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Traditional cardiovascular risk factors but not homocysteine are associated with obstructive sleep apnea
Nutrition Research 26 (2006) 59 – 64 www.elsevier.com/locate/nutres
Traditional cardiovascular risk factors but not homocysteine are associated with obstructive sleep apnea Chien-Hsiang Chenga,b, Men-Chung Huangc, Shao-Chun Liud, Keh-Liang Line, Yi-Chia Huangf,4 a
Critical Care and Respiratory Therapy, Taichung Veterans General Hospital, Taichung 400, Taiwan b Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan c Department of Public Health, School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan d Department of Food and Nutrition, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan e Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan f School of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan Received 30 November 2005; revised 19 January 2006; accepted 8 February 2006
Abstract The objective of this study was to determine if obstructive sleep apnea (OSA) subjects had elevated plasma homocysteine levels and a greater incidence of traditional cardiovascular risk factors. Case subjects (OSA group, n = 24) without cardiovascular disease had an apnea-hypopnea index of 5 or higher; control subjects without cardiovascular disease served as a non-OSA group (n = 65). Demographic and anthropometric (ie, weight, height, body mass index [BMI], neck, waist, and hip circumferences) data were collected. Systolic and diastolic blood pressure (DBP) were measured. Fasting venous blood samples were collected to determine total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, creatinine, homocysteine, vitamin B6, vitamin B12, and folate status. In univariate analysis, BMI; neck, waist, and hip circumferences; serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and DBP were all positively associated with OSA. Plasma homocysteine concentration, however, had no effect on OSA. The age-adjusted odds ratio (OR) for all OSA and control subjects was significantly increased in the third tertile of homocysteine concentration (OR, 9.29; 95% CI, 1.25-69.12). However, the third tertile of plasma homocysteine showed no effect (OR, 3.24; 95% CI, 0.02-497.80) on OSA after additional adjustment for all cardiovascular risk factors. Homocysteine had no association with OSA; however, obesity, DBP, and serum total cholesterol are associated with OSA. Indices of central obesity (BMI and waist and neck circumferences) and a combination with DBP and serum total cholesterol level should be screened in patients with OSA. D 2006 Elsevier Inc. All rights reserved. Keywords:
Obstructive sleep apnea; Homocysteine; Cardiovascular risk factors; Central obesity; Humans
1. Introduction Obstructive sleep apnea (OSA) is defined as a lack of airflow despite continuous respiratory efforts; sleep apnea often results in sleep fragmentation and intermittent 4 Corresponding author. Fax: +886 4 23248175. E-mail address: [email protected] (Y.-C. Huang). 0271-5317/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nutres.2006.02.003
oxyhemoglobin desaturation [1]. Obstructive sleep apnea has been shown to be an important risk factor for the development of cardiovascular disease [2-5]. Studies have shown that patients with OSA have a higher cardiovascular mortality risk, especially in middle-aged patients [6,7]. Hyperhomocysteinemia is a strongly independent risk factor for cardiovascular disease [8-10]. It has been shown that the elevation of 5 lmol/L in plasma homocysteine
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concentration would increase the incidence of cardiovascular artery disease by 60% to 80% [9]. Recently, Lavie et al [11] indicated that patients with the combination of ischemic heart disease and OSA had significantly elevated homocysteine level when compared with OSA-only and control groups. Because there are strong associations between cardiovascular diseases and homocysteine, it has also been known that OSA is indeed an independent risk factor for cardiovascular morbidity and mortality. Little information, however, on the relationship between OSA and homocysteine has been reported. The increase in cardiovascular disease and mortality in patients with OSA is often associated with obesity, hypertension, and other risk factors [6,12,13]. Age, hypertension, hyperlipidemia, and obesity are traditional risk factors of cardiovascular disease; these characteristics likely place patients with OSA at higher overall risk of cardiovascular disease. However, it is not clear whether these traditional cardiovascular risk factors have a direct impact on OSA. To identify possible cardiovascular risk factors involved in OSA morbidity is of great interest. The purpose of this study, therefore, was to prospectively determine if OSA subjects had elevated plasma homocysteine levels and a greater incidence of traditional cardiovascular risk factors.
Twenty-four OSA patients and 65 control subjects were recruited in this study. Informed consent was obtained from each subject. The study protocol was approved as ethical when the research proposal was reviewed by the Chung Shan Medical University, Taiwan. 2.2. Polysomnographic measurement
2. Subjects and Methods
Overnight, from 10:00 pm to 7:00 am, polysomnography examination was performed at the sleep laboratory at Taichung Veterans General Hospital, Taiwan. The polysomnography (Marietta, Alice 4, Healthdyne Technologies, Atlanta, GA) consisted of a continuous polygraphic recording from surface leads for electroencephalography, electro-oculography, electromyography, and electrocardiography. Respiration was monitored using thermistors for nasal and oral airflow and thoracic and abdominal impedance belts for respiratory effort. Arterial oxygen saturation (SaO2) was monitored with a pulse oximeter. Snoring was detected by using a tracheal microphone. Each polysomnographic recording was scored manually. An abnormal breathing event was defined as a complete cessation of airflow of 10 seconds or longer and a heart rate drop z 12.5%, SpO2 drop z 3% (apnea), or a discernible reduction in airflow accompanied by a decrease of z 50% in oxyhemoglobin saturation (hypopnea). The average number of episodes of apnea and hypopnea per hour of sleep (AHI score) was calculated as the summary measurement of sleep-disordered breathing.
