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(Chest. 2001;120:900-908.)
© 2001 American College of Chest Physicians

Plasma Homocysteine Levels in Obstructive Sleep Apnea*

Association With Cardiovascular Morbidity

Lena Lavie, DSc; Ana Perelman, MSc and Peretz Lavie, PhD

* From the Unit of Anatomy and Cell Biology (Dr. L. Lavie and Ms. Perelman), and Sleep Laboratory (Dr. P. Lavie), Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Correspondence to: Lena Lavie, DSc, Unit of Anatomy and Cell Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; e-mail: lenal{at}tx.technion.ac.il


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: Obstructive sleep apnea (OSA) is associated with cardiovascular morbidity and mortality. Plasma levels of homocysteine are also associated with cardiovascular morbidity and mortality. We therefore investigated homocysteine and conventional cardiovascular risk factors in OSA patients with and without cardiovascular morbidity in comparison with normal control subjects and ischemic heart disease (IHD) patients without OSA.

Setting: Technion Sleep Medicine Center, Haifa, Israel.

Methods and participants: Levels of homocysteine, cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, creatinine, vitamins B12 and B6, and folic acid were determined in 345 participants after overnight fasting. These included OSA patients with IHD (n = 49), with hypertension (n = 61), or without any cardiovascular disease (n = 127). Two control groups were employed: IHD patients without or with low likelihood for sleep apnea (n = 35), and healthy control subjects (n = 73).

Results: After adjustment for age, body mass index, creatinine, and existence of diabetes mellitus, OSA patients with IHD had significantly higher homocysteine levels (14.6 ± 6.77 µmol/L) than all other groups including the IHD-only patients. Hypertensive OSA patients had comparable homocysteine levels to IHD patients (11.80 ± 5.28 µmol/L and 11.92 ± 5.7 µmol/L, respectively), while patients with OSA only had comparable levels to normal control subjects (9.85 ± 2.99 µmol/L and 9.78 ± 3.49 µmol/L, respectively). No differences in conventional cardiovascular risk factors or in vitamin levels were found between groups.

Conclusions: Patients with the combination of IHD and OSA have elevated homocysteine levels. We hypothesize that these results may be explained by endothelial dysfunction combined with excess free-radical formation in OSA patients.

Key Words: homocysteine • hypertension • ischemic heart disease • obstructive sleep apnea


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Obstructive sleep apnea (OSA) syndrome is a common health problem affecting as much as 4 to 9% of the adult population.1 2 It is characterized by repeated breathing arrests during sleep, leading to repeated arterial oxygen desaturations. The syndrome is associated with sleep fragmentation and excessive daytime sleepiness that may result in intellectual deterioration and mood changes. A strong independent association was established between OSA and cardiovascular morbidity, such as systemic hypertension,3 4 5 coronary heart disease,6 7 8 9 atherosclerosis,10 and stroke.11 12 Furthermore, OSA patients were shown to have elevated levels of circulating endothelin-1,13 14 as well as vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and L-selectin,15 and platelet activation and aggregation,16 all established markers of cardiovascular morbidity. Lavie et al17 and He et al18 reported increased cardiovascular mortality risk in OSA patients, particularly in middle-aged patients. Therefore, identifying possible risk factors involved in OSA cardiovascular morbidity is of great clinical importance.

Since the pioneering observation of McCully19 in infants with inborn errors of metabolism, linking elevated levels of the nonprotein, sulfur-containing amino acid homocysteine in the plasma with vascular diseases, many clinical and epidemiologic studies20 21 22 23 24 25 26 27 have shown a clear correlation between mildly elevated total blood homocysteine concentrations and premature coronary artery diseases, peripheral artery diseases, stroke, or venous thrombosis. In a large-scale study based on the European Concerted Action Project, Graham et al27 concluded that an increased plasma homocysteine level conferred an independent risk for vascular disease similar to other conventional risk factors such as hyperlipidemia or smoking. In a meta-analysis based on 27 studies that included about 4,000 patients, Boushey et al28 concluded that a 5 µmol/L homocysteine increment elevates cardiovascular risk by as much as cholesterol increases of 20 mg/dL (0.5 mmol/L). Nygard et al29 prospectively investigated the relation between plasma total homocysteine concentration and mortality among 587 patients with angiographically confirmed coronary artery disease. They found a strong graded relation between plasma homocysteine and overall mortality. Anderson et al30 further emphasized the importance of homocysteine as a significant predictor of mortality independent of traditional risk factors in 1,412 patients with severe, angiographically defined coronary artery disease.

