Risk of Obstructive Sleep Apnea
Research on sex-specific aspects of cardiovascular disease and its prevention has been hampered on many fronts. In the past, women were excluded from clinical research studies as a result of efforts to protect them from risk. In 1985, the US Public Health Service Task Force on Women’s Health Issues concluded that this exclusion of women from clinical trials had led to a lack of sufficient knowledge about women’s biology and that this had compromised the health of women.1 The National Institutes of Health (NIH) changed its policy on the inclusion of women of childbearing age in clinical research in 1986.2 In 1990, a General Accounting Office report examined change in the inclusion of women in NIH-sponsored research and found that the NIH guidelines were not being followed, because the number of women included had not appreciably improved.3 The report also noted that even in those studies that included women, sex-specific analysis was rarely undertaken or reported. The General Accounting Office report led to the establishment of the NIH Office on Research on Women’s Health to ensure that women are included in NIH-funded clinical studies unless a clear justification existed for their exclusion. Guidelines established stated that the NIH would ensure that trials were designed and performed in such a manner that sex-specific results could be validly analyzed and that progress reports be required.4 The passage of the NIH Revitalization Act in 1993 turned these guidelines into law.5 In addition to requiring the inclusion of women and minorities in clinical trials, the Act stipulated that cost could not be used as an excuse for excluding these groups and that outreach efforts be put in place for recruitment.
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Although progress has been made over time in the recruitment of women into trials,6 the representation of women in trials of cardiovascular disease and prevention has lagged as has the reporting of sex-specific outcomes.7–11 To remedy this, the International Committee of Medical Journal Editors makes sex-specific reporting part of the International Committee of Medical Journal Editors Uniform Requirements, stating that “where scientifically appropriate, analyses of the data by such variables as age and sex should be included.”12
In this issue of Circulation, Querejeta Roca et al13 help to rectify this data gap to illuminate the sex-specific cardiovascular risk of obstructive sleep apnea (OSA). As the authors note, there have been inconsistent data regarding the relationship of OSA to cardiovascular (CV) outcomes in men in comparison with women.14 To address this, the authors used data from the Atherosclerosis Risk in Communities (ARIC) study15 and the Sleep Heart Health Study (SHHS)16 to evaluate the association of OSA and CV outcomes. The ARIC population has been a rich source of data, and the authors are to be congratulated on highlighting important sex-specific differences in risk factors and disease prevalence. ARIC is a prospective study designed to investigate the etiology of atherosclerosis and its clinical sequelae and variation in CV risk factors, medical care, and disease by race, sex, place, and time. In the communities of Forsyth County, NC, Jackson, MS, the suburbs of Minneapolis, MN, and Washington County, MD, adults aged 45 to 64 years were examined at intervals. Examinations included ultrasound scanning of carotid and popliteal arteries; lipids, lipoproteins, and apolipoproteins; and coagulation, inhibition, and platelet and fibrinolytic activity. Subsequent surveillance for coronary heart disease (CHD) has involved review of hospitalizations and deaths. Subjects were free of prevalent (CHD) or heart failure (HF) at baseline assessment and were followed for an average of 13 years and assessed for incident CHD, HF, and CV and all-cause mortality.
The SHHS is a prospective cohort study designed to investigate OSA and other sleep-disordered breathing as risk factors for the development of CV disease. Participants of the SHHS were recruited from cohort studies and underwent a home polysomnogram and lung function tests to assess the presence of OSA and other sleep-disordered breathing, and follow-up and outcome information pertaining to CV disease, as well. The cohort evaluated in the current report includes men and women who participated in both the SHHS and visit 4 of the ARIC study. Visit 4 occurred between 1996 and 1998, at which time high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide, and high-sensitivity C-reactive protein were measured in surviving subjects. Subjects with prevalent HF or CHD at the later of either ARIC visit 4 or the SHHS visit were excluded, as were those with missing hs-TnT data, leaving 752 men and 893 women in this analysis. Surviving subjects were invited for a fifth visit, and, between 2011 and 2013, 906 subjects of 1328 surviving participants, free of HF or CHD, underwent echocardiography.
