Published ahead of print on July 24, 2008, doi:10.1164/rccm.200805-717OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200805-717OC
Endothelial Function and Arterial Stiffness in Minimally Symptomatic Obstructive Sleep Apnea1 Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford, United Kingdom; and 2 Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, United Kingdom Correspondence and requests for reprints should be addressed to Malcolm Kohler, M.D., Oxford Centre for Respiratory Medicine, Churchill Hospital, Headington, Oxford OX3 7LJ, UK. E-mail: malcolm.k{at}bluewin.ch
Rationale: Moderate–severe obstructive sleep apnea (OSA) is associated with endothelial dysfunction, increased arterial stiffness, and hypertension. It is not known whether minimally symptomatic OSA is also associated with impaired vascular function. Objectives: To determine whether minimally symptomatic OSA is associated with impaired vascular function. Methods: In 64 patients (7 females) with minimally symptomatic OSA (oxygen desaturation index, 23.1 [SD, 15.6]; Epworth Sleepiness Scale score, 8 [SD, 3.8]), and 15 matched control subjects without OSA, endothelial function was assessed by ultrasonographic measurement of flow-mediated dilatation, and by applanation tonometry–derived pulse wave analysis (forearm ischemia and salbutamol-induced changes in augmentation index, AIx). Arterial stiffness was assessed by AIx and ambulatory blood pressure (ABP) was measured over 1 week. Measurements and Main Results: In patients with OSA, flow-mediated dilatation was significantly lower than in control subjects (5.0% [SD, 2.7%] and 7.5% [SD, 3.3%], respectively; P = 0.003). AIx was significantly higher in the OSA group compared with the control group (26.0% [interquartile range (IQR), 19.0–29.5%] and 21.0% [IQR, 8.0–27.0%], respectively; P = 0.04). Change in AIx after both forearm ischemia and salbutamol was significantly smaller in patients with OSA (–2.0% [IQR, –5.0 to +4.0%] and –3.0% [IQR, –7.0 to 0.0%], respectively), than in control subjects (–6.0% [IQR, –8.0 to –5.0%] and –7.0% [IQR, –10.0 to –3.0%]; P = 0.005 and P = 0.04, respectively). ABP was similar (97.6 mm Hg [SD, 7.9 mm Hg] and 94.8 mm Hg [SD, 7.4 mm Hg], OSA and control groups, respectively; P = 0.21). Conclusions: In patients with minimally symptomatic OSA, diverse properties of endothelial function are impaired and arterial stiffness is increased. Although this was not associated with a significantly increased ABP, the findings suggest that patients with minimally symptomatic OSA are at increased cardiovascular risk.
Key Words: obstructive sleep apnea • endothelial function • atherosclerosis • arterial stiffness • vascular reactivity
Obstructive sleep apnea (OSA) is characterized by repetitive apneas/hypopneas during sleep, associated with oxygen desaturations and sleep disruption. It has been estimated that between 2 and 4% of the adult population in Western countries experience moderate–severe OSA with daytime symptoms, and it is becoming more prevalent as the average population body weight rises (1). The prevalence of minimally symptomatic OSA among middle-aged adults has been shown to be as high as 26% (1), making OSA one of the most frequent disorders and thus of epidemiologic interest. Cross-sectional and prospective studies have implicated OSA as an important causal factor in the development of cardiovascular disease (2). The mechanisms underlying the association between OSA and cardiovascular disease are currently not fully understood, and indeed may not be causal. Multiple causal factors leading to vessel wall damage and atherosclerotic plaques have been proposed, including reflex sympathetic activation, consequent increases in blood pressure, endothelial dysfunction, systemic inflammation, and reactive oxygen species (3–5). Endothelial dysfunction and increased arterial stiffness play a central role in the initiation of atherosclerosis and are associated with cardiovascular risk factors (6–9). As a result, there is growing interest in early detection of these measures of cardiovascular risk with the anticipation that an intervention will benefit patients who are at increased risk for future cardiovascular events. Moderate to severe OSA has been associated with endothelial dysfunction, increased arterial stiffness, and hypertension, all of which have been shown to improve after continuous positive airway pressure (CPAP) therapy (5, 10, 11). In contrast to the fall in blood pressure seen with CPAP in hypersomnolent patients with OSA, blood pressure did not decrease after therapy in nonsleepy hypertensive patients with OSA (12). However, there are no data on endothelial dysfunction and arterial stiffness, potentially reflecting earlier changes in vascular function in patients with minimally symptomatic OSA. More importantly, because of the absence of daytime symptoms, these patients might not be treated with CPAP. To investigate the hypothesis that vascular function is impaired in patients with minimally symptomatic OSA, we performed a controlled cross-sectional study investigating different aspects of endothelial function, arterial stiffness, and ambulatory blood pressure in patients with minimally symptomatic OSA. Some of the results of this study have been previously reported in the form of an abstract (13).