In view of the strong associations between OSA and cardiovascular morbidity and mortality, and between homocysteine and cardiovascular morbidity and mortality, we investigated the levels of homocysteine as well as conventional cardiovascular risk factors such as total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in OSA patients with and without ischemic heart disease (IHD), and in OSA patients with hypertension. We compared them to normal control subjects and to patients with IHD but without OSA. Since sleep apnea is much more prevalent in men and homocysteine levels are dependent on menopausal status, we focused in this study on men only. Folate levels, B12 and B6, were studied as well, due to their involvement in homocysteine metabolism.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Participants
We investigated fasting levels of homocysteine in a total of 345 male participants. These included three groups of OSA patients: (1) OSA patients with IHD (IHD-OSA; n = 49), of whom 21 patients had a history of myocardial infarction, 3 patients had a history of cerebrovascular accident, and 1 patient had a history of peripheral vascular disease); (2) OSA patients with hypertension only (HT-OSA; n = 61), defined as either having a history of antihypertensive treatment or BP > 140/90 mm Hg (1 patient had a history of cerebrovascular accident); and (3) OSA patients without any cardiovascular morbidity (OSA-only; n = 127). The control subjects consisted of two groups: (1) a group of patients with IHD only (IHD-only; n = 35), of whom 13 patients had a history of myocardial infarction; and (2) control subjects without OSA and free of any major disease (CON; n = 73). The study was approved by the local ethical committee, and all participants signed an informed consent before being enrolled in the study. Sleep apnea patients were recruited from the patients’ population of the Technion Sleep Medicine Center laboratory in Haifa during 1997–98. This eight-bed laboratory serves the northern part of Israel. The total number of patients studied during that period was 3,000, most of them because of suspected OSA. Consecutive patients were recruited for the study. Their assignment to the study groups was based on medical history and sleep laboratory findings. A diagnosis of OSA was based on at least 1 night of polysomnographic recording. This included monitoring of respiration using chest and abdomen respiratory belts and oronasal temperature sensors, as substitute measurements of respiratory effort and flow, and oxygen saturation. From these measures, we obtained the apnea-hypopnea index (AHI; the total number of apneas plus hypopneas divided by the hours of sleep), and lowest and mean nocturnal oxygen saturation; the percentage of sleep time spent with oxygen saturation < 90% was also recorded. Apnea was defined as a cessation in airflow of at least 10 s, and hypopnea was defined as a decrease in the amplitude of the respiratory signal of at least 50% for a minimum of 10 s followed by either a decrease in oxygen saturation of 4%, or signs of physiologic arousal. Height and weight were recorded, and the body mass index (BMI) was calculated. Each patient was also interviewed by one of the Sleep Medicine Center physicians regarding their sleep-related complaints and medical history. A sleep laboratory finding of at least AHI > 10 plus characteristic symptoms such as excessive daytime sleepiness, chronic fatigue, and restless sleep established the diagnosis of OSA. Inclusion in the HT-OSA and IHD-OSA groups was based on a documented clinical history. The history of IHD was based on the results of either angiography or thallium single-photon emission CT. Patients in the IHD-only group were recruited from two sources: patients with documented IHD referred to the sleep laboratory because of suspected OSA who were found to have normal sleep (n = 8), and from the patients’ population of a large cardiology department (n = 27). Approximately 60 patients with IHD diagnosed in this department either by angiography or thallium single-photon emission CT during a 6-month period were contacted by telephone and offered to participate in the study. All consenting patients were interviewed about their sleep, and those with low risk for OSA were included in the study. Normal control subjects were recruited from the population referred to the sleep laboratory and found to have normal sleep (n = 22), and from the hospital, sleep laboratory, and university personnel (n = 51). In both groups, a decision on a low likelihood of OSA was based on lack of characteristic symptoms such as snoring, witnessed episodes of nocturnal apneas, and excessive daytime sleepiness. An exclusion criterion applied to all groups was regular use of vitamins.

Blood Collection
Twenty milliliters of venous blood was obtained from each participant after overnight fasting. For homocysteine determinations, blood samples were collected to precooled ethylenediaminetetra-acetic acid-containing specimen tubes (Vacutainers; Becton-Dickenson; Plymouth, UK) and kept on ice. Plasma was separated within 2 h in a refrigerated centrifuge, aliquoted, and stored at - 70°C until assayed. Serum was obtained for the determination of B12, folate, cholesterol, triglycerides, LDL, HDL, and creatinine. B6 was determined in randomly selected plasma samples (n = 186) of the patients and control subjects.