2.1. Subjects
2.3. Anthropometric and blood pressure measurements
Because sleep apnea is much more common and severe in men than women, we recruited only male subjects for the present study. Study subjects came from the respiratory care clinic of Taichung Veterans General Hospital, Taiwan. Patients suspected of having OSA syndrome underwent a whole right laboratory polysomnography examination. Case subjects (OSA group) were identified through polysomnography as having an apnea-hypopnea index (AHI) of 5 or higher. Control subjects without OSA (non-OSA group) were recruited from the physical check unit of Taichung Veterans General Hospital, Taiwan. Case and control subjects with any kinds of cardiovascular disease were excluded. Case and control subjects with diabetes (defined by history of antidiabetic drugs use or fasting plasma glucose concentration N 140 mg/dL) and liver or renal diseases (identified by serum creatinine and aspartate aminotransferase analyses) were also excluded to minimize the influence of other cardiovascular risk factors. Subjects currently taking vitamin supplements were also excluded. Demographic and health questionnaires were collected. The questionnaire consisted of questions concerning demographic data, sleeping habits, snoring history, daytime sleepiness, medical history (ie, chronic rhinitis, deviation of the nasal septum, hypertrophic tonsil, pituitary gland or thyroid gland disorder, and stroke), traffic or job-related accidents, drinking habits, and medication use (ie, hypnotics).
The body mass index (BMI) [weight (kg)/height2 (m2)] was calculated when height and weight were measured. Overweight and obesity was defined as a BMI value z 24 kg/m2 and z 27 kg/m2, respectively (Department of Health, Taiwan, 2003). Waist and hip circumferences were measured at the level of the umbilicus and maximum hip girth. Waist-to-hip ratio (WHR) was then calculated. The cut-off value for the central obesity was set as a value of waist circumference z 90 cm or WHR ratio N 0.9 in men (Department of Health, 2003). Neck circumference was measured at the level of the cricothyroid membrane. Blood pressure was measured after a resting period of 5 minutes or longer. Hypertension was defined as systolic blood pressure (SBP) z 140 mm Hg and/or diastolic blood pressure (DBP) z 90 mm Hg or known hypertension treated with antihypertensive medication. 2.4. Biochemical measurements Fasting venous blood samples were collected in Vacutainer tubes (Becton Dickinson, Rutherford, NJ) containing an EDTA anticoagulant as an anticoagulant to determine plasma homocysteine and vitamin B6 (pyridoxal 5V-phosphate [PLP]) and no anticoagulant to determine serum total cholesterol, high- density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, creatinine, vitamin B12, and folate status.
C.-H. Cheng et al. / Nutrition Research 26 (2006) 59–64 Table 1 Homocysteine, B-vitamins, and traditional cardiovascular risk factors in patients with OSA and control subjectsa Characteristics
OSA (n = 24)
Body mass index (kg/m2) b 24 z 24 Neck circumference (cm) Waist circumference (cm) b 90 z 90 Hip circumference (cm) Waist-to-hip ratio (WHR) b 0.9 z 0.9 Blood Pressure SBP (mm Hg) b 140 z 140 DBP (mm Hg) b 90 z 90 Cholesterol Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Triglycerides (mg/dL) Creatinine (mg/dL) Total fasting homocysteine (lmol/L) Pyridoxal 5V-phosphate (nmol/L) Folate (nmol/L) Vitamin B12 (pmol/L)
27.7 2 22 40.1 93.4 9 15 102.8 0.91 10 14
Non-OSA (n = 65)
F 3.74 (8.3%) (91.7%) F 3.14 F 9.74 (37.5%) (62.5%) F 7.44 F 0.06 (41.7%) (58.3%)
23.6 36 29 37.4 81.6 57 8 93.2 0.87 41 24
F 3.3 (55.4%) (44.6%) F 2.4 F 8.2 (87.7%) (12.3%) F 6.0 F 0.05 (63.1%) (36.9%)
126.6 F 14.14 20 (83.3%) 4 (16.7%) 86.8 F 8.44 13 (54.2%) 11 (45.8%)
119.1 F 17.5 55 (84.6%) 10 (15.4%) 76.0 F 12.2 55 (84.6%) 10 (15.4%)
225.5 45.8 151.4 141.3 1.1 9.2 79.6 35.1 327.7
184.5 59.1 100.4 125.6 1.2 8.5 73.4 27.6 408.1
F F F F F F F F F
44.94 7.64 44.74 76.8 0.14 3.2 43.9 21.5 98.9
F 31.0 F 13.1 F 25.6 F 82.3 F 0.1 F 2.2 F 57.6 F 12.5 F 347.0
a
Values are presented as mean F SD. 4 Significantly different from the non-OSA group ( P b .05).
Plasma homocysteine was measured by using high-performance liquid chromatography according to the method of Araki and Sako [14]. The intraassay and interassay of plasma homocysteine variabilities were 2.87% (n = 5) and 2.15% (n = 11), respectively. Plasma PLP was determined by high-performance liquid chromatography as previously described [15]. The intraassay and interassay of plasma PLP variabilities were 1.17% (n = 5) and 0.37% (n = 20), respectively. Serum folate and vitamin B12 were analyzed by using standard competitive immunochemiluminometric methods on a Chiron Diagnostics ACS:180 Automated Chemiluminescence Systems (Chiron Diagnostics Corporation, East Walpole, MA, USA). All analyses were performed in duplicate. The normal serum creatinine value was considered as 0.7-1.4 mg/dL. The lipoprotein risk profile was considered as total cholesterol z 200 mg/dL, HDL-C b 35 mg/dL, LDL-C z 130 mg/dL, and/or triglyceride z 200 mg/dL. Hyperhomocysteinemia was defined as a plasma homocysteine concentration 14 lmol/L or more. Vitamin B12 and folate deficiencies were defined as serum concentrations of less than 125 pmol/mL, and 6.8 nmol/mL, respectively. Vitamin B6 deficiency was defined as plasma PLP concentration less than 20 nmol/L.
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2.5. Statistical analyses Data were analyzed by using the SAS software package (version 6.12; SAS Institute Inc, Cary, NC). Mean differences between OSA and non-OSA groups were analyzed using the Student t test. For some data that were skewed rather than normally distributed, the Mann-Whitney Rank test was used. For categorical response variables, differences between groups were assessed by v 2 or Fisher exact test. Adjusted odds ratios (ORs) with 95% CIs for OSA were calculated from the logistic regression model according to the tertile of plasma homocysteine concentration across subjects. Odds ratios were computed with adjustment for the other cardiovascular risk factors. Differences were considered statistically significant when P b .05 or when 95% CI range was not included in the unity. Values presented in the text are means F SD.
