume related to pleural pressure in obstructive sleep apnea. J Appl Physiol55198317181724
33. Stoohs R, Guilleminault CCardiovascular changes associated with obstructive sleep apnea syndrome. J Appl Physiol721992583589
34. Parker JD, Brooks D, Kozar LF, Render-Teixeira CL, Horner RL, Bradley TD, Phillipson EAAcute and chronic effects of airway obstruction on canine left ventricular performance. Am J Respir Crit Care Med160199918881896
35. Seals DR, Suwarno NO, Joyner MJ, Iber C, Copeland JG, Dempsey JARespiratory modulation of muscle sympathetic nerve activity in intact and lung denervated humans. Circ Res721993440454
36. Morgan BJ, Denahan T, Ebert TJNeurocirculatory consequences of negative intrathoracic pressure vs. asphyxia during voluntary apnea. J Appl Physiol74199329692975
37. Somers VK, Dyken ME, Skinner JLAutonomic and hemodynamic responses and interactions during the Mueller maneuver in humans. J Auton Nerv Syst441993253259
38. Tkacova R, Rankin F, Fitzgerald FS, Floras JS, Bradley TDEffects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation98199822692275
39. Somers VK, Mark AL, Zavala DC, Abboud FMContrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol67198921012106
40. Hall MJ, Xie A, Rutherford R, Ando S, Floras JS, Bradley TDCycle length of periodic breathing in patients with and without heart failure. Am J Respir Crit Care Med1541996376381
41. Somers VK, Dyken ME, Clary MP, Abboud FMSympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest96199518971904
42. Kusuoka H, Weisfeldt ML, Zweier JL, Jacobus WE, Marban EMechanism of early contractile failure during hypoxia in intact ferret heart: evidence for modulation of maximal Ca2+-activated force by inorganic phosphate. Circ Res591986270282
43. van den Aardweg JG, Karemaker JMRepetitive apneas induce periodic hypertension in normal subjects through hypoxia. J Appl Physiol721992821827
44. Schneider H, Schaub CD, Chen CA, Andreoni KA, Schwartz AR, Smith PL, Robotham JL, O'Donnell CPNeural and local effects of hypoxia on cardiovascular responses to obstructive apnea. J Appl Physiol88200010931102
45. Daly MdB, Scott MJ. The effects of stimulation of the carotid body chemoreceptors on heart rate in the dog. J Physiol 1958;144:148–166.
46. Daly MdB, Scott MJ. The cardiovascular responses to stimulation of the carotid chemoreceptors in the dog. J Physiol 1963;165:179–197.
47. Douglas NJ, White DP, Weil JV, Pickett CK, Martin RJ, Hudgel DW, Zwillich CWHypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis1251982286289
48. Sato F, Nishimura M, Shinano H, Saito H, Miyamoto K, Kawakami YHeart rate during obstructive sleep apnea depends on individual hypoxic chemosensitivity of the carotid body. Circulation961997274281
49. Bonsignore MR, Romano S, Marrone O, Chiodi M, Bonsignore GDifferent heart rate patterns in obstructive apneas during NREM sleep. Sleep20199711671174
50. Kato H, Menon AS, Slutsky ASMechanisms mediating the heart rate response to hypoxemia. Circulation771988407414
51. Zwillich C, Devlin T, White D, Douglas N, Weil J, Martin RBradycardia during sleep apnea. Characteristics and mechanism. J Clin Invest69198212861292
52. Lorenzi-Filho G, Dajani HR, Leung RS, Floras JS, Bradley TDEntrainment of blood pressure and heart rate oscillations by periodic breathing. Am J Respir Crit Care Med159199911471154
53. Hedner J, Ejnell H, Sellgren J, Hedner T, Wallin GIs high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens Suppl61988S529S531
54. Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BGAugmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest103199317631768
55. Narkiewicz K, Montano N, Cogliati C, van de Borne PJ, Dyken ME, Somers VKAltered cardiovascular variability in obstructive sleep apnea. Circulation98199810711077
56. Narkiewicz K, van de Borne PJ, Cooley RL, Dyken ME, Somers VKSympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation981998772776
57. Fletcher EC, Miller J, Schaaf JW, Fletcher JGUrinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep1019873544
58. Hedner J, Darpo B, Ejnell H, Carlson J, Caidahl KReduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J81995222229
59. Narkiewicz K, Kato M, Phillips BG, Pesek CA, Davison DE, Somers VKNocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation100199923322335
60. Waradekar NV, Sinoway LI, Zwillich CW, Leuenberger UAInfluence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit Care Med153199613331338
61. Peled N, Greenberg A, Pillar G, Zinder O, Levi N, Lavie PContributions of hypoxia and respiratory disturbance index to sympathetic activation and blood pressure in obstructive sleep apnea syndrome. Am J Hypertens11199812841289
62. Morgan BJ, Crabtree DC, Palta M, Skatrud JBCombined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol791995205213
