| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From the Department of Respirology (Drs. Kono, Tatsumi, Nakamura, Tanabe, Takiguchi, and Kuriyama), Graduate School of Medicine, Chiba University, Chiba; and Department of Gastroenterology and Hepatology (Dr. Saibara), Kochi Medical School, Nankoku, Japan.
Correspondence to: Koichiro Tatsumi, MD, FCCP, Department of Respirology, Graduate School of Medicine, Chiba University, 1–8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan; e-mail: tatsumi{at}faculty.chiba-u.jp
Abstract
Background: Obesity, hypertension, dyslipidemia, and hyperglycemia are prevalent in obstructive sleep apnea syndrome (OSAS). Metabolic syndrome, however, is defined by visceral fat obesity plus at least two of these factors. However, whether OSAS contributes to the development of metabolic syndrome has not been defined. We investigated whether the components of metabolic syndrome were associated with OSAS in nonobese patients.
Methods: We investigated the occurrence of hypertension, dyslipidemia, and hyperglycemia in 42 men with OSAS and 52 men without OSAS matched for age, body mass index (BMI), and visceral fat accumulation.
Results: Although serum levels of triglycerides, high-density lipoprotein cholesterol, and diastolic BP did not differ significantly between the two groups, fasting blood glucose (111 ± 6 mg/dL vs 93 ± 3 mg/dL) [mean ± SE] and the percentage of hypertensive patients (45% vs 15%) were significantly higher in the group with OSAS. In addition, a significantly higher percentage of patients with OSAS (19% vs 4%) had at least two of the following: hypertension, hyperglycemia, and dyslipidemia. Logistic regression analysis showed that the apnea-hypopnea index value was the predictor of number of metabolic syndrome parameters such as hypertension, hyperglycemia, and dyslipidemia, while BMI and lowest arterial oxygen saturation during sleep did not.
Conclusion: Independent of visceral fat obesity, OSAS was associated with hypertension, dyslipidemia, and hyperglycemia. It is possible that OSAS may predispose even nonobese patients to the development of metabolic syndrome.
Key Words: atherosclerosis • hypertension • hypoxia • insulin resistance • sleep apnea
The group of patients with multiple risk factors for cardiovascular diseases related to arteriosclerotic plaques has been highlighted. This group includes those with metabolic syndrome, which has been defined by multiple organizations.123 In the pathogenesis of metabolic syndrome, insulin resistance and visceral obesity seem to be key factors.123 The criteria defining metabolic syndrome include visceral obesity because studies45 have revealed that visceral fat produces a great amount of cytokines and hormones such as tumor necrosis factor-
, interleukin-6, and leptin, which may be associated with the development of atherosclerosis. Insulin resistance is thought to play a part in the pathogenesis of metabolic syndrome, although the precise relationship between insulin resistance and visceral obesity has not been defined.6
Obstructive sleep apnea syndrome (OSAS) is a prevalent disorder particularly among middle-aged, obese men. Several features of OSAS suggest that sleep apnea is a manifestation of metabolic syndrome.789 Indeed, there is a strong association of OSAS with obesity, male gender, hypertension,1011 and diabetes,812 which are also found in patients with metabolic syndrome. Visceral fat accumulation (VFA) correlates with the severity of OSAS13 and is a key factor for the development of metabolic syndrome.123
Although obesity, hypertension, and diabetes are frequently present in patients with OSAS, whether OSAS directly contributes to the development of metabolic syndrome has not been defined. OSAS may be associated with a number of cardiovascular risk factors such as hypertension,1011 insulin resistance,812 and dyslipidemia1415 independent of obesity. The purpose of this study was to investigate whether some components (hypertension, hyperglycemia, and dyslipidemia) of metabolic syndrome were present in nonobese patients with OSAS. Only men were enrolled into the study because of avoiding the confounding effects of gender and insufficient number of women (approximately one eighth of men) for statistical analysis.
Materials and Methods
Subjects
From April 2002 to March 2006, 1,205 consecutive male patients with clinical symptoms of sleep apnea were examined by polysomnography and classified into two groups by their apnea-hypopnea index (AHI) [AHI 
5/h, n = 1,153; AHI < 5/h, n = 52]. Presenting symptoms were either snoring or daytime sleepiness or both. The subjects were all Japanese.