3. Results Subjects with OSA showed significant differences in some of the sleep-related features not exhibited by non-OSA subjects (data not shown). Subjects with OSA snored more, woke up frequently, fell asleep during the day, exhibited daytime fatigue, and had a car or occupational accident because of sleepiness more frequently than did subjects without OSA. Subjects’ ages ranged from 34 to 75 years, with median ages of 46.5 and 50 years for the OSA and non-OSA groups, respectively. The 2 groups were of comparable age (OSA, 49.7 F 9.6 vs non-OSA, 51.4 F 9.9 years). The mean AHI score for 24 OSA subjects was 33.2 F 25.8 (range, 6.3-89.6), whereas that for subjects without OSA was AHI b5. Values of homocysteine, B vitamins, and other cardiovascular risk factors are shown in Table 1. Subjects in the OSA group had significantly higher body weight and BMI than did non-OSA group, as indicated by an 11.4-kg weight difference and a 4.1-kg/m2 difference in BMI. The OSA group also had significantly greater neck, waist, and hip circumferences; SBP; and DBP than did subjects in the nonOSA group. Moreover, the OSA group had a mean value of BMI N 27, waist circumference N90 cm, and WHR value N0.9, indicating a central obesity. There were no significant differences in height and WHR values between OSA and non-OSA subjects. The OSA group did have significantly higher mean serum total cholesterol and LDL-C values and lower mean HDL-C value than the non-OSA group. Subjects with OSA had mean serum total cholesterol and LDL-C levels beyond the reference range, which may indicate hyperlipidemia. There were no significant differences in plasma total fasting homocysteine, PLP, serum folate, and vitamin B12 levels between the 2 groups. Moreover, mean values of PLP, folate, and vitamin B12 were higher than the suggested value for adequate vitamin status in both groups; mean
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plasma homocysteine levels were lower than 14 lmol/L in both groups, which is the suggested value for ideal homocysteine level. In univariate analysis (Table 2), BMI z 24 kg/m2, neck circumference z 38 cm, waist circumference z 90 cm, hip circumference z 100 cm, total cholesterol z 200 mg/dL, LDL-C z 130 mg/dL, HDL-C b 45 mg/dL, and DBP z 90 mm Hg were positively associated with OSA. However, SBP, triglycerides, and homocysteine had no correlation with OSA. We calculated risks of OSA by tertile of plasma homocysteine according to the distribution of all subjects (Table 3). The age-adjusted OR for all OSA and control subjects was significantly increased in the third tertile of homocysteine concentration (OR, 9.29; 95% CI, 1.2569.12). Likewise, when neck circumference, total cholesterol, or triglycerides was included in the regression model, the relationship between OSA and homocysteine was also significantly increased in the third tertile of plasma homocysteine concentration after adjusting for age. However, plasma homocysteine showed no effect on OSA after additional adjustment for BMI, waist and hip circumTable 2 Univariate analysis of homocysteine and cardiovascular risk factors in relation to OSA Risk factors Body mass index (kg/m2) b 24 z 24 Neck circumference (cm) b 38 z 38 Waist circumference (cm) b 90 z 90 Hip circumference (cm) b 100 z 100 Systolic blood pressure (mm Hg) b 140 z 140 Diastolic blood pressure (mm Hg) b 90 z 90 Total cholesterol (mg/dL) b 200 z 200 LDL-C b 130 z 130 HDL-C (mg/dL) z 45 b 45 Triglycerides (mg/dL) b 200 z 200 Homocysteine (lmol/L) b 14 z 14 4 P b .05.
Age-adjusted OR (95% CI)
Table 3 Multivariate adjusted odds ratios of OSA according to the tripartite of plasmahomocysteine concentration analyzed by logistic regression Adjusted factors
None
BMI
Neck circumference
Waist circumference
Hip
SBP
DBP
Total cholesterol
LDL-C
1 13.4 (2.9-62.0)4
HDL-C
1 8.0 (2.4-26.1)4
Triglycerides
1 12.3 (4.0-37.7)4
All
Tripartite of homocysteine (lmol/L)
Age-adjusted OR (95% CIs)
b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6-12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4
1 0.96 9.29 1 0.76 6.98 1 0.75 9.13 1 0.91 9.13 1 0.83 6.95 1 0.84 5.41 1 0.69 6.07 1 0.99 13.31 1 0.69 8.67 1 1.24 2.39 1 0.99 9.18 1 0.75 3.24
P
(0.35 -2.68) (1.25 - 69.12)
.9447 .0296
(0.23-2.50) (0.82-59.34)
.6448 .0754
(0.24 -2.40) (1.06 -78.48)
.6307 .0439
(0.27-3.09) (0.87-95.54)
.8790 .0649
(0.23 -3.01) (0.87-95.54)
.7750 .0896
(0.29 -2.42) (0.65 - 45.20)
.7443 .1193
(0.22-2.15) (0.64 -57.86)
.5217 .1172
(0.31-3.16) (1.25 -141.33)
.9864 .0318
(0.19 -2.54) (0.56 -135.56)
.5731 .1236
(0.40 -3.87) (0.23-25.22)
.7149 .4692
(0.35 -2.77) (1.23 - 68.54)
.9769 .0307
(0.07-7.82) (0.02- 497.80)
.8113 .6473
1 14.2 (4.4-46.0)4 1 1.4 (0.4-5.6)
ference, SBP, DBP, LDL-C, HDL-C, and/or all cardiovascular risk factors.
