Sleep Apnea and Cardiovascular Disease

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					State of the Art
Sleep Apnea and Cardiovascular Disease
University of Toronto Centre for Sleep and Chronobiology, the Cardiopulmonary Sleep Disorders and Research Centre of the Toronto General
Hospital/University Health Network and the Toronto Rehabilitation Institute, Toronto, Ontario, Canada

Contents                                                                             arrythmias will not be covered. Although the effects of treating
                                                                                     sleep apnea on cardiovascular outcomes will be discussed, this
        Cardiovascular Effects of Normal Sleep
                                                                                     discussion will of necessity be brief owing to the paucity of well-
        Cardiovascular Effects of Obstructive Sleep Apnea
                                                                                     conducted clinical trials in this area. Finally, we wish to high-
          Acute Physiological Effects
                                                                                     light gaps in knowledge and important controversies in need of
          Chronic Physiological Effects
                                                                                     resolution that could direct future research.
        Clinical Cardiovascular Disease and Obstructive Sleep
                                                                                     CARDIOVASCULAR EFFECTS OF NORMAL SLEEP
          Hypertension                                                               The transition from wakefulness to non-rapid eye movement
          Stroke                                                                     (NREM) sleep is accompanied by marked alterations in respi-
          Ischemic Heart Disease                                                     ratory and cardiovascular regulation. Normally, there is a sud-
          Congestive Heart Failure                                                   den withdrawal of the nonchemical wakefulness drive to breathe
        Cheyne–Stokes Respiration and Congestive Heart Failure                       resulting in a slight but abrupt decrease in minute ventilation
          Epidemiology                                                               and increase in PaCO2 (3, 4). Subsequently, there is a further pro-
          Pathophysiology                                                            gressive reduction in central respiratory drive accompanied by a
          Clinical Significance                                                      decrease in minute ventilation, an increase in PaCO2, and a de-
          Treatment                                                                  crease in PaO2 from stages 1 through 4 NREM sleep (4). In the
        Conclusion                                                                   deeper stages of NREM sleep, respiration is under predomi-
                                                                                     nantly metabolic control, resulting in a very regular pattern of
Cardiovascular and cerebrovascular diseases are the most com-                        breathing (4, 5). Alterations in cardiovascular autonomic reg-
mon life-threatening and debilitating diseases in the industrial-                    ulation mirror these changes in respiratory control. As the met-
ized world. However, the incidence and mortality rates of these                      abolic rate declines from wakefulness to a relatively constant
diseases have recently begun to decline largely owing to the                         lower level during stages 1 to 4 NREM sleep, parasympathetic
identification of their underlying pathophysiologies, promotion                      nervous system tone increases, and sympathetic nervous system
of preventative behavior, and development of effective thera-                        activity (SNA), heart rate (HR), blood pressure (BP), stroke
pies. Nevertheless, much remains to be done to reduce the bur-                       volume, cardiac output, and systemic vascular resistance decrease
den of these diseases further. An examination of the potential                       (6–12). As a result, the cardiovascular system is in a state of hemo-
role of sleep apnea in the pathogenesis of these disorders holds                     dynamic and autonomic quiescence during which myocardial
promise to further this end. Over the past decade, the concerted                     workload is reduced. Parallel declines in central respiratory and
efforts of many investigators throughout the world have trans-                       sympathetic nervous outflow related to the transition from wake-
formed our understanding of the many mechanisms by which                             fulness to sleep may be related, in part, to central connections be-
sleep apnea may contribute to the pathophysiology and compli-                        tween the respiratory-related and central cardiovascular sympa-
cations of cardiovascular diseases. The primary objectives of                        thetic neurons in the brainstem (13). Increases in parasympathetic
this article, therefore, are to critically review the possible ad-                   activity and decreases in SNA contribute to an increase in barore-
verse physiological consequences of sleep apnea on the cardio-                       flex sensitivity during NREM sleep compared with wakefulness
vascular system, and to assess whether such adverse effects con-                     (14, 15).
stitute a risk for the development of chronic cardiovascular and                         Although NREM sleep is characterized by relative stability
cerebrovascular diseases. However, we will not consider pulmo-                       of the respiratory, cardiovascular, and autonomic systems, K
nary hypertension, as this has been reviewed in detail elsewhere                     complexes and spontaneous arousals from sleep intermittently
(1, 2). Similarly, owing to a lack of experimental data, cardiac                     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 ac-
(Received in original form July 10, 2001; accepted in final form October 29, 2001)
                                                                                     companied by augmented ventilation, which exceeds that ex-
This work was supported by the Canadian Institutes of Health Research (Grants
                                                                                     pected for the ambient PaCO2 and reinstitution of the wakeful-
MOT 11607 and UI 14909). R.S.T. Leung is the recipient of a Canadian Institutes      ness drive. Abrupt increases in BP and HR, due to sudden
of Health Research Clinician Scientist Phase I Award, and T.D. Bradley is sup-       increases in SNA and withdrawal of cardiac vagal activity, also
ported by a Canadian Institutes of Health Research Senior Scientist Award.           exceed waking levels (16). It appears that increases in BP and
Correspondence and requests for reprints should be addressed to T. Douglas           HR from NREM sleep to relaxed wakefulness involve aug-
Bradley, M.D., Toronto General Hospital/University Health Network, NU 9-112,         mented SNA, but not parasympathetic withdrawal. This indi-
200 Elizabeth Street, Toronto, Ontario, M5G 2C4 Canada. E-mail: douglas.bradley@
                                                                                     cates that arousal is a distinct transient state of heightened re-
                                                                                     spiratory and cardiovascular activity (17, 18).
Am J Respir Crit Care Med Vol 164. pp 2147–2165, 2001
DOI: 10.1164/rccm2107045                                                                 During the transition from NREM to rapid eye movement
Internet address:                                                (REM) sleep there are further, but to some extent divergent
2148                                               AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE           VOL 164   2001

alterations in respiratory and cardiovascular activity. Breath-     tive intrathoracic pressure causes transmural intrathoracic aor-
ing becomes less dependent on metabolic drive and more so           tic pressure to increase, which activates aortic baroreceptors
on behavioral factors (4, 19). The combination of an increase       and inhibits sympathetic outflow (36, 37). On the other hand,
in the threshold for a ventilatory response, a further reduction    there is a simultaneous fall in BP due to the reduction in
in ventilatory responsiveness to chemostimulation, and skele-       stroke volume, which suppresses carotid sinus baroreceptor
tal muscle atonia affecting the nondiaphragmatic respiratory        activity and tends to reflexively augment sympathetic outflow.
muscles leads to decreases in ventilation and increases in          Because the influence of the aortic baroreceptors predomi-
PaCO2 (20, 21). This is accompanied by an irregular pattern of      nates, the net effect is suppression of MSNA. Toward the end
breathing, particularly during phasic REM sleep, that is proba-     of these events, however, MSNA rises in response to hypoxia.
bly related to dream content. In contrast to ventilation during     Depending on the strength of the hypoxic stimulus and the
REM sleep, SNA, BP, and HR increase to levels similar to re-        sympathetic vasoconstrictor response, BP can, but does not in-
laxed wakefulness (7, 9). Like ventilation, there are irregular     variably increase toward the end of apneas (24, 26, 34, 38).
surges in SNA, HR, and BP linked to phasic REM sleep events             Hypoxia. During obstructive apneas, the sympathoexcita-
(22). The cause of the dissociation between central respiratory     tory effect of hypoxia is amplified by apnea and CO2 reten-
drive and sympathetic outflow during REM sleep is not yet           tion. This results in increased sympathetic vasoconstrictor tone
clear. One possibility is that the sympathetic nervous system is    (39). However, as discussed above, these sympathoexcitatory
not subject to any functional equivalent of the postsynaptic in-    effects are not engaged until several seconds into the apnea.
hibition of skeletal muscle that affects the respiratory system.    Owing to the circulatory delay between the lung and the pe-
In any case, because adults spend 85% of their total sleep time     ripheral chemoreceptors, the sensing of nadir SaO2 that occurs
in NREM sleep, sleep is generally a time of cardiovascular re-      in the lungs at the end of apnea is not detected at the carotid
laxation. However, sleep apnea disrupts this state of cardio-       bodies until several seconds later (40). As a result, the maxi-
vascular quiescence.                                                mum vasoconstrictor and chronotropic effects of apnea-related
                                                                    hypoxia occur during the postapneic ventilatory phase and are
CARDIOVASCULAR EFFECTS OF OBSTRUCTIVE                               associated with surges in BP and HR (41) (Figure 1). These ef-
SLEEP APNEA                                                         fects increase the metabolic demands of the myocardium in the
                                                                    face of reduced O2 supply. Moreover, intermittent hypoxia dur-
Acute Physiological Effects                                         ing obstructive apneas may directly depress cardiac contractility
As a consequence of repetitive obstructive apneas, hemody-          (42), or reduce cardiac performance indirectly by causing pul-
namic variables and cardiovascular autonomic activity oscil-
late 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 ob-
structive sleep apnea (OSA). Three key pathophyiological fea-
tures of OSA give rise to these abnormal cardiovascular oscilla-
tions: generation of exaggerated negative intrathoracic pressure
against the occluded pharynx, hypoxia, and arousals from sleep.
    Negative intrathoracic pressure. Ineffective inspiratory ef-
forts are a hallmark of obstructive apneas. The resulting exag-
gerated negative intrathoracic pressure swings increase left ven-
tricular (LV) transmural pressure by increasing the difference
between extracardiac and intracardiac pressures, and hence af-
terload, 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 ex-
aggerated negative intrathoracic pressure during apnea can im-
pair 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 obstruc-
tive apneas that is proportional to the negative intrathoracic
pressure generated (1, 30–33). However, it appears that exag-
gerated negative intrathoracic pressure does not acutely im-
pair 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 sympa-
thetic outflow, whereas apnea disinhibits it (35). Thus, during
a breath hold, sympathetic vasoconstrictor outflow to muscle
(MSNA) increases progressively from its onset until its termi-
nation owing to progressive hypoxic stimulation (36). How-
ever, during the initial phase of an obstructive apnea or Muel-     Figure 1. Repetitive elevations in muscle sympathetic nerve activity
ler maneuver, MSNA is suppressed (36, 37). This is due to the       and blood pressure associated with recurrent obstructive apneas and
effects of obstructive apneas on baroreceptor activity. Nega-       hypoxia. From Hedner and coworkers (53), with permission.
State of the Art                                                                                                                 2149

