© 2004 American Thoracic Society
Endothelial Dysfunction and Sleep ApneaTo the Editor:We are interested in the articles by Nieto and colleagues (1) and Ip and colleagues (2) on the association between sleep apnea and endothelial dysfunction as reflected by the flow-mediated vasodilation measured by the change of brachial artery diameter after a 4-minute period of forearm ischemia. In an accompanying editorial, Imadojemu and colleagues (3) suggested that the reduced flow-mediated vasodilator responses may not be solely due to impaired endothelial function, but rather to other pathophysiologic mechanisms associated with sleep apnea, for example, increased resting sympathetic activity in sleep apnea. We suggest that the vascular dysfunction may indeed be mediated by other mechanisms, and it is not confined to adults or is it present only in sleep apnea. In a study of 30 children (mean age, 9.5 ± 2.8 years) with "primary snoring" (i.e., obstructive apnea and hypopnea less than one episode per hour), we compared the pulse wave velocity over the forearm between these snoring children with 30 healthy children matched for age, sex, and body size (4). The pulse wave velocity is inversely related to the square root of arterial distensibility. We found a higher pulse wave velocity in these primary snoring children (9.7 ± 1.6 m/second vs. 7.9 ± 2.0 m/second; p = 0.001). This was most likely secondary to increased resting sympathetic activity in these "primary snorers." The systolic and diastolic blood pressures were also found to be higher in the snoring children (112 ± 10 mm Hg vs. 105 ± 8 mm Hg, p = 0.001; and 60 ± 7 mm Hg vs. 53 ± 9 mm Hg, p = 0.004, respectively). Multiple regression analysis identified primary snoring as the only significant factor for increased pulse wave velocity. For systemic blood pressure, age, body mass index, and snoring were identified as significant factors. Thus, the vascular dysfunction could also be found in snoring children without sleep apnea. We believe that this vascular dysfunction is related to a multitude of mechanisms set off by a whole spectrum of sleep-disordered breathing ranging from primary snoring to obstructive sleep apnea syndrome.
Kwong Wah Hospital Hong Kong FOOTNOTES Conflict of Interest Statement: D.K.N. and K.L.K. do not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
From the Authors: We thank Drs. Ng and Kwok for their comments on our article (1). It is important, however, to recognize that arterial distensibility and flow-mediated vasodilator responses, although related, might reflect very distinct features of vascular anatomy and physiology. The first is a reflection of the stiffness of the vessel, mostly determined by the mechanoelastic properties of the vessel wall and mean vascular tone. The second is a function of the active release of nitric oxide and subsequent transient relaxation of the vascular smooth muscle. Nevertheless, there is some recent interest in the "dynamic" nature of arterial distensibility, with data to suggest that it may also be modulated by nitric oxide activity (2). Thus, the two phenotypes may be more strongly correlated than previously thought (3), and both may be adversely affected by sleep-disordered breathing and other cardiovascular risk factors. Ng and Kwok's observation suggests the possibility that vascular dysfunction and diminished arterial distensibility may occur in children, years before pathologic arterial changes are detected, and that sleep-disordered breathing may lead to a broad range of manifestations of vascular dysfunction (4).
a Wake Forest University School of Medicine Winston-Salem, North Carolina FOOTNOTES Conflict of Interest Statement: D.H., E.B., F.J.N., S.R., and J.R. do not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
From the Authors: We believe that vascular dysfunction in obstructive sleep apnea (OSA) is due to several underlying mechanisms, of which endothelial dysfunction is one. The method of Doppler measurement of hyperemic flow–mediated dilation of the brachial artery that we used (1) has been demonstrated to reflect endothelial function, although other mechanisms may be involved in the hyperemia response to forearm ischemia as stipulated by Imadojemu and colleagues (2). In our study, hyperemia flow-mediated dilation was found to be significantly different between subjects with OSA and control subjects without OSA (who did have snoring to variable extents) without significant difference in the hyperemia flow itself, and the flow-mediated dilation improved significantly after treatment of OSA. Hence, our conclusion was that endothelial function was adversely affected in OSA in adults. As explained, the lack of positive finding in nitroglycerin-induced dilation in our study could not exclude endothelium-independent mechanisms of vasculopathy, such as that related to sympathetic tone of the vessel, in OSA. The study was not designed to look into the effects of snoring itself. On the other hand, arterial distensibility as measured by the method described by Kwok and colleagues (3) was a measurement of pulse wave velocity without stimulus. The measurement would reflect multiple underlying mechanisms that control arterial distensibility, both endothelium-dependent and endothelium-independent.
University of Hong Kong Hong Kong SAR, China Acknowledgments M.I., H.F.T., and B.L. do not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
From the Editorialists: In their letter, Ng and Kwok suggest that the reduced flow-mediated vasodilator responses in patients with obstructive sleep apnea reported in the Journal by Ip and colleagues (1) and by Nieto and colleagues (2) may be due to mechanisms other than endothelial dysfunction and may not be confined to adults or to frank sleep apnea. They base this notion on their findings in children with "primary snoring" in whom sleep apnea was excluded by a polysomnogram. Compared with nonsnoring control subjects that were matched for age, sex, and body mass index, these children were found to exhibit increased arterial pulse wave velocity measured noninvasively in the conduit arteries of the forearm (3). Arterial pulse wave velocity is inversely related to arterial distensibility and, similar to flow-mediated dilation, has been found to predict cardiovascular risk in clinical studies (4). Thus, in this young age group, even a mild form of sleep-disordered breathing appears to be associated with altered vascular function. This observation is intriguing and indeed suggests that among different groups of patients and degrees of sleep-disordered breathing different mechanisms may be responsible for vascular dysfunction. However, direct comparisons between these studies require caution because Ip and colleagues (1) and Nieto and colleagues (2) did not distinctly examine patients with primary snoring, and Kwok and colleagues (3) did not include patients with frank sleep apnea in their studies. Furthermore, it is likely that the flow-mediated dilation and the pulse wave velocity techniques assess different aspects of vascular function. In the report by Ip and colleagues (1), the impairment of flow-mediated dilation was reversible with continuous positive airway pressure therapy and reemerged after therapy was discontinued. Thus, intermittent airway obstruction and/or the associated hypoxia or sleep disruption are likely responsible for the vascular dysfunction in their patients. In contrast, unless nonflow-limiting upper airway obstruction was overlooked in the snorers without apnea examined by Kwok and colleagues (3), a mechanism independent of airway obstruction, hypoxia, or sleep disruption may also be capable of altering vascular function. Clearly, snoring in children and sleep apnea in adults are not the same. Because primary snoring, when strictly defined, is not a well established independent risk factor for hypertension, cardiovascular events, or both (5), a careful examination of neural and vascular regulation in snoring in the absence of sleep apnea and other confounding factors is important.
Penn State College of Medicine Hershey, Pennsylvania FOOTNOTES Conflict of Interest Statement: V.A.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; L.I.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; U.A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
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