1 4.6 (1.6-13.1)4 1 6.7 (2.3-19.9)4 1 17.3 (5.5-55.0)4 1 7.0 (2.3-21.3)4 1 2.6 (0.8-7.9) 1 9.6 (0.6-139.2)
4. Discussion Studies have consistently shown that OSA is a strong independent risk factor for the development of cardiovascular disease [2-5]. Other than traditional cardiovascular risk factors, plasma homocysteine has been demonstrated to be a strongly independent risk factor for cardiovascular diseases [8-10]. It would be of great interest to investigate the interrelationship between traditional cardiovascular risk factors, homocysteine, and OSA. In agreement with the study of Lavie et al [11], the OSA and non-OSA groups had similar homocysteine levels, and mean homocysteine levels were less than the cut-off value of 14 lmol/L. According to the results of Lavie et al and
C.-H. Cheng et al. / Nutrition Research 26 (2006) 59–64
univariate analysis of our study, it appears that the homocysteine level does not show significant association with OSA. However, it is highly likely that our limited sample size is a major methodological limitation to see no association between homocysteine and OSA. Therefore, we further looked at the distribution of plasma homocysteine in our subjects; plasma homocysteine was then divided into tertile based on all subjects. We found that the risk of OSA was significantly increased in subjects with plasma homocysteine of at least 12.4 lmol/L when only age was adjusted. However, homocysteine showed no effect on OSA when age and some of cardiovascular risk factors were adjusted individually or simultaneously. It seemed that other risk factors, but not homocysteine, had direct association with OSA. Several studies have consistently found that patients with OSA are often obese and typically had central obesity [16-20]. In the present study, we not only observed most OSA subjects having central obesity but also found that higher BMI and waist and hip circumferences significantly associated with OSA. In addition, neck circumference is also an important predictor of sleep apnea [21-24]. Davies and Stradling [25] reported that neck circumference could be up to 77% sensitive and 82% specific in the diagnosis of OSA. Although fat distribution in the upper airway might be an important etiologic factor in the development of OSA [26], neck circumference compared with other anthropometric measurements was the less predictive value of OSA in our study. Sch7fer et al [12] also found that fat accumulation in the neck and parapharyngeal region analyzed by magnetic resonance imaging had no correlation with the degree of sleep-related breathing disorder. The presence of central obesity seems to be of much greater importance for the diagnosis of OSA. The hypertension that occurs in subjects with OSA has been proposed to be due to long-term sympathetic nervous system stimulation. Our OSA group did have higher SBP and DBP than the non-OSA group; however, only subjects with a higher DBP had an association with OSA. Sharabi et al [27] reported that subjects with OSA had a higher DBP (4 mm Hg difference) than the control group, without elevation in SBP. Davies et al [28] compared patients with OSA with a matched control group and found that patients with OSA have increased ambulatory DBP during both day and night and increased SBP only at night. Our blood pressure measurements and those of Sharabi et al [27] were taken only in the daytime, therefore not demonstrating possible nocturnal high SBP. Although an ambulatory continuous 24-hour blood pressure recording could have provided a more accurate and representative arterial pressure and also has been more predictive of hypertensive cardiovascular results, it is not typical or practical for blood pressure measurements to be recorded in the clinical setting. We thus suggest that DBP rather than SBP should be carefully monitored in casual clinic blood pressure measurements when OSA symptoms are diagnosed by a physician.
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Elevated lipid profiles have been known to be high-risk factors for morbidity and mortality of cardiovascular diseases. Sharabi et al [27] found that there was no significant difference in lipid profile (total cholesterol, HDL-C, LDL-C, and triglycerides) between the OSA and control groups. However, higher total cholesterol level was found in participants with AHI of 5 or higher and selfreported snores [29]. The results of our data also indicate that the OSA group had significantly elevated lipid profiles. Patients suspected of having OSA, therefore, should be considered for lipid profile monitoring. Although interindividual variability does exist among cardiovascular risk factors, the significance of this study is finding that fasting plasma homocysteine concentration had no association with OSA; however, obesity, DBP, and serum total cholesterol are associated with OSA for male subjects without cardiovascular, diabetes mellitus, or renal and liver diseases. Indices of central obesity (BMI and waist and neck circumferences) and a combination with DBP and serum total cholesterol level should be screened in patients with OSA. References [1] Guilleminault C. Clinical features and evaluation of obstructive sleep apnea. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. Philadelphia7 WB Saunders; 1994. p. 667 - 77. [2] Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial infarction in men. Lancet 1990;336:261 - 4. [3] Mooe T, Rabben T, Wiklund U, Franklin K, Eriksson P. Sleepdisordered breathing in men with coronary artery disease. Chest 1996; 109:659 - 63. [4] Mooe T, Rabben T, Wiklund U, Franklin KA, Eriksson P. Sleepdisordered breathing in women: occurrence and association with coronary artery disease. Am J Med 1996;101:251 - 6. [5] Peker Y, Kraiczi H, Hedner J, Loth S, Johansson A, Bende M. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999;14:179 - 84. [6] Lavie P, Herer P, Peled R, Berger I, Yoffe N, Zomer J, et al. Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep 1995;18:149 - 57. [7] He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988;94:9 - 14. [8] Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268: 877 - 81. [9] Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of fasting plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049 - 57. [10] Bautista LE, Arenas IA, Penuela A, Martinez LX. Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. J Clin Epidemiol 2002;55:882 - 7. [11] Lavie L, Perelman A, Lavie P. Plasma homocysteine levels in obstructive sleep apnea-association with cardiovascular morbidity. Chest 2001;120:900 - 8. [12] Sch7fer H, Pauleit D, Sudhop T, Gouni-Berthold I, Ewig S, Berthold HK. Body fat distribution, serum leptin, and cardiovascular risk factors in men with obstructive sleep apnea. Chest 2002;122:829 - 39.
