Metabolic syndrome correlates intracoronary stenosis detected by multislice computed tomography in male subjects with sleep-disordered breathing
© Nakanishi-Minami et al; licensee BioMed Central Ltd. 2012
Received: 20 January 2012
Accepted: 1 March 2012
Published: 1 March 2012
Sleep-disordered breathing (SDB), especially obstructive sleep apnea (OSA), has frequent complications include hypertension, dyslipidemia and insulin resistance based on abdominal obesity or excess visceral fat (called Syndrome Z). OSA is a potential risk factor for cardiovascular diseases. The clinical characteristics of Japanese OSA subjects with OSA remain unclear. The present study investigated prevalence and predictive factors of intracoronary stenosis detected by multislice computed tomography (MSCT) in Japanese male subjects with SDB/OSA.
The study (O-VFStudy) subjects were 39 Japanese men with SDB/OSA who underwent all-night cardiorespiratory monitoring with fully attended polysomnography, and moreover both fat computed tomography (CT) scan and 64-row MSCT coronary angiography. The prevalence of coronary stenosis in this selected population with SDB/OSA was 15%. Logistic regression analysis showed a significant relationship between age-adjusted CAD and metabolic syndrome (p < 0.05), but not serum adiponectin levels and nocturnal fall in adiponectin. Subjects with the metabolic syndrome had significantly higher prevalence of CAD (31.3 versus 4.3%, p = 0.033), and lower levels of serum adiponectin (4.5 ± 0.6 versus 6.4 ± 0.6 μg/mL, p = 0.014), compared with groups without the metabolic syndrome.
The present study describes that the prevalence of greater than 50% intracoronary stenotic lesions detected by MSCT was 15% and the metabolic syndrome was correlated with intracoronary stenosis detected by MSCT in Japanese SDB/OSA subjects.
KeywordsCoronary Stenosis Sleep apnea-hypopnea Visceral fat Adiponectin
Sleep-disordered breathing (SDB), especially obstructive sleep apnea (OSA), is a potential risk factor for cardiovascular diseases, including coronary artery disease (CAD) and stroke [1–3]. OSA is common in middle-age men , and frequent complications include hypertension, dyslipidemia and insulin resistance based on abdominal obesity or excess visceral fat [5–8]. Visceral fat is a huge endocrine organ producing a variety of bioactive substances, conceptualized as 'adipocytokines' . Our group discovered adiponectin as an adipocytokine in the human adipose cDNA library , which has anti-atherosclerotic property . We have recently demonstrated that, 1) production of adiponectin is dysregulated in intra-abdominal obese patients with severe OSA [12, 13], and 2) night-time onset of acute coronary syndrome is associated with excess visceral fat and SDB , which is called "Syndrome Z" . However, there is little information on clinical features of Japanese OSA subjects with CAD.
The present study investigated prevalence and predictive factors of intracoronary stenosis detected by multislice computed tomography (MSCT) in Japanese male subjects with OSA.
Methods and procedures
Subjects were recruited from 50 consecutive Japanese male subjects with a history of snoring and/or witnessed apneas, who underwent all-night cardiorespiratory monitoring in the Yoshida Suimin-kokyu Clinic (Osaka, Japan) and had no history of CAD, which was defined as documentation of medication and history of myocardial infarction, angina, and/or previous coronary intervention. The study (O-VFStudy) subjects comprised 39 Japanese, who moreover underwent both fat computed tomography (CT) scan and 64-row MSCT coronary angiography (GE-LightSpeed VCT) in Kenporen Osaka Central Hospital (Osaka, Japan), excluding subjects with contrast-allergic disease and/or renal dysfunction (serum creatinine > 1.5 mg/dL) (n = 6), and apnea hypopnea index (AHI) < 5 events/hour (n = 5). The study was approved by the human ethics committee of each participating hospital and informed consent was obtained from each participant.
All participants underwent overnight cardiorespiratory monitoring with fully attended polysomnography (Alice®4 Diagnostics Sleep System, Philips Respironics). The recorded signals were analyzed for the number of apneas and hypopneas. Apnea represented a decrease in the amplitude of airflow signal or thoracoabdominal motion decreased to < 10% of the baseline for at least 10 seconds. Hypopnea was defined as a decrease in airflow or respiratory effort to < 70% of baseline for at least 10 seconds associated with > 4% desaturation but did not meet the criteria for an apnea. The AHI was defined as the total number of apneas/hypopneas per hour of sleep time [16, 17]. An AHI ≥ 5 established the diagnosis of SDB. All recordings were scored manually by an experienced polysomnographic technologist. The Epworth Sleepiness Scale (ESS) was used to report subjective day-time sleepiness . Excessive daytime sleepiness was defined as an ESS score greater than 10.