The diagnostic criteria for metabolic syndrome in Japan16 include a VFA 100 cm2. First, we selected patients with a body mass index (BMI) 
30 kg/m2 for both groups. When matching patients with and without OSAS for BMI, VFA tends to be higher in those with OSAS. Therefore, we selected patients with OSAS whose VFA was < 90 cm2 and patients without OSAS whose VFA was < 100 cm2. In the end, we selected 42 patients with OSAS and 52 without OSAS, matched for age, BMI, and VFA.
None of the patients had heart failure or other respiratory problems such as COPD at the time of polysomnography. They were asked to complete a questionnaire on sleep symptoms, medical history, and medications. OSAS was established on the basis of clinical and polysomnography criteria. AHI was calculated as the sum of sleep-disordered breathing. In addition to clinical symptoms, an AHI > 5/h was also used as a selection criterion of OSAS.
Pulmonary function tests were performed to determine FVC and FEV1 using a standard spirometer (Fudac-60; Fukuda Denshi; Tokyo, Japan). Patients with obstructive airway disease (FEV1/FVC < 70%) were excluded. Arterial blood for the analysis of gases during room air breathing was drawn with the patient in the supine position, and PaO2 and PaCO2 were measured in a blood gas analyzer (Model ABL3000; Radiometer; Tokyo, Japan). The study protocol was approved by the Research Ethics Committee of Chiba University School of Medicine, and all patients gave their informed consent prior to the study.
Polysomnography
Polysomnography (P Series Sleep System; Compumedics; Melbourne, Australia) was performed overnight between 9:00 PM and 6:00 AM. Polysomnography consisted of continuous polygraphic recording from surface leads for EEG, electrooculography, electromyography, ECG, thermistors for nasal and oral airflow, thoracic and abdominal impedance belts for respiratory effort, pulse oximetry for oxyhemoglobin level, and tracheal microphone for snoring and sensor to assess changing of the position during sleep. Polysomnography records were staged manually according to standard criteria.1718 The severity of OSAS was determined by the AHI and mean and lowest arterial oxygen saturation (SaO2) during sleep.
On the morning after the sleep study, BP was measured twice on waking up between 7:00 AM and 8:00 AM with the subjects in the seated position after a 5-min rest. Venous blood was obtained in the fasting state at 7:00 AM after polysomnography to measure triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), and fasting insulin. Insulin resistance was estimated using the homeostasis model assessment method (HOMA-R) and calculated with the following formula: fasting serum insulin (µU/mL) x FPG (mg/dL)/405.
Radiologic Assessment
VFA and subcutaneous fat accumulation (SFA) were assessed by CT (TSX-101A/4E; Toshiba; Tokyo, Japan) and commercially available software (Fat Scan; N2 System; Ashiya, Japan) for personal computer. The areas of SFA and VFA were measured in a single cross-sectional scan at the level of the umbilicus. A CT range of – 150 to – 50 Hounsfield units was used to encompass all fat. VFA was measured by drawing a line within the muscular wall surrounding the abdominal cavity. The area after subtraction of the VFA from the total fat area was defined as SFA,19 and the visceral/subcutaneous fat ratio was calculated (Fig 1
).
|
150 mg/dL and/or HDL-C 40 mg/dL; hypertension as either systolic BP 130 mm Hg and/or diastolic BP 85 mm Hg; and hyperglycemia as FPG 110 mg/dL. Patients with a previous diagnosis of dyslipidemia, hypertension, or diabetes mellitus, and were receiving drugs for any of these conditions were also included in this category.
Statistical Analysis
Results are expressed as mean ± SE. All clinical parameters are summarized by descriptive statistics. Continuous clinical parameters in patients with and without OSAS were compared using Mann-Whitney test, and categorical parameters using 
2 test. Logistic regression analysis was applied to predict the number of metabolic syndrome parameters such as hypertension, hyperglycemia, and dyslipidemia using the values of AHI, lowest SaO2 during sleep, and BMI as potential predictors; p < 0.05 was considered statistically significant.