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[22] Davies RJO, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax 1992;47:101 - 5. [23] Hoffstein V, Mateika S. Differences in abdominal and neck circumferences in patients with and without obstructive sleep apnoea. Eur Respir J 1992;5:377 - 81. [24] Dixon JB, Schachter LM, O’Brien PE. Predicting sleep apnea and excessive day sleepiness in the severely obese-indicators for polymnography. Chest 2003;123:1134 - 41. [25] Davies RJO, Stradling JR. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J 1990;3:509 - 14. [26] Horner RL, Mohiaddin RH, Lowell DG, Shea SA, Burman ED, Longmore DB, et al. Sites and sizes of fat deposits around the pharynx in obese patients with obstructive sleep apnoea and weight matched controls. Eur Respir J 1989;2:613 - 22. [27] Sharabi Y, Scope A, Chorney N, Grotto I, Dagan Y. Diastolic blood pressure is the first to rise in association with early subclinical obstructive sleep apnea: lessons from periodic examination screening. Am J Hypertens 2003;16:236 - 9. [28] Davies CWH, Crosby JH, Mullins RL, Barbour C, Davies RJO, Stradling JR. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. Thorax 2000;55:736 - 40. [29] Jennum P, Sjol A. Snoring, sleep apnoea and cardiovascular risk factors: the MONICA II Study. Int J Epidemiol 1993;22:439 - 44.
Traditional cardiovascular risk factors but not homocysteine are associated with obstructive sleep apnea Chien-Hsiang Chenga,b, Men-Chung Huangc, Shao-Chun Liud, Keh-Liang Line, Yi-Chia Huangf,4 a
Critical Care and Respiratory Therapy, Taichung Veterans General Hospital, Taichung 400, Taiwan b Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan c Department of Public Health, School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan d Department of Food and Nutrition, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan e Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan f School of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan Received 30 November 2005; revised 19 January 2006; accepted 8 February 2006
Abstract The objective of this study was to determine if obstructive sleep apnea (OSA) subjects had elevated plasma homocysteine levels and a greater incidence of traditional cardiovascular risk factors. Case subjects (OSA group, n = 24) without cardiovascular disease had an apnea-hypopnea index of 5 or higher; control subjects without cardiovascular disease served as a non-OSA group (n = 65). Demographic and anthropometric (ie, weight, height, body mass index [BMI], neck, waist, and hip circumferences) data were collected. Systolic and diastolic blood pressure (DBP) were measured. Fasting venous blood samples were collected to determine total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, creatinine, homocysteine, vitamin B6, vitamin B12, and folate status. In univariate analysis, BMI; neck, waist, and hip circumferences; serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and DBP were all positively associated with OSA. Plasma homocysteine concentration, however, had no effect on OSA. The age-adjusted odds ratio (OR) for all OSA and control subjects was significantly increased in the third tertile of homocysteine concentration (OR, 9.29; 95% CI, 1.25-69.12). However, the third tertile of plasma homocysteine showed no effect (OR, 3.24; 95% CI, 0.02-497.80) on OSA after additional adjustment for all cardiovascular risk factors. Homocysteine had no association with OSA; however, obesity, DBP, and serum total cholesterol are associated with OSA. Indices of central obesity (BMI and waist and neck circumferences) and a combination with DBP and serum total cholesterol level should be screened in patients with OSA. D 2006 Elsevier Inc. All rights reserved. Keywords:
Obstructive sleep apnea; Homocysteine; Cardiovascular risk factors; Central obesity; Humans
1. Introduction Obstructive sleep apnea (OSA) is defined as a lack of airflow despite continuous respiratory efforts; sleep apnea often results in sleep fragmentation and intermittent 4 Corresponding author. Fax: +886 4 23248175. E-mail address: [email protected] (Y.-C. Huang). 0271-5317/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nutres.2006.02.003
oxyhemoglobin desaturation [1]. Obstructive sleep apnea has been shown to be an important risk factor for the development of cardiovascular disease [2-5]. Studies have shown that patients with OSA have a higher cardiovascular mortality risk, especially in middle-aged patients [6,7]. Hyperhomocysteinemia is a strongly independent risk factor for cardiovascular disease [8-10]. It has been shown that the elevation of 5 lmol/L in plasma homocysteine
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concentration would increase the incidence of cardiovascular artery disease by 60% to 80% [9]. Recently, Lavie et al [11] indicated that patients with the combination of ischemic heart disease and OSA had significantly elevated homocysteine level when compared with OSA-only and control groups. Because there are strong associations between cardiovascular diseases and homocysteine, it has also been known that OSA is indeed an independent risk factor for cardiovascular morbidity and mortality. Little information, however, on the relationship between OSA and homocysteine has been reported. The increase in cardiovascular disease and mortality in patients with OSA is often associated with obesity, hypertension, and other risk factors [6,12,13]. Age, hypertension, hyperlipidemia, and obesity are traditional risk factors of cardiovascular disease; these characteristics likely place patients with OSA at higher overall risk of cardiovascular disease. However, it is not clear whether these traditional cardiovascular risk factors have a direct impact on OSA. To identify possible cardiovascular risk factors involved in OSA morbidity is of great interest. The purpose of this study, therefore, was to prospectively determine if OSA subjects had elevated plasma homocysteine levels and a greater incidence of traditional cardiovascular risk factors.
Twenty-four OSA patients and 65 control subjects were recruited in this study. Informed consent was obtained from each subject. The study protocol was approved as ethical when the research proposal was reviewed by the Chung Shan Medical University, Taiwan. 2.2. Polysomnographic measurement
2. Subjects and Methods
Overnight, from 10:00 pm to 7:00 am, polysomnography examination was performed at the sleep laboratory at Taichung Veterans General Hospital, Taiwan. The polysomnography (Marietta, Alice 4, Healthdyne Technologies, Atlanta, GA) consisted of a continuous polygraphic recording from surface leads for electroencephalography, electro-oculography, electromyography, and electrocardiography. Respiration was monitored using thermistors for nasal and oral airflow and thoracic and abdominal impedance belts for respiratory effort. Arterial oxygen saturation (SaO2) was monitored with a pulse oximeter. Snoring was detected by using a tracheal microphone. Each polysomnographic recording was scored manually. An abnormal breathing event was defined as a complete cessation of airflow of 10 seconds or longer and a heart rate drop z 12.5%, SpO2 drop z 3% (apnea), or a discernible reduction in airflow accompanied by a decrease of z 50% in oxyhemoglobin saturation (hypopnea). The average number of episodes of apnea and hypopnea per hour of sleep (AHI score) was calculated as the summary measurement of sleep-disordered breathing.