Total fat area, visceral fat area and subcutaneous fat area were computed and measured automatically using commercial software on CT scans taken at the umbilical level in a supine position (120 kV, 400 mAsec, section thickness of 5-10 mm, field of view of 400 mm, window width of 800-1000 Hounsfield units). All MSCT angiograms were scanned by trained technicians, according to a standard protocol. All MSCT angiograms were evaluated by at least two experienced examiners. The presence of stenosis with coronary plaque was evaluated visually on axial and cross-sectional images and curved multiplanar reconstructions. Intracoronary lesion was identified as atherosclerotic stenosis and/or highly calcification lesion of at least one segment of a major coronary artery confirmed by MSCT coronary angiograms, which is greater than 50% stenosis as a candidate for revascularization [19, 20]. Patients with intracoronary lesion were considered to have CAD.
Anthropometry and laboratory measurements
Height (cm), weight (kg) (and body mass index in kg/m2), neck circumference at the level of the cricothyroid cartilage, waist circumference at the umbilical level and hip circumference horizontally at the level of the greater trochanter of the femur, were measured in the standing position. Systolic and diastolic blood pressures were measured with a standard mercury sphygmomanometer on the right or left arm after the subjects had rested in a sitting position for at least 10 minutes. Smoking habit was documented on the routine baseline questionnaire. Metabolic syndrome was defined according to the Japanese criteria .
Venous blood samples were collected in the morning after overnight fast for measurements of glucose, lipids, and immunoreactive insulin. In each sleep study that included high-sensitivity C-reactive protein (hsCRP) and adiponectin monitoring, venous blood samples were obtained after wake-up while the subject was in the supine position. For the purpose of the present study, serum samples that were obtained at baseline from each study participant and stored at -20°C, were thawed and mesured for serum hsCRP (N-Latex CRP II, Dade Behring Inc, Marburg, Germany, intra-coefficients of variation (CV); 2.0%, inter-CV 2.3%) and adiponectin concentrations (Otsuka Pharmaceutical Co., Tokushima, Japan, intra-CV; 3.0%, inter-CV 5.1%) [12–14, 22]. Serum concentration of thiobarbituric acid-reacting substance (TBARS), an important biomarker of systemic oxidative stress reflecting serum lipid peroxidation products, was determined by the method of Yagi (Japan Institute for the Control of Aging, Nikken SEIL Co., Shizuoka, Japan), as reported previously by our group [14, 22].
The correlations between CAD and clinical features were first analyzed by simple logistic regression analysis. In all cases, p values < 0.05 were considered statistically significant. All analyses were performed with the JMP Statistical Discovery Software 9.0 (SAS Institute, Cary, NC).
Characteristics of male subjects with SDB/OSA
Baseline characteristics of the subjects (males, n = 39)
mean ± SEM (%)
52 ± 1
Body mass index (kg/m2)
27.8 ± 0.6
Neck circumference (cm)
40 ± 0.4
Waist circumference (cm)
95 ± 1
Hip circumference (cm)
100 ± 1
Total fat area (cm2)
330 ± 35
Visceral fat area (cm2)
163 ± 31
Subcutaneous fat area (cm2)
167 ± 9
Systolic blood pressure (mmHg)
131 ± 2
Diastolic blood pressure (mmHg)
82 ± 2
Fasting blood glucose (mg/dL)
80 ± 3
Fasting immunoreactive insulin (μIU/mL)
11 ± 1
158 ± 12
High-density lipoprotein-cholesterol (mg/dL)
49 ± 2
Low-density lipoprotein-cholesterol (mg/dL)
133 ± 3
Epworth Sleepiness Scale
13 ± 1
Cardiorespiratory monitoring findings
Apnea-hypopnea index (AHI) (events/hour)
39 ± 4
Baseline SpO2 (%)
98 ± 0.1
Lowest SpO2 (%)
72 ± 2
4% oxygen desaturation index (events/hour)
27 ± 3
% < 90% time
7 ± 2
Apnea-hypopnea index (AHI) ≥ 5 to < 15 (mild)
≥ 15 to < 30 (moderate)
≥ 30 (severe)
Computed tomography scan findings
< 50% stenosis of coronary arteries
≥ 50% stenosis of coronary arteries
Serum high-sensitive C-reactive protein (hsCRP) (ng/dL)
2131 ± 830
Serum thiobarbituric acid reactive substance (TBARS), nmol/mL
5.5 ± 0.2
Serum adiponectin (μg/mL)
5.6 ± 0.5
Relationship between CAD and various parameters
Results of simple logistic analysis for coronary artery disease (CAD)
Body mass index
Log-Total fat area*
Log-Visceral fat area*
Log-Subcutaneous fat area*
Systolic blood pressure
Diastolic blood pressure
Fasting blood glucose
Fasting immunoreactive insulin
Comparison of parameters in subjects without and with the metabolic syndrome
The two major findings of the present study of SDB/OSA subjects with a history of snoring and/or witnessed apneas were: 1) Identification of greater than 50% intracoronary narrowing in 15% (6/39) of total, and in 4.3% (1/23) of subjects without the metabolic syndrome and in 31.3% (5/16) of those with the metabolic syndrome. Differences in the above rates were significant (p = 0.033). 2) The metabolic syndrome as well as systemic oxidative stress, i.e. TBARS, correlated with intracoronary stenosis detected by MSCT. However, multiple logistic regression analysis (adopted factors; age, metabolic syndrome, TBARS), did not identify both metabolic syndrome and TBARS as significant and independent determinants of CAD (p = 0.366, p = 0.062, respectively). The study included a limited number of patients and further replication studies of larger sample need to be designed in the future. Our results may provide a rationale to conduct such studies.
