Portal de Periódicos da CAPES

Sleep Apnea and Cardiovascular Disease

2008; Lippincott Williams & Wilkins; Volume: 118; Issue: 10 Linguagem: Inglês

10.1161/circulationaha.107.189420

1524-4539

Virend K. Somers, David P. White, Raouf Amin, William T. Abraham, Fernando Costa, Antonio Culebras, Stephen R. Daniels, John S. Floras, Carl E. Hunt, Lyle J. Olson, Thomas G. Pickering, Richard Russell, Mary Woo, Terry Young,

Gastroesophageal reflux and treatments

HomeCirculationVol. 118, No. 10Sleep 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 DiseaseAn American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health) Virend K. Somers, David P. White, Raouf Amin, William T. Abraham, Fernando Costa, Antonio Culebras, Stephen Daniels, John S. Floras, Carl E. Hunt, Lyle J. Olson, Thomas G. Pickering, Richard Russell, Mary Woo and Terry Young Virend K. SomersVirend K. Somers Search for more papers by this author , David P. WhiteDavid P. White Search for more papers by this author , Raouf AminRaouf Amin Search for more papers by this author , William T. AbrahamWilliam T. Abraham Search for more papers by this author , Fernando CostaFernando Costa Search for more papers by this author , Antonio CulebrasAntonio Culebras Search for more papers by this author , Stephen DanielsStephen Daniels Search for more papers by this author , John S. FlorasJohn S. Floras Search for more papers by this author , Carl E. HuntCarl E. Hunt Search for more papers by this author , Lyle J. OlsonLyle J. Olson Search for more papers by this author , Thomas G. PickeringThomas G. Pickering Search for more papers by this author , Richard RussellRichard Russell Search for more papers by this author , Mary WooMary Woo Search for more papers by this author and Terry YoungTerry Young Search for more papers by this author Originally published28 Jul 2008https://doi.org/10.1161/CIRCULATIONAHA.107.189420Circulation. 2008;118:1080–1111is corrected byCorrectionOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 28, 2008: Previous Version 1 Sleep-related breathing disorders are highly prevalent in patients with established cardiovascular disease. Obstructive sleep apnea (OSA) affects an estimated 15 million adult Americans and is present in a large proportion of patients with hypertension and in those with other cardiovascular disorders, including coronary artery disease, stroke, and atrial fibrillation.1–14 In contrast, central sleep apnea (CSA) occurs mainly in patients with heart failure.15–19 The purpose of this Scientific Statement is to describe the types and prevalence of sleep apnea and its relevance to individuals who either are at risk for or already have established cardiovascular disease. Special emphasis is given to recognizing the patient with cardiovascular disease who has coexisting sleep apnea, to understanding the mechanisms by which sleep apnea may contribute to the progression of the cardiovascular condition, and to identifying strategies for treatment. This document is not intended as a systematic review but rather seeks to highlight concepts and evidence important to understanding the interactions between sleep apnea and cardiovascular disease, with particular attention to more recent advances in patient-oriented research. Implicit in this first American Heart Association/American College of Cardiology Scientific Statement on Sleep Apnea and Cardiovascular Disease is the recognition that, although holding great promise, this general area is in need of a substantially expanded knowledge base. Specific questions include whether sleep apnea is important in initiating the development of cardiac and vascular disease, whether sleep apnea in patients with established cardiovascular disease accelerates disease progression, and whether treatment of sleep apnea results in clinical improvement, fewer cardiovascular events, and reduced mortality.Experimental approaches directed at addressing these issues are limited by several considerations. First, the close association between obesity and OSA often obscures differentiation between the effects of obesity, the effects of OSA, and the effects of synergies between these conditions. Second, multiple comorbidities, including cardiovascular disease, metabolic syndrome, and diabetes, often are present in patients with sleep apnea. Hence, it becomes unclear whether abnormalities evident in the sleep apnea patient with cardiovascular disease are secondary to the sleep apnea, the cardiovascular condition, or both. The third consideration relates to randomization of sleep apnea patients to active or no treatment. Although this is a reasonable strategy for identifying the mechanistic and prognostic consequences of sleep apnea per se, it is limited by the difficulties inherent in any placebo-controlled treatment study of sleep apnea and the need to consider