Obstructive sleep apnea: role of intermittent hypoxia and inflammation.

531

Obstructive Sleep Apnea: Role of Intermittent Hypoxia and Inflammation Anna M. May, MD1

Reena Mehra, MD, MS, FCCP, FAASM2

1 Division of Pulmonary, Critical Care and Sleep Medicine, University

Hospitals Case Medical Center, Cleveland, Ohio 2 Neurologic Institute, Respiratory Institute, Heart and Vascular Institute and Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Research University, Cleveland Clinic Foundation, Cleveland, Ohio

Address for correspondence Reena Mehra, MD, MS, Department of Medicine, Cleveland Clinic Foundation, 9500 Euclid Ave. FA-20, Cleveland, OH 44195 (e-mail: [email protected]).

Abstract Keywords

► obstructive sleep apnea ► inflammation ► intermittent hypoxia ► sympathetic nervous system activation

Obstructive sleep apnea results in intermittent hypoxia via repetitive upper airway obstruction leading to partial or complete upper airway closure, apneas and hypopneas, respectively. Intermittent hypoxia leads to sympathetic nervous system activation and oxidative stress with a resultant systemic inflammatory cascade. The putative mechanism by which obstructive sleep apnea has been linked to numerous pathologic conditions including stoke, cardiovascular disease, hypertension, and metabolic derangements is through these systemic effects. Treatment of obstructive sleep apnea appears to reduce systemic markers of inflammation and ameliorates the adverse sequelae of this disease.

Obstructive sleep apnea (OSA) is defined by recurrent upper airway collapse leading to cessation or decrement in airflow in the presence of continued thoraco-abdominal effort reflecting attempts to breathe against a closed airway. These recurrent episodes lead to intermittent hypoxemia and are terminated by increased respiratory efforts leading to resumption of respiration accompanied by arousals. The standard metric to gauge the severity of OSA is the apnea hypopnea index (AHI) which is an average of the combined number of apneas and hypopneas per hour of sleep.1 An AHI of less than 5 is considered normal, whereas mild, moderate, and severe sleep apnea is defined by the following categories, respectively: 5 to 15, 15 to 30, and more than 30.1 Affecting in excess of 10% of the general population, OSA is a common sleep disorder.2,3 Epidemiologic studies have found that males have a prevalence of 9% and females 4% if defined by AHI greater than or equal to 15.3 Risk factors for OSA include increasing age,3–5 male gender,5–7 obesity,2,5,7,8 upper airway and craniofacial abnormalities,7,9 postmenopausal status,10,11 and family history.12 The first-line treatment for OSA is continuous positive airway pressure (CPAP), although several other viable alternatives are available which include

Issue Theme Clinical Consequences and Management of Sleep Disordered Breathing; Guest Editors, Ravi Aysola, MD, Teofilo L. Lee-Chiong, Jr., MD

other modes of noninvasive ventilation, oral appliances, implantable devices, and surgery. Multiple pathologic conditions have recently been linked with OSA including cardiovascular, neurologic, and metabolic diseases. Important underlying mechanisms for the development of these conditions include intermittent hypoxia and increased systemic inflammation associated with OSA.

Obstructive Sleep Apnea and Intermittent Hypoxia OSA is characterized by cyclical upper airway instability causing apneas—complete cessation of airflow—and hypopneas—partial reduction in airflow either leading to an arousal or desaturation. These apneic and hypopneic events that define OSA lead to intermittent hypercapnia and hypoxia by decreasing oxygen and carbon dioxide exchange which usually proceeds via passive diffusion across the thin alveolar membrane into adjoining capillaries. After resumption of respiration, compensatory hyperventilation ensues. OSA is through these mechanisms exemplified by chronic intermittent hypoxia often subsequently followed by ventilatory

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1390023. ISSN 1069-3424.

Downloaded by: University of Florida. Copyrighted material.

Semin Respir Crit Care Med 2014;35:531–544.

Role of Intermittent Hypoxia and Inflammation

May, Mehra

overshoot hyperoxia. Characterizing the severity of sleep apnea based on the standard AHI metric does have inherent limitations in capturing the true pathophysiology of OSA particularly in terms of hypoxia, as it often does not effectively convey the extent of hypoxia exposure or duration of sleep time spent in hypoxia. For example, the same AHI can be seen in patients who have a markedly different degree of oxygen desaturation accompanying their respective apneas and hypopneas. There are ample data to support that chronic intermittent hypoxia leads to sustained sympathoexcitation during the day and alterations in the vasculature resulting in hypertension in OSA. These underlying mechanisms involve not only augmentation of peripheral chemoreflex sensitivity but also direct effects on central sites of sympathetic regulation.13 Intermittent hypoxia models in rodents have revealed an increase in noradrenergic terminals in neurons as well as increased pathways in the medulla.14–16 These alterations modify the neurologic substrate and thereby increase sympathetic activation and adrenal catecholamine release in response to hypoxia.14,15,17,18 Furthermore, oxidative stress has been implicated as a mechanism by which chronic intermittent hypoxia increases catecholamine release.17 Intermittent hypoxia in OSA creates the ideal milieu for oxidative stress and generation of free radicals particularly with vulnerability in the phase of ventilatory overshoot hyperoxia likely leading to an ischemia–reperfusion state. Evaluation of sympathetic activity of humans has shown increased plasma norepinephrine and muscle sympathetic activity in patients with OSA compared with matched controls which can be ameliorated with CPAP therapy.19,20 The increased sympathomimetic activity seen in OSA leads to many of the unfortunate comorbid sequelae of this disease.

Obstructive Sleep Apnea and Systemic Inflammation In vitro studies of intermittent hypoxia have shown increased systemic inflammation secondary to an increase in reactive oxygen species via mitochondrial dysfunction, activation of hypoxia-inducible transcription factors, and reduction in antioxidants.16,21 This effect appears to exhibit attenuation with the administration of antioxidants.16 Multiple studies have demonstrated increased proinflammatory cytokines in participants with OSA compared with controls. C-reactive protein elevation in patients with OSA has been shown in several studies22–25; however, further studies that adjusted for body mass index (BMI) did not show this association.26–28 In addition, the Wisconsin Sleep Cohort did not find an association between OSA and increased levels of C-reactive protein.29 Although several studies have shown decreases in C-reactive protein levels with CPAP treatment,25,30 others have failed to confirm this finding.26,28,31 In contrast, tumor necrosis factor-α levels are increased in OSA and fall with CPAP treatment; the putative etiology of this derangement is intermittent hypoxia.32–35 IL-8 levels in the same fashion are increased in OSA and decreased with therapy.35–38 Results have been mixed in terms of the relationship of IL-6 levels in Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

OSA with some studies indicating increased levels while others failing to demonstrate a significant association. Sleep disordered breathing (SDB), however, has been implicated in increased soluble IL-6 receptor levels even after consideration of obesity and exhibiting diurnal variation predisposing to increased levels in the morning compared with evening perhaps reflecting overnight OSA-related physiologic stress.25,32,35,39,40 Cell adhesion molecules such as intracellular cell adhesion molecule 1, vascular adhesion molecule 1, and L-selectin effectuate adherence of leukocytes to endothelium. Multiple studies have shown that these molecules are elevated in patients with OSA.41–44 In addition, CPAP treatment for 1 month has been demonstrated to decrease soluble cell adhesion molecules in OSA patients.45 Patients with OSA also appear to have a hypercoagulable state. For example, in the Cleveland Family Study we have shown increased levels of fibrinogen and plasminogen activator inhibitor-1 particularly with exposure to a more mild degree of apnea.13 Elevations of activated coagulation factors have been demonstrated in OSA; however, 1 month of CPAP treatment did not affect these levels.46 Several studies have documented increased platelet activation and aggregation in OSA patients, which is reversed with CPAP therapy.47–49 In addition, several studies have documented increased fibrinogen levels in patients with OSA; however, only one trial demonstrated improvement in fibrinogen after CPAP therapy.33,50–54 These inflammatory effects on the coagulation system may increase propensity for cardiac and neurologic vascular morbidity.

