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Postgraduate Education Corner |

Obstructive Sleep Apnea*: Implications for Cardiac and Vascular Disease FREE TO VIEW

Francisco Lopez-Jimenez, MD, MSc; Fatima H. Sert Kuniyoshi, MSc; Apoor Gami, MD; Virend K. Somers, MD, PhD, FCCP
Author and Funding Information

*From the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.

Correspondence to: Virend K. Somers, MD, PhD, Department of Cardiovascular Diseases, Mayo Clinic, 200 1st St SW, Rochester, MN 55905; e-mail: somers.virend@mayo.edu


Chest. 2008;133(3):793-804. doi:10.1378/chest.07-0800
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An estimated 15 to 20 million American adults have obstructive sleep apnea (OSA), a prevalence comparable to diabetes.1 OSA occurs when inspiratory airflow is either partly (hypopnea) or completely (apnea) occluded during sleep. The combination of sleep-disordered breathing with daytime sleepiness is referred to as the OSA syndrome.

Although loud snoring and severely disturbed sleep have made OSA a social curiosity, several factors have contributed to its emergence as an important medical condition. First, sleep deprivation with consequent daytime somnolence has been linked to motor vehicle and workplace-related accidents. Second, the epidemic of obesity has led to a high and rising prevalence of OSA. Third, and especially important, has been the evolving recognition of OSA as a mediator of cardiovascular disease. In this review, we will examine the characteristics, pathophysiology, and epidemiology of OSA, the cardiovascular disease mechanisms activated by OSA, and the evidence implicating OSA in cardiac, vascular, and related disease conditions. Particular emphasis will be placed on recent data linking OSA to inflammatory and metabolic dysregulation, and on newer information implicating OSA in atrial fibrillation (AF), stroke, myocardial infarction, and sudden cardiac death.

Obstructive apnea occurs when there is complete cessation of airflow for ≥ 10 s. Obstructive hypopnea occurs when airflow decreases, resulting in a fall in oxygen saturation or arousal from sleep.2 Obstructive apneas and hypopneas occur despite ongoing and often strenuous breathing efforts, thus distinguishing OSA from central sleep apnea, which is covered elsewhere. OSA is quantified on the basis of the apnea-hypopnea index (AHI), which refers to the number of apneas and hypopneas occurring per hour of sleep. OSA is presumed to be significant at an AHI ≥ 5 events per hour. Although the AHI is an accepted measure for defining OSA severity, it is not clear that it is primarily or exclusively the number of events per hour of sleep that elicits daytime sleepiness and cardiovascular damage. This is important because some patients may have many hypopneas during sleep with only modest decrements in oxygen saturation, whereas others may manifest relatively fewer but prolonged apneas resulting in nocturnal oxygen desaturation to levels as low as 60%.

Patients with very severe OSA may exhibit increased airway resistance to inspiratory airflow even during supine wakefulness. However, it is only during sleep that obstructive apnea usually becomes evident. Thus, while mandibular and upper airway structure may be important in predisposing to OSA, the occurrence of obstruction primarily during sleep speaks directly to the importance of functional contributions to inspiratory airway occlusion.

The upper airway is a muscular and compliant structure susceptible to inspiratory collapse because of negative airway pressures generated during inspiration (Fig 1 ). Tonic and phasic neural activation of pharyngeal dilator muscles are important in maintaining upper airway patency. This is particularly important during inspiration, when intermittent inspiration-linked phasic activation of pharyngeal dilator muscles elicits the heightened muscular activity necessary to maintain airway patency. During sleep, however, neural activation of dilator muscles is attenuated, thus predisposing to airway collapse.

Structural factors linked to the development of OSA include fat deposition in the neck, with reduced luminal diameter. The marked increases in airway resistance resulting from the decreased lumen diameter (Poiseuille law) necessitates greater inspiratory negative pressure generation so as to maintain airflow. In the setting of attenuated pharyngeal dilator muscle activity during sleep, the heightened negative inspiratory pressures generate further airway narrowing with even greater increases in airway resistance, hence resulting in a vicious cycle leading to eventual complete airway collapse. Humoral factors that influence central breathing control may also be important in understanding the genesis of OSA. Leptin, the protein product of the adipocyte ob gene, is increased in obesity and especially in OSA, as discussed later. Evidence that leptin may modulate central ventilatory control mechanisms3 has provided new opportunities for better understanding the interaction between obesity and OSA.

