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Original Research: SLEEP MEDICINE |

Circulating Carbon Monoxide Level Is Elevated After Sleep in Patients With Obstructive Sleep Apnea FREE TO VIEW

Masayoshi Kobayashi, MD; Naoki Miyazawa, MD, PhD; Mitsuhiro Takeno, MD, PhD; Shuji Murakami, MD; Yohei Kirino, MD, PhD; Akiko Okouchi, MD; Takeshi Kaneko, MD, PhD; Yoshiaki Ishigatsubo, MD, PhD
Author and Funding Information

*From the Department of Internal Medicine and Clinical Immunology (Drs. Kobayashi, Miyazawa, Takeno, Murakami, Kirino, and Ishigatsubo), Yokohama City University Graduate School of Medicine; the Department of Internal Medicine (Dr. Okouchi), Yokohama Seamen's Insurance Hospital; and the Respiratory Center, Yokohama City University Medical Center (Dr. Kaneko), Yokohama, Japan.

Correspondence to: Yoshiaki Ishigatsubo, MD, PhD, Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan; e-mail: ishigats@med.yokohama-cu.ac.jp


For editorial comment see page 895

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Dr. Takeno was supported by a 2006 grant from the Yokohama Foundation for Advancement of Medical Science. Dr. Ishigatsubo was supported by grants from the Ministry of Education, Culture, Sports, and Technology of Japan (Yokohama City University Center of Excellence Program), and Yokohama City University (2006 Strategic Research project K18006).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(5):904-910. doi:10.1378/chest.07-2904
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Background:  Patients with obstructive sleep apnea (OSA) have an increased risk of cardiovascular morbidity. This study aimed to determine circulating carbon monoxide (CO) levels, which have been suggested to be a marker of cardiovascular risk in patients with OSA.

Methods:  Venous blood samples were obtained from 35 patients with OSA and 17 age-matched, healthy control subjects before and after polysomnography. Concentrations of venous CO and serum heme oxygenase (HO)-1 were determined by gas chromatography and enzyme-linked immunosorbent assay, respectively.

Results:  Circulating CO levels in OSA patients were significantly increased in the morning, but not in the evening. The change in CO level, which was defined as a gap between the presleep and postsleep CO levels, correlated with apnea-hypopnea index and hypoxia duration as a percentage of total sleep time. No difference was found in serum HO-1 levels between OSA patients and control subjects. Treatment with continuous positive airway pressure (CPAP) resulted in normalization of the postsleep CO level.

Conclusions:  The postsleep circulating CO level is helpful for assessing the clinical severity of OSA. Moreover, treatment of OSA with CPAP can potentially reduce the risk of the disease associated cardiovascular events.

Figures in this Article

Obstructive sleep apnea (OSA) is a common chronic respiratory disorder that is characterized by episodic apnea/hypopnea due to airway obstruction during sleep.1 Although daytime sleepiness is a major subjective symptom in patients, accumulating evidence has shown that OSA is associated with increased cardiovascular morbidity and mortality.2,3 Therefore, the eventual therapeutic goal is to reduce the cardiovascular risks in patients with OSA. Indeed, continuous positive airway pressure (CPAP) therapy has been shown to contribute not only to an improvement in oxygen conditions, but also to a significant reduction in cardiovascular morbidities in OSA patients.2,3

Episodic apnea/hypopnea causes transient hypoxia followed by the normalization of oxygen level during sleep in OSA patients. Some studies4 have shown that hypoxia and reoxygenation occur as oxidative stress triggers the generation of reactive oxygen species (ROS), which have been implicated in endothelial dysfunction in OSA patients. Indeed, increased levels of urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) suggest an overload of oxidative stress in patients.5 ROS also cause the activation of nuclear factor (NF)-κB and activator protein-1, leading to the synthesis of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin-6, and interleukin-8, and the up-regulation of endothelial adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.4,68 Oxidative stress, particularly hypoxia, activates hypoxia-inducible factor-1, which is responsible for the production of vascular endothelial growth factor, endothelin-1, and heme oxygenase (HO)-1.4,9,10 These molecules are implicated in endothelial dysfunction and subsequent cardiovascular disorders in patients with OSA.

