American Journal of Respiratory and Critical Care Medicine

The field of sleep-disordered breathing has continued to evolve. In this review, we have summarized some of the key articles relevant to sleep-disordered breathing that have been published in the Journal and selected articles published elsewhere in the last year.

The Multifactorial Nature of Obstructive Sleep Apnea and Measuring Phenotypic Traits

An anatomical predisposition is necessary for obstructive sleep apnea (OSA). In some cases, the upper airway is so collapsible that this is sufficient alone to cause disease. But in many cases, other factors determine whether an individual with vulnerable anatomy develops OSA or achieves stable breathing. Thus, it is recognized increasingly that OSA is a multifactorial disorder. Many patients, even those with moderate to severe disease, do not have an extremely collapsible upper airway that would inevitably lead to OSA (1). Instead, many patients have a vulnerable anatomy paired with other traits such as weak upper airway muscles (muscles that do not effectively maintain airway patency), unstable control of breathing (which can lead to times of low output to the upper airway muscles), or a low respiratory arousal threshold (the subject wakes up before achieving muscle recruitment and stable breathing) that together predispose them to OSA (2). It is hoped that understanding the underlying pathophysiology in an individual will lead to personalized or “targeted” therapy for OSA.

One of the limitations to this approach is the difficulty in measuring these traits in individuals. An additional night of monitored sleep, specialized equipment that can vary the airway pressure precisely, and mathematical modeling tools are all required to “phenotype” patients and have prohibited wider acceptance. Thus, the ability to easily determine the traits, ideally from a clinical study, is needed. Edwards and colleagues have taken the first step forward (3). They used their cohort of more than 100 fully phenotyped patients with OSA and control subjects to try to define markers of the respiratory arousal threshold (ArTH), defined as the negative intrathoracic pressure that precedes cortical arousal from sleep. In a hypothesis-driven approach, they identified three factors from the clinical polysomnogram (PSG) that identified subjects with a low ArTH: apnea–hypopnea index (AHI) less than 30 events/hour; nadir oxygen saturation greater than 82.5%; and fraction of all respiratory events that are hypopneas greater than 58.3%. Meeting two or more of these criteria correctly predicted a low ArTH with a sensitivity and specificity of 80 and 88%, respectively, which was maintained across a wide range of OSA severity. Based on these criteria, patients with mild OSA were more likely to have a low ArTH; however, there were still many subjects with severe OSA who also had a low arousal threshold. The accompanying editorial by Decker and colleagues lauded this general concept to “use the clinical PSG not only as an AHI generator but as a tool to reveal mechanisms in the individual patient” (4).

Other traits might also be obtainable from baseline studies, such as measures of ventilatory control (5). In an unrelated editorial, Kirkness showed how REM AHI correlated strongly with the pharyngeal closing pressure (Pcrit), a useful measure of upper airway collapsibility that is measured only in select research laboratories (6). The potential ability to determine important traits from clinical studies is exciting. Although the concept is currently speculative, this may eventually open up the possibility of targeted therapy based on phenotypic traits. For example, one might consider treatment with a sedative hypnotic in patients with a low respiratory arousal threshold (7) and avoid these drugs in patients who already have a high arousal threshold. Another challenge to this approach is that much of the work to date has been performed using in-laboratory or physiological research studies. Given trends in OSA diagnosis, trait measurement will need to be validated with portable sleep monitoring equipment.

The Upper Airway Muscles

Besides anatomy, perhaps the single most important trait is the effectiveness of upper airway muscles. Patil and colleagues previously measured passive and active pharyngeal closing pressures of the upper airway in subjects with and without OSA, matched for age, sex, and body mass index (BMI) (8). They determined that patients with OSA had two “hits”—both poor anatomy and ineffective muscles. In the past year, Sands and colleagues put a slightly different spin on this two-hit hypothesis (9). They measured anatomy and muscle responsiveness in three groups: normal-weight nonapneics (n = 11), overweight and obese subjects without OSA (n = 18), and overweight and obese subjects with OSA (n = 25). Obese subjects with OSA had normal, not deficient, upper airway (UA) muscle responsiveness. In fact, those obese subjects without OSA had robust responses that protected them from OSA. Although the size of the study was relatively modest, these results suggest that robust UA responses can protect against OSA.