Metabolic Risk Diabetes Mellitus and Insulin Resistance Obesity and OSA have bidirectional relationships which complicate the discussion of disorders which are linked to both of these diseases. In addition to increased oxidative stress and inflammation associated with OSA, intermittent hypoxia leads to sympathetic system activation which spurs gluconeogenesis in the liver.55 Increased levels of inflammation have been linked to increased adiposity and insulin resistance.56 Adipose tissue has multiple hormonal roles in the body including secretion of leptin and adiponectin.57 Obesity is correlated with downregulation of adiponectin secretion, a hormone that increases insulin sensitivity. Leptin has been implicated in satiety, decreased glucose, and reductions in adiposity and body weight.57 Although leptin levels are increased with increased adiposity, there is evidence of resistance to its effects in obese individuals which would predispose them to derangements in control of glucose. Experiments in animal models of mice have shown that animals with either diet-induced or genetic obesity exposed to chronic intermittent hypoxia develop insulin resistance via changes in leptin secretion.58,59 A study of humans has shown that treatment of OSA with CPAP leads to significant decrease in leptin levels lending credence to the theory that OSA leads to leptin resistance and not vice versa.60–62 Lean animals exposed to intermittent hypoxia also developed insulin resistance, an effect that appeared to be independent of autonomic system activation.63


532

Experiments in animal models have demonstrated that intermittent hypoxia results in insulin resistance and glucose intolerance. Some of these effects are likely mediated by OSArelated autonomic nervous system dysregulation; however, evidence also points to effects independent of this as well. Specifically, β-cell dysfunction in intermittent hypoxia models occurs due to catecholamine-mediated inhibition of insulin secretion by activating α-2 adrenoreceptors in β cells64 and also impairment of insulin sensitivity with a lack of compensatory hyperinsulinemia.65 In human studies, interventional data demonstrate that exposure to intermittent hypoxia predisposes to metabolic derangements via pathways of insulin sensitivity, glucose handling, and insulin secretion; thus, identifying hypoxic stress as an important pathophysiologic mechanism.66 It is well known that obesity predisposes individuals to insulin resistance and diabetes. OSA-associated intermittent hypoxia appears to concomitantly induce insulin resistance primarily through mechanisms of elevated oxidative stress, increased lipid peroxidation, and upregulation of nuclear factor-κB and hypoxia-inducible factor-1.66 In healthy volunteers, 6 hours of intermittent hypoxia caused reduced insulin secretion as well as increased insulin resistance.67 Several cross-sectional epidemiologic studies have demonstrated a link between OSA and insulin resistance and diabetes.68–74 The Sleep Heart Health Study analyzed quartiles of AHI and oxygen desaturation and found an increased risk of glucose intolerance with increasing AHI which was exacerbated by hypoxia.75 In addition, several studies have shown that treatment with CPAP improves insulin resistance in nondiabetic patients and those with metabolic syndrome.33,76 Two studies which compared CPAP to a sham control did not show improvements in glycemic control or insulin resistance but suffered from poor CPAP adherence or short follow-up time.77,78 A study comparing 3 months of CPAP in people with OSA with obese controls did not find a significant change in insulin sensitivity or fasting glucose levels; however, once treatment adherence was taken into account, the sample size may have been too low to see a significant effect (n ¼ 10 for good compliance and n ¼ 6 for poor compliance).79 Combined, these studies indicate that OSA likely increases the risk of insulin resistance, which can predispose individuals to overt development of diabetes.

Cardiopulmonary Risk Hypertension Intermittent hypoxia, a cardinal feature of OSA, has been shown to stimulate the cardiac parasympathetic system resulting in bradycardia as well as peripheral sympathetic activation via the carotid body chemoreceptors.80–82 Therefore, repeated OSA-related intermittent hypoxia and hypercapnia trigger alterations in both sympathetic and parasympathetic activation.83 Resumption of normoxia culminates in transient tachycardia and hypertension via unopposed sympathetic activation. The increased sympathetic tone secondary to intermittent hypoxia may be further augmented by arousals leading to abrupt increases in blood

May, Mehra

pressure.81,84–88 Data suggest, however, that apneas are required in addition to arousals to induce hypertension.89 OSA precipitates not only nocturnal hypertension but also increased blood pressure during the day, which may be secondary to sustained increased daytime sympathetic tone.19,85 Other mechanisms linking OSA to hypertension include increased renin–angiotensin–aldosterone system activity, impairment of endothelium-dependent vasodilation, and genetic predisposition.90 In particular, the contribution of endothelial dysfunction via reduction in nitric oxide bioavailability may be mediated by increased NF-kappa B activity induced by OSA-related intermittent hypoxia by increasing inducible nitric oxide synthase levels.91 Molecular mechanisms have been implicated including activation of nuclear factor of activated T cells (NFAT) of which NFATc3 induction by endothlelin-1 results in hypertension subsequent to chronic intermittent hypoxia.92 Normal sleep is characterized by parasympathetic tone increases which causes a reduction in blood pressure from the awake state by approximately 10% of the awake value, the socalled dipping pattern.93 Even in the background of increased cardiovascular risk, moderate-to-severe OSA, in particular intermittent hypoxia characterized by the oxygen desaturation index, has been associated with nondipping systolic and mean arterial blood pressure profiles based on 24-hour ambulatory blood pressure monitoring.94 These findings are of importance as nondipping blood pressure represents a clinically relevant marker of adverse cardiovascular outcomes and mortality.95 Recent data highlight the loss of normal blood pressure diurnal rhythm such that the increase in nighttime and morning blood pressure values were more pronounced than the daytime and evening values in patients with OSA.96 Furthermore, OSA also represents the most common secondary cause of resistant hypertension supporting the utility of treating OSA to improve blood pressure in this population97 with the renin–angiotensin–aldosterone system and rostral fluid shifts as potential culprits of resistant hypertension in OSA.98 Several large-scale population-based studies have documented increased hypertension incidence in individuals with OSA. The Wisconsin Sleep Cohort reported a dose–response relationship between increasing OSA severity category and increased incidence of hypertension even after consideration of obesity and other potential confounding factors.99 The Sleep Heart Health Study, the largest observational study of the cardiovascular consequences of sleep apnea in a geographically diverse cohort, observed stronger relationships of OSA and incident hypertension in the nonobese participants suggesting that the relationship may be unrelated to obesity or findings are stronger in a group with less competing risk factors.100 Multiple meta-analyses have also confirmed the ability of CPAP to decrease both daytime and nocturnal blood pressure.101–105 Overall, PAP treatment for OSA has been associated with modest but significant reductions in diurnal and nocturnal systolic and diastolic blood pressure levels. A randomized controlled trial of CPAP in patient with OSA showed that therapy decreases both daytime and nocturnal blood pressure with particular effect in persons with higher Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

533




May, Mehra

AHI or those on antihypertensives.106 Two recent randomized controlled studies of CPAP therapy in OSA patients with drugresistant hypertension decreased daytime blood pressure.107,108 Importantly, the results of these studies have informed guidelines on the detection and treatment of difficult-to-treat hypertension.109

Ischemic Heart Disease and Cardiovascular Mortality Augmented systemic inflammation not only fosters the early development and growth of atherosclerotic lesions but also promotes plaque rupture leading to clinically manifest coronary artery disease.110 Two studies that investigated intermittent hypoxia in mice with dyslipidemia observed evolution of atheromatous plaque formation.110,111 Vascular relaxation is governed by endothelium-derived vasodilators such as nitric oxide; impaired vascular relaxation is an important precursor of atherosclerosis and may precede structural changes.110 Rat models of chronic intermittent hypoxia have demonstrated endothelin-induced vascular contraction.112,113 In addition, healthy nonsmoking people with OSA have reduced vascular relaxation, an effect that can be attenuated with CPAP therapy.114 Carotid intima-media thickness, a noninvasive, readily recognized marker of early atherosclerosis even in asymptomatic individuals, predicts coronary artery disease and stroke; this marker of early atherosclerosis has been associated with inflammation and oxidative stress.115–121 OSA has been linked to increased carotid intima-media thickness in a meta-analysis of 16 studies with a combined total of 1,415 patients.116 Although a 90-day study of CPAP did not show improvement in intimamedia thickness, a randomized sham-controlled trial of 4 months of CPAP therapy on carotid intima-media thickness showed a decrease with therapy in severe OSA.20,37 In an observational study of day–night variation of myocardial infarction, individuals with OSA had a 4.5-fold increased risk of chest pain starting at night compared with non-OSA controls with similar levels of cardiac comorbidities including obesity.122 In addition, people whose myocardial infarctions were initiated at night were six times more likely to have OSA: 91% of the patients with nocturnal myocardial infarction had OSA.122 A retrospective study of sudden cardiac death revealed increased rate of nocturnal events in individuals with OSA (46% in OSA vs. 21% in non-OSA controls).123 Increasing severity of OSA as defined by AHI was associated with increased risk of nocturnal sudden cardiac death with individuals with AHI > 40 at 2.6-fold increased risk compared with people with AHI < 5.123 Several large cohort studies have shown that lack of nocturnal blood pressure decrease is predictive of cardiovascular disease even in the absence of daytime hypertension.124–126 In a large cohort study of men with untreated OSA, simple snorers without OSA, and controls without sleep apnea showed a severity–dependent association of untreated OSA with cardiovascular events even after adjustment for confounders; treatment with CPAP decreased the risk to that of snorers without OSA.127 Specifically, in this cohort, an increased fatal and nonfatal cardiovascular event rate in OSA was observed which was ameliorated with CPAP therapy.127 Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

Several other studies have corroborated these findings by demonstrating increased cardiovascular risk with OSA, which is attenuated in response to CPAP treatment.127–130

