American Journal of Respiratory and Critical Care Medicine

Background: Obstructive sleep apnea (OSA) is associated with several cardiovascular diseases. However, the mechanisms are not completely understood. Recent studies have shown that OSA is associated with multiple markers of endothelial damage. We hypothesized that OSA affects functional and structural properties of large arteries, contributing to atherosclerosis progression. Methods and Measurements: Twelve healthy volunteers, 15 patients with mild to moderate OSA, and 15 with severe OSA matched for age, sex, and body mass index were studied by using (1) full standard overnight polysomnography; (2) carotid-femoral pulse wave velocity with a noninvasive automatic device; and (3) a high-definition echo-tracking device to measure intima-media thickness, diameter, and distensibility. All participants were free of hypertension, diabetes, and smoking, and were not on any medications. Patients with OSA were naive to treatment. Main Results: Significant differences existed between control subjects and patients with mild to moderate and severe OSA (apnea–hypopnea index, 3.1 ± 0.3, 16.2 ± 1.7, and 55.7 ± 5.9 events/hour, respectively) in pulse wave velocity (8.7 ± 0.2, 9.2 ± 0.2, and 10.3 ± 0.2 m/second; p < 0.0001), intima-media thickness (604.4 ± 25.2, 580.2 ± 29.0, and 722.2 ± 35.2 μm; p = 0.004), and carotid diameter (6,607.8 ± 126.7, 7,152.3 ± 114.4, and 7,539.9 ± 161.2 μm; p < 0.0001). Multivariate analyses showed that the apnea–hypopnea index correlated independently with pulse wave velocity and intima-media thickness variability (r = 0.61, p < 0.0001, and r = 0.44, p = 0.004, respectively), whereas minimal oxygen saturation correlated with the carotid diameter (r = −0.60, p < 0.0001). Conclusions: Middle-aged patients with OSA who are free of overt cardiovascular diseases have early signs of atherosclerosis. All vascular abnormalities correlated significantly with the severity of the OSA, which further supports the hypothesis that OSA plays an independent role in atherosclerosis progression.

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial or complete obstruction of the upper airway during sleep, with a consequent decrease in oxygen saturation. Epidemiologic studies have shown a strong association between OSA and cardiovascular diseases (1), including the following: hypertension (2), coronary artery disease (3), stroke (4), and heart failure (3). Most notably, compelling evidence indicates that OSA participates in the genesis of these conditions (5). Recent studies have indicated that OSA is associated with multiple causal factors of endothelial damage and atherosclerosis (6). These include the following: inflammation (7); increased levels of plasma vascular endothelial growth factor (VEGF) (8), an important promoter of the growth of smooth muscle cells; production of reactive oxygen species (9); increased levels of soluble adhesion molecules (10); and coagulation factors (11). Furthermore, all of these factors have been reported to significantly decrease after treatment with continuous positive airway pressure (913).

Atherosclerosis is a dynamic disease process characterized by vessel wall remodeling that occurs over decades, ultimately becoming clinically manifest as acute cardiovascular events in many individuals. Obesity, aging, hypertension, diabetes, and hyperlipidemia have a major impact on the progression of atherosclerosis. In contrast, some strategies, such as statin therapy, may attenuate or even promote regression of atherosclerotic plaque (14). Because several of these factors are frequently present in patients with OSA and are difficult to control, evidence of the association between OSA and atherosclerosis remains scanty (3, 1517). Atherosclerosis can be evaluated by both vascular functional and structural parameters. Pulse wave velocity (PWV) is a noninvasive, accurate technique to determine elastic properties of the aorta and the large arteries (18). The mechanical properties of the large arteries are important determinants of circulatory physiology in health and disease. Increased arterial stiffness may precede the onset of systemic hypertension in humans (19) and is an independent risk marker of premature coronary artery disease, atherosclerosis, and cardiovascular mortality (20, 21). Recent studies have shown that measurements of arterial compliance may be useful for the detection of subclinical atherosclerosis (22). Atherosclerosis leads ultimately to changes in vascular structure. Ultrasound devices, such as echo tracking, provide reliable measurements of lumen size, distensibility, wall thickness, and the presence of atheroma in large arteries (23). The measure of common carotid artery intima-media thickness (IMT) has been extensively used as an early marker of atherosclerosis in epidemiologic and clinical studies (2427). Longitudinal studies showed that increased IMT predicts carotid plaque occurrence (28) and stroke (29). In addition, carotid artery dilatation indicates compensatory vascular mechanism and is found in early stages of atherosclerosis (30).