63. Xie A, Skatrud JB, Crabtree DC, Puleo DS, Goodman BM, Morgan BJNeurocirculatory consequences of intermittent asphyxia in humans. J Appl Physiol89200013331339
64. Xie A, Skatrud JB, Puleo DS, Morgan BJExposure to hypoxia produces long-lasting sympathetic activation in humans. J Appl Physiol91200115551562
65. Narkiewicz K, van de Borne PJ, Pesek CA, Dyken ME, Montano N, Somers VKSelective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation99199911831189
66. Hedner JA, Wilcox I, Laks L, Grunstein RR, Sullivan CEA specific and potent pressor effect of hypoxia in patients with sleep apnea. Am Rev Respir Dis146199212401245
67. Mahamed S, Duffin JRepeated hypoxic exposures change respiratory control in humans. J Physiol5342001595603
68. Remsburg S, Launois SH, Weiss JWPatients with obstructive sleep apnea have an abnormal peripheral vascular response to hypoxia. J Appl Physiol87199911481153
69. Osanai S, Akiba Y, Fujiuchi S, Nakano H, Matsumoto H, Ohsaki Y, Kikuchi KDepression of peripheral chemosensitivity by a dopaminergic mechanism in patients with obstructive sleep apnoea syndrome. Eur Respir J131999418423
70. Kimoff RJ, Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Champagne V, Mayer P, Phillipson EAVentilatory and arousal responses to hypoxia and hypercapnia in a canine model of obstructive sleep apnea. Am J Respir Crit Care Med1561997886894
71. Lesske J, Fletcher EC, Bao G, Unger THypertension caused by chronic intermittent hypoxia—influence of chemoreceptors and sympathetic nervous system. J Hypertens15199715931603
72. Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VKContribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation971998943945
73. Parati G, Di Rienzo M, Bonsignore MR, Insalaco G, Marrone O, Castiglioni P, Bonsignore G, Mancia GAutonomic cardiac regulation in obstructive sleep apnea syndrome: evidence from spontaneous baroreflex analysis during sleep. J Hypertens15199716211626
74. Carlson JT, Hedner JA, Sellgren J, Elam M, Wallin BGDepressed baroreflex sensitivity in patients with obstructive sleep apnea. Am J Respir Crit Care Med154199614901496
75. Ziegler MG, Nelesen RA, Mills PJ, Ancoli-Israel S, Clausen JL, Watkins L, Dimsdale JEThe effect of hypoxia on baroreflexes and pressor sensitivity in sleep apnea and hypertension. Sleep181995859865
76. Brooks D, Horner RL, Floras JS, Kozar LF, Render-Teixeira CL, Phillipson EABaroreflex control of heart rate in a canine model of obstructive sleep apnea. Am J Respir Crit Care Med159199912931297
77. Sleight PRole of the baroreceptor reflexes in circulatory control, with particular reference to hypertension. Hypertension181991III3134
78. Tkacova R, Dajani HR, Rankin F, Fitzgerald FS, Floras JS, Bradley TDContinuous positive airway pressure improves nocturnal baroreflex sensitivity of patients with heart failure and obstructive sleep apnea. J Hypertens18200012571262
79. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 1996;93:1043–1065.
80. Noda A, Yasuma F, Okada T, Yokota MCircadian rhythm of autonomic activity in patients with obstructive sleep apnea syndrome. Clin Cardiol211998271276
81. Wiklund U, Olofsson BO, Franklin K, Blom H, Bjerle P, Niklasson UAutonomic cardiovascular regulation in patients with obstructive sleep apnoea: a study based on spectral analysis of heart rate variability. Clin Physiol202000234241
82. Khoo MC, Kim TS, Berry RBSpectral indices of cardiac autonomic function in obstructive sleep apnea. Sleep221999443451
83. Roche F, Court-Fortune I, Pichot V, Duverney D, Costes F, Emonot A, Vergnon JM, Geyssant A, Lacour JR, Barthelemy JCReduced cardiac sympathetic autonomic tone after long-term nasal continuous positive airway pressure in obstructive sleep apnoea syndrome. Clin Physiol191999127134
84. Saarelainen S, Hasan J, Siitonen S, Seppala EEffect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea. J Sleep Res51996181185
85. Maillard D, Fineyre F, Dreyfuss D, Djedaini K, Blanchet F, Paycha F, Dussaule JC, Nitenberg APressure-heart rate responses to alpha-adrenergic stimulation and hormonal regulation in normotensive patients with obstructive sleep apnea. Am J Hypertens1019972431
86. Follenius M, Krieger J, Krauth MO, Sforza F, Brandenberger GObstructive sleep apnea treatment: peripheral and central effects on plasma renin activity and aldosterone. Sleep141991211217
87. Edwards BS, Zimmerman RS, Schwab TR, Heublein DM, Burnett JCAtrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ Res621988191195
88. Baruzzi A, Riva R, Cirignotta F, Zucconi M, Cappelli M, Lugaresi EAtrial natriuretic peptide and catecholamines in obstructive sleep apnea syndrome. Sleep1419918386
89. Ehlenz K, Peter JH, Kaffarnik H, von Wichert P. Disturbances in volume regulating hormone system—a key to the pathogenesis of hypertension in obstructive sleep apnea syndrome? Pneumologie 1991;45(Suppl 1):239–245.