Of the oxidative stress-related metabolites, circulating carbon monoxide (CO) has been shown11 to be a marker for cardiovascular risk, irrespective of smoking history. CO in vascular cells modulates blood flow and blood fluidity by regulating vasomotor tone and inhibiting smooth muscle cell proliferation and platelet aggregation.1215 HO-1-deficient mice, in which endogenous CO synthesis is impaired, are susceptible to photochemical- induced vascular injury and subsequent thrombosis, which is rescued by CO inhalation.16 The protective effects of CO on endothelial vascular injury are mediated by down-regulating homologous CCAAT enhancer binding protein expression via p38 mitogen-activating protein kinase activation and by up-regulating NF erythroid 2-related factor 2-dependent HO-1 expression via R-like endoplasmic reticulum kinase (or PERK). CO also inhibits the production of antiangiogenic circulating factors, soluble Fit-1 and soluble endoglin, which are involved in preeclampsia.16,17 Thus, the HO-1/CO system plays a regulatory role in the cardiovascular system through multiple pathways.

The blood CO level is determined by the sum of ambient and endogenous CO, the latter of which is derived from heme degradation catalyzed by HO.18 HO-1 is up-regulated by various stimuli, including hypoxia, oxidative stress, inflammatory cytokines, and some drugs, and plays a protective role in various pathologic conditions.19,20 Indeed, we have previously demonstrated the beneficial effects of HO-1 gene therapy on respiratory diseases2125 and of chemical-induced HO-1 on inflammatory disorders.26,27 HO-1 is also pathologically implicated in several diseases including adult-onset Still disease, hemophagocytic syndrome, rheumatoid arthritis (RA), and pneumosilicosis, as shown in our previous work.26,28,29 Interestingly, elevated CO levels have also suggested the involvement of HO-1 in several respiratory diseases (ie, bronchial asthma, bronchiectasis and COPD).3033 A possible role for HO-1 in the treatment of OSA has also been proposed10 by increasing the levels of indirect bilirubin, which is another heme degradation product, in patients. In the current study, venous CO levels were determined presleep and postsleep in OSA patients, including those who had been treated with CPAP.

Subjects

Thirty-five patients in whom OSA had been diagnosed by full polysomnography (PSG) at Yokohama City University Hospital and the Yokohama Seamen's Insurance Hospital (mean [± SD] age, 53.7 ± 13.6 years; 27 men and 8 women) were enrolled in this study (Table 1). Seventeen age-matched healthy subjects served as control subjects (mean age, 50.1 ± 14.4 years; 13 men and 4 women). The patients were asked about their medical history and smoking habits. Patients who had a history of cardiovascular events, such as ischemic heart diseases and cerebrovascular attacks, were excluded from this study. Current smokers and ex-smokers who had smoked until within 12 months before the start of the study were excluded. To confirm the current smoking status, including the inhalation of second-hand smoke, serum levels of cotinine were measured and a questionnaire was administered to the patients. The severity of subjective symptoms was assessed by the Epworth sleepiness scale (ESS) score.34 All studies were performed after obtaining written informed consent based on approval by the local institutional review board.

Table Graphic Jump Location
Table 1 Subject Characteristics*

*Values are given as the mean ± SD, unless otherwise indicated.

SBP = systolic BP; DBP = diastolic BP; Spo2 = pulse oximetric saturation; NS = not significant.

PSG

All subjects underwent overnight PSG (Alice 3 Diagnostics System; Respironics; Murrysville, PA), with documentation of sleep stages by EEG, of respiratory movement by impedance plethysmograph, of airflow by thermistors, of snoring by tracheal microphone, of sleep position by a position sensor, and of arterial oxygen saturation by pulse oximeter (model 930; Healthdyne Technologies; Marietta, GA). According to the American Sleep Disorders Association criteria,35 apnea was defined as the pause of airflow at the nose and mouth lasting for > 10 s. Hypopnea was defined as a decrease of ≥ 30% in thoracoabdominal motion associated with a fall in baseline oxygen saturation of > 4%. The apnea-hypopnea index (AHI) was expressed as the number of episodes of apnea and hypopnea per hour of total sleep time (TST). The severity of hypoxia was assessed by calculating the percentage of TST spent with oxygen saturation at < 90%.

