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Department of Geriatric Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113, Japan
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Obstructive sleep apnea syndrome (OSAS) may be one of the most important risk factors of cardiovascular disorders, although the exact mechanism remains to be elucidated. In the present study, we hypothesized that OSAS-induced hypoxic stress might be involved in the etiology of cardiovascular disorders by activating adhesion molecules, including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and L-selectin. To examine this hypothesis, we measured circulating ICAM-1, VCAM-1, and L-selectin levels before and after sleep in OSAS patients and age-matched controls. The circulating ICAM-1, VCAM-1, and L-selectin levels increased in the OSAS patients before sleep compared with the normal subjects (ICAM-1: 392.9 ± 48.5 vs. 201.2 ± 55.0 ng/ml, P < 0.05; VCAM-1: 811.0 ± 87.8 vs. 574.2 ± 42.7 ng/ml, P < 0.05; L-selectin: 1,386.6 ± 77.9 vs. 1,038.8 ± 78.6 ng/ml, P < 0.01, respectively). After sleep, significantly greater levels of ICAM-1 and L-selectin, but not VCAM-1, were observed in the OSAS group. These observations suggest that OSAS-induced hypoxia activates adhesion molecules, resulting in the important risk factor of cardiovascular disorders. Treatment of OSAS can be, therefore, a potential approach to prevention of cardiovascular events.
adhesion molecules; cardiovascular disorders; ischemic heart disease; desaturation index; hypoxic stress
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENT STUDIES HAVE SHOWN that obstructive sleep apnea syndrome (OSAS) may be one of the most important risk factors of cardiovascular disorders, including hypertension, ischemic heart disease, and cerebrovascular events (9, 10, 18, 20). OSAS is also associated with obesity, insulin resistance, and diabetes mellitus (12, 23, 29). Although it is postulated that hypoxic stress induced by OSAS may be involved in the etiology of cardiovascular disorders, the exact mechanism remains to be elucidated. One of the potential mechanisms is that OSAS-induced hypoxic stress increases circulating inflammatory mediators, leading to cardiovascular lesions.
To induce leukocyte migration to inflamed tissue, it is essential for leukocytes to adhere to microvascular endothelium (28). Potential adhesion molecules responsible for leukocyte attachment to endothelium include intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and L-selectin. ICAM-1 and VCAM-1 are members of the immunoglobulin superfamily, whereas the L-selectin family includes lectin adhesion molecule 1. It has been reported that ICAM-1, VCAM-1, and L-selectin are required for leukocyte migration into an inflamed area (3, 4, 27), which plays an important role in inflammatory disease, including bronchial asthma and reperfusion injury associated with myocardial infarction (8, 11, 14, 16, 26, 30). Recently, it has been postulated that atherosclerosis is related to the inflammatory process induced by activation of proinflammatory mediators, including adhesion molecules (8). To assess the expression levels of cell surface adhesion molecules, the measurements of circulating adhesion molecules have been made on the basis of the assumption that the number of circulating adhesion molecules could reflect the number of cell surface adhesion molecules (8, 15).
Recent studies have demonstrated that hypoxia per se enhances adhesion
molecules in various cells such as endothelium and leukocytes (2, 5, 7,
31). Hypoxia increases the adherence of neutrophils to endothelial
cells, and this increased adherence is mediated by adhesion molecules,
including ICAM-1 (2). In addition, it has been reported that hypoxia
induces the synthesis and expression of the adhesion molecule ICAM-1
via the activation of nuclear transcription factor-
B (5, 31).
In the present study, we hypothesized that OSAS-induced hypoxic stress might activate the adhesion molecules expressed on the cell surface of endothelium and leukocytes, resulting in the damage of cardiovascular system. To examine this hypothesis, we measured circulating ICAM-1, VCAM-1, and L-selectin levels before and after sleep in OSAS patients and age-matched controls.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects.
Among patients who underwent sleep polysomnography in our department,
seven male patients with OSAS participated in the present study. As
age-matched controls, six male subjects were chosen and studied. No
subjects had any history of cardiovascular, pulmonary, metabolic, or
neuromuscular diseases. The OSAS and control groups included three and
two smokers, respectively (not significant, 
2 analysis), but there was no
significant difference in the smoking dose between OSAS and control
groups (12.1 ± 5.8 and 10.0 ± 6.3 cigarettes/day,
respectively). These smokers ceased smoking 1 wk before the study in
accordance with the instructions of the medical staff. All
subjects were in a stable condition for 1 mo before the study. The
characteristics of the subjects in the OSAS and normal groups are shown
in Table 1. There were no significant differences in age, height, weight, or body mass index between the two
groups. Data from pulmonary function test are shown in Table
2. Before the study, there was
no difference in arterial PO2
(PaO2) between the OSAS and normal
groups.