Homocysteine Determination
Total plasma homocysteine analysis was carried out on a Biochrom 20 Amino-Acid analyzer (Pharmacia Biothech; Cambridge, UK) using a high-performance column and a modified physiologic sample separation according to manufacturers’ instructions,31 32 and as published.33 Briefly, a 200-µL plasma sample was mixed with 10 µL of sodium tetraborate (0.14 mol/L; pH, 9) and 10 µL of dithiothereitol (1.08 mol/L), and let stand for 25 min at room temperature to ensure complete reduction of all S-S bonds. Norleucine (100 nmol in 50 µL of double-distilled water) was added as an internal standard. Proteins were precipitated with 130 µL of 15% sulfosalicylic acid and centrifuged. The pH of the clear supernatant was adjusted to 2.5 by adding 50 µL of lithium hydroxide at 0.75 mol/L. One-hundred microliters of the treated sample (40 µL of plasma) was loaded by programmed autosampler to the column. Data were collected and calculated by EZchrom chromatography data system (EZchrom Scientific Software; San Ramon, CA), using five concentrations of D,L-homocysteine as a standard. The linearity of the standard was maintained from 20 pmol to 50 nmol. For quality control, aliquots of known plasma samples were used in each batch analysis. Each sample was analyzed in duplicate determinations. The coefficient of variation of this assay was at the most 5%. The correlation coefficient based on the 186 samples determined by both high-performance liquid chromatography (HPLC) and the amino acid analyzer was 0.99.

Vitamin B12 and Folate
These were determined in serum by commercially available kits from Abbott Laboratories (Diagnostic Division; Abbott Park, IL). The assays were performed on an Abbott IMX analyzer that utilizes ion capture technology for folate determination and microparticle enzyme immunoassay technology for B12. The assays were performed according to the manufacturers’ instructions and used quality control sera supplied by Abbott.

B6 (Pyridoxal-5'-phosphate)
Plasma B6 (pyridoxal-5'-phosphate) was determined for some of the patients in the OSA-only group (n = 84), the IHD-OSA group (n = 35), the IHD-only group (n = 32), and the CON group (n = 31) enzymatically using tyrosine decarboxylase based on the method described by Shin-Buehring et al.34 Since B6 was within normal levels in all groups (means varied from 43.5 to 58.12 pmol/mL) and it was unrelated to homocysteine, these data are not presented in detail.

Blood Chemistry
Cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and creatinine were analyzed from serum with a Vitros 250 Chemistry system (Johnson & Johnson, Clinical Diagnostics; Rochester, NY) by the American Medical Laboratories, Israel.

Statistical Analysis
Categorical data were analyzed by {chi}2 with Fisher Exact Probability Tests. The continuous values were analyzed by one-way analysis of variance followed by Duncan’s multiple-range test, or by the Kruskal-Wallis test for the variables that were not normally distributed. This was followed by analysis of the covariance on ranked homocysteine levels after adjusting homocysteine for age, BMI, creatinine levels, and the presence of diabetes mellitus. Planned post hoc comparisons were made to compare homocysteine levels among the five groups. Spearman correlation analysis was used to examine the relationship among homocysteine, folate, B12, B6, and creatinine, within groups; p < 0.05 was considered statistically significant. Scatter diagrams to demonstrate these relationships are also provided.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographic, clinical, and biochemical data of the five groups are presented in Tables 1 , 2 . Overall, the three OSA groups were of similar severity, with mean AHI and minimum oxygen saturation varying from 33.74 to 30.1 and from 85.09 to 79.95%, respectively, with large variability within groups. The five groups were statistically significantly different in age and BMI and had a different prevalence of diabetes mellitus. In addition, they had statistically significant different homocysteine and creatinine levels. Post hoc testing revealed that the IHD-OSA and IHD-only groups were of similar age (60.75 ± 10.8 years vs 59.69 ± 8.51 years, respectively); the HT-OSA group (55.15 ± 9.33 years) was approximately 5 years younger than the IHD-OSA and IHD-only groups, and older than the CON group (47.82 ± 11.15 years) and the OSA-only group (47.78 ± 11.64 years). The CON and OSA-only groups were also of similar age. The CON and IHD-only groups had borderline statistically significantly different BMI (26.59 ± 3.21 kg/m2 vs 28.67 ± 7.23 kg/m2; p < 0.06); they were less obese than the three OSA groups (OSA-only, 30.38 ± 5.5 kg/m2; HT-OSA, 30.98 ± 5.44 kg/m2; and IHD-OSA, 30.15 ± 4.32 kg/m2). The CON and OSA-only groups had lower prevalence of diabetes (2.7% and 0.79%, respectively) than the three cardiovascular groups (HT-OSA, 11.29%; IHD-OSA, 20.41%; and IHD-only, 20%). The IHD-only group had a higher usage of medications than the other groups (97.14%). The CON and OSA-only groups had similar medication usage (13.5% and 7.87%, respectively); the IHD-OSA and the HT-OSA groups had similar medication usage (73.47% and 62.9%, respectively). There were no significant differences, however, between the IHD-OSA and IHD-only groups with respect to the type of medications used: antiaggregants, 69.4% vs 88.6%; ß-blockers, 34.7% vs 62.8%; calcium channel blockers and angiotensin-converting enzyme inhibitors, 45% vs 42.8%; nitrates, 24.5% vs 45.7%; lipid-lowering drugs, 28.6% vs 42.8%; and antidiabetic medications, 12.2% vs 20%, respectively.