Measurement of the Venous Blood CO Levels

Venous blood samples were drawn in the evening (8:00 pm [presleep]) before patients underwent PSG and the next morning (6:00 am [postsleep]), and were stored at −70°C until they were used. The tetraborate pH standard solution (1.0 mL; pH 9.18) and saturated potassium ferricyanide water solution (1.0 mL) was sequentially added to 0.1 mL of whole blood in a 3.0-mL vial. After 10 min of incubation in the closed vial at 37°C, 1.0 mL of headspace gas was absorbed and injected into an analyzer equipped with a semiconductor detector (TRIlyzer m3000; Taiyo Instruments; Osaka, Japan), which can detect CO with 0.1 ppm sensitivity.36,37

Measurement of Serum HO-1, Indirect Bilirubin, TNF-α, C-Reactive Protein, and 8-OHdG

Enzyme-linked immunosorbent assay kits were utilized to determine serum cotinine levels (COSMIC; Tokyo, Japan), serum levels of HO-1 (Stressgen Biotechnologies; San Diego, CA), TNF-α (R&D Systems; Minneapolis, MN), and 8-OHdG (JaICA; Shizuoka, Japan). Serum C-reactive protein (CRP) and indirect bilirubin were analyzed by highly sensitive immunonephelometry.

CPAP Treatment

Of the 35 OSA patients studied, CPAP therapy using a CPAP device (Autoset-S; ResMed; North Ryde, NSW, Australia) was introduced into 22 patients who had subjective symptoms and an AHI > 20/h. Of these patients, seven patients who agreed to undergo another PSG were reexamined during the first night of CPAP therapy.

Statistical Analysis

Results were expressed as the mean ± SD. Differences were assessed using a paired t test and the Mann-Whitney U test. Correlation variables were assessed with the Pearson correlation test. Multiple regression analyses were performed after the identification of significant variables by simple linear regression and with appropriate adjustments. A p value of < 0.05 was considered to be significant.

Subject Characteristics

Table 1 shows the clinical characteristics of the patients with OSA and of age-matched, healthy control subjects. In all of the subjects, the cotinine levels were < 20 ng/mL, indicating that none of the subjects had been exposed to smoke, including secondhand smoke. There were no significant differences in body mass index (BMI), systolic BP, and diastolic BP between the two groups. ESS score and AHI were significantly higher in patients with OSA than in control subjects. PSG detected significant periods of desaturation (during which pulse oximetric saturation was < 90%) during sleep in 26 of 35 patients with OSA, but not in the control subjects (Table 1).

CO Levels in Venous Blood From Patients With OSA

CO levels were determined by gas chromatography in venous blood during the evening (ie, 8:00 pm [presleep]) and the next morning (ie, 6:00 am [postsleep]), before and after PSG, respectively. There was no difference in the CO levels between the OSA patients (mean CO level, 13.90 ± 4.29 ppm) and control subjects (mean CO level, 15.17 ± 4.95 ppm [difference was not significant]), whereas the morning level was significantly higher in the OSA patients (mean CO level, 17.69 ± 4.92 ppm) when compared to that in the control group (mean CO level, 14.81 ± 4.30 ppm; p < 0.05) [Fig 1, top, A]. The postsleep CO levels were significantly higher than presleep levels in OSA patients (p < 0.0001) [Fig 1, top, A], but not in the control subjects. The CO level was elevated during sleep in all OSA patients except 1, and in 6 of 17 healthy control subjects. Interestingly, the postsleep CO level correlated with the percentage of TST spent in desaturation (r = 0.45; p < 0.01) [Fig 1, bottom, B], suggesting that hypoxia caused an accumulation of CO during sleep in patients with OSA.