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Polysomnography. The subjects underwent polysomnography for 2 consecutive nights. The polysomnography included an electroencephalogram, an electrooculogram, an electromyogram of the chin, and an electrocardiogram (DG Compact32, Medelec). We monitored ventilation and airflow by using inductive plethysmography (Respitrace, Ambulatory Monitoring, Ardsley, NY) and thermistors (Fukuda-Sangyo, Chiba, Japan) placed at the nostrils and mouth. Arterial oxygen saturation (SaO2) was continuously measured via pulse oximeter (Datex, Helsinki, Finland). Data acquisition was performed overnight starting from 9:00 PM to 6:00 AM the next morning.
Assessment of hypoxic episodes.
To assess OSAS-induced hypoxia, we applied desaturation index (DI) in
this study. Desaturation episodes were defined as hypoxia of
SaO2 
90%. We defined DI as
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Measurements of circulating adhesion molecules.
We obtained peripheral blood from the subjects at 8:00 PM before the
polysomnography on the second night and at 8:00 AM after the sleep
study. The blood samples were centrifuged at 250 g and 4°C for 10 min. The serum
samples were then stored at 
80°C until measurement of
adhesion molecules. The concentrations of ICAM-1, VCAM-1, and
L-selectin in the serum were measured by the ELISA method.
Data analysis. Comparisons of data among each experimental group were carried out with analysis of variance (Scheffé's test). Data are expressed as mean ± SE. P values <0.05 were taken as significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Assessment of hypoxic episodes.
Hypoxic episodes assessed by DI are shown in Fig.
2. There were significant differences in DI
between the OSAS and normal groups, suggesting that the OSAS patients
were exposed to a significantly greater degree of hypoxia.
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Measurements of circulating adhesion molecules.
Figure 3 summarizes the circulating ICAM-1
levels in the present study. Both before and after sleep, the ICAM-1
level in the OSAS group was significantly greater than that in the
normal group. There were no significant differences in the ICAM-1 level
between the two samples obtained at 8:00 PM and 8:00 AM in either the OSAS or normal group.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study demonstrate that the circulating ICAM-1 and L-selectin levels increased in the OSAS patients before and after sleep compared with the normal subjects. Significant increases in the VCAM-1 level were observed in the OSAS group only before sleep but not after sleep. These observations suggest that OSAS-induced hypoxia may be involved in the pathogenesis of cardiovascular disorders by stimulating inflammatory responses via the elevation of these adhesion molecules.
Several issues warrant consideration before the present results are discussed. First, we made measurements of circulating adhesion molecules to assess the expression of cell-associated adhesion molecules. Although this approach has been widely used in the previous studies (8, 15), it remains unclear whether the circulating levels of adhesion molecules might accurately reflect the actual numbers of adhesion molecules attached to the endothelium. To assess the cell-associated adhesion molecules, experimental procedures, including vascular biopsy, might be required and warrant further examination. Second, the number of subjects in this study is relatively low, and the present observations still remain preliminary. Increased numbers of subjects may be required to confirm the present results and we should acknowledge this point.
Recently, it has been shown that the inflammatory process has a major
role in the pathogenesis of atherosclerosis, leading to the
cardiovascular disorders (1, 6, 8). To promote migration of leukocytes
from the circulation to the inflamed area, it is essential for
leukocytes to adhere to vascular endothelium via adhesion molecules
(28). Especially, ICAM-1 has been reported to play important roles in
leukocyte migration to an inflamed area (2, 3, 24). ICAM-1
is an 80- to 110-kDa glycoprotein consisting of five
immunoglobulin-like domains and a ligand for lymphocyte
function-associated antigen 1
(LFA-1) (13, 28). It has been
demonstrated that the ICAM-1/LFA-1 pathway evolves to function in
cell-cell adhesion (28) and mediates various inflammatory diseases (11,
14, 16, 26, 30). VCAM-1 is one of the immunoglobulin superfamily and a
ligand for very late antigen-4, which is present on monocytes and
lymphocytes but not on neutrophils (21, 28). L-selectin is
a cell membrane-surface receptor on leukocytes and is responsible for
leukocyte attachment to the inflamed tissue (8). In the present study,
we focused on these adhesion molecules, i.e., ICAM-1, VCAM-1, and
L-selectin. The circulating forms of these adhesion molecules reflect
the degree of expression on endothelium and leukocytes, and it is possible to make accurate measurements by the ELISA method (8, 24, 25).