One way to augment UA muscle responsiveness is via direct nerve stimulation. Strollo and colleagues published the results of an uncontrolled trial with an implantable device that showed, on average, a substantial reduction in OSA severity (26.3 vs. 9.0 events/h) in 126 patients (10). Similar to an implantable pacemaker, the device can sense respiratory effort and then stimulates the hypoglossal nerve to activate the genioglossus muscle and drive the tongue forward (hypoglossal nerve stimulator). It is important to note that these patients were carefully selected and that the results in individual patients were quite heterogeneous, including some patients who worsened with therapy. Because one-third of patients failed to improve, acceptance of this type of device will require better understanding of predictors of treatment success or failure. In general, the adoption of non–positive airway pressure therapies, such as hypoglossal nerve stimulators, oral appliances, and oral suction devices, is hampered by the variability in response—this variability will need to be examined.

Given the importance of the upper airway muscles, understanding why they fail to hold the airway open during sleep is critical. One model of OSA assumes that essentially normal muscles work harder (as measured by EMG) during wakefulness to hold open a collapsible airway, but with sleep, this protective reflex is lost. Consistent with this model is the finding of increased tongue fat in subjects with OSA compared with matched control subjects, which may reduce the tongue’s contractile force for a given neuronal stimulation (11). Another possibility, however, is that repetitive collapse, injury, edema, and/or hypoxemia lead to progressive UA muscle dysfunction over time. Kim and colleagues used fluorodeoxyglucose positron emission tomography imaging to measure the metabolic activity of the tongue in more than 100 obese patients with and without OSA (12). Surprisingly, despite prior reports of increased EMG activity in those with OSA, the metabolic activity of the subjects with OSA was reduced compared with control subjects. The authors suggested that denervation–reinnervation of the tongue muscle, as might occur with repetitive injury, could explain these results, although so too might previously described changes in tongue muscle fiber type. This longstanding controversy is well summarized in the accompanying editorial by O’Hallaron, and might be resolved only with measures of UA muscle mechanical effectiveness in future studies (13).

Neurophysiology of Arousal

Arousal from sleep is obviously life-saving in patients with OSA. However, it may also contribute to some of the adverse health consequences of the disease. Understanding the physiology of arousal is thus important. The rostral ventrolateral medulla contains the C1 neurons; these neurons were previously thought to regulate blood pressure selectively. This interpretation seemed excessively narrow given that the C1 neurons also innervate CNS nuclei known to participate in breathing, stress responses, and the control of vigilance. The possibility that the C1 neurons might produce arousal was addressed in an elegant study by Burke and colleagues (14). Using transgenic rats, the investigators were able to selectively activate these neurons using light (optogenetics). C1 neuron activation caused EEG desynchronization and cardiorespiratory stimulation (increased blood pressure, tachypnea, sighs) in non-REM sleep and quiet resting; in REM sleep, blood pressure was increased but EEG arousal and respiratory excitation did not occur. In other words, stimulation of the C1 neurons in non-REM sleep reproduced the physiological effects seen in acute hypoxia. Because the C1 neurons are vigorously activated by hypoxia, these results raise the possibility that these neurons contribute to the cardiovascular and arousal responses in patients with sleep apnea.

Sleep Apnea and Metabolic Disease (Renal Dysfunction and Diabetes)

It is being increasingly recognized that sleep apnea may accelerate the loss of kidney function (15). The potential mechanisms of renal damage from OSA are unclear, but activation of the renin–angiotensin system (RAS) has been proposed as one contributor. Nicholl and colleagues examined the potential effects of OSA by studying the effects of continuous positive airway pressure (CPAP) on renal hemodynamics and the RAS (16). Twenty normotensive patients with OSA were studied before and after CPAP with measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF, a surrogate marker of intraglomerular pressure). CPAP had significant beneficial renal physiological effects with a reduction in GFR, increased RPF, and reduced FF. Furthermore, blood pressure, aldosterone levels, and urinary protein excretion also improved. The greater RPF responses to angiotensin after CPAP suggested that RAS activity was also reduced by CPAP. Although highly interesting from a mechanistic standpoint, the applicability of these results to clinical practice is unclear as the patients had normal GFR, were on high-salt diets, and were not taking medications that affect the RAS (17). It would be interesting to see whether OSA treatment has a renoprotective effect in patients with preexisting kidney impairment.

