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 Impaired endothelium-dependent vascular relaxation is a prognos-
evaluate vascular reactivity, in particular endothelium-dependent tic marker of atherosclerosis and cardiovascular disease. We evalu-
flow-mediated dilation (FMD), in the brachial artery in subjects ated endothelium-dependent flow-mediated dilation (FMD) and
with OSA compared with subjects without OSA, and its response endothelium-independent nitroglycerin (NTG)–induced dilation of
to OSA treatment with nCPAP, in a randomized controlled the brachial artery with Doppler ultrasound in 28 men with obstruc-
tive sleep apnea (OSA) and 12 men without OSA. Subjects with
OSA (apnea–hypopnea index; mean
Ϯ SD, 46.0 Ϯ 14.5) had lower
FMD compared with subjects without OSA (5.3 Ϯ 1.7% vs. 8.3 Ϯ
1.0%, p Ͻ 0.001), and major determinants of FMD were the apnea–
Subjects and Study Protocol
hypopnea index and age. There was no significant difference in
Subjects were recruited from the Sleep Laboratory, University Depart- NTG-induced dilation. Subjects with OSA were randomized to nasal
ment of Medicine, Queen Mary Hospital. For sleep apnea subjects, continuous positive airway pressure (nCPAP) or observation for 4
inclusion criteria were apnea–hypopnea index (AHI) of 15 or more weeks. Subjects on nCPAP had significant increase in FMD, whereas
and male sex. Exclusion criteria were previous treatment for OSA, those on observation had no change (4.4% vs. Ϫ0.8%, difference
presence of structural heart disease, history of hypertension, dyslipide- of 5.2%, p Ͻ 0.001). Neither group showed significant change in
mia, diabetes mellitus, other chronic illness or medications (including NTG-induced vasodilation. Eight subjects who used nCPAP for over
over-the-counter medicines or “health tonics”), acute illness, or medica- 3 months were reassessed on withdrawing treatment for 1 week.
tions within the past 2 weeks. Male subjects with an AHI of less than On nCPAP withdrawal, FMD became lower than during treatment
5, matched to subjects with OSA for body mass index, were recruited (p ϭ 0.02) and were similar to baseline values. Our findings demon-
with similar exclusion criteria to form the normal control group.
strated that men with moderate/severe OSA have endothelial dys-
At baseline, all subjects underwent evaluation of clinical profile, function and treatment with nCPAP could reverse the dysfunction;
polysomnography, echocardiography, and vascular reactivity study.
the effect, however, was dependent on ongoing use.
Sleep apnea subjects were then randomized to receive nCPAP treat-ment or no intervention. After 4 weeks, they were reassessed with all Keywords: vascular reactivity; flow-mediated dilation; obstructive sleep
measurements except echocardiography. Patients who continued to use apnea; endothelial function; nasal continuous positive airway pressure nCPAP for at least 3 months were asked to stop nCPAP for 1 weekand were reassessed.
Obstructive sleep apnea (OSA) is associated with cardiovascular The study was approved by the ethics committee of The University diseases, including hypertension, coronary artery disease, heart of Hong Kong, and patients gave informed consent.
failure, and stroke (1–3). Various pathophysiologic mechanismsin sleep apnea have been proposed to contribute to the pathogen- Polysomnography
esis of vascular morbidity (4, 5). Repetitive episodes of hypo- Subjects underwent overnight polysomnography in the sleep laboratory xemia, hypercarbia, sympathetic activation, and intrathoracic (Alice 3 Diagnostics System; Respironics, Murrysville, PA) as pre- pressure swings in OSA (6–8) may trigger cellular and biochemi- viously described (19). Sleep data and respiratory events were manually cal processes, which predispose to atherosclerosis (9–12).
scored according to established criteria (20–22). AHI referred to theaverage number of apneas and hypopneas per sleep hour.
