© 2004 American Thoracic Society
Vascular Dysfunction in Sleep ApneaA Reversible Link to Cardiovascular Disease?Pennsylvania State University College of Medicine Hershey, Pennsylvania In the past decade, obstructive sleep apnea has been increasingly recognized as an important and independent risk factor for cardiovascular disease. In addition, large cross-sectional and prospective studies have demonstrated that sleep-disordered breathing predicts hypertension, a major risk factor for cardiovascular disease, in a dose-dependent fashion (1, 2). The precise mechanism underlying this association, however, is not fully understood. Moreover, the independent contribution of obesity, which frequently coexists in these patients, to cardiovascular complications of sleep apnea is not clear. Two studies in this issue of the Journal add important insights regarding these questions. The investigators propose that sleep apnea is associated with endothelial dysfunction and that it may be reversible with nocturnal continuous positive airway pressure therapy (3, 4). These studies add further weight to the concept that sleep-disordered breathing has profound adverse consequences on cardiovascular health. Nieto and colleagues (3) report findings on flow-mediated vasodilation measured via high-frequency ultrasound in a subset of the Sleep Heart Health/Cardiovascular Health Study cohort comprising 1,037 largely asymptomatic subjects with variable degrees of sleep-disordered breathing. All subjects were elderly (older than 68 years) and most were female. Thus, these subjects were somewhat different from the typical patient with sleep apnea: a middle-aged man. Flow-mediated vasodilation was measured as the change of brachial artery diameter following a 4-minute period of forearm ischemia produced by inflation of a pneumatic cuff at the lower arm to suprasystolic pressure. The reactive hyperemia that follows the cuff deflation is associated with a transient brachial artery dilation, which is dependent on the release of the endothelial-derived relaxing factor nitric oxide (5). Therefore, flow-mediated vasodilation is commonly assumed to be an index of endothelial function. In a number of clinical settings, flow-mediated vasodilation has been shown to be a predictor of cardiovascular disease (6). Nieto and coworkers (3) found that: the percent of flow-mediated vasodilation was correlated inversely with the degree of sleep-disordered breathing; resting brachial artery diameter was linked directly to indices of sleep-disordered breathing; and both relationships were weakened when corrections for body-mass-index were made, suggesting that obesity per se may have deleterious effects on vascular structure and function. Whether increased resting arterial diameter can be considered a manifestation of vascular remodeling due to the atherosclerotic process is not clear. In the second report, Ip and coworkers (4) examined endothelium-dependent (flow-mediated vasodilation) and endothelium-independent vasodilation (sublingual nitroglycerin) in a younger group of men—28 patients with moderately severe sleep apnea and 12 control subjects. Flow-mediated vasodilation was lower in patients with sleep apnea than in the control subjects, and it varied inversely as a function of the apnea–hypopnea index, measures of nocturnal hypoxemia, and the arousal index. In contrast to the report by Nieto and coworkers (3), no independent effect of body-mass-index on flow-mediated vasodilation was noted. Importantly, Ip and coworkers (4) found that continuous positive airway pressure therapy increased the flow-mediated dilator response toward normal, suggesting nocturnal obstructive apneas as the cause of impaired vascular function in sleep apnea. These reports add to our understanding of sleep apnea by establishing a strong link between this disease process and the responses of conduit vessels in the forearm to ischemia. Despite the importance of these observations, however, when interpreting these findings several issues should be considered. First, the response of the brachial artery diameter to forearm ischemia may not be entirely linked to the release of nitric oxide, the putative mediator of flow-mediated vasodilation released by the vascular endothelium. Recent studies suggest that in endothelial nitric oxide synthase–deficient mice, conduit vessel dilation in response to shear stress still occurs (7). Second, the magnitude of the increase in brachial artery diameter following forearm ischemia is directly related to the peak flow response that follows the restoration of blood flow (8, 9). This is relevant because change in peak flow (and therefore shear stress) in response to forearm ischemia is attenuated in patients with sleep apnea (10). Third, the flow-mediated increase in brachial artery diameter is reduced when the sympathetic nervous system is activated (11) and resting sympathetic activity is increased in sleep apnea (12–14). For these reasons, the reduced flow-mediated vasodilator responses demonstrated in the reports published in this issue of the Journal may not be solely due to impaired endothelial function, but rather to other pathophysiologic mechanisms associated with sleep apnea that are capable of indirectly altering flow-mediated vascular responses. As is true of all good research, these reports raise as many important questions as they answer. For example, is impaired flow-mediated vasodilation in the human forearm representative of vascular dysfunction in other vascular beds? If impaired vasodilator function is endothelially mediated, are other biological functions accomplished by the endothelium also abnormal in sleep apnea? Are the peripheral vascular abnormalities seen in this syndrome independent of or are they linked to obesity? How does continuous positive airway pressure therapy improve vascular responses to ischemia in subjects with sleep-disordered breathing? And finally, is vascular dysfunction in sleep apnea a manifestation of enhanced oxidative stress and/or of systemic inflammation? Interest in the cardiovascular manifestations of sleep apnea has grown dramatically over the past few years. The reports on vascular function presented in this issue of the Journal represent important steps in the evolution of our understanding of the reasons cardiovascular morbidity and mortality are increased in sleep apnea. FOOTNOTES Conflict of Interest Statement: V.A.I., L.I.S., and U.A.L. have no declared conflicts of interest. REFERENCES
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