Epidemiologic data consistently show a high prevalence of OSA in North American, European, and Asian nations. Approximately 20% of adults have at least mild OSA (AHI ≥ 5/h), and approximately 7% of adults have moderate-to-severe OSA (AHI ≥ 15/h). The prevalence of OSA is twice as high in men than in women, and OSA is especially common in obese individuals. Longitudinal studies1,4 have confirmed progression of AHI over time, with the risk of OSA being especially exacerbated as body mass index (BMI) increases.

Although sleep occupies a third of life, it is only recently that the traditional review of systems inquiry has begun to incorporate questions related to sleep. Disruptive snoring and witnessed apneas are often reported by spouses of patients seen in cardiovascular disease clinics, and may be accompanied by clinical sleep deprivation in the bed partner.5 OSA is often but not always accompanied by obesity and/or significant daytime somnolence. Snoring and apneas are often worst when patients sleep on their backs (positional apnea) and sleeping on the side is often associated with attenuation of both. Although definitive diagnosis and comprehensive treatment of OSA requires overnight polysomnography, history and screening tests may help determine the threshold for suspicion. The most commonly used screening test is overnight oximetry, during which decreases in oxygen saturation are recorded. Technical advances in data acquisition and storage have accelerated the development of comprehensive portable/home polysomnographic devices. Although more economical, these unmonitored options are yet to be widely validated and accepted by the professional sleep associations.

OSA occurs predominantly at night. However, the severe repetitive nocturnal stresses of hypoxemia, strenuous inspiratory effort against an occluded upper airway, and arousal from sleep elicit a breadth of neural, humoral, vascular, inflammatory, and metabolic responses. These may carry over into disrupted regulatory mechanisms evident even during normoxic daytime wakefulness. A thorough understanding of cardiovascular disease mechanisms activated by OSA has been limited by the frequent comorbidity of OSA with obesity and/or established cardiovascular disease.6Hence, many studies78 noting the presence of features suggestive of increased cardiovascular risk in OSA patients have been limited by the presence of obesity and existing cardiovascular disease in these patients. Another limitation has been the absence of control subjects matched for obesity and proven to be free of OSA by overnight polysomnography. Relevant to this is that seemingly healthy obese subjects have a high likelihood of occult OSA. Nevertheless, a number of well-controlled and methodologically robust studies have consistently shown acute and striking changes during apneic events, and disturbed homeostatic mechanisms during the daytime, as described below (Fig 2 ).

Neural Mechanisms

Hypoxemia and carbon dioxide retention during apnea excite peripheral and central chemoreceptors, eliciting increased sympathetic vasoconstrictor activity.910 Absence of breathing results in elimination of the sympathetic-inhibitory influence of thoracic afferents, enhancing sympathetic activation during apnea. Sympathetic activation is even further exacerbated by a potentiated sensitivity of the chemoreflex response to hypoxemia in OSA patients.11 Sympathetic-mediated vasoconstriction during apnea results in often precipitous increases in BP, particularly at the end of apnea when resumption of breathing increases cardiac output into a vasoconstricted periphery. These hemodynamic responses occur at a time of severe hypoxemia, hypercapnia, and acidosis, thus imposing severe stress on the cardiac and vascular system.

Normotensive otherwise healthy patients with newly diagnosed sleep apnea have heightened tonic levels of sympathetic activity evident during quiet daytime resting wakefulness.12They also have faster heart rates, diminished heart rate variability, and increased BP variability,13which predispose to increased risk of future hypertension14and target organ damage.1516

Vascular Responses

Endothelin, a potent vasoconstrictor, increases during several hours of untreated OSA,17probably in response to hypoxemia,18and decreases after several hours of treatment with continuous positive airway pressure (CPAP). OSA may also impair endothelial production of nitric oxide,19thus resulting in endothelial dysfunction, both at the level of the resistance20and conduit vessels.21Data have suggested that impaired brachial artery (conduit vessel) dilation improves after treatment with CPAP.2223

Oxidative stress, as a consequence of the repetitive “hypoxemia-reperfusion” injury associated with severe nocturnal apnea, may also contribute to endothelial and vascular damage due to production of free radicals. However, although measures of oxidative stress have been shown to be increased in sleep apneic patients with cardiovascular disease,2425 whether this is secondary to OSA or to the presence of cardiovascular disease is unclear because studies2627 in otherwise healthy OSA patients have not confirmed the presence of uncompensated oxidative stress, even in those who are severely hypoxemic.