2.1. Subjects
2.3. Anthropometric and blood pressure measurements
Because sleep apnea is much more common and severe in men than women, we recruited only male subjects for the present study. Study subjects came from the respiratory care clinic of Taichung Veterans General Hospital, Taiwan. Patients suspected of having OSA syndrome underwent a whole right laboratory polysomnography examination. Case subjects (OSA group) were identified through polysomnography as having an apnea-hypopnea index (AHI) of 5 or higher. Control subjects without OSA (non-OSA group) were recruited from the physical check unit of Taichung Veterans General Hospital, Taiwan. Case and control subjects with any kinds of cardiovascular disease were excluded. Case and control subjects with diabetes (defined by history of antidiabetic drugs use or fasting plasma glucose concentration N 140 mg/dL) and liver or renal diseases (identified by serum creatinine and aspartate aminotransferase analyses) were also excluded to minimize the influence of other cardiovascular risk factors. Subjects currently taking vitamin supplements were also excluded. Demographic and health questionnaires were collected. The questionnaire consisted of questions concerning demographic data, sleeping habits, snoring history, daytime sleepiness, medical history (ie, chronic rhinitis, deviation of the nasal septum, hypertrophic tonsil, pituitary gland or thyroid gland disorder, and stroke), traffic or job-related accidents, drinking habits, and medication use (ie, hypnotics).
The body mass index (BMI) [weight (kg)/height2 (m2)] was calculated when height and weight were measured. Overweight and obesity was defined as a BMI value z 24 kg/m2 and z 27 kg/m2, respectively (Department of Health, Taiwan, 2003). Waist and hip circumferences were measured at the level of the umbilicus and maximum hip girth. Waist-to-hip ratio (WHR) was then calculated. The cut-off value for the central obesity was set as a value of waist circumference z 90 cm or WHR ratio N 0.9 in men (Department of Health, 2003). Neck circumference was measured at the level of the cricothyroid membrane. Blood pressure was measured after a resting period of 5 minutes or longer. Hypertension was defined as systolic blood pressure (SBP) z 140 mm Hg and/or diastolic blood pressure (DBP) z 90 mm Hg or known hypertension treated with antihypertensive medication. 2.4. Biochemical measurements Fasting venous blood samples were collected in Vacutainer tubes (Becton Dickinson, Rutherford, NJ) containing an EDTA anticoagulant as an anticoagulant to determine plasma homocysteine and vitamin B6 (pyridoxal 5V-phosphate [PLP]) and no anticoagulant to determine serum total cholesterol, high- density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, creatinine, vitamin B12, and folate status.
C.-H. Cheng et al. / Nutrition Research 26 (2006) 59–64 Table 1 Homocysteine, B-vitamins, and traditional cardiovascular risk factors in patients with OSA and control subjectsa Characteristics
OSA (n = 24)
Body mass index (kg/m2) b 24 z 24 Neck circumference (cm) Waist circumference (cm) b 90 z 90 Hip circumference (cm) Waist-to-hip ratio (WHR) b 0.9 z 0.9 Blood Pressure SBP (mm Hg) b 140 z 140 DBP (mm Hg) b 90 z 90 Cholesterol Total cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Triglycerides (mg/dL) Creatinine (mg/dL) Total fasting homocysteine (lmol/L) Pyridoxal 5V-phosphate (nmol/L) Folate (nmol/L) Vitamin B12 (pmol/L)
27.7 2 22 40.1 93.4 9 15 102.8 0.91 10 14
Non-OSA (n = 65)
F 3.74 (8.3%) (91.7%) F 3.14 F 9.74 (37.5%) (62.5%) F 7.44 F 0.06 (41.7%) (58.3%)
23.6 36 29 37.4 81.6 57 8 93.2 0.87 41 24
F 3.3 (55.4%) (44.6%) F 2.4 F 8.2 (87.7%) (12.3%) F 6.0 F 0.05 (63.1%) (36.9%)
126.6 F 14.14 20 (83.3%) 4 (16.7%) 86.8 F 8.44 13 (54.2%) 11 (45.8%)
119.1 F 17.5 55 (84.6%) 10 (15.4%) 76.0 F 12.2 55 (84.6%) 10 (15.4%)
225.5 45.8 151.4 141.3 1.1 9.2 79.6 35.1 327.7
184.5 59.1 100.4 125.6 1.2 8.5 73.4 27.6 408.1
F F F F F F F F F
44.94 7.64 44.74 76.8 0.14 3.2 43.9 21.5 98.9
F 31.0 F 13.1 F 25.6 F 82.3 F 0.1 F 2.2 F 57.6 F 12.5 F 347.0
a
Values are presented as mean F SD. 4 Significantly different from the non-OSA group ( P b .05).
Plasma homocysteine was measured by using high-performance liquid chromatography according to the method of Araki and Sako [14]. The intraassay and interassay of plasma homocysteine variabilities were 2.87% (n = 5) and 2.15% (n = 11), respectively. Plasma PLP was determined by high-performance liquid chromatography as previously described [15]. The intraassay and interassay of plasma PLP variabilities were 1.17% (n = 5) and 0.37% (n = 20), respectively. Serum folate and vitamin B12 were analyzed by using standard competitive immunochemiluminometric methods on a Chiron Diagnostics ACS:180 Automated Chemiluminescence Systems (Chiron Diagnostics Corporation, East Walpole, MA, USA). All analyses were performed in duplicate. The normal serum creatinine value was considered as 0.7-1.4 mg/dL. The lipoprotein risk profile was considered as total cholesterol z 200 mg/dL, HDL-C b 35 mg/dL, LDL-C z 130 mg/dL, and/or triglyceride z 200 mg/dL. Hyperhomocysteinemia was defined as a plasma homocysteine concentration 14 lmol/L or more. Vitamin B12 and folate deficiencies were defined as serum concentrations of less than 125 pmol/mL, and 6.8 nmol/mL, respectively. Vitamin B6 deficiency was defined as plasma PLP concentration less than 20 nmol/L.
