Using a prospective cohort study, which included middle-aged and older adults from several United States communities, we examined the independent association between sleep-disordered breathing and mortality. The results of this study demonstrate that, independent of several confounding variables, sleep-disordered breathing was associated with all-cause and cardiovascular disease–related mortality. The association was most apparent in men aged 40–70 y with severe disease (AHI≥30 events/h). The degree of sleep-related hypoxemia was found to be independently associated with mortality, whereas the arousal frequency and the central sleep apnea index were not.
The question of whether sleep-disordered breathing decreases survival has great clinical and public health significance. To date, a number of studies on clinical populations have been carried out on the association between sleep-disordered breathing and mortality and the findings have been conflicting 
. Discrepancies across the available clinic-based studies have resulted, in part, from inconsistencies in methods used to assess breathing abnormalities during sleep, differences in disease definition, and variable attention to potential confounding factors. In one of the earliest case series of 1,620 patients with sleep-disordered breathing, Lavie et al. 
showed that an apnea index of more than 30 events/h was associated with all-cause mortality in young and middle-aged men. While this study highlighted the importance of sleep-disordered breathing as a risk factor for mortality, its findings are limited by the exclusion of women, the lack of consideration of treatment effects, and the concern for referral bias that is inherent in clinical populations. Although a subsequent report, which included 14,589 male patients from the same clinical center, confirmed the earlier observation that sleep-disordered breathing is independently associated with mortality, all of the methodological concerns remained 
Several groups have also examined the association of sleep-disordered breathing and mortality in community or population cohorts. Unfortunately, even in these studies, the use of snoring as a surrogate for sleep-disordered breathing 
or the assessment of only elderly participants 
limits inferences regarding the association between sleep-disordered breathing and mortality for the general population. Recent findings from the Wisconsin Sleep Cohort and the Busselton Sleep Cohort studies, which have incorporated objective measures of sleep-disordered breathing in general population samples, show an independent association between sleep-disordered breathing and all-cause mortality 
. In the Wisconsin study, the fully adjusted hazard ratio for all-cause mortality comparing people with severe disease to those without disease (AHI≥30 events/h versus. <5 events/h) was 2.7 (95% CI: 1.3–5.7). Cardiovascular disease-related mortality in the Wisconsin study was also higher in people with severe disease than those without disease (hazard ratio: 5.2; 95% CI: 1.4–19.2). While the Busselton study did not examine cause-specific mortality, it too found that moderate-to-severe sleep-disordered breathing was associated with all-cause mortality with an adjusted hazard ratio of 6.2 (95% CI: 2.0–19.4). Although results from both of these studies are congruent with each other and with the results presented herein, the relatively small number of participants with moderate-to-severe sleep-disordered breathing and the limited number of deaths in either cohort (33 in the Busselton cohort and 80 in the Wisconsin cohort) limited the ability to assess effect modification by age and sex and characterize dose–response associations between sleep-disordered breathing and mortality. Furthermore, the potential associations between sleep-related oxyhemoglobin desaturation, recurrent arousals from sleep, occurrence of central sleep apneas, and mortality were not assessed by either study.
The Sleep Heart Health Study adds to the available evidence by demonstrating that sleep-disordered breathing is associated with mortality and that this association is potentially mediated by the degree of sleep-related intermittent hypoxemia. The association with mortality was observed in only those participants with an AHI≥30 events/h. The current study also finds that excess mortality is most apparent in men aged ≤70 y. Although a similar association was also observed in younger women, particularly with severe disease (AHI≥30 events/h), the adjusted hazard ratios did not reach statistical significance. Because of the limited number of deaths in younger women with moderate to severe disease in our study, we cannot exclude an independent association between sleep-disordered breathing and mortality in women. Additional research is needed to determine whether a longer period of follow-up with a sufficient number of diseased people would uncover whether sleep-disordered breathing is independently related to mortality in women. Furthermore, the negative finding in older adults (age >70 y) should not obviate the clinical concern for identifying and treating sleep-disordered breathing in this subgroup. With increasing age, the likelihood of death from other causes rises so that quantifying the potential association between sleep-disordered breathing and mortality becomes more difficult. It is also possible that, compared to younger or middle-aged adults, sleep-disordered breathing in the older adults may be distinct in its impact on clinical outcomes.
Several potential mechanisms could underlie the higher mortality risk in sleep-disordered breathing. A number of studies over the last decade, including the Sleep Heart Health Study 
, have shown that sleep-disordered breathing is associated with hypertension, CAD, congestive heart failure, and stroke 
. Sleep-disordered breathing has also been implicated as a risk factor for insulin resistance and type 2 diabetes mellitus 
. Although many of these consequences have been documented in cross-sectional analyses, several lines of evidence indicate that sleep-disordered breathing may be a causal factor. Perhaps the most persuasive evidence is that treatment with positive airway pressure improves blood pressure 
and may decrease cardiovascular events 
. In addition, there are data suggesting that sleep-disordered breathing can shift the temporal vulnerability for sudden cardiac death 
. In the absence of sleep-disordered breathing, the greatest risk for sudden cardiac death is between 6 a
. and 11 a
. However, in patients with sleep-disordered breathing, more than half of sudden cardiac deaths occur between 10 p
. and 6 a
., suggesting that the associated hemodynamic and physiologic stress may trigger malignant arrhythmias. Finally, in addition to cardiovascular mortality, noncardiovascular causes of death may also contribute to excess mortality, given that people with sleep-disordered breathing are more prone to motor vehicle accidents particularly those associated with personal injury 
There are several limitations of the current study that merit discussion. First, because cause-specific death was only adjudicated for cardiovascular disease, hypothesis testing regarding mortality from non-cardiovascular causes was not possible. Second, measurement error from short-term variability in sleep and breathing patterns might have diluted the mortality risk, as only one night of recording was used to assess disease severity. However, previous work on night-to-night variability on sleep and breathing patterns has shown that one night of recording provides a reasonably accurate estimate of sleep-disordered breathing severity 
. Third, a number of the potentially confounding covariates (e.g., smoking status) were obtained by self-report. Nonetheless, in all probability, any bias in self-reported data is likely to be unrelated to the abnormalities on the sleep study and thus would not lead to biased estimates of mortality risk. Fourth, because the Sleep Heart Health Study participants were recruited from ongoing epidemiological studies of cardiovascular and respiratory disease, survival bias may have contributed to some of our findings on sleep-disordered breathing and mortality, particularly in older participants. Finally, it is important to recognize that the threshold used to present the age-stratified results (≤70 versus >70 y) was based on sensitivity analyses that examined several different age cutoff points. Multiple examinations of any data can lead to identification of statistically significant findings just based on chance. Thus, while the Sleep Heart Health Study data indicate a differential relation between sleep-disordered breathing and mortality in younger and older participants, the age threshold of 70 years should not be overinterpreted. These limitations notwithstanding, the current study also has several strengths including the longitudinal assessment of a large community sample with careful characterization of sleep and breathing abnormalities, comprehensive assessment of key covariates and outcomes, and analytic consideration of effect modification by age and sex.
In conclusion, the Sleep Heart Health Study shows that sleep-disordered breathing is an independent predictor of mortality and that this association is not attributable to age, obesity, or other chronic medical conditions. Although the degree of nocturnal hypoxemia was an independent predictor of mortality, arousal frequency and occurrence of central apneas were not. Given the high and likely increasing prevalence of sleep-disordered breathing in the general population, additional research in the form of randomized clinical trials should be undertaken to assess if treatment can reduce premature mortality associated with this common and chronic disorder.