The Link between Sleep Apnea and Cardiovascular Disease
Time to Target the Nonsleepy Sleep Apneics?

Jan Hedner and Ludger Grote

Sleep Laboratory, Department of Pulmonary Medicine, Sahlgrenska University Hospital, Göteborg, Sweden

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Sleep-disordered breathing (SDB) is common in the general population. More than five apneas and/or hypopneas per hour of sleep (apnea-hypopnea index, AHI) were identified in 24 and 9% of middle-aged men and women, respectively, in the Wisconsin Sleep Cohort Study (1). However, the SDB diagnosis reflects only the breathing disorder. The current main treatment criterion, daytime sleepiness, is found in only approximately 10% of these patients. Perceived quality of life is adversely affected in this subgroup. Treatment of the breathing disorder is highly rewarding with respect to symptomatic improvement among "sleepy sleep apneics" (2, 3). The decision to treat is less obvious for "nonsleepy sleep apneics." Although a causative association between SDB and systemic hypertension is suggested by a wealth of data (4, 5), the study published by Shahar and collaborators in this issue of the AJRCCM (pp. 19-25) (6) expands the association between SDB and cardiovascular disease (CVD) to include stroke, coronary artery disease, and cardiac failure. The study provides two important findings. First, an increased risk for CVD was seen already in association with proportionally mild SDB. Second, the effect on CVD manifestations was only modest to moderate.

Shahar and coworkers (6) have analyzed data from the Sleep Heart Health Study (7). The 6,424 investigated individuals have been recruited from previous epidemiological cohort studies and mild to moderate SDB was highly prevalent. The median AHI was 4.4 (interquartile range, 1.3 to 11.0) and compared with the first AHI quartile, the odds ratios for prevalent CVD for the second, third, and fourth AHI quartiles were 0.98 (0.77-1.24), 1.28 (1.02-1.61), and 1.42 (1.13-1.78), respectively. Interestingly, SDB was more strongly associated with reported stroke and heart failure than with coronary artery disease, but odds ratios were generally low. The prevalence odds of each disease entity increased mainly within the range of mild SDB (AHI 1-10), whereas, somewhat unexpectedly, no further increase in risk of CVD occurred in the higher range (AHI > 10). Only the association with stroke showed a stronger dose relationship.

In addition to its size, this study has several important merits. It used polysomnography for quantification of SDB, and thus the precision for detecting low-degree SDB activity was optimized. In contrast to several previous cohort studies, there was a standardized assessment of important cardiovascular confounders. The cross-sectional database will also give excellent opportunities for future follow-up assessments of cardiovascular morbidity and mortality in this cohort.

The study, however, also bears some methodological limitations. Any cross-sectional study provides only associations and does not allow for conclusions about potential causal relationships. The mean age of the cohort was 65 yr, whereas the mean age of a typical sleep laboratory patient sample is 50 to 55 yr. As pointed out in the discussion, this study is therefore hampered by a selection bias, as SDB is likely to have started at an earlier age. It is possible that mortality had been higher in younger individuals who are no longer represented in the study sample. Indeed, a previous sleep laboratory-based study (8) suggested that SDB exerts the strongest effect on CV mortality in subjects younger than 60 yr. Work has also implied that SDB has a stronger impact on surrogate markers, for example, hypertension and hypertension control, in subjects aged 50 yr and younger than in subjects older than 50 yr (9). Therefore, it may be speculated that the mild to moderate effect of SDB on CV risk in this study is in part attributed to high mean age. This would lead to an underestimation of the "real impact" of SBD on CV morbidity in the entire population.

The study by Shahar and colleagues (6) and several other reports (10, 13) identify potential adverse effects on health brought about by SDB. In the context of cardiovascular implications there is reason to ask why SDB has not been included among factors discussed in the risk stratification of CVD (16). Probably, this may be explained by the lack of data meeting current epidemiological standards, but it may also be due to the imprecise definition of SDB and to the standards of treatment. Clearly, it is a task for the research community to provide a consensus on the following three points:

1. Stringent definitions of the disease and appropriate diagnostic cutoff levels in relation to the various forms of comorbidity; for instance, the study by Shahar and colleagues (6) provides evidence that even low-intensity SDB was associated with CVD, whereas other data suggest that daytime hypersomnolence is only poorly correlated with severity of SDB.

2. Definition of the treatment indications in SDB: Although these may be obvious in symptomatic SDB (hypersomnolence), data (4, 8, 13, 15) and the present study (6) generate a novel potential treatment dilemma. If, for instance, nasal continuous positive airway pressure (nCPAP) provides a preventive effect on cardiovascular morbidity in SDB, treatment indications may be massively expanded to include asymptomatic SDB patients. However, compliance with nCPAP is likely to be low when the burden of treatment exceeds the subjective perception of health gain.

3. Definition of the goal of the treatment: The study by Shahar and coworkers (6) suggests that a reasonable treatment goal for reduction of cardiovascular morbidity in their population would be an AHI below 5. In fact, only 50% of symptomatic sleep apnea patients use their CPAP for more than 50% of the time asleep (17). Permanent AHI below 5 is therefore achieved only in a limited group of nCPAP-treated SDB patients.

Cross-sectional and epidemiological studies of SDB have taught us that asymptomatic SDB is common. As with most other medical disorders it is the symptom that brings the patient to medical attention. Adverse health effects associated with asymptomatic SDB would have considerable implications for diagnostic efforts in potential high-risk groups, for example, patients with cardiovascular disease, multiple cardiovascular risk factors, or the obese. Screening programs in such extended cohorts will require simple and reliable diagnostic tools. Next in line are educational efforts whereby public and professional awareness of SDB as a clinical entity and its associated morbidity is improved.

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