treatment in patients with severe daytime somnolence, even in the absence of associated cardiovascular disease.Definitions, Classifications, Diagnosis, and PathophysiologyObstructive Sleep ApneaOSA is characterized by repetitive interruption of ventilation during sleep caused by collapse of the pharyngeal airway. An obstructive apnea is a ≥10-second pause in respiration associated with ongoing ventilatory effort. Obstructive hypopneas are decreases in, but not complete cessation of, ventilation, with an associated fall in oxygen saturation or arousal. A diagnosis of OSA syndrome is accepted when a patient has an apnea-hypopnea index (AHI; number of apneas and hypopneas per hour of sleep) >5 and symptoms of excessive daytime sleepiness20 (Figure 1 and Table 1; see Table 25 for definitions of terms). Download figureDownload PowerPointFigure 1. Partial and complete airway obstruction resulting in hypopnea and apnea, respectively. Reprinted from Hahn PY, Somers VK. Sleep apnea and hypertension. In: Lip GYH, Hall JE, eds. Comprehensive Hypertension. St. Louis, Mo: Mosby; 2007:201–207. Copyright Elsevier 2007. Used with permission.Table 1. Obstructive Sleep ApneaSigns, symptoms, and risk factors Disruptive snoring Witnessed apnea or gasping Obesity and/or enlarged neck size Hypersomnolence (not common in children or in heart failure) Other signs and symptoms include male gender, crowded-appearing pharyngeal airway, increased blood pressure, morning headache, sexual dysfunction, behavioral changes (especially in children)Screening and diagnostic tests Questionnaires Holter monitoring Overnight oximetry Home-based/ambulatory unattended polysomnography In-hospital attended overnight polysomnographyTreatment options Positional therapy Weight loss Avoidance of alcohol and sedatives Positive airway pressure Oral appliances Surgery Uvulopalatopharyngoplasty Tonsillectomy TracheostomyTable 2. Definitions of Terms5TermDefinitionReprinted from Bradley et al,5 with permission from Lippincott Wiliams & Wilkins. Copyright 2003, American Heart Association.ApneaCessation of airflow for >10 sHypopneaA reduction in but not complete cessation of airflow to <50% of normal, usually in association with a reduction in oxyhemoglobin saturationAHIThe frequency of apneas and hypopneas per hour of sleep; a measure of the severity of sleep apneaOSA and hypopneaApnea or hypopnea resulting from complete or partial collapse, respectively, of the pharynx during sleepCSA and hypopneaApnea or hypopnea resulting from complete or partial withdrawal of central respiratory drive, respectively, to the muscles of respiration during sleepOxygen desaturationReduction in oxyhemoglobin saturation, usually as a result of an apnea or hypopneaSleep apnea syndromeAt least 10 to 15 apneas and hypopneas per hour of sleep associated with symptoms of sleep apnea, including loud snoring, restless sleep, nocturnal dyspnea, headaches in the morning, and excessive daytime sleepinessPolysomnographyMultichannel electrophysiological recording of electroencephalographic, electroculographic, electromyographic, ECG, and respiratory activity to detect disturbance of breathing during sleepNREM sleepNon–rapid eye movement or quiet sleepREM sleepRapid eye movement or active sleep; associated with skeletal muscle atonia, rapid movements of the eyes, and dreamingArousalTransient awakening from sleep lasting 6000 adults participating in the Sleep Heart Health Study noted that hypopneas accompanied by oxyhemoglobin desaturation of ≥4% were associated with prevalent cardiovascular disease independently of confounding covariates.21 In contrast, no association was observed between cardiovascular disease and hypopneas associated with milder desaturation or arousals. The investigators noted several limitations of their data, including the facts that causality cannot be inferred from their cross-sectional analysis and that additional cross-sectional and longitudinal studies are needed to compare interactions between event definitions and other sleep-disordered breathing (SDB)–related consequences.Pharyngeal collapse in patients with OSA generally occurs posterior to the tongue, uvula, and soft palate or some combination of these structures. This portion of the pharyngeal airway (from the posterior nasal septum to the epiglottis) has relatively little bony or rigid support and is therefore largely dependent on muscle activity to maintain patency. The primary abnormality in patients with OSA is an anatomically small pharyngeal airway resulting from obesity, bone and soft tissue structures, or, in children, tonsils and adenoids.22 During wakefulness, this leads to increased airflow resistance and greater intrapharyngeal negative pressure during inspiration. Mechanoreceptors located primarily in the larynx respond reflexively to this negative pressure and increase