Although patients with OSA have a high prevalence of diabetes, whether OSA is an independent predictor is unclear. Kendzerska and colleagues tried to address this issue by studying a large cohort (n = 8,678) of patients referred for a sleep study followed over time and linked to an administrative database (18). Over a median follow-up of 67 months, 9.1% developed incident diabetes. After adjustment for confounders including BMI, patients with an AHI greater than 30/hour had a 30% increased hazard for developing diabetes. These findings are consistent with animal and human studies that have demonstrated insulin resistance with experimentally induced intermittent hypoxia (19). CPAP treatment was not associated with a reduction in diabetes risk in this study, but this may have been due to limitations in ascertaining CPAP use with the administrative database. As mentioned in an editorial by Bakker and Patel (19), patients with OSA are at high risk of developing diabetes and they should at the least be counseled on interventions focused on reducing this risk (such as weight loss).

Sleep Apnea and Vascular Disease

The pattern of sleep-disordered breathing might confer different cardiovascular risks. Mokhlesi and colleagues examined the impact of REM sleep apnea on both the prevalence and incidence of hypertension, using data from a community-based cohort (n = 1,451) (20). REM AHI was significantly associated with both prevalent and incident hypertension whereas non-REM AHI was not. Specifically, the odds ratio for developing hypertension in patients with an REM AHI equal to or greater than 15/hour (compared with REM AHI < 1) was 1.77 (95% confidence interval [CI], 1.08–2.92); interestingly, even in patients with a non-REM AHI not exceeding 5/hour, an REM AHI equal to or greater than 15/hour was associated with increased odds of hypertension. This study highlights the need to improve the personalization of OSA therapy by better characterizing the patient’s physiology, a similar theme to the previous discussion about OSA pathophysiology (21). Although speculative, in patients with REM-predominant OSA, consideration of ensuring greater CPAP adherence at the end of the night should be considered.

There are accumulating data implicating OSA as a risk factor for the development of cardiovascular and cerebrovascular disease. However, many of the studies have consisted mostly of men. Campos-Rodriguez and colleagues studied the association between OSA and incident stroke or coronary heart disease in a group of 967 women referred for suspected OSA in Spain (22). Over a median follow-up of 6.8 years, the hazard ratio for the composite outcome was 2.75 (95% CI, 1.35–5.62) for the untreated OSA group (AHI ≥ 10/h) compared with 0.91 (0.43–1.95) for the group treated with CPAP when compared with control subjects without OSA. This study adds to the growing body of observational evidence that OSA is associated with cardiovascular and cerebrovascular disease, and that CPAP mitigates the increased risk (23).

Two randomized controlled trials involving cardiovascular biomarkers were published in the New England Journal of Medicine in 2014. In a study by Gottlieb and colleagues, 318 patients with cardiovascular disease or underlying cardiovascular risk factors were recruited from cardiology clinics (24). Patients with an AHI between 15 and 50/hour by ambulatory study were randomized to education alone (control), education with CPAP, or education with supplemental oxygen. After 12 weeks, patients who received CPAP had significantly greater reduction in 24-hour mean blood pressure compared with both control and oxygen groups (by 2.4 and 2.8 mm Hg, respectively); there was no significant difference between the oxygen and control groups. The C-reactive protein level was also reduced in the CPAP group. CPAP adherence was relatively low in the study (mean, 3.5 h per night), perhaps partially because the patients were recruited from a cardiology clinic and may not have been as symptomatic as a sleep clinic population. The lack of reduction in blood pressure with oxygen was somewhat surprising; other mechanisms such as arousal, hypercapnia, and intrathoracic pressure swings might play a role in the blood pressure response to apnea, but this is speculative.

In another study published in the same issue, Chirinos and colleagues randomly assigned 181 patients with obesity (BMI > 30 kg/m2), moderate to severe OSA, and increased C-reactive protein to a weight loss intervention, CPAP, or both CPAP and a weight loss intervention for 24 weeks (25). One hundred and forty-six patients had follow-up data. Weight declined in the weight loss alone group and in the weight loss and CPAP group (6.8 and 7.0 kg, respectively) but not in the CPAP group. CPAP alone did not significantly reduce C-reactive protein, insulin resistance, or triglyceride levels, but they were all significantly reduced in the other two groups. However, the addition of CPAP to weight loss did not confer an additional significant benefit to weight loss alone. Blood pressure was reduced in all three groups, but the effect was greatest in the combined group (reduction in systolic pressure, 14.1 mm Hg) compared with either weight loss (6.8 mm Hg) or CPAP alone (3.0 mm Hg). How these data should be used in clinical practice is unclear, and longer term randomized studies in this field are sorely needed.

