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Original Research: SLEEP MEDICINE |

C-Reactive Protein Is Associated With Obstructive Sleep Apnea Independent of Visceral Obesity FREE TO VIEW

Macy Mei-sze Lui, MBBS; Jamie Chung-mei Lam, MBBS, FCCP; Henry Ka-Fung Mak, MD; Aimin Xu, PhD; Clara Ooi, MD; David Chi-leung Lam, PhD, FCCP; Judith Choi-wo Mak, PhD; Pek Lan Khong, MD; Mary Sau-Man Ip, MBBS, MD, FCCP
Author and Funding Information

*From the Departments of Medicine (Drs. Lui, D. Lam, J. Lam, and J. Mak), and Diagnostic Radiology (Drs. Khong, H. Mak, and Ooi), and Research Centre of Heart, Brain, Hormone and Healthy Aging (Drs. Xu and Ip), Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.

Correspondence to: Mary Sau-Man Ip, MBBS, MD, FCCP, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China; e-mail: msmip@hkucc.hku.hk


This study is supported by a grant from Lee Wing Tat Cardiorespiratory Fund (20000575.20600.400.01) and Hong Kong Research Grants Council grant award (HKU 7582/06M).

The authors have no conflicts of interest to disclose.

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


Chest. 2009;135(4):950-956. doi:10.1378/chest.08-1798
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Background:  Obstructive sleep apnea (OSA) is associated with adverse cardiovascular outcomes. C-reactive protein (CRP) predicts atherosclerotic complications. Our study evaluates whether OSA is associated with an elevated CRP level, after elimination of known confounders including visceral obesity.

Methods:  Men without significant chronic medical illness, regular medications, or illness in the preceding 4 weeks were enrolled. Subjects with morbid obesity, newly detected high BP, or fasting glucose were excluded. They underwent polysomnography and MRI of abdomen to quantify visceral fat volume. High-sensitivity CRP levels were measured.

Results:  111 men with mean body mass index (BMI) 26.3 ± 3.8 kg/m2 were evaluated. After adjustment for age, smoking, BMI, waist circumference, and sleep efficiency, CRP correlated positively with the apnea-hypopnea index (AHI) [r = 0.35, p < 0.001], duration of O2 saturation < 90% (r = 0.29, p = 0.002), and arousal index (r = 0.32, p = 0.001), and it correlated negatively with minimal O2 saturation (r = −0.29, p = 0.002). These correlations were consistent when adjustment was made for MRI visceral fat volume instead of waist circumference. In the regression model, significant predictors of CRP included AHI, waist circumference, and triglycerides (adjusted R2, 0.33, p = 0.001, p = 0.002, p = 0.018, respectively). Among the 111 subjects, 32 subjects with no or mild OSA (AHI < 15 events/h) were matched with 32 subjects with moderate-to-severe OSA (AHI ≥ 15 events/h) in MRI visceral fat volume. CRP was higher in subjects with moderate-to-severe OSA (median, 1.32; 0.45 to 2.34 mg/L) when compared to subjects with no or mild OSA (median, 0.54; 0.25 to 0.89 mg/L; p = 0.001).

Conclusions:  In healthy middle-aged men, elevated CRP level is associated with OSA independent of visceral obesity.

Figures in this Article

Obstructive sleep apnea (OSA) is an independent risk factor for hypertension and implicated in the occurrence of cardiovascular events. The Sleep Heart Health Study showed that cardiovascular morbidity is elevated even in subjects with mild elevation of the apnea-hypopnea index (AHI).1

Inflammation plays an important role in arterial plaque formation, rupture, and thrombosis.2 In the past decade, C-reactive protein (CRP), a sensitive marker of inflammation, has been the focus of intense research.3 CRP is believed to be both a by-product and a mediator of the low-grade inflammation that occurs in atherosclerosis.4,5 Several large-scale prospective studies have shown that the CRP level is an independent predictor of risk of myocardial infarction, stroke, peripheral vascular disease, and vascular death,611 making it a useful marker for cardiovascular risk stratification.1216

Aging, smoking, obesity/visceral obesity, insulin resistance, and hypertension were linked to elevated CRP level.3,1720 Obesity, especially visceral obesity, is one of the major confounders in the analysis of association between CRP and OSA.2123 Visceral adipocytes produce numerous cytokines and are metabolically more active than subcutaneous fat. Hence visceral obesity is most closely related to cardiovascular diseases and metabolic syndrome.2426 A number of works2733 have demonstrated the independent association between OSA and an elevated CRP level, but this association was inconsistent in several studies.3439 Many of these previous works were limited by relatively small sample size, inclusion of subjects with vascular comorbidities, inadequate control of confounders, or the use of insensitive CRP assays.

