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      Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study

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          Abstract

          In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.

          Abstract

          Background

          Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

          Methods and Findings

          We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

          Conclusions

          Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.

          Please see later in the article for the Editors' Summary

          Editors' Summary

          Background

          About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.

          Why Was This Study Done?

          Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.

          What Did the Researchers Do and Find?

          At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.

          What Do These Findings Mean?

          These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.

          Additional Information

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000132.

          Related collections

          Most cited references 29

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          Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.

          The effect of obstructive sleep apnoea-hypopnoea as a cardiovascular risk factor and the potential protective effect of its treatment with continuous positive airway pressure (CPAP) is unclear. We did an observational study to compare incidence of fatal and non-fatal cardiovascular events in simple snorers, patients with untreated obstructive sleep apnoea-hypopnoea, patients treated with CPAP, and healthy men recruited from the general population. We recruited men with obstructive sleep apnoea-hypopnoea or simple snorers from a sleep clinic, and a population-based sample of healthy men, matched for age and body-mass index with the patients with untreated severe obstructive sleep apnoea-hypopnoea. The presence and severity of the disorder was determined with full polysomnography, and the apnoea-hypopnoea index (AHI) was calculated as the average number of apnoeas and hypopnoeas per hour of sleep. Participants were followed-up at least once per year for a mean of 10.1 years (SD 1.6) and CPAP compliance was checked with the built-in meter. Endpoints were fatal cardiovascular events (death from myocardial infarction or stroke) and non-fatal cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, coronary artery bypass surgery, and percutaneous transluminal coronary angiography). 264 healthy men, 377 simple snorers, 403 with untreated mild-moderate obstructive sleep apnoea-hypopnoea, 235 with untreated severe disease, and 372 with the disease and treated with CPAP were included in the analysis. Patients with untreated severe disease had a higher incidence of fatal cardiovascular events (1.06 per 100 person-years) and non-fatal cardiovascular events (2.13 per 100 person-years) than did untreated patients with mild-moderate disease (0.55, p=0.02 and 0.89, p<0.0001), simple snorers (0.34, p=0.0006 and 0.58, p<0.0001), patients treated with CPAP (0.35, p=0.0008 and 0.64, p<0.0001), and healthy participants (0.3, p=0.0012 and 0.45, p<0.0001). Multivariate analysis, adjusted for potential confounders, showed that untreated severe obstructive sleep apnoea-hypopnoea significantly increased the risk of fatal (odds ratio 2.87, 95%CI 1.17-7.51) and non-fatal (3.17, 1.12-7.51) cardiovascular events compared with healthy participants. In men, severe obstructive sleep apnoea-hypopnoea significantly increases the risk of fatal and non-fatal cardiovascular events. CPAP treatment reduces this risk.
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            Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study.

            Disordered breathing during sleep is associated with acute, unfavorable effects on cardiovascular physiology, but few studies have examined its postulated association with cardiovascular disease (CVD). We examined the cross-sectional association between sleep- disordered breathing and self-reported CVD in 6,424 free-living individuals who underwent overnight, unattended polysomnography at home. Sleep-disordered breathing was quantified by the apnea-hypopnea index (AHI)-the average number of apneas and hypopneas per hour of sleep. Mild to moderate disordered breathing during sleep was highly prevalent in the sample (median AHI: 4.4; interquartile range: 1.3 to 11.0). A total of 1,023 participants (16%) reported at least one manifestation of CVD (myocardial infarction, angina, coronary revascularization procedure, heart failure, or stroke). The multivariable-adjusted relative odds (95% CI) of prevalent CVD for the second, third, and fourth quartiles of the AHI (versus the first) were 0.98 (0.77-1.24), 1.28 (1.02-1.61), and 1.42 (1.13-1.78), respectively. Sleep-disordered breathing was associated more strongly with self-reported heart failure and stroke than with self-reported coronary heart disease: the relative odds (95% CI) of heart failure, stroke, and coronary heart disease (upper versus lower AHI quartile) were 2.38 (1.22-4.62), 1.58 (1.02- 2.46), and 1.27 (0.99-1.62), respectively. These findings are compatible with modest to moderate effects of sleep-disordered breathing on heterogeneous manifestations of CVD within a range of AHI values that are considered normal or only mildly elevated.
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              Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort.

