Sleep Apnea and Cardiovascular Disease
2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 12 Linguagem: Inglês
10.1161/circulationaha.111.070813
ISSN1524-4539
AutoresTakatoshi Kasai, John S. Floras, T. Douglas Bradley,
Tópico(s)Sleep and Wakefulness Research
ResumoHomeCirculationVol. 126, No. 12Sleep Apnea and Cardiovascular Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBSleep Apnea and Cardiovascular DiseaseA Bidirectional Relationship Takatoshi Kasai, MD, PhD, John S. Floras, MD, DPhil and T. Douglas Bradley, MD Takatoshi KasaiTakatoshi Kasai From the Sleep Research Laboratory, Centre for Sleep Health and Research, and Department of Medicine of the University Health Network Toronto Rehabilitation Institute and Toronto General Hospital (T.K., J.S.F., T.D.B.); Centre for Sleep Medicine and Circadian Biology, University of Toronto (T.K., T.D.B.); and Department of Medicine of the Mount Sinai Hospital, Toronto, Ontario, Canada (J.S.F.). , John S. FlorasJohn S. Floras From the Sleep Research Laboratory, Centre for Sleep Health and Research, and Department of Medicine of the University Health Network Toronto Rehabilitation Institute and Toronto General Hospital (T.K., J.S.F., T.D.B.); Centre for Sleep Medicine and Circadian Biology, University of Toronto (T.K., T.D.B.); and Department of Medicine of the Mount Sinai Hospital, Toronto, Ontario, Canada (J.S.F.). and T. Douglas BradleyT. Douglas Bradley From the Sleep Research Laboratory, Centre for Sleep Health and Research, and Department of Medicine of the University Health Network Toronto Rehabilitation Institute and Toronto General Hospital (T.K., J.S.F., T.D.B.); Centre for Sleep Medicine and Circadian Biology, University of Toronto (T.K., T.D.B.); and Department of Medicine of the Mount Sinai Hospital, Toronto, Ontario, Canada (J.S.F.). Originally published18 Sep 2012https://doi.org/10.1161/CIRCULATIONAHA.111.070813Circulation. 2012;126:1495–1510IntroductionSleep apnea occurs in ≈5% to 10% of the general population, regardless of race and ethnicity.1 By contrast, in patients with cardiovascular diseases (CVDs), its prevalence, depending on the specific disorder surveyed, can range between 47% and 83%.2–4 One form, central sleep apnea (CSA), is rare in the general population, but is detected often in conditions characterized by sodium and water retention, such as heart failure (HF).2 Such epidemiological observations raise several important and as yet unresolved questions: What accounts for this remarkable concentration of sleep apnea among patients with CVD and its association with fluid retaining states? Does obstructive sleep apnea (OSA) predispose at-risk individuals to develop, over time, hypertension, coronary artery disease, stroke, or HF? Conversely, could mechanisms engaged by CVD, such as activation of the sympathetic nervous and renin-angiotensin-aldosterone systems, with consequences including renal sodium retention, contribute over time to the development or exacerbation of sleep apnea? From the clinical perspective, is sleep apnea, when present in patients with CVD an epiphenomenon, perhaps related to ageing, or a causal contributor to worse prognosis? And if so, are there now sufficient data to recommend randomized controlled trials to determine whether specific treatment of sleep apnea can reduce mortality or cardiovascular event rates? Our objectives, in this review, are to provide novel insight into each of these specific questions by integrating into our contemporary understanding of relationships between sleep apnea and CVD5 newer epidemiological, observational, mechanistic, and trial data; to introduce a hypothetical model of bidirectional causality; and to consider directions for future research.Normal SleepIn healthy subjects, during non–rapid eye movement sleep (which constitutes ≈85% of total sleep time), efferent sympathetic nerve activity (SNA) diminishes and vagal tone increases, resulting in reductions in metabolic rate, blood pressure (BP), and heart rate (HR).6,7 Thus, although sleep is, in general, a stable state of cardiovascular quiescence, this tableau can be interrupted both normally, by the intermittent surges in SNA, BP, and HR characteristic of rapid eye movement sleep (but comprising only 15% of total sleep time),6 and pathologically, whether because of fitful sleep or shorter overall sleep time, as evident in patients with HF or drug-resistant hypertension,8,9 or by coexisting sleep apnea, whether obstructive (OSA) or central (CSA).Sleep Apnea: Epidemiology and PathophysiologyObstructive Sleep ApneaBoth in the general population and in those with CVD, OSA is 2 to 3 times more common in men than in women, and in older adults than in the young.2–4,10 Although obesity is associated with OSA in patients with coronary artery disease and hypertension2,3 among patients with HF and stroke, in comparison with the general population, a larger proportion with OSA patients are nonobese, and there is little or no relationship between body mass