Patients Patients with possible obstructive sleep apnea were referred to the Oxford Sleep Unit, Oxford Centre for Respiratory Medicine (Oxford, UK), by general practitioners; ear, nose, and throat surgeons; or other hospital consultants, usually because of severe snoring or witnessed apneas. Patients were eligible for the study if they were between 45 and 75 years of age, had proven obstructive sleep apnea with a severity defined as more than 7.5 oxygen desaturations exceeding 4% per hour (oxygen desaturation index [ODI] > 7.5/h), and no history of excessive daytime sleepiness or any other daytime symptoms of OSA that would have justified CPAP therapy. All eligible patients were offered participation in the study. Control subjects were mainly identified and recruited from a general practitioners' database and were eligible for the study if they were between 45 and 75 years of age with no history of OSA, had fewer than five oxygen desaturations exceeding 4% per hour (ODI < 5/h), and an apnea/hypopnea index less than 5 per hour (AHI < 5/h). Control subjects were matched to patients with OSA for sex, age, body mass index, waist-to-hip ratio, and cardiovascular comorbidities. The study was approved by the Oxford Research Ethics Committee (record no. 05/Q1604/159), and written informed consent was obtained from all participants.
Sleep Study and Assessment of Sleepiness The results of the sleep study were scored automatically, with manual review to ensure accuracy of the data. OSA was diagnosed from review of all data, and the severity was quantified as the number of oxygen desaturations exceeding 4% per hour of study (ODI). In control subjects, OSA was excluded by home sleep studies using the ApneaLink device (ResMed; MAP Medicine Technology, Martinsried, Germany). The device records the patient's nasal respiratory pressure signal and finger oximetry during sleep; it has been validated as an accurate instrument with which to detect snoring, apnea/hypopnea, and oxygen desaturations (16). The results of the sleep study were scored automatically with dedicated software (ResMed; MAP Medicine Technology), with manual review to ensure accuracy of the data. Apneas were defined as a cessation of airflow lasting more than 10 seconds, and hypopneas as a reduction in airflow of at least 50% lasting more than 10 seconds, associated with a drop in oxygen saturation exceeding 4%. Subjective sleepiness was assessed with the Epworth Sleepiness Scale, which assesses the tendency to fall asleep during eight typical daytime situations (17). Objective sleepiness was measured with one sleep resistance challenge (Oxford Sleep Resistance [OSLER] test), which tests the ability to stay awake in a darkened and sound-isolated room (18).
Cardiovascular Risk Score
Flow-mediated Dilatation
Pulse Wave Analysis First, a baseline measurement of AIx was performed as a measure of arterial stiffness. To assess an endothelium-dependent change of AIx, reactive hyperemia was induced by inflation of a pneumatic tourniquet around the forearm to 200 mm Hg for 5 minutes and a repeated measurement of AIx was performed between 120 and 180 seconds after cuff deflation. A sublingual dose of 0.5 mg of NTG was then administered for 3 minutes to assess endothelium-independent vascular reaction, followed by a repeated measurement of AIx after 4 minutes. Previous studies have shown that 20 minutes is sufficient for hemodynamic changes after NTG to return to baseline (26). Therefore, after a 30-minute break, 400 µg of salbutamol was administered by inhalation as an alternative method to induce endothelium-dependent vascular dilatation (26), and AIx was remeasured after 10 minutes; at this time the peak plasma concentration of salbutamol occurs (26). A minimum of 10 radial artery pulse waveforms is required by the software to calculate the AIx and also to derive an operator index (indicating the quality and reproducibility of the arterial signal) (SphygmoCor; At-Cor Medical). Several estimates of AIx were performed on each occasion and the measurement with the highest operator index was used for statistical analysis.