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  		Table 1. Demographic and Clinical Data of Study Groups*

 
Post hoc testing of the unadjusted homocysteine levels revealed that the CON and OSA-only groups had similar homocysteine levels (9.78 ± 3.49 µmol/L and 9.85 ± 2.99 µmol/L, respectively), which were lower than the HT-OSA group (11.8 ± 5.28 µmol/L) and the IHD-only group (11.92 ± 5.77 µmol/L). The latter two groups had similar homocysteine levels. The IHD-OSA group had statistically significantly higher homocysteine levels (14.6 µmol/L) than all the other groups (by 49%, 48.2%, 23.7%, and 22.4% higher than CON, OSA-only, HT-OSA, and IHD-only; p < 0.05 for each, or better). Analysis of the covariance on the ranks of homocysteine with age, BMI, creatinine level, and the existence of diabetes mellitus as covariates revealed statistically significant differences in homocysteine (p < 0.002). Again, the IHD-OSA group differed from all the groups (p < 0.0001, p < 0.03, p < 0.03, and p < 0.001 against CON, IHD-only, HT-OSA, and OSA-only, respectively). The CON group differed from the HT-OSA group (p < 0.03) and tended to differ from the IHD-only group (p < 0.10). The percentages of patients having homocysteine levels above the 90th percentile of the control subjects (13.2 µmol/L) were 40.82%, 22.86% 12.5%, and 11.81% in the IHD-OSA, IHD-only, OSA-HT, and OSA-only groups, respectively. The IHD-OSA group had significantly higher percentage than all other groups ({chi}2 = 24.42; p < 0.00001).

Correlation Analysis
Figures 1 -4 present the scatter diagrams for homocysteine and folic acid, B12, B6, and creatinine for all groups combined. As can be seen, there was an overall negative relationship between homocysteine and folic acid and B12, no relationship with B6, and a positive relationship with creatinine. These relationships held for each of the groups separately as was revealed by Spearman rank-order correlation analysis (Table 3 ). Significant or nearly significant correlations between homocysteine and B12 were found in the CON group (- 0.22, p< 0.05), the IHD-OSA group (- 0.32, p< 0.02), the HT-OSA group (- 0.22, p < 0.08), and the IHD-only group (- 0.32, p< 0.06), and for all groups combined (- 0.20, p< 0.0006). Folate and homocysteine were significantly or nearly significantly correlated in the CON group (- 0.40, p< 0.0004), the OSA-only group (- 0.31, p < 0.0003), the IHD-OSA group (- 0.25, p< 0.07), and the HT-OSA group (- 0.29, p< 0.02), and for all groups combined (- 0.26, p< 0.0001). Creatinine and homocysteine were significantly or nearly significantly correlated in the CON group (0.20, p< 0.08), the OSA-only group (0.22, p< 0.02), the HT-OSA group (0.48, p< 0.003), and the IHD-only group (0.58, p< 0.0007), and for all groups combined (0.31, p< 0.0001).



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  		Figure 1. Relation between plasma homocysteine and vitamin B12 for all groups (n = 339). Linear regression equation and R2 are presented in upper-right corner.

 

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  		Table 3. Spearman Correlation Coefficients Between Homocysteine and Creatinine, Folate, B12, and B6 for All Groups and for All Patients Combined*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The major finding of the present study is that the IHD-OSA group had significantly higher homocysteine levels than the IHD-only group after adjustment for major potential confounding factors. Homocysteine levels in the IHD-OSA group were also higher than those of the HT-OSA and OSA-only groups, as well as the CON group. Furthermore, the HT-OSA group had comparable levels of homocysteine to the IHD-only group.

