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Published ahead of print on October 9, 2003, doi:10.1164/rccm.200306-767OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 348-353, (2004)
© 2004 American Thoracic Society

Endothelial Function in Obstructive Sleep Apnea and Response to Treatment

Mary S. M. Ip, Hung-Fat Tse, Bing Lam, Kenneth W. T. Tsang and Wah-Kit Lam

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Correspondence and requests for reprints should be addressed to Mary S. M. Ip, M.D., Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China. E-mail: msmip{at}hkucc.hku.hk


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Impaired endothelium-dependent vascular relaxation is a prognostic marker of atherosclerosis and cardiovascular disease. We evaluated endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin (NTG)–induced dilation of the brachial artery with Doppler ultrasound in 28 men with obstructive sleep apnea (OSA) and 12 men without OSA. Subjects with OSA (apnea–hypopnea index; mean ± SD, 46.0 ± 14.5) had lower FMD compared with subjects without OSA (5.3 ± 1.7% vs. 8.3 ± 1.0%, p < 0.001), and major determinants of FMD were the apnea–hypopnea index and age. There was no significant difference in NTG-induced dilation. Subjects with OSA were randomized to nasal continuous positive airway pressure (nCPAP) or observation for 4 weeks. Subjects on nCPAP had significant increase in FMD, whereas those on observation had no change (4.4% vs. -0.8%, difference of 5.2%, p < 0.001). Neither group showed significant change in NTG-induced vasodilation. Eight subjects who used nCPAP for over 3 months were reassessed on withdrawing treatment for 1 week. On nCPAP withdrawal, FMD became lower than during treatment (p = 0.02) and were similar to baseline values. Our findings demonstrated that men with moderate/severe OSA have endothelial dysfunction and treatment with nCPAP could reverse the dysfunction; the effect, however, was dependent on ongoing use.

Key Words: vascular reactivity • flow-mediated dilation • obstructive sleep apnea • endothelial function • nasal continuous positive airway pressure

Obstructive sleep apnea (OSA) is associated with cardiovascular diseases, including hypertension, coronary artery disease, heart failure, and stroke (1–3). Various pathophysiologic mechanisms in sleep apnea have been proposed to contribute to the pathogenesis of vascular morbidity (4, 5). Repetitive episodes of hypoxemia, hypercarbia, sympathetic activation, and intrathoracic pressure swings in OSA (6–8) may trigger cellular and biochemical processes, which predispose to atherosclerosis (9–12).

Endothelial dysfunction has been found to occur in response to cardiovascular risk factors and to precede or accelerate the development of atherosclerosis (11, 12). It has also been shown to have a clear predictive value for future cardiovascular disease (13, 14). Impairment of endothelium-dependent vasodilation, which is mainly mediated by nitric oxide, has been reported in OSA (15–18). We have previously shown that circulating nitric oxide levels were decreased in OSA, and this could be reversed by application of overnight nasal continuous positive airway pressure (nCPAP) (19). We hypothesize that OSA contributes to endothelial dysfunction. The present study was undertaken to evaluate vascular reactivity, in particular endothelium-dependent flow-mediated dilation (FMD), in the brachial artery in subjects with OSA compared with subjects without OSA, and its response to OSA treatment with nCPAP, in a randomized controlled study.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Study Protocol
Subjects were recruited from the Sleep Laboratory, University Department of Medicine, Queen Mary Hospital. For sleep apnea subjects, inclusion criteria were apnea–hypopnea index (AHI) of 15 or more and male sex. Exclusion criteria were previous treatment for OSA, presence of structural heart disease, history of hypertension, dyslipidemia, diabetes mellitus, other chronic illness or medications (including over-the-counter medicines or "health tonics"), acute illness, or medications within the past 2 weeks. Male subjects with an AHI of less than 5, matched to subjects with OSA for body mass index, were recruited with similar exclusion criteria to form the normal control group.

At baseline, all subjects underwent evaluation of clinical profile, polysomnography, echocardiography, and vascular reactivity study. Sleep apnea subjects were then randomized to receive nCPAP treatment or no intervention. After 4 weeks, they were reassessed with all measurements except echocardiography. Patients who continued to use nCPAP for at least 3 months were asked to stop nCPAP for 1 week and were reassessed.

The study was approved by the ethics committee of The University of Hong Kong, and patients gave informed consent.