Mechanical Factors

Occluded inspiration (the Mueller maneuver) may generate levels of negative intrathoracic pressure approaching − 60 to − 80 mm Hg, and severely disturb cardiac morphology and left ventricular performance.28Since increased intrathoracic pressure reduces afterload and assists left ventricular ejection,29the negative intrathoracic pressure will heighten left ventricular afterload. Acute effects on left ventricular functional characteristics may eventually translate into structural left ventricular changes with consequent wall thickening and diastolic dysfunction.30

Altered performance of the muscular left ventricle during obstructed breathing suggests that even greater effects may be evident in the thinner walled, more compliant atria. Abrupt severe negative intrathoracic pressures with consequent increases in transmural pressure gradients across the atrial wall may conceivably result in repetitive atrial stretch with eventual left atrial enlargement.31

Thrombosis

Only limited data are available regarding effects of OSA on coagulation, and whether OSA predisposes to intracardiac and intravascular thromboembolic disease remains unproven. Patients with OSA may have increased levels of fibrinogen, hematocrit, plasminogen activator inhibitor-1, and platelet aggregability.3237 Unfortunately, very few studies assessing the association between OSA and coagulation have controlled for other comorbidities like diabetes mellitus or obesity, known to induce a procoagulant state.38

Systemic Inflammation

Inflammatory mediators such as adhesion molecules and cytokines are reportedly increased in OSA.3941 These substances contribute to leukocyte attachment to the endothelium, endothelial damage, and hence to atherosclerosis. Leukocytes from patients with untreated OSA manifest increased adherence to cultured endothelial cells. This affinity is attenuated after patients are treated with CPAP.41Markers of systemic inflammation, such as C-reactive protein (CRP) and serum amyloid A, which have been linked to poorer cardiovascular outcomes, are also increased in patients with OSA (Fig 3 ).44 CRP levels are elevated even in children with OSA,4547 independent of BMI and waist hip ratio.

Heightened systemic inflammation may be explained by several factors including repetitive hypoxemia and sleep deprivation, both of which are present in OSA and ameliorated by CPAP. An intriguing randomized double-blind placebo controlled study48 showed that etanercept, a tumor necrosis factor-α antagonist, significantly decreased sleepiness in patients with OSA, suggesting that proinflammatory cytokines may contribute to sleepiness.

Metabolic Dysregulation
Obesity:

Although OSA can occur in lean individuals, it is particularly evident in obesity, and change in weight directly affects OSA severity. It is highly probable that obesity contributes etiologically to OSA. There is also some evidence suggesting a bidirectional relationship in that OSA may predispose to worsening obesity. Patients with newly diagnosed OSA have a history of significant weight gain during the year prior to diagnosis, substantially greater than weight gain present in similarly obese individuals without OSA.49Intriguing data from Chin and colleagues50suggest that treatment of OSA is accompanied by changes in body fat distribution; in those patients who lost weight after OSA treatment, both subcutaneous and visceral fat decreased. However, even in those OSA patients who did not lose weight after treatment, visceral fat decreased. Why OSA should contribute to changes in weight and/or fat distribution is unclear. Decreased daytime activity due to somnolence, increased hunger due to sleep deprivation,5153 and/or disrupted metabolic regulation by leptin and related substances discussed below may be implicated.

Leptin:

Leptin, produced by fat cells, is increased in obese individuals. Since leptin suppresses appetite and promotes weight loss, high leptin levels in obesity suggest that obese subjects are resistant to the weight-reducing effects of leptin. Patients with OSA have leptin levels significantly higher than OSA-free individuals with similar BMIs,54suggesting that OSA may further potentiate resistance to leptin. Linkage of leptin levels in families with sleep apnea suggest that genetic factors may contribute to increased leptin in OSA.55Increased leptin may also be a consequence of hypoxia or hypercapnia. In patients with OSA and BMI < 27 kg/m2, the severity of nocturnal hypoxemia rather than AHI or visceral or subcutaneous fat content was shown to be the main predictor of circulating leptin.56 Other data have suggested that leptin in OSA is associated with hypercapnia, independent of BMI, vital capacity, and AHI.57Elevated leptin in OSA may have implications not only for breathing control but also for increased cardiovascular risk because leptin has been associated with sympathetic activation, platelet aggregation, and an increased likelihood of cardiovascular events.5859

Neuropeptide Y and Ghrelin:

These peptides contribute to appetite and body fat regulation and are also altered in OSA. Neuropeptide Y, an orexigenic hypothalamic peptide important in regulating body weight, energy balance, and sympathetic tone, is increased in patients with OSA and is reduced after CPAP treatment.60Similarly, plasma ghrelin, a peptide produced in the stomach that regulates appetite control and satiety,61is also elevated in OSA. Within 2 days of initiation of CPAP treatment, ghrelin levels decrease.62

Insulin Resistance and the Metabolic Syndrome:

Core characteristics of the metabolic syndrome, a major risk factor for cardiovascular disease,63 are increases in waist circumference, BP, fasting glucose, and triglycerides, with decreased high-density lipoprotein. Other features include microalbuminuria, systemic inflammation, sympathetic activation, endothelial dysfunction, and physical deconditioning. These changes have also been consistently noted in patients with OSA, and attention has focused on the nature of the OSA-metabolic syndrome relationship.