In comparison with literature data on large-scale epidemiologic studies in nonselected cardiovascular patients, homocysteine levels in the IHD-OSA group were very high. The mean homocysteine level in seven studies investigating large groups of nonselected cardiovascular patients was 12.2 ± 1.3 µmol/L.26 This is similar to the level of homocysteine observed in our IHD-only group (11.92 ± 5.77 µmol/L) but 20% lower than the mean level in the IHD-OSA group (14.6 ± 6.77 µmol/L). Likewise, the mean percentage of nonselected IHD patients having abnormal fasting levels of homocysteine in seven studies with a total of 1,201 patients was 21.1%,28 which is similar to the percentage (22%) of abnormal homocysteine levels in the IHD-only group of this study. This, however, is almost half the percentage of IHD-OSA having homocysteine levels higher than the 90th percentiles of normal control subjects. The fact that homocysteine levels in the control group (10.8 µmol/L) and in the OSA-only group (10.6 µmol/L) were within the range of the control values in the above studies (10.5 to 11.9 µmol/L) rules out the possibility that the results obtained for the IHD-OSA group were due to methodologic differences in homocysteine determination. Furthermore, a 1999 Israeli study35 reported homocysteine levels of 12.1 ± 5.8 µmol/L in nonselected hypertensive patients with documented cardiovascular disease as compared to 11.1 ± 4.7 µmol/L for age- and gender-matched hypertensive patients without cardiovascular disease, which closely agree with the present results. Finally, for quality control, we reanalyzed 186 randomly selected samples using HPLC and obtained identical results.

None of the conventional risk factors for cardiovascular diseases, ie, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, were significantly different between the groups. This, most likely, reflects the fact that 45.7% of the IHD-only group and 28.5% of the IHD-OSA group regularly used lipid-lowering medications.

Homocysteine, a nonprotein, sulfur-containing amino acid, and an intermediate in the metabolism of the essential amino acid methionine, was implicated in the development and progression of cardiovascular disease. The mechanisms by which it exerts its effects have not yet been fully elucidated, but cumulative data clearly demonstrate that it affects multiple vascular functions in vitro and in vivo, such as promoting prothrombotic phenotype of the endothelium by increasing platelet aggregation and activation, stimulating vascular smooth-muscle cell proliferation, and altering endothelial function.36 37 Currently, endothelial injury and dysfunction are among the leading mechanisms proposed to contribute to the development of atherothrombotic vascular disease due to mildly and chronically increased homocysteine levels. The leading mechanism suggested for the adverse vascular effects of homocysteine on endothelial function involves oxidative stress and depletion of bioactive nitric oxide (NO).38

Although we do not have an immediate explanation why the IHD-OSA group had such high levels of homocysteine, we can rule out the possibility that it results from folate or vitamins B12 or B6 deficiency or from increased creatinine levels. Although within-group individual differences in homocysteine levels were moderately related to folate and B12 levels, which is in agreement with several reports in the literature,39 there were no significant differences in vitamin levels between groups. The lack of correlation between B6 and homocysteine levels is explained by the fact thatB6 participates in homocysteine metabolism only in cases where there are extremely high levels of homocysteine, such as after methionine loading.39 Likewise, neither age nor the rate of hypertension, diabetes, history of myocardial infarction, smoking, or usage of medications could account for these differences. Also, the potential contribution of BMI, which was significantly higher in the IHD-OSA group, was controlled by the statistical analysis. We would like to propose that the high levels of homocysteine in sleep apnea patients who also have IHD may be explained by a specific impairment in their ability to neutralize excess homocysteine resulting from impaired endothelial function. Homocysteine, like other thiols, is a reactive molecule. It is auto-oxidized in the plasma, forming in the process hydrogen peroxide, and accompanying free radicals that are toxic to endothelial cells. Also, homocysteine specifically inhibits glutathione peroxidase activity, leading to further increase in hydrogen peroxide.40 Normally, endothelial cells detoxify homocysteine by releasing NO, which forms S-nitroso-homocysteine adducts by binding to homocysteine.41 This protective effect of NO is eventually compromised, as long-term exposure to high homocysteine concentrations damages the endothelium, and thus limits NO production. In addition, homocysteine may also decrease the bioavailability of NO by impairing its synthesis.38 42

Recent studies43 44 have shown that OSA syndrome is associated with decreased levels of circulating NO. In both studies, this was reversed by effective treatment with nasal continuous positive airway pressure. In addition, elevated plasma levels of the endogenous NO-synthase inhibitor, asymmetric dimethylarginine, were reported in normotensive OSA patients as compared to normotensive control subjects.45 Asymmetric dimethylarginine was shown46 to be a novel marker of atherosclerosis. Furthermore, sleep apnea was also shown to be associated with endothelial dysfunction. Kato et al47 and Carlson et al48 reported that endothelium-dependent but not endothelium-independent vasodilation was impaired in OSA patients. Kraiczi et al49 reported on an increased vasoconstrictor sensitivity to angiotensin II, and Duchna et al50 reported on a decreased vasodilator response to bradykinin in sleep apnea patients. These findings point to an impairment in endothelial functioning in sleep apnea patients. Similarly, utilizing a mouse model with chronic mild hyperhomocysteinemia due to heterozygous cystathionine-ß synthase deficiency leads to endothelial dysfunction, partly due to increased oxidative stress and depletion in NO bioactivity.51 More interestingly though, these hyperhomocysteinemic mice exhibited a paradoxical vasoconstriction to bradykinin as observed in OSA patients.50