Endothelial dysfunction has been found to occur in response to cardiovascular risk factors and to precede or accelerate the Echocardiography and Vascular Reactivity Study
development of atherosclerosis (11, 12). It has also been shown Standard two-dimensional and Doppler echocardiogram was performed to have a clear predictive value for future cardiovascular disease at baseline. The method for measuring endothelium-dependent and (13, 14). Impairment of endothelium-dependent vasodilation, endothelium-independent brachial artery dilation has been described which is mainly mediated by nitric oxide, has been reported in previously (23). The brachial artery diameter was measured on B-mode OSA (15–18). We have previously shown that circulating nitric ultrasound images, with a 7.0-MHz linear-array transducer and Acuson oxide levels were decreased in OSA, and this could be reversed 128XP/10 system (Mountain View, CA). Longitudinal scans of the bra- by application of overnight nasal continuous positive airway pres- chial artery were obtained at rest, then during reactive hyperemia pro- sure (nCPAP) (19). We hypothesize that OSA contributes to duced by inflation of a pneumatic tourniquet placed on the forearm endothelial dysfunction. The present study was undertaken to followed by release, and finally after sublingual nitroglycerin (NTG)spray. FMD and NTG-induced dilation were defined as the percentagechange in diameter between the initial scan and after cuff deflation andNTG, respectively. Doppler-derived arterial flow was also measured atrest, during hyperemia, and after sublingual NTG, as described pre- (Received in original form June 10, 2003; accepted in final form October 7, 2003) viously (23). All scans were performed by H-F.T., who was blinded to Supported by grant no. 7307/00, Hong Kong Research Grants Council.
the status of sleep-disordered breathing or treatment of the subjects.
Correspondence and requests for reprints should be addressed to Mary S. M. Ip, Statistical Analysis
M.D., Department of Medicine, The University of Hong Kong, Queen Mary Hospi-tal, Pokfulam Road, Hong Kong SAR, China. E-mail: msmip@hkucc.hku.hk Continuous data were given as mean Ϯ SD. Between-group compari- This article has an online supplement, which is accessible from this issue’s table sons for continuous variables were made by Mann-Whitney U test and of contents online at www.atsjournals.org t test. Multiplicity of comparisons among groups was accounted byusing Bonferroni correction. Within-group comparisons for continuous Am J Respir Crit Care Med
Vol 169. pp 348–353, 2004
Originally Published in Press as DOI: 10.1164/rccm.200306-767OC on October 9, 2003
variables were made by Wilcoxon signed rank test and Friedman test Internet address: www.atsjournals.org
and for categorical variables by chi-square test. Associations between Ip, Tse, Lam, et al.: Endothelial Dysfunction in Sleep Apnea FMD and continuous parameters were described by Spearman’s rank Echocardiography and Vascular Reactivity Study
correlation coefficient and between FMD and categorical variables by Echocardiography did not demonstrate any overt abnormality Fisher’s exact test. Forward stepwise linear regression with baselineFMD as dependent variable was done. Deleted studentized residuals in all subjects, with left ventricular ejection fraction at 67.3 Ϯ of the regression model were examined for validity of model assump- 7.0%. At baseline, subjects with OSA had significantly lower tions. A two-sided p value of less than 0.05 was considered statistically FMD at 5.3 Ϯ 1.7% compared with subjects without OSA at significant. Statistical analysis was made with SPSS for Windows (ver- 8.4 Ϯ 1.0%, with a mean difference of 3.03% (p Ͻ 0.001; 95% sion 11.0.1; SPSS, Inc., Chicago, IL).
confidence interval, 1.96–4.1%). NTG-induced dilation was simi-lar at 15.7 Ϯ 4.0% in subjects with OSA and 17.7 Ϯ 4.6% in those without OSA (p ϭ 0.17) (Table E4).