the activity of a number of pharyngeal dilator muscles, thereby maintaining airway patency while awake.22,23 However, during sleep, the reflex pharyngeal muscle activity that drives this neuromuscular compensation is reduced or lost, leading to reduced dilator muscle activity and ultimately to pharyngeal narrowing and intermittent complete collapse.24 During the subsequent apnea or hypopnea, hypoxia and hypercapnia stimulate ventilatory effort and ultimately arousal from sleep to terminate the apneic event. Thus, an upper airway that requires reflex-driven muscle activation to maintain patency during wakefulness may be vulnerable to collapse during sleep.The pathophysiology of obstructive apneas is complex and varies between patients. Although deficient pharyngeal anatomy and variable upper airway dilator muscle control awake and asleep are likely the predominant causes of pharyngeal collapse in most patients with OSA, other mechanisms also likely contribute.25–28 Loss of lung volume during sleep reduces longitudinal traction on the upper airway, rendering it more collapsible. In addition, ventilatory control system instability is associated with cycling respiratory output to ventilatory pump muscles and upper airway dilator muscles. As a result, at the nadir of such cycling, the pharyngeal airway may collapse completely or partially, yielding obstructive apneas or hypopneas. Accordingly, in the individual with ventilatory control instability, apneas/hypopneas may be central or obstructive, depending on the collapsibility of the upper airway. Finally, mechanisms such as variable surface tension in the pharyngeal airway, arousal threshold, and asynchronous timing of activation of upper airway versus pump muscles may contribute to apnea pathogenesis.Screening of patients for SDB can be accomplished by several different methods, although the sensitivity and specificity of these have not been well documented, particularly in cardiovascular patients, and may be expected to be affected by pretest probability. Some of these options include the Epworth Sleepiness Scale,29 the Berlin questionnaire,30 overnight oximetry, and devices combining limited respiratory assessment, ECG, and oximetry.31 Specialized analysis of 24-hour ECG recordings also has been proposed as a possible screening tool.32 The available options have many shortcomings. The most often used in clinical practice is overnight oximetry.In patients with suspected OSA, a definitive diagnosis often requires spending a night in a sleep laboratory during which multiple physiological variables are continuously recorded (polysomnography). These variables generally include sleep staging using the electroencephalogram, electromyogram, electrooculogram, respiration (flow, effort, oxygen saturation), and snoring. With these signals, disordered breathing, in addition to its effect on sleep and oxygenation, can be precisely quantified. The importance of the cardiovascular response to sleep has been recognized in the recently revised Sleep Scoring Manual from the American Association of Sleep Medicine (AASM),33 which now includes scoring of a continuous-lead ECG as a recommended component of polysomnography.34There is controversy as to whether disordered breathing during sleep can be adequately assessed using fewer signals recorded in the home. Most of these systems are limited to monitoring the respiratory channels listed above and do not include sleep staging or other nonrespiratory signals. After careful assessment, the American Academy of Sleep Medicine concluded that certain home diagnostic methodologies probably do have a role in the diagnosis of obstructive sleep apnea if used by an experienced clinician.35 Although this remains controversial, the Center for Medicare Services recently decided to pay for CPAP when the diagnosis of OSA was made with portable systems in the home. Thus, the use of such methodologies will likely increase in the future.Central Sleep ApneaCSA is characterized by repetitive cessation of ventilation during sleep resulting from loss of ventilatory drive. A central apnea is a ≥10-second pause in ventilation with no associated respiratory effort. Generally, >5 such events per hour are considered abnormal. CSA syndrome is present when a patient has >5 central apneas per hour of sleep and the associated symptoms of disrupted sleep (frequent arousals) and/or hypersomnolence during the day.20 Because central apneas also may occur in an individual with obstructive apneas, care must be exercised in deciding that CSA rather than OSA is the principal problem. Although there is no absolute standard in this regard, studies of patients with CSA require that >50% of all events be central, with >80% central events often being required.CSA does not have any single cause (Figure 2). As a result, a number of syndromes