Polysomnography
Subjects underwent overnight polysomnography in the sleep laboratory (Alice 3 Diagnostics System; Respironics, Murrysville, PA) as previously described (19). Sleep data and respiratory events were manually scored according to established criteria (20–22). AHI referred to the average number of apneas and hypopneas per sleep hour.

Echocardiography and Vascular Reactivity Study
Standard two-dimensional and Doppler echocardiogram was performed at baseline. The method for measuring endothelium-dependent and endothelium-independent brachial artery dilation has been described previously (23). The brachial artery diameter was measured on B-mode ultrasound images, with a 7.0-MHz linear-array transducer and Acuson 128XP/10 system (Mountain View, CA). Longitudinal scans of the brachial artery were obtained at rest, then during reactive hyperemia produced by inflation of a pneumatic tourniquet placed on the forearm followed by release, and finally after sublingual nitroglycerin (NTG) spray. FMD and NTG-induced dilation were defined as the percentage change in diameter between the initial scan and after cuff deflation and NTG, respectively. Doppler-derived arterial flow was also measured at rest, during hyperemia, and after sublingual NTG, as described previously (23). All scans were performed by H-F.T., who was blinded to the status of sleep-disordered breathing or treatment of the subjects.

Statistical Analysis
Continuous data were given as mean ± SD. Between-group comparisons for continuous variables were made by Mann-Whitney U test and t test. Multiplicity of comparisons among groups was accounted by using Bonferroni correction. Within-group comparisons for continuous variables were made by Wilcoxon signed rank test and Friedman test and for categorical variables by chi-square test. Associations between FMD and continuous parameters were described by Spearman's rank correlation coefficient and between FMD and categorical variables by Fisher's exact test. Forward stepwise linear regression with baseline FMD as dependent variable was done. Deleted studentized residuals of the regression model were examined for validity of model assumptions. A two-sided p value of less than 0.05 was considered statistically significant. Statistical analysis was made with SPSS for Windows (version 11.0.1; SPSS, Inc., Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Twenty-eight men with OSA (AHI, 46.0 ± 14.5) were recruited and randomized to treatment (nCPAP) group and the control (observation) group, and 12 men without OSA (AHI 2.4 ± 2.0), matched to OSA group for body mass index, were recruited. Their baseline characteristics are shown in Table 1 and Table E1 in online supplement.


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  		TABLE 1. Baseline characteristics

 
All subjects in the nCPAP group completed the 4-week evaluation, but one subject in the control group withdrew (he decided to use nCPAP). Objective data on use of nCPAP during the 4 weeks averaged 4.3 hours per night. The two groups were comparable at baseline, and both groups had no significant change in anthropometric and metabolic profile over the 4-week study period (Table E2 in online supplement). Diastolic blood pressure decreased in the nCPAP group (77.9 ± 11.1 to 69.2 ± 15.2 mm Hg, p = 0.04) but not in the control group.

Eight subjects who have used nCPAP for a median duration of 15 weeks, range of 12–30 weeks, were reassessed after stopping nCPAP for 1 week. Self-reported compliance to nCPAP was at an average of 5 nights per week, 4.2 hours per night. There was no significant change in anthropometric, metabolic profile, and blood pressure during the study period (see Table E3 in online supplement).

Polysomnography Data
At baseline, OSA patients had moderate to severe sleep-disordered breathing, with no significant difference between nCPAP and control group (Table 2) . At 4 weeks, the treatment group demonstrated abolition of apneas and hypopneas while using nCPAP, and the control group showed little change from baseline (Table 2).


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  		TABLE 2. Polysomnogram data of obstructive sleep apnea subjects

 
The eight subjects who were further reassessed longitudinally demonstrated no significant change in the severity of sleep-disordered breathing after several months compared with baseline (baseline vs. off treatment, AHI, 52.4 ± 13.4 vs. 53.2 ± 21.5; minimum oxygen saturation, 64.0 ± 10.9% vs. 66.3 ± 16.2%; time with oxygen saturation less than 90%, 112.9 ± 79.5 vs. 91.6 ± 78.5 minutes; all p > 0.05).