Correlation analysis (n ϭ 40) showed that FMD correlated Patient Characteristics
negatively with AHI (r ϭ Ϫ0.655, p Ͻ 0.001) (Figure 1), time Twenty-eight men with OSA (AHI, 46.0 Ϯ 14.5) were recruited with oxygen saturation of less than 90% (r ϭ Ϫ0.620, p Ͻ 0.001), and randomized to treatment (nCPAP) group and the control and arousal index (r ϭ Ϫ0.516, p ϭ 0.001) and positively with (observation) group, and 12 men without OSA (AHI 2.4 Ϯ 2.0), minimum oxygen saturation (r ϭ 0.577, p Ͻ 0.001). FMD did matched to OSA group for body mass index, were recruited.
not show significant correlation with age, body mass index, waist Their baseline characteristics are shown in Table 1 and Table E1 circumference, lipids, glucose, blood pressure, and Epworth All subjects in the nCPAP group completed the 4-week evalu- Stepwise multiple linear regression analysis showed that AHI ation, but one subject in the control group withdrew (he decided and age were significant determinants of baseline FMD, indepen- to use nCPAP). Objective data on use of nCPAP during the dent of body mass index, diastolic blood pressure, total choles- 4 weeks averaged 4.3 hours per night. The two groups were terol, and smoking status (Table 3). When AHI was replaced comparable at baseline, and both groups had no significant by other sleep parameters (time with oxygen saturation of less change in anthropometric and metabolic profile over the 4-week than 90%, minimum oxygen saturation, arousal index), the sleep study period (Table E2 in online supplement). Diastolic blood indices were shown up as significant determinants of FMD, re- pressure decreased in the nCPAP group (77.9 Ϯ 11.1 to 69.2 Ϯ spectively (Table E5 in online supplement).
15.2 mm Hg, p ϭ 0.04) but not in the control group.
After 4 weeks, those who received nCPAP had a significant Eight subjects who have used nCPAP for a median duration increase in FMD from 5.1 Ϯ 1.4% to 9.6 Ϯ 1.6% (p ϭ 0.001) of 15 weeks, range of 12–30 weeks, were reassessed after stopping (Figure 2A), whereas those on observation had no significant nCPAP for 1 week. Self-reported compliance to nCPAP was at change from 5.6 Ϯ 2.0% to 4.7 Ϯ 1.2% (p ϭ 0.12) (Figure 2B).
an average of 5 nights per week, 4.2 hours per night. There was The between-group difference of the change in FMD was highly no significant change in anthropometric, metabolic profile, and significant (4.5% vs. Ϫ0.9%, difference of 5.4%, p Ͻ 0.001).
Both groups had no significant change in NTG-induced dilation, blood pressure during the study period (see Table E3 in online and the between-group difference of the change in NTG-induced dilation was not significant (1.5% vs. 1.1%, difference of 0.4%, Polysomnography Data
p ϭ 0.67) (Table 4 and Table E6 in the online supplement).
In the eight subjects who further used nCPAP and then with- At baseline, OSA patients had moderate to severe sleep- drew for 1 week, FMD after nCPAP withdrawal was significantly disordered breathing, with no significant difference between lower than that at 4 weeks of nCPAP (on nCPAP 8.9 Ϯ 1.9%, nCPAP and control group (Table 2). At 4 weeks, the treatment off nCPAP 5.0 Ϯ 0.7%, p ϭ 0.02) and was similar to baseline group demonstrated abolition of apneas and hypopneas while (Figure 3). NTG-induced dilation showed no significant change using nCPAP, and the control group showed little change from at the three assessments (see Table E7 in online supplement).
The eight subjects who were further reassessed longitudinally DISCUSSION
demonstrated no significant change in the severity of sleep-disordered breathing after several months compared with base- The findings demonstrated that otherwise healthy subjects with line (baseline vs. off treatment, AHI, 52.4 Ϯ 13.4 vs. 53.2 Ϯ 21.5; OSA have impaired endothelium-dependent flow-mediated vaso- minimum oxygen saturation, 64.0 Ϯ 10.9% vs. 66.3 Ϯ 16.2%; dilation in the brachial artery compared with subjects without time with oxygen saturation less than 90%, 112.9 Ϯ 79.5 vs.
OSA, and the endothelial dysfunction was reversed after treat- 91.6 Ϯ 78.5 minutes; all p Ͼ 0.05).
ment with nCPAP for 4 weeks. This improvement in endothelial TABLE 1. BASELINE CHARACTERISTICS
Definition of abbreviations: nCPAP ϭ nasal continuous positive airway pressure; OSA ϭ obstructive sleep apnea.