monary vasoconstriction and increasing pulmonary arterial pres-     ability, and increased BP variability (41, 53–56). A number of
sure (33). The degree of desaturation during each obstructive       studies have shown that patients with OSA have higher SNA
apnea has been directly related to the magnitude of the increase    during sleep and wakefulness than control subjects (41, 53, 54)
in BP following the apnea (8, 43). Although these effects can be    (Figure 2). Treatment of OSA either by tracheostomy (57) or
partly inhibited by administration of O2 during voluntary Muel-     continuous positive airway pressure (CPAP) leads to a reduc-
ler maneuvers (36), supplemental O2 has little effect on BP         tion in nocturnal and daytime SNA. The latter effect appears
surges following apneas in patients with OSA (24, 44). This ob-     to require several months of CPAP therapy (58–60). This ben-
servation indicates that factors other than hypoxia, such as hy-    eficial effect is presumably related to elimination of OSA, noc-
percapnia and arousals from sleep, must also be contributing to     turnal hypoxia, and arousals from sleep.
surges in postapneic BP (16, 18, 39).                                   Peripheral chemoreceptors and sympathetic nervous sys-
    Hypoxia has varying influences on HR according to the           tem activity. The mechanisms by which OSA leads to persis-
presence or absence of airflow, and the balance of its parasym-     tent sympathetic activation are incompletely understood. There
pathetic and sympathetic stimulatory effects. In the absence of     are several lines of evidence favoring an important role for hy-
airflow, hypoxic stimulation of the carotid body is vagotonic,      poxia in this phenomenon. Urinary norepinephrine concentra-
and causes bradycardia (45, 46). Conversely, in the presence        tions are inversely proportional to minimal nocturnal SaO2 in
of airflow (e.g., hypoxic rebreathing), hypoxia causes tachycar-    patients with OSA (61). In addition, both short-term sustained
dia because stretching of the lungs inhibits vagal outflow to the   and intermittent challenges with combined hypoxia and hy-
heart and permits unopposed cardiac sympathetic discharge.          percapnia cause elevations in MSNA that persist for at least
Nevertheless, HR responses to obstructive apneas vary greatly       20 min following withdrawal of the exposure (62, 63). This
among individuals. This variability in HR responses is proba-       prolonged sympathetic effect appears to be due to hypoxia
bly due to differences in severity of hypoxia, intrinsic hypoxic    rather than hypercapnia (64).
chemosensitivity, and the relative influence of hypoxia on va-          The carotid bodies may be an important intermediate step
gal and sympathetic input to the sinoatrial node (47, 48). Ac-      in the pathway between exposure to intermittent hypoxia and
cordingly, where parasympathetic influence predominates, HR         development of sustained elevations in SNA. For example, it
may slow, where sympathetic influence predominates, HR may          has been reported that patients with OSA have increased pe-
rise, and where vagal and sympathetic influences are relatively     ripheral chemoreflex sensitivity (65) and pressor responses to
equal, HR may remain unchanged (49). However, upon resump-          hypoxia (66). A mechanism for this is suggested by the obser-
tion of airflow at termination of apnea, HR invariably rises ow-    vation that daily short-term exposure to hypoxia increases
ing to disengagement of hypoxia-mediated cardiac vagal out-         peripheral hypoxic chemosensitivity (67). However, other in-
flow and unopposed cardiac sympathetic discharge (16, 39,           vestigators have reported either normal (68) or depressed hy-
50). When bradycardia occurs during obstructive apneas, ad-         poxic ventilatory responses in patients and animals with OSA
ministration of supplemental O2 or atropine attenuates it (51).     (69, 70). Nevertheless, carotid body denervation prevents the
    Arousals. Arousal is a critical defense mechanism that ac-      development of hypertension in rats exposed to intermittent
tivates upper airway dilator muscles and prevents asphyxiation      hypoxia (71), and desensitization of the peripheral chemore-
in OSA (21). However, it also contributes to the abrupt surges      ceptors by administration of 100% O2 in awake normoxic pa-
in HR and BP following termination of apnea (16), but the de-       tients with OSA reduces MSNA, HR, and BP (72). These
gree to which it does so remains controversial. O’Donnell and       findings suggest that the peripheral chemoreceptors stimulate
colleagues (26) induced obstructive apneas of similar length in     cardiovascular sympathetic outflow in patients with OSA even
dogs with and without arousal. Apneas terminated prior to           when they are normoxic and awake.
arousal caused increases in BP, but termination by an arousal           Baroreflexes. Under normal conditions, activation of the
caused a further increase. Similarly, Trinder and coworkers         carotid sinus and aortic arch baroreceptors by an increase in
(18) described augmentation in HR and BP during the ventila-        BP reflexively inhibits sympathetic outflow, increases cardiac
tory phase of Cheyne–Stokes respiration, both awake and dur-        vagal outflow, and reduces HR. A decrease in BP does the op-
ing sleep in the absence of arousals. Arousals caused only a        posite. Therefore, depression of baroreceptor sensitivity could
small further increment in HR and BP. One confounding fac-          contribute to sympathetic activation and parasympathetic with-
tor is that arousals are accompanied by an abrupt increase in       drawal (73). In patients with OSA, repetitive nocturnal surges
ventilation that precedes increases in HR and BP. This sug-         in BP may downregulate baroreceptors and blunt their sensitiv-
gests that the increased ventilatory drive at termination of ap-    ity. However, studies of baroreflex sensitivity in patients with
nea coactivates cardiovascular sympathetic neurons that are         OSA have yielded inconsistent results; some investigators re-
closely linked with respiratory neurons in the brainstem (13).      port that it is depressed (73, 74), and others report that it is
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 ap-
nea counteracts asphyxia-induced sympathetic activation caus-
ing an abrupt decrease in MSNA, which plays a role in the fall                                              Figure 2. Increased mus-
in BP prior to the onset of the next apnea (41). Taken together,                                            cle sympathetic nerve ac-
these observations indicate that although arousals from sleep                                               tivity during wakefulness
can contribute, they are not critical to the development of post-                                           in patients with obstructive
                                                                                                            sleep apnea (OSA) com-
apneic surges in HR and BP.                                                                                 pared with normal sub-
                                                                                                            jects. From Somers and
Chronic Physiological Effects                                                                               coworkers (41), with per-
Autonomic cardiovascular function. OSA is associated with                                                   mission.
chronic abnormalities of cardiovascular autonomic regulation
both during sleep and wakefulness. These are characterized by
increased SNA, reduced baroreflex sensitivity and HR vari-
2150                                                 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE         VOL 164    2001