The aim of this study was to test the hypothesis that early signs of atherosclerosis are present in patients with OSA and correlate with OSA severity. To this end, independent, validated indicators of early signs of atherosclerosis, including PWV, carotid diameter, and IMT, were performed in patients with OSA naive to treatment and in appropriate control subjects. We carefully excluded potential confounding factors for atherosclerosis, including hypertension, smoking, diabetes, regular use of medications, and increased age. Some of the results of this study have been previously reported in the form of an abstract (31).

We studied 12 matched healthy volunteers, 15 patients with mild to moderate OSA, and 15 with severe OSA, matched for age, sex, and body mass index (BMI). The volunteers were recruited from the hospital staff after they completed a Berlin Questionnaire (32), indicating a low risk of OSA. Particular attention was paid to morphometric characteristics to obtain three groups with a comparable BMI.

Exclusion criteria included the following: age younger than 30 or older than 55 years; BMI more than 40 kg/m2; hypertension; diabetes mellitus; cerebrovascular, aortic, or cardiac disease; smoking habit; and chronic use of medications (including nonsteroidal antiinflammatory drugs, oral anticoagulants, and statins). All participants had at least two fasting glucose measurements to exclude diabetes. Hypertension was carefully excluded based on the average of two or more properly measured, seated blood pressure readings on at least two office visits, according to current guidelines (33), by experienced physicians not involved in the study. In addition, venous blood was collected for the measurement of glucose, cholesterol, and hemoglobin levels.

All participants underwent a standard overnight polysomnography (EMBLA; Flagra hf. Medical Devices, Reykjavik, Iceland), including EEG, electrooculography, EMG, oximetry, thermistor, and pressure cannula measurements of airflow, and measurements of ribcage and abdominal movements during breathing. Apnea was defined as complete cessation of airflow for at least 10 seconds. Hypopnea was defined as a reduction in respiratory signals for at least 10 seconds associated with oxygen desaturation of 3%. The apnea–hypopnea index (AHI) was calculated as the total number of respiratory events (apneas plus hypopneas) per hour of sleep. The AHI cutoff for control subjects, patients with mild to moderate OSA, and patients with severe OSA was less than 5, 5 to 30, and more than 30 events per hour of sleep, respectively. Patients with OSA had been recently diagnosed and were naive to treatment.

All participants had their vascular properties evaluated within 2 weeks after polysomnography. Carotid-femoral PWV was analyzed with a noninvasive automatic device, Complior (Colson, Garges les Gonesses, France), and carotid measurements (IMT and carotid diameter) were made with a high-definition echo-tracking device (Wall Track System, Medical Systems Arnhem, Oosterbeck, The Netherlands) by an experienced observer blinded to the clinical condition of each participant. All measurements were taken between 2:00 and 4:00 p.m., with the patient in a recumbent position while awake. During PWV and carotid assessment, continuous noninvasive blood pressure recording was obtained by using the Portapres device (TNO Biomedical Instrumentation, Amsterdam, The Netherlands), which has been shown to accurately estimate intraarterial blood pressure (34). This method has a height correction unit to compensate finger measurements with the heart level. The means of six stable measurements were used for the final analysis. The PWV measurement technique has been described previously (35). Briefly, common carotid artery and femoral artery pressure waveforms were recorded noninvasively by using a TY-306 Fukuda pressure-sensitive transducer (Fukuda, Tokyo, Japan). The pressure waveforms were digitized at the sample acquisition frequency of 500 Hz. The two pressure waveforms were then stored in a memory buffer. A preprocessing system automatically analyzed the gain in each waveform and adjusted it for equality of the two signals. When the operator observed a pulse waveform of sufficient quality on the computer screen, digitization was suspended and calculation of the time delay between the two pressure upstrokes was initiated. Measurements were repeated over 10 different cardiac cycles, and the mean was used for the final analysis. The distance traveled by the pulse wave was measured over the body surface as the distance between the two recording sites (D), whereas pulse transit time (t) was automatically determined by the Complior; PWV was automatically calculated as PWV = D/t. The validation of this automatic method and its reproducibility has been previously described (35). Carotid diameter and IMT were evaluated with a high-resolution echo-tracking system (Wall Track System) coupled with a conventional two-dimensional vascular echograph (Sigma 44 Kontrom Instruments, Watford, UK) equipped with a 7.5-MHz probe. Measurements were performed on the right common carotid arteries 1 cm below the bifurcation at the site of the distal wall. IMT was measured at the thickest point, not including plaques, on the near and far walls with a specially designed computer program. A high rate of IMT reproduction has been previously demonstrated (36). Plaque was defined as a localized thickening greater than 1.2 mm that did not uniformly involve the whole artery. Distensibility was calculated by using the following equation: Distensibility (D) = (2Δd · d + Δd2)/(ΔP · d2), where Δd means change in artery diameter during heart cycle, d means artery diameter, and ΔP means pulse pressure (37).