Blood Pressure Participants were asked to measure their ambulatory blood pressure at home three times per day in triplicate on seven continuous days with a standard digital automatic monitor (Omron Healthcare Co.) in the sitting position after a period of rest for 5 minutes. The mean value of the 7 days of readings was used for analysis.
Data Analysis
Subject Characteristics Sixty-four patients with minimally symptomatic OSA and 15 control subjects without OSA were recruited. Control subjects were well matched for age, sex, body mass index, waist-to-hip ratio, and cardiovascular risk profile. As expected, patients with OSA had a higher ODI, a greater neck circumference, and tended to have a higher score on the Epworth Sleepiness Scale although objective sleepiness assessed by the OSLER test was similar in the two groups (Table 1).
Blood Pressure Mean office blood pressure, and blood pressures averaged from the 7-day period of ambulatory measurements, were similar in patients with OSA and in control subjects (Table 2). Systolic office blood pressure, and averaged 7-day systolic blood pressure, tended to be higher in patients with minimally symptomatic OSA than in control subjects (Table 2).
Flow-mediated Dilatation Mean baseline brachial artery diameter was 4.7 (0.8) mm in patients with OSA and 4.3 (0.6) mm in the control group (mean difference, +0.4 mm; 95% confidence interval [CI], –0.04 to +0.84 mm; P = 0.13). Endothelial function, as assessed by measurement of flow-mediated dilatation of the brachial artery, was impaired in patients with OSA (mean FMD, 5.0 [2.7]%) compared with control subjects (mean FMD, 7.5 [3.3]%) (mean difference, 2.5%; 95% CI, –4.1 to –0.9%; P = 0.003) (Figure 1). As would be expected, mean NTG-induced endothelium-independent vasodilation was not different between patients with OSA and control subjects: 14.1 (5.0)% and 15.7 (6.1)%, respectively (mean difference, –1.6%; 95% CI, –4.6 to 1.4%; P = 0.28). Flow-mediated dilatation was correlated with the cardiovascular risk score (r = –0.36; n = 79; 95% CI, –0.54 to –0.15; P = 0.001), but there was no significant correlation between FMD and ODI.
Pulse Wave Analysis Pulse wave analysis could be performed in 60 patients with OSA (measurements were not possible in 4 patients with atrial fibrillation) and 15 control subjects. Arterial stiffness, assessed by AIx, was higher in patients with OSA compared with matched control subjects (Table 2). The endothelial-dependent changes in AIx after ischemia-induced hyperemia and application of salbutamol were greater in control subjects than in patients with OSA (Table 3). As expected, the endothelial-independent response to NTG was not different between the two groups (Table 3). AIx at baseline was correlated with ODI (r = 0.30; 95% CI, 0.08 to 0.50; P = 0.01).