Figure Jump LinkFigure 1 Venous blood CO levels measured by gas chromatography. Top, A: venous blood CO levels in 35 OSA patients (black column) and 17 healthy control subjects (open column) before sleep (8:00 pm) and after sleep (6:00 am). The data represent the mean ± SD. Bottom, B: correlation between postsleep venous blood CO levels and the percentage of TST spent with an oxygen saturation of < 90% among OSA patients. * = p < 0.0001 (determined by paired t test); † = p < 0.05 (determined by Mann-Whitney U test)Grahic Jump Location

The change in CO levels (ΔCO) was determined by subtracting the CO level in the morning from that of the previous night. OSA patients showed a significantly greater ΔCO than the control subjects (p < 0.0001) [Fig 2]. Moreover, the increased ΔCO was correlated with AHI and hypoxia duration as a percentage of TST (AHI: r = 0.36; p < 0.05 [Fig 3, top, A]; hypoxia duration as a percentage of TST: r = 0.52; p < 0.01 [Fig 3, bottom, B]). In a stepwise multiple regression analysis, ΔCO was used as a dependant variable, and the order of inclusion in the model of the following independent variables was evaluated: age; BMI; ESS; AHI; and the duration of desaturation as a percentage of TST. Of these variables, the duration of desaturation as a percentage of TST was the strongest predictor of ΔCO in patients with OSA (p = 0.014).

Figure Jump LinkFigure 2 Venous blood CO levels in the morning vs in the previous night (ΔCO) in 17 healthy control subjects and 35 OSA patients. Dots represent individual data points. Horizontal lines with error bars indicate the mean ± SD in individual groups. The dashed line indicates the cutoff level (ΔCO, 2.0 ppm), which was determined by receiver operating characteristic curve analysis. † = p < 0.0001 (by Mann-Whitney U test)Grahic Jump Location
Figure Jump LinkFigure 3 Top, A: correlation between ΔCO and apnea AHI. Bottom, B: correlation between ΔCO and the percentage of TST spent with an oxygen saturation of < 90%Grahic Jump Location
CO Levels in OSA Patients Treated With CPAP Therapy

Of 35 patients, CPAP therapy was indicated for 22 patients by the results of the first PSG. Seven of 22 patients were enrolled in the second PSG on the first night of CPAP therapy on the basis of written agreement. To confirm whether the seven patients (mean age, 57.3 ± 15.9 years) represent all OSA patients who require CPAP therapy (mean age, 57.7 ± 14.4 years), clinical backgrounds were compared between the 7 patients (second study group) and the remaining 15 patients (the remaining group). Between the two groups, no difference was found in AHI (second study group, 46.54 ± 16.79 events per hour; remaining group, 45.11 ± 18.95 events per hour; difference was not significant) and BMI (second study group, 26.63 ± 4.10 kg/m2; remaining group, 26.56 ± 5.62 kg/m2; difference was not significant). CO levels at the time of the first PSG were not different in terms of the presleep CO level (second study group, 15.0 ± 2.97 ppm; remaining group, 12.88 ± 5.11 ppm; difference was not significant), the postsleep CO level (second study group, 18.27 ± 3.29 ppm; remaining group, 18.04 ± 5.95 ppm; difference was not significant), and the ΔCO (second study group, 3.27 ± 1.27 ppm; remaining group, 5.16 ± 2.51 ppm; difference was not significant). Thus, there was no difference of backgrounds between the second study group and the remaining patients.

The second PSG in the seven patients revealed that the mean AHI was significantly decreased from 46.5 ± 16.8 to 3.4 ± 3.3 events per hour by CPAP therapy. Hypoxia duration as a percentage of TST was 0.0% in six patients and 0.4% in a patient at the time of CPAP therapy, while the mean baseline level was 6.0 ± 8.3%. While the mean presleep CO levels were similar at the time of the first PSG (13.77 ± 4.53 ppm) and the second PSG (15.00 ± 2.97 ppm; difference was not significant), CPAP therapy significantly reduced postsleep CO levels (p < 0.05) [Fig 4, top, A] and the ΔCO (p < 0.05) [Fig 4, bottom, B]. Exceptionally, the postsleep CO level and the ΔCO did not decrease in the patient who had a hypoxia duration of 0.4% of TST. Thus, our data indicated that the therapeutic efficacy of CPAP was associated with the normalization of morning CO levels in OSA patients.