No significant difference was detected between obstructive sleep apnea and normal subjects or between obstructive sleep apnea–continuous positive airway pressure and obstructive sleep apnea–control groups.
Time with oxygen saturation of less than 90%, min For definition of abbreviations see Table 1.
* p р 0.001 for comparison between baseline and 4-week within the nasal continuous positive airway pressure group. No significant differences were found within the control group.
† p р 0.001 for comparison between nasal continuous positive airway pressure and control groups at 4 weeks. No significant differences were found between the two groups at baseline.
The obstructive sleep apnea–control group data excludes one patient who withdrew from study.
function was not sustained after stopping nCPAP treatment for endothelial function in OSA have shown conflicting data.
1 week, despite previous use for several months.
Blunted vasodilation in response to infusion of acetylcholine, a OSA syndrome is a global problem that occurs in 1–5% of vasodilator that stimulates endothelial release of nitric oxide, adult men and 1–2% of adult women of various ethnic popula- was demonstrated in forearm resistance vessels using occlusion tions (24). OSA has many adverse physiologic consequences that plethysmography (15, 16), but not confirmed in a more recent potentially constitute risks for development of cardiovascular study (32). Impaired relaxation response to bradykinin in the diseases. One of the postulated mechanisms is that it can precipi- forearm venous vasculature has been reported, suggesting endo- tate or accelerate atherosclerosis, although to date there is no thelial dysfunction in the venous vasculature (18). Using ultra- sound Doppler method similar to ours, impairment of FMD in The vascular endothelium participates in control of various the brachial artery was reported to correlate with minimum vascular functions through regulation of vasoactive mediators oxygen saturation in subjects with OSA (17). In contrast to in response to physical or biochemical stimuli in the body. Endo- our findings, another study found no significant difference in thelial injury, at cellular level or tissue level, is an important conduit–vessel dilation between sleep apnea and control subjects initial event in atherogenesis, preceding thickening of intima (16). In that study, subjects underwent conduit–vessel studies at and formation of atherosclerotic plaques (11, 12). Endothelial least 1 hour after resistance–vessel studies, which involved intra-arterial infusion of acetylcholine, nitroprusside and verapamil, dysfunction has been detected in disease states characterized by and residual effect of drugs on the vasculature, which affected atherosclerosis (11, 12) and also in conditions that predispose their response to reactive hyperemia, cannot be completely to atherosclerosis such as hypercholesterolemia and cigarette excluded. Recently, impaired hyperemic blood flow response mea- smoking, indicating that it is a marker of early atherogenesis sured by forearm plethysmography, an indicator of altered myo- (23, 25, 26). Endothelial dysfunction was shown to have a pre- genic and/or endothelial activity, was reported, and seven subjects dictive value for cardiovascular events in patients with chest pain showed improvement with use of nCPAP for 2 weeks (33).
and/or coronary artery disease (13, 14).
These studies have used different methods for evaluation Various circulating markers of endothelial dysfunction (27), of vascular endothelial function. The mechanisms of vascular including nitric oxide, soluble cell adhesion molecules, fibrino- response to vessel occlusion followed by reactive hyperemia are gen, and plasminogen activator inhibitor, have been reported to clearly complex, involving myogenic, neurogenic, and vasculo- be altered in OSA (1, 10, 28–31). Previous studies on vascular genic components, mediated by a variety of metabolic alterationsand vasoactive factors (34–36). The exact mechanisms appar-ently differ with vascular beds and evoking stimuli (35, 36). Usingsimilar techniques, hyperemic FMD in the brachial artery orother conduit vessels has been demonstrated to reflect endothe-lial 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 TABLE 3. STEPWISE MULTIPLE LINEAR REGRESSION MODEL
Figure 1. Correlation between baseline flow-mediated dilation of bra-
The excluded parameters include body mass index, diastolic blood pressure, chial artery and apnea–hypopnea index in obstructive sleep apnea (OSA) total cholesterol, and smoking history.
and subjects without OSA (n ϭ 40, r ϭ Ϫ0.655, p Ͻ 0.001).