Although speculative at this stage, it is possible that endothelial impairment is much more profound in OSA patients who also suffer from cardiovascular diseases. This may be responsible for the diminution in NO production or bioavailability, and consequently for the accelerated accumulation of plasma homocysteine.

The diminution in NO may be accelerated in OSA patients by yet another mechanism. The apnea-related recurrent hypoxia/reoxygenation occurring throughout sleep in OSA may be analogous to the well-documented ischemia/reoxygenation injury as suggested by Dean and Wilcox.52 This leads to an excess formation of oxygen-free radicals through depletion of adenosine triphosphate and activation of xanthine oxidase. This possibility is supported by the findings that adenosine triphosphate metabolic products such as adenosine and uric acid in the plasma are increased in OSA patients.53 54 Moreover, hypoxia/reoxygenation can also cause increased free-radical formation via activation of inflammatory cells as observed for neutrophils and monocytes in OSA patients.55 56 Excess in superoxide production due to hypoxia/reoxygenation may also inactivate NO resulting in the formation of the toxic peroxynitrite. This may further prevent the inactivation of homocysteine leading to an increase in its levels,38 40 putting OSA patients with cardiovascular morbidity at a greater risk. Further studies are needed in order to determine what is the exact mechanism by which OSA patients with cardiovascular diseases have such exceptional plasma levels of homocysteine, and if this can be reversed by effective nasal continuous positive airway pressure treatment.

In view of the increased mortality risks associated with increasing levels of homocysteine,29 its high levels in cardiovascular OSA patients may confer an added risk in addition to the risk conferred by the repeated apneic and hypoxemic events. This may at least partially explain the high cardiovascular mortality risk reported in sleep apnea patients.17 57 Future studies should determine if supplementary treatment with vitamins (ie, folic acid, B12, and B6) that were reported to normalize homocysteine levels28 58 may have beneficial effects in ameliorating cardiovascular risks in OSA patients.


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  		Table 2. Biochemical Data of Study Groups*

 


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  		Figure 2. Relation between plasma homocysteine and vitamin B6 for a sample of the participants from all groups except for HT-OSA (n = 182). Linear regression equation and R2 are presented in upper-right corner.

 


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  		Figure 3. Relation between plasma homocysteine and folic acid for all groups (n = 341). Linear regression equation and R2 are presented in upper-right corner.

 


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  		Figure 4. Relation between plasma homocysteine and creatinine for all groups (n = 309). Linear regression equation and R2 are presented in upper-right corner.

 

   Acknowledgements
 
We are grateful to J. Selhub and M.R. Nadeau for performing the B6 determination and the HPLC determination for homocysteine quality control. We are grateful to the Technion Sleep Disorders Center staff for their help, and to Ms. Paula Herer who carried out the statistical analysis.


   Footnotes
 
Abbreviations: AHI = apnea-hypopnea index; BMI = body mass index; CON = control subjects without obstructive sleep apnea and free of any major disease; HDL = high-density lipoprotein; HPLC = high-performance liquid chromatography; HT-OSA = obstructive sleep apnea patients with hypertension only; IHD = ischemic heart disease; IHD-only = patients with ischemic heart disease only; IHD-OSA = ischemic heart disease patients with obstructive sleep apnea; LDL = low-density lipoprotein; NO = nitric oxide; OSA = obstructive sleep apnea; OSA-only = obstructive sleep apnea patients without any cardiovascular morbidity

This study was supported in part by a grant from the Ministry of Health to Drs. L. Lavie and P. Lavie.