Echocardiography and Vascular Reactivity Study
Echocardiography did not demonstrate any overt abnormality in all subjects, with left ventricular ejection fraction at 67.3 ± 7.0%. At baseline, subjects with OSA had significantly lower FMD at 5.3 ± 1.7% compared with subjects without OSA at 8.4 ± 1.0%, with a mean difference of 3.03% (p < 0.001; 95% confidence interval, 1.96–4.1%). NTG-induced dilation was similar at 15.7 ± 4.0% in subjects with OSA and 17.7 ± 4.6% in those without OSA (p = 0.17) (Table E4).

Correlation analysis (n = 40) showed that FMD correlated negatively with AHI (r = -0.655, p < 0.001) (Figure 1) , time with oxygen saturation of less than 90% (r = -0.620, p < 0.001), and arousal index (r = -0.516, p = 0.001) and positively with minimum oxygen saturation (r = 0.577, p < 0.001). FMD did not show significant correlation with age, body mass index, waist circumference, lipids, glucose, blood pressure, and Epworth Sleepiness Scale score.



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  		Figure 1. Correlation between baseline flow-mediated dilation of brachial artery and apnea–hypopnea index in obstructive sleep apnea (OSA) and subjects without OSA (n = 40, r = -0.655, p < 0.001).

 
Stepwise multiple linear regression analysis showed that AHI and age were significant determinants of baseline FMD, independent of body mass index, diastolic blood pressure, total cholesterol, and smoking status (Table 3) . When AHI was replaced by other sleep parameters (time with oxygen saturation of less than 90%, minimum oxygen saturation, arousal index), the sleep indices were shown up as significant determinants of FMD, respectively (Table E5 in online supplement).


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  		TABLE 3. Stepwise multiple linear regression model of baseline flow-mediated dilation*

 
After 4 weeks, those who received nCPAP had a significant increase in FMD from 5.1 ± 1.4% to 9.6 ± 1.6% (p = 0.001) (Figure 2A) , whereas those on observation had no significant change from 5.6 ± 2.0% to 4.7 ± 1.2% (p = 0.12) (Figure 2B). The between-group difference of the change in FMD was highly significant (4.5% vs. -0.9%, difference of 5.4%, p < 0.001). Both groups had no significant change in NTG-induced dilation, and the between-group difference of the change in NTG-induced dilation was not significant (1.5% vs. 1.1%, difference of 0.4%, p = 0.67) (Table 4 and Table E6 in the online supplement).




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  		Figure 2. (A) Flow-mediated dilation of brachial artery in 14 subjects with OSA at baseline and after 4 weeks of nasal continuous positive airway pressure (nCPAP), showing significant increase in flow-mediated dilation (p = 0.001). (B) Flow-mediated dilation of brachial artery in 13 subjects with OSA at baseline and after 4 weeks of observation, showing no change in flow-mediated dilation (p = 0.12).

 

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  		TABLE 4. Vascular reactivity of brachial artery in obstructive sleep apnea subjects

 
In the eight subjects who further used nCPAP and then withdrew for 1 week, FMD after nCPAP withdrawal was significantly lower than that at 4 weeks of nCPAP (on nCPAP 8.9 ± 1.9%, off nCPAP 5.0 ± 0.7%, p = 0.02) and was similar to baseline (Figure 3) . NTG-induced dilation showed no significant change at the three assessments (see Table E7 in online supplement).



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  		Figure 3. Serial changes in flow-mediated dilation of brachial artery at baseline, after 4 weeks of nCPAP, and 1 week after withdrawal of nCPAP in eight subjects with OSA. After withdrawal of nCPAP, flow-mediated dilation was lower than during treatment (p = 0.02).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The findings demonstrated that otherwise healthy subjects with OSA have impaired endothelium-dependent flow-mediated vasodilation in the brachial artery compared with subjects without OSA, and the endothelial dysfunction was reversed after treatment with nCPAP for 4 weeks. This improvement in endothelial function was not sustained after stopping nCPAP treatment for 1 week, despite previous use for several months.

OSA syndrome is a global problem that occurs in 1–5% of adult men and 1–2% of adult women of various ethnic populations (24). OSA has many adverse physiologic consequences that potentially constitute risks for development of cardiovascular diseases. One of the postulated mechanisms is that it can precipitate or accelerate atherosclerosis, although to date there is no direct evidence for this (1, 4, 5).

