The current investigation presents several unique findings. First, SDB in a community sample of middle-aged and older adults is characterized more by the occurrence of hypopneas than apneas. Second, independent of apnea index, the hypopnea index was associated with self-reported prevalent cardiovascular disease. Third, while keeping a fixed threshold of airflow reduction and regardless of an arousal criterion, the current study identified a clinically relevant hypopnea definition that best correlated with prevalent cardiovascular disease after accounting for several confounding covariates. Specifically, the frequency of hypopneas defined by a threshold of oxyhemoglobin desaturation of at least 4% was associated with cardiovascular disease. The strength or precision of association was not improved by reducing the desaturation threshold criterion to less than 4% or by including arousals in the definition. Similarly, examination of the ODI, which does not include the degree of airflow reduction, showed that desaturations based on a threshold of 4% or more were also associated with cardiovascular disease. Including less severe desaturation events showed no improvement in the association with cardiovascular disease compared with the 4% threshold.
Over the last decade, substantial evidence has accumulated linking SDB to excess morbidity and mortality. The risk of many clinical sequelae attributed to SDB appears to increase as the AHI increases. By including both apneas and hypopneas in this disease-defining metric, an implicit assumption is that these events are alike in their impact on clinical outcomes. Although this assumption may in fact be correct, there is a relative paucity of supporting evidence. Moreover, there are no empirical data indicating whether certain criteria for defining hypopneas are better associated with adverse SDB-related outcomes than others. A major challenge in defining the health-related implications of hypopneas is the inconsistency in defining these events. Differences in the amount of airflow reduction, degree of oxyhemoglobin desaturation, and the inclusion of arousal can lead to significant variability in hypopnea detection across different laboratories. Compounding this variability are the differences in the methods used to detect breathing abnormalities during sleep (e.g., thermistor vs. nasal pressure transducer). Thus, an outcome-based hypopnea definition is lacking and consensus recommendations are commonly used in research and clinical practice. For example, in a 2001 consensus report (10
) by a task force of the American Academy of Sleep Medicine (AASM), it was recommended that a hypopnea be defined as an abnormal respiratory event characterized by a 30% or more reduction in airflow that is associated with an oxyhemoglobin desaturation of at least 4%. A 2005 update of those recommendations incorporated alternate criteria that included a discernible reduction in airflow associated with an oxyhemoglobin desaturation of at least 3% or an arousal from sleep (11
). Most recently, the AASM published a comprehensive manual for scoring sleep and associated events in which both of the aforementioned definitions were also permitted (6
). By allowing alternate criteria, there is an embedded recognition that the current level of evidence is insufficient for defining event criteria that are associated with adverse health outcomes. The work presented herein attempts to fill some of these gaps by carefully considering different thresholds of oxyhemoglobin desaturation and by including and excluding arousal from the definition of a hypopnea. Overall, our results suggest that hypopneas associated with an oxyhemoglobin desaturation of at least 4% are correlated with cardiovascular disease, whereas those associated with lesser degrees of hypoxemia or arousals show no association. Whether similar findings also emerge for other SDB-related outcomes, such as daytime sleepiness, neurocognitive dysfunction, and altered glucose homeostasis, remains to be determined.