In the OSAS group, the circulating ICAM-1 and L-selectin levels were significantly increased both before and after sleep compared with those of the control group. Of note, no significant differences in these adhesion molecule levels were observed between the samples obtained before and after sleep in the OSAS or normal groups. These findings may suggest that OSAS-induced hypoxia provokes sustained increases in the circulating ICAM-1 and L-selectin levels. The patients with OSAS suffer from repetitive hypoxic stress every night. This hypoxic stress may induce the activation of ICAM-1 and L-selectin, resulting in the elevation of circulating levels of these inflammatory mediators. Alternatively, sustained increases in these adhesion molecules may reflect the continuous inflammation of endothelium in patients with OSAS. Presumably, the circadian rhythm may have little effect on the variation of the circulating ICAM-1 and L-selectin levels.
Recently, it has been reported that the circulating ICAM-1 levels are higher in patients with ischemic heart disease than those levels in controls (15). Moreover, the circulating ICAM-1 level may indicate a risk of future myocardial infarction, suggesting that antiadhesion therapies can be considered as a novel therapeutic means to treat cardiovascular disease (22). Our results indicate that therapy for OSAS might be a potential approach to prevention of cardiovascular disorders via an antiadhesion mechanism.
Increased levels in VCAM-1 were observed in the OSAS patients before sleep compared with those levels in the controls. After sleep, however, the significant difference disappeared. No significant differences in the VCAM-1 level were detected between the samples obtained before and after sleep in either the OSAS or normal group. Although it is difficult to understand this observation, one of the possible explanations is that the circulating VCAM-1 level might not directly reflect hypoxia-induced inflammation. Indeed, it has been reported that there is no significant difference in the serum VCAM-1 level between patients with ischemic heart disease and controls (15). Of interest, heat shock protein 72 level decreases during sleep in OSAS patients (19); this resembles the present finding regarding the VCAM-1 levels. That finding reflects the protective mechanism of the treatment of OSAS, but the exact mechanism remains unclear.
To assess the severity of hypoxia induced by OSAS, we used a new index, DI. On the basis of the fact that SaO2 = 90-91% reflects PaO2 = 60 Torr, we defined DI as reported. This index may reflect OSAS-induced hypoxia more directly than does the apnea index. The usual ways to assess the degree of OSAS include the nadir of SaO2 and time spent below 90%, whereas DI could reflect both decreases in SaO2 and time spent below 90%, as shown in Fig. 1.
In laboratory experiments, increasing evidence has been found showing
that antiadhesion by using monoclonal antibodies (MAbs) is effective in
the models of various inflammatory disorders. For example, antagonism
of the ICAM-1/LFA-1 pathway by using MAbs might have the potential
therapeutic value in the treatment of bronchial asthma and acute
respiratory distress syndrome (16, 17). Meanwhile,
considering the cost of MAbs, it may not be easy to perform
antiadhesion therapy by using MAb administration in the treatment of
human diseases. The present observations suggest that
therapy for OSAS may be important to decrease risk of the progression
of cardiovascular disorders via adhesive mechanism.
In summary, the circulating ICAM-1, VCAM-1, and L-selectin levels increased in the OSAS patients before sleep compared with those in the normal subjects. After sleep, significantly greater levels of ICAM-1 and L-selectin, but not VCAM-1, were observed in the OSAS group. Taken together, our findings suggest that OSAS-induced hypoxia activates adhesion molecules, resulting in the development of an important risk factor of cardiovascular disorders. Treatment of OSAS can be, therefore, a potential approach to prevention of cardiovascular events.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Nagase, Dept. of Geriatric Medicine, Faculty of Medicine, Univ. of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Received 13 November 1998; accepted in final form 9 March 1999.