index and severity of OSA.8,11OSA arises when sleep-related withdrawal of respiratory drive to the upper airway (UA) dilator muscles is superimposed on an UA predisposed to collapse because it is narrow and highly compliant.12 The UA may be narrowed if surrounded by a small boney envelope, as with retrognathia, or if soft tissue mass within this boney envelope is increased, as with tonsillar hypertrophy or macroglossia. In obese individuals, pharyngeal fat deposition facilitates UA narrowing and collapse by increasing external peripharyngeal soft tissue pressure. Peripharyngeal fluid accumulation increases soft tissue mass, and it has been shown that fluid shifting from the legs during inflation of antishock trousers causes narrowing and increased UA resistance.13,14 The most likely mechanism for this is increased peripharyngeal tissue pressure. It may also be possible that fluid shifting into the peripharyngeal tissues might inhibit pharyngeal dilator muscle activity, thereby increasing UA collapsibility, but this seems less likely than an increase in tissue pressure. Nasal obstruction can also increase the risk for developing OSA, possibly by causing increased collapsibility of the UA owing to increased airway resistance upstream from the collapsible portion on inspiration.15 Hereditary factors and respiratory control system instability may also contribute to the pathogenesis of OSA, but these possibilities remain controversial.15 UA collapse during sleep can cause partial or complete cessation of airflow (hypopnea and apnea, respectively). Because the drive to breathe persists, inspiratory efforts against the now-occluded UA generate negative intrathoracic pressure, out-of-phase thoracoabdominal motions, distortion of the chest wall, and diminished airflow.Central Sleep ApneaCSA, in contrast, occurs when Paco2 during sleep falls below the apnea threshold, resulting in withdrawal of central drive to respiratory muscles. The UA remains for the most part patent. Respiratory movements are either absent (apnea) or attenuated in proportion to the decrease in respiratory drive (hypopnea), but are in-phase and are not accompanied by airflow limitation. In HF, CSA is manifest as Cheyne-Stokes respiration (CSR), a form of periodic breathing with a crescendo-decrescendo pattern of tidal volume accompanied by a long periodic cycle duration. Prolonged hyperpnea alternates with central apnea or hypopnea. In the context of the present review, CSA should be considered synonymous with CSR unless indicated otherwise.Although CSA occurs in <1% of the general population,16 it is common in patients with HF, atrial fibrillation (AF), and stroke, where its prevalence ranges from 12% to 53%.2,17,18 In patients with HF, neither the presence nor severity of CSA relates to body mass index. Rather, its risk factors include male sex, older age, low Paco2, coexistence of AF, and use of diuretics.2 Central apneas occur in HF because of inherent respiratory control system instability. This arises from stimulation of pulmonary vagal irritant receptors by pulmonary congestion secondary to increased left ventricular (LV) volume and filling pressure19,20 that augments respiratory drive reflexively, and from increased central and peripheral chemosensitivity,21 as well as arousals from sleep.22 Each of these can elicit hyperventilation that causes Paco2 to fall below the apnea threshold, thereby abolishing central respiratory drive to the muscles of respiration. Airflow ceases until metabolic CO2 production causes Paco2 to rise above the apnea threshold, triggering hyperventilation, which again causes Paco2 to fall below the apnea threshold.23 Raising pco2 above the apnea threshold either by inhalation of a CO2-enriched gas24 or by application of increased dead space via a facemask25 abolishes CSA in patients with HF, demonstrating the fundamental role of hypocapnia in its pathogenesis. In AF, CSA probably arises through factors similar to those related to HF, that is, subtle degrees of nocturnal pulmonary congestion and a tendency to hyperventilate because of atrial dilation, elevated left atrial pressure, and reduced cardiac output. Following stroke, CSA with a CSR pattern is strongly associated with coexisting occult LV systolic dysfunction, rather than with the type, location, or severity of the stroke, suggesting that cardiac dysfunction, rather than the neurological lesion per se, is the major factor contributing to CSA in this setting.26Contribution of Fluid Retention to the Pathogenesis of Sleep ApneaThe high prevalence of OSA in nonobese patients with HF, in drug-resistant hypertension, and in renal failure,4,8,27 and the higher prevalence of CSA in HF patients than in general population,2,28 led us to hypothesize that fluid retention and, more specifically, nocturnal shift of dependent fluid rostrally while recumbent during sleep, is intimately involved in the pathogenesis of both forms of apnea. Distension of neck veins or edema of the peripharyngeal