Sleep-disordered Breathing in Specific Populations

One issue concerns whether we need to direct our attention to more vulnerable patient populations. As noted previously, detecting and treating sleep-disordered breathing (SDB) in diabetics, hypertensive patients, and patients at risk of renal disease might be considered a priority. A study by Redline and colleagues suggests that we should also consider certain ethnic groups as particularly vulnerable (26). In their study of 14,440 individuals of Hispanic/Latino background as part of the Hispanic Community Health Study, moderate to severe SDB (AHI ≥ 15/h) was found in 9.8%. However, only 1.3% of participants reported a physician diagnosis of sleep apnea (5% of those with an AHI ≥ 15/h), suggesting a large proportion of undiagnosed SDB. In addition, an AHI of at least 15/hour was significantly associated with impaired glucose tolerance (odds ratio, 1.7), diabetes (odds ratio, 2.3), and hypertension (odds ratio, 1.4) even after controlling for BMI. This highlights that the prevalence of SDB in this population is high, underdiagnosed, and associated with a variety of cardiovascular risk factors including obesity, diabetes, and hypertension.

In an interesting study by Patil and colleagues, sleep studies were performed in a subset of subjects from the Multicenter AIDS Cohort Study, an ongoing prospective study of homosexual and bisexual men designed to study the natural and treated histories of HIV infection (27). The prevalence of SDB (defined as an AHI ≥ 5/h) was high in HIV-positive men (71% in those who were using highly active retrovirals; 73% in those not receiving highly active antiretroviral therapy [HAART]) and was associated with sleepiness but not fatigue. Lipohypertrophy was also significantly associated with SDB. However, the prevalence in the HIV-negative men was also high (87%), although this was not significantly greater than in the other groups after controlling for confounders. Although the high rate in this cohort overall might have been partially explained by the nature of recruitment (potential subjects were contacted by mail and asked to participate) potentially leading to a selection bias, further studies are needed to confirm and explain the high prevalence in this population.

From the treatment standpoint, McMillan and colleagues completed a randomized controlled trial of CPAP versus supportive care in 278 older patients (age, ≥65 yr) with OSA (28). In this multicenter study, patients were randomized to CPAP with best supportive care, or best supportive care alone for 12 months. The Epworth Sleepiness Scale score was significantly reduced in the CPAP group compared with the control group (by 2.0 points at 12 mo). CPAP also improved objective sleepiness, mobility, and cholesterol levels at 3 months, but these were not sustained over 12 months. CPAP was also found to be marginally more cost effective. As such, CPAP should be offered to appropriate elderly patients with OSA.

Sleep Apnea and Cancer

The previous update in Sleep Medicine reviewed studies from 2013 that highlighted the potential links between cancer and sleep apnea (29). In 2014, more studies have been published on this subject. First, Almendros and colleagues (30) exposed 80 mice to either experimentally induced intermittent hypoxia or intermittent air. After 2 weeks, epithelial tumor cells were injected into the flank. After 4 weeks, compared with mice exposed to room air, mice exposed to intermittent hypoxia had increased tumor growth, and more muscle invasion. In addition, tumor-associated macrophages from the mice exposed to intermittent hypoxia demonstrated a shift toward a protumoral phenotype, with increased effects on tumor migration and extravasation.

The findings from this animal study are consistent with the deleterious effect of OSA on tumor growth, and are consistent with two other studies in 2014. In one study, a significant relationship was found between melanoma aggressiveness and sleep apnea severity in 82 patients diagnosed with cutaneous melanoma (31). In another study, 5,427 patients with suspected OSA were studied for a median of 4.5 years. Of them, 9.7% developed cancer. The percentage of sleep time spent below 90% oxygen saturation was significantly associated with cancer mortality, especially in patients younger than 65 years of age (32).

However, another epidemiologic study was not able to confirm the link between sleep apnea and cancer. In a study from Canada, 9,629 patients who underwent a sleep study for suspected sleep apnea and did not have cancer at baseline were monitored for cancer incidence, using administrative health data. In this study, severity of sleep apnea was not significantly associated with cancer incidence after controlling for a variety of confounders including age, sex, BMI, and smoking (33).