Results
Table 1 summarizes the characteristics of the subjects. Two patients each in both groups were receiving antihypertensive drugs. Three patients in the OSAS group and two patients in the non-OSAS group had diabetes; of them, two patients in the OSAS group and one patient in the non-OSAS group were receiving an oral hypoglycemic agent, while the others were receiving diet therapy.
|
|
150 mg/dL and/or HDL-C 40 mg/dL) was significantly higher in the OSAS group (48% vs 25%; p < 0.05) [Table 2].
FPG was higher in the OSAS group, and the percentage of subjects with hyperglycemia (FPG 110 mg/dL) was also significantly higher in the OSAS group (33% vs 10%; p < 0.01) [Table 2]. The calculated HOMA-R was significantly higher in the OSAS group as well (p < 0.05) [Table 2].
Nineteen percent of patients in the OSAS group, compared with only 4% in the non-OSAS group, had at least two of the following: hypertension, hyperglycemia, and dyslipidemia (Table 2). Logistic regression analysis showed that AHI value was the predictor (p = 0.0001) of the number of metabolic syndrome parameters such as hypertension, hyperglycemia and dyslipidemia, while BMI (p = 0.10) and lowest SaO2 during sleep (p = 0.85) did not.
Discussion
This cross-sectional analysis involved a selected group of male patients with and without OSAS matched for age, BMI, and VFA. Since they were matched for abdominal obesity, we compared them for the other components of metabolic syndrome. The main finding of this study was that 19% of the men with OSAS, compared with only 4% of those without it, had at least two of the following: hypertension, hyperglycemia, and dyslipidemia. It is possible that even in nonobese OSAS subjects might be predisposed to metabolic syndrome. In addition, the logistic regression analysis, in which AHI value was the predictor of number of metabolic syndrome parameters such as hypertension, hyperglycemia, and dyslipidemia, while BMI and lowest SaO2 during sleep were not, may support our results.
Obesity and VFA are known to be risk factors for the development of OSAS.1320 Especially, VFA increases the risk for obesity-related disorders such as vascular-related diseases.1234 OSAS itself is a risk for VFA,13 which increases insulin resistance,812 an important factor involved in the pathogenesis of metabolic syndrome. In an abdominal CT scan, a VFA > 100 cm2 is a diagnostic feature of metabolic syndrome.12316 The subjects with OSAS in the present study did not meet this criterion of metabolic syndrome, since the VFA (62.0 ± 3.2 cm2) was 90 cm2. If OSAS was a risk factor for metabolic syndrome, any factor related to the pathophysiology of OSAS, such as intermittent hypoxia, increased oxygen-radical production, and membrane lipid peroxidation, would contribute to the development of metabolic syndrome.
Hypoxia is known to increase hypoxia-inducible factor 1 gene transcription and messenger RNA stabilization, while intermittent hypoxia also up-regulates hypoxia-inducible factor 1 expression.21 In experimental animals, intermittent hypoxia resulted in an increase of FPG and serum leptin levels. Microarray messenger RNA analysis of adipose tissue revealed that leptin was the only up-regulated gene affecting glucose uptake.22 Leptin may play an important role in mitigating the metabolic disturbances that accompany intermittent hypoxia.
Obesity, especially the presence of VFA, could worsen metabolic abnormalities such as insulin resistance; while insulin resistance, a putative background of the metabolic syndrome, could be associated with OSAS.812 Since continuous positive airway pressure treatment improves insulin sensitivity in patients with OSAS within a few days before any possible changes in body weight or lifestyle, OSAS itself appears to predispose to insulin resistance.23 The severity of OSAS may affect insulin resistance to a greater extent in nonobese patients with OSAS.23 These results indicate that OSAS per se may be associated with insulin resistance, although concomitant obesity or VFA are predominant risk factors for insulin resistance. Increased production of tumor necrosis factor-24 and increased sympathetic drive2526 may partly explain changes of glucose homeostasis in OSAS. In the present study, both FPG and calculated HOMA-R were higher in the OSAS group. Thus, intermittent hypoxia is likely to aggravate the insulin resistance associated with significant VFA in patients with OSAS.