The implications for using outcome-based thresholds for hypopnea definition in SDB are numerous. Although it is appealing to believe that using less stringent thresholds for SDB may benefit the individual patient, there are reasons to believe that this may not be the case. First, the evidence supporting the use of less stringent criteria for SDB events is lacking. Such evidence should be based on rigorous analyses that test hypotheses on whether a threshold in oxyhemoglobin desaturation or the inclusion of arousals for defining hypopneas is associated with a clinical outcome in cross-sectional and longitudinal studies. A simple comparison of the AHI based on a 3% versus a 4% oxyhemoglobin desaturation threshold as a predictor of a clinical outcome is insufficient. Rather, analyses that examine a specific level of oxyhemoglobin desaturation for a hypopnea need to take into account events with oxyhemoglobin desaturation that are above the threshold. Moreover, because endpoints may vary with the type and severity of SDB events, the clinical value for different event definitions has to be individually determined. Second, lowering the criteria for detecting hypopneas will undoubtedly increase the number of patients who are diagnosed with SDB and started on treatment. Although serious side effects of positive-pressure therapy are rare, the benefits of treatment may be small, particularly for those patients who received a diagnosis on less stringent criteria. Third, given the large reservoir of undiagnosed disease, priority should be initially placed on identifying and treating those patients who meet the most stringent and uncontroversial definition of SDB. Finally, lowering disease-defining thresholds without supporting evidence will raise the prevalence of disease and impose additional burden on already limited public heath resources. The foregoing considerations argue that adopting a particular set of criteria will require a concerted effort to define the clinical sequelae associated with varying definitions of SDB.
There are several important limitations in this study that merit discussion. The first limitation is that causal inferences are not possible given the cross-sectional nature of our analysis. Thus, although including arousals in the hypopnea definition did not augment the association with cardiovascular disease, sleep fragmentation cannot be excluded as a putative factor linking SDB to cardiovascular outcomes. The lack of an association with hypopnea-related arousals may merely reflect the poor reliability of scoring EEG arousals (12
). Similarly, hypoxemia cannot be implicated as a causal factor because reverse causality (i.e., cardiovascular disease causing SDB) is also certainly possible. The second limitation is that assessments of breathing abnormalities during sleep were based on inductive plethysmography and an oronasal thermistor. A comprehensive survey of validity and reliability of scoring respiratory events concluded that the thermistor, as used in the SHHS, is far inferior in detecting hypopneas when compared with a nasal pressure device (13
). However, the underdetection of hypopneas is likely to be similar in those with and without cardiovascular disease and thus any bias in the measures of association is probably small. The use of a thermistor to assess airflow also limited our ability to examine whether different levels of airflow reduction would be associated with prevalent cardiovascular disease. The third limitation comes from our use of self-reports to assess prevalent cardiovascular disease. Previous work from one of the SHHS parent cohorts has shown that proportions of confirmed self-reported myocardial infarction is 75.5 and 60.6% in men and women, respectively (14
). For a diagnosis of heart failure, these estimates were 73.3 and 76.6%, respectively, confirming an underreporting of cardiovascular conditions. Nonetheless, in all probability, the degree of underreporting is likely to be unrelated to the abnormalities on the polysomnogram and thus would not lead to biased estimates of association. Finally, it is also important to recognize that the SHHS cohort is not representative of a population-based cohort. The older age of the sample, the recruitment of subjects from other epidemiologic cohorts with oversampling on snoring subjects, and the relatively low burden of SDB limit the generalizability of the reported results. These limitations notwithstanding, the current study also has several strengths. These include the use of full-montage polysomnography to characterize SDB with varying event definitions in a large community cohort. Furthermore, adjustments for cardiovascular risk factors and other demographic factors allowed for an unconfounded examination of how different hypopnea definitions correlate with prevalent cardiovascular disease. Finally, inclusion of hypopneas associated with severe oxyhemoglobin desaturation in multivariable models for a specific oxyhemoglobin desaturation threshold is also a major strength. Such adjustments are necessary to ensure that the measures of association derived for a specific threshold in oxyhemoglobin desaturation are not biased by events that are associated with severe degrees of oxyhemoglobin desaturation.
In summary, the results of this cross-sectional analysis of the SHHS data show that hypopneas with a 4% reduction in oxyhemoglobin saturation are associated with cardiovascular disease, even after accounting for events with greater degrees of desaturation. In contrast, there was no association between the frequency of hypopneas with less than 4% desaturation and cardiovascular disease. Additional research is needed to compare different event definitions in their association with other SDB-related consequences in cross-sectional and longitudinal analyses. Without such evidence, expanding event definitions will certainly increase the number of patients with mild disease, but at the expense of identifying and adequately treating those that are severely affected but remain undiagnosed.