have emerged, each of which may have somewhat different underlying pathophysiological mechanisms. Cheyne-Stokes respiration (CSR) generally occurs in patients with heart failure, although it has been described in association with neurological disorders, including neurovascular disorders and dementia. It is characterized by a crescendo-decrescendo pattern of breathing with a central apnea or hypopnea at the nadir of ventilatory effort. In patients with heart failure, CSR is believed to result from a high-gain ventilatory control system (increased hypercapnic responsiveness) combined with a prolonged circulation time.15,36 This combination leads to unstable ventilatory control and this particular pattern of periodic breathing. Idiopathic CSA37 also is characterized by unstable ventilation, which is due to a very steep ventilatory response to hypercapnia. Unstable ventilatory control in patients with both CSR and idiopathic CSA can promote obstructive events (apneas and hypopneas) in an individual with a collapsible pharyngeal airway resulting from diminished upper airway muscle activation at the nadir of the cycling respiration. Thus, both central and obstructive events are commonly seen in these patients, as discussed later. Download figureDownload PowerPointFigure 2. Schematic outlining possible mechanisms underlying development of CSA and the possible feedback from CSA resulting in exacerbation of heart failure.16 Reproduced with permission.The diagnosis of CSA may not be readily recognized by the clinician and currently requires a full-night polysomnogram to determine the frequency and pattern of central apnea (Table 3). Simplified monitoring systems or oximetry alone in the diagnosis of CSA has not been broadly accepted; full-night polysomnography remains the standard. Some patients with heart failure will demonstrate a periodic breathing pattern even during wakefulness and exercise.38,39 In this case, a polysomnogram is often helpful to exclude concurrent obstructive apnea and to guide treatment for the nocturnal periodic breathing. Table 3. Central Sleep ApneaSigns, symptoms, and risk factors Congestive heart failure Paroxysmal nocturnal dyspnea Witnessed apnea Fatigue/hypersomnolence Other signs and symptoms include male gender, older age, mitral regurgitation, atrial fibrillation, CSR while awake, periodic breathing during exercise, hyperventilation with hypocapniaScreening and diagnostic tests Overnight oximetry Ambulatory (unattended) polysomnography In-hospital (attended) polysomnographyTreatment options Optimize treatment of heart failure Positive airway pressure Supplemental oxygenObstructive Sleep ApneaEpidemiologyThe high prevalence and wide spectrum of severity of OSA in adults have been well documented by several population-based cohort studies conducted in the United States, Europe, Australia, and Asia. Although measurement techniques and definitions have varied, most of these studies have shown that ≈1 in 5 adults has at least mild OSA (eg, AHI ≥5) and 1 in 15 has moderate or severe OSA (eg, AHI ≥15). Two population studies with AHI measured longitudinally have shown significant progression in OSA over time. In the Wisconsin Sleep Cohort,40 the mean 8-year increase in AHI was greatest for habitual snorers compared with nonhabitual snorers, those with body mass index (BMI) ≥30 versus 54 years of age and BMI ≥31 versus 85% of patients with clinically significant and treatable OSA have never been diagnosed, and referral populations of OSA patients represent only the “tip of the iceberg” of OSA prevalence.42,43 In addition to emphasizing the large burden of untreated OSA in the general population, the low level of medical detection demands caution in generalizing observations of OSA patients diagnosed in sleep clinics to cardiovascular disease patients with occult OSA. Understanding predictors of OSA free from sleep clinic referral bias is necessary to recognize cardiovascular disease patients likely to have OSA. When OSA was initially being documented as a diagnosable condition, patients were collectively described as “Pickwickian”: morbidly obese, sleepy, middle aged, and male. This stereotype has undoubtedly influenced case finding and led to an overrepresentation of these characteristics in OSA patient populations. Large studies of OSA detected in population-based screening have shown that although male sex and obesity are clearly risk factors for OSA (associated with 2- and 4-fold-higher prevalences, respectively), clinically significant OSA is not rare in women or in nonobese persons and is even more common in older age compared with middle age. Furthermore, in contrast to the high prevalence of pathological sleepiness in OSA patient populations, excessive daytime sleepiness and OSA are not strongly correlated in general population studies.40,44,45Few studies