The objective of this review is to identify significant contributions to the field of sleep medicine in the preceding year. Four “representative” articles will be discussed to highlight the spectrum of contributions including: 1) a genetic risk factor for periodic limb movement disorder (PLMD) and restless leg syndrome (RLS),1 2) metabolic dysregulation in sleep-disordered breathing among adolescents,2 3) the effects of CPAP on early signs of atherosclerosis in obstructive sleep apnea,3 and 4) sleep-disordered breathing and mortality in the 18-year follow-up of the Wisconsin Sleep Cohort.4
A GENETIC RISK FACTOR FOR PERIODIC LIMB MOVEMENTS
Restless leg syndrome is manifested by uncomfortable and often distressful sensations in the legs during rest, and sleep is often interrupted by highly stereotypic and regularly occurring periodic limb movements. A familial predisposition has been well documented in these syndromes, but until now, no gene has been identified.
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The study by Stefansson and colleagues1 focuses on patients (and their first degree relatives) with RLS assessed by a validated questionnaire who also had documented periodic limb movements in sleep using a portable monitor as an objective physiologic metric. The study utilized an Icelandic discovery sample and was replicated in a second Icelandic sample as well as a US sample. A significant genome-wide association was observed between RLS with PLMD and a common variant in an intron of the BTBD9 domain on chromosome 6p21.2 (odds ratio = 1.8, P = 2×10-9). This was replicated in the other independent samples. With this common variant, the population attributable risk (the proportion of disease in these populations that is due to the genetic variant) was 50%, which is very high. Interestingly, a simultaneously published report by Winkelmann and colleagues5 showed an association between RLS and the same sequence variant as well as two additional polymorphisms in both German and Canadian cohorts, making this finding more secure.
Closer inspection of the data from Stefansson and colleagues, however, shows that the genetic variant identified does not appear to be a gene for RLS but rather for periodic limb movements in sleep. The investigators observed the highest risk among patients with just periodic limb movements, and this association disappeared completely in subjects with RLS without periodic limb movements. Also of interest, none of the genetic regions identified by Winkelmann or Stefansson are known to be involved in dopaminergic transmission, which has been directly implicated in the underlying pathogenesis of both RLS and PLMD. However, Stefansson and colleagues did find an association between the presence of the genetic variant and lower ferritin levels, implicating the genetic variant in iron storage. Iron is a cofactor for tyrosine hydroxylase, which is an important enzyme implicated in dopamine synthesis.
The clinical implications of this work include the high population attributable risk, a new explanation for some of the familial clustering in RLS and PLMD, the potential to improve diagnostic accuracy, and the hope that the pathophysiology of this disorder will be better understood, which may lead to future durable therapies. The strengths of this study are the use of an objective physiologic metric, large sample size with appropriate statistical corrections for the large number of statistical tests performed, and the findings were replicated in independent samples. Important unanswered questions include: Does a genetic factor for periodic limb movement disorder exist outside of restless leg syndrome? What is the functional significance of the genetic factor identified? Does the variant allele identify a clinical subgroup with a differential response to various treatments (eg, dopamine agonists, iron, opiates)? And finally, are these polymorphisms related to the age of onset of RLS/PLMD?
ASSOCIATION BETWEEN METABOLIC SYNDROME AND SDB IN ADOLESCENTS
Another investigation published this past year did help to clarify the age of onset of a different sleep-associated morbidity by examining the association between sleep-disordered breathing and metabolic syndrome among adolescents.2 The metabolic syndrome is a cluster of risk factors in individuals who often progress to type 2 diabetes and premature cardiovascular disease. Impaired sleep, in the form of sleep restriction or sleep-disordered breathing, has been linked to metabolic dysregulation among adults.6-9 It has not been established whether sleep-disordered breathing is associated with metabolic syndrome among children.