Figure Jump LinkFigure 4 Effects of CPAP therapy on venous blood CO levels in seven patients with OSA. Top, A: venous blood CO levels with (+) and without (−) CPAP therapy after sleep (6:00 am). Bottom, B: ΔCO with (+) and without (−) CPAP therapy. Data represent the mean ± SD. * = p < 0.05 (by paired t test)Grahic Jump Location
Serum Levels of Indirect Bilirubin and HO-1

CO is endogenously generated as a product of heme degradation, which is catalyzed by HO. Elevated levels of indirect bilirubin have previously been demonstrated in OSA patients.10 Similarly, our data also showed that the change in indirect bilirubin levels (ie, the gap between the presleep and postsleep indirect bilirubin levels) was significantly higher in the OSA patients (mean change, 0.07 ± 0.14 mg/mL) than in the control subjects (mean change, −0.07 ± 0.22 mg/mL; p < 0.05). Although the increase in heme degradation products suggested increased HO activity during sleep, the postsleep serum level of HO-1 did not statistically differ between OSA patients (2.03 ± 1.25 pg/mL) and control subjects (1.70 ± 0.65 pg/mL; difference was not significant).

Serum Levels of 8-OHdG, TNF-α, and CRP

The increased urine excretion of 8-OHdG, which is another parameter of oxidant stress, has been demonstrated in OSA patients.31 However, our study revealed that mean serum 8-OHdG levels were comparable between OSA patients (1.68 ± 1.00 pg/mL) and control subjects (1.45 ± 0.92 pg/mL; difference was not significant). Elevated serum levels of TNF-α and CRP have been also demonstrated in OSA patients.6,8 In concordance with these previous reports, the current study reproduced the fact that mean postsleep serum TNF-α levels were significantly higher in OSA patients (1.62 ± 0.99 pg/mL) than in control subjects (0.91 ± 1.92 pg/m; p < 0.001), whereas no difference was found in mean serum CRP levels between OSA patients (0.98 ± 1.25 mg/L) and control subjects (0.57 ± 0.65 mg/L; difference was not significant).

This study revealed a significant elevation of circulating CO levels in the morning but not in the evening in OSA patients. The ΔCO, which is the gap between the presleep and postsleep venous CO levels, was positively correlated with AHI and with hypoxia duration as a percentage of TST. There was no relationship between venous CO levels and other background factors such as BMI and age. Moreover, the increased CO levels were normalized by treatment with CPAP in OSA patients.

In this study, the venous CO level was determined by gas chromatography, which is more sensitive than the measurement of arterial blood carboxyhemoglobin levels and avoids environmental factors.36,37 Smoking is the most well-known exogenous factor that affects the venous CO level. Tobacco smoking not only contributes to the accumulation of CO exogenously but also stimulates the synthesis of endogenous CO through oxidative stress-dependent HO-1 expression. Therefore, we confirmed that serum cotinine levels were undetectable in all subjects before enrolling in the study.

Increased levels of CO and indirect bilirubin suggested the presence of increased HO enzymatic activity in OSA patients. Because the ho-1 gene promoter region contains multiple binding sites of transcriptional factors such as hypoxia-inducible factor-1α, NF-κB, and activator protein-1, it is plausible that HO-1 is up-regulated by ROS and proinflammatory cytokines, which are excessively synthesized in OSA patients. Unexpectedly, serum HO-1 levels were not elevated in OSA patients. However, the induction of HO-1 is not always accompanied by increased serum HO-1 levels. Despite the abundant expression of HO-1 in synovial tissue obtained from patients with RA,29,38 serum HO-1 levels are not elevated in RA patients.28 Nevertheless, elevated serum bilirubin levels have been shown in RA patients having nonerosive joint lesions.38 These findings suggest that heme degradation products, CO and bilirubin, in the serum are more sensitive for detecting the up-regulation of HO-1 in the body than are serum HO-1 levels.