normal (75). Brooks and coworkers (76) found that in concert          gators found depressed circulating nitric oxide levels and a
with an increase in BP, induction of OSA in dogs caused a             selective defect in endothelium-dependent vascular relaxation
parallel shift of the baroreflex curve to the right, indicating an    (95, 96), whereas others did not (97). Taken together, the
increase in the set point to a higher BP, but without any             above findings do not provide persuasive evidence of either a
change in sensitivity. Thus, the baroreflex appeared no longer        primary vascular lesion or abnormal vascular responsiveness
capable of counteracting the higher BP, and may have been             to hypoxia or to endothelially dependent vasoconstrictors or
contributing to it by indirectly maintaining a higher sympa-          dilators.
thetic outflow (77). However, because dogs are quadrupeds                It has been hypothesized that intermittent hypoxia with
that do not undergo as extreme postural changes as humans, it         abrupt decreases and increases in cardiac output in association
is unclear what implications these findings have for patients         with OSA could provoke elaboration of oxygen free radicals
with OSA. On the other hand, Tkacova and colleagues (78)              and ischemia–reperfusion injury to the vascular wall (98).
demonstrated that acute elimination of OSA by CPAP in pa-             Such a process could precipitate or accelerate the formation of
tients with congestive heart failure (CHF) caused both an im-         atherosclerotic plaques and vascular smooth muscle prolifera-
mediate increase in baroreflex sensitivity and a decrease in the      tion (99, 100). A recent study demonstrated increased super-
set point in association with a reduction in BP. These findings       oxide anion production in patients with OSA that was mark-
have two important implications. First, they suggest that OSA         edly diminished following CPAP therapy (101). However,
may both increase the set point and depress the sensitivity of        there is no direct evidence that OSA can precipitate or accel-
the baroreflex. Second, such abnormalities are to some extent         erate atherosclerosis.
reversible.                                                              Coagulation. Platelet aggregability is enhanced by cate-
    Heart rate variability. Cardiovascular autonomic function         cholamines and is associated with an increased risk of cardio-
has also been assessed in patients with OSA by examination of         vascular events (102, 103). Shortly after arising in the morning,
daytime heart rate variability using power spectral analysis.         there is a surge in plasma catecholamines and a simultaneous
Normally, HR varies at high frequency (HF) as a function of           increase in platelet aggregability to peak levels, which corre-
respiration. This respiratory sinus arrhythmia is modulated           sponds to the peak incidence of cardiovascular and cerebrovas-
primarily by cardiac vagal activity. Heart rate variability at        cular events (103–107). The hypothesis that OSA might predis-
lower frequencies is thought to be modulated by sympathetic           pose to such ischemic events is plausible because the longest
activity, although there is controversy on this point (79). In        REM episode with the most severe apneas generally occurs just
general, patients with OSA have a decrease in the HF compo-           before awakening in the morning. Moreover, in contrast to
nent of HR variability and an increase in the low-frequency           healthy subjects, in patients with OSA, platelet aggregability in-
component (55, 80, 81). This abnormal pattern is thought to           creases significantly overnight in association with elevated noc-
reflect decreased parasympathetic and increased sympathetic           turnal catecholamine levels (108–111). Abolition of OSA by
modulation of HR. Treatment of OSA with CPAP has been                 CPAP has been reported to reduce platelet aggregability in as-
shown to restore these indices toward normal, both acutely            sociation with reductions in overnight catecholamine levels (109,
(82) and chronically (83).                                            110, 112).
    Circulating hormones. In addition to catecholamines, lev-            OSA is also associated with laboratory evidence of a pre-
els of other circulating hormones involved in the regulation of       disposition to clot formation. For example, hematocrit is in-
BP and fluid volume, such as renin, aldosterone, and vaso-            creased, probably due to nocturnal hypoxemia (113). Overnight
pressin, have been studied in relation to OSA. All of these           and daytime fibrinogen levels (114), as well as whole blood vis-
hormones have pressor or fluid- and sodium-retaining effects          cosity (115), are also elevated. The mechanisms for these associ-
that would predispose to hypertension. However, there is no           ations remain to be determined. Nevertheless, the observations
clear indication what, if any, effect OSA has on the levels of        that CPAP therapy can alleviate some of these abnormalities
these hormones (84–86).                                               and can reduce Factor VII clotting activity (116) suggest that
    Results have been more consistent in the case of atrial           OSA is contributing to them. However, definitive evidence that
natriuretic peptide, a vasoactive hormone secreted primarily          OSA predisposes to clot formation awaits further research.
in response to right atrial distension (87). In patients with OSA,       Potential adverse cardiovascular physiological effects of
its concentration is elevated in proportion to the degree of hy-      sleep apnea are listed in Table 1.
poxemia-induced increases in pulmonary artery pressure and
negative intrathoracic pressure swings (85, 88–90). Atrial natri-     CLINICAL CARDIOVASCULAR DISEASE AND
uretic peptide promotes diuresis, natriuresis, and vasodilation       OBSTRUCTIVE SLEEP APNEA
and thereby counteracts the pressor and fluid-retaining effects
of the hormones mentioned above (91). Consequently, high              Background
nocturnal atrial natriuretic peptide levels probably contribute       Despite the large number of cross-sectional or case-controlled
to nocturia, a common feature of OSA. In uncontrolled stud-           epidemiological studies describing associations between OSA
ies, abolition of OSA by CPAP was associated with reductions          and various cardiovascular diseases (CVD), the issue of whether
in nocturnal urinary atrial natriuretic peptide and urine excre-      OSA independently increases the risk of CVD has been conten-
tion (90, 91).                                                        tious. However, as the results of well-designed large-scale stud-
     Vascular and endothelial effects, and atherosclerosis. Ab-.      ies are becoming available, the issue is approaching resolution in
normalities of vascular responsiveness could contribute to chronic    favor of a significant relationship.
elevations in BP in patients with OSA. However, experiments on            The difficulty in establishing whether there is a causal link
vascular responses to hypoxia, and - and -adrenergic stimula-         between OSA and CVD is made particularly challenging by at
tion in OSA have yielded inconsistent results (66, 68, 92). Studies   least four factors. First, any associations between OSA and
of the potential role of the potent endogenous vasoconstrictor,       CVD observed in cross-sectional studies must always be inter-
endothelin-1, in the pathogenesis of systemic hypertension in         preted in light of numerous potentially confounding variables,
patients with OSA have also been inconclusive (93, 94). Simi-         such as obesity. Second, the results of many epidemiological
larly, studies of responses to endogenous vasodilators in pa-         studies may not be comparable because of the use of different
tients with OSA have yielded conflicting results: some investi-       techniques to establish the diagnosis and severity of sleep-disor-
State of the Art                                                                                                                2151