The study by Redline and colleagues is a cross-sectional analysis of a community-based sample of 270 adolescents who underwent overnight polysomnography.2 Direct measurements of metabolic parameters were also obtained and the metabolic syndrome was defined based on adult criteria adapted to a pediatric population.10 Nearly 20% of this adolescent sample met criteria for metabolic syndrome. After adjusting for age, race, sex, and preterm status, children with sleep-disordered breathing (defined as an AHI Ž5) had significantly increased odds of metabolic syndrome compared to children without sleep-disordered breathing (odds ratio = 6.49; 95% CI 2.52-16.7). Severity of oxygen desaturation was a strong predictor of this risk. Even after adjusting for body mass index (BMI), the group with sleep-disordered breathing was observed to have significantly higher levels of key components of the metabolic syndrome including systolic and diastolic blood pressure, LDL, and fasting insulin levels. The strong association between metabolic syndrome and sleep-disordered breathing is a novel finding among adolescents where it has the potential to alter physiology at potentially critical developmental stages, and, if the exposure is persistent, alter long-term health profiles. The association observed between key components of the metabolic syndrome and sleep-disordered breathing (independent of BMI) suggests that sleep-disordered breathing may contribute to metabolic dysfunction beyond the effects of overweight and obesity. The strong association between various measures of sleep-related oxygen desaturation suggests that the relationship between sleep-disordered breathing and metabolic dysregulation may in part be mediated through hypoxic stress.
The strengths of this study include the use of a community-based sample, full overnight polysomnography to define sleep-disordered breathing, and direct measurement of key components of the metabolic syndrome. Limitations include the low range of sleep apnea severity, the potential for residual confounding with central obesity, and the cross-sectional study design, which prevents a precise assessment of the “causal” role of sleep-disordered breathing in the pathogenesis of metabolic syndrome.
EFFECTS OF CPAP ON EARLY SIGNS OF ATHEROSCLEROSIS IN OSA
In contrast to largely cross-sectional analyses linking sleep-disordered breathing to the metabolic syndrome, there have been a number of prospective studies that have independently linked sleep apnea to cardiovascular outcomes.11-14 In addition, physiologic studies suggest that sleep apnea provides a substrate for the development of atherosclerosis through a variety of mechanisms including intermittent hypoxia, oxidative stress, inflammation, endothelial dysfunction, sympathetic activation, and negative intrathoracic pressure.15 However, the gap in knowledge that exists between cause and effect with respect to cardiovascular outcomes and sleep apnea is treatment studies. The paper published by Drager and colleagues3 this past year provides evidence that helps to begin to fill this gap. From 400 patients with severe OSA, the investigators enrolled 24 patients free of cardiovascular and metabolic comorbidity. They randomized these 24 patients to CPAP versus no CPAP. At baseline and after 4 months, multiple vascular parameters were measured including carotid intima-media thickness (primary outcome), arterial stiffness, carotid diameter, 24-hour blood pressure, lipid profiles, c-reactive protein, and catecholamines. There was excellent CPAP compliance, no losses to follow-up, and no significant differences in vascular parameters at baseline. After 4 months of CPAP therapy, there was a 9% reduction in carotid intima-media thickness, and a 10% reduction in carotid-to-femoral pulse wave velocity as a measure of arterial stiffness. Importantly, with these reductions in vascular parameters, there were no concurrent changes in weight, lipid levels, or blood pressure (patients were normotensive at baseline). However, the improvements in vascular parameters were associated with reductions in markers of inflammation and sympathetic activation as evaluated by c-reactive protein and catecholamines, respectively.
How valid are carotid intima-media thickness and pulse wave velocity as an early sign of atherosclerosis? It turns out that they are fairly robust. They correlate well with histologic evidence of subclinical atherosclerosis,16 and are associated with increased risk of atherosclerotic and cardiovascular disease.17,18
There are significant clinical implications to this work. First, it provides evidence that obstructive sleep apnea may contribute to the causation of atherosclerosis. Treatment with CPAP resulted in a regression of atherosclerosis in the absence of changes in blood pressure and lipid profile but in association with measures of decreased sympathetic activity and inflammation. Second, the magnitude of this regression was similar to that of lipid-lowering agents.19 Finally, these findings also imply that treatment of sleep apnea with CPAP may reduce atherosclerosis and consequently lower the risk of ischemic cardiovascular disease. However, there are several limitations to consider. The small sample size of highly selected patients with severe sleep apnea free of comorbidity may not be generalizable to the overall OSA population. Additionally, because of the short duration of follow-up, this study is not able to determine whether randomized treatment of sleep apnea actually reduces cardiovascular and cerebrovascular events. Such longer-term randomized trials are greatly needed, and international efforts are currently under way to perform such trials.