To our knowledge, this is the first well-controlled, cross-sectional study on endothelial function, arterial stiffness, and blood pressure in patients with minimally symptomatic obstructive sleep apnea. We found that patients with minimally symptomatic obstructive sleep apnea had impaired endothelial function, assessed by flow-mediated dilatation and pulse wave analysis measurements, and increased arterial stiffness, compared with matched control subjects without obstructive sleep apnea. However, both office and averaged 7-day mean ambulatory blood pressure were similar in patients with minimally symptomatic OSA and control subjects. We found that endothelial function assessed by two different techniques was impaired in patients with minimally symptomatic OSA compared with well-matched control subjects without OSA. The average flow-mediated dilatation (FMD) was 5% in the OSA group, which is lower than the reported FMD in a healthy control population (8). Moreover, the observed difference in FMD between the patients with OSA and matched control subjects was 2.5% (see Figure 1) in our study; the size of this difference has been shown to be of clinical significance in studies looking at the association between flow-mediated dilatation and subsequent cardiovascular events (27, 28). In agreement with our study, Ip and coworkers (5) found that FMD was similarly impaired (FMD was 5.3%) in 28 patients with moderate–severe OSA without comorbidities, as was the observed difference in FMD (3%) between subjects with and without OSA. One of the potential underlying mechanisms for endothelial dysfunction in patients with OSA seems to be a downregulation of endothelial nitric oxide (NO) synthase as a result of increased oxidative stress (29), excessive arterial wall shear stress caused by recurrent surges in blood pressure during apneic events (3), as well as increased endothelial cell apoptosis (30), and increased levels of coagulation factors and cholesterol (31). The augmentation index, a measure of central arterial stiffness and pressure wave reflection, independently predicts cardiovascular events in high-risk populations (32). In our study, the augmentation index was significantly higher in patients with minimally symptomatic OSA compared with matched control subjects. The observed difference is comparable in size to the effect seen after 4 weeks of CPAP therapy in patients with moderate–severe OSA (11). The mechanism responsible for the increase in arterial stiffness is speculative at present. A higher sympathetic activity, due to recurrent sleep fragmentation or intermittent hypoxia, may contribute to the observed increase in arterial stiffness (11). Alternatively, the augmentation index has been shown to increase with the plasma level of asymmetric dimethylarginine (an endogenous inhibitor of endothelial NO synthase), suggesting that impaired endothelial function secondary to a lower bioavailability of NO may be a further cause for increased arterial stiffness in patients with OSA (5). Consistent with an impaired FMD, we found that endothelial function assessed by pulse wave analysis (change in augmentation index [AIx] induced by both salbutamol and reactive hyperemia) was worse in patients with minimally symptomatic OSA than in matched control subjects. In contrast to FMD measurements, the augmentation index reflects the vascular function of a composite of the whole arterial tree (33), and therefore the decreased endothelial-dependent change in AIx we found in OSA reflects impaired endothelial function of differently sized arteries compared with FMD. To our knowledge, there are no other published studies that have investigated endothelial function in OSA by the same technique. In contrast to the observed differences in endothelial function and arterial stiffness (measures representing early and sensitive changes in vascular function), we found no statistically significant difference in either office blood pressure or ambulatory blood pressure (measured during a period of 1 wk) between patients with minimally symptomatic OSA and matched control subjects; although there was a trend toward higher systolic blood pressure in patients with OSA (Table 2). This negative finding is supported by our previous work, in which we found that CPAP did not reduce blood pressure in nonsleepy hypertensive patients with moderate–severe OSA (12). However, the current study was not powered to look at blood pressure differences as a primary outcome, and therefore studies including a larger number of patients with minimally symptomatic OSA are needed to clarify this point. It must be mentioned that although our control group was meticulously matched, neck circumference was greater in patients with OSA although waist-to-hip circumference was not; this might suggest that subtle differences in fat distribution could be a possible confounder as it has been shown that neck circumference may be a better measure of upper body obesity in some circumstances and is strongly correlated with cardiovascular risk (34). In conclusion, this controlled cross-sectional study has shown that in patients with minimally symptomatic OSA, diverse properties of endothelial function are impaired, and arterial stiffness is increased, when compared with well-matched control subjects without OSA. Although this was not associated with significantly increased blood pressure, the findings of this study suggest that patients with minimally symptomatic OSA are at increased cardiovascular risk, as has been demonstrated in more severe disease. However, final proof that this association is causal, and not due to confounders, must await a randomized and controlled intervention study.
Supported by an unrestricted charitable donation from ResMed UK in 1998 and 2006 for research work in the Oxford Sleep Unit. M.K. is a recipient of a European Respiratory Society (No. 118) and University of Zurich research fellowship. Originally Published in Press as DOI: 10.1164/rccm.200805-717OC on July 24, 2008 Conflict of Interest Statement: M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.J.O.D. has no personal conflict of interest. ResMed UK made an unrestricted charitable donation to support research work in the Oxford Sleep Unit in 2006 and provides CPAP machines for a currently running multicenter trial. J.R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form May 12, 2008; accepted in final form July 23, 2008
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ABSTRACT
AT A GLANCE COMMENTARY
2 test of independence was used. Spearman's rank test was used for correlation analysis. A P value less than 0.05 was considered to be statistically significant. 