soft tissue could increase tissue pressure around the UA, predisposing to UA obstruction, whereas pulmonary congestion could initiate CSA by provoking hyperventilation (Figure 1). Sodium and water retention in conditions such as obesity, hypertension, and HF may be dietary,29 neurogenic, as a consequence of increased renal sympathetic nerve discharge, which stimulates renin release and renal sodium retention,30 or humoral, for example, secondary to activation of the renin-angiotensin-aldosterone axis.31Download figureDownload PowerPointFigure 1. Fluid retention in the legs and its rostral shift. Similar to fluid movement from the bottom of the bottle while upright into the neck when horizontal, dependent fluid accumulated in the legs while upright during the day shifts rostrally and could redistribute into the neck or the lungs when recumbent during sleep in response to gravity.As an initial test of this hypothesis, we demonstrated that in response to a 5-minute application of lower-body positive pressure, neck circumference increased, the pharyngeal cross-sectional area decreased, and pharyngeal resistance and collapsibility increased simultaneously with a reduction in leg fluid volume in healthy subjects.13,14,32 Such rapid changes in neck circumference and UA properties could only be caused by a change in fluid volume within the peripharyngeal area. Redolfi et al33 identified, in 23 otherwise healthy nonobese men, direct relationships between the volume of fluid displaced gravitationally from the legs overnight and both the overnight increase in neck circumference and the severity of OSA as assessed by frequency of apneas and hypopneas per hour of sleep (ie, apnea-hypopnea index, AHI). These novel findings were replicated in men with HF (Figure 2)34 and renal failure,35 and in patients with hypertension.36 Fluid volume displaced from the legs overnight was in turn directly proportional to the time spent sitting during the day and the degree of leg edema, and inversely proportional to physical fitness.33,34 Thus, the volume of fluid available for displacement from the legs appears to be a function of sedentary living and leg edema. These observations strongly suggest that in CVD patients prone to fluid retention, overnight rostral fluid displacement from the legs could initiate or contribute to the severity of OSA by causing fluid accumulation in the neck, narrowing the pharynx and increasing its propensity to collapse during sleep.13,14,32 In a recent study, the absence of any change in the severity of OSA from the first to the second half of the night was advanced as an argument against the role of overnight rostral fluid displacement in the pathogenesis of OSA.37 However, because overnight leg fluid volume changes were not assessed, no conclusions about the role of overnight fluid shifts in the pathogenesis of OSA could reasonably have been drawn from this observation.Download figureDownload PowerPointFigure 2. Relationship between overnight change in leg fluid volume (LFV) and apnea-hypopnea index (AHI) in patients with heart failure. The open circles and solid line represent the relationship between the AHI and the change in LFV in those with predominantly obstructive sleep apnea. The closed circles and dashed line represent the relationship between the AHI and the change in LFV in those with predominantly central sleep apnea. Reprinted from Yumino et al.34More recent evidence that nocturnal rostral fluid shift can cause OSA was provided by the observation in both nonobese men with OSA and in patients with chronic venous insufficiency that the use of venous compression stockings reduced daytime-dependent fluid accumulation, the volume of nocturnal rostral fluid shift, and the AHI by ≈35%.38,39 Further evidence favoring this concept comes from several observations. First, it has also been shown that the severity of OSA and CSA in HF patients is proportional to dietary sodium intake, likely as a consequence of salt and water retention.29 Second, in patients with OSA and drug resistant hypertension, antagonism of aldosterone by spironolactone,31 and blunting of renal sodium and water retention by radiofrequency sympathetic denervation30 reduce the AHI. Third, in 2 studies, Tang et al40,41 demonstrated that fluid removal at night by cycled peritoneal dialysis in patients with renal failure reduced the severity of OSA in comparison with removing the same amount of fluid over 24 hours and was associated with an increase in pharyngeal caliber. Similar observations were made by Hanly and Pierratos42 when patients with renal failure were transitioned from daytime to nocturnal hemodialysis. Finally, in patients with acute exacerbations of diastolic HF, diuretic therapy was associated with an increase in pharyngeal caliber accompanied by a modest reduction in the AHI.43The volume of fluid that leaves the legs overnight in HF patients with predominantly CSA also relates directly to the AHI. However, the amount that shifts is double