Heart Failure Epidemiologic work has identified OSA as an independent predictor of incident heart failure with findings most pronounced in younger middle-aged men even after accounting for confounding factors.131 Both OSA and central sleep apnea, the latter with or without Cheyne Stokes respirations, are common often unrecognized comorbidities with heart failure occurring in 50 to 75% of those with either reduced ejection fraction systolic heart failure or heart failure with preserved ejection fraction.132–137 Hypoxia impairs myocardial oxygen delivery causing direct effects on cardiac performance. Studies have shown increased afterload after hypoxia secondary to increased left ventricular stiffness and impaired relaxation.138 In addition, increased sympathetic activity from hypoxia leads to tachycardia and hypertension which further increases cardiac strain and afterload, potentially contributing to heart failure progression. Chronic exposure to hypoxia and hypercapnia may lead to pulmonary vascular remodeling. This may lead to ventricular hypertension, atrial dilatation, and increased transmural pressures impinging on endocardial vessels, thereby altering the distribution of blood flow and further perpetuating heart failure progression. Hypoxia and oxygen-derived free radicals can also damage cardiac myocytes and, thereby, increase the likelihood of deterioration of cardiac function. Upregulation of pathways of systemic inflammation may represent a final common pathway of autonomic dysfunction, hypoxia/hypercapnia, and mechanical cardiac influences from increasingly negative intrathoracic pressures. Recent data have identified the association of central sleep apnea and upregulation of pathways of inflammation with arrhythmia in patients with heart failure. Specifically, central apnea was related to nighttime arrhythmia and increased C-reactive protein in heart failure.139 Oxidative stress also contributes to myocardial cell injury as exhibited by increased troponin levels in rodent models as well as myocyte hypertrophy and fibrosis eventually culminating in left ventricular dysfunction.140–142 Chronic intermittent hypoxia leads to increased lipid peroxides which are associated in animal models with cardiac dysfunction as exhibited by increased left ventricular end-diastolic pressure.141 In addition, canine models demonstrate decreased ejection fraction and left ventricular hypertrophy in the face of chronic intermittent hypoxia.143 The benefit of the use of supplemental oxygen therapy in terms of sleep apnea in heart failure supports the biologic plausibility of the impact of hypoxia and alterations in ventilator responsiveness as pathophysiologic culprits. Specifically, supplemental oxygen results in reduced chemoreceptor sensitivity to PaCO2, reduced central apnea, and decreased sympathetic nervous system activity in heart failure. Heart failure patients with untreated OSA have a higher cardiovascular mortality compared with controls.144 Heart failure patients with OSA who are noncompliant with CPAP therapy had higher all-cause mortality.145 CPAP


534

treatment has been shown to decrease the diastolic dysfunction which is more prevalent in patients with OSA.146 In those with OSA and heart failure, there are several trials which have shown improvement in left ventricular ejection fraction, left ventricular dilatation, systolic blood pressure, sympathetic activity, and quality of life with CPAP treatment.147 In the Canadian Continuous Positive Airway Pressure for Central Sleep Apnea and HF (CANPAP) trial, the largest randomized controlled trial to date testing the efficacy of nocturnal CPAP in reducing mortality and transplant-free survival in patients with advanced heart failure, no difference in mortality was noted. However, improvements in the secondary outcomes of ejection fraction, norepinephrine levels, and distance walked in 6 minutes were observed.148 Several reasons have been postulated for the unexpected findings including increasing use of β blockers during the course of the study which may have precluded ascertaining PAP benefit, suboptimal PAP adherence, persistent apnea due to Cheyne Stoke respirations, and hemodynamic disadvantage of PAP in those with low volume state. A post hoc analysis of this study was performed to evaluate potential differences on outcome between those who were effectively treated for SDB and those who were not, and findings demonstrated that a substantial improvement in sleep apnea was associated with an improved survival until transplantation.149

Cardiac Arrhythmias Unlike in normal sleep which is characterized by reductions in heart rate, derangements in parasympathetic and sympathetic tone during and after episodes of intermittent hypoxia provide a substrate that increases potential for cardiac arrhythmogenesis. During episodes of hypoxia, vagal tone increases causing bradycardia which can lead to bradyarrhythmias and heart block during apneic episodes.80 The increased sympathetic tone following resumption of breathing characterized by hyperpnea can lead to tachyarrhythmias. In addition, cardiac structural changes can predispose to arrhythmias by promoting cardiac repolarization abnormalities.21 The hypoxia–reoxygenation which accompanies OSA increases free radical formation by activating lines of cellular inflammation including neutrophils and monocytes, and these inflammatory mediators may adversely affect cardiac myocyte function. Intermittent hypoxia results in activation of stress genes such as hypoxia-inducible factor-1 which influences transcription of genes which regulate oxygen delivery.150 Concordantly, atrial fibrillation is associated with hypoxia-inducible factor-1 which is upregulated in OSA.151 Tissue hypoxia in the fibrillated atria ascertained by HIF-1a and vascular endothelial growth factor-(1 mRNA are upregulated and may play a role in perpetuating atrial structural remodeling in OSA.150 Atrial fibrillation (AF) can be instigated by intermittent hypoxia. Increased vagal activation is followed by unopposed sympathetic activation when hypoxia ceases and increases likelihood of AF by shortening the atrial refractory period which predisposes to focal atrial discharges.152,153 In addition, increased systemic inflammation and oxidative stress lead to changes in cardiac structure which creates heteroge-

May, Mehra

neous regions of myocyte excitability and increases the risk for reentrant arrhythmias.21 The reoxygenation period after intermittent hypoxia is characterized by increased pulmonary vein burst firing.154 Several epidemiologic observational studies have highlighted a relatively strong magnitude of association of SDB and AF (odds ratio point estimates of 2–4) even after taking into account a host of potential confounding factors including age, BMI, and self-reported cardiovascular comorbidities including heart failure.155,156 Among elderly individuals, stronger associations have been reported between AF and central sleep apnea compared with OSA even after consideration of confounding factors.156 In this article, a threshold effect was noted such that a moderate-tosevere degree of SDB conferred the greatest increased odds of AF independent of self-reported heart failure and cardiovascular disease.156 In clinic-based studies, hypoxia has been identified as a likely pathophysiologic factor in OSA which results in increased incidence of atrial fibrillation157 and also increased recurrence of atrial fibrillation. 83 In elderly individuals, it appears that hypoxia defined by the percentage of sleep time spent less than 90% oxygen saturation may serve as a more pronounced contributor to ventricular arrhythmia rather than atrial arrhythmia.156 In terms of atrioventricular conduction delay, initial investigations reported high prevalence of second-and thirddegree heart block and sinus arrest in patients with OSA; however, subsequent studies have shown the prevalence to be around 1 to 5%.158 Participants with SDB had higher rates of first- and second-degree heart block (1.8 vs. 0.3% and 2.2 vs. 0.9%, respectively) in the Sleep Heart Health Study; however, these results did not reach statistical significance.155 OSA severity has been positively linked with nocturnal ventricular tachycardia, fibrillation, and asystole.159–161 Treatment with either CPAP or tracheostomy appears to abolish or severely reduce the rate of arrhythmias.159–161 In retrospective studies, treatment of OSA also appears to consistently mitigate the recurrence of AF after ablation or cardioversion.83,89,90

Pulmonary Hypertension Chronic intermittent hypoxemia causes oscillatory vasoconstriction and relaxation which cause cyclical alterations in the pulmonary arterial pressure.162,163 Several studies have shown that degree of hypoxia is correlated with a rise in pulmonary artery pressure.164,165 Over time, chronic intermittent hypoxia can cause irreversible changes in the pulmonary vasculature leading to pulmonary hypertension. Chronic hypoxia has been shown to lead to smooth muscle hypertrophy of pulmonary arteries as well as muscularization of previously nonmuscularized blood vessels.166 Mouse studies have shown that chronic intermittent hypoxia can engender changes of pulmonary hypertension including increased pulmonary arterial pressure, right heart failure, and muscularization of distal pulmonary arteries.167,168 These changes have been associated with activation of NADPH oxidase leading to increases in reactive oxygen species.169 Moreover, release of endothelial nitric oxide may be impaired in the pulmonary circulation of those with OSA which may Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

535




May, Mehra

adversely affect vascular smooth muscle tone of the pulmonary vasculature and promote vascular remodeling.170 Modest increases in pulmonary arterial pressure have been documented in patients with OSA.170 Interestingly, pulmonary artery pressures are increased from the initial phase of the apneic period (28 12 mm Hg) to the termination of the apnea (39 16 mm Hg) when measuring the transmural pulmonary artery pressure measures, that is, adjusting for apnea-related intrathoracic pressure swings, and these changes appear to be more pronounced in rapid eye movement (REM) versus non-rapid eye movement (NREM) sleep.170 The primary mechanisms involved include not only hypoxic pulmonary vasoconstriction but also mechanical factors due to increased inspiratory effort, reflex mechanisms affecting vasculature, and increased left-sided filling pressures.170 However, it has not been clearly elucidated as to whether the pulmonary hypertension observed in OSA is attributable to a precapillary or postcapillary process. Abnormalities of right ventricular function and structure have been highlighted by data from the Sleep Heart Health study involving a subset of participants with echocardiogram data demonstrating increased right ventricular wall thickness in those with severe OSA compared with mild OSA and other data supporting reduced right ventricular contractility.170 Pulmonary hypertension is most pronounced in individuals with OSA who have hypoxic pulmonary or heart disease.171–175 When clinically significant pulmonary disease was excluded, studies have found that OSA patients have a 20 to 43% prevalence of pulmonary hypertension with a fairly large percentage of latent pulmonary hypertension.174,176–182 Noteworthy to these studies is the observation of association of pulmonary hypertension with mild daytime hypoxia or small airway function abnormalities.170 After 3 to 6 months of CPAP treatment versus sham CPAP in several randomized controlled trials, pulmonary artery pressure was reduced without any substantial change in daytime awake hypoxemia or lung function indices; moreover, improvement in reactivity of the pulmonary circulation to hypoxia was observed.176,178,183 Overall, these studies in animals and humans have uncovered the role of OSA in the development of mild pulmonary hypertension which appears to be ameliorated by OSA therapy.