The vascular endothelium participates in control of various vascular functions through regulation of vasoactive mediators in response to physical or biochemical stimuli in the body. Endothelial injury, at cellular level or tissue level, is an important initial event in atherogenesis, preceding thickening of intima and formation of atherosclerotic plaques (11, 12). Endothelial dysfunction has been detected in disease states characterized by atherosclerosis (11, 12) and also in conditions that predispose to atherosclerosis such as hypercholesterolemia and cigarette smoking, indicating that it is a marker of early atherogenesis (23, 25, 26). Endothelial dysfunction was shown to have a predictive value for cardiovascular events in patients with chest pain and/or coronary artery disease (13, 14).

Various circulating markers of endothelial dysfunction (27), including nitric oxide, soluble cell adhesion molecules, fibrinogen, and plasminogen activator inhibitor, have been reported to be altered in OSA (1, 10, 28–31). Previous studies on vascular endothelial function in OSA have shown conflicting data. Blunted vasodilation in response to infusion of acetylcholine, a vasodilator that stimulates endothelial release of nitric oxide, was demonstrated in forearm resistance vessels using occlusion plethysmography (15, 16), but not confirmed in a more recent study (32). Impaired relaxation response to bradykinin in the forearm venous vasculature has been reported, suggesting endothelial dysfunction in the venous vasculature (18). Using ultrasound Doppler method similar to ours, impairment of FMD in the brachial artery was reported to correlate with minimum oxygen saturation in subjects with OSA (17). In contrast to our findings, another study found no significant difference in conduit–vessel dilation between sleep apnea and control subjects (16). In that study, subjects underwent conduit–vessel studies at least 1 hour after resistance–vessel studies, which involved intra-arterial infusion of acetylcholine, nitroprusside and verapamil, and residual effect of drugs on the vasculature, which affected their response to reactive hyperemia, cannot be completely excluded. Recently, impaired hyperemic blood flow response measured by forearm plethysmography, an indicator of altered myogenic and/or endothelial activity, was reported, and seven subjects showed improvement with use of nCPAP for 2 weeks (33).

These studies have used different methods for evaluation of vascular endothelial function. The mechanisms of vascular response to vessel occlusion followed by reactive hyperemia are clearly complex, involving myogenic, neurogenic, and vasculogenic components, mediated by a variety of metabolic alterations and vasoactive factors (34–36). The exact mechanisms apparently differ with vascular beds and evoking stimuli (35, 36). Using similar techniques, hyperemic FMD in the brachial artery or other conduit vessels has been demonstrated to reflect endothelial function, mainly mediated by endothelial nitric oxide (37–39). The test has been shown to be accurate and reproducible (40). It is regarded as a useful surrogate in assessing predisposition to coronary atherosclerosis because it has been shown to correlate closely with endothelium-dependent vasomotor response of the coronary arteries (41, 42).

We have not been able to demonstrate any significant change in response to NTG, which produces brachial artery dilation mediated by vascular smooth muscle, independent of the endothelium (38). In studies of subjects with OSA, results of vascular smooth muscle function have been variable. Again, studies have used different evaluation techniques. Two studies that used ultrasound Doppler to evaluate the brachial artery did not show any impairment of NTG-induced vasodilation in subjects with OSA (16) nor correlation with any measure of sleep apnea (17) . In studies using other methods, conflicting data have been reported. One study showed heightened vasoconstrictor sensitivity in OSA (32), whereas others did not demonstrate significant differences (15, 16, 18). However, the numbers of subjects in individual studies, including ours, have been small, and it is possible that with substantially larger numbers of subjects, significant differences in the response to endothelium-independent smooth muscle vasodilators might emerge.

"Uncomplicated" central obesity has been reported to be associated with impaired endothelial function (43), but the OSA status of those subjects has not been defined. We postulate that the endothelial dysfunction attributed to obesity was at least partly related to the presence of OSA in some of these subjects. In this study, OSA and subjects without OSA were matched for obesity, and the body mass index was not a significant independent determinant of FMD on multiple regression analysis. The change in FMD with treatment of OSA without any concomitant change in body weight and the use of a control group who did not receive nCPAP treatment provided further evidence that the improvement in endothelial function in this study sample, most of whom were obese, was attributed to the use of nCPAP, whereas a placebo effect could not be definitively excluded.