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2.5. Statistical analyses Data were analyzed by using the SAS software package (version 6.12; SAS Institute Inc, Cary, NC). Mean differences between OSA and non-OSA groups were analyzed using the Student t test. For some data that were skewed rather than normally distributed, the Mann-Whitney Rank test was used. For categorical response variables, differences between groups were assessed by v 2 or Fisher exact test. Adjusted odds ratios (ORs) with 95% CIs for OSA were calculated from the logistic regression model according to the tertile of plasma homocysteine concentration across subjects. Odds ratios were computed with adjustment for the other cardiovascular risk factors. Differences were considered statistically significant when P b .05 or when 95% CI range was not included in the unity. Values presented in the text are means F SD.
3. Results Subjects with OSA showed significant differences in some of the sleep-related features not exhibited by non-OSA subjects (data not shown). Subjects with OSA snored more, woke up frequently, fell asleep during the day, exhibited daytime fatigue, and had a car or occupational accident because of sleepiness more frequently than did subjects without OSA. Subjects’ ages ranged from 34 to 75 years, with median ages of 46.5 and 50 years for the OSA and non-OSA groups, respectively. The 2 groups were of comparable age (OSA, 49.7 F 9.6 vs non-OSA, 51.4 F 9.9 years). The mean AHI score for 24 OSA subjects was 33.2 F 25.8 (range, 6.3-89.6), whereas that for subjects without OSA was AHI b5. Values of homocysteine, B vitamins, and other cardiovascular risk factors are shown in Table 1. Subjects in the OSA group had significantly higher body weight and BMI than did non-OSA group, as indicated by an 11.4-kg weight difference and a 4.1-kg/m2 difference in BMI. The OSA group also had significantly greater neck, waist, and hip circumferences; SBP; and DBP than did subjects in the nonOSA group. Moreover, the OSA group had a mean value of BMI N 27, waist circumference N90 cm, and WHR value N0.9, indicating a central obesity. There were no significant differences in height and WHR values between OSA and non-OSA subjects. The OSA group did have significantly higher mean serum total cholesterol and LDL-C values and lower mean HDL-C value than the non-OSA group. Subjects with OSA had mean serum total cholesterol and LDL-C levels beyond the reference range, which may indicate hyperlipidemia. There were no significant differences in plasma total fasting homocysteine, PLP, serum folate, and vitamin B12 levels between the 2 groups. Moreover, mean values of PLP, folate, and vitamin B12 were higher than the suggested value for adequate vitamin status in both groups; mean
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plasma homocysteine levels were lower than 14 lmol/L in both groups, which is the suggested value for ideal homocysteine level. In univariate analysis (Table 2), BMI z 24 kg/m2, neck circumference z 38 cm, waist circumference z 90 cm, hip circumference z 100 cm, total cholesterol z 200 mg/dL, LDL-C z 130 mg/dL, HDL-C b 45 mg/dL, and DBP z 90 mm Hg were positively associated with OSA. However, SBP, triglycerides, and homocysteine had no correlation with OSA. We calculated risks of OSA by tertile of plasma homocysteine according to the distribution of all subjects (Table 3). The age-adjusted OR for all OSA and control subjects was significantly increased in the third tertile of homocysteine concentration (OR, 9.29; 95% CI, 1.2569.12). Likewise, when neck circumference, total cholesterol, or triglycerides was included in the regression model, the relationship between OSA and homocysteine was also significantly increased in the third tertile of plasma homocysteine concentration after adjusting for age. However, plasma homocysteine showed no effect on OSA after additional adjustment for BMI, waist and hip circumTable 2 Univariate analysis of homocysteine and cardiovascular risk factors in relation to OSA Risk factors Body mass index (kg/m2) b 24 z 24 Neck circumference (cm) b 38 z 38 Waist circumference (cm) b 90 z 90 Hip circumference (cm) b 100 z 100 Systolic blood pressure (mm Hg) b 140 z 140 Diastolic blood pressure (mm Hg) b 90 z 90 Total cholesterol (mg/dL) b 200 z 200 LDL-C b 130 z 130 HDL-C (mg/dL) z 45 b 45 Triglycerides (mg/dL) b 200 z 200 Homocysteine (lmol/L) b 14 z 14 4 P b .05.
Age-adjusted OR (95% CI)
Table 3 Multivariate adjusted odds ratios of OSA according to the tripartite of plasmahomocysteine concentration analyzed by logistic regression Adjusted factors
None
BMI
Neck circumference
Waist circumference
Hip
SBP
DBP
Total cholesterol
LDL-C
1 13.4 (2.9-62.0)4
HDL-C
1 8.0 (2.4-26.1)4
Triglycerides
1 12.3 (4.0-37.7)4
All
Tripartite of homocysteine (lmol/L)
Age-adjusted OR (95% CIs)
b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6-12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4 b 8.6 8.6 -12.4 N 12.4
1 0.96 9.29 1 0.76 6.98 1 0.75 9.13 1 0.91 9.13 1 0.83 6.95 1 0.84 5.41 1 0.69 6.07 1 0.99 13.31 1 0.69 8.67 1 1.24 2.39 1 0.99 9.18 1 0.75 3.24
P
(0.35 -2.68) (1.25 - 69.12)
.9447 .0296
(0.23-2.50) (0.82-59.34)
.6448 .0754
(0.24 -2.40) (1.06 -78.48)
.6307 .0439
(0.27-3.09) (0.87-95.54)
.8790 .0649
(0.23 -3.01) (0.87-95.54)
.7750 .0896
(0.29 -2.42) (0.65 - 45.20)
.7443 .1193
(0.22-2.15) (0.64 -57.86)
.5217 .1172
(0.31-3.16) (1.25 -141.33)
.9864 .0318
(0.19 -2.54) (0.56 -135.56)
.5731 .1236
(0.40 -3.87) (0.23-25.22)
.7149 .4692
(0.35 -2.77) (1.23 - 68.54)
.9769 .0307
(0.07-7.82) (0.02- 497.80)
.8113 .6473
1 14.2 (4.4-46.0)4 1 1.4 (0.4-5.6)
ference, SBP, DBP, LDL-C, HDL-C, and/or all cardiovascular risk factors.