Insulin resistance, a key pathophysiologic component of the metabolic syndrome, is also evident in patients with OSA, is associated with OSA severity, but is independent of adiposity.64Punjabi et al65have demonstrated a significant trend for glucose intolerance and insulin resistance across levels of AHI severity. Impaired glucose tolerance was associated with the severity of nocturnal oxygen desaturation. Patients with OSA also have a higher prevalence of diabetes mellitus, independent of BMI.66Some authors67report that treatment of OSA is accompanied by improvement in glucose metabolism, suggesting that OSA may be an independent contributor to glucose intolerance, and eventual diabetes mellitus. However, other data show no such improvement.68

There are only limited data specifically addressing the association between OSA and the metabolic syndrome. In a comparison of patients with and without OSA, but with similar BMI, patients with OSA were more likely to have metabolic syndrome,69These findings may provide further insight into increased cardiovascular risk in OSA.7071 Whether OSA occurs as part of the fundamental pathophysiology of the metabolic syndrome or whether OSA promotes development of metabolic syndrome remains to be determined.

Hypertension

The Wisconsin Sleep Cohort Study demonstrated a dose-response association between OSA at baseline and the incidence of new hypertension 4 years later, independent of obesity and other comorbidities.72Animal models of sleep apnea support OSA as a causal contributor to hypertension,73as do randomized controlled studies7475 showing decreases in systolic and diastolic BP as soon as 1 week after initiation of CPAP therapy of OSA. Evidence also suggest that the association of OSA with hypertension may be moduated importantly by age.76

The association between OSA and hypertension has been attributed to an enhanced sympathetic tone, but other disease mechanisms may be implicated. Subjects at high risk for sleep apnea were almost twice as likely to have primary hyperaldosteronism, and had increased 24-h urinary aldosterone excretion, compared to subjects at low risk for sleep apnea.77Genetic factors may also contribute to the association between OSA and hypertension.7879 The seventh Joint National Committee on Hypertension guidelines80 have identified OSA as a treatable cause of hypertension. Therefore, patients with hypertension who are suspected of having OSA because of snoring, daytime sleepiness, or obesity, or because of resistant hypertension should be consider for an overnight sleep study and receive treatment if necessary.

Erectile Dysfunction

Patients with erectile dysfunction may often have established but subclinical cardiac and vascular disease. Erectile dysfunction has been linked to OSA. Twenty percent of patients with erectile dysfunction were noted to have OSA,81and erectile dysfunction or decreased libido has been reported in 33%82of patients with OSA. Mechanisms by which OSA may predispose to erectile dysfunction include dysregulation of autonomic vascular control, endothelial dysfunction, and sleep deprivation. In young patients with OSA, nocturnal production of testosterone is suppressed and approaches levels seen in elderly subjects.8384

AF

AF is an emerging epidemic with multifactorial and often uncertain etiology.85AF can be triggered by mechanisms frequently seen in patients with OSA, such as a high sympathetic activity, surges in BP, hypoxemia, CO2 retention and acidosis, systemic inflammation, abrupt increases in ventricular afterload, and increased intrathoracic transmural pressure gradients with consequent stretch of the atria and pulmonary veins. Indeed, several studies have suggested an association between AF and OSA. Guilleminault et al,86 using Holter monitoring in 400 middle-aged subjects with moderate-to-severe OSA, noted that approximately 3% of these patients had AF, greater than the estimated prevalence of AF in the general population. Complementing these findings are data showing a high prevalence of OSA in patients with AF. In 59 selected patients with lone AF free of obesity, hypertension, diabetes, and heart disease, one third of subjects had moderate-to-severe AHI (≥ 15/h).87In another study88of 150 patients with established AF presenting for electrocardioversion, the risk for OSA was identified by a validated sleep questionnaire. Half of the AF patients were at high risk for OSA, compared to a third of control subjects (n = 460) who had no history of AF. The odds ratio for the association between OSA and AF was 2.2 (Fig 4 ). Another study89 showed that untreated sleep apnea in patients successfully cardioverted to normal sinus rhythm was accompanied by an 80% likelihood of recurrence of AF within 1 year, twice as high as the recurrence rate in patients in whom sleep apnea was appropriately treated. A more recent study63 showed that nocturnal desaturation in patients with OSA was associated with a higher incidence of AF, independent of the degree of obesity. However, whether OSA is a cause of AF remains to be determined.