Although SDB/OSA is associated with cardiovascular diseases [1–3], there is little information on SDB/OSA subjects with CAD remain to be understood. The present study showed that metabolic syndrome predicts intracoronary stenotic lesions in SDB/OSA subjects. A cluster of multiple risk factors based on visceral fat accumulation accelerates atherosclerogenesis, i.e. metabolic syndrome . The co-existence of metabolic syndrome and SDB/OSA based on visceral fat accumulation, i.e. "Syndrome Z", may represent two sides of the same coin, given the common pathophysiological processes evident in both conditions, such as insulin resistance and atherosclerosis [7, 15]. Although adiponectin per se did not correlate with CAD in SDB/OSA subjects, serum adiponectin levels were lower in subjects with the metabolic syndrome than those without the metabolic syndrome. Metabolic syndrome was related with serum levels of adiponectin (p = 0.029), but not with hsCRP and TBARS (p = 0.850, p = 0.102, respectively). The results suggest that the metabolic syndrome and hypoadiponectinemia may play a role in the development of CAD in subjects with SDB/OSA. The metabolic syndrome and hypoadiponectinemia might be a target for prevention of potential CAD in SDB/OSA.
Nasal continuous positive airway pressure (CPAP) is the "gold standard" treatment of OSA. A recent double-blind, placebo-controlled, randomized, and crossover trial reported that 3 months of nasal CPAP therapy improved control of elevated blood pressure and a reduction in metabolic abnormalities including abdominal obesity . Nasal CPAP also reduces the risk of fatal and non-fatal cardiovascular outcomes . However, whether visceral fat reduction prevents cardiovascular events in SDB/OSA subjects remains unclear. Longer observational and interventional trials should be conducted to assess the effect of visceral fat reduction on the incidence of cardiovascular events in SDB/OSA subjects.
We described that metabolic syndrome was correlated with intracoronary stenosis detected by MSCT in Japanese SDB/OSA subjects, suggesting that any program designed to prevent cardiovascular diseases in SDB/OSA subjects should include continuous evaluation of metabolic syndrome.
The present study has several limitations. First, all patients in this study were Japanese males and any differences from other ethnicities are unknown. Second, there is bias in single center trials. Finally, based upon 80% power to detect statistically significant correlations between CAD and the various parameters (p = 0.05; two-sided, r = 0.5, α = 0.05, 1-β = 0.8), a sample size of at least 38 patients was required to demonstrate. The number of patients may be still small, and further investigations might be required to confirm the present results.
Coronary artery disease
Continuous positive airway pressure
Coefficients of variation
Epworth Sleepiness Scale
high-sensitivity C-reactive protein
multislice computed tomography
obstructive sleep apnea
thiobarbituric acid-reacting substance.
We thank the staff of Yoshida Suimin-kokyu Clinic and Kenporen Osaka Central Hospital for the excellent medical care and technical assistance, and Mr, Jun-ichi Funahashi, Dr. Noriyuki Komura, Dr. Masaya Yamaoka, Dr. Ayumu Hirata, Mr. Ryohei Sekimoto and Mrs. Miyuki Nakamura for the excellent technical assistance. This research was supported in part by a Grant-in-Aid for Scientific Research No. (C) 21591177 (Chiyoda-ku, Tokyo, to K.K.).
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