characterizing OSA in cardiovascular patients have been conducted. Available data indicate that OSA prevalence is 2 to 3 times higher than in reference populations without cardiovascular disease.11,46 Risk factors for undiagnosed OSA in heart failure patients may differ from those based on observations of other OSA patients. In 450 heart failure patients referred for polysomnography, the odds ratio (OR) for OSA with male gender (OR, 2.8) was similar to that seen in population studies.47 However, for men, only obesity was significantly related to OSA, and for women, age but not obesity was related to OSA. Of particular importance, and for reasons that are not well understood, OSA may not manifest with sleepiness in heart failure patients.48,49Population-based epidemiology studies and observations of OSA patients have consistently shown the prevalence of hypertension, type II diabetes, cardiovascular disease, and stroke to be higher in people with OSA.7,10,46,50–57 Because all these conditions are chronic, have multifactorial and overlapping origins, and have long latent periods before symptoms appear, identifying a causal role of OSA is difficult. In cross-sectional studies that rely on a diagnosis of cardiovascular disease as the end point, subjects with preclinical and asymptomatic disease will be missed. Risk factors or causes common to both conditions, including male sex, age, overweight, central body fat deposition, alcohol, smoking, and lack of exercise, explain some but not all of the correlation between OSA and cardiovascular disease. In addition to concern about these as “confounding” factors in investigating the independent role of OSA in promotion of cardiovascular disease, there also is interest in the concurrent presence of the constellation of OSA, cardiovascular disease, and their common risk factors.10,51,58Before widespread use of continuous positive airway pressure (CPAP) as a standard of care,59,60 patients with OSA treated conservatively had increased mortality compared with OSA patients who had undergone tracheostomy, even though the latter group had a higher BMI (34 versus 31 kg/m2) and more severe OSA (AHI, 69 versus 43).61 Most deaths were cardiovascular. Similarly, another study showed that mortality in OSA patients with an AHI >20 was 0% over 8 years in those treated with tracheostomy or nasal CPAP, significantly lower than those treated with uvulopalatopharyngoplasty or those left untreated.62 Population-based longitudinal studies with objective measurement of OSA, initiated over the past 15 years, have begun to clarify the nature of the OSA–cardiovascular disease link. An 11-year follow-up of older residents in San Diego (Calif) showed the mortality rate for cardiovascular disease to be higher for those with OSA (35% for AHI <15, 56% for AHI ≥15).46 Prospective analyses of the Wisconsin Sleep Cohort Study indicate that OSA increases the risk of incident hypertension.56 Snoring, as a marker of OSA, predicted hypertension, cardiovascular disease, and type II diabetes in the Nurses Health Study,50,53,54 as did short sleep duration.63 In 1995, the Sleep Heart Health Study was initiated to investigate the role of OSA in cardiovascular disease using in-home polysomnography; baseline and follow-up data have been collected on a sample of ≈3000 adults, and longitudinal analyses are now underway.64Clinical PresentationOSA affects male individuals more commonly than female individuals and may present with a number of signs and symptoms suggestive of the disorder (Table 1) or with no symptoms whatsoever. However, clinical judgment ultimately must be used in deciding which patients deserve further evaluation. For example, virtually all patients with OSA snore, but not all snorers have sleep apnea.Signs and symptoms apply to large patient cohorts that include patients with and without cardiovascular disease, raising the question of whether there are specific indications for apnea evaluation in patients with cardiac or vascular disease. The answer is likely “yes,” given the high prevalence of OSA in hypertension, including resistant hypertension (requiring ≥3 medications), atrial fibrillation, and nocturnal angina. Both OSA and CSA occur commonly in patients with heart failure and may contribute to disease progression. Treating sleep apnea may be particularly relevant in these patients, and the diagnosis should be carefully considered. However, this does not imply that all patients with hypertension, atrial fibrillation, nocturnal angina, or heart failure should undergo formal testing for sleep apnea. If other indicators also are present (witnessed apneas, disruptive snoring, obesity, waking hypersomnolence) or if the cardiovascular condition is refractory to standard therapy, there should be a low threshold for pursuing this diagnosis.Early studies suggested the