TABLE 1. PROPOSED PATHOPHYSIOLOGICAL EFFECTS OF                      true of OSA. Therefore, the best means of investigating the
OBSTRUCTIVE SLEEP APNEA ON THE CARDIOVASCULAR SYSTEM                 potential impact of OSA on CVD risk is through large-scale,
Acute Effects                                                        long-term prospective epidemiological studies. Another ap-
  Reduced myocardial oxygen delivery                                 proach to determine whether OSA causes CVD is through the
    Intermittent hypoxia                                             use of animal models. Fortunately, a canine model of OSA has
    Decreased cardiac output                                         been developed (119) that allows chronic exposure of dogs to
  Increased myocardial oxygen demand
    Arousals from sleep
                                                                     repetitive upper airway occlusions during sleep.
    Sympathetic nervous system activation                               In view of the above, it is clear that studies that have ad-
    Increase in left ventricular afterload                           hered to the principles of controlling for confounding vari-
       Negative intrathoracic pressure                               ables, use of proper instrumentation and prospective designs
       Increased blood pressure                                      for epidemiological studies, and exploitation of appropriate
    Increased heart rate                                             animal models of disease are those most likely to yield reliable
  Nocturnal myocardial ischemia
  Nocturnal pulmonary edema
                                                                     results. Consequently, in the following discussion, we empha-
  Cardiac arrhythmias                                                size the findings of those studies that have employed one or
                                                                     more of the above principles to establish the clearest picture
Chronic Effects
  Autonomic cardiovascular derangements
                                                                     of the extent to which OSA may be a risk factor for various
    Sympathetic nervous system activation                            CVDs.
    Reduced heart rate variability
    Impaired baroreflex control of heart rate                        Hypertension
    Systemic hypertension—nocturnal and diurnal                      Epidemiology. Hypertension, which affects 20% of the adult
  Myocardial effects
    Left ventricular hypertrophy
                                                                     population, is one of the commonest diseases in North Amer-
    Left ventricular dysfunction and failure                         ica (118). It is a major risk factor for the development of coro-
  Increased platelet aggregability and blood coagulability           nary artery disease, CHF, and strokes. Moreover, effective
    Increased susceptibility to thrombotic and embolic cardiac and   therapy of hypertension reduces the risk of developing these
       cerebrovascular events                                        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 pos-
                                                                     sibly treatable cause of hypertension must be viewed.
dered breathing. Third, it may require many years to decades             Methodologically rigorous population-based studies have
for any CVD to develop as a result of exposure to OSA. Fi-           yielded convincing evidence in favor of a modest, but definite
nally, until recently there has not been a suitable animal           association between OSA and systemic hypertension, indepen-
model to study the long-term cardiovascular effects of OSA.          dent of age, obesity, or other confounding factors (120–122).
    Attempts to control for confounding variables may them-          The Sleep Heart Health study employed in-home polysomnog-
selves introduce problems, especially if statistical adjustments     raphy (120) in a cross-sectional analysis of 6,132 subjects. A
are made for variables that are part of the causal pathway (117).    clear independent association between OSA and hypertension
For instance, some studies investigating the link between OSA        was observed in which the prevalence of hypertension increased
and CVD control for preexisting hypertension. However, if            with increasing AHI. However, the association was quite modest
OSA leads to CVD through its effects on BP, any statistical          with an adjusted odds ratio for the most severe OSA category,
adjustment for hypertension will tend to “overcontrol” for this      AHI 30 (versus AHI 1.5) of only 1.37 (CI 1.03–1.83). Simi-
variable, concealing a genuine association. Moreover, current        larly, in a cross-sectional analysis of 1,069 subjects who under-
measurements of OSA, such as apnea–hypopnea index, may               went in-laboratory polysomnography in the Wisconsin Sleep Co-
not accurately reflect the most relevant pathophysiologic as-        hort Study (121) a significant linear increase in daytime BP with
pects of OSA contributing to CVD. Because the frequency of           increasing AHI was observed. The association between OSA
apnea and hypopneas per hour of sleep (apnea–hypopnea in-            and hypertension was stronger in this study with an adjusted
dex or AHI) is likely a very imperfect reflection of the physio-     odds ratio for hypertension associated with AHI 30 (versus
logical burden of OSA in a given individual, the resulting ex-           1) of 3.1 (CI 1.7–5.7). Furthermore, results have recently
traneous variability will obscure attempts to find associations      been reported from prospective follow-up of 893 of those sub-
between this measure of OSA and CVD. Some combination                jects over 4 to 8 yr (122). The odds ratio for the new onset of
of frequency and duration of apneas, frequency and degree of         hypertension at follow-up assessments, associated with the
desaturations, and PCO2 and frequency of arousals might pro-         presence of OSA at baseline, was 2.89 (CI 1.46–5.64 for an
vide a better overall index of the cardiovascular burden of          AHI 15 versus 0). These are the strongest epidemiological
OSA. For all these reasons, it is critically important that the      data yet demonstrating an association between OSA and day-
design of epidemiological studies takes into account these is-       time hypertension. Indeed, they support the notion that OSA
sues, and that it controls for the right potentially confounding     contributes to the development of hypertension.
independent variables, but that it does not “overcontrol” for            Pathophysiology. The most compelling experimental evi-
other variables that may not be independent of sleep apnea.          dence that OSA can cause hypertension comes from studies in
    With respect to sleep recording techniques, the use of so-       animals. Brooks and coworkers (119) demonstrated that expo-
phisticated instrumentation under well-controlled conditions         sure of dogs to obstructive apneas during sleep for 1–3 mo
is the best way to detect, classify, and quantify sleep-disor-       caused chronic elevations in BP both during sleep and wake-
dered breathing, and its influence on respiratory, neurological,     fulness. In addition, reversal of OSA caused nocturnal and
and cardiovascular variables. Accordingly, epidemiological           daytime BP to fall back to baseline levels within 1–4 wk. How-
studies that employ full polysomnography are more likely to          ever, exposure of the same dogs to acoustic stimuli during
yield reliable results than are those in which only one or a few     sleep, which provoked arousals and acute BP elevations equal
variables, such as O2 saturation, are recorded.                      to those observed during OSA, did not lead to diurnal hyper-
    It is well established that hypertension leads to CVD only       tension. Similar results have been described in rats (123).
after years to decades of exposure (118). The same may be            These findings indicated that arousals from sleep were insuffi-
2152                                                   AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE         VOL 164   2001

cient to cause diurnal hypertension, but that additional stimuli         with essential hypertension (i.e., “dippers”). In contrast, many
related to OSA were necessary for its development.                       OSA patients are “nondippers” because they have an attenu-
   The mechanisms through which OSA promotes hyperten-                   ated or absent fall in nocturnal BP (133–135). It is therefore
sion have not been fully elucidated. However, converging evi-            possible that many patients with essential hypertension who
dence from physiological studies in humans and animals                   have a “nondipping” pattern of nocturnal BP have undiag-
points toward intermittent hypoxia and sympathetic nervous               nosed OSA. For example, Portaluppi and coworkers (135) re-
system activation playing central roles. As described above,             ported the presence of unsuspected OSA in 10 of 11 “nondip-
elevated sympathetic vasoconstrictor nerve traffic in OSA ap-            ping” patients with hypertension but in none of 10 “dipping”
pears to be sustained into wakefulness through chronic alter-            patients with hypertension. These results imply that the “non-
ations in chemoreflex sensitivity and baroreflex set point.              dipping” condition is probably related to sleep apnea in many
Together, these may promote upregulation of sympathetic                  cases of essential hypertension. Because “nondipping” is asso-
vasoconstrictor tone. Conversely, when OSA is eliminated by              ciated with a higher risk of cardiovascular complications inde-
CPAP, sympathetic vasoconstrictor activity falls both acutely            pendent of daytime BP levels (129–132), the debate about
at night (41) and chronically during wakefulness (58, 59) in as-         whether OSA leads to daytime hypertension may be less im-
sociation with reductions in BP.                                         portant than previously supposed.
   Consistent with these observations, Fletcher and colleagues               Treatment. A number of studies have suggested that hy-
demonstrated that intermittent exposure of rats to hypoxia for           pertension in patients with OSA is more difficult to control by
8 h/d over 35 d induced sustained arterial hypertension (124).           conventional means than is hypertension in nonapneic pa-
Elevations in BP were prevented by both carotid body and                 tients (136). Conversely, OSA is common in patients with dif-
sympathetic nervous system denervation (125, 126). These ob-             ficult to control hypertension (137). Furthermore, it has been
servations indicated that episodic hypoxia exerted its long-             recently reported that in patients whose hypertension was re-
term effects on BP through stimulation of the peripheral                 fractory to maximal medical therapy, 87% had OSA (138).
chemoreceptors, which are potent stimulators of brainstem                Taken together, these findings suggest that hypertensive pa-
sympathetic vasoconstrictor outflow. Additional studies dem-             tients with OSA may be relatively resistant to the antihyper-
onstrated that exposure of rats to intermittent hypoxia pro-             tensive medications.
voked increased activity of the adrenal glands, renal sympa-                 Among the commonly prescribed antihypertensive agents,
thetic nerves, and the renin angiotensin system, all of which              -blockers have been reported to be the most effective in low-
could promote increases in BP (127, 128). Recent work also               ering daytime BP in hypertensive patients with OSA (139). This
suggests that patients with OSA have an increased pressor re-            observation is in keeping with the hypothesis that sympathetic
sponse to hypoxia (66). However, although abnormal vascular              overactivity is involved in the pathogenesis of OSA-induced
endothelial-mediated vasodilatory and constrictor responsive-            hypertension. However, antihypertensive medications have lit-
ness has been postulated as contributing to hypertension in              tle effect on nocturnal BP in OSA, possibly because they do not
OSA, data on these points are inconclusive (66, 68, 93–97).              alleviate OSA (139, 140).
   Another interesting observation arising from these experi-                A number of uncontrolled studies have reported that re-
ments was that sustained elevations in BP in response to inter-          versal of OSA by tracheostomy or CPAP in patients who were
mittent hypoxia occurred only in certain spontaneously hyper-            normotensive while awake was associated with a reduction in
tensive strains of rats. These observations therefore suggest            BP and MSNA during sleep (41, 57). Similar results have been
that vascular responses to intermittent hypoxia are at least             reported in patients with heart failure with OSA who were on
partially under genetic control. They further imply that there           BP lowering medications (38).
may be a subset of humans and animals with a genetic predis-                 Several randomized (141–143) and nonrandomized (144–
position to the development of systemic hypertension in re-              147) clinical trials have addressed the effects of CPAP on day-
sponse to OSA. If so, this might explain why, among patients             time BP in patients with OSA. However, these studies suffered
with OSA of equal severity, some develop hypertension and                from a serious flaw in design; the great majority of patients
others do not.                                                           studied were normotensive while awake. Not surprisingly, the
   In summary, animal models of OSA strongly support the                 effects of CPAP on diurnal BP were trivial or nonexistent. Only
notion that sustained diurnal hypertension can arise from                one nonrandomized trial has examined the effects of CPAP in
chronic exposure to recurrent obstructive apneas. However,               patients with OSA all of whom were hypertensive while awake
findings from these experiments in animals must be inter-                despite aggressive antihypertensive therapy. Logan and co-
preted with a few caveats. First, there may be important dif-            workers (148) found that treatment of these patients with
ferences in response to apneas between species. Second, OSA              CPAP over a 2-mo period led to clinically significant reduc-
in humans probably evolves over many years, which could al-              tions in both nocturnal and daytime BP. Although not defini-
low for the development of compensatory protective mecha-                tive, these results do emphasize the need for well-designed
nisms. Findings derived from animal models in which severe               randomized trials to ascertain with certainty whether treating
sleep apnea is rapidly introduced may not be generalizable to            OSA will lower daytime BP in patients with hypertension. The
the human disease state. Notwithstanding these reservations,             findings of such studies will be very important because OSA
animal models have provided powerful evidence for a direct               may well prove to be the commonest, potentially treatable
causative link between OSA and daytime hypertension.                     secondary cause of hypertension.
   Clinical significance. In the controversy about whether OSA
can lead to daytime hypertension, one point that is frequently           Stroke
overlooked is that OSA undoubtedly causes elevations in BP dur-          Epidemiology. In North America, stroke is the third leading
ing sleep. Considering that humans typically spend one-third of          cause of death and the leading cause of long-term disability
their lives sleeping, it is necessary to consider the possibility that   (149, 150). The first large-scale population-based study to
these nocturnal increases in BP might in themselves contribute           examine the potential relationship between sleep apnea and
to hypertensive cardiovascular complications (129–132).                  stroke was in 6,424 subjects in the Sleep Heart Health Study.
   The normal nocturnal decrease in BP averages about 15%                The presence of OSA was associated with a clear, but modestly
below daytime levels and is generally preserved in patients              increased prevalence of stroke; the odds ratio for the highest
State of the Art                                                                                                                     2153