SDB AND MORTALITY: 18-YEAR FOLLOW-UP OF THE WISCONSIN COHORT
Despite the availability of effective treatment for sleep-disordered breathing, and evidence that sleep-disordered breathing contributes to significant metabolic and cardiovascular morbidity, at least 75% of severe cases remain undiagnosed.20 This makes the findings of a high-mortality risk with untreated sleep-disordered breathing in a general population sample from the Wisconsin Sleep Cohort all the more concerning. In this study, Young et al estimated the mortality associated with sleep-disordered breathing in their 18 years of follow-up of 1,522 adults assessed with full polysomnography.
The study found a significantly increased risk of mortality conferred by severe obstructive sleep apnea even after adjustment for confounding (hazard ratio = 3.0; 95% CI 1.4-6.3). After excluding patients who had used CPAP treatment, the risk was even higher (hazard ratio = 3.8; 95% CI 1.6-9.0). There was also a significantly increased risk for cardiovascular mortality (hazard ratio = 5.2; 95% CI 1.4-19.2). Importantly, these results were unchanged after accounting for daytime sleepiness. Although the benefit of treating SDB patients who are not sleepy is controversial,21 findings from this study suggest that SDB should not necessarily be contingent on daytime sleepiness symptoms. Although mortality risk was 50% greater for those with mild and moderate sleep-disordered breathing compared to those without sleep-disordered breathing, the estimates were not statistically significant.
These findings from the Wisconsin Sleep Cohort provide important insights into the public health burden of sleep-disordered breathing. Interestingly, these findings are similar to those from two recent clinical studies using the same polysomnographic methods and apnea and hypopnea definitions. Yaggi et al14 found a twofold increased adjusted risk for either incident stroke or death for patients diagnosed with sleep apnea (mean AHI = 35) versus not diagnosed with sleep apnea (mean AHI = 2 ). Marin et al12 reported a threefold greater odds of cardiovascular mortality with severe sleep apnea, compared with community controls and patients without sleep-disordered breathing. Given the inevitable increase in prevalence of sleep-disordered breathing with the growing epidemic of obesity, these findings underscore the need for heightened clinical recognition and treatment of sleep-disordered breathing.
The field of sleep medicine sits at the intersection of a number of different areas of investigation. This past year exemplifies the breadth of contributions possible from numerous disciplines including genomics, metabolic disease, cardiovascular disease, and epidemiology that have important implications for the care of patients with underlying sleep disorders. As sleep medicine specialists, we can look forward to the exciting contributions in the years to come.
H. Klar Yaggi, MD, MPH, is assistant professor of medicine at Yale University School of Medicine, Section of Pulmonary and Critical Care Medicine. He can be reached at [email protected]
- Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357:639-647.
- Redline S, Storfer-Isser A, Rosen CL, et al. Association between metabolic syndrome and sleep-disordered breathing in adolescents. Am J Respir Crit Care Med. 2007;176:401-408.
- 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;176:706-712.
- Young T, Finn L, Peppard P, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin Sleep Cohort. Sleep. 2008;31:1071-1078.
- Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39:1000-1006.
- 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;165:670-676.
- Punjabi NM, Bandeen-Roche K, Marx JJ, Neubauer DN, Smith PL, Schwartz AR. The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep. Sleep. 2002;25:307-314.
- Yaggi HK, Araujo AB, McKinlay JB. Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes Care. 2006;29:657-661.
- Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435-1439.
- de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW, Rifai N. Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation. 2004;110:2494-2497.
- Arzt M, Young T, Finn L, Skatrud JB, Bradley TD. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med. 2005;172:1447-51.
- 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.
- Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J. 2006;28:596-602.
- Yaggi H, Concato J, Kernan W, Lichtman J, Brass L, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353:2034-2041.
- Wolk R, Somers VK. Cardiovascular consequences of obstructive sleep apnea. Clin Chest Med. 2003;24:195-205.
- Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation. 1986;74:1399-1406.
- Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115:459-467.
- Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux RB. Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. J Am Coll Cardiol. 1993;22:1873-1880.
- Grobbee DE, Bots ML. Atherosclerotic disease regression with statins: studies using vascular markers. Int J Cardiol. 2004;96:447-459.
- Young T, Evans L, Finn L, Palta M. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep. 1997;20:705-706.
- Levy P, Pepin JL, McNicholas WT. Should all sleep apnoea patients be treated? Yes. Sleep Med Rev. 2002;6(1):17-26; discussion, 27.