Overlap Syndrome: Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea The combined comorbidity of chronic obstructive pulmonary disease (COPD) and OSA is termed overlap syndrome. Of note, OSA and COPD are among the most prevalent pulmonary diseases and share common pathophysiological mechanisms; therefore, the term overlap syndrome was coined, as this entity is a distinct process from either disease in isolation.184 Individuals with overlap syndrome are more likely to suffer from hypoxia than patients with either COPD or OSA alone and appear to have increased vulnerability to incident atrial fibrillation than either OSA or COPD patients.185 There are likely bidirectional mechanisms at play with COPD-associated skeletal myopathy and smoking, increasing upper airway collapsibility, and adversely affecting pharyngeal dilator acSeminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

tivity in conjunction with increased end-expiratory volumes in emphysema resulting in loss of lung recoil predisposing to increased airway collapsibility.186 Alternatively, OSA-related repetitive airway collapse leads to increases in lower airway resistance, and those with OSA may increase use of tobacco to counteract symptoms of sleepiness or to facilitate weight loss.187 Sleep even in the absence of OSA is accompanied by reduction in functional residual capacity during NREM sleep which becomes further pronounced during REM sleep due to blunting of the hypoxic and hypercapnic ventilator drive and skeletal muscle hypotonia. The degree of hypoxia during sleep occurring in COPD is even further accentuated due to starting on a steeper portion of the oxyhemoglobin curve and a reduction in minute ventilation of up to 32% during REM sleep.91 Increase sleep fragmentation, reduction in total sleep time and slow wave sleep as well as REM sleep are observed in COPD as are cough, nocturnal dyspnea, and medication side effects which can further disrupt sleep.91 Nocturnal oxygen desaturation in COPD occurs during sleep primarily due to alveolar hypoventilation, ventilation–perfusion mismatch, and reduction in end-expiratory volumes. Circadian influences are important to recognize as more severe nocturnal oxygen desaturation occurs during the early morning hours due to an increased amount of REM sleep during this portion of the sleep period and REM-related increase in parasympathetic nervous system activity may increase bronchoconstriction.91 Individuals with overlap syndrome have lower PaO2 levels compared with those with pure OSA and also higher PaCO2 compared with those with pure COPD.188 Overall, those with overlap syndrome are at higher risk of pulmonary hypertension, right-sided heart failure, and hypercapnia than either disorder alone with hypoxia likely serving as an important mediator. The role of OSA in the increase in mortality associated with COPD189 is highlighted by studies demonstrating a reduction in fatal and nonfatal cardiovascular event mortality conferred by CPAP in overlap syndrome patients compared with COPD.190 Hypoxia appears to be an important mechanism conferring increased morbidity and mortality in overlap syndrome as evidenced by data which showed improved survival in those treated with long-term oxygen treatment (LTOT) compared with those without treatment; however, CPAP combined with LTOT appeared to provide further augmentation of this survival benefit compared with LTOT alone.191

Neurologic Risk Stroke A hypercoagulable state, metabolic syndrome, and increased atherosclerosis predispose individuals with OSA to increased incidence of stroke. In addition, early morning blood viscosity likely mediated in part by hypoxia has been observed to be increased in OSA patients but not healthy controls, which may predispose these individuals to cerebrovascular accidents.192 Compounding these derangements, increased atrial fibrillation risk in OSA also makes these individuals more susceptible


536

to embolic strokes. Early indications of elevated stroke risk in OSA led to evaluation of patients with cerebrovascular accidents for evidence of increased prevalence of sleep apnea. A study of acute stroke patients showed an independent correlation between amount of white matter disease and severity of OSA defined by the AHI.193 A meta-analysis of stroke and transient ischemic attack patients found that OSA was very prevalent in this cohort (72% with AHI > 5 and 38% with AHI > 20); sleep apnea was found to be more prevalent after recurrent strokes than initial strokes (74 vs. 57%).194 Multiple cross-sectional studies have shown an association between OSA and stroke. A cohort study of sleep clinic patients older than 50 years found an association between the combined outcome of incident stroke and death from any cause with OSA even after adjustment for confounders.195 In addition, the unadjusted rate of stroke was more than five times higher in the OSA group.195 In patients with coronary artery disease, OSA predicted not only cerebrovascular events but also a composite of stroke, myocardial infarction, and death.196 One of the first studies to examine the longitudinal relationship of OSA and stroke showed that OSA was associated with increased stroke and mortality compared with patients with nonrespiratory sleep disorders.195 One of the largest studies to examine the relationship of OSA and stroke involved more than 5,000 participants of the Sleep Heart Health Study which identified a significant association between the AHI (incorporating hypopnea associated with a 3% oxygen desaturation) in the severe category and increased incident ischemic stroke in men and women at levels of OSA above the moderate range.197 A recent meta-analysis of prospective cohort studies identified a twofold increase in risk of stroke in OSA patients.198 A study examining OSA patients found not only that their risk was increased compared with the general population at baseline but also that treatment with tracheostomy seemed to mitigate stroke risk when compared with weight loss recommendations.199 Two randomized controlled studies of CPAP treatment of OSA in stroke patients showed improvements in stroke-related impairment.200,201 Furthermore, a prospective observational 5-year trial of CPAP therapy for moderate-to-severe OSA in acute stroke patients showed decreased risk of mortality after adjustment for confounders including cardiovascular risk and metabolic variables.202

Neurocognitive Function Cognitive impairment—including sleepiness, fatigue, poor concentration or memory, and depression—are well known to be associated with OSA.203,204 Animal models have been paramount in characterizing the cause of these abnormalities. Rat models of intermittent hypoxia have shown oxidative stress-induced neuronal loss via activation of apoptosis in the hippocampus and cortex and decrements in spatial memory.205–209 Administration of antioxidants led to less apoptosis in rodents exposed to intermittent hypoxia.210 Mechanistic underpinnings of neurocognitive deficits observed in OSA include high levels of glutamate as well as molecular path-

May, Mehra

ways of downregulation of hippocampal brain-derived neurotrophic factor.211 Human studies have also shown decrements in cognitive function associated with OSA. Initial cross-sectional data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES) involving more than 1,000 participants in a multicenter randomized controlled trial demonstrated that the compromise in neurocognitive performance in OSA was associated with the severity of hypoxemia in terms of intelligence, attention, and processing speed.212 The interventional trial results demonstrated that CPAP treatment improved subjective and objective measures of sleepiness particularly in participants with severe OSA and resulted in transient improvement in measures of executive and frontal lobe function in those with severe apnea.213 A meta-analysis of the effect of OSA on neurocognitive function noted adverse effects on attention and executive functioning as well as possible decrements in visual and motor ability.214 A dose– response relationship between the severity of OSA and vigilance has also been noted, and treatment of OSA seemed to reverse this effect.215 A fairly consistent findings across studies includes impairment in executive functioning related to OSA as well as improvement in this domain in response to OSA treatment.204 A study of 100 patients with OSA showed that nocturnal hypoxemia was associated with impaired processing speed, mental flexibility, and visual constructional ability.216 Alternatively, studies of visuospatial and construction ability impairments in OSA have been overall inconsistent and none reported improvement with OSA treatment.204,215 Brain imaging techniques provide indirect evidence of the role of OSA in inducing brain damage and leading to cognitive impairment. Studies have documented loss of cortical density in the hippocampal region, an area of the brain located in the medial temporal lobe which plays an important role in memory consolidation. In addition, there is weaker evidence of frontal cortex and generalized gray matter loss as well.217–222 MRI studies have revealed decrements in verbal memory, executive functioning, and information processing in patients with OSA.223 Three months of OSA treatment with CPAP showed not only improvements in neurocognitive indices of memory, vigilance, and executive function but also increased hippocampal and frontal gray matter.224 It seems clear that OSA has a negative effect on cognitive function in multiple domains, a result which is buttressed by evidence of loss of brain matter. Current science also seems to indicate that at least some of the functional loss can be recovered with OSA treatment.