AHI quartile (AHI 11) was 1.58 times (CI 1.02–2.46) that of          leading cause of death following stroke (170). It is therefore
the lowest quartile (AHI 1.4) (151).                                 possible that in the older studies of Cheyne–Stokes respiration
    Among subjects who have suffered a stroke, sleep apnea is        in poststroke patients, underlying cardiac dysfunction may
extremely common and is reported to occur in 43–91% of pa-           have been present, but undetected (165, 166, 169). Conse-
tients (152–156). These prevalences are significantly higher         quently, the pathophysiology and clinical significance of CSA
than in control subjects without stroke. In all these studies,       following stroke remain to be elucidated.
OSA predominated, whereas central sleep apnea (CSA) was                 Clinical significance. When sleep apnea is present follow-
observed in only a small minority of patients (less than 10%). It    ing a stroke, it could further compromise cognitive and physi-
remains unclear, however, to what extent sleep apnea detected        cal functioning. For example, OSA is associated with excessive
following a stroke might be a consequence of the stroke, rather      daytime sleepiness and impaired cognitive function, reaction
than a preexisting condition. Bassetti and Aldrich (154) argued      times, and simulated driving performance (171, 172). In addi-
that OSA most likely preceded stroke, based on the observa-          tion, apnea-related hypoxia can lead to the elaboration of neu-
tion that the frequency and severity of sleep apnea did not dif-     roinhibitory peptides, such as -aminobutyric acid, which could
fer between patients with stroke and those with transient ische-     also further compromise cerebral function (173). Indeed, fol-
mic attacks. In addition, Parra and colleagues (156) found that      lowing a stroke, patients with OSA have worse functional ca-
the frequency of obstructive apneas did not decline between          pacity than patients without OSA. This difference could not
the period immediately after the stroke to 3 mo later. How-          be attributed to differences in the severity of the stroke (152, 153).
ever, there was a decline in frequency of central apneas. These         Treatment. Well-designed randomized clinical trials in which
data suggested that acute stroke predisposed to development          the effects of treating sleep apnea on neurological outcomes in
of CSA, but that OSA was more likely already present at the          patients with strokes have yet to be performed. Such studies need
time of the stroke.                                                  to be undertaken, for they will provide the evidence upon which
    Pathophysiology. A number of mechanisms through which            a rational approach to the diagnosis and treatment of sleep ap-
OSA could predispose to cerebrovascular events are discussed         nea in patients with strokes will be based.
above. These include systemic hypertension, increased platelet
aggregability, and blood coagulability (109, 110, 112). In addi-     Ischemic Heart Disease
tion, during obstructive apneas there is a significant decline in    Epidemiology. In a cross-sectional analysis of the Sleep Heart
cerebral blood flow due mainly to a reduction in cardiac out-        Health Study cohort, OSA was found to be an independent
put (157, 158). The decline in cerebral perfusion is also tightly    risk factor for coronary artery disease (CAD) (151). However,
linked with reductions in BP, which could predispose to cere-        the association was modest; the odds ratio for CAD of the
brovascular accidents in subjects with flow-limiting lesions of      highest AHI quartile (AHI 11) was 1.27 times (CI 0.99–1.62)
the carotid or vertebral circulations. This would be of particu-     that of the lowest quartile (AHI 1.4). Prospective follow-up
lar relevance during REM sleep when cerebral blood flow and          of the cohort should provide additional insights into the rela-
oxygen demands are normally highest, but when apneas are ac-         tionship between OSA and CAD. Because it has been estab-
companied by the greatest degrees of hypoxia (159). Such an          lished that OSA increases the risk for hypertension, it seems
imbalance could put the cerebral circulation at risk, especially     likely that it would also increase the risk for disorders, such as
during the early morning hours during, or immediately follow-        CAD, that are associated with hypertension.
ing, the longest episode of REM sleep (106, 153, 160). In addi-          Pathophysiology. As described above, OSA exerts several
tion, abrupt and marked alterations in blood flow velocity as-       acute physiological effects that could predispose to myocardial
sociated with alternating obstructive apneas and hyperpneas          ischemia during sleep. In dogs with experimentally induced cor-
could lead to abrupt alterations in vascular shear forces, and       onary artery stenosis, obstructive apneas can lead to myocardial
acceleration of atherosclerosis (159, 161, 162).                     ischemia even in the absence of hypoxia (174, 175). However, in
    Central apneas have been reported, in a number of older          the absence of a coronary stenosis, myocardial ischemia was not
studies, to be associated with bilateral hemispheric and brain-      observed. Others have reported that electrocardiographic signs
stem infarctions (163–167). However, in all except one of            of ischemia in patients with OSA with CAD were more closely
these studies (167), sleep monitoring was not performed and          linked to increases in HR and BP related to apneas than to O2
potential behavioral influences related to wakefulness could         desaturation. These observations suggested that the main trig-
not be ruled out. More recent data have not detected an asso-        ger of ischemia was an increase in O2 demand rather than a re-
ciation between stroke location and apnea type (156). The ob-        duction in supply (176). In another study, Mueller maneuvers,
servation that central apneas dissipate over time following          which simulated the effects of obstructive apneas, caused more
stroke suggests that strokes may promote central apneas in           pronounced reductions in LV ejection fraction (LVEF) in hu-
the immediate poststroke period, but as brain inflammation           mans with, than in those without CAD (177). These findings
and edema resolve, so do central apneas. However, there are          emphasize that the diseased myocardium is more susceptible
as yet insufficient physiological data to determine the type         to the adverse effects of obstructive apneas than is the normal
(hypercapnic or nonhypercapnic) or etiology of central apneas        myocardium.
in the poststroke period (168).                                          Clinical significance. Nocturnal ST-segment changes con-
    What has become clear, however, is that Cheyne–Stokes            sistent with myocardial ischemia are quite common among pa-
respiration is decidedly uncommon following stroke. Thus the         tients with OSA and coexisting CAD. Various studies have re-
attribution of Cheyne–Stokes respiration to cerebral damage          ported prevalences of such ischemic changes ranging from 20
in the older literature (169) must be reevaluated in light of        to 100% (176, 178–182). ST-segment depressions are more fre-
more recent findings. Because Cheyne–Stokes respiration is           quent in those with more severe OSA or prior complaints of
essentially periodic breathing with a long cycle length, and be-     nocturnal angina (179, 180). Ischemic episodes have been re-
cause cycle length is inversely proportional to cardiac output       lated both to O2 desaturation and to the postapneic surges in
(40), it is possible that this breathing disorder is a sign of un-   HR and BP (176, 179, 180), and can provoke awakening with
derlying cardiac dysfunction (see below). In fact, coronary ar-      complaints of angina (179–181) (Figure 3). Myocardial ischemia
tery disease is present in approximately one-third of patients       during sleep in patients with OSA may also be asymptomatic
with stroke and, over the long term, cardiac events are the          (i.e., silent). However, to date, there are no reports of the
2154                                                 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE         VOL 164    2001