that in HF patients with predominantly OSA, and, in contrast to OSA, there is an inverse relationship between the volume displaced and Paco2 during sleep (Figure 2).34 A substantial portion of the fluid leaving the legs of HF patients with CSA likely accumulates in the lungs where it can cause pulmonary congestion and stimulate hyperventilation (Figure 1). It has been shown that a low Paco2 in HF patients is related to elevated LV filling pressure, presumably by stimulation of pulmonary vagal irritant receptors by pulmonary congestion.44 In addition, it is well known that paroxysmal nocturnal dyspnea and orthopnea are due to posturally dependent redistribution of fluid from the lower body to the lungs.45 These observations are consistent with the concept that fluid displaced from the legs can redistribute to the lungs while the patient is recumbent during sleep.Importantly, this series of observations has stimulated 3 novel concepts: nocturnal rostral fluid shift contributes to the pathogenesis of both OSA and CSA; once sleep apnea develops, its severity, as assessed by the AHI, relates to the volume of fluid so displaced; and the magnitude of overnight rostral fluid movement contributes to the type of apnea that predominates. Based on these findings, it is reasonable to propose, first, that the prevalence of sleep apnea is increased in patients with CVD in comparison with the general population because the former are more likely to manifest sodium-retaining physiology, and second, that reports in HF patients of transformations, over time, from OSA to CSA and vice versa, can be explained by disease progression or therapy that alters daytime fluid retention and, as a consequence, the volume of fluid available to shift rostrally overnight.46,47What, then, of the opposite scenario: can OSA predispose at-risk individuals to develop, over time, hypertension, coronary artery disease, HF, or stroke?Cardiovascular Effects of OSARepetitive obstructive apneas expose the heart and circulation to a cascade of noxious stimuli that, over time, may initiate or contribute to the progression of most cardiovascular disorders.Negative Intrathoracic PressureA unique feature of OSA is the generation of exaggerated negative intrathoracic pressure during futile inspiratory efforts against the occluded pharynx.5 This will immediately increase LV transmural pressure (ie, intraventricular minus intrathoracic pressure), a key element of LV afterload. It also increases venous return, augmenting right ventricular preload, whereas OSA-induced hypoxic pulmonary vasoconstriction increases right ventricular afterload. Consequent right ventricular distension and leftward septal displacement during diastole impairs LV filling. The combination of increased LV afterload and diminished LV preload during obstructive apneas causes a progressive reduction in stroke volume and cardiac output that is more pronounced in patients with LV systolic dysfunction than in those with normal LV function.5 Increased LV transmural pressure also raises myocardial oxygen demand, while simultaneously triggering a fall in coronary blood flow, this at a time when apnea-related hypoxia reduces oxygen supply and increases efferent sympathetic nerve traffic (see below).48,49 Together, these mechanisms can precipitate myocardial ischemia in those with preexisting coronary disease and impair cardiac contractility and diastolic relaxation.5 Cerebral blood flow also declines significantly during obstructive apneas, probably secondary to the fall in cardiac output.50Over months to years, these repetitive increases in wall tension can stimulate a range of processes involved in ventricular remodeling, resulting in asymmetrical septal or concentric LV hypertrophy51 or ventricular dilatation.52 The latter may be exacerbated at times that other adverse remodeling processes are active, such as after myocardial infarction.53Negative intrathoracic pressure swings during obstructive events also increase atrial and intrathoracic aortic wall stress, thereby increasing the likelihood of nocturnal atrial arrhythmias and thoracic aortic dissection.54–57Autonomic DysregulationOSA immediately elicits both sympathetic excess and parasympathetic withdrawal.58 The sympathetic nervous system is activated simultaneously by cycles of apnea-induced hypoxia and CO2 retention, which stimulate both central and peripheral chemoreceptors, apnea-induced cessation of pulmonary stretch receptor-mediated inhibition of central sympathetic outflow, and silencing of sympathoinhibitory input from carotid sinus baroreceptors by reductions in stroke volume and BP during obstructive apneas. When the apnea is interrupted by arousal from sleep, the latter process simultaneously augments SNA and reduces cardiac vagal activity. The result is a postapneic surge in both BP and HR.These acute adverse effects of OSA on the autonomic nervous system are not confined to sleep. Elevations in sleep BP that arise if dogs are exposed chronically