interesting and clinically relevant possibility that OSA may have more deleterious cardiovascular consequences in subjects <50 years of age.62 This concept has found support in more recent data showing that younger people with OSA may be more likely to have hypertension65 and atrial fibrillation66 and to suffer greater all-cause mortality.67 These data may argue in favor of a more aggressive diagnostic and therapeutic strategy in younger and middle-aged subjects with OSA. Differential effects of race, gender, and other demographics also merit consideration and require further investigation.Mechanisms of Disease and Associated Cardiovascular RiskObstructive apneas may induce severe intermittent hypoxemia and CO2 retention during sleep, with oxygen saturation sometimes dropping to ≤60%, disrupting the normal structured autonomic and hemodynamic responses to sleep.68 Apneas can occur repetitively through the night and are accompanied by chemoreflex-mediated increases in sympathetic activity to peripheral blood vessels and consequent vasoconstriction.69,70 Toward the end of apneic episodes, blood pressure (BP) can reach levels as high as 240/130 mm Hg.71 This level of hemodynamic stress occurs at a time of severe hypoxemia, hypercapnia, and adrenergic activation. Nocturnal apneas initiate a range of pathophysiological mechanisms outlined below, which may act to promote cardiac and vascular disease (Figure 3). Download figureDownload PowerPointFigure 3. Schematic outlining proposed pathophysiological components of OSA, activation of cardiovascular disease mechanisms, and consequent development of established cardiovascular disease.Sympathetic ActivationHeightened sympathetic drive elicited by recurrent apneas during sleep persists into normoxic daytime wakefulness.71 Sympathetic traffic to peripheral blood vessels is increased even in people with OSA who are otherwise healthy independently of obesity.72 Patients with OSA also have faster heart rates during resting wakefulness, suggesting that there also is increased cardiac sympathetic drive.73 The mechanisms for this heightened sympathetic activation are not known. One possibility is that increased chemoreflex gain in OSA results in tonic chemoreflex activation even during normoxia, with consequent increased sympathetic activity. Administration of 100% oxygen (to eliminate tonic chemoreflex drive) significantly lowers sympathetic activity, heart rate, and BP in OSA patients during daytime wakefulness.74Cardiovascular VariabilityCompared with similarly obese control subjects, resting awake OSA patients have diminished heart rate variability and increased BP variability.73 In patients with cardiovascular disease, reduced heart rate variability is associated with poorer outcomes.75–77 The Framingham Heart Study has implicated lower heart rate variability as a precursor to the development of future hypertension,78 and increased BP variability has been implicated in increased risk of end-organ damage in patients with hypertension.79Vasoactive SubstancesRecurrent hypoxemic stress induces increased release of vasoactive and trophic substances that may elicit vasoconstriction persisting for hours. Endothelin is released in cell culture during hypoxia.80 In patients with OSA, untreated severe sleep apnea lasting several hours results in increased endothelin levels, which fall after 4 hours of treatment with CPAP.81 More recent data support a role for endothelin in raising BP in OSA patients.82 A positive correlation also has been reported between aldosterone and OSA severity, but this correlation was true only for patients with resistant hypertension and was not evident in normotensive controls.83InflammationHypoxemia appears to be an important mechanism for triggering systemic inflammation. Healthy subjects at altitude manifest increased levels of inflammatory molecules such as interleukin-6 and C-reactive protein.84 Sleep deprivation also may trigger systemic inflammation.85,86 The combination of repetitive hypoxemia and sleep deprivation in OSA patients may be associated with increased levels of plasma cytokines, adhesion molecules,87,88 serum amyloid A,89 and C-reactive protein.88,90–92 Although the increase in C-reactive protein in OSA appears to be independent of adiposity,92 this question remains controversial.93 There also is evidence for enhanced leukocyte activation in OSA.94,95 Monocytes from OSA patients bind more actively to cultured endothelial cells than do monocytes from control subjects, and treatment by CPAP attenuates this monocyte binding.94 Ryan et al96 reported that in vitro, intermittent hypoxia and reoxygenation selectively activated the proinflammatory transcription factor nuclear factor-κB, whereas the adaptive regulator hypoxia-inducible factor-1α was not activated. Related studies in OSA patients also noted in