This study evaluates the relationship between OSA and CRP levels, with cautious exclusion of any prevailing comorbidity that might affect CRP levels. To minimize the confounding effect of obesity, we also excluded those with severe adiposity with body mass index (BMI) > 35 kg/m2, and utilized a more precise quantification of visceral adiposity with abdominal MRI.

Subjects and Protocol

Consecutive men (age ≥ 18 years) undergoing overnight polysomnography (PSG) at the Sleep Laboratory, Department of Medicine, Queen Mary Hospital, Hong Kong, have been prospectively recruited since October 2002 (except March to September 2003 when sleep laboratory services were suspended) to explore various cardiometabolic aspects in relation to OSA (OSACMS cohort). In the current study on CRP, subjects were recruited between October 2002 and April 2007. Exclusion criteria were history of hypertension, diabetes mellitus or hyperlipidemia on medications, atherosclerotic vascular diseases, and other chronic medical diseases; newly detected high BP with systolic BP > 160 mm Hg or diastolic BP > 95 mm Hg; fasting glucose ≥ 7.0 mmol/L; regular medications; acute illness in preceding 4 weeks; and BMI > 35 kg/m2.

All subjects completed a standardized questionnaire including the Epworth sleepiness scale (ESS) score, demographic data, and clinical history. After the PSG, a fasting blood sample was obtained in the morning for an assay of glucose and lipids and centrifuged for plasma, which was stored at −70°C for a subsequent batch assay of high-sensitivity CRP. MRI abdomen was done within 2 weeks of the PSG.40

The study was approved by the institutional review board of the University of Hong Kong and Hospital Authority Hong Kong. All subjects gave written informed consent.

Measurements

Anthropometric measurements were performed in the fasting state. BMI was calculated from body weight in kilograms divided by the square of height in meters. Waist circumference was measured at a level halfway between the lower rib margin and the iliac crest. BP was also measured (Dinamap; Critikon Inc; Tampa, FL). After resting for an hour, three BP measurements, each 1 min apart, were taken from each subject, and the average of the three readings was calculated.

PSG

Subjects underwent an overnight 16-channel PSG (Alice 3/5 Diagnostics System; Respironics; Murrysville, PA), which consisted of recording for EEG, electrooculography, electromyography, ECG, nasal pressure transducer, thermistor for nasal airflow, thoracic and abdominal impedance belts, pulse oximetry, tracheal microphone for snoring, and sensors for leg and sleep position. PSG recordings were manually scored by a single registered technologist as described previously.41 Apnea was defined as complete cessation of airflow for at least 10 s; hypopnea was defined as a reduction in airflow that was associated with at least a 4% drop in O2 saturation. OSA was defined by AHI ≥ 5/h.

High-Sensitivity CRP Assay

Plasma levels of high-sensitivity CRP were measured with a monoclonal antibody-based one-step immunoassay method as previously described.42 Plasma was diluted 1:200 before assay. Then 100 μL of diluted plasma, calibrators, and quality control samples were applied to 96-well microtiter plates coated with a monoclonal antibody specific to human CRP. After extensive washing, the captured antigens were detected by incubation with the detection monoclonal antibody conjugated with horseradish peroxidase for 30 min, followed by tetramethyl-benzidine reagent for 10 min. A total of 100 μL of 2 mol/L H2SO4 was added to each well to stop the reaction, and the absorbance at 450 nm was measured. The intraassay and interassay variations, as determined by measuring two different samples in 10 replicates in a single assay, or in duplicate in five consecutive assays, were 2.7 to 4.8% and 3.6 to 5.5%, respectively.

MRI for Abdominal Fat

Abdominal fat was characterized with MRI using a 1.5-T magnet (Signa Horizon LX; General Electric Medical Systems; Milwaukee, WI)40 in the morning, having fasted for at least 4 h. Four-slice parasagittal localizer scans were performed to locate the lumbar vertebra. Axial spin-echo scans (TR/TE 350/12 ms; slice thickness, 10 mm) were obtained from the inferior endplate of L1 to inferior endplate of L5. A total of 15 to 19 consecutive slices were obtained from each subject for interrogation of the visceral adipose tissue (VAT), subcutaneous adipose tissue, and total adipose tissue. Given the high grayscale variation within the image regions representing fat tissue and other tissues, the determination of an appropriate threshold of the signal intensity for fat was performed in each patient individually. The images were then segmented, and regions of interest of VAT were created and their respective areas measured using appropriate software (Analyze 7.0; Biomedical Imaging Resource; Mayo Clinic; Rochester, MN).