to experimental OSA are sustained into wakefulness.59 Patients with OSA and cardiac dysfunction also have elevated SNA and depressed cardiac vagal activity when awake.60 Reversal of OSA by continuous positive airway pressure (CPAP) lowers SNA and increases cardiac vagal modulation of high-frequency HR variability both at night and during wakefulness.61,62 The mechanisms for such daytime carryover effects remain unclear but may relate to the adaptation of chemoreceptor reflexes or central processes governing autonomic outflow.Cardiac vagal withdrawal increases HR and reduces HR variability at high frequencies (ie, respiratory sinus arrhythmia). The latter is a marker of adverse outcomes, including malignant arrhythmias.63 Sympathetic overactivation also acts to increase HR, itself an adverse, albeit, nonspecific prognostic signal,64 and can worsen the prognosis of patients with CVD specifically by causing cardiac β-adrenoreceptor desensitization, arrhythmias, myocyte injury and necrosis, and peripheral vasoconstriction (leading to increased afterload and BP), and promoting renal sodium retention, both directly and via stimulation of the renin-angiotensin-aldosterone axis.58Oxidative Stress, Inflammation, and Endothelial DysfunctionIntermittent apnea-related hypoxia and postapneic reoxygenation can induce oxidative stress with production of reactive oxygen species, and activation of inflammatory mediators that are capable of impairing vascular endothelial function and promoting atherogenesis.65 Patients with OSA have low plasma nitrate and nitrite concentrations and high levels of oxidative stress markers, abnormalities reversible by CPAP.66 Intermittent hypoxia can also activate nuclear transcriptional factors, including nuclear factor κ-B, which stimulates production of inflammatory mediators, and several intracellular and vascular cell adhesion molecules, as well.67 This could facilitate endothelial damage and atherogenesis. In subjects with OSA, but otherwise healthy, endothelium-dependent vasodilatation is impaired,65 and, in randomized trials, treating OSA by CPAP improved both endothelium-dependent and/or -independent vasodilatation without reducing plasma biomarkers of inflammation.65 Butt and colleagues68 recently reported that otherwise healthy patients with OSA had impaired myocardial perfusion that improved with CPAP. Enhanced apoptosis of endothelial cells and fewer circulating endothelial progenitor cells in OSA patients may contribute to these processes.69In comparison with control subjects, patients with OSA display greater signs of early atherosclerosis, including increased carotid intima-media thickness and increased arterial stiffness.67 In a randomized trial involving such subjects, CPAP reduced both carotid intima-media thickness and arterial stiffness, supporting a causal relationship between OSA and atherosclerosis.70Platelet Activation and HypercoagulabilityIn OSA patients, platelet markers of thrombotic risk increase during sleep; in nonrandomized trials, these decreased in CPAP-treated subjects.71 Morning fibrinogen concentration and plasminogen activator inhibitor type-1 level also are increased in OSA patients.72,73 Mehra and colleagues74 showed, in an epidemiological study, that both fibrinogen and plasminogen activator inhibitor type-1 increase with increasing AHI even after adjustment for confounders. These indicate less fibrinolytic potential and a hypercoagulable state. In a nonrandomized study, morning fibrinogen concentration was shown to decrease after 1 night of CPAP.72 One randomized study showed that 2 weeks of CPAP therapy for OSA was associated with a significant decrease in plasminogen activator inhibitor type-1.73 Taken together, these observations suggest that increased platelet activation and hypercoagulability could play a role in the increased susceptibility of OSA patients to thromboembolic phenomena such as stroke.75Cardiovascular Effects of CSACSA is more likely a consequence, rather than a cause, of HF. However, because it elicits many of the pathophysiologic mechanisms associated with OSA, with the notable exception of the extremes of negative intrathoracic pressure, CSA also has the capacity to initiate a vicious cycle that could cause further deterioration in cardiovascular function. Muscle SNA and cardiac SNA during wakefulness are higher in HF patients with CSA than in those without CSA, or those with OSA, possibly because of greater HF severity.20,60 Cycles of CSR entrain, rhythmically, low-frequency oscillations in BP and HR in patients in sinus rhythm,23 and the ventricular response to AF, as well.76 No studies have examined the influence of CSA on oxidative stress, inflammatory mediators, or endothelial function.Relationships Between Sleep Apnea and Cardiovascular DiseaseAlthough capable of exacerbating certain CVDs, once present, is there evidence that OSA, in particular, can initiate one or more of these conditions in susceptible individuals? Current epidemiological