Stroke

The relationship between stroke and OSA is controversial. There is reason to suppose that patients with OSA are predisposed to stroke. Mechanical and pressor responses to obstructive apneas may raise intracranial pressure and reduce cerebral perfusion pressure. Hypoxic and hypercapnic cerebral vasodilation further contribute to increases in intracranial blood volume, reducing cerebral tissue blood flow and predisposing to cerebral ischemia.90Carotid intimal-medial thickness, a proposed surrogate for stroke risk, is reportedly increased in patients with severe OSA.91Any predisposition to intravascular thrombosis in OSA would similarly predispose to thrombotic stroke. Paroxysmal and occult AF in OSA patients, particularly in the setting of any prothrombotic tendency, would increase risk of intracardiac thrombus formation with consequent embolic stroke. OSA may also provoke increased right to left shunting through a patent foramen ovale,92thus theoretically predisposing to paradoxical embolism.93

Other studies such as the Sleep Heart Health Study94reported an odds ratio of 1.6 (95% confidence interval [CI], 1.0 to 2.5) of stroke comparing the lowest quartile of AHI with the highest quartile. The Wisconsin Sleep Cohort Study95 reported that in cross-sectional analysis, subjects with an AHI ≥ 20/h had an odds ratio of 4.3 for stroke compared to those without sleep-disordered breathing, after adjustment for known confounding factors. Longitudinal analysis showed that subjects with an AHI ≥ 20/h had an increased risk for first ever stroke over 4 years of follow-up. However, after adjusting for BMI, the risk for stroke was not significant.95A more recent longitudinal study96 showed that the association between OSA and stroke remained even after controlling for multiple potential confounding variables.

Cardiac Ischemia and Myocardial Infarction

The multiple disease mechanisms activated by OSA, together with the often severe hypoxemia, speak strongly to OSA as a cause of cardiac ischemia and possibly infarction. Nocturnal ST-segment changes consistent with myocardial ischemia are evident even in patients with OSA who do not have clinically significant coronary artery disease.97 OSA may contribute to nocturnal angina, and ST-segment depression during sleep appears to be related to the severity of oxygen desaturation.9798 Treatment with CPAP may attenuate nocturnal ST-segment depression.99Data confirm that OSA is accompanied by a higher likelihood of cardiovascular events100; over 7 years, patients with OSA were five times more likely to have cardiovascular disease than those without OSA, even after controlling for age, BMI, and BP. More than half of the patients with incompletely treated OSA had cardiovascular events, compared to < 10% of those appropriately treated.100Similar findings have been reported in patients with proven preexisting coronary artery disease. In a small study101 of patients with at least one coronary artery stenosis ≥ 70% and with moderate-to-severe OSA (AHI ≥ 15/h), treatment with CPAP was accompanied by an estimated risk reduction of 76% for a composite end point (cardiovascular death, acute coronary syndrome, hospitalization for heart failure, and coronary revascularization).

Marin and colleagues102 studied 264 healthy men, 377 simple snorers, 403 subjects with untreated mild-to-moderate OSA, 235 subjects with untreated severe OSA, and 372 subjects who were treated with CPAP. Participants were followed up at yearly intervals over a mean of 10 years. End points were fatal cardiovascular events (death from myocardial infarction or stroke) and nonfatal cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, coronary artery bypass surgery, and coronary angiography). The risk of fatal (odds ratio, 2.9; 95% CI, 1.2 to 7.5) and nonfatal cardiovascular events (odds ratio, 3.2; 95% CI, 1.1 to 7.5) was significantly increased in patients with untreated severe OSA compared to healthy subjects. Risk for events in patients with treated OSA was similar to that noted in snorers and those with mild OSA (Fig 5 ).

The observational data described above provide a sound basis for suspecting a causal relationship between OSA and cardiovascular outcomes. Nevertheless, prospective randomized control studies are needed for definitive confirmation of OSA as an independent risk factor for cardiovascular events and death.

Cardiac Failure

Although central sleep apnea is the sleep breathing disorder commonly linked to heart failure, increasing obesity has made OSA a prevalent condition in Western heart failure populations. Data from the Framingham study103 show that increasing levels of obesity in both men and women is a predictor of the development of new onset heart failure over 20 years of follow-up; the presence of OSA was not taken into account in this study. The levels of obesity that conferred a high risk of heart failure are also those that would be accompanied by a high likelihood of OSA. The role of OSA in the development of heart failure in obese subjects remains to be defined.