90. Krieger J, Laks L, Wilcox I, Grunstein RR, Costas LJ, McDougall JG, Sullivan CEAtrial natriuretic peptide release during sleep in patients with obstructive sleep apnoea before and during treatment with nasal continuous positive airway pressure. Clin Sci771989407411
91. Krieger J, Follenius M, Sforza E, Brandenberger G, Peter JDEffects of treatment with nasal continuous positive airway pressure on atrial natriuretic peptide and arginine vasopressin release during sleep in patients with obstructive sleep apnoea. Clin Sci (Colch)801991443449
92. Grote L, Kraiczi H, Hedner JReduced alpha- and beta(2)-adrenergic vascular response in patients with obstructive sleep apnea. Am J Respir Crit Care Med162200014801487
93. Saarelainen S, Seppala E, Laasonen K, Hasan JCirculating endothelin-1 in obstructive sleep apnea. Endothelium51997115118
94. Grimpen F, Kanne P, Schulz E, Hagenah G, Hasenfuss G, Andreas SEndothelin-1 plasma levels are not elevated in patients with obstructive sleep apnoea. Eur Respir J152000320325
95. Carlson JT, Rangemark C, Hedner JAAttenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. J Hypertens141996577584
96. Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, Somers VKImpairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation102200026072610
97. Kraiczi H, Hedner J, Peker Y, Carlson JIncreased vasoconstrictor sensitivity in obstructive sleep apnea. J Appl Physiol892000493498
98. Dean RT, Wilcox I. Possible atherogenic effects of hypoxia during obstructive sleep apnea. Sleep 1993;16:S15–S21; discussion S21–S22.
99. Bedwell S, Dean RT, Jessup WThe action of defined oxygen-centered free radicals on human low-density lipoprotein. Biochem J2621989707712
100. Faller DVEndothelial cell responses to hypoxic stress. Clin Exp Pharmacol Physiol2619997484
101. Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, Seeger W, Grimminger FEnhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med1622000566570
102. Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn PFBlood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation841991613617
103. Muller JE, Tofler GHCircadian variation and cardiovascular disease. N Engl J Med325199110381039
104. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R, Robertson Tet al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med313198513151322
105. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JEConcurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med316198715141518
106. Marler JR, Price TR, Clark GL, Muller JE, Robertson T, Mohr JP, Hier DB, Wolf PA, Caplan LR, Foulkes MAMorning increase in onset of ischemic stroke. Stroke201989473476
107. Marsh EE, Biller J, Adams HP, Marler JR, Hulbert JR, Love BB, Gordon DLCircadian variation in onset of acute ischemic stroke. Arch Neurol47199011781180
108. Larsson PT, Wallen NH, Hjemdahl PNorepinephrine-induced human platelet activation in vivo is only partly counteracted by aspirin. Circulation89199419511957
109. Sanner BM, Konermann M, Tepel M, Groetz J, Mummenhoff C, Zidek WPlatelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J162000648652
110. Bokinsky G, Miller M, Ault K, Husband P, Mitchell JSpontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest1081995625630
111. Dimsdale JE, Coy T, Ziegler MG, Ancoli-Israel S, Clausen JThe effect of sleep apnea on plasma and urinary catecholamines. Sleep181995377381
112. Eisensehr I, Ehrenberg BL, Noachtar S, Korbett K, Byrne A, McAuley A, Palabrica TPlatelet activation, epinephrine, and blood pressure in obstructive sleep apnea syndrome. Neurology511998188195
113. Hoffstein V, Herridge M, Mateika S, Redline S, Strohl KPHematocrit levels in sleep apnea. Chest1061994787791
114. Chin K, Ohi M, Kita H, Noguchi T, Otsuka N, Tsuboi T, Mishima M, Kuno KEffects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med153199619721976
115. Nobili L, Schiavi G, Bozano E, De Carli F, Ferrillo F, Nobili FMorning increase of whole blood viscosity in obstructive sleep apnea syndrome. Clin Hemorheol Microcirc2220002127
116. Chin K, Kita H, Noguchi T, Otsuka N, Tsuboi T, Nakamura T, Shimizu K, Mishima M, Ohi MImprovement of factor VII clotting activity following long-term NCPAP treatment in obstructive sleep apnoea syndrome. QJM911998627633
117. Young T, Peppard PE. Epidemiological evidence for an association of sleep-disordered breathing with hypertension and cardiovascular disease. In: Bradley TD and Floras JS, editors. Sleep apnea: implications in cardiovascular and cerebrovascular disease. New York: Marcel Dekker; 2000. p. 261–283.