                                                                      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 condi-
                                                                      tion 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.
Figure 3. ST segment depressions, expressed as ST segment change
                                                                          On the other hand, there remains the possibility that CHF
vector magnitude (STC-VM) in a patient with coronary artery disease   itself can contribute to the development of OSA. Two lines of
during recurrent obstructive apneas. Increased STC-VM indicates ST    evidence support this view. First, it has long been hypothe-
segment depression. The most pronounced fall in oxyhemoglobin sat-    sized that an underlying tendency to periodic breathing could
uration (SaO2) is accompanied by the greatest degree of ST segment    destabilize the upper airway and predispose to collapse. Pa-
depression during which the patient woke up with angina. From Fran-   tients with CHF are predisposed to periodic breathing because
klin and coworkers (179), with permission.
                                                                      of increased chemosensitivity, hyperventilation, and, possibly,
                                                                      prolonged circulation time (192–194). According to this view,
                                                                      as respiratory drive declines during the waning phase of peri-
                                                                      odic breathing, drive to the pharyngeal dilator muscles declines
prevalence of OSA among patients with CAD with silent noc-            as well (195, 196). Should the relative reduction in pharyngeal
turnal ischemia.                                                      dilator muscle tone exceed that of the diaphragm, upper air-
   Studies in patients with OSA without coexisting CAD have           way collapse could ensue. Indeed, in contrast to the abrupt
been less consistent. In some, no evidence of nocturnal is-           rise and rapid fall in tidal volume that characterizes OSA in
chemic episodes in such patients was reported (176, 183, 184),        patients with normal cardiac function, in patients with CHF
whereas in another, ST-segment depressions during the night           with OSA, tidal volumes during hyperpneas often have a wax-
occurred in 30% of patients (185). Acute application of CPAP          ing–waning appearance typical of Cheyne–Stokes respiration
to these patients significantly reduced the total duration of ST-     (38). This suggests the presence of an underlying periodic
segment depression. The reason for discrepancies between these        breathing disorder. Second, since patients with CHF suffer
studies remains unclear. Accordingly, there is uncertainty as to      from fluid retention and dependent edema, it is possible that
whether OSA causes nocturnal myocardial ischemia in the ab-           upon reclining, accumulation of edema in the soft tissues of the
sence of CAD.                                                         neck and pharynx could narrow the upper airway and make it
   In patients with CAD, OSA may be a poor prognostic indi-           more collapsible (197). Nevertheless, regardless of the underlying
cator. Among 62 patients with CAD followed prospectively              cause of upper airway collapse in patients with CHF with OSA, it
for 5 yr, Peker and coworkers (186) found that those with OSA         is rapidly reversed by acute application of CPAP (38, 198).
had a significantly higher mortality rate (38%) than those with-          Pathophysiology. As discussed above, and illustrated in
out OSA (9%, p 0.018), even after controlling for potentially         Figure 4, OSA exposes the left ventricle to several factors that
confounding factors.                                                  could impair its function. It is conceivable that over months to
   Treatment. There are no published randomized trials on             years, these factors could have cumulative adverse effects on
the effects of treating OSA on nocturnal myocardial ischemia          LV structure and diastolic and systolic function in some indi-
and angina. However, in uncontrolled studies, treatment of            viduals.
OSA with CPAP in patients with nocturnal angina was associ-               There are several case reports of patients presenting with
ated acutely with reduced frequency of ST-segment depres-             acute nocturnal pulmonary edema who were subsequently found
sion and chronically with relief of nocturnal angina (176, 179,       to have OSA, but normal LV systolic function (199, 200). Treat-
180). Nevertheless, larger, longer term randomized trials are         ment of OSA with CPAP was associated with a reduction in epi-
required to more clearly delineate the role of diagnosing and         sodes of pulmonary edema. These cases suggest that the adverse
treating OSA in patients with CAD.                                    effects of OSA can be sufficient to cause acute LV failure during
                                                                      sleep in susceptible individuals.
Congestive Heart Failure                                                  Hypertension is the single most important predisposing fac-
Epidemiology. Observations from epidemiological studies in-           tor for the development of LV hypertrophy and systolic and
dicate an association between OSA and CHF. In the Sleep               diastolic LV failure (201, 202). Accordingly, the most obvious
Heart Health Study, the presence of OSA (i.e., AHI 11) was            mechanism through which OSA could lead to the development
associated with a 2.38 relative odds for CHF independent of           or progression of LV failure is systemic hypertension. How-
other known risk factors (151). This risk exceeded that for all       ever, ischemia and reduced contractility due to hypoxia (42), as
other cardiovascular diseases examined including hyperten-            well as cardiac myocyte injury or necrosis due to increased cat-
sion, CAD, and stroke. In the two largest series of patients          echolamine stimulation (203), could also contribute. Regardless
with CHF with systolic dysfunction evaluated for sleep-disor-         of the precise mechanisms involved, there is now direct experi-
dered breathing, 11% of 81 patients (187) and 37% of 450 pa-          mental evidence that OSA can lead to interstitial pulmonary
tients (188) had OSA. This prevalence exceeds the approxi-            edema as well as LV hypertrophy and dysfunction. In anesthe-
mate 5–10% prevalence of OSA reported in otherwise healthy            tized dogs, Fletcher and colleagues (204) demonstrated the de-
adults (189). Risk factors for OSA among patients with CHF            velopment of subtle degrees of interstitial pulmonary edema af-
State of the Art                                                                                                                    2155

                                                                                Figure 4. Schematic representation of the pathophysiologi-
                                                                                cal effects of OSA on the cardiovascular system. Modified
                                                                                from Hall and Bradley (275), with permission.

ter 8 h of exposure to recurrent obstructive apneas. In addition,      ternate with ventilatory periods having a waxing–waning pattern
Parker and coworkers (34) showed that exposure of dogs to ex-          of tidal volume (Figure 5). CSR–CSA is common among patients
perimental obstructive apneas during sleep for several weeks           with CHF, being present in 30–40% in the largest reported se-
to months led to the development of increased LV mass and              ries (187, 188). Growing evidence indicates that CSR–CSA is
reduced ejection fraction in association with systemic hyper-          part of a vicious pathophysiological cycle involving the cardio-
tension. However, it is not clear whether OSA can lead to LV           vascular, pulmonary, and autonomic nervous systems that con-
hypertrophy in humans. Whereas one study reported greater              tributes to the progression of CHF (210–212). However, although
LV wall thickness in normotensive OSA patients than in nor-            CSR–CSA is common in men, it is seldom seen in women with
motensive control subjects (205), another did not (206).               CHF for reasons that remain to be fully elucidated (188). This
    Clinical significance. Because the diseased left ventricle is      observation may help to account for the higher mortality rate for
more susceptible to the negative hemodynamic effects of in-            men than for women following the onset of CHF (213).
creases in afterload than the normal left ventricle (207), OSA
may have particularly deleterious effects in patients with coex-
isting heart disease. For example, when humans with CHF are
exposed to exaggerated negative intrathoracic pressure during          Figure 6 provides a schematic representation of the patho-
Mueller maneuvers, they experience greater reductions in stroke        physiology of CSR–CSA. The key pathophysiological mecha-
volume and cardiac output that persist longer into the postap-         nism leading to CSR–CSA is a fluctuation of PaCO2 below and
neic period than in subjects with normal ventricular function          above the apneic threshold. When PaCO2 is periodically driven
(208). In addition, survival in CHF is inversely proportional to       below threshold by intervening episodes of hyperventilation,
cardiac noradrenergic drive (209). Therefore, elevated SNA as-         central neural outflow to the respiratory muscles is temporarily
sociated with OSA (41, 53, 54) would have particularly adverse         suppressed and central apneas ensue. A number of factors can
prognostic implications in patients with coexisting heart failure.     contribute to respiratory control system instability and predis-
    Treatment. Only one study has examined the effects of treat-       pose to fluctuations in PaCO2.
ing OSA on LV systolic function in patients with CHF. Malone              Hypocapnia. Patients with CHF with CSR–CSA have lower
and colleagues (198) demonstrated, in eight patients with idio-        PaCO2 both during wakefulness and sleep than those without
pathic dilated cardiomyopathy, that treatment of coexisting OSA        CSR–CSA (194, 214, 215). Moreover, episodes of CSR–CSA are
by CPAP for 1 mo caused dramatic improvements in LVEF (from            usually triggered by abrupt increases in ventilation and reduc-
37% to 49%) and cardiac functional status. Although these data         tions in PaCO2 below the apneic threshold (194). Inhalation of a
are encouraging, larger randomized trials will be required to deter-   CO2-enriched gas mixture sufficient to raise PaCO2 by just 1–3
mine whether treatment of OSA in patients with systolic and dia-       mm Hg eliminates central apneas and hypopneas both in pa-
stolic heart failure improves cardiac function and other cardio-       tients with CSR–CSA and idiopathic CSA (216, 217). These
vascular outcomes. The findings of the above mentioned study           findings also emphasize that the prevailing PCO2 in patients
also suggested that OSA can contribute to the development of           with CSR–CSA is closer to their sleeping apneic threshold (i.e.,
LV systolic dysfunction in patients with CHF of otherwise un-          within 1–3 mm Hg) than it is in healthy subjects whose prevail-
known etiology.                                                        ing PaCO2 is 3–5 mm Hg above the sleeping apneic threshold
                                                                       (218). Under this condition, even a modest increase in ventila-
CHEYNE–STOKES RESPIRATION AND CONGESTIVE                               tion can drive PaCO2 below the apneic threshold (194, 219).
HEART FAILURE                                                             The mechanisms responsible for chronic hypocapnia in pa-
                                                                       tients with CSR–CSA have not been fully elucidated. One pos-
Epidemiology                                                           sible explanation is hypoxia. However, both awake and mean
Cheyne–Stokes respiration with central sleep apnea (CSR–CSA)           nocturnal SaO2 in patients with CHF with CSR–CSA are usually
is a form of periodic breathing in which apneas and hypopneas al-      within normal limits and do not differ from those in patients
2156                                                 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE             VOL 164      2001