1 4.6 (1.6-13.1)4 1 6.7 (2.3-19.9)4 1 17.3 (5.5-55.0)4 1 7.0 (2.3-21.3)4 1 2.6 (0.8-7.9) 1 9.6 (0.6-139.2)
4. Discussion Studies have consistently shown that OSA is a strong independent risk factor for the development of cardiovascular disease [2-5]. Other than traditional cardiovascular risk factors, plasma homocysteine has been demonstrated to be a strongly independent risk factor for cardiovascular diseases [8-10]. It would be of great interest to investigate the interrelationship between traditional cardiovascular risk factors, homocysteine, and OSA. In agreement with the study of Lavie et al [11], the OSA and non-OSA groups had similar homocysteine levels, and mean homocysteine levels were less than the cut-off value of 14 lmol/L. According to the results of Lavie et al and
C.-H. Cheng et al. / Nutrition Research 26 (2006) 59–64
univariate analysis of our study, it appears that the homocysteine level does not show significant association with OSA. However, it is highly likely that our limited sample size is a major methodological limitation to see no association between homocysteine and OSA. Therefore, we further looked at the distribution of plasma homocysteine in our subjects; plasma homocysteine was then divided into tertile based on all subjects. We found that the risk of OSA was significantly increased in subjects with plasma homocysteine of at least 12.4 lmol/L when only age was adjusted. However, homocysteine showed no effect on OSA when age and some of cardiovascular risk factors were adjusted individually or simultaneously. It seemed that other risk factors, but not homocysteine, had direct association with OSA. Several studies have consistently found that patients with OSA are often obese and typically had central obesity [16-20]. In the present study, we not only observed most OSA subjects having central obesity but also found that higher BMI and waist and hip circumferences significantly associated with OSA. In addition, neck circumference is also an important predictor of sleep apnea [21-24]. Davies and Stradling [25] reported that neck circumference could be up to 77% sensitive and 82% specific in the diagnosis of OSA. Although fat distribution in the upper airway might be an important etiologic factor in the development of OSA [26], neck circumference compared with other anthropometric measurements was the less predictive value of OSA in our study. Sch7fer et al [12] also found that fat accumulation in the neck and parapharyngeal region analyzed by magnetic resonance imaging had no correlation with the degree of sleep-related breathing disorder. The presence of central obesity seems to be of much greater importance for the diagnosis of OSA. The hypertension that occurs in subjects with OSA has been proposed to be due to long-term sympathetic nervous system stimulation. Our OSA group did have higher SBP and DBP than the non-OSA group; however, only subjects with a higher DBP had an association with OSA. Sharabi et al [27] reported that subjects with OSA had a higher DBP (4 mm Hg difference) than the control group, without elevation in SBP. Davies et al [28] compared patients with OSA with a matched control group and found that patients with OSA have increased ambulatory DBP during both day and night and increased SBP only at night. Our blood pressure measurements and those of Sharabi et al [27] were taken only in the daytime, therefore not demonstrating possible nocturnal high SBP. Although an ambulatory continuous 24-hour blood pressure recording could have provided a more accurate and representative arterial pressure and also has been more predictive of hypertensive cardiovascular results, it is not typical or practical for blood pressure measurements to be recorded in the clinical setting. We thus suggest that DBP rather than SBP should be carefully monitored in casual clinic blood pressure measurements when OSA symptoms are diagnosed by a physician.
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Elevated lipid profiles have been known to be high-risk factors for morbidity and mortality of cardiovascular diseases. Sharabi et al [27] found that there was no significant difference in lipid profile (total cholesterol, HDL-C, LDL-C, and triglycerides) between the OSA and control groups. However, higher total cholesterol level was found in participants with AHI of 5 or higher and selfreported snores [29]. The results of our data also indicate that the OSA group had significantly elevated lipid profiles. Patients suspected of having OSA, therefore, should be considered for lipid profile monitoring. Although interindividual variability does exist among cardiovascular risk factors, the significance of this study is finding that fasting plasma homocysteine concentration had no association with OSA; however, obesity, DBP, and serum total cholesterol are associated with OSA for male subjects without cardiovascular, diabetes mellitus, or renal and liver diseases. Indices of central obesity (BMI and waist and neck circumferences) and a combination with DBP and serum total cholesterol level should be screened in patients with OSA. References [1] Guilleminault C. Clinical features and evaluation of obstructive sleep apnea. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. Philadelphia7 WB Saunders; 1994. p. 667 - 77. [2] Hung J, Whitford EG, Parsons RW, Hillman DR. Association of sleep apnoea with myocardial infarction in men. Lancet 1990;336:261 - 4. [3] Mooe T, Rabben T, Wiklund U, Franklin K, Eriksson P. Sleepdisordered breathing in men with coronary artery disease. Chest 1996; 109:659 - 63. [4] Mooe T, Rabben T, Wiklund U, Franklin KA, Eriksson P. Sleepdisordered breathing in women: occurrence and association with coronary artery disease. Am J Med 1996;101:251 - 6. [5] Peker Y, Kraiczi H, Hedner J, Loth S, Johansson A, Bende M. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999;14:179 - 84. [6] Lavie P, Herer P, Peled R, Berger I, Yoffe N, Zomer J, et al. Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep 1995;18:149 - 57. [7] He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988;94:9 - 14. [8] Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268: 877 - 81. [9] Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of fasting plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049 - 57. [10] Bautista LE, Arenas IA, Penuela A, Martinez LX. Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. J Clin Epidemiol 2002;55:882 - 7. [11] Lavie L, Perelman A, Lavie P. Plasma homocysteine levels in obstructive sleep apnea-association with cardiovascular morbidity. Chest 2001;120:900 - 8. [12] Sch7fer H, Pauleit D, Sudhop T, Gouni-Berthold I, Ewig S, Berthold HK. Body fat distribution, serum leptin, and cardiovascular risk factors in men with obstructive sleep apnea. Chest 2002;122:829 - 39.
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