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 M. Joyeux-Faure, F. Stanke-Labesque, B. Lefebvre, P. Beguin, D. Godin-Ribuot, C. Ribuot, S. H. Launois, G. Bessard, and P. Levy Chronic intermittent hypoxia increases infarction in the isolated rat heart J Appl Physiol, May 1, 2005; 98(5): 1691 - 1696. [Abstract] [Full Text] [PDF]
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A. G. Kaditis, E. I. Alexopoulos, E. Kalampouka, E. Kostadima, A. Germenis, E. Zintzaras, and K. Gourgoulianis Morning Levels of C-Reactive Protein in Children with Obstructive Sleep-disordered Breathing Am. J. Respir. Crit. Care Med., February 1, 2005; 171(3): 282 - 286. [Abstract] [Full Text] [PDF]
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A.G. Kaditis, E.I. Alexopoulos, E. Kalampouka, E. Kostadima, N. Angelopoulos, A. Germenis, E. Zintzaras, and K. Gourgoulianis Morning levels of fibrinogen in children with sleep-disordered breathing Eur. Respir. J., November 1, 2004; 24(5): 790 - 797. [Abstract] [Full Text] [PDF]
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K. Minoguchi, T. Tazaki, T. Yokoe, H. Minoguchi, Y. Watanabe, M. Yamamoto, and M. Adachi Elevated Production of Tumor Necrosis Factor-{alpha} by Monocytes in Patients With Obstructive Sleep Apnea Syndrome Chest, November 1, 2004; 126(5): 1473 - 1479. [Abstract] [Full Text] [PDF]
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 O. Milleron, R. Pilliere, A. Foucher, F. de Roquefeuil, P. Aegerter, G. Jondeau, B. G Raffestin, and O. Dubourg Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study Eur. Heart J., May 1, 2004; 25(9): 728 - 734. [Abstract] [Full Text] [PDF]
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T. Altay, E. R. Gonzales, T. S. Park, and J. M. Gidday Cerebrovascular inflammation after brief episodic hypoxia: modulation by neuronal and endothelial nitric oxide synthase J Appl Physiol, March 1, 2004; 96(3): 1223 - 1230. [Abstract] [Full Text] [PDF]
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F. J. Nieto, D. M. Herrington, S. Redline, E. J. Benjamin, and J. A. Robbins Sleep Apnea and Markers of Vascular Endothelial Function in a Large Community Sample of Older Adults Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 354 - 360. [Abstract] [Full Text] [PDF]
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M. S. M. Ip, H.-F. Tse, B. Lam, K. W. T. Tsang, and W.-K. Lam Endothelial Function in Obstructive Sleep Apnea and Response to Treatment Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 348 - 353. [Abstract] [Full Text] [PDF]
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R. von Kanel and J. E. Dimsdale Hemostatic Alterations in Patients With Obstructive Sleep Apnea and the Implications for Cardiovascular Disease Chest, November 1, 2003; 124(5): 1956 - 1967. [Abstract] [Full Text] [PDF]
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 A. S. M. Shamsuzzaman, B. J. Gersh, and V. K. Somers Obstructive Sleep Apnea: Implications for Cardiac and Vascular Disease JAMA, October 8, 2003; 290(14): 1906 - 1914. [Abstract] [Full Text] [PDF]
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M. Hayashi, K. Fujimoto, K. Urushibata, S.-i. Uchikawa, H. Imamura, and K. Kubo Nocturnal Oxygen Desaturation Correlates With the Severity of Coronary Atherosclerosis in Coronary Artery Disease Chest, September 1, 2003; 124(3): 936 - 941. [Abstract] [Full Text] [PDF]
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E. Ohga, T. Tomita, H. Wada, H. Yamamoto, T. Nagase, and Y. Ouchi Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1 J Appl Physiol, January 1, 2003; 94(1): 179 - 184. [Abstract] [Full Text] [PDF]
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A. A. El-Solh, M. J. Mador, P. Sikka, R. S. Dhillon, D. Amsterdam, and B. J. B. Grant Adhesion Molecules in Patients With Coronary Artery Disease and Moderate-to-Severe Obstructive Sleep Apnea* Chest, May 1, 2002; 121(5): 1541 - 1547. [Abstract] [Full Text] [PDF]
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L. DYUGOVSKAYA, P. LAVIE, and L. LAVIE Increased Adhesion Molecules Expression and Production of Reactive Oxygen Species in Leukocytes of Sleep Apnea Patients Am. J. Respir. Crit. Care Med., April 1, 2002; 165(7): 934 - 939. [Abstract] [Full Text] [PDF]
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 W. Droge Free Radicals in the Physiological Control of Cell Function Physiol Rev, January 1, 2002; 82(1): 47 - 95. [Abstract] [Full Text] [PDF]
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L. Lavie, A. Perelman, and P. Lavie Plasma Homocysteine Levels in Obstructive Sleep Apnea : Association With Cardiovascular Morbidity Chest, September 1, 2001; 120(3): 900 - 908. [Abstract] [Full Text] [PDF]
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R. SCHULZ, S. MAHMOUDI, K. HATTAR, U. SIBELIUS, H. OLSCHEWSKI, K. MAYER, W. SEEGER, and F. GRIMMINGER Enhanced Release of Superoxide from Polymorphonuclear Neutrophils in Obstructive Sleep Apnea . Impact of Continuous Positive Airway Pressure Therapy Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 566 - 570. [Abstract] [Full Text] [PDF]
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