                                                                                                 Figure 5. Cheyne–Stokes respiration with
                                                                                                 central sleep apneas (CSR–CSA) in a patient
                                                                                                 with CHF (left panel). Note waxing–waning
                                                                                                 pattern of tidal volume (VT) during hyper-
                                                                                                 pneas and absence of ribcage and ab-
                                                                                                 dominal motion during apneas indicating
                                                                                                 their central nature. In contrast to the case
                                                                                                 in OSA, arousals, indicated by increases
                                                                                                 in submental electromyographic activity
                                                                                                 (EMGsm), occur after the onset of ventila-
                                                                                                 tion. The right panel illustrates abolition of
                                                                                                 CSR–CSA after 1 mo on nasal CPAP (NC-
                                                                                                 PAP) of 10 cm H2O in the same patient, in
                                                                                                 association with a reduction in minute ven-
                                                                                                 tilation (VI), which was accompanied by an
                                                                                                 increase in nocturnal PaCO2 above the ap-
                                                                                                 nea threshold. From Naughton and co-
                                                                                                 workers (258), with permission.

with CHF without CSR–CSA (194, 214, 220). Another possibil-           trol system, both by decreasing the prevailing PaCO2 and by
ity is that hyperventilation arises from stimulation of pulmo-        increasing the tendency to hyperventilate, thus precipitating ven-
nary vagal irritant receptors by increased LV volumes, filling        tilatory overshoot (193, 225, 226). Several studies have demon-
pressures, and pulmonary congestion (220–222). In favor of            strated higher central (227, 228) and peripheral chemorespon-
this hypothesis, Solin and coworkers (223) demonstrated sig-          siveness (229, 230) in patients with CHF with either periodic
nificantly higher pulmonary capillary wedge pressures and             breathing while awake or CSR–CSA than among those either
lower PaCO2 in patients with CHF than in those without CSR–           with OSA or without any sleep apnea. It remains to be deter-
CSA. Others have demonstrated an inverse relationship be-             mined whether such increases in central and peripheral chemo-
tween PaCO2 and LV filling pressure in patients with CHF              responsiveness predates or is a consequence of the develop-
(224). Accordingly, CSR–CSA may be a respiratory manifes-             ment of CHF (231). Evidence for the latter hypothesis comes
tation of elevated LV filling pressure (220).                         from experiments in rabbits in whom induction of CHF led to
    Increased chemoreceptor responsiveness. Elevated chemore-         increased peripheral but not central chemosensitivity (193).
ceptor responsiveness (gain) could destabilize the respiratory con-   These results support the notion that CHF itself can sensitize

                                                                                                       Figure 6. Pathophysiological scheme
                                                                                                       of central sleep apnea in congestive
                                                                                                       heart failure. Modified from Hall and
                                                                                                       Bradley (275), with permission.
State of the Art                                                                                                                   2157

the peripheral chemoreceptors, possibly by impairing the ven-         less common here than in NREM sleep probably because of
tilatory inhibitory effect of carotid body nitric oxide produc-       nonmetabolic and behavioral influences.
tion (193).                                                               Upper airway instability. Upper airway obstruction has been
    Hypoxia. The role of hypoxia in the pathogenesis of CSR–          described at the onset and at the end of central apneas in some pa-
CSA in heart failure is uncertain. Studies of patients with CHF       tients with CHF (195) and could promote ventilatory overshoot
and CSR–CSA have consistently shown them to be normoxic               upon the abrupt decrease in upper airways resistance at the ter-
while awake (194, 214). Nevertheless, hypoxic dips during ap-         mination of apneas (196). It is also possible that upper airway
neas may propagate CSR–CSA by provoking arousals and                  collapse itself can reflexively precipitate central apneas (239).
amplifying the ventilatory response to CO2 at the termination         A more likely possibility in the setting of CHF, however, is
of central apneas (225). A number of studies have investigated        that adverse effects of OSA on cardiac function can predis-
the effects of supplemental O2 in patients with CHF and CSR–          pose to central apneas. In patients with CHF having approxi-
CSA, with varying results. In general, where O2 was adminis-          mately equal numbers of obstructive and central apneas, ob-
tered at high flow rates, the frequency of central respiratory        structive apneas predominate at the beginning of the night,
events was significantly reduced (232–234). In one study, re-         whereas central apneas predominate at the end. The shift
ductions in central apneas were associated with increases in          from obstructive to central events occurred in association with
PCO2 (235). This observation suggested that increases in PaO2         a decrease in PCO2 and prolongation of circulation time (240).
suppressed respiratory drive allowing PaCO2 to rise above the         Thus, obstructive events likely converted to central events as
apnea threshold (235). In contrast, during studies in which O2        PCO2 fell below the apneic threshold due to an overnight dete-
was administered to patients with CSR–CSA at lower flow               rioration in cardiac function. Such deterioration probably
rates just sufficient to raise SaO2 into the normoxic range, little   arose from the combined effects of OSA and of increasing
or no effect was observed on the frequency of central events          venous return in the recumbent position that raised LV filling
or on PCO2 (216, 236). It is therefore likely that where supple-      pressure and lowered PCO2 (240, 241). These observations
mental O2 reduces the severity of CSR–CSA, it does so partly          raise the question as to whether OSA could, over time, predis-
by raising PaCO2.                                                     pose to CSR–CSA after the onset of cardiac failure.
    State changes and arousals. Shifts in the state of conscious-         Prolonged circulation time. Prolonged circulation time caus-
ness are likely to destabilize breathing. With the transition         ing delays in transmitting changes in arterial blood gas tensions
from wakefulness to NREM sleep, the waking neural drive to            within the lungs to the chemoreceptors could theoretically desta-
breathe is lost, and the threshold for a ventilatory response to      bilize the respiratory control system. It could do so by changing a
CO2 is increased (4). Therefore, if the ambient PaCO2 during          negative feedback into a positive feedback system (226). In
wakefulness is below this higher sleeping threshold, the transi-      support of this theory, Guyton (242) induced periodic breath-
tion to NREM sleep will be accompanied by a transient loss of         ing in dogs by inserting a length of tubing between the heart
respiratory drive resulting in a central apnea. During the ap-        and cerebral circulation to prolong transit time between the
nea, PaCO2 rises until it reaches the new higher threshold level      lungs and the chemoreceptors. However, CSR–CSA could be
and initiates breathing. If sleep becomes firmly established,         generated only when the circulatory delay was a few minutes
regular breathing resumes (237). However, if an arousal should        in duration, far exceeding that seen in patients with CHF. In
occur, the increased PaCO2 level associated with sleep now rep-       humans, lung to peripheral chemoreceptor circulation time is
resents a state of relative hypercapnia for wakefulness and will      inversely proportional to stroke volume and cardiac output
stimulate hyperpnea. In addition, other studies have demon-           (40). Mortara and coworkers (243) found, in patients with
strated that arousals cause ventilation to rise above the wak-        CHF, that prolonged circulation time was a major determi-
ing level independent of PaCO2 (17). Accordingly, arousal con-        nant of the presence of CSR–CSA. In contrast, other investi-
tributes independently to ventilatory control system instability.     gators have found no significant differences in LVEF, circula-
    The role of arousal in CSR–CSA contrasts with its role in         tion time, or cardiac output between patients with CHF with
OSA where it is a critical defense mechanism that terminates          and without CSR–CSA (194, 210, 223). Taken together, these
apneas by triggering opening of the upper airway. In CSR–             data suggest that prolonged circulatory delay is probably not
CSA, however, arousals often occur after airflow has resumed.         the critical factor predisposing to central apneas in CHF.
It therefore appears that resumption of airflow following cen-        However, circulatory delay influences periodic breathing cycle
tral apneas is not always dependent on an arousal (194, 214,          length such that cycle length is proportional to lung to carotid
219). Paradoxically, arousals actually trigger and propagate          body circulation time (40). This accounts for the greater
central apneas and therefore contribute to their genesis. In-         length of the periodic breathing cycle in patients with CHF
deed, the critical role of arousals in sustaining ventilatory         than in subjects with idiopathic CSA whose cardiac function is
overshoot during periodic breathing has been demonstrated             normal.
both in patients with CSR–CSA and those with idiopathic
CSA, a disorder that shares many features of CSR–CSA (194,            Clinical Significance
237, 238).                                                            CSR–CSA shares several pathophysiological features of OSA
    In contrast to OSA, CSR–CSA is more pronounced during             including episodic hypoxia and arousals from sleep. However,
NREM sleep, where chemical–metabolic factors are the pre-             unlike OSA, generation of exaggerated negative intrathoracic
dominant influence on ventilatory control, than during REM            pressure is not a feature of CSR–CSA. Therefore, the overall
sleep where behavioral nonmetabolic factors predominate               burden of CSR–CSA may not be as great as that of OSA.
(21, 194, 219). In addition, during REM sleep arousability to         Nevertheless, several studies indicate that this burden is clini-
respiratory stimuli is diminished compared with the lighter           cally significant.
stages of NREM sleep. As a result, the tendency to ventilatory            Frequent arousals in association with CSR–CSA contribute
overshoot and hypocapnia is diminished in REM sleep, which            to sleep fragmentation and excessive daytime sleepiness in pa-
dampens CSR–CSA. Similarly, in the deeper (i.e., slow wave)           tients with CHF (244, 245). More importantly, CSR–CSA con-
stages of NREM sleep where arousability is also decreased,            tributes to higher rates of death and cardiac transplantation in
CSR–CSA tends to dissipate (194). Although Cheyne–Stokes              patients with CHF in proportion to the frequency of central
respiration can be observed in wakefulness (18, 219), it is much      events, independently of other risk factors (210–212) (Figure 7).
2158                                                  AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE             VOL 164   2001