Malignancy Risk A recent surge of literature has uncovered relationships of OSA and risk of malignancy. Increased inflammation and oxidative stress have been linked to cellular damage. Cellular models of cancer growth have consistently shown the negative effects of intermittent hypoxia.225–227 Two lung cancer cell lines exposed to chronic intermittent hypoxia showed lower levels of apoptosis and higher invasion which may lead Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

537




May, Mehra

to resistance to anticancer treatment.226 In addition, this stimulus leads to increased secretion of angiogenic hormones which may potentiate cancer growth.227 Animal studies have also shown the negative consequences of intermittent hypoxia. Intermittently hypoxic mice had a higher level of lung micrometastases compared with normoxia or chronic hypoxia.228 Similar experiments have shown increased melanoma lung metastases compared with normoxic controls.229 Furthermore, the relationship of OSA-related hypoxia ascertained by the oxygen desaturation index has been shown to be associated with increased 2,3-deoxyguanosine levels, a marker of oxidized DNA.230 The adverse cancer outcomes associated with OSA are likely mediated by intermittent hypoxia-induced changes in host immune responses as evidenced by experimental animal data demonstrating alterations in tumor-associated macrophages in response to intermittent hypoxia.231 Compelling data also demonstrate downregulation of expression patterns of peripheral blood leukocyte-enriched gene sets involved in neoplastic processes in response to CPAP in the setting of severe OSA.232 A large prospective cohort study using surveys to assess for snoring, breathing cessation, and somnolence found evidence of increased malignancy risk in sleepy participants younger than 50 years; however, this study suffers from not collecting objective data on SDB prevalence in the cohort.233 In a recent large Spanish cohort (n ¼ 4,910) of OSA patients followed over 4.5 years, increasing tertiles of hypoxia but not AHI were related to an increasing incidence of malignancy in fully adjusted analyses.234 In particular, an association of increasing AHI tertiles and cancer incidence was observed in those younger 65 years and in men.234 The Wisconsin Sleep Cohort, a community-based epidemiologic study, found increased cancer mortality associated with SDB after adjusting for age, sex, BMI, and smoking.235 There was a dose–response relationship observed in both increasing severity of SDB as well as increasing time with hypoxia.235 These studies point to a potential link between OSA and cancer development and mortality.

References 1 Sleep-related breathing disorders in adults: recommendations

2

3

4

5

6

7 8

9

10

11

12 13

14

15

Summary Overall, data support a link between OSA and adverse health consequences which are likely mediated by bouts of intermittent hypoxia, ventilatory overshoot hyperoxia, and upregulation of pathways of oxidative stress and systemic inflammation. Although the preponderance of data describes these relationships in terms of cardiovascular disease, cardiac arrhythmias, pulmonary hypertension, COPD, stroke, and neurocognition; emerging compelling data also highlight the importance of the influence of OSA on development of malignancy and risk of increased cancer-specific mortality. Reversal of OSA pathophysiology appears to improve many of these adverse cardiopulmonary and neurologic sequelae; albeit further rigorously performed studies are needed to identify specific thresholds of disease which would most benefit from OSA treatment as well as better delineating subgroup susceptibilities and responsiveness to therapy. Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

16

17

18

19

20

for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22(5):667–689 Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013;177(9):1006–1014 Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ 2009;108(5):246–249 Jennum P, Riha RL. Epidemiology of sleep apnoea/hypopnoea syndrome and sleep-disordered breathing. Eur Respir J 2009; 33(4):907–914 Tufik S, Santos-Silva R, Taddei JA, Bittencourt LR. Obstructive sleep apnea syndrome in the Sao Paulo Epidemiologic Sleep Study. Sleep Med 2010;11(5):441–446 Quintana-Gallego E, Carmona-Bernal C, Capote F, et al. Gender differences in obstructive sleep apnea syndrome: a clinical study of 1166 patients. Respir Med 2004;98(10):984–989 Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA 2004;291(16):2013–2016 Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000;284(23):3015–3021 Li KK, Kushida C, Powell NB, Riley RW, Guilleminault C. Obstructive sleep apnea syndrome: a comparison between Far-East Asian and white men. Laryngoscope 2000;110(10, Pt 1): 1689–1693 Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleepdisordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163(3, Pt 1):608–613 Young T, Finn L, Austin D, Peterson A. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003;167(9):1181–1185 Redline S, Tishler PV. The genetics of sleep apnea. Sleep Med Rev 2000;4(6):583–602 Mehra R, Xu F, Babineau DC, et al. Sleep-disordered breathing and prothrombotic biomarkers: cross-sectional results of the Cleveland Family Study. Am J Respir Crit Care Med 2010;182(6): 826–833 Mody P, Rukhadze I, Kubin L. Rats subjected to chronic-intermittent hypoxia have increased density of noradrenergic terminals in the trigeminal sensory and motor nuclei. Neurosci Lett 2011; 505(2):176–179 Rukhadze I, Fenik VB, Benincasa KE, Price A, Kubin L. Chronic intermittent hypoxia alters density of aminergic terminals and receptors in the hypoglossal motor nucleus. Am J Respir Crit Care Med 2010;182(10):1321–1329 Prabhakar NR, Kumar GK. Oxidative stress in the systemic and cellular responses to intermittent hypoxia. Biol Chem 2004; 385(3-4):217–221 Kumar GK, Rai V, Sharma SD, et al. Chronic intermittent hypoxia induces hypoxia-evoked catecholamine efflux in adult rat adrenal medulla via oxidative stress. J Physiol 2006;575(Pt 1): 229–239 Souvannakitti D, Kumar GK, Fox A, Prabhakar NR. Contrasting effects of intermittent and continuous hypoxia on low O(2) evoked catecholamine secretion from neonatal rat chromaffin cells. Adv Exp Med Biol 2009;648:345–349 Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 1993;103(6): 1763–1768 Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007;176(7):706–712


538

May, Mehra

21 Rossi VA, Stradling JR, Kohler M. Effects of obstructive sleep

41 El-Solh AA, Mador MJ, Sikka P, Dhillon RS, Amsterdam D, Grant BJ.

apnoea on heart rhythm. Eur Respir J 2013;41(6):1439–1451 Can M, Açikgöz S, Mungan G, et al. Serum cardiovascular risk factors in obstructive sleep apnea. Chest 2006;129(2):233–237 Kokturk O, Ciftci TU, Mollarecep E, Ciftci B. Elevated C-reactive protein levels and increased cardiovascular risk in patients with obstructive sleep apnea syndrome. Int Heart J 2005;46(5): 801–809 Shamsuzzaman AS, Winnicki M, Lanfranchi P, et al. Elevated Creactive protein in patients with obstructive sleep apnea. Circulation 2002;105(21):2462–2464 Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of Creactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107(8):1129–1134 Barceló A, Barbé F, Llompart E, et al. Effects of obesity on Creactive protein level and metabolic disturbances in male patients with obstructive sleep apnea. Am J Med 2004;117(2): 118–121 Guilleminault C, Kirisoglu C, Ohayon MM. C-reactive protein and sleep-disordered breathing. Sleep 2004;27(8):1507–1511 Ryan S, Nolan GM, Hannigan E, Cunningham S, Taylor C, McNicholas WT. Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity. Thorax 2007; 62(6):509–514 Taheri S, Austin D, Lin L, Nieto FJ, Young T, Mignot E. Correlates of serum C-reactive protein (CRP)—no association with sleep duration or sleep disordered breathing. Sleep 2007;30(8):991–996 Steiropoulos P, Tsara V, Nena E, et al. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest 2007;132(3):843–851 Akashiba T, Akahoshi T, Kawahara S, Majima T, Horie T. Effects of long-term nasal continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea syndrome. Intern Med 2005;44(8):899–900 Ciftci TU, Kokturk O, Bukan N, Bilgihan A. The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine 2004;28(2):87–91 Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008;134(4):686–692 Minoguchi K, Tazaki T, Yokoe T, et al. Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome. Chest 2004;126(5): 1473–1479 Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174(7):824–830 Alzoghaibi MA, Bahammam AS. Lipid peroxides, superoxide dismutase and circulating IL-8 and GCP-2 in patients with severe obstructive sleep apnea: a pilot study. Sleep Breath 2005;9(3): 119–126 Li C, Zhang XL, Liu H, Wang ZG, Yin KS. Association among plasma interleukin-18 levels, carotid intima- media thickness and severity of obstructive sleep apnea. Chin Med J (Engl) 2009;122(1): 24–29 Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y. Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP1. J Appl Physiol (1985) 2003;94(1):179–184 Mehra R, Storfer-Isser A, Kirchner HL, et al. Soluble interleukin 6 receptor: A novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med 2006;166(16):1725–1731 Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997;82(5):1313–1316

Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea. Chest 2002;121(5): 1541–1547 Ohga E, Nagase T, Tomita T, et al. Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J Appl Physiol (1985) 1999;87(1):10–14 Ursavaş A, Karadağ M, Rodoplu E, Yilmaztepe A, Oral HB, Gözü RO. Circulating ICAM-1 and VCAM-1 levels in patients with obstructive sleep apnea syndrome. Respiration 2007;74(5):525–532 Zamarrón-Sanz C, Ricoy-Galbaldon J, Gude-Sampedro F, RiveiroRiveiro A. Plasma levels of vascular endothelial markers in obstructive sleep apnea. Arch Med Res 2006;37(4):552–555 Chin K, Nakamura T, Shimizu K, et al. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 2000; 109(7):562–567 Robinson GV, Pepperell JC, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 2004; 59(9):777–782 Bokinsky G, Miller M, Ault K, Husband P, Mitchell J. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. A preliminary investigation. Chest 1995;108(3): 625–630 Eisensehr I, Ehrenberg BL, Noachtar S, et al. Platelet activation, epinephrine, and blood pressure in obstructive sleep apnea syndrome. Neurology 1998;51(1):188–195 Sanner BM, Konermann M, Tepel M, Groetz J, Mummenhoff C, Zidek W. Platelet function in patients with obstructive sleep apnoea syndrome. Eur Respir J 2000;16(4):648–652 Chin K, Ohi M, Kita H, et al. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996;153(6, Pt 1):1972–1976 Peled N, Kassirer M, Kramer MR, et al. Increased erythrocyte adhesiveness and aggregation in obstructive sleep apnea syndrome. Thromb Res 2008;121(5):631–636 Phillips CL, McEwen BJ, Morel-Kopp MC, et al. Effects of continuous positive airway pressure on coagulability in obstructive sleep apnoea: a randomised, placebo-controlled crossover study. Thorax 2012;67(7):639–644 von Känel R, Natarajan L, Ancoli-Israel S, et al. Effect of continuous positive airway pressure on day/night rhythm of prothrombotic markers in obstructive sleep apnea. Sleep Med 2013;14(1): 58–65 Wessendorf TE, Thilmann AF, Wang YM, Schreiber A, Konietzko N, Teschler H. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000;162(6):2039–2042 Nannapaneni S, Ramar K, Surani S. Effect of obstructive sleep apnea on type 2 diabetes mellitus: A comprehensive literature review. World J Diabetes 2013;4(6):238–244 Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999;19(4):972–978 Yadav A, Kataria MA, Saini V, Yadav A. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta 2013;417:80–84 Polotsky VY, Li J, Punjabi NM, et al. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 2003;552(Pt 1):253–264 Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring) 2011;19(11):2167–2174 Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000;118(3): 580–586

22 23

24

25

26

27 28

29

30

31

32

33

34

35

36

37

38

39

40

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57 58

59

60

Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 5/2014

539




May, Mehra

61 Cuhadaroğlu C, Utkusavaş A, Oztürk L, Salman S, Ece T. Effects of

82 Iturriaga R, Rey S, Del Río R. Cardiovascular and ventilatory

nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea. Lung 2009;187(2):75–81 Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999;100(7):706–712 Iiyori N, Alonso LC, Li J, et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 2007;175(8):851–857 Chan SL, Perrett CW, Morgan NG. Differential expression of alpha 2-adrenoceptor subtypes in purified rat pancreatic islet A- and Bcells. Cell Signal 1997;9(1):71–78 Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol (1985) 2009;106(5):1538–1544 Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004;114(12):1752–1761 Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol (1985) 2009;106(5):1538–1544 Botros N, Concato J, Mohsenin V, Selim B, Doctor K, Yaggi HK. Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med 2009;122(12):1122–1127 Strohl KP, Novak RD, Singer W, et al. Insulin levels, blood pressure and sleep apnea. Sleep 1994;17(7):614–618 Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000;85(3):1151–1158 Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002;165(5):670–676 Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE; Sleep Heart Health Study Investigators. Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 2004;160(6):521–530 Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med 2005;172(12):1590–1595 Togeiro SM, Carneiro G, Ribeiro Filho FF, et al. Consequences of obstructive sleep apnea on metabolic profile: a Population-Based Survey. Obesity (Silver Spring) 2013;21(4):847–851 Stamatakis K, Sanders MH, Caffo B, et al. Fasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation. Sleep 2008;31(7):1018–1024 Iftikhar IH, Khan MF, Das A, Magalang UJ. Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes. Ann Am Thorac Soc 2013;10(2):115–120 West SD, Nicoll DJ, Wallace TM, Matthews DR, Stradling JR. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 2007;62(11):969–974 Coughlin SR, Mawdsley L, Mugarza JA, Wilding JP, Calverley PM. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007;29(4):720–727 Vgontzas AN, Zoumakis E, Bixler EO, et al. Selective effects of CPAP on sleep apnoea-associated manifestations. Eur J Clin Invest 2008;38(8):585–595 Zwillich C, Devlin T, White D, Douglas N, Weil J, Martin R. Bradycardia during sleep apnea. Characteristics and mechanism. J Clin Invest 1982;69(6):1286–1292 Lesske J, Fletcher EC, Bao G, Unger T. Hypertension caused by chronic intermittent hypoxia—influence of chemoreceptors and sympathetic nervous system. J Hypertens 1997;15(12, Pt 2): 1593–1603

acclimatization induced by chronic intermittent hypoxia: a role for the carotid body in the pathophysiology of sleep apnea. Biol Res 2005;38(4):335–340 Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003; 107(20):2589–2594 Allahdadi KJ, Cherng TW, Pai H, et al. Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia. Am J Physiol Heart Circ Physiol 2008; 295(1):H434–H440 Narkiewicz K, Montano N, Cogliati C, van de Borne PJ, Dyken ME, Somers VK. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998;98(11):1071–1077 Kanagy NL, Walker BR, Nelin LD. Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension 2001;37(2, Pt 2):511–515 Marcus NJ, Olson EB Jr, Bird CE, Philippi NR, Morgan BJ. Timedependent adaptation in the hemodynamic response to hypoxia. Respir Physiol Neurobiol 2009;165(1):90–96 Troncoso Brindeiro CM, da Silva AQ, Allahdadi KJ, Youngblood V, Kanagy NL. Reactive oxygen species contribute to sleep apneainduced hypertension in rats. Am J Physiol Heart Circ Physiol 2007;293(5):H2971–H2976 Patel D, Mohanty P, Di Biase L, et al. Safety and efficacy of pulmonary vein antral isolation in patients with obstructive sleep apnea: the impact of continuous positive airway pressure. Circ Arrhythm Electrophysiol 2010;3(5):445–451 Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013;62(4):300–305 Owens RL, Malhotra A. Sleep-disordered breathing and COPD: the overlap syndrome. Respir Care 2010;55(10):1333–1344, discussion 1344–1346 Friedman JK, Nitta CH, Henderson KM, et al. Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 incrasing endothelin-1 vasoconstrictor reactivity. Vascul Pharmacol 2014;60(1):17–24 Leung RS. Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis 2009;51(4):324–338 Liu LC, Damman K, Lipsic E, Maass AH, Rienstra M, Westenbrink BD. Heart failure highlights in 2012-2013. Eur J Heart Fail 2014; 16(2):122–132 Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129(8):837–847 Rienstra M, Yin X, Larson MG, et al. Relation between soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I and incident atrial fibrillation. Am Heart J 2014;167(1):109–115, e2 Pedrosa RP, Drager LF, Gonzaga CC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension 2011; 58(5):811–817 Konecny T, Kara T, Somers VK. Obstructive sleep apnea and hypertension: an update. Hypertension 2014;63(2):203–209 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342(19):1378–1384 Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large communitybased study. Sleep Heart Health Study. JAMA 2000;283(14): 1829–1836 Haentjens P, Van Meerhaeghe A, Moscariello A, et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med 2007;167(8):757–764

62

63

64

65

66

67

68

69 70

71

72

73

74

75

76

77

78

79

80

81


Vol. 35

No. 5/2014

83

84

85

86

87

88

89

90

91

92

93 94

95

96

97

98 99

100

101


540

May, Mehra

102 Giles TL, Lasserson TJ, Smith BH, White J, Wright J, Cates CJ.

120 O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson

Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006;(3):CD001106 Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Clin Sleep Med 2012;8(5):587–596 Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50(2):417–423 Alajmi M, Mulgrew AT, Fox J, et al. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007;185(2):67–72 Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359(9302): 204–210 Pedrosa RP, Drager LF, de Paula LK, Amaro AC, Bortolotto LA, Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest 2013;144(5): 1487–1494 Martínez-García MA, Capote F, Campos-Rodríguez F, et al; Spanish Sleep Network. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA 2013;310(22): 2407–2415 Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289(19):2560–2572 Lévy P, Pépin JL, Arnaud C, Baguet JP, Dematteis M, Mach F. Obstructive sleep apnea and atherosclerosis. Prog Cardiovasc Dis 2009;51(5):400–410 Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 2007;175(12):1290–1297 Allahdadi KJ, Walker BR, Kanagy NL. Augmented endothelin vasoconstriction in intermittent hypoxia-induced hypertension. Hypertension 2005;45(4):705–709 Lefebvre B, Godin-Ribuot D, Joyeux-Faure M, et al. Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat. Respir Physiol Neurobiol 2006;150(2-3):278–286 Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169(3):348–353 Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96(5): 1432–1437 Nadeem R, Harvey M, Singh M, et al. Patients with obstructive sleep apnea display increased carotid intima media: a metaanalysis. Int J Vasc Med 2013;2013:839582 Chambless LE, Folsom AR, Clegg LX, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000;151(5): 478–487 Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997;146(6):483–494 Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128(4):262–269