Data were analyzed with SPSS 10.0 statistical software (SPSS, Inc., Chicago, IL). Quantitative variables were expressed as the mean ± SEM. After checking normality with the Kolmogorov-Smirnov test, one-way analysis of variance with the Bonferroni post hoc test was used to compare means. Pearson correlation coefficients between polysomnographic and vascular data were obtained. Linear regression models with vascular parameters, including PWV, IMT, and carotid diameter as dependent variables, were constructed. Multiple regression analysis was used to identify variables that were independently associated with the vascular parameters and to adjust for possible confounding factors. Categoric variables were expressed by the frequency distribution, and their association was tested with likelihood ratio tests. A value of p < 0.05 was considered significant.

The local ethics committee approved the protocol, and all participants gave written, informed consent.

Of approximately 450 patients with established OSA, we initially invited for the study 45 patients who were eligible according to our rigorous exclusion criteria. We enrolled 30 patients because five refused to participate and 10 had already initiated continuous positive airway pressure therapy. Seventeen volunteers were studied by overnight polysomnography, but five were excluded because of mild OSA, leaving 12 for the vascular study.

Baseline characteristics of the study population, including control, mild-to-moderate, and severe OSA groups, are described in Table 1

TABLE 1. Baseline characteristics

 (n = 12)

Mild to moderate
 OSA (n = 15)

Severe OSA
 (n = 15)

p Value
Age, yr42 ± 243 ± 144 ± 10.67
Males, %9393840.64
Body mass index, kg/m228.9 ± 0.728.4 ± 0.629.3 ± 0.80.66
Whites, %8367800.35
Systolic blood pressure, mm Hg115.4 ± 3.5114.2 ± 2.5117.4 ± 3.00.74
Diastolic blood pressure, mm Hg58.9 ± 2.457.2 ± 1.358.0 ± 1.90.83
Pulse pressure, mm Hg56.6 ± 1.857.0 ± 1.959.4 ± 2.40.60
Heart rate, bpm75 ± 275 ± 276 ± 20.87
Fasting glucose, mg/dl96 ± 295 ± 398 ± 10.74
Cholesterol, mg/dl226 ± 14226 ± 6236 ± 80.67
LDL, mg/dl156 ± 8137 ± 11152 ± 80.46
HDL, mg/dl47 ± 544 ± 345 ± 20.73
Hemoglobin, g/dL15.0 ± 0.415.5 ± 0.415.3 ± 0.40.52
Hematocrit, %43.5 ± 1.245.8 ± 0.845.1 ± 0.90.26
Awake oxygen saturation, %95 ± 0.495 ± 0.495 ± 0.41.00
AHI, events/hour3.1 ± 0.316.2 ± 1.755.7 ± 5.9< 0.0001
SaO2min90 ± 181 ± 173 ± 1< 0.0001
SaO2 < 90%
0.5 ± 0.4
3.7 ± 0.9
30.3 ± 5.7
< 0.0001

Definition of abbreviations: AHI = apnea–hypopnea index; bpm = beats/minute; HDL = high-density lipoprotein; LDL = low-density lipoprotein; OSA = obstructive sleep apnea; SaO2min = minimal oxygen saturation; TST = total sleep time.

Values are mean (± SEM).

. The three groups were similar regarding age, sex, BMI, blood pressure, heart rate, glucose, and cholesterol levels. The AHI was 3.1 ± 0.3, 16.2 ± 1.7, and 55.7 ± 5.9 events/hour in control subjects, patients with mild to moderate OSA, and patients with severe OSA, respectively (p < 0.0001). As expected for the characteristics of the population included in this study, no carotid plaque was observed in any participant, including all patients with OSA. However, significant differences did occur among the three groups concerning PWV (p < 0.0001), IMT (p = 0.004), and carotid diameter (p < 0.0001), and the results are summarized in Figure 1. In general, a trend occurred toward a direct correlation between OSA severity and early signs of atherosclerosis, as measured by the three different vascular parameters analyzed in this study. PWV in patients with severe OSA was significantly higher than that in patients with mild to moderate OSA (p < 0.01) and control subjects (p < 0.001), whereas variations between control subjects and patients with mild to moderate OSA were not statistically different. IMT in severe OSA was higher than in both mild-to-moderate (p < 0.05) and control groups (p < 0.05), whereas control and mild-to-moderate OSA groups had similar values. Carotid diameter in patients with mild to moderate OSA was higher than that in control subjects (p < 0.05) and was not statistically different from that in patients with severe OSA. In this group, carotid diameter was significantly higher than that in control subjects (p < 0.0001). Carotid distensibility in control subjects (14.9 kPa × 10−3 ± 1.6), patients with mild to moderate OSA (15.3 kPa × 10−3 ± 1.0), and patients with severe OSA (14.3 kPa × 10−3 ± 1.1) was not statistically significant.

Univariate analysis (Table 2)

TABLE 2. Univariate correlation coefficients between levels of pulse wave velocity, intima-media thickness, and carotid diameter with anthropometric, metabolic, blood pressure, and obstructive sleep apnea variables


p Value


p Value


p Value
Age, yr0.390.0110.23NS0.28NS
BMI, kg/m20.30NS−0.02NS0.21NS
SBP, mm Hg0.25NS0.031NS0.006NS
PP, mm Hg0.28NS0.070NS0.13NS
Cholesterol, mg/dl0.27NS0.25NS0.06NS
AHI, events/hour0.61< 0.00010.440.0040.450.004
SaO2min−0.420.005−0.24NS–0.60< 0.0001
SaO2 < 90% , % TST

Definition of abbreviations: AHI = apnea hypopnea index; BMI = body mass index; CD = carotid diameter; IMT = intima-media thickness; NS = not significant; PP = pulse pressure; PWV = pulse wave velocity; SBP = systolic blood pressure; TST = total sleep time.

Values in boldface type are the only independent variables related to vascular parameters remaining in multivariate analysis.

showed that PWV significantly correlated with age, AHI, and SaO2 less than 90% (% total sleep time), and inversely with the minimal SaO2 . IMT correlated significantly only with AHI. Carotid diameter correlated directly with AHI and SaO2 less than 90% (% total sleep time), and inversely with the SaO2min.

In the multivariate analysis, AHI was the only significant variable remaining to explain PWV and IMT variability. The best and only variable to explain carotid diameter in the multivariate analysis was the SaO2min. These differences remained significant after adjustment for age and systolic blood pressure. No significant correlations were noted with any other parameter analyzed, including age, BMI, systolic blood pressure, pulse pressure, heart rate, and cholesterol levels. Figure 2

shows the correlations that remained significant in multivariate analysis (i.e., PWV and IMT with AHI and carotid diameter with SaO2min).

The novel finding in the present study is that middle-aged patients with severe OSA, without overt cardiovascular diseases, demonstrate early signs of atherosclerosis by means of increased arterial stiffness and carotid remodeling measured by noninvasive, validated methods. In these patients, we observed a significant increase in PWV, IMT, and carotid diameter. Moreover, OSA severity was significantly and independently correlated with the vascular parameters evaluated by univariate analyses and were the only significant variables remaining in multivariate analyses. These signs of impaired arterial properties and arterial remodeling in patients with OSA were not present in the well-matched control subjects. Patients with OSA and control subjects were otherwise free from hypertension and other cardiovascular diseases, and differences cannot be explained by demographic or clinical conditions, including age, BMI, blood pressure levels, heart rate, glucose, and cholesterol levels. Because the different study groups presented no difference in classical cardiovascular risk factors, the vascular abnormalities are independently associated with OSA.

Atherosclerosis is much more complex than mere lipid storage, determined by environment associated with genetic factors. It involves several highly interrelated processes, including endothelial dysfunction, inflammation, oxidative stress, vascular smooth cell activation, platelet activation, and thrombosis. It is remarkable that OSA is also associated with the majority of these factors. Venous (38) and arterial (6, 39) endothelial dysfunction, systemic inflammation (7), increased levels of plasma VEGF (8), reactive oxygen species (9), soluble adhesion molecules (10), coagulation factors (11), and endothelin-1 (40) have been reported in patients with OSA. There is also evidence that some of these factors directly influence vascular elastic properties. For instance, it was recently demonstrated that endothelin-1 directly regulates PWV in vivo (41). Therefore, several or all these factors may contribute and help to explain the early signs of vascular dysfunction and remodeling observed in our relatively young patients with OSA who were otherwise free of overt cardiovascular diseases.

Two recent studies evaluated vascular elastic properties in patients with OSA. Nagahama and colleagues (15) found a significant increase in brachial-ankle PWV in patients with OSA as compared with that in control subjects. However, polysomnography was not performed in the control group. More importantly, patients with OSA were older and had more risk factors for atherosclerosis. Jelic and colleagues (42) described acute oscillations with an increase in arterial stiffness during OSAs assessed by applanation tonometry in the radial artery. In contrast, to avoid possible cyclic variations or immediate effects of apneas to arterial properties, all measurements in our study were performed in the afternoon while the patients were awake with stable breathing. Therefore, the repetitive increase in arterial stiffness during apneas, as described by Jelic and coworkers, may ultimately lead to the long-lasting changes in arterial stiffness observed in our study.

Previous studies have suggested an increased IMT in patients with OSA (16, 17). However, the population studied by Silvestrini and coworkers (16) included 22% smokers, 65% hypertensive subjects, and 17% patients with diabetes who were on average 20 years older than our sample. Similarly, almost 50% of the patients studied by Suzuki and colleagues (17) had hypertension. In contrast, we carefully excluded classical cardiovascular risk factors, including hypertension, smoking, and diabetes. In addition, a narrow range of age was studied, excluding elderly patients. Therefore, our unique study design allowed us to demonstrate the association of OSA with these vascular abnormalities.

An important finding in our study is the increased carotid diameter in patients with OSA. Nieto and colleagues (43) also reported increased diameters of large arteries in patients with OSA during the study of resting brachial artery diameter during flow-mediated vasodilation in a subset of elderly subjects of the Sleep Heart Health Study cohort. Previous studies showed that carotid artery dilatation is a compensatory mechanism in early stages of atherosclerosis (30). Vascular remodeling implies the concept of compensatory vessel enlargement to preserve luminal dimensions during atheromatous plaque development. Enlargement of large arteries with aging and high blood pressure has been extensively described (44, 45) and is generally attributed to the fracture of the load-bearing elastin fibers in response to the fatiguing effect of tensile stress. Increased artery diameter has been recently associated with mortality in patients with impaired glucose tolerance (46) and in patients with end-stage renal disease (47). According to our results, OSA is emerging as a new factor that promotes artery enlargement.

Although we observed several structural changes in the carotid arteries of patients with OSA, the functional properties evaluated by arterial distensibility were unchanged. These latter results suggest that structural modifications of the carotid artery associated with OSA could be a means by which arteries maintain normal distensibility, as was previously demonstrated in another study (48).

The exact mechanism by which OSA triggers all mediators that ultimately will lead to atherosclerosis is not completely understood. Previous experimental studies demonstrated the effects of intermittent and continuous hypoxia on the aortic wall in rabbits (4951). Neither intermittent nor continuous hypoxia induced gross or microscopic alterations in the aorta. However, significant reductions in the amount of glycosaminoglycans and collagen were observed, directly influencing the mechanical properties of the aorta and impaired healing of vascular injury, without a significant alteration in arterial blood pressure. Supporting these findings, arterial hypoxia increased the severity of atherosclerosis in cholesterol-fed rabbits (52), and hyperoxia reversed plaque formation in this model (53), providing biological plausibility to justify the results observed in humans. Because all severity parameters in OSA, including oxygen parameters and AHI, are correlated, our study is limited and does not allow the isolation of which factor is more important for determining vascular dysfunction and structural changes. Although PWV and IMT correlated more with AHI, carotid diameter was more strongly related to SaO2min. In contrast to our results, Suzuki and coworkers (17) and Schulz and colleagues (54) found that IMT was related to the degree of nocturnal hypoxia. Independent of the exact mechanism, our study further supports the hypothesis that OSA is a potential atherogenic factor (55), leading to damage of the arterial wall of large arteries.

The biological relevance of our data can be evidenced when we compare the vascular parameters in different populations with traditional risk factors to cardiovascular diseases. The range of IMT values observed in our patients with severe OSA is similar to those observed in the intermediate quartiles in a longitudinal population that was almost 20 years older (age range, 59–71 years) (28) than our sample. This particular subgroup presented an age- and sex-adjusted odds ratio to carotid plaque occurrence of 2.66 (95% confidence interval, 1.58–4.46; p < 0.001) in a 4-year follow-up. In a population of patients with end-stage renal disease, a PWV greater than 9.4 m/second (as compared with 9.2 and 10.3 m/second in our patients with mild to moderate and severe OSA, respectively) was an independent predictor of all-cause and mainly cardiovascular mortality in a 7-year follow-up. For each PWV increase of 1 m/second, the all-cause mortality adjusted odds ratio was 1.39 (95% confidence interval, 1.19–1.62) (56). Similarly, in a population with type 2 diabetes, aortic PWV independently predicted all-cause and cardiovascular mortality for each 1 m/second increase (hazard ratio, 1.08; 95% confidence interval, 1.03–1.14) (57). Therefore, the vascular abnormalities observed in our population with OSA strongly suggest an increased risk for cardiovascular diseases.

In conclusion, early signs of atherosclerosis are present in young adults with OSA, who are free of cardiovascular diseases. These findings are proportional to OSA severity and support the hypothesis that OSA plays an independent role in atherosclerosis progression.

1. Peker Y, Hedner J, Norum J, Kraiczi H, Carlson J. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 2002;166:159–165.
2. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384.
3. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, O'Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25.
4. Yaggi H, Mohsenin V. Obstructive sleep apnoea and stroke. Lancet Neurol 2004;3:333–342.
5. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003;290:1906–1914.
6. Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, Somers VK. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102:2607–2610.
7. Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105(21):2462–2464.
8. Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F. Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med 2002;165:67–70.
9. Carpagnano GE, Kharitonov SA, Resta O, Foschino-Barbaro MP, Gramiccioni E, Barnes PJ. 8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy. Chest 2003;124:1386–1392.
10. Chin K, Nakamura T, Shimizu K, Mishima M, Nakamura T, Miyasaka M, Ohi M. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 2000;109:562–567.
11. Chin K, Ohi M, Kita H, Noguchi T, Otsuka N, Tsuboi T, Mishima M, Kuno K. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996;153:1972–1976.
12. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129–1134.
13. Lavie L, Kraiczi H, Hefetz A, Ghandour H, Perelman A, Hedner J, Lavie P. Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. Am J Respir Crit Care Med 2002;165:1624–1628.
14. Lima JA, Desai MY, Steen H, Warren WP, Gautam S, Lai S. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation 2004;110:2336–2341.
15. Nagahama H, Soejima M, Uenomachi H, Higashi Y, Yotsumoto K, Samukawa T, Arima T. Pulse wave velocity as an indicator of atherosclerosis in obstructive sleep apnea syndrome patients. Intern Med 2004;43:184–188.
16. Silvestrini M, Rizzato B, Placidi F, Baruffaldi R, Bianconi A, Diomedi M. Carotid artery wall thickness in patients with obstructive sleep apnea syndrome. Stroke 2002;33:1782–1785.
17. Suzuki T, Nakano H, Maekawa J, Okamoto Y, Ohnishi Y, Yamauchi M, Kimura H. Obstructive sleep apnea and carotid-artery intima-media thickness. Sleep 2004;27:129–133.
18. Belz GG. Elastic properties and Windkessel function of the human aorta. Cardiovasc Drugs Ther 1995;9:73–83.
19. Weber T, Auer J, O'Rourke MF, Kvas E, Lassnig E, Berent R, Eber B. Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 2004;109:184–189.
20. de Simone G, Roman MJ, Koren MJ, Mensah GA, Ganau A, Devereux RB. Stroke volume/pulse pressure ratio and cardiovascular risk in arterial hypertension. Hypertension 1999;33:800–805.
21. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999;33:1111–1117.
22. Herrington DM, Brown WV, Mosca L, Davis W, Eggleston B, Hundley WG, Raines J. Relationship between arterial stiffness and subclinical aortic atherosclerosis. Circulation 2004;110:432–437.
23. Safar H, Mourad JJ, Safar M, Blacher J. Aortic pulse wave velocity, an independent marker of cardiovascular risk. Arch Mal Coeur Vaiss 2002;95:1215–1218.
24. Heiss G, Sharrett AR, Barnes R, Chambless LE, Szklo M, Alzola C. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol 1991;134:250–256.
25. O'Leary DH, Polak JF, Wolfson SK Jr, Bond MG, Bommer W, Sheth S, Psaty BM, Sharrett AR, Manolio TA. Use of sonography to evaluate carotid atherosclerosis in the elderly: the Cardiovascular Health Study. CHS Collaborative Research Group. Stroke 1991;22:1155–1163.
26. Bonithon-Kopp C, Touboul PJ, Berr C, Leroux C, Mainard F, Courbon D, Ducimetiere P. Relation of intima-media thickness to atherosclerotic plaques in carotid arteries. The Vascular Aging (EVA) Study. Arterioscler Thromb Vasc Biol 1996;16:310–316.
27. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Liu C, Alaupovic P, Kwong-Fu H, Azen SP. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann Intern Med 1996;124:548–556.
28. Zureik M, Ducimetiere P, Touboul PJ, Courbon D, Bonithon-Kopp C, Berr C, Magne C. Common carotid intima-media thickness predicts occurrence of carotid atherosclerotic plaques: longitudinal results from the Aging Vascular Study (EVA). Arterioscler Thromb Vasc Biol 2000;20:1622–1629.
29. Kitamura A, Iso H, Imano H, Ohira T, Okada T, Sato S, Kiyama M, Tanigawa T, Yamagishi K, Shimamoto T. Carotid intima-media thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men. Stroke 2004;35:2788–2794.
30. Steinke W, Els T, Hennerici M. Compensatory carotid artery dilatation in early atherosclerosis. Circulation 1994;89:2578–2581.
31. Drager LF, Bortolotto LA, Lorenzi MC, Figueiredo AC, Krieger EM, Lorenzi-Filho G. Arterial stiffness and carotid diameter are increased in normotensive patients with obstructive sleep apnea [abstract]. J Am Coll Cardiol 2005;45:388A.
32. Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med 1999;131:485–491.
33. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206–1252.
34. Devereux RB, Roman MJ. Ultrasonic techniques for the evaluation of hypertension. Curr Opin Nephrol Hypertens 1994;3:644–651.
35. Asmar R, Benetos A, Topouchian J, Laurent S, Pannier B, Brisac AM, Target R, Levy BI. Assessment of arterial distensibility by automatic pulse wave velocity measurement: validation and clinical application studies. Hypertension 1995;26:485–490.
36. Hanon O, Luong V, Mourad JJ, Bortolotto LA, Jeunemaitre X, Girerd X. Aging, carotid artery distensibility, and the Ser422Gly elastin gene polymorphism in humans. Hypertension 2001;38:1185–1189.
37. Laurent S, Caviezel B, Beck L, Girerd X, Billaud E, Boutouyrie P, Hoeks A, Safar M. Carotid artery distensibility and distending pressure in hypertensive humans. Hypertension 1994;23:878–883.
38. Duchna HW, Guilleminault C, Stoohs RA, Faul JL, Moreno H, Hoffman BB, Blaschke TF. Vascular reactivity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2000;161:187–191.
39. Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169:348–353.
40. Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 1999;17:61–66.
41. McEniery CM, Qasem A, Schmitt M, Avolio AP, Cockcroft JR, Wilkinson IB. Endothelin-1 regulates arterial pulse wave velocity in vivo. J Am Coll Cardiol 2003;42:1975–1981.
42. Jelic S, Bartels MN, Mateika JH, Ngai P, DeMeersman RE, Basner RC. Arterial stiffness increases during obstructive sleep apneas. Sleep 2002;25:850–855.
43. Nieto FJ, Herrington DM, Redline S, Benjamin EJ, Robbins JA. Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. Am J Respir Crit Care Med 2004;169:354–360.
44. Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S. Association between local pulse pressure, mean blood pressure, and large-artery remodeling. Circulation 1999;100:1387–1393.
45. Jondeau G, Boutouyrie P, Lacolley P, Laloux B, Dubourg O, Bourdarias JP, Laurent S. Central pulse pressure is a major determinant of ascending aorta dilation in Marfan syndrome. Circulation 1999;99:2677–2681.
46. van Dijk RA, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Brachial artery pulse pressure and common carotid artery diameter: mutually independent associations with mortality in subjects with a recent history of impaired glucose tolerance. Eur J Clin Invest 2001;31:756–763.
47. Safar ME, London GM. Arterial stiffness in hypertensive subjects with or without end-stage renal disease. Kidney Blood Press Res 1997;20:82–89.
48. Bortolotto LA, Hanon O, Franconi G, Boutouyrie P, Legrain S, Girerd X. The aging process modifies the distensibility of elastic but not muscular arteries. Hypertension. 1999;34:889–892.
49. Helin G, Helin P, Lorenzen I. The aortic glycosaminoglycans in arteriosclerosis induced by systemic hypoxia. Atherosclerosis 1970;12:235–240.
50. Helin P, Garbarsch C, Lorenzen I. Effects of intermittent and continuous hypoxia on the aortic wall in rabbits. Atherosclerosis 1975;21:325–335.
51. Turto H, Lindy S, Uitto J, Helin P, Garbarsch C, Lorenzen IB. Increased collagen prolyl hydroxylase activity in the aortic wall of rabbits exposed to chronic hypoxia. Atherosclerosis 1979;33:379–384.
52. Kjeldsen K, Wanstrup J, Astrup P. Enhancing influence of arterial hypoxia on the development of atheromatosis in cholesterol-fed rabbits. J Atheroscler Res 1968;8:835–845.
53. Kjeldsen K, Astrup P, Wanstrup J. Reversal of rabbit atheromatosis by hyperoxia. J Atheroscler Res 1969;10:173–178.
54. Schulz R, Seeger W, Fegbeutel C, Husken H, Bodeker RH, Tillmanns H, Grebe M. Changes in extracranial arteries in obstructive sleep apnoea. Eur Respir J 2005;25:69–74.
55. Dean RT, Wilcox I. Possible atherogenic effects of hypoxia during obstructive sleep apnea. Sleep 1993;16:S15–S21.
56. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99:2434–2439.
57. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation 2002;106:2085–2090.
Correspondence and requests for reprints should be addressed to Luciano F. Drager, M.D., Hypertension Unit, Heart Institute (InCor), University of São Paulo Medical School, Av Dr Enéas Carvalho de Aguiar, 44, CEP 05403-900 São Paulo, Brazil. E-mail:


No related items
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record