Hypertension is associated with endothelial dysfunction (25). Our subjects were normotensive, although there was a trend for higher diastolic blood pressure in subjects with OSA and a significant decrease in those treated with nCPAP, findings that were consistent with previous studies of OSA (44). There are few data regarding the effect of blood pressure within the normotensive range on endothelial function. Hence, the role played by the differences in blood pressure, if any, in the changes in endothelial function seen in these subjects is not known.

Sleep debt per se has been reported to result in increased sympathetic nervous system activity and decreased glucose tolerance (45), which theoretically may lead to alterations in endothelial function. The lack of correlation between endothelial function and sleepiness score, an indicator of sleep debt, apparently did not support this speculation. However, our study was not designed to investigate this issue, and the relationship between sleep debt and endothelial function remains to be explored.

Endothelial nitric oxide plays a central role in endothelial function (46) and endothelium-dependent flow mediated vasodilation of the brachial artery (36–38). Many pathogenetic mechanisms that may impair endothelium-dependent nitric oxide–mediated vasodilation have been shown to be present in OSA. During recurrent apneas and hypopneas, the vascular endothelium is conceivably subjected to recurrent shear stress and hypoxemia–reoxygenation, which may result in decreased synthesis or enhanced degradation of endothelial nitric oxide (10, 46), and recent studies have demonstrated that circulating nitric oxide levels were decreased in subjects with OSA (10, 19). Other mechanisms for impaired nitric oxide–mediated endothelial function, including increased oxidant load, enhanced oxidation of low density lipoprotein, insulin resistance, and increased sympathetic activity (46, 47), have been demonstrated to be present in OSA (10, 33, 48, 49).

Because recurrent hypoxia–reoxygenation is believed to be a key process that triggers endothelial dysfunction in OSA, it is interesting to note that AHI instead of hypoxemia indices showed the best predictive value for reduced FMD. The ideal parameter of stress quantification in sleep-disordered breathing is still to be delineated. AHI embraces some information of hypoxemia because of the defining criteria for apnea and hypopnea and, in addition, indicates the frequency of events that pose recurrent oxidative, mechanical, or neurohormonal stimuli. It may therefore be able to reflect total endothelial stress due to sleep-disordered breathing despite many limitations.

Some risk factor intervention or drug treatment have shown favorable effects on endothelial function, including smoking cessation, lipid lowering drugs, antioxidants, and antihypertensive drugs (14, 25, 37, 50). Some of these therapeutic maneuvers also result in a decrease in clinical ischemic events (50, 51), suggesting that at least part of the observed clinical benefits may be related to reversal of endothelial dysfunction. Our findings demonstrated that nCPAP therapy can correct endothelial dysfunction in OSA, but the beneficial effect was not apparent on withdrawal of nCPAP for 1 week, despite previous treatment for several months, suggesting that the endothelial dysfunction was related to relatively acute pathophysiologic changes. However, our study design does not allow more precise information to be derived regarding the temporal relationship between changes in endothelial function and OSA treatment.

In summary, the findings of endothelium-dependent vascular dysfunction in otherwise healthy subjects with OSA and the reversibility of such dysfunction with treatment of sleep apnea lend strong circumstantial evidence to an independent contribution of OSA to atherosclerosis. They also connotate the possibility that treatment of OSA may prevent its long-term cardiovascular morbidity. However, the subjects in this study are men with moderate to severe OSA, and findings may not extrapolate to those with mild sleep apnea or to women. Furthermore, the study subjects had no overt atherosclerotic disease, and it is not known whether endothelial dysfunction attributable to OSA will be similarly reversible in those subjects who also have established hypertension or other atherosclerotic vascular diseases.


   Acknowledgments
 
The authors gratefully acknowledge Dr. Daniel Fong, Senior Medical Statistician, Clinical Trials Centre, The University of Hong Kong, for expert statistical advice; Ms. Audrey Ip for technical assistance; and Ms. Agnes Lai and Ms. Wendy Mok for assistance in statistical analysis.


   FOOTNOTES
 
Supported by grant no. 7307/00, Hong Kong Research Grants Council.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: M.S.M.I. has no declared conflict of interest; H-F.T. has no declared conflict of interest; B.L. has no declared conflict of interest; K.W.T.T. has no declared conflict of interest; W-K.L. has no declared conflict of interest.

Received in original form June 10, 2003; accepted in final form October 7, 2003


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