The present study indicated that increased serum CO levels are related to hypoxia during sleep in OSA patients. In addition to positive correlations of CO with hypoxia duration in terms of TST and AHI, the improvement in the oxidative condition by CPAP therapy is associated with the normalization of serum CO levels, indicating that OSA-related hypoxia is responsible for increased CO levels in OSA patients.

Concerning other proinflammatory markers and oxidative stress markers, the present study confirmed previous reports that the levels of TNF-α were elevated in patients with OSA. Unlike those previous reports, we failed to show significant increased serum levels of CRP and 8-OHdG. These discrepancies between previous reports and the current study may have been caused by the difference in the backgrounds of the patients, because all of these parameters are not specific for OSA and can be very much affected by various physical and pathologic conditions, except for OSA-related hypoxia.

In conclusion, increased levels of circulating CO increased hypoxia during sleep in OSA patients and were helpful in assessing the clinical severity. Moreover, the normalization of venous CO levels by CPAP therapy can potentially reduce the risk of disease associated cardiovascular events, which is most critical for patients with OSA.

AHI

apnea-hypopnea index

BMI

body mass index

CO

carbon monoxide

CPAP

continuous positive airway pressure

CRP

C-reactive protein

ΔCO

change in carbon monoxide level

8-OHdG

8-hydroxy-2′-deoxyguanosine

ESS

Epworth sleepiness scale

HO

heme oxygenase

NF

nuclear factor

OSA

obstructive sleep apnea

PSG

polysomnography

RA

rheumatoid arthritis

ROS

reactive oxygen species

TNF

tumor necrosis factor

TST

total sleep time

The authors wish to thank the laboratory staff of Yokohama City University School of Medicine and Yokohama Seamen's Insurance Hospital. The authors are also indebted to Mr. Tom Kiper (Yokosuka, Japan) for his review of the manuscript.

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Figures

Figure Jump LinkFigure 1 Venous blood CO levels measured by gas chromatography. Top, A: venous blood CO levels in 35 OSA patients (black column) and 17 healthy control subjects (open column) before sleep (8:00 pm) and after sleep (6:00 am). The data represent the mean ± SD. Bottom, B: correlation between postsleep venous blood CO levels and the percentage of TST spent with an oxygen saturation of < 90% among OSA patients. * = p < 0.0001 (determined by paired t test); † = p < 0.05 (determined by Mann-Whitney U test)Grahic Jump Location
Figure Jump LinkFigure 2 Venous blood CO levels in the morning vs in the previous night (ΔCO) in 17 healthy control subjects and 35 OSA patients. Dots represent individual data points. Horizontal lines with error bars indicate the mean ± SD in individual groups. The dashed line indicates the cutoff level (ΔCO, 2.0 ppm), which was determined by receiver operating characteristic curve analysis. † = p < 0.0001 (by Mann-Whitney U test)Grahic Jump Location
Figure Jump LinkFigure 3 Top, A: correlation between ΔCO and apnea AHI. Bottom, B: correlation between ΔCO and the percentage of TST spent with an oxygen saturation of < 90%Grahic Jump Location
Figure Jump LinkFigure 4 Effects of CPAP therapy on venous blood CO levels in seven patients with OSA. Top, A: venous blood CO levels with (+) and without (−) CPAP therapy after sleep (6:00 am). Bottom, B: ΔCO with (+) and without (−) CPAP therapy. Data represent the mean ± SD. * = p < 0.05 (by paired t test)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Subject Characteristics*

*Values are given as the mean ± SD, unless otherwise indicated.

SBP = systolic BP; DBP = diastolic BP; Spo2 = pulse oximetric saturation; NS = not significant.

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