Ip, Tse, Lam, et al.: Endothelial Dysfunction in Sleep Apnea ences in the response to endothelium-independent smooth mus-cle vasodilators might emerge.
“Uncomplicated” central obesity has been reported to be associated with impaired endothelial function (43), but the OSAstatus of those subjects has not been defined. We postulate thatthe endothelial dysfunction attributed to obesity was at leastpartly related to the presence of OSA in some of these subjects.
In this study, OSA and subjects without OSA were matched forobesity, and the body mass index was not a significant indepen-dent determinant of FMD on multiple regression analysis. Thechange in FMD with treatment of OSA without any concomitantchange in body weight and the use of a control group who didnot receive nCPAP treatment provided further evidence thatthe 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 trendfor higher diastolic blood pressure in subjects with OSA and asignificant decrease in those treated with nCPAP, findings thatwere consistent with previous studies of OSA (44). There arefew data regarding the effect of blood pressure within the normo-tensive range on endothelial function. Hence, the role playedby the differences in blood pressure, if any, in the changes inendothelial function seen in these subjects is not known.
Figure 2. (A) Flow-mediated dilation of brachial artery in 14 subjects
Sleep debt per se has been reported to result in increased with OSA at baseline and after 4 weeks of nasal continuous positive sympathetic nervous system activity and decreased glucose airway pressure (nCPAP), showing significant increase in flow-mediated tolerance (45), which theoretically may lead to alterations in dilation (p ϭ 0.001). (B) Flow-mediated dilation of brachial artery in endothelial function. The lack of correlation between endothelial 13 subjects with OSA at baseline and after 4 weeks of observation, function and sleepiness score, an indicator of sleep debt, appar- showing no change in flow-mediated dilation (p ϭ 0.12).
ently did not support this speculation. However, our study wasnot designed to investigate this issue, and the relationship be-tween sleep debt and endothelial function remains to beexplored.
to coronary atherosclerosis because it has been shown to corre- Endothelial nitric oxide plays a central role in endothelial func- late closely with endothelium-dependent vasomotor response of tion (46) and endothelium-dependent flow mediated vasodilation of the brachial artery (36–38). Many pathogenetic mechanisms We have not been able to demonstrate any significant change that may impair endothelium-dependent nitric oxide–mediated in response to NTG, which produces brachial artery dilation vasodilation have been shown to be present in OSA. During mediated by vascular smooth muscle, independent of the endo- recurrent apneas and hypopneas, the vascular endothelium is thelium (38). In studies of subjects with OSA, results of vascular conceivably subjected to recurrent shear stress and hypoxemia– smooth muscle function have been variable. Again, studies have reoxygenation, which may result in decreased synthesis or en- used different evaluation techniques. Two studies that used ultra- hanced degradation of endothelial nitric oxide (10, 46), and sound Doppler to evaluate the brachial artery did not show any recent studies have demonstrated that circulating nitric oxide impairment of NTG-induced vasodilation in subjects with OSA levels were decreased in subjects with OSA (10, 19). Other (16) nor correlation with any measure of sleep apnea (17) . In mechanisms for impaired nitric oxide–mediated endothelial studies using other methods, conflicting data have been reported.
function, including increased oxidant load, enhanced oxidation One study showed heightened vasoconstrictor sensitivity in OSA of low density lipoprotein, insulin resistance, and increased sym- (32), whereas others did not demonstrate significant differences pathetic activity (46, 47), have been demonstrated to be present (15, 16, 18). However, the numbers of subjects in individual studies, including ours, have been small, and it is possible that Because recurrent hypoxia–reoxygenation is believed to be with substantially larger numbers of subjects, significant differ- a key process that triggers endothelial dysfunction in OSA, it is TABLE 4. VASCULAR REACTIVITY OF BRACHIAL ARTERY IN OBSTRUCTIVE SLEEP APNEA SUBJECTS
For definition of abbreviations see Table 1.
* p р 0.001 for within-group comparison between baseline and 4 weeks.
† p р 0.001 for between-group comparison of changes at 4 weeks.
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