118. Stamler J, Stamler R, Neaton JDBlood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med1531993598615
119. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EAObstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest991997106109
120. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD, Pickering TGAssociation of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA283200018291836
121. Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, Skatrud JPopulation-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med157199717461752
122. Peppard PE, Young T, Palta M, Skatrud JProspective study of the association between sleep-disordered breathing and hypertension. N Engl J Med342200013781384
123. Bao G, Metreveli N, Fletcher ECAcute and chronic blood pressure response to recurrent acoustic arousal in rats. Am J Hypertens121999504510
124. Fletcher EC, Lesske J, Qian W, Miller CCd, Unger T. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 1992;19:555–561.
125. Fletcher EC, Lesske J, Behm R, Miller CCd, Stauss H, Unger T. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 1992;72:1978–1984.
126. Fletcher EC, Lesske J, Culman J, Miller CC, Unger TSympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension201992612619
127. Bao G, Metreveli N, Li R, Taylor A, Fletcher ECBlood pressure response to chronic episodic hypoxia: role of the sympathetic nervous system. J Appl Physiol83199795101
128. Fletcher EC, Bao GEffect of episodic eucapnic and hypocapnic hypoxia on systemic blood pressure in hypertension-prone rats. J Appl Physiol81199620882094
129. O'Brien E, Sheridan J, O'Malley KDippers and non-dippers. Lancet21988397
130. Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci Aet al. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension241994793801
131. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Sacchi N, Battistelli M, Guerrieri M, Comparato E, Porcellati CGender, day-night blood pressure changes, and left ventricular mass in essential hypertension. Dippers and peakers. Am J Hypertens81995193196
132. Staessen JA, Thijs L, Fagard R, O'Brien ET, Clement D, de Leeuw PW, Mancia G, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster JPredicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA2821999539546
133. Hoffstein V, Mateika JEvening-to-morning blood pressure variations in snoring patients with and without obstructive sleep apnea. Chest1011992379384
134. Suzuki M, Guilleminault C, Otsuka K, Shiomi TBlood pressure “dipping” and “non-dipping” in obstructive sleep apnea syndrome patients. Sleep191996382387
135. Portaluppi F, Provini F, Cortelli P, Plazzi G, Bertozzi N, Manfredini R, Fersini C, Lugaresi EUndiagnosed sleep-disordered breathing among male nondippers with essential hypertension. J Hypertens15199712271233
136. Hirshkowitz M, Karacan I, Gurakar A, Williams RLHypertension, erectile dysfunction, and occult sleep apnea. Sleep121989223232
137. Grote L, Hedner J, Peter JHSleep-related breathing disorder is an independent risk factor for uncontrolled hypertension. J Hypertens182000679685
138. Logan AG, Tkacova R, Tisler A, Leung RS, Fitzgerald FS, Bradley TD. High prevalence of obstructive sleep apnea in refractory hypertension. J Hypertension 2001. (In press)
139. Kraiczi H, Hedner J, Peker Y, Grote LComparison of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan for antihypertensive treatment in patients with obstructive sleep apnea. Am J Respir Crit Care Med161200014231428
140. Pelttari LH, Hietanen EK, Salo TT, Kataja MJ, Kantola IMLittle effect of ordinary antihypertensive therapy on nocturnal high blood pressure in patients with sleep disordered breathing. Am J Hypertens111998272279
141. Dimsdale JE, Loredo JS, Profant JEffect of continuous positive airway pressure on blood pressure: a placebo trial. Hypertension352000144147
142. Faccenda JF, Mackay TW, Boon NA, Douglas NJRandomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med1632001344348
143. Engleman HM, Gough K, Martin SE, Kingshott RN, Padfield PL, Douglas NJAmbulatory blood pressure on and off continuous positive airway pressure therapy for the sleep apnea/hypopnea syndrome: effects in “non-dippers.” Sleep191996378381
144. Suzuki M, Otsuka K, Guilleminault CLong-term nasal continuous positive airway pressure administration can normalize hypertension in obstructive sleep apnea patients. Sleep161993545549
145. Worsnop CJ, Pierce RJ, Naughton MSystemic hypertension and obstructive sleep apnea. Sleep161993S148S149
146. Akashiba T, Kurashina K, Minemura H, Yamamoto H, Horie TDaytime hypertension and the effects of short-term nasal continuous positive airway pressure treatment in obstructive sleep apnea syndrome. Intern Med341995528532
147. Mayer J, Becker H, Brandenburg U, Penzel T, Peter JH, von Wichert PBlood pressure and sleep apnea: results of long-term nasal continuous positive airway pressure therapy. Cardiology7919918492
148. Logan AG, Tkacova R, Perlikowski SM, Leung RS, Tisler A, Floras JS, Bradley TD. Effects of continuous positive airway pressure on blood pressure in refractory hypertensive patients with sleep apnea. J Hypertens 2001. (In press)
149. 2000 Heart and stroke statistical update. Dallas, TX: American Heart Association; 1999.
150. Hankey GJStroke: how large a public health problem, and how can the neurologist help? Arch Neurol561999748754
151. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O'Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163: 19–25.