Received for publication November 21, 2000. Accepted for publication April 3, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Lavie, P (1983) Incidence of sleep apnea in presumably healthy working population: a significant relationship with excessive daytime sleepiness. Sleep 6,321-328
  2. Young, T, Palta, M, Dempsy, J, et al (1993) Occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328,1230-1235[Abstract/Free Full Text]
  3. Lavie, P, Herer, P, Hoffstein, V (2000) Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 320,479-482[Abstract/Free Full Text]
  4. Peppard, PE, Young, T, Palta, M, et al (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342,1738-1784
  5. Nieto, FJ, Young, TB, Lind, BK, et al (2000) Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 283,1829-1836[Abstract/Free Full Text]
  6. Mooe, T, Rabben, T, Wiklund, U, et al (1996) Sleep-disordered breathing in men with coronary artery disease. Chest 109,659-663[Abstract/Free Full Text]
  7. Peker, Y, Kraiczi, H, Hedner, J, et al (1999) An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 14,179-184[Abstract]
  8. Peled, N, Abinader, EG, Pillar, G, et al (1999) Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease: effects of continuous positive air pressure treatment. J Am Coll Cardiol 15,1744-1749
  9. Schafer, H, Koehler, U, Ewig, S, et al (1999) Obstructive sleep apnea as a risk marker in coronary artery disease. Cardiology 92,79-84[CrossRef][ISI][Medline]
  10. Aboyans, V, Lacroix, P, Virot, P, et al (1999) Sleep apnoea syndrome and the extent of atherosclerotic lesions in middle-aged men with myocardial infarction. Int Angiol 18,70-73[ISI][Medline]
  11. Basseti, C, Aldrich, MS, Chervin, RD, et al (1996) Sleep apnea in patients with ischemic attacks and stroke: a prospective study of 59 patients. Neurology 47,1167-1173[Abstract/Free Full Text]
  12. Dyken ME, Somers VK, Yamada T, et al. Investigating the relationship between stroke and obstructive sleep apnea 1996; 27:401–407
  13. Saarelainen, S, Seppala, E, Laasonen, K, et al (1997) Circulating endothelin-1 in obstructive sleep apnea. Endothelium 5,115-118[ISI][Medline]
  14. Phillips, BG, Narkiewicz, K, Pesek, CA, et al (1999) Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 17,61-66[ISI][Medline]
  15. Ohga, E, Nagase, T, Tomita, T, et al (1999) Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J Appl Physiol 87,10-14[Abstract/Free Full Text]
  16. Bokinsky, G, Miller, M, Ault, K, et al (1995) Spontaneous platelet activation and aggregation during obstructive sleep-apnea and its response to therapy with nasal continuous positive air pressure. Chest 108,625-630[Abstract/Free Full Text]
  17. Lavie, P, Peled, R, Berger, I, et al (1995) Mortality in sleep-apnea patients: a multivariate analysis of risk factors. Sleep 18,149-157[ISI][Medline]
  18. He, J, Kryger, MH, Zorick, FJ, et al (1988) Mortality and apnea index in obstructive sleep apnea: experience in 385 male patients. Chest 94,9-14[Abstract/Free Full Text]
  19. McCully, KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56,111-128[ISI][Medline]
  20. Brattstrom, L, Israelsson, B, Norrving, B, et al (1990) Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Atherosclerosis 81,51-60[CrossRef][ISI][Medline]
  21. D’Angelo, A, Selhub, J (1997) Homocysteine and thrombotic disease. Blood 90,1-11[Free Full Text]
  22. Den Heijer, M, Koster, T, Blom, HJ, et al (1996) Hyperhomocysteinemia as a risk factor for deep vein thrombosis. N Engl J Med 334,759-762[Abstract/Free Full Text]
  23. Kang, SS, Wong, PW, Malinow, MR (1992) Hyperhomocysteinemia as a risk factor for occlusive vascular disease. Ann Rev Nutr 12,279-298[CrossRef][ISI][Medline]
  24. Mayer, EL, Jacobson, DW, Robinson, K (1996) Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 27,517-527[Abstract]
  25. Stampfer, MJ, Malinow, MR, Willett, WC, et al (1992) A prospective study of plasma homocysteine and risk of myocardial infarction in US Physicians. JAMA 268,877-881[Abstract]
  26. Welch, GN, Loscalzo, J (1998) Homocysteine and atherothrombosis. N Engl J Med 338,1042-1050[Free Full Text]
  27. Graham, IM, Daly, EL, Refsum, HM, et al (1997) Plasma homocysteine as a risk factor for vascular disease: the European concerted action project. JAMA 277,1775-1781[Abstract]
  28. Boushey, CJ, Beresford, SA, Omenn, GS, et al (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 274,1049-1057[Abstract]
  29. Nygard, O, Nordrehaug, JE, Refsum, H, et al (1997) Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337,230-236[Abstract/Free Full Text]
