community-based cohort study of the relation of OSA to incident cardiovascular disease in adults age 40 and over found an association of OSA with incident CHD in men that was considerably weaker than the association reported from prior clinic-based studies. One such study found that untreated severe OSA was associated with an increase in both non-fatal and fatal coronary and cerebrovascular disease over a mean 10.1 years of follow-up, in a cohort of men with a mean age of 49.9 years, with hazard ratios of 2.9 and 3.2, respectively, for fatal and non-fatal cardiovascular disease events 9
. The difference may be attributable in part to pooling coronary and cerebrovascular disease, as two other studies suggest that OSA may increase the risk of stroke more than the risk of CHD34, 35
. Three smaller clinic-based studies suggested an even larger association of OSA with CHD risk7, 8, 10
. These studies also found increased risk only among untreated individuals, a study design that may have overestimated the risk associated with OSA, as untreated patients were generally self-selected by refusal of or non-adherence to CPAP. Such patients may represent a group with poorer adherence to medical treatments and health recommendations generally. It has been reported, for example, that non-adherence to CPAP is associated with non-adherence to prescribed statin medications36
, which are known to reduce both the risk of myocardial infarction and the need for cardiac revascularization.
The SHHS also differs from previous clinic-based studies in that subjects were older and a community-based recruitment strategy was employed. Screening a non-clinic-based population for the SHHS identified many asymptomatic individuals with OSA37
. It is possible that OSA in such individuals carries a lower cardiovascular risk than OSA in individuals presenting for evaluation in a sleep laboratory. A re-analysis of data from Marin, et al.9
, found the increased risk of cardiovascular mortality primarily among those aged 30–50 years38
. If cardiovascular risk associated with OSA decreases with age, the SHHS cohort, with a median age of 62 years, may underestimate the true cardiovascular risk associated with OSA. Indeed, in the present study, CHD risk associated with OSA was of greater magnitude and was nominally statistically significant in men under the age of 70, although effect modification by age was not statistically significant and this finding could reflect a Type 1 statistical error. Cardiovascular risk could decrease with age due to biological differences in OSA pathophysiology between older and younger individuals; however, a healthy survivor effect is a likely cause of bias toward a null result in this study, as individuals with OSA who are more susceptible to the cardiovascular consequences of OSA are less likely to be alive and free of cardiovascular disease at the time the cohort is enrolled than are those with OSA who are resistant to its cardiovascular consequences. The same phenomenon could explain the apparent age-related decrease in cardiovascular risk in clinic-based studies. Competing causes of cardiovascular disease could also diminish the hazard ratio estimates, if the risks are additive, as the baseline rate of cardiovascular events is higher in the elderly independent of OSA.
Several studies have documented a high prevalence of OSA in patients with systolic11–13
heart failure. Heart failure causes ventilatory control instability and, through periodic reduction in neural output to both the diaphragm and pharyngeal dilator muscles, may cause either central or obstructive sleep apnea. Conversely, a causal role for OSA in the development or progression of heart failure is suggested by several small clinical trials that found improved cardiac function in patients with heart failure following treatment of OSA with CPAP14–16
; however, only 6 of 106 patients in these studies were women. The present study demonstrates that men with severe OSA have a 58% higher adjusted risk of incident heart failure than men without OSA. There is little attenuation in the estimated association when adjusting for blood pressure or antihypertensive medication use, suggesting that increased daytime blood pressure does not mediate this association. This may reflect the pathophysiologic importance of large intrathoracic pressure changes resulting from respiratory efforts against a collapsed upper airway, with consequent increases in left ventricular transmural pressure. Alternatively, nocturnal blood pressure elevation, which is known to occur in OSA, may contribute to heart failure without being reflected in waking blood pressure.
Mechanisms by which OSA may cause CHD have been recently reviewed, and include sympathetic nervous system activation resulting from intermittent hypoxemia and hypercapnia during sleep, as well as both hypoxic and oxidative stress resulting from repeated episodes of hypoxemia and reoxygenation39
. It is hypothesized that these factors cause systemic inflammation, endothelial dysfunction, increased production of vasoactive substances and insulin resistance, with resultant hypertension, hyperlipidemia and diabetes mediating the cardiovascular consequences of OSA. This argument is strongest for hypertension, with OSA recognized as a preventable cause of hypertension in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure40
. Although less well established than for hypertension, there is growing evidence that OSA is also a cause of diabetes41,42
. We have therefore presented models both including and excluding these variables, whose impact on the estimates of OSA-related risk could reflect either mediation or confounding; the true magnitude of the risk associated with OSA is likely to fall between the estimates with and without these variables.