              Sleep-disordered breathing (SDB) is a treatable but markedly under-diagnosed condition of frequent breathing pauses during sleep. SDB is linked to incident cardiovascular disease, stroke, and other morbidity. However, the risk of mortality with untreated SDB, determined by polysomnography screening, in the general population has not been established. An 18-year mortality follow-up was conducted on the population-based Wisconsin Sleep Cohort sample (n = 1522), assessed at baseline for SDB with polysomnography, the clinical diagnostic standard. SDB was described by the number of apnea and hypopnea episodes/hour of sleep; cutpoints at 5, 15 and 30 identified mild, moderate, and severe SDB, respectively. Cox proportional hazards regression was used to estimate all-cause and cardiovascular mortality risks, adjusted for potential confounding factors, associated with SDB severity levels. All-cause mortality risk, adjusted for age, sex, BMI, and other factors was significantly increased with SDB severity. The adjusted hazard ratio (HR, 95% CI) for all-cause mortality with severe versus no SDB was 3.0 (1.4,6.3). After excluding persons who had used CPAP treatment (n = 126), the adjusted HR (95% CI) for all-cause mortality with severe versus no SDB was 3.8 (1.6,9.0); the adjusted HR (95% CI) for cardiovascular mortality was 5.2 (1.4,19.2). Results were unchanged after accounting for daytime sleepiness. Our findings of a significant, high mortality risk with untreated SDB, independent of age, sex, and BMI underscore the need for heightened clinical recognition and treatment of SDB, indicated by frequent episodes of apnea and hypopnea, irrespective of symptoms of sleepiness.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                August 2009
                August 2009
                18 August 2009
                : 6
                : 8
                Affiliations
                [1 ]Johns Hopkins University, Baltimore, Maryland, United States of America
                [2 ]University of Arizona, Tucson, Arizona, United States of America
                [3 ]VA Boston Healthcare System, Boston, Massachusetts, United States of America
                [4 ]University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
                [5 ]Boston University School of Medicine, Boston, Massachusetts, United States of America
                [6 ]New York University School of Medicine, New York, New York, United States of America
                [7 ]Case Western Reserve University, Cleveland, Ohio, United States of America
                [8 ]American Association of Homes and Services for the Aging, Washington, D. C., United States of America
                [9 ]University of California, Davis, California, United States of America
                [10 ]University of Southern California, Los Angeles, California, United States of America
                The George Institute for International Health, Australia
                Author notes

                ICMJE criteria for authorship read and met: NMP BSC JLG DJG ABN GTO DMR SR HER JR ES MLU JMS. Agree with the manuscript's results and conclusions: NMP BSC JLG DJG ABN GTO DMR SR HER JR ES MLU JMS. Designed the experiments/the study: DJG ABN GTO DMR SR JR ES JMS. Analyzed the data: NMP BSC DJG ABN GTO DMR HER. Collected data/did experiments for the study: NMP JLG DJG ABN GTO DMR SR HER JR ES. Enrolled patients: NMP JLG DJG ABN GTO DMR HER JR. Wrote the first draft of the paper: NMP. Contributed to the writing of the paper: NMP BSC JLG DJG ABN GTO DMR SR HER JR ES MLU JMS. Helped obtain funding: JR. Ran study coordinating center: JMS.

                Article
                09-PLME-RA-0418R3
                10.1371/journal.pmed.1000132
                2722083
                19688045
                d53c93ea-3c76-4ce7-afc2-b150080c405b
                Punjabi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 9
                Categories
                Research Article
                Respiratory Medicine/Sleep and Ventilation Disorders

                Medicine

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