SK Jr; Cardiovascular Health Study Collaborative Research Group. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999;340(1):14–22 Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991;11(5):1245–1249 Kuniyoshi FH, Garcia-Touchard A, Gami AS, et al. Day-night variation of acute myocardial infarction in obstructive sleep apnea. J Am Coll Cardiol 2008;52(5):343–346 Gami AS, Howard DE, Olson EJ, Somers VK. Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 2005; 352(12):1206–1214 Cuspidi C, Meani S, Valerio C, Fusi V, Zanchetti A. Nocturnal nondipping pattern in untreated hypertensives at different cardiovascular risk according to the 2003 ESH/ESC guidelines. Blood Press 2006;15(1):37–44 Eguchi K, Pickering TG, Hoshide S, et al. Ambulatory blood pressure is a better marker than clinic blood pressure in predicting cardiovascular events in patients with/without type 2 diabetes. Am J Hypertens 2008;21(4):443–450 Gorostidi M, Sobrino J, Segura J, et al; Spanish Society of Hypertension ABPM Registry investigators. Ambulatory blood pressure monitoring in hypertensive patients with high cardiovascular risk: a cross-sectional analysis of a 20,000-patient database in Spain. J Hypertens 2007;25(5):977–984 Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365(9464): 1046–1053 Lavie P, Herer P, Peled R, et al. Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep 1995;18(3):149–157 Cassar A, Morgenthaler TI, Lennon RJ, Rihal CS, Lerman A. Treatment of obstructive sleep apnea is associated with decreased cardiac death after percutaneous coronary intervention. J Am Coll Cardiol 2007;50(14):1310–1314 Milleron O, Pillière R, Foucher A, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J 2004;25(9):728–734 Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010; 122(4):352–360 Chan J, Sanderson J, Chan W, et al. Prevalence of sleep-disordered breathing in diastolic heart failure. Chest 1997;111(6): 1488–1493 Wang HQ, Chen G, Li J, et al. Subjective sleepiness in heart failure patients with sleep-related breathing disorder. Chin Med J (Engl) 2009;122(12):1375–1379 Ferrier K, Campbell A, Yee B, et al. Sleep-disordered breathing occurs frequently in stable outpatients with congestive heart failure. Chest 2005;128(4):2116–2122 Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97(21):2154–2159 Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160(4):1101–1106 Vazir A, Hastings PC, Dayer M, et al. A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction. Eur J Heart Fail 2007;9(3):243–250 Serizawa T, Vogel WM, Apstein CS, Grossman W. Comparison of acute alterations in left ventricular relaxation and diastolic

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

121

122

123

124

125

126

127

128 129

130

131

132

133

134

135

136

137

138


Vol. 35

No. 5/2014

541




139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

May, Mehra

chamber stiffness induced by hypoxia and ischemia. Role of myocardial oxygen supply-demand imbalance. J Clin Invest 1981;68(1):91–102 Sano K, Watanabe E, Hayano J, et al. Central sleep apnoea and inflammation are independently associated with arrhythmia in patients with heart failure. Eur J Heart Fail 2013;15(9): 1003–1010 Liu JN, Zhang JX, Lu G, et al. The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia. Chin Med J (Engl) 2010;123(1):74–78 Chen L, Einbinder E, Zhang Q, Hasday J, Balke CW, Scharf SM. Oxidative stress and left ventricular function with chronic intermittent hypoxia in rats. Am J Respir Crit Care Med 2005;172(7): 915–920 Hayashi T, Yamashita C, Matsumoto C, et al. Role of gp91phoxcontaining NADPH oxidase in left ventricular remodeling induced by intermittent hypoxic stress. Am J Physiol Heart Circ Physiol 2008;294(5):H2197–H2203 Parker JD, Brooks D, Kozar LF, et al. Acute and chronic effects of airway obstruction on canine left ventricular performance. Am J Respir Crit Care Med 1999;160(6):1888–1896 Wang H, Parker JD, Newton GE, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol 2007;49(15):1625–1631 Kasai T, Narui K, Dohi T, et al. Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure. Chest 2008;133(3):690–696 Arias MA, García-Río F, Alonso-Fernández A, Mediano O, Martínez I, Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation 2005;112(3):375–383 Kahwash R, Kikta D, Khayat R. Recognition and management of sleep-disordered breathing in chronic heart failure. Curr Heart Fail Rep 2011;8(1):72–79 Bradley TD, Logan AG, Kimoff RJ, et al; CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353(19):2025–2033 Arzt M, Floras JS, Logan AG, et al; CANPAP Investigators. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007;115(25):3173–3180 Yuan G, Nanduri J, Khan S, Semenza GL, Prabhakar NR. Induction of HIF-1alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2þ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol 2008;217(3):674–685 Dudley SC Jr, Hoch NE, McCann LA, et al. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 2005;112(9):1266–1273 Bayés de Luna A, Bayés Genís A, Guindo J, et al. Mechanisms favoring and triggering atrial fibrillation [in French]. Arch Mal Coeur Vaiss 1994;87(1 Spec No):19–25 Tse HF, Lau CP. Electrophysiological properties of the fibrillating atrium: implications for therapy. Clin Exp Pharmacol Physiol 1998;25(5):293–302 Lin YK, Lai MS, Chen YC, et al. Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium. Clin Sci (Lond) 2012;122(3):121–132 Mehra R, Benjamin EJ, Shahar E, et al; Sleep Heart Health Study. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173(8):910–916 Mehra R, Stone KL, Varosy PD, et al. Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009;169(12):1147–1155


Vol. 35

No. 5/2014

157 Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea,

158

159

160

161

162 163

164

165

166

167

168

169

170 171

172

173

174 175

176

177

obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49(5):565–571 Leung RS, Comondore VR, Ryan CM, Stevens D. Mechanisms of sleep-disordered breathing: causes and consequences. Pflugers Arch 2012;463(1):213–230 Simantirakis EN, Schiza SI, Marketou ME, et al. Severe bradyarrhythmias in patients with sleep apnoea: the effect of continuous positive airway pressure treatment: a long-term evaluation using an insertable loop recorder. Eur Heart J 2004;25(12):1070–1076 Harbison J, O’Reilly P, McNicholas WT. Cardiac rhythm disturbances in the obstructive sleep apnea syndrome: effects of nasal continuous positive airway pressure therapy. Chest 2000;118(3): 591–595 Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52(5):490–494 Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010;90(1):47–112 Niijima M, Kimura H, Edo H, et al. Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1999;159(6):1766–1772 Marrone O, Bonsignore MR, Romano S, Bonsignore G. Slow and fast changes in transmural pulmonary artery pressure in obstructive sleep apnoea. Eur Respir J 1994;7(12):2192–2198 Schäfer H, Hasper E, Ewig S, et al. Pulmonary haemodynamics in obstructive sleep apnoea: time course and associated factors. Eur Respir J 1998;12(3):679–684 Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 2006;99(7):675–691 Campen MJ, Shimoda LA, O’Donnell CP. Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice. J Appl Physiol (1985) 2005;99(5):2028–2035 Fagan KA. Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia. J Appl Physiol (1985) 2001;90(6):2502–2507 Nisbet RE, Graves AS, Kleinhenz DJ, et al. The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. Am J Respir Cell Mol Biol 2009;40(5): 601–609 Sajkov D, McEvoy RD. Obstructive sleep apnea and pulmonary hypertension. Prog Cardiovasc Dis 2009;51(5):363–370 Bradley TD, Rutherford R, Grossman RF, et al. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131(6):835–839 Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest 1996;109(2): 380–386 Krieger J, Sforza E, Apprill M, Lampert E, Weitzenblum E, Ratomaharo J. Pulmonary hypertension, hypoxemia, and hypercapnia in obstructive sleep apnea patients. Chest 1989;96(4): 729–737 Weitzenblum E, Chaouat A. Obstructive sleep apnea syndrome and the pulmonary circulation. Ital Heart J 2005;6(10):795–798 Weitzenblum E, Krieger J, Apprill M, et al. Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 1988;138(2):345–349 Alchanatis M, Tourkohoriti G, Kakouros S, Kosmas E, Podaras S, Jordanoglou JB. Daytime pulmonary hypertension in patients with obstructive sleep apnea: the effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration 2001;68(6):566–572 Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hypertension in patients with obstructive sleep apnea syndrome. Arch Intern Med 1997;157(21):2483–2487