There are a number of mechanisms by which OSA may lead to the development and progression of heart failure. Hypertension, left ventricular diastolic dysfunction, and AF, all of which have been linked to OSA, are important causes of heart failure. Randomized studies104105 in heart failure patients over 1 to 3 months of CPAP treatment reported an improved ejection fraction, but BP changes were inconsistent. There are presently no randomized controlled studies examining whether CPAP is accompanied by attenuation of heart failure morbidity and mortality.

Aortic Dissection

The abrupt decreases in intrathoracic pressures generated by obstructive apneas would result in rapid and marked increases in transmural pressure gradients across the aortic wall, with wall stretch from systolic BP being further accentuated by the extramural negative pressure. Patients with Marfan syndrome may have a high prevalence of OSA.106107 OSA has been proposed as a possible contributor to aortic dilation, which may be attenuated by CPAP in these patients. Increased aortic transmural pressures have also been implicated in the etiology of aortic dissection. Patients with aortic dissection are more likely to have OSA than control subjects, independent of hypertension.108

Sudden Cardiac Death

Acute responses to obstructive apneas, with marked increases in adrenergic drive, BP, ventricular afterload, hypoxemia, and hypercapnia, induce substantial and repetitive nocturnal cardiovascular stress. Supporting this premise is evidence97,109suggesting that sleep apnea may be accompanied by nocturnal ST-segment depression and angina. However, although anecdotal and unpublished observations have suggested that severe OSA may be associated with death during sleep, only few studies110111 have addressed this question. Population studies112113 of the timing of sudden cardiac death have consistently suggested a peak incidence in the morning between 6:00 am and 11:00 am and a nadir during sleep; these studies did not take into account the presence and effects of OSA.

An examination of time distribution of sudden cardiac deaths among Minnesota residents who had undergone polysomnography and subsequently died suddenly from cardiac causes compared the time distribution of sudden cardiac death among those with and without OSA. From midnight to 6:00 am, sudden death from cardiac causes occurred in 46% of people with OSA but in only 21% of those without OSA. For the period between 10:00 pm and 6:00 am, which could reasonably be anticipated as usual sleep time, sudden death occurred in 54% of the OSA subjects as compared to 24% of those without OSA (Fig 6 ). Whether sudden death from cardiac causes occurred as a consequence of cardiac ischemia, arrhythmias, or through other mechanisms remains to be determined.

General treatment recommendations for patients with OSA are weight loss, avoidance of alcohol and upper airway mucosal irritants, and not sleeping in the supine posture, when apneas are usually worse. The primary treatment of OSA is nasal CPAP, which helps maintain patency of the upper airway and usually enables complete or almost complete resolution of apnea, even in patients with severe OSA. CPAP is sometimes not well tolerated, and up to 30% of patients stop using CPAP within a few months after initiation of therapy. Although CPAP devices were often poorly tolerated in the past, new and improved masks and pressure delivery systems have greatly enhanced patient tolerance and compliance as well as therapeutic efficacy. Thus, in those patients who did not tolerate older CPAP delivery systems, it may be reasonable to consider a second referral to the sleep clinic. Other options include mechanical devices directed at altering the configuration or compliance of the upper airway, by surgical procedures like tonsillectomy or uvulopalatopharyngoplasty, or by orthodontic devices or tongue-retaining appliances. Rarely, tracheostomy can be considered for intractable and life-threatening OSA.

Definitive thresholds for treating OSA are not yet established. Current practice is based on the severity of the AHI, and many patients are treated at an AHI ≥ 10/h. Patients with lower AHIs may require treatment if they have comorbidities associated with OSA or if they have significant daytime somnolence. However, since the primary noxious stimulus in OSA remains to be determined, some patients may receive CPAP intervention based on the severity of nocturnal oxygen desaturation.

Significant weight loss is usually followed by improvement or resolution of OSA. Morbidly obese patients who undergo bariatric surgery have shown the most remarkable results: 85% have resolution or significant amelioration of OSA.114Because bariatric surgery is the only treatment proven to induce long-lasting, significant weight loss with subsequent improvement in other cardiovascular risk factors, and is relatively safe even in patients with established coronary artery disease,115it may be considered in the treatment of severely obese patients with refractory OSA. The effectiveness of anorexic drugs on weight loss and subsequent improvement of OSA is still under investigation.116