evidence concerning hypertension, CVD, and cardiovascular mortality is summarized in Tables 1 to 3.77–88 Although most of them strongly suggested causal relationships between OSA and CVDs and cardiovascular mortality, these observations must be interpreted with caution. Because these studies were observational in nature, even after adjusting for known risk factors, other unknown confounders might have affected the outcomes. In addition, some studies focused on subgroups which were not prespecified, making associations difficult to interpret.Table 1. Summary of Community-Based Cohort Studies Regarding Obstructive Sleep Apnea and Incidence of HypertensionCohortNMale, %Mean Age, yMean BMI, kg/m2Diagnostic Technique for OSADuration, yFindingsPeppard et al77WSC893564729In-lab PSG4 or 8Adjusted OR (95% CI) of AHI ≥15, compared with AHI=0: 2.89 (1.46–5.64)O'Connor et al78SHHS2470456028In-home PSG5 (mean)OR increased with increasing baseline AHI category, but became insignificant after adjustment for BMI: adjusted OR (95% CI) of AHI ≥30, compared with AHI <5: 1.50 (0.91–2.46)Cano-Pumarega et al79Vitoria Sleep Cohort1180454726In-home cardiorespiratory monitoring*7.5 (mean)OR increased with increasing baseline AHI category, but became insignificant after adjustment for age and other confounders: adjusted OR (95% CI) of AHI ≥14, compared with AHI <3: 0.98 (0.62–1.57)AHI indicates apnea-hypopnea index; BMI, body mass index; CI, confidence interval; OR, odds ratio; OSA, obstructive sleep apnea; SHHS, Sleep Heart Health Study; WSC, Wisconsin Sleep Cohort; and PSG, polysomnography.*This system does not record sleep stages or arousals.HypertensionThe prevalence of OSA in primary hypertension is ≈35%.89 However, whether OSA is truly an independent risk factor for the development of hypertension has yet to be definitively established. It is known that intermittent hypoxia or experimentally induced OSA can cause persistent daytime hypertension in rats and dogs, respectively.59,90 In rats, hypertension was prevented by sympathectomy or peripheral chemoreceptor denervation.90 In the Wisconsin Sleep Cohort, subjects with an AHI ≥15 had a 2.89 greater likelihood of developing hypertension than those with an AHI of 0.77 In contrast, in the more recent 5-year follow-up from the Sleep Heart Health Study (SHHS),78 O'Connor et al reported that the unadjusted risk of hypertension increased in concert with AHI, but that this association was not significant after adjustment for body mass index. The Vitoria Sleep Cohort also found no association between OSA and incident hypertension after adjustment for potential confounding variables.79 These discordant conclusions may be related to differences in the characteristics of the populations sampled, the techniques used to diagnose sleep apnea, the AHI cutoff point applied to the reference group, or mechanistic redundancy between the prohypertensive effects of OSA itself and the variables adjusted for (Table 1). Nevertheless, the remarkable finding that among patients with drug-resistant hypertension, OSA, present in ≈65% to 80%,4,91 was by far the most common secondary cause identified, and that its treatment may lower BP in such patients,92 does suggest that OSA plays a provocative role in hypertension.It is now appreciated that nighttime systolic and diastolic BP confer greater long-term cardiovascular risk than daytime, 24-hour ambulatory, or conventional clinic BPs.93,94 Because hypertensive patients whose BP does not fall normally at night (ie, nondippers) are at greater risk for LV hypertrophy and failure than normal dippers,95 and because OSA, as a consequence of nocturnal sympathetic activation, is an important cause of nondipping, it may be a particularly potent yet reversible stimulus to LV hypertrophy and failure. In 1 recent human study a 5 mm Hg reduction in sleep-time systolic BP caused a 17% reduction in adverse cardiovascular events in a hypertensive population,96 and, in hypertensive mice, captopril prevented cardiovascular remodeling only when administered before sleep.97Coronary Artery DiseaseThe prevalence of OSA in patients with coronary artery disease (CAD) is ≈30%.98 A cross-sectional analysis of the SHHS reported that the risk of CAD was increased modestly in OSA subjects in the highest AHI quartile in comparison with those in the lowest (odds ratio, 1.27; 95% confidence interval, 0.99–1.62).99 However, a subsequent longitudinal analysis of data from the same cohort found that the presence of OSA at baseline was not a significant predictor of incident CAD after adjustment for other risk factors.82 Of note, a subgroup analysis suggested that OSA conferred a slightly increased risk of developing CAD in men ≤70 years of age (Table 2).Table 2. Summary of Cohort Studies Regarding Obstructive Sleep Apnea and Incidence of Cardiovascular DiseasesCohortNMale, %Mean Age, yMean BMI, kg/m2Diagnostic Technique for OSADuration, yFindingsAF Mooe et al8
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