The authors found that after 13.6±3.2 years of clinical follow-up, 28% of the men and 17% of the women had died or experienced incident HF. In the unadjusted analysis, OSA severity was significantly associated with incident HF or death in women but not in men. This association among women was no longer significant after adjusting for hs-TnT level at visit 4, and mediation analysis suggested that hs-TnT level at the time of OSA assessment accounted for ≈30% of the association between OSA and incident HF or death among women. OSA was independently associated with hs-TnT among women but not in men.
In women, OSA severity was independently associated with higher left ventricular mass index, whereas in men this association was not significant after adjustment for potential confounders. In women, but not men, OSA severity was associated with the composite outcome of incident HF, CHD, death, or left ventricular hypertrophy even in fully adjusted models.
Querejeta Roca and colleagues have made a major contribution to our understanding of the role of OSA as a CV risk factor in women; however, there are several important limitations to this study that need to be considered in interpreting these findings. Prime among them is the fact that 99% of the women and men studied were white. This lack of racial diversity is particularly important because 27% of the entire ARIC cohort was not white. The 2 ARIC cohorts that participated in the SHHS were those in suburban Minneapolis, MN, and Washington County, MD. Recruitment occurred between 1987 and 1989 at which time 99% of the population of both these geographic regions was white.16 Whether or not this important finding defining the role of OSA as a CV risk factor in women in a middle-aged white population can be extrapolated to less homogeneous populations remains to be determined.
These limitations aside, we should now add OSA to the list of factors that differentially affect a woman’s risk of developing CHD and HF. Women with hypertension and diabetes mellitus have already been demonstrated to be at higher risk than men with these same conditions. Data from the Framingham study has demonstrated that the risk of developing HF was doubled for men who were hypertensive, but the risk was tripled for women in comparison with similar normotensive subjects.17 Similarly, diabetes mellitus increases the risk of HF up to 5-fold in women, in comparison with a doubling of risk in men with diabetes mellitus, and it imparts a significantly greater risk of death from ischemic heart disease.18–20
And how should these findings inform our discussions with and recommendations to the middle-aged woman without CHD or HF whom we will see in the office tomorrow? If she has symptoms suggestive of OSA, we can with fair assurance recommend screening for OSA to her, along with assessment for other CV risks factors. The current study should be a catalyst for our more vigilant efforts to uncover such symptoms. If a polysomnogram demonstrates OSA in a woman, however, we are on less firm footing recommending treatment to her as a specific strategy to lower her CV risk. The principal clinical indication to treat OSA in the general population is excessive daytime sleepiness. Observational and nonrandomized studies have suggested a link between OSA and fatal and nonfatal CVD, and similar studies suggest that treatment of OSA has the potential to be preventive.21 Although randomized trial data are lacking in this area, lifestyle changes such as weight loss and the avoidance of sedatives and alcohol in the evening can be effective. In the absence of symptoms, our woman patients deserve to understand the significant CV risk posed by OSA so that they, too, can be vigilant for symptoms and seek prompt evaluation and treatment. Future guidelines and policy statements are needed to address changes in screening and care strategies.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
- © 2015 American Heart Association, Inc.
- 2.↵Inclusion of women in study populations. NIH Guide Grants Contracts. 1986;15:1.
- 3.↵US General Accounting Office. National Institutes of Health: Problems in Implementing Policy on Women in Study Populations. July 1990. GAO/THRD-90-50.
- 4.↵NIH/ADAMHA policy concerning inclusion of women in study populations. NIH Guide Grants Contracts. 1990;19:1.
- 5.↵NIH guidelines on the inclusion of women and minorities as subjects in clinical research. Fed Register. 1994;59:14508–14513.
- 6.↵US General Accounting Office. NIH Has Increased Its Efforts to Include Women in Research. May 2000. GAO/HEHS-00-96.
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