152. Good DC, Henkle JQ, Gelber D, Welsh J, Verhulst SSleep-disordered breathing and poor functional outcome after stroke. Stroke271996252259
153. Dyken ME, Somers VK, Yamada T, Ren ZY, Zimmerman MBInvestigating the relationship between stroke and obstructive sleep apnea. Stroke271996401407
154. Bassetti C, Aldrich MSSleep apnea in acute cerebrovascular diseases: final report on 128 patients. Sleep221999217223
155. Wessendorf TE, Teschler H, Wang YM, Konietzko N, Thilmann AFSleep-disordered breathing among patients with first-ever stroke. J Neurol24720004147
156. Parra O, Arboix A, Bechich S, Garcia-Eroles L, Montserrat JM, Lopez JA, Ballester E, Guerra JM, Sopena JJTime course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med1612000375380
157. Balfors EM, Franklin KAImpairment of cerebral perfusion during obstructive sleep apneas. Am J Respir Crit Care Med150199415871591
158. Netzer N, Werner P, Jochums I, Lehmann M, Strohl KPBlood flow of the middle cerebral artery with sleep-disordered breathing: correlation with obstructive hypopneas. Stroke2919988793
159. Klingelhofer J, Hajak G, Sander D, Schulz-Varszegi M, Ruther E, Conrad BAssessment of intracranial hemodynamics in sleep apnea syndrome. Stroke23199214271433
160. Palomaki H, Partinen M, Juvela S, Kaste MSnoring as a risk factor for sleep-related brain infarction. Stroke20198913111315
161. Lehoux S, Tedgui ASignal transduction of mechanical stresses in the vascular wall. Hypertension321998338345
162. Jiang Y, Kohara K, Hiwada KAssociation between risk factors for atherosclerosis and mechanical forces in carotid artery. Stroke31200023192324
163. Heyman A, Birchfield RI, Sieker HOEffects of bilateral cerebral infarction on respiratory center sensitivity. Neurology81958694700
164. Plum F, Leigh RJ. Abnormalities of central mechanisms. In: Hornbein TF, editor. Regulation of breathing: Part II. New York: Marcel Dekker; 1981. p. 989–1087.
165. Lee MC, Klassen AC, Heaney LM, Resch JARespiratory rate and pattern disturbances in acute brain stem infarction. Stroke71976382385
166. Levin BE, Margolis GAcute failure of automatic respirations secondary to a unilateral brainstem infarct. Ann Neurol11977583586
167. Askenasy JJ, Goldhammer ISleep apnea as a feature of bulbar stroke. Stroke191988637639
168. Bradley TD, McNicholas WT, Rutherford R, Popkin J, Zamel N, Phillipson EAClinical and physiologic heterogeneity of the central sleep apnea syndrome. Am Rev Respir Dis1341986217221
169. Brown HW, Plum FThe neurological basis of Cheyne-Stokes respiration. Am J Med301961849861
170. Sen S, Oppenheimer SMCardiac disorders and stroke. Curr Opin Neurol1119985156
171. Powell NB, Riley RW, Schechtman KB, Blumen MB, Dinges DF, Guilleminault CA comparative model: reaction time performance in sleep-disordered breathing versus alcohol-impaired controls. Laryngoscope109199916481654
172. Findley LJ, Fabrizio MJ, Knight H, Norcross BB, LaForte AJ, Suratt PMDriving simulator performance in patients with sleep apnea. Am Rev Respir Dis1401989529530
173. Melton JE, Neubauer JA, Edelman NHGABA antagonism reverses hypoxic respiratory depression in the cat. J Appl Physiol69199012961301
174. Chen L, Scharf SMSystemic and myocardial hemodynamics during periodic obstructive apneas in sedated pigs. J Appl Physiol84199812891298
175. Scharf SM, Graver LM, Balaban KCardiovascular effects of periodic occlusions of the upper airways in dogs. Am Rev Respir Dis1461992321329
176. Peled N, Abinader EG, Pillar G, Sharif D, Lavie PNocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease: effects of continuous positive air pressure treatment. J Am Coll Cardiol34199917441749
177. Scharf SM, Bianco JA, Tow DE, Brown RThe effects of large negative intrathoracic pressure on left ventricular function in patients with coronary artery disease. Circulation631981871875
178. Goldman MD, Reeder MK, Muir AD, Loh L, Young JD, Gitlin DA, Casey KR, Smart D, Fry JMRepetitive nocturnal arterial oxygen desaturation and silent myocardial ischemia in patients presenting for vascular surgery. J Am Geriatr Soc411993703709
179. Franklin KA, Nilsson JB, Sahlin C, Naslund USleep apnoea and nocturnal angina. Lancet345199510851087
180. Philip P, Guilleminault CST segment abnormality, angina during sleep and obstructive sleep apnea. Sleep161993558559
181. Schafer H, Koehler U, Ploch T, Peter JHSleep-related myocardial ischemia and sleep structure in patients with obstructive sleep apnea and coronary heart disease. Chest1111997387393
182. Mooe T, Franklin KA, Wiklund U, Rabben T, Holmstrom KSleep-disordered breathing and myocardial ischemia in patients with coronary artery disease. Chest117200015971602
183. Koehler U, Dubler H, Glaremin T, Junkermann H, Lubbers C, Ploch T, Peter JH, Pomykaj T, von Wichert PNocturnal myocardial ischemia and cardiac arrhythmia in patients with sleep apnea with and without coronary heart disease. Klin Wochenschr691991474482