    CSR–CSA provokes oscillations in HR and BP, similar to              associated with augmented central and peripheral chemosensi-
those seen during OSA: peaks occur during hyperpnea and                 tivity (228, 230). Because augmented chemosensitivity plays an
troughs during apnea. However, increases in HR and BP                   important role in generating CSR–CSA, it became obvious that
progress to peak levels more gradually, paralleling gradual in-         the relationship between augmented peripheral chemosensitiv-
creases in ventilation (18). This probably reflects the gradual         ity and VLF oscillations in HR variability was through the inter-
progression of hypoxia and sympathetic activation due to pro-           mediate step of CSR–CSA (52, 192, 216, 246, 250).
longed circulatory delay. The mechanisms mediating these os-                CSR–CSA in patients with CHF is associated with increased
cillations are not completely understood. They could be related         SNA (251). In one study, norepinephrine concentrations were
to the same mechanisms that have been implicated in OSA (see            proportional to the frequency of arousals from sleep and degree
above), including hypoxia and arousals from sleep. However, in          of apnea-related hypoxia (252). These data strongly suggest that
cases of CSR–CSA in which central apneas continue despite               sympathetic activation in these patients is not simply a com-
abolition of apnea-related hypoxia by supplemental O2, peri-            pensatory response to low cardiac output, but is directly re-
odic oscillations in HR and BP persist (236). This observation          lated to the presence of CSR–CSA. This excessive and patholog-
indicates that mechanisms other than hypoxia are involved.              ical sympathoexcitation is likely one factor that contributes to the
    Arousals may contribute to oscillations in BP during CSR–           increased risk of death in patients with CSR–CSA (210–212).
CSA. However, Trinder and colleagues (18) found that the ma-                Because of hypoxic dips, arousals from sleep, sympathetic
jor contribution to BP oscillations during CSR–CSA in NREM              activation, and elevations in HR and BP, CSR–CSA may facil-
sleep were ventilatory oscillations. Arousals caused small, but         itate ventricular arrhythmias. Javaheri and Corbett (215) found
significant further increases in BP, but these were proportional        that patients with CHF with hypocapnia (PaCO2 35) had both
to the accompanying increase in ventilation. In addition, among         a higher prevalence of central apneas and a higher rate of ven-
those patients with CHF who had Cheyne–Stokes respiration               tricular ectopy than eucapnic patients. Because one-third of the
while awake, periodic oscillations in BP, related to oscillations       patients with CHF die suddenly (253), the potential relationship
in ventilation, persisted in the absence of arousals. Similarly,        of CSR–CSA with ventricular arrhythmias warrants further in-
voluntary periodic breathing in awake healthy subjects, under           vestigation.
normoxic conditions, causes oscillations in HR and BP pro-
portional to the augmentation of ventilation during the venti-
latory phase (52). Accordingly, periodic breathing itself may           Treatment
entrain oscillations in HR and BP (18, 246).                            Because CSR–CSA is associated with a poor prognosis, it
    Entrainment of HR and BP by periodic breathing may be               should be considered a therapeutic target in CHF (254). How-
due to phase linking of central sympathetic neuronal output to          ever, a detailed discussion of the treatment of CSR–CSA in pa-
central respiratory drive (247). Regardless of their exact causes,      tients with CHF is beyond the scope of this review. Readers wish-
when these HR and BP oscillations are analyzed by frequency             ing an in depth discussion of this subject are referred to two
spectral analysis, they occur at very low frequency (VLF, 0.05          recent articles (255, 256). The therapeutic approach to CSR–CSA
Hz). Indeed, HR and BP variability of patients with CHF is of-          must take into account that CSR–CSA arises from CHF. Accord-
ten dominated by variability within the VLF range in associa-           ingly, the first consideration is to optimize anti-heart failure drug
tion with markedly decreased variability in the low-frequency           therapy (257). Should CSR–CSA persist, a number of other ther-
(LF, 0.05–0.15 Hz) and high-frequency (HF, 0.15 Hz) ranges.             apeutic options that specifically target CSR–CSA are available.
This abnormal HR variability in patients with CHF is a sign of              Various forms of positive airway pressure including CPAP,
autonomic derangement characterized by sympathetic nervous              bilevel, and adaptive pressure support servo-ventilation have
activation and cardiac vagal withdrawal (248, 249). It is also a        been shown to reduce the frequency of central events in pa-
marker of increased risk of death (229).                                tients with CHF (244, 258, 259). The most extensively tested of
    However, the potential importance of CSR–CSA in gener-              these over clinically relevant time periods is CPAP. Short-term
ating such VLF oscillations has only recently been recognized           application of CPAP to patients with stable chronic CHF has
through the convergence of two observations. First, in patients         been shown to reduce LV afterload (260), augment stroke vol-
with CHF, VLF oscillations in HR are associated with increased          ume in those with elevated LV filling pressure (261), and re-
peripheral chemosensitivity (229). Second, CSR–CSA is also              duce cardiac SNA (262). Long-term nightly use of CPAP over 1
                                                                        to 3 mo has been shown to alleviate CSR–CSA (244, 258) (Fig-
                                                                        ure 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 qual-
                                                                        ity 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, pa-
                                                                        tients in the CSR–CSA group who complied with CPAP expe-
                                                                        rienced a significant reduction in the combined rate of mortal-
                                                                        ity 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 mor-
                                                                        tality–cardiac transplantation rate. However, these results
                                                                        cannot be considered definitive because of the small number
                                                                        of patients involved. Nevertheless, they do indicate the need
Figure 7. In 66 patients with CHF, those with CSR–CSA had signifi-
                                                                        for a larger long-term multicenter trial involving patients with
cantly reduced survival without cardiac transplantation (i.e., trans-   CHF with CSR–CSA. Such a trial, the Canadian Continuous
plant-free survival) than those without CSR–CSA, after adjustment for   Positive Airway Pressure Trial for Congestive Heart Failure
confounding factors. From Sin and coworkers (212), with permission.     (CANPAP), is presently underway (266).
State of the Art                                                                                                                                 2159

                                                                        becomes even more daunting when population studies indicate
                                                                        that the majority of patients with OSA identified on polysom-
                                                                        nography 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 hyper-
                                                                        tension and hypercholesterolemia, can lead to significant reduc-
                                                                        tions in cardiovascular events (118, 274). Armed with this knowl-
                                                                        edge, investigators are now in a position to test the possibility that
                                                                        the diagnosis and treatment of sleep-related breathing disorders
Figure 8. Patients with CHF and CSR–CSA who were randomized to          can improve health outcomes in patients suffering from or at risk
CPAP and who complied with therapy had a significantly greater rate     for cardiovascular disease.
of transplant-free survival than patients randomized to the control
group. From Sin and coworkers (212), with permission.
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