A striking feature of these findings is that the association of OSA with incident CHD and heart failure was observed in men but not in women. Sex differences were not assessed in prior studies, which included few if any women. There are a number of possible explanations for the observed sex difference. We had less power to detect a significant association in women than in men, due to the low prevalence of severe OSA in women. Another possible explanation is the later age of onset of OSA in women than in men, with OSA prevalence increasing in women following menopause. Thus, at baseline, women may have had less cumulative exposure to OSA than men with a similar AHI. It is also possible, however, that there are differences between men and women in the physiologic response to OSA. For example, men have a greater ventilatory response than women to acoustic tone-induced arousal from sleep43
, as well as a greater ventilatory response to carbon dioxide and greater augmentation of this response by hypoxemia44
. The cardiovascular response also appears greater in men: acoustic arousal is associated with more pronounced peripheral vasoconstriction43
and hypoxic hypercapnia results in a greater increase in sympatho-vagal balance45
in men than in women. Sex differences in the prevalence of cardiovascular disease are well recognized and may reflect a protective effect of female sex against cardiovascular risk, including risk related to OSA. Men have larger increases in left ventricular mass for a given increase in BMI or blood pressure46
, for example. Sex differences in unmeasured health behaviors, such as diet or exercise, or greater change over time in risk factors such as obesity, cannot be excluded as causes of the sex difference in OSA-associated cardiovascular risk. Differences in rates of OSA treatment or cardioprotective medication use do not explain the findings, however, as treatment for OSA was reported by a slightly higher percentage of men than women with AHI ≥ 15 and patterns of medication use were similar in men and women for aspirin (34.0% vs. 28.3%), beta-adrenergic blockers (8.8% vs. 9.4%), angiotensin converting enzyme inhibitors (11.7% vs. 10.4%) and lipid-lowering agents (9.0% vs. 9.5%).
This study has a number of advantages over prior prospective studies of the cardiovascular consequences of OSA. These include prospective collection of detailed covariate data on cardiovascular disease risk factors, formal adjudication of incident cardiovascular disease events following explicit protocols at sites with extensive experience in cardiovascular disease epidemiology, and exclusion of cases of prevalent CHD and heart failure to identify a cohort that is optimal for the study of incident disease. As subjects were recruited from the community rather than the clinic, there is less chance of referral bias causing a spurious association of OSA with risk of cardiovascular disease and, as few subjects received treatment for OSA, a better assessment of the natural history of untreated OSA is possible. The SHHS includes both women and men and the sample is ethnically diverse.
Several limitations must also be acknowledged. The older age of the cohort increases the likelihood of a healthy survivor effect biasing toward a null result, and precludes assessment of CHD risk in younger adults, in whom the risk from OSA appears greatest. Although heart failure was identified according to standards established by the participating cardiovascular epidemiology studies, echocardiograms were not routinely performed in all studies and there was no attempt to distinguish between systolic and diastolic heart failure, nor was New York Heart Association heart failure grade routinely ascertained. Body mass index is an imperfect proxy for adiposity, in particular for visceral adiposity, which may be more important than total body adiposity to cardiovascular risk; therefore, residual confounding by adiposity is possible despite adjustment for BMI. Unmeasured cardiovascular risk factors, such as diet and exercise habits, were not uniformly assessed across cohorts and confounding by these variables cannot be excluded. Despite these limitations, the current study provides prospective evidence that OSA is associated with an increase in the risk of incident heart failure in community-dwelling middle-aged and older men, and is consistent with a modest increase in CHD risk in middle-aged men. It also suggests the possibility of sex differences in cardiovascular risk from OSA.
Prior clinic-based observational studies have reported that obstructive sleep apnea (OSA) is associated with an increased incidence of coronary heart disease and an increased prevalence of heart failure in men. In the present study, we assess the relation of OSA to incident coronary heart disease and heart failure in a general community sample of adult men and women. In this prospective study of 1927 men and 2495 women aged 40 years or greater and free of coronary heart disease and heart failure at baseline, we found that over a median follow-up period of 8.7 years, OSA was a significant independent predictor of incident heart failure in men but not in women (adjusted hazard ratio 1.58 for men with AHI ≥ 30 compared to men with AHI <5). OSA predicted incident coronary heart disease only in men age ≤ 70 years (adjusted hazard ratio 1.68 for those with AHI ≥ 30 compared to those with AHI <5). The finding of an increased incidence of heart failure in individuals with severe OSA is novel; whether women are truly at lower risk of heart failure than are men with similarly severe OSA requires further study. The association of OSA with incident coronary heart disease in this study is much weaker than that reported from previous clinic-based studies, possibly reflecting the older age of this cohort.