184. Andreas S, Hajak G, Natt P, Auge D, Ruther E, Kreuzer H[ST segmental changes and arrhythmias in obstructive sleep apnea]. Pneumologie451991720724
185. Hanly P, Sasson Z, Zuberi N, Lunn KST-segment depression during sleep in obstructive sleep apnea. Am J Cardiol71199313411345
186. Peker Y, Hedner J, Kraiczi H, Loth SRespiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med16220008186
187. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, Roselle GASleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation97199821542159
188. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TDRisk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med160199911011106
189. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr SThe occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med328199312301235
190. Dougherty AH, Naccarelli GV, Gray EL, Hicks CH, Goldstein RACongestive heart failure with normal systolic function. Am J Cardiol541984778782
191. Chan J, Sanderson J, Chan W, Lai C, Choy D, Ho A, Leung RPrevalence of sleep-disordered breathing in diastolic heart failure. Chest111199714881493
192. Ponikowski P, Chua TP, Piepoli M, Amadi AA, Harrington D, Webb-Peploe K, Volterrani M, Colombo R, Mazzuero G, Giordano A, Coats AJChemoreceptor dependence of very low frequency rhythms in advanced chronic heart failure. Am J Physiol2721997H438H447
193. Sun SY, Wang W, Zucker IH, Schultz HDEnhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol86199912641272
194. Naughton M, Benard D, Tam A, Rutherford R, Bradley TDRole of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure. Am Rev Respir Dis1481993330338
195. Alex CG, Onal E, Lopata MUpper airway occlusion during sleep in patients with Cheyne-Stokes respiration. Am Rev Respir Dis13319864245
196. Younes MThe physiologic basis of central apnea and periodic breathing. Curr Pulmonol101989265326
197. Shepard JW, Pevernagie DA, Stanson AW, Daniels BK, Sheedy PFEffects of changes in central venous pressure on upper airway size in patients with obstructive sleep apnea. Am J Respir Crit Care Med1531996250254
198. Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TDObstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet338199114801484
199. Chan HS, Chiu HF, Tse LK, Woo KSObstructive sleep apnea presenting with nocturnal angina, heart failure, and near-miss sudden death. Chest99199110231025
200. Chaudhary BA, Nadimi M, Chaudhary TK, Speir WAPulmonary edema due to obstructive sleep apnea. South Med J771984499501
201. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KKThe progression from hypertension to congestive heart failure. JAMA275199615571562
202. Mandinov L, Eberli FR, Seiler C, Hess OMDiastolic heart failure. Cardiovasc Res452000813825
203. Daly PA, Sole MJMyocardial catecholamines and the pathophysiology of heart failure. Circulation821990I35I43
204. Fletcher EC, Proctor M, Yu J, Zhang J, Guardiola JJ, Hornung C, Bao GPulmonary edema develops after recurrent obstructive apneas. Am J Respir Crit Care Med160199916881696
205. Hedner J, Ejnell H, Caidahl KLeft ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnoea. J Hypertens81990941946
206. Niroumand M, Kuperstein R, Sasson Z, Hanly PJImpact of obstructive sleep apnea on left ventricular mass and diastolic function. Am J Respir Crit Care Med163200116321636
207. Ross JAfterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis181976255264
208. Bradley TD, Hall MJ, Ando S, Floras JSHemodynamic effects of simulated obstructive apneas in humans with and without heart failure. Chest119200118271835
209. Kaye DM, Lambert GW, Lefkovits J, Morris M, Jennings G, Esler MDNeurochemical evidence of cardiac sympathetic activation and increased central nervous system norepinephrine turnover in severe congestive heart failure. J Am Coll Cardiol231994570578
210. Hanly PJ, Zuberi-Khokhar NSIncreased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med1531996272276
211. Lanfranchi PA, Braghiroli A, Bosimini E, Mazzuero G, Colombo R, Donner CF, Giannuzzi PPrognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation99199914351440
212. Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TDEffects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation10220006166
213. Ho KK, Pinsky JL, Kannel WB, Levy DThe epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol2219936A13A
214. Hanly P, Zuberi N, Gray RPathogenesis of Cheyne-Stokes respiration in patients with congestive heart failure. Relationship to arterial PCO2. Chest104199310791084
215. Javaheri S, Corbett WSAssociation of lowPaCO2 with central sleep apnea and ventricular arrhythmias in ambulatory patients with stable heart failure. Ann Intern Med1281998204207
216. Lorenzi-Filho G, Rankin F, Bies I, Bradley TDEffects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med159199914901498
217. Xie A, Rankin F, Rutherford R, Bradley TDEffects of inhaled CO2 and added dead space on idiopathic central sleep apnea. J Appl Physiol821997918926
218. Berssenbrugge A, Dempsey J, Iber C, Skatrud J, Wilson PMechanisms of hypoxia-induced periodic breathing during sleep in humans. J Physiol (Lond)3431983507526
219. Bradley TD, Phillipson EACentral sleep apnea. Clin Chest Med131992493505
220. Tkacova R, Hall MJ, Liu PP, Fitzgerald FS, Bradley TDLeft ventricular volume in patients with heart failure and Cheyne-Stokes respiration during sleep. Am J Respir Crit Care Med156199715491555
221. Yu J, Zhang JF, Fletcher ECStimulation of breathing by activation of pulmonary peripheral afferents in rabbits. J Appl Physiol85199814851492
222. Churchill ED, Cope OThe rapid shallow breathing resulting from pulmonary congestion and edema. J Exp Med491929531537
223. Solin P, Bergin P, Richardson M, Kaye DM, Walters EH, Naughton MTInfluence of pulmonary capillary wedge pressure on central apnea in heart failure. Circulation99199915741579
224. Lorenzi-Filho G, Azevedo ER, Parker JD, Bradley TD. Relationship of PaCO2 to pulmonary wedge pressure in heart failure. Eur Respir J 2001. (In press)
225. Khoo MC, Kronauer RE, Strohl KP, Slutsky ASFactors inducing periodic breathing in humans: a general model. J Appl Physiol531982644659
226. Cherniack NS, Longobardo GSCheyne-Stokes breathing. An instability in physiologic control. N Engl J Med2881973952957
227. Wilcox I, McNamara SG, Dodd MJ, Sullivan CEVentilatory control in patients with sleep apnoea and left ventricular dysfunction: comparison of obstructive and central sleep apnoea. Eur Respir J111998713
228. Javaheri SA mechanism of central sleep apnea in patients with heart failure. N Engl J Med3411999949954
229. Ponikowski P, Anker SD, Chua TP, Francis D, Banasiak W, Poole-Wilson PA, Coats AJ, Piepoli MOscillatory breathing patterns during wakefulness in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity. Circulation100199924182424
230. Solin P, Roebuck T, Johns DP, Haydn Walters E, Naughton MT. Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure. Am J Respir Crit Care Med 2000;162:2194–2200.
231. Wilcox I, McNamara SG, Sullivan CE. Central sleep apnea and heart failure. N Engl J Med 2000;342:293; discussion 293–294.
232. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MHThe effect of oxygen on respiration and sleep in patients with congestive heart failure. Ann Intern Med1111989777782
233. Andreas S, Clemens C, Sandholzer H, Figulla HR, Kreuzer HImprovement of exercise capacity with treatment of Cheyne-Stokes respiration in patients with congestive heart failure. J Am Coll Cardiol27199614861490
234. Staniforth AD, Kinnear WJ, Starling R, Hetmanski DJ, Cowley AJEffect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J191998922928
235. Franklin KA, Eriksson P, Sahlin C, Lundgren RReversal of central sleep apnea with oxygen. Chest1111997163169
236. Franklin KA, Sandstrom E, Johansson G, Balfors EMHemodynamics, cerebral circulation, and oxygen saturation in Cheyne-Stokes respiration. J Appl Physiol83199711841191
237. Xie A, Wong B, Phillipson EA, Slutsky AS, Bradley TDInteraction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea. Am J Respir Crit Care Med1501994489495
238. Xie A, Rutherford R, Rankin F, Wong B, Bradley TDHypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med152199519501955
239. Sullivan CE, Murphy E, Kozar LF, Phillipson EAWaking and ventilatory responses to laryngeal stimulation in sleeping dogs. J Appl Physiol451978681689
240. Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TDOvernight shift from obstructive to central apneas in patients with heart failure: role of PCO(2) and circulatory delay. Circulation1032001238243
241. Gibbs JS, Cunningham D, Shapiro LM, Park A, Poole-Wilson PA, Fox KMDiurnal variation of pulmonary artery pressure in chronic heart failure. Br Heart J6219893035
242. Guyton ACBasic oscillating mechanism of Cheyne-Stokes breathing. Am J Physiol1871956395398
243. Mortara A, Sleight P, Pinna GD, Maestri R, Capomolla S, Febo O, La Rovere MT, Cobelli FAssociation between hemodynamic impairment and Cheyne-Stokes respiration and periodic breathing in chronic stable congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol841999900904
244. Takasaki Y, Orr D, Popkin J, Rutherford R, Liu P, Bradley TDEffect of nasal continuous positive airway pressure on sleep apnea in congestive heart failure. Am Rev Respir Dis140198915781584
245. Hanly P, Zuberi-Khokhar NDaytime sleepiness in patients with congestive heart failure and Cheyne-Stokes respiration. Chest1071995952958
246. Mortara A, Sleight P, Pinna GD, Maestri R, Prpa A, La Rovere MT, Cobelli F, Tavazzi LAbnormal awake respiratory patterns are common in chronic heart failure and may prevent evaluation of autonomic tone by measures of heart rate variability. Circulation961997246252
247. Guyenet PG, Koshiya N, Huangfu D, Verberne AJ, Riley TACentral respiratory control of A5 and A6 pontine noradrenergic neurons. Am J Physiol2641993R1035R1044
248. Saul JP, Arai Y, Berger RD, Lilly LS, Colucci WS, Cohen RJAssessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am J Cardiol61198812921299
249. Floras JSClinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol22199372A84A
250. Pinna GD, Maestri R, Rovere MT, Mortara AAn oscillation of the respiratory control system accounts for most of the heart period variability of chronic heart failure patients. Clin Sci (Colch)9119968991
251. van de Borne P, Oren R, Abouassaly C, Anderson E, Somers VKEffect of Cheyne-Stokes respiration on muscle sympathetic nerve activity in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol811998432436
252. Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TDEffects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med1521995473479
253. Francis GSDevelopment of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol5719863B7B
254. Floras JS, Bradley TDSleep apnoea: a therapeutic target in congestive heart failure. Eur Heart J191998820821
255. Naughton MT, Bradley TDSleep apnea in congestive heart failure. Clin Chest Med19199899113
256. Tkacova R, Bradley TD. Therapy of obstructive and central sleep apnea in patients with congestive heart failure. In: Bradley TD and Floras JS, editors. Sleep apnea: implications in cardiovascular and cerebrovascular disease. New York: Marcel Dekker; 2000. p. 461–494.
257. Dark DS, Pingleton SK, Kerby GR, Crabb JE, Gollub SB, Glatter TR, Dunn MIBreathing pattern abnormalities and arterial oxygen desaturation during sleep in the congestive heart failure syndrome. Improvement following medical therapy. Chest911987833836
258. Naughton MT, Benard DC, Rutherford R, Bradley TDEffect of continuous positive airway pressure on central sleep apnea and nocturnal PCO2 in heart failure. Am J Respir Crit Care Med150199415981604
259. Teschler H, Dohring J, Wang YM, Berthon-Jones MAdaptive pressure support servo-ventilation. A novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med1642001614619
260. Naughton MT, Rahman MA, Hara K, Floras JS, Bradley TDEffect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation91199517251731
261. Bradley TD, Holloway RM, McLaughlin PR, Ross BL, Walters J, Liu PPCardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis1451992377382
262. Kaye DM, Mansfield D, Aggarwal A, Naughton MT, Esler MDAcute effects of continuous positive airway pressure on cardiac sympathetic tone in congestive heart failure. Circulation103200123362338
263. Naughton MT, Liu PP, Bernard DC, Goldstein RS, Bradley TDTreatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med15119959297
264. Granton JT, Naughton MT, Benard DC, Liu PP, Goldstein RS, Bradley TDCPAP improves inspiratory muscle strength in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med1531996277282
265. Tkacova R, Liu PP, Naughton MT, Bradley TDEffect of continuous positive airway pressure on mitral regurgitant fraction and atrial natriuretic peptide in patients with heart failure. J Am Coll Cardiol301997739745
266. Bradley TD, Logan AG, Floras JSRationale and design of the Canadian Continuous Positive Airway Pressure Trial for Congestive Heart Failure patients with Central Sleep Apnea—CANPAP. Can J Cardiol172001677684
267. Javaheri S, Ahmed M, Parker TJ, Brown CREffects of nasal O2 on sleep-related disordered breathing in ambulatory patients with stable heart failure. Sleep22199911011106
268. Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GAEffect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med3351996562567
269. Sullivan CE, Issa FG, Berthon-Jones M, Eves LReversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet11981862865
270. Engleman HM, Martin SE, Deary IJ, Douglas NJEffect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet3431994572575
271. Jenkinson C, Davies RJ, Mullins R, Stradling JRComparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet353199921002105
272. Hedner J, Grote LThe link between sleep apnea and cardiovascular disease: time to target the nonsleepy sleep apneics? Am J Respir Crit Care Med163200156
273. Barbe F, Mayoralas LR, Duran J, Masa JF, Maimo A, Montserrat JM, Monasterio C, Bosch M, Ladaria A, Rubio M, Rubio R, Medinas M, Hernandez L, Vidal S, Douglas NJ, Agusti AGTreatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. A randomized, controlled trial. Ann Intern Med134200110151023
274. Blumenthal RSStatins: effective antiatherosclerotic therapy. Am Heart J1392000577583
275. Hall MJ, Bradley TDCardiovascular disease and sleep apnea. Curr Opin Pulmon Med11995512518
Correspondence and requests for reprints should be addressed to T. Douglas Bradley, M.D., Toronto General Hospital/University Health Network, NU 9-112, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4 Canada. E-mail:


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