This study confirmed the association of OSAS with hypertension,1011 even though the subjects of the present study were not obese. The percentage of subjects with a systolic BP 130 mm Hg and/or a diastolic BP 85 mm Hg was significantly higher in the OSAS group. OSAS may contribute to hypertension in obese individuals through increased sympathetic activation,2526 leptin, aldosterone, fatty acids and oxidative stress, and insulin resistance.27 Insulin resistance predisposes patients with OSAS to hypertension, although several factors can lead to hypertension regardless of obesity.
The percentage of subjects who met the criteria of dyslipidemia (serum triglycerides 150 mg/dL and/or HDL-C 40 mg/dL) was significantly higher in the OSAS group. Disorders of lipid metabolism are known to play a part in atherosclerotic changes of vascular walls. The association between OSAS and lipid metabolism was addressed in the Sleep Heart Health Study.15 However, serum triglycerides, TC, and HDL-C did not differ significantly between the OSAS and non-OSAS groups in this study, suggesting that the severity of intermittent hypoxia (lowest SaO2, 81.9 ± 1.3% in the OSAS group, vs 87.4 ± 0.7% in the non-OSAS group) may not have been too severe to affect lipid metabolism.
OSAS may be independently associated with an increased prevalence of metabolic syndrome, although subjects with OSAS in previous studies789 were more obese compared with control subjects. In previous research9 regarding the prevalence of metabolic syndrome in Japanese patients with OSAS, it was found that metabolic syndrome was more common in patients with OSAS than in control subjects (50% vs 22%). Our present subjects were not obese according to the standard for white people, and did not meet the criteria of the metabolic syndrome. However, the percentage of subjects with high FBG levels or hypertension was significantly higher in the OSAS group. In addition, the percentage of patients presenting at least two metabolic abnormalities was also significantly higher in the OSAS group. These results suggest that even nonobese patients with OSAS may be prone to metabolic syndrome.
This was a cross-sectional descriptive study and did not provide direct evidence that patients with OSAS are at an increased risk for cardiovascular mortality. It has not been defined whether OSAS directly enhances the factors that comprise the metabolic syndrome. OSAS and metabolic syndrome may share a common pathomechanism other than visceral obesity. An interventional study using continuous positive airway pressure may clarify this question. Due to absence of women in this study, our conclusions cannot be extrapolated to other cohorts. In addition, the results of this study cannot be extrapolated to other ethnic groups. This study was intended to analyze all consecutive male patients with clinical symptoms of sleep apnea who were examined using polysomnography. A limitation of our study is that our strict selection criteria allowed us to evaluate only a small number of patients.
In conclusion, the percentage of patients presenting at least two metabolic abnormalities (among hypertension, dyslipidemia, and hyperglycemia) was significantly higher in the OSAS group than in the non-OSAS group matched for age, BMI, and VFA. Early intervention may help to decrease the cardiovascular morbidity and mortality associated with OSAS and metabolic syndrome.
Footnotes
Abbreviations: AHI = apnea-hypopnea index; BMI = body mass index; FPG = fasting plasma glucose; HDL-C = high-density lipoprotein cholesterol; HOMA-R = homeostasis model assessment method; OSAS = obstructive sleep apnea syndrome; SaO2 = arterial oxygen saturation; SFA = subcutaneous fat accumulation; TC = total cholesterol; VFA = visceral fat accumulation
Dr. Tatsumi is supported by a Grant-in-Aid for Scientific Research (C)(16590735) from the Ministry of Education, Science, Sports and Culture; and grants to the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare, Japan.
Dr. Kuriyama is supported by a grant to Respiratory Failure Research
The authors have no conflicts of interest to disclose.
Received for publication July 24, 2006. Accepted for publication January 16, 2007.
References
function. Nature 1997;389,610-614[CrossRef][Medline]This article has been cited by other articles:
|
|
 |
|
  E. Tasali, B. Mokhlesi, and E. Van Cauter Obstructive Sleep Apnea and Type 2 Diabetes: Interacting Epidemics Chest, February 1, 2008; 133(2): 496 - 506. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