OSA is accompanied by activation of multiple cardiovascular disease mechanisms. The role of OSA as a potential contributor to obesity, metabolic syndrome, insulin resistance, and systemic inflammation provides exciting alternative perspectives on these disease conditions These pathologic processes may lead to eventual overt cardiovascular disease, but evidence conclusively demonstrating any causal interaction is lacking. What is known is that sleep apnea is a likely and probably common cause of hypertension and that effective treatment of apnea will often lower BP both at night and during the daytime. Although observational data suggest that CPAP may favorably influence cardiovascular prognosis, there are no definitive studies that have examined whether CPAP decreases cardiovascular events or death from cardiac causes. Randomized controlled studies are needed to definitively establish any such effect. Pending such data, whether and when patients with OSA should be treated will need to be based on assessment of the individual patient. Ongoing research studies will improve our understanding of pathophysiologic mechanisms and benefits of treatment of OSA, which is emerging as one of the most promising areas for future preventative and therapeutic advances in cardiovascular disease.

Abbreviations: AF = atrial fibrillation; AHI = apnea-hypopnea index; BMI = body mass index; CI = confidence interval; CPAP = continuous positive airway pressure; CRP = C-reactive protein; OSA = obstructive sleep apnea

Dr. Lopez-Jimenez is supported by a Scientist Development Grant from the American Heart Association.

Ms. Sert Kuniyoshi is supported by grant 06–15709Z,Greater Midwest Affiliate Predoctoral Fellowship from American Heart Association, and a Perkins Memorial Award from the American Physiologic Society.

Dr. Somers is supported by National Institutes of Health grants HL-65176, HL-70602, HL-70302, HL-73211, and M01-RR00585.

Dr. Somers has served as a consultant for Respironics and Cardiac Concepts, and has received research funding from the ResMed Foundation and the Respironics Foundation for Sleep and Breathing.

Dr. Lopez-Jimenez, Ms. Sert Kuniyoshi, and Dr. Gami have no conflicts of interest to disclose.

Figure Jump LinkFigure 1. Illustration of the upper airway. During inspiration there is activation of pharyngeal dilator muscles that elicits the heightened muscular activity necessary to maintain airway patency. Reproduced with permission from Mayo Clinic Foundation.Grahic Jump Location
Figure Jump LinkFigure 2. Association between OSA and cardiovascular disease; partial list of the disease mechanisms associated with OSA considered as possible links to several cardiovascular diseases and metabolic dysregulation. CHF = congestive heart failure; CAD = coronary artery disease; LV = left ventricular.Grahic Jump Location
Figure Jump LinkFigure 3. CRP is higher in patients with OSA than in control subjects; box plot showing plasma CRP in OSA patients (n = 22) and control subjects (n = 20). Middle horizontal line inside box indicates median. The bottom and top of the box are 25th and 75th percentiles, respectively. Reprinted from Shamsuzzaman et al. Circulation 2002; 105:2462, with permission of Lippincott, Williams & Wilkins.Grahic Jump Location
Figure Jump LinkFigure 4. Association between AF and OSA, with adjusted odds ratio (OR) and 95% CI for the association between AF and OSA. After adjustment for BMI, neck circumference (neck circ), hypertension, and diabetes mellitus, AF is significantly associated with OSA (odds ratio, 2.19; p = 0.0006). Reprinted from Gami et al. Circulation 2004; 110:364, with permission of Lippincott, Williams & Wilkins.Grahic Jump Location
Figure Jump LinkFigure 5. Long-term risk for cardiovascular events according to the presence of OSA and treatment with CPAP; cumulative percentage of individuals with new fatal (A) and nonfatal (B) cardiovascular events in each of the five groups studied. OSAH = OSA/hypopnea; CVS = cardiovascular. Reprinted with permission from Marin et al. Lancet 2005; 365:1046.Grahic Jump Location
Figure Jump LinkFigure 6. Sudden death from cardiac causes according to usual sleep-wake cycles. Top, A: Day-night patterns of sudden death from cardiac causes on the basis of 8-h time intervals for 78 persons with OSA and 34 persons without OSA. Center, B: AHI for persons with sudden death from cardiac causes during 8-h intervals. The line within each box represents the median AHI, and the box represents the interquartile range (25 to 75th percentiles). The figure includes data from persons with OSA and persons without OSA (p = 0.001) for the comparison of the AHI according to the time of sudden death. Bottom, C: Relative risk of sudden death from cardiac causes during 8-h intervals, as compared with the remaining 16 h of the day, for 78 persons with OSA and 34 persons without obstructive sleep apnea. The squares represent the relative risk point estimates, and the I bars indicate 95% CIs. Reprinted from Gami et al. N Engl J Med 2005; 352:1206–1214, with permission of the Massachusetts Medical Society.Grahic Jump Location
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Tatasciore, A, Renda, G, Zimarino, M, et al Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects.Hypertension2007;50,325-332
 