542

May, Mehra

178 Arias MA, García-Río F, Alonso-Fernández A, Martínez I, Villamor

198 Li M, Hou WS, Zhang XW, Tang ZY. Obstructive sleep apnea and

J. Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure: a randomized, controlled cross-over study. Eur Heart J 2006;27(9):1106–1113 Bady E, Achkar A, Pascal S, Orvoen-Frija E, Laaban JP. Pulmonary arterial hypertension in patients with sleep apnoea syndrome. Thorax 2000;55(11):934–939 Hetzel M, Kochs M, Marx N, et al. Pulmonary hemodynamics in obstructive sleep apnea: frequency and causes of pulmonary hypertension. Lung 2003;181(3):157–166 Sajkov D, Cowie RJ, Thornton AT, Espinoza HA, McEvoy RD. Pulmonary hypertension and hypoxemia in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1994;149(2, Pt 1): 416–422 Sajkov D, Wang T, Saunders NA, Bune AJ, Neill AM, Douglas Mcevoy R. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med 1999;159(5, Pt 1):1518–1526 Sajkov D, Wang T, Saunders NA, Bune AJ, Mcevoy RD. Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2002;165(2):152–158 Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995; 151(1):82–86 Ganga HV, Nair SU, Puppala VK, Miller WL. Risk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: a retrospective cohort study. J Geriatr Cardiol 2013;10(2):129–134 Owens RL, Malhotra A, Eckert DJ, White DP, Jordan AS. The influence of end-expiratory lung volume on measurements of pharyngeal collapsibility. J Appl Physiol (1985) 2010;108(2): 445–451 Nadel JA, Widdicombe JG. Reflex effects of upper airway irritation on total lung resistance and blood pressure. J Appl Physiol 1962; 17:861–865 Resta O, Foschino Barbaro MP, Brindicci C, Nocerino MC, Caratozzolo G, Carbonara M. Hypercapnia in overlap syndrome: possible determinant factors. Sleep Breath 2002;6(1):11–18 Thun MJ, Carter BD, Feskanich D, et al. 50-year trends in smokingrelated mortality in the United States. N Engl J Med 2013;368(4): 351–364 Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010;182(3):325–331 Machado MC, Vollmer WM, Togeiro SM, et al. CPAP and survival in moderate-to-severe obstructive sleep apnoea syndrome and hypoxaemic COPD. Eur Respir J 2010;35(1):132–137 Nobili L, Schiavi G, Bozano E, De Carli F, Ferrillo F, Nobili F. Morning increase of whole blood viscosity in obstructive sleep apnea syndrome. Clin Hemorheol Microcirc 2000;22(1):21–27 Harbison J, Gibson GJ, Birchall D, Zammit-Maempel I, Ford GA. White matter disease and sleep-disordered breathing after acute stroke. Neurology 2003;61(7):959–963 Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med 2010;6(2): 131–137 Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353(19):2034–2041 Mooe T, Franklin KA, Holmström K, Rabben T, Wiklund U. Sleepdisordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001;164(10, Pt 1): 1910–1913 Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apneahypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010;182(2):269–277

risk of stroke: a meta-analysis of prospective studies. Int J Cardiol 2014;172(2):466–469 Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest 1990;97(1):27–32 Ryan CM, Bayley M, Green R, Murray BJ, Bradley TD. Influence of continuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea. Stroke 2011; 42(4):1062–1067 Bravata DM, Concato J, Fried T, et al. Continuous positive airway pressure: evaluation of a novel therapy for patients with acute ischemic stroke. Sleep 2011;34(9):1271–1277 Martínez-García MA, Soler-Cataluña JJ, Ejarque-Martínez L, et al. Continuous positive airway pressure treatment reduces mortality in patients with ischemic stroke and obstructive sleep apnea: a 5-year follow-up study. Am J Respir Crit Care Med 2009;180(1):36–41 Xie H, Yung WH. Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brainderived neurotrophic factor. Acta Pharmacol Sin 2012;33(1):5–10 Bucks RS, Olaithe M, Eastwood P. Neurocognitive function in obstructive sleep apnoea: a meta-review. Respirology 2013; 18(1):61–70 Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci 2001;21(7):2442–2450 Row BW, Kheirandish L, Neville JJ, Gozal D. Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia. Pediatr Res 2002;52(3):449–453 Goldbart A, Cheng ZJ, Brittian KR, Gozal D. Intermittent hypoxia induces time-dependent changes in the protein kinase B signaling pathway in the hippocampal CA1 region of the rat. Neurobiol Dis 2003;14(3):440–446 Gozal D, Row BW, Gozal E, et al. Temporal aspects of spatial task performance during intermittent hypoxia in the rat: evidence for neurogenesis. Eur J Neurosci 2003;18(8):2335–2342 Kheirandish L, Row BW, Li RC, Brittian KR, Gozal D. Apolipoprotein E-deficient mice exhibit increased vulnerability to intermittent hypoxia-induced spatial learning deficits. Sleep 2005; 28(11):1412–1417 Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 2003;167(11): 1548–1553 Lal C, Strange C, Bachman D. Neurocognitive impairment in obstructive sleep apnea. Chest 2012;141(6):1601–1610 Quan SF, Chan CS, Dement WC, et al. The association between obstructive sleep apnea and neurocognitive performance—the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2011;34(3):303–314B Kushida CA, Nichols DA, Holmes TH, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35(12):1593–1602 Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 2003;26(3): 298–307 Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D. Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review. J Int Neuropsychol Soc 2004;10(5):772–785 Naismith S, Winter V, Gotsopoulos H, Hickie I, Cistulli P. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol 2004;26(1):43–54 Bartlett DJ, Rae C, Thompson CH, et al. Hippocampal area metabolites relate to severity and cognitive function in obstructive sleep apnea. Sleep Med 2004;5(6):593–596

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

199

200

201

202

203

204

205

206

207

208

209

210

211 212

213

214

215

216

217


Vol. 35

No. 5/2014

543




May, Mehra

218 Weng HH, Tsai YH, Chen CF, et al. Mapping gray matter reductions

227 Dewhirst MW. Intermittent hypoxia furthers the rationale for

in obstructive sleep apnea: an activation likelihood estimation meta-analysis. Sleep 2014;37(1):167–175 Hatipoğlu U, Rubinstein I. Inflammation and obstructive sleep apnea syndrome: how many ways do I look at thee? Chest 2004; 126(1):1–2 Hopkins RO, Kesner RP, Goldstein M. Memory for novel and familiar spatial and linguistic temporal distance information in hypoxic subjects. J Int Neuropsychol Soc 1995;1(5): 454–468 Kesner RP, Hopkins RO. Short-term memory for duration and distance in humans: role of the hippocampus. Neuropsychology 2001;15(1):58–68 Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166(10):1382–1387 Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 2002;11(1):1–16 Canessa N, Castronovo V, Cappa SF, et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am J Respir Crit Care Med 2011;183(10): 1419–1426 Toffoli S, Michiels C. Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours. FEBS J 2008; 275(12):2991–3002 Liu Y, Song X, Wang X, et al. Effect of chronic intermittent hypoxia on biological behavior and hypoxia-associated gene expression in lung cancer cells. J Cell Biochem 2010;111(3):554–563

hypoxia-inducible factor-1 targeting. Cancer Res 2007;67(3): 854–855 Cairns RA, Kalliomaki T, Hill RP. Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 2001; 61(24):8903–8908 Almendros I, Montserrat JM, Torres M, et al. Intermittent hypoxia increases melanoma metastasis to the lung in a mouse model of sleep apnea. Respir Physiol Neurobiol 2013;186(3):303–307 Yamauchi M, Nakano H, Maekawa J, et al. Oxidative stress in obstructive sleep apnea. Chest 2005;127(5):1674–1679 Almendros I, Wang Y, Becker L, et al. Intermittent hypoxiainduced changes in tumor-associated macrophages and tumor malignancy in a mouse model of sleep apnea. Am J Respir Crit Care Med 2014;189(5):593–601 Gharib SA, Seiger AN, Hayes AL, Mehra R, Patel SR. Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes. Sleep 2014;37(4):709–714, 714A–714T Christensen AS, Clark A, Salo P, et al. Symptoms of sleep disordered breathing and risk of cancer: a prospective cohort study. Sleep 2013;36(10):1429–1435 Campos-Rodriguez F, Martinez-Garcia MA, Martinez M, et al; Spanish Sleep Network. Association between obstructive sleep apnea and cancer incidence in a large multicenter Spanish cohort. Am J Respir Crit Care Med 2013;187(1):99–105 Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farré R. Sleepdisordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2012; 186(2):190–194

219

220

221

222

223

224

225

226


Vol. 35

No. 5/2014

228

229

230 231

232

233

234

235


544

Intermittent hypoxia for obstructive sleep apnea?

Correction of intermittent hypoxia reduces inflammation in obese subjects with obstructive sleep apnea.

Obstructive sleep apnea and intermittent hypoxia increase expression of dual specificity phosphatase 1.

Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach.

Simulating obstructive sleep apnea patients' oxygenation characteristics into a mouse model of cyclical intermittent hypoxia.

The role of high loop gain induced by intermittent hypoxia in the pathophysiology of obstructive sleep apnea.

Effect of ovariectomy on inflammation induced by intermittent hypoxia in a mouse model of sleep apnea.

Obstructive Sleep Apnea: Role of an Otorhinolaryngologist.

Roles and Mechanisms of Obstructive Sleep Apnea-Hypopnea Syndrome and Chronic Intermittent Hypoxia in Atherosclerosis: Evidence and Prospective.

White matter damage and systemic inflammation in obstructive sleep apnea.

Relationship between chronic intermittent hypoxia and intraoperative mean arterial pressure in obstructive sleep apnea patients having laparoscopic bariatric surgery.

Morning pentraxin3 levels reflect obstructive sleep apnea-related acute inflammation.

Early intermittent hypoxia induces proatherogenic changes in aortic wall macrophages in a murine model of obstructive sleep apnea.

Hippocampal mitogen-activated protein kinase activation is associated with intermittent hypoxia in a rat model of obstructive sleep apnea syndrome.

Obstructive sleep apnea.

Obstructive sleep apnoea syndrome: a new paradigm by chronic nocturnal intermittent hypoxia and sleep disruption.

Breaking barriers in obstructive sleep apnea. Focus on "Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation".

Familial obstructive sleep apnea.

Asthma and Obstructive Sleep Apnea.

The role of physical exercise in obstructive sleep apnea.

Diagnosis and treatment for obstructive sleep apnea: Fundamental and clinical knowledge in obstructive sleep apnea.

Mechanisms of obstructive sleep apnea.

Obstructive Sleep Apnea: Women's Perspective.

Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea.