- Email: [email protected]
Plasma Levels of Vascular Endothelial Markers in Obstructive Sleep Apnea
Archives of Medical Research 37 (2006) 552–555
BRIEF REPORT
Plasma Levels of Vascular Endothelial Markers in Obstructive Sleep Apnea Carlos Zamarro´n-Sanz,a Jorge Ricoy-Galbaldon,a Francisco Gude-Sampedro,b and Alberto Riveiro-Riveiroc a
Department of Medicine, bSleep Unit, Division of Respiratory Medicine and Clinical Epidemiology Unit and cDepartment of Biochemistry, Hospital Clinico Universitario, Santiago de Compostela, Spain Received for publication June 27, 2005; accepted October 10, 2005 (ARCMED-D-05-00243).
Although the link between obstructive sleep apnea syndrome and risk for cardiovascular disorders has yet to be fully described, the hypothetical involvement of endothelial dysfunction is pathophysiologically plausible. In order to test this hypothesis, we measured plasma levels of endothelial markers in 82 male subjects (41 subjects with obstructive sleep apnea syndrome and a 41-subject control group). Obstructive sleep apnea syndrome patients presented higher circulating levels of intercellular cell adhesion molecule-1, E-selectin, and endothelin-1 than the control group. On the other hand, no differences were found in the von Willebrand factor. Levels of E-selectin and intercellular cell adhesion molecule-1 were significantly correlated to total oxygen desaturation. However, no significant correlation was found in either endothelin-1 or von Willebrand factor. We conclude that obstructive sleep apnea syndrome is associated with changes in levels of adhesion molecules, and that this could be the result of obstructive sleep apnea syndrome-induced hypoxia. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: Sleep apnea syndromes, Intercellular adhesion molecule, E-selectin. Endothelin, von Willebrand factor.
Introduction Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder characterized by recurrent airflow obstruction caused by total or partial collapse of the upper airway. Epidemiological studies have shown prevalence for OSAS of 7% among people 50–70 years of age (1). In middle-aged populations the prevalence is estimated to be 4% in males and 2% in females (2). OSAS has been associated with hypertension and cardiovascular disease in both crosssectional and prospective studies (3–5). Explaining these associations, increased sympathetic activity and hypoxia in apneic episodes have been proposed as possible mechanisms (6–8). Furthermore, the endothelial dysfunction process also seems to be involved. In fact, a number of studies have shown that OSAS patients present an
Address reprint requests to: Carlos Zamarro´n, MD, Associate Professor of Medicine, Hospital Clinico Universitario de Santiago, Departamento de Medicina, Travesia de la Choupana s/n, Santiago, La Corun˜a 15706, Spain; E-mail: [email protected]
abnormal vasodilatory response to reactive hyperemia in brachial circulation (9–12). However, when endothelial dysfunction is studied in OSAS patients via plasma levels of endothelial markers, some authors report changes in certain markers (13–15), whereas others report no such changes (16). The aim of the present study was to measure plasma levels of four endothelial markers in patients with OSAS.
Patients and Methods Subjects The present study included 41 male subjects between 30 and 60 years of age suspected of having OSAS because of daytime sleepiness, loud snoring, nocturnal choking and awakenings, apneic events, or all four as reported by the patient or bedmate. A control group composed of 41 male subjects from the general population was also included. Exclusion criteria were previous treatment for OSAS, chronic obstructive lung disease, vascular disease, history
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.10.011
Vascular Endothelial Markers in Obstructive Sleep Apnea
of hypertension, dyslipidemia, diabetes mellitus, or chronic renal illness. The Review Board on Human Studies at our institution approved the protocol, and each patient gave informed consent to participate in the study.
Interventions An OSAS-validated sleep questionnaire covering the most important cardiovascular risk factors was applied to all subjects. In addition, patients received a complete general physical examination, biochemistry test with lipid profile and polysomnography tests. All subjects including controls underwent sleep studies. Polysomnographies were carried out in our Sleep Unit usually from midnight to 8 a.m. This technique consisted of continuous monitoring using a polygraph (Ultrasom Network, Nicolet, Madison, WI) and included electroencephalogram, electrooculogram, chin electromyogram, airflow, electrocardiogram and measurement of chest wall movement. The polysomnographic register was analyzed in periods of 30 sec and during stages 1, 2, 3, 4 and REM according to standard criteria. Desaturation was defined as a fall in baseline oxygen saturation of $4%. The number of desaturation episodes during total sleep time was recorded. Apnea was defined as the absence of airflow for more than 10 sec and hypopnea as the reduction of respiratory flow for at least 10 sec accompanied by a 4% or more decrease in the saturation of hemoglobin (17). The average of apnea2hypopnea index (AHI) was calculated in hourly samples of sleep. In this study an AHI $10 was considered as diagnostic of OSA. If the subject had !3 h of total sleep, the sleep study was repeated.
Serum Assays Whole blood was obtained by venipuncture in all subjects between 8 a.m. and 10 a.m. after polysomnographic study. A total of four endothelial plasma markers were measured including intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, endothelin-1 and von Willebrand factor (vWf). Commercially available enzyme-linked immunosorbent assay (ELISA) methods were used to determine serum levels of ICAM-1 and soluble E-selectin (R & D Systems, Minneapolis, MN), EDTA-plasma levels of endothelin-1 (Biomedica, Vienna, Austria), and citrated plasma levels of vWf (Diagnostica Stago, Asnieres, France). Blood samples were centrifuged at 1000 3g for 10 min, and plasma was frozen and stored at 220 C. The minimal detectable dose was determined by adding two standard deviations to the mean optical density value of 20 zero standard replicates and calculating the corresponding concentrations.
553
Statistical Analyses Continuous variables were expressed as the mean 6 standard deviation or median (interquartile range) in the case of non-normal distributed data. Two-tailed t-test was applied to test differences between performance levels; non-normally distributed variables were compared using Mann-Whitney test. Association between test results was explored using Spearman analysis correlation. Linear regression analysis was employed to estimate the relationship between Eselectin and ICAM-1 and total desaturation dips during sleep, adjusting by age and body mass index (BMI). For that purpose, E-selectin values were transformed into their logarithm to meet the assumption of linearity between E-selectin and covariates. Statistical significance was accepted at p !0.05. All analyses were developed using the Statistical Package for Social Sciences (SPSS, v. 11.0; SPSS Inc., Chicago, IL).
Results Baseline clinical characteristics of patients and control subjects were similar for age and smoking habit, as well as for cholesterol and triglyceride levels. BMI and systolic blood pressure were higher in the OSAS group (Table 1). Regarding levels for circulating endothelial markers, ICAM-1, E-selectin and endothelin-1 were significantly elevated in OSAS patients as compared to controls. No changes were found in vWf and fibrinogen levels (Table 2). Total oxygen desaturation dips were significantly correlated to E-selectin (r 5 0.45, p 5 0.004) (Figure 1) and to ICAM-1 (r 5 0.37, p 5 0.021). After adjustment by BMI and age, the correlation between E-selectin or ICAM-1 and total desaturation dips during sleep persists ( p !0.05)
Discussion The present study demonstrates that endothelial dysfunction, represented by changes in certain circulating Table 1. Cardiovascular risk factors in OSAS and control groups Variable Age, years Smokers, n (%) BMI, kg/m2 Heart rate, bpm SBP, mmHg DBP, mmHg Total cholesterol, mg/dL Tryglicerides, mg/dL
OSAS n 5 41 Non-OSAS n 5 41 50 8 32.1 80 135 82 221 122
(9) (20) (4.9) (10) (12) (12) (35) (57)
47 5 27.7 80 124 80 204 112
(12) (12) (3.3) (17) (12) (12) (28) (70)
p value 0.199 0.364 !0.001 0.946 !0.001 0.503 0.068 0.571
BMI, body mass index; bpm, beats per minute; SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are expressed as mean 6 SD.
Zamarro´n-Sanz et al./ Archives of Medical Research 37 (2006) 552–555
554
Table 2. Plasma levels of vascular endothelial markers in OSAS and control groups OSAS n 5 41 Non-OSAS n 5 41 p value
Variable ICAM-1 (ng/mL) E-selectin (ng/mL) Endothelin (fmol/mL) von Willebrand factor (%) Fibrinogen, mg/dL
255 67 0.34 75 326
(197) (38) (0.32) (36) (63)
210 51 0.27 76 293
(49) (26) (0.15) (30) (62)
0.040 0.019 0.002 0.819 0.145
Data are expressed as median (interquartile range) or mean 6 SD.
endothelial markers, is present in OSAS. These changes could be the result of OSAS-induced hypoxia. OSAS is associated with cardiovascular morbidity, and the link may involve abnormal vascular function. The vascular endothelium secretes multiple factors that regulate vascular tone as well as cell migration and proliferation (18). A number of authors have shown that in OSAS vascular tone undergoes alterations that can generate endothelial dysfunction (19–23). In our study, changes found in levels of adhesion molecules (ICAM-1, E-selectin) and endothelin-1 lead to the conclusion that OSAS is associated with endothelial dysfunction. Moreover, we have found that levels of E-selectin and ICAM-1 correlated with the number of desaturations during the night. This suggests that OSAS-induced hypoxia provokes sustained increases in circulating ICAM-1 and E-selectin levels. Several previous studies report changes in circulating levels of adhesion molecules (13,14). Ohga et al. reported increased levels of ICAM-1, VCAM-1, and L-selectin in seven OSA patients compared to a control group, but there were certain limitations. First of all, the OSA group in Ohga’s study was older than the control group. Secondly, subjects were not evaluated for coexisting cardiac disease;
E-selectin (ng/mL)
200
thus, it is not clear whether the elevated adhesion molecules were due to OSA or a pre-existing heart condition. Finally, no correlation between the degree of hypoxia and the levels of adhesion molecules was established. Our methodology takes these issues into account. Endothelin-1 is a peptide hormone secreted predominantly by endothelial cells under the influence of hypoxia (24). The present study shows that patients with OSAS have significantly higher levels of endothelin-1 than a control group (25,26). This finding has previously been discussed in the literature. Saarelainen et al. (25) and Phillips et al. (26) also reported higher endothelin-1 levels in OSAS patients; however, Grimpen et al. (16) reported no such increase. This divergence might be explained by differences in group characteristics. The patients studied by Saarelainen et al. and Phillips et al. had more severe disease and, thus, underwent more severe oxygen desaturations that could have acted as a trigger for endothelin-1 secretion. Although it seems that OSAS severity has an influence on endothelin-1 secretion, our patients did not present a correlation between number of oxygen desaturations during the night and levels of endothelin-1. Consensus does not yet exist regarding the association of OSAS with hemostatic alterations (27). Our study analyzes levels of VW and fibrinogen and we find no changes in either. Certain limitations in the present study need to be taken into consideration. First, measurements of circulating adhesion molecules were based on the assumption that the number of circulating adhesion molecules reflect the number of cell surface adhesion molecules. Secondly, plasma samples were obtained only in the morning, which may have affected random variability because oscillations during the day were not considered. In summary, the present study demonstrates that obstructive sleep apnea syndrome is associated with changes in levels of adhesion molecules, and that this could be the result of OSAS-induced hypoxia. These findings suggest potential mechanisms involving endothelial dysfunction that could help explain the association between OSAS and cardiovascular disease.
150
Acknowledgments This study was supported by Fondo Investigacio´n Sanitaria grant (01/0634) and Secretaria Xeral de Investigacio´n e Desenvolvemento Grant (PGIDT99PXI90201A).
100
50
References 0 0
100
200
300
400
500
600
700
800
Total desaturation dips during sleep Figure 1. Scatter plot of E-selectin and total oxygen desaturation dips during sleep.
1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;28:1230–1235. 2. Zamarro´n C, Gude F, Otero Y, Alvarez JM, Golpe A, Rodriguez JR. Prevalence of sleep disordered breathing and sleep apnea in 50 to 70 year old individuals. A survey. Respiration 1999;66:317–322. 3. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension
Vascular Endothelial Markers in Obstructive Sleep Apnea
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in a large community-based study: Sleep Heart Health Study. JAMA 2000;283:1829–1836. 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. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217–1239. Bonsignore MR, Marrone O, Insalaco G, Bonsignore G. The cardiovascular effects of obstructive sleep apnoeas: analysis of pathogenic mechanisms. Eur Respir J 1994;7:786–805. Somers VK, Kyken ME, Clary MP, Abbound FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897– 1904. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003;290: 1906–1914. Carlson JT, Rangemark C, Hedner JA. Attenuated endotheliumdependent vascular relaxation in patients with sleep apnoea. J Hypertens 1996;14:577–584. Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, et al. Impairment of endothelium-dependent vasodilatation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102:2607–2610. Imadojemu VA, Gleeson K, Quraishi SA, Kunselman AR, Sinoway LI, Leuenberger UA. Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy. Am J Respir Crit Care Med 2002;165:950–953. 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. Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T, Katayama H, et al. Increased levels of circulating ICAM-1, VCAM-1, and L-selection in obstructive sleep apnea syndrome. J Appl Physiol 1999;87:10–14. Chin K, Nakamura T, Shimizu K, Mishima M, Miyasaka M, Ohi M. Effects of nasal continuous positive airway pressure on soluble cell
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adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 2000;109:562–567. Lavie L, Kraiczi H, Hefetz A, Ghandour H, Perelman A, Hedner J, et al. 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. Grimpen F, Kanne P, Schulz E, Hagenah G, Hasenfuss G, Andreas S. Endothelin-1 plasma levels are not elevated in patients with obstructive sleep apnoea. Eur Respir J 2000;15:320–325. Meoli AL, Casey KR, Clark RW, Coleman JA Jr, Fayle RW, Troell RJ, et al. Hypopnea in sleep-disordered breathing in adults. Sleep 2001; 24:469–470. Quyyumi AA. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 1998;105:32S– 39S. Rangemark C, Hedner JA, Carlson JT, Gleerup G, Winther K. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients. Sleep 1995;18:188–194. Anderson TJ. Assessment and treatment of endothelial dysfunction in human. J Am Coll Cardiol 1999;34:631–638. Wessendorf TE, Thilmann AF, Wang YM, Wang YM, Schreiber A, Konietzko N, et al. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000;162:2039–2042. Leung RS, Bradley TD. Sleep apnea and cardiovascular disease. Am J Respir Crit Care Med 2001;164:2147–2165. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002;165:934–939. Levin ER. Endothelins. N Engl J Med 1995;333:356–363. Saarelainen S, Seppala E, Laasonen K, Hasan J. Circulating endothelin-1 in obstructive sleep apnoea. Endothelium 1997;5:115–118. 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. Von Kanel R, Dimsdale JE. Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease. Chest 2003;124:1956–1967.
BRIEF REPORT
Plasma Levels of Vascular Endothelial Markers in Obstructive Sleep Apnea Carlos Zamarro´n-Sanz,a Jorge Ricoy-Galbaldon,a Francisco Gude-Sampedro,b and Alberto Riveiro-Riveiroc a
Department of Medicine, bSleep Unit, Division of Respiratory Medicine and Clinical Epidemiology Unit and cDepartment of Biochemistry, Hospital Clinico Universitario, Santiago de Compostela, Spain Received for publication June 27, 2005; accepted October 10, 2005 (ARCMED-D-05-00243).
Although the link between obstructive sleep apnea syndrome and risk for cardiovascular disorders has yet to be fully described, the hypothetical involvement of endothelial dysfunction is pathophysiologically plausible. In order to test this hypothesis, we measured plasma levels of endothelial markers in 82 male subjects (41 subjects with obstructive sleep apnea syndrome and a 41-subject control group). Obstructive sleep apnea syndrome patients presented higher circulating levels of intercellular cell adhesion molecule-1, E-selectin, and endothelin-1 than the control group. On the other hand, no differences were found in the von Willebrand factor. Levels of E-selectin and intercellular cell adhesion molecule-1 were significantly correlated to total oxygen desaturation. However, no significant correlation was found in either endothelin-1 or von Willebrand factor. We conclude that obstructive sleep apnea syndrome is associated with changes in levels of adhesion molecules, and that this could be the result of obstructive sleep apnea syndrome-induced hypoxia. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: Sleep apnea syndromes, Intercellular adhesion molecule, E-selectin. Endothelin, von Willebrand factor.
Introduction Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder characterized by recurrent airflow obstruction caused by total or partial collapse of the upper airway. Epidemiological studies have shown prevalence for OSAS of 7% among people 50–70 years of age (1). In middle-aged populations the prevalence is estimated to be 4% in males and 2% in females (2). OSAS has been associated with hypertension and cardiovascular disease in both crosssectional and prospective studies (3–5). Explaining these associations, increased sympathetic activity and hypoxia in apneic episodes have been proposed as possible mechanisms (6–8). Furthermore, the endothelial dysfunction process also seems to be involved. In fact, a number of studies have shown that OSAS patients present an
Address reprint requests to: Carlos Zamarro´n, MD, Associate Professor of Medicine, Hospital Clinico Universitario de Santiago, Departamento de Medicina, Travesia de la Choupana s/n, Santiago, La Corun˜a 15706, Spain; E-mail: [email protected]
abnormal vasodilatory response to reactive hyperemia in brachial circulation (9–12). However, when endothelial dysfunction is studied in OSAS patients via plasma levels of endothelial markers, some authors report changes in certain markers (13–15), whereas others report no such changes (16). The aim of the present study was to measure plasma levels of four endothelial markers in patients with OSAS.
Patients and Methods Subjects The present study included 41 male subjects between 30 and 60 years of age suspected of having OSAS because of daytime sleepiness, loud snoring, nocturnal choking and awakenings, apneic events, or all four as reported by the patient or bedmate. A control group composed of 41 male subjects from the general population was also included. Exclusion criteria were previous treatment for OSAS, chronic obstructive lung disease, vascular disease, history
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.10.011
Vascular Endothelial Markers in Obstructive Sleep Apnea
of hypertension, dyslipidemia, diabetes mellitus, or chronic renal illness. The Review Board on Human Studies at our institution approved the protocol, and each patient gave informed consent to participate in the study.
Interventions An OSAS-validated sleep questionnaire covering the most important cardiovascular risk factors was applied to all subjects. In addition, patients received a complete general physical examination, biochemistry test with lipid profile and polysomnography tests. All subjects including controls underwent sleep studies. Polysomnographies were carried out in our Sleep Unit usually from midnight to 8 a.m. This technique consisted of continuous monitoring using a polygraph (Ultrasom Network, Nicolet, Madison, WI) and included electroencephalogram, electrooculogram, chin electromyogram, airflow, electrocardiogram and measurement of chest wall movement. The polysomnographic register was analyzed in periods of 30 sec and during stages 1, 2, 3, 4 and REM according to standard criteria. Desaturation was defined as a fall in baseline oxygen saturation of $4%. The number of desaturation episodes during total sleep time was recorded. Apnea was defined as the absence of airflow for more than 10 sec and hypopnea as the reduction of respiratory flow for at least 10 sec accompanied by a 4% or more decrease in the saturation of hemoglobin (17). The average of apnea2hypopnea index (AHI) was calculated in hourly samples of sleep. In this study an AHI $10 was considered as diagnostic of OSA. If the subject had !3 h of total sleep, the sleep study was repeated.
Serum Assays Whole blood was obtained by venipuncture in all subjects between 8 a.m. and 10 a.m. after polysomnographic study. A total of four endothelial plasma markers were measured including intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, endothelin-1 and von Willebrand factor (vWf). Commercially available enzyme-linked immunosorbent assay (ELISA) methods were used to determine serum levels of ICAM-1 and soluble E-selectin (R & D Systems, Minneapolis, MN), EDTA-plasma levels of endothelin-1 (Biomedica, Vienna, Austria), and citrated plasma levels of vWf (Diagnostica Stago, Asnieres, France). Blood samples were centrifuged at 1000 3g for 10 min, and plasma was frozen and stored at 220 C. The minimal detectable dose was determined by adding two standard deviations to the mean optical density value of 20 zero standard replicates and calculating the corresponding concentrations.
553
Statistical Analyses Continuous variables were expressed as the mean 6 standard deviation or median (interquartile range) in the case of non-normal distributed data. Two-tailed t-test was applied to test differences between performance levels; non-normally distributed variables were compared using Mann-Whitney test. Association between test results was explored using Spearman analysis correlation. Linear regression analysis was employed to estimate the relationship between Eselectin and ICAM-1 and total desaturation dips during sleep, adjusting by age and body mass index (BMI). For that purpose, E-selectin values were transformed into their logarithm to meet the assumption of linearity between E-selectin and covariates. Statistical significance was accepted at p !0.05. All analyses were developed using the Statistical Package for Social Sciences (SPSS, v. 11.0; SPSS Inc., Chicago, IL).
Results Baseline clinical characteristics of patients and control subjects were similar for age and smoking habit, as well as for cholesterol and triglyceride levels. BMI and systolic blood pressure were higher in the OSAS group (Table 1). Regarding levels for circulating endothelial markers, ICAM-1, E-selectin and endothelin-1 were significantly elevated in OSAS patients as compared to controls. No changes were found in vWf and fibrinogen levels (Table 2). Total oxygen desaturation dips were significantly correlated to E-selectin (r 5 0.45, p 5 0.004) (Figure 1) and to ICAM-1 (r 5 0.37, p 5 0.021). After adjustment by BMI and age, the correlation between E-selectin or ICAM-1 and total desaturation dips during sleep persists ( p !0.05)
Discussion The present study demonstrates that endothelial dysfunction, represented by changes in certain circulating Table 1. Cardiovascular risk factors in OSAS and control groups Variable Age, years Smokers, n (%) BMI, kg/m2 Heart rate, bpm SBP, mmHg DBP, mmHg Total cholesterol, mg/dL Tryglicerides, mg/dL
OSAS n 5 41 Non-OSAS n 5 41 50 8 32.1 80 135 82 221 122
(9) (20) (4.9) (10) (12) (12) (35) (57)
47 5 27.7 80 124 80 204 112
(12) (12) (3.3) (17) (12) (12) (28) (70)
p value 0.199 0.364 !0.001 0.946 !0.001 0.503 0.068 0.571
BMI, body mass index; bpm, beats per minute; SBP, systolic blood pressure; DBP, diastolic blood pressure. Data are expressed as mean 6 SD.
Zamarro´n-Sanz et al./ Archives of Medical Research 37 (2006) 552–555
554
Table 2. Plasma levels of vascular endothelial markers in OSAS and control groups OSAS n 5 41 Non-OSAS n 5 41 p value
Variable ICAM-1 (ng/mL) E-selectin (ng/mL) Endothelin (fmol/mL) von Willebrand factor (%) Fibrinogen, mg/dL
255 67 0.34 75 326
(197) (38) (0.32) (36) (63)
210 51 0.27 76 293
(49) (26) (0.15) (30) (62)
0.040 0.019 0.002 0.819 0.145
Data are expressed as median (interquartile range) or mean 6 SD.
endothelial markers, is present in OSAS. These changes could be the result of OSAS-induced hypoxia. OSAS is associated with cardiovascular morbidity, and the link may involve abnormal vascular function. The vascular endothelium secretes multiple factors that regulate vascular tone as well as cell migration and proliferation (18). A number of authors have shown that in OSAS vascular tone undergoes alterations that can generate endothelial dysfunction (19–23). In our study, changes found in levels of adhesion molecules (ICAM-1, E-selectin) and endothelin-1 lead to the conclusion that OSAS is associated with endothelial dysfunction. Moreover, we have found that levels of E-selectin and ICAM-1 correlated with the number of desaturations during the night. This suggests that OSAS-induced hypoxia provokes sustained increases in circulating ICAM-1 and E-selectin levels. Several previous studies report changes in circulating levels of adhesion molecules (13,14). Ohga et al. reported increased levels of ICAM-1, VCAM-1, and L-selectin in seven OSA patients compared to a control group, but there were certain limitations. First of all, the OSA group in Ohga’s study was older than the control group. Secondly, subjects were not evaluated for coexisting cardiac disease;
E-selectin (ng/mL)
200
thus, it is not clear whether the elevated adhesion molecules were due to OSA or a pre-existing heart condition. Finally, no correlation between the degree of hypoxia and the levels of adhesion molecules was established. Our methodology takes these issues into account. Endothelin-1 is a peptide hormone secreted predominantly by endothelial cells under the influence of hypoxia (24). The present study shows that patients with OSAS have significantly higher levels of endothelin-1 than a control group (25,26). This finding has previously been discussed in the literature. Saarelainen et al. (25) and Phillips et al. (26) also reported higher endothelin-1 levels in OSAS patients; however, Grimpen et al. (16) reported no such increase. This divergence might be explained by differences in group characteristics. The patients studied by Saarelainen et al. and Phillips et al. had more severe disease and, thus, underwent more severe oxygen desaturations that could have acted as a trigger for endothelin-1 secretion. Although it seems that OSAS severity has an influence on endothelin-1 secretion, our patients did not present a correlation between number of oxygen desaturations during the night and levels of endothelin-1. Consensus does not yet exist regarding the association of OSAS with hemostatic alterations (27). Our study analyzes levels of VW and fibrinogen and we find no changes in either. Certain limitations in the present study need to be taken into consideration. First, measurements of circulating adhesion molecules were based on the assumption that the number of circulating adhesion molecules reflect the number of cell surface adhesion molecules. Secondly, plasma samples were obtained only in the morning, which may have affected random variability because oscillations during the day were not considered. In summary, the present study demonstrates that obstructive sleep apnea syndrome is associated with changes in levels of adhesion molecules, and that this could be the result of OSAS-induced hypoxia. These findings suggest potential mechanisms involving endothelial dysfunction that could help explain the association between OSAS and cardiovascular disease.
150
Acknowledgments This study was supported by Fondo Investigacio´n Sanitaria grant (01/0634) and Secretaria Xeral de Investigacio´n e Desenvolvemento Grant (PGIDT99PXI90201A).
100
50
References 0 0
100
200
300
400
500
600
700
800
Total desaturation dips during sleep Figure 1. Scatter plot of E-selectin and total oxygen desaturation dips during sleep.
1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;28:1230–1235. 2. Zamarro´n C, Gude F, Otero Y, Alvarez JM, Golpe A, Rodriguez JR. Prevalence of sleep disordered breathing and sleep apnea in 50 to 70 year old individuals. A survey. Respiration 1999;66:317–322. 3. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension
Vascular Endothelial Markers in Obstructive Sleep Apnea
4.
5.
6.
7.
8.
9.
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11.
12.
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