Phillips, BG, Narkiewicz, K, Pesek, CA, et al Effects of obstructive sleep apnea on endothelin-1 and blood pressure.J Hypertens1999;17,61-66
 
Allahdadi, KJ, Walker, BR, Kanagy, NL Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension.Hypertension2005;45,705-709
 
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Lavie, L Obstructive sleep apnoea syndrome: an oxidative stress disorder.Sleep Med Rev2003;7,35-51
 
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Svatikova, A, Wolk, R, Lerman, LO, et al Oxidative stress in obstructive sleep apnoea.Eur Heart J2005;26,2435-2439
 
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Arias, MA, Garcia-Rio, F, Alonso-Fernandez, A, et al Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men.Circulation2005;112,375-383
 
Otto, ME, Belohlavek, M, Romero-Corral, A, et al Comparison of cardiac structural and functional changes in obese otherwise healthy adults with versus without obstructive sleep apnea.Am J Cardiol2007;99,1298-1302
 
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Nobili, L, Schiavi, G, Bozano, E, et al Morning increase of whole blood viscosity in obstructive sleep apnea syndrome.Clin Hemorheol Microcirc2000;22,21-27
 
von Kanel, R, Dimsdale, JE Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease.Chest2003;124,1956-1967
 
Ohga, E, Tomita, T, Wada, H, et al Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1.J Appl Physiol2003;94,179-184
 
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Svatikova, A, Wolk, R, Shamsuzzaman, AS, et al Serum amyloid A in obstructive sleep apnea.Circulation2003;108,1451-1454
 
Yokoe, T, Minoguchi, K, Matsuo, H, et al Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.Circulation2003;107,1129-1134
 
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Figures

Figure Jump LinkFigure 1. Illustration of the upper airway. During inspiration there is activation of pharyngeal dilator muscles that elicits the heightened muscular activity necessary to maintain airway patency. Reproduced with permission from Mayo Clinic Foundation.Grahic Jump Location
Figure Jump LinkFigure 2. Association between OSA and cardiovascular disease; partial list of the disease mechanisms associated with OSA considered as possible links to several cardiovascular diseases and metabolic dysregulation. CHF = congestive heart failure; CAD = coronary artery disease; LV = left ventricular.Grahic Jump Location
Figure Jump LinkFigure 3. CRP is higher in patients with OSA than in control subjects; box plot showing plasma CRP in OSA patients (n = 22) and control subjects (n = 20). Middle horizontal line inside box indicates median. The bottom and top of the box are 25th and 75th percentiles, respectively. Reprinted from Shamsuzzaman et al. Circulation 2002; 105:2462, with permission of Lippincott, Williams & Wilkins.Grahic Jump Location
Figure Jump LinkFigure 4. Association between AF and OSA, with adjusted odds ratio (OR) and 95% CI for the association between AF and OSA. After adjustment for BMI, neck circumference (neck circ), hypertension, and diabetes mellitus, AF is significantly associated with OSA (odds ratio, 2.19; p = 0.0006). Reprinted from Gami et al. Circulation 2004; 110:364, with permission of Lippincott, Williams & Wilkins.Grahic Jump Location
Figure Jump LinkFigure 5. Long-term risk for cardiovascular events according to the presence of OSA and treatment with CPAP; cumulative percentage of individuals with new fatal (A) and nonfatal (B) cardiovascular events in each of the five groups studied. OSAH = OSA/hypopnea; CVS = cardiovascular. Reprinted with permission from Marin et al. Lancet 2005; 365:1046.Grahic Jump Location
Figure Jump LinkFigure 6. Sudden death from cardiac causes according to usual sleep-wake cycles. Top, A: Day-night patterns of sudden death from cardiac causes on the basis of 8-h time intervals for 78 persons with OSA and 34 persons without OSA. Center, B: AHI for persons with sudden death from cardiac causes during 8-h intervals. The line within each box represents the median AHI, and the box represents the interquartile range (25 to 75th percentiles). The figure includes data from persons with OSA and persons without OSA (p = 0.001) for the comparison of the AHI according to the time of sudden death. Bottom, C: Relative risk of sudden death from cardiac causes during 8-h intervals, as compared with the remaining 16 h of the day, for 78 persons with OSA and 34 persons without obstructive sleep apnea. The squares represent the relative risk point estimates, and the I bars indicate 95% CIs. Reprinted from Gami et al. N Engl J Med 2005; 352:1206–1214, with permission of the Massachusetts Medical Society.Grahic Jump Location

Tables

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