  30. Anderson, JL, Muhalstein, JB, Horne, BD, et al (2000) Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation 102,1227-1232[Abstract/Free Full Text]
  31. Davies, MG (1995) Amino acid method 45. Biochrom UK Cambridge, UK.
  32. Samyn, W (1998) Amino acid method 60. Biochrom UK Cambridge, UK.
  33. Briddon, A (1998) Total plasma homocysteine as a part of routine aminigram by ion-exchange chromatography. Amino Acids 15,235-239[CrossRef][ISI][Medline]
  34. Shin-Buehring, Y, Rasshofer, R, Enders, W (1981) A new enzymatic method for pyridoxal-5'-phosphate determination. J Inherit Metab Disord 4,123-124
  35. Sharabi, Y, Doolman, R, Rosenthal, T, et al (1999) Homocysteine levels in hypertensive patients with a history of a cardiac or cerebral atherothrombotic events. Am J Hypertens 12,766-771[CrossRef][ISI][Medline]
  36. Harker, LA, Slichter, SJ, Scott, CR, et al (1974) Homocysteinemia: vascular injury and arterial thrombosis. N Engl J Med 291,537-543
  37. Harker, LA, Ross, R, Slichter, SJ, et al (1976) Homocysteine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest 58,731-741
  38. Loscalzo, J (1996) The oxidant stress of hyperhocyt(e)inemia. J Clin Invest 98,5-7[ISI][Medline]
  39. Selhub, J (1999) Homocysteine metabolism. Annu Rev Nutr 19,217-246[CrossRef][ISI][Medline]
  40. Upchurch, GR, Jr, Welch, GN, Fabian, AJ, et al (1997) Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 272,17012-17017[Abstract/Free Full Text]
  41. Stamler, JS, Osborne, JA, Jaraki, O, et al (1993) Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 91,308-318
  42. Tawakol, A, Torbjorn, O, Gerhard, M, et al (1997) Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 95,1119-1121[Abstract/Free Full Text]
  43. Schulz, R, Schmidt, D, Blum, A, et al (2000) Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy. Thorax 55,1046-1051[Abstract/Free Full Text]
  44. Ip, MSM, Lam, B, Chan, L-Y, et al (2000) Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 162,2166-2171[Abstract/Free Full Text]
  45. Hedner, J (1995) Daytime waking autonomic function and vascular control. J Sleep Res 4(suppl 1),171-175[ISI][Medline]
  46. Miyazaki, H, Matsuoka, H, Cooke, JP, et al (1999) Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 99,1141-1146[Abstract/Free Full Text]
  47. Kato, M, Roberts-Thomson, P, Phillips, BG, et al (2000) Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102,2607-2610[Abstract/Free Full Text]
  48. Carlson, JT, Rangemark, C, Hedner, JA (1996) Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. J Hypertens 14,557-584[CrossRef][ISI][Medline]
  49. Kraiczi, H, Hedner, J, Peker, Y, et al (2000) Increased vasoconstrictor sensitivity in obstructive sleep apnea. J Appl Physiol 89,493-498[Abstract/Free Full Text]
  50. Duchna, HW, Guilleminault, C, Stoohs, RA, et al (2000) Vascular reactivity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 161,187-191[Abstract/Free Full Text]
  51. Eberhardt, RT, Forgione, MA, Cap, A, et al (2000) Endothelial dysfunction in a murine model of mild hyperhomocysteinemia. J Clin Invest 106,483-491[ISI][Medline]
  52. Dean, RT, Wilcox, I (1993) Possible atherogenic effects of hypoxia during obstructive sleep apnea. Sleep 16,S15-S22[ISI][Medline]
  53. Findley, LJ, Boykin, M, Fallon, T, et al (1988) Plasma adenosine and hypoxemia in patients with sleep apnea. J Appl Physiol 64,556-561[Abstract/Free Full Text]
  54. Braghiroli, A, Sacco, C, Erbetta, , et al (1993) Overnight uric acid: creatinine ratio for detection of sleep hypoxemia: validation study in chronic obstructive pulmonary disease and obstructive sleep apnea before and after treatment with nasal continuous positive airway pressure Am J Rev Respir Dis 148,173-178
  55. Schulz, R, Mahmoudi, S, Hattar, K, et al (2000) Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea: impact of continuous positive airway pressure therapy Am J Respir Crit Care Med 162,566-570[Abstract/Free Full Text]
  56. Dugovskaya, L, Lavie, L (2000) Activation of oxidative metabolism and CD64 and CD11c expression in peripheral blood monocytes and neutrophils in obstructive sleep apnea syndrome [abstract] J Sleep Res 9(suppl 1),57
  57. Peker, Y, Hedner, J, Kraiczi, H, et al (2000) Respiratory disturbance index: an independent predictor of mortality in coronary artery disease Am J Respir Crit Care Med 162,81-86[Abstract/Free Full Text]
  58. Ubbink, JB, Vermaak, WHJ, Van Der Merwe, A, et al (1994) Vitamin requirements for the treatment of hyperhomocysteinemia in humans J Nutr 124,1927-1933



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