Evidence on the morbid consequences of pediatric OSA has continued to emerge with increased focus on the potential mechanisms that may underlie such adverse outcomes, with particular emphasis on cognitive, cardiovascular, and metabolic systems. Because of the initial observations raising the potential concurrence of cognitive and vascular dysfunction in children with OSA (34), the potential links between disrupted processing of autonomic signals and neurocognitive outcomes prompted Immanuel and collaborators (35) to investigate associations between heart beat evoked cortical potentials (HEPs) during sleep in healthy children and in children with SDB before and after treatment. In their elegant study, they reported that children with OSA manifested reduced HEP responses, particularly during non-REM sleep, and that individual HEP amplitudes and behavioral scores were inversely correlated. Furthermore, treatment of OSA by adenotonsillectomy led to the reversal of the altered neural processing of interoceptive autonomic stimuli. These findings promote the possibility that OSA-induced abnormalities in central and peripheral autonomic regulation (36) may either provide correlates of other cognitive and behavioral functions, or alternatively reflect the vulnerabilities and functional interdependencies of these two systems in the context of sleep-disordered breathing.

The overall obesity pandemic has not spared the pediatric age range. In this perspective, we have witnessed the increased prevalence of OSA among obese children (37). One of the worrisome consequences of obesity is the appearance of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), whereby a two-hit hypothesis, in which obesity constitutes one of the two hits, has been proposed (38). As a corollary to the significant adverse interactions between obesity and OSA, Nobili and colleagues prospectively evaluated sleep patterns among 65 of 66 consecutive obese children with abnormally elevated alanine aminotransferase (ALT) and NAFLD, a frequent occurrence in obese children with OSA, and performed a diagnostic liver biopsy for suspected NASH (39). In their cohort, 60% of children with NAFLD had concurrent OSA, and the prevalence of OSA in children with NASH was higher than in those without biopsy evidence of NASH. Indeed, 34 (87%) subjects with OSA had NASH (vs. 8% of children without OSA; P = 0.00001). Notably, the severity of OSA, particularly that of hypoxemia, was associated with biochemical and histological measures of NAFLD both by Nobili and colleagues and by Sundaram and colleagues (40). In addition, as previously shown in the Journal (41), obese children with OSA were significantly more likely to manifest features of metabolic syndrome. In an accompanying editorial, Van Hoorenbeeck and Verhulst further emphasized the urgent need for interventional studies (e.g., antioxidants, probiotics) aimed at reducing the risk of NASH in this highly susceptible population, as well as the unique opportunity afforded by the OSA–NASH association to identify genotype–phenotype and environmental determiners of susceptibility (42).

Finally, the impact of adenotonsillectomy treatment on specific risk factors associated with pediatric OSA revealed intriguing and potentially clinically important findings. In a sequel analysis of the original randomized controlled trial on adenotonsillectomy in pediatric OSA (Childhood Adenotonsillectomy Trial [CHAT; 43]), Katz and colleagues pointed to the excessive increases in weight trajectories exhibited by children subject to adenotonsillectomy for treatment of their underlying OSA (44). Such findings suggest the possibility that some of the treated children may be at increased risk for recurrence of SDB and cardiometabolic morbidities due to the exaggerated increases over time in BMI. Notwithstanding, the beneficial effects of adenotonsillectomy have also emerged in the context of asthma in children, whereby asthmatic children who underwent this surgical procedure, most likely for underlying SDB, exhibited not only more severe clinical phenotype before surgery but also showed marked improvements in their asthma control after adenotonsillectomy (45).

Over the last year, the field of sleep-disordered breathing has continued to evolve and much has been learned about the pathophysiology, epidemiology, treatment, and health consequences of both pediatric and adult sleep apnea. For example, we are becoming increasingly aware of the potential multifactorial nature of obstructive sleep apnea, and drawing closer to potentially being able to measure specific phenotypic traits in the disease. Although more work needs to be done before more widespread clinical acceptance, hypoglossal nerve stimulation has been shown to be effective in some patients with OSA. The beneficial impact of CPAP on elderly patients is better understood, as well as the benefits of adenotonsillectomy in children with OSA. The potential interactions between OSA and a variety of other disorders including renal disease, liver disease, HIV, cancer, and cardiovascular disease are being increasingly recognized. We look forward to more excellent work, which will undoubtedly be published over the upcoming year.

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Correspondence and requests for reprints should be addressed to Najib T. Ayas, M.D., M.P.H., Divisions of Respiratory and Critical Care Medicine, Department of Medicine, Diamond Centre, University of British Columbia, Vancouver, BC, V5Z 1M9 Canada. E-mail:

Author disclosures are available with the text of this article at www.atsjournals.org.

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