All adipose tissue pixels within the intraabdominal cavity at the innermost aspect of the abdominal and oblique wall musculature and the anterior aspect of the vertebral body were considered VAT. High-intensity nonfat pixels arising from fatty intestinal contents were avoided or manually removed when possible. These areas were multiplied by slice thickness and the products summated to get the volume of adipose tissue.

Statistical Analysis

Variables not in normal distribution were log-transformed (CRP, duration of O2 saturation < 90%, arousal index, high-density lipoprotein [LDL]), square-root transformed (AHI) or logit-transformed (minimal O2 saturation) to achieve normality, and subsequently analyzed with parametric tests. One-way analysis of variance was used to assess the difference between groups of different OSA severity. Pearson correlation was used to assess the linear association between continuous variables without adjustment and their residuals after adjustment for covariates including age, BMI, central obesity indexes (waist circumference, MRI visceral fat volume), sleep efficiency, and smoking status. Stepwise multiple regression analysis was performed with CRP as the dependent variable. Independent variables considered were age, waist circumference, BMI, MRI visceral fat volume, smoking status, sleep efficiency, AHI, arousal index, duration of O2 saturation < 90%, minimum O2 saturation, total cholesterol, LDL, high-density lipoprotein, and triglyceride levels. For case-control analysis, subjects were divided into two groups according to their OSA severity: those with no/mild OSA (AHI < 15 events/h) and those with moderate-to-severe OSA (AHI ≥ 15 events/h). Each no or mild OSA subject was matched with a moderate-to-severe OSA subject in terms of MRI visceral fat volume ± 10%. The comparisons of the two groups were made with the Student's t test for continuous data and χ2 test for categorical data. A p value of < 0.05 indicates significance. Statistical analysis was performed using a commercial software package (SPSS, version 15; SPSS; Chicago, IL).

The 129 men who fulfilled the inclusion criteria were recruited, and 18 subjects were further excluded from the analyses: exceedingly high triglycerides (n = 1), total sleep time < 240 min during PSG recording (n = 3), and 14 subjects did not undergo MRI measurement of abdominal fat. Ultimately, 111 men were included in the analysis. Table 1 shows the characteristics of these subjects by OSA severity. The mean age was 44.3 years (SD, 9.6 years), and the mean BMI was 26.3 (SD, 3.8). Waist circumference and MRI visceral fat volume were used as indexes of central obesity.

Table Graphic Jump Location
Table 1 Characteristics of Recruited Subjects by OSA Severity*

*Values represent mean (SD) or median (interquartile range) depending on the data distribution. HDL = high-density lipoprotein; SBP = systolic BP; DBP = diastolic BP. The groups were compared using one-way analysis of variance.

†p < 0.001.

By Pearson correlation, CRP was positively correlated with waist circumference (r = 0.47, p < 0.001), BMI (r = 0.38, p < 0.001) and MRI visceral fat volume (r = 0.32, p = 0.001). After adjustment for age, smoking, sleep efficiency, BMI, and waist circumference, CRP was positively correlated with AHI (r = 0.35, p < 0.001) [Fig 1], duration of O2 saturation < 90% (r = 0.29, p = 0.002), and arousal index (r = 0.32, p = 0.001), and it was negatively correlated with minimal O2 saturation (r = −0.28, p = 0.003). This significant correlation between CRP and PSG parameters was similar when MRI visceral fat volume substituted waist circumference as the confounding factor for adjustment: CRP was positively correlated with AHI (r = 0.35, p < 0.001), duration of O2 saturation < 90% (r = 0.30, p = 0.001), and arousal index (r = 0.28, p = 0.003), and it was negatively correlated with minimal O2 saturation (r = −0.29, p = 0.002).

Figure Jump LinkFigure 1 Log transformed CRP vs square-root AHI with adjustment for age, BMI, waist circumference, smoking, and sleep efficiency.Grahic Jump Location

In the stepwise multiple regression analysis, predictors of CRP levels included AHI (p = 0.001), waist circumference (p = 0.002), and triglycerides (p = 0.018; adjusted R2 = 0.33) [Table 2].

Table Graphic Jump Location
Table 2 Stepwise Multiple Regression Models of CRP*

*Independent variables considered: age, waist circumference, BMI, MRI visceral fat volume, MRI total fat volume, smoking status, sleep efficiency (logit-transformed before analysis), AHI (square root transformed before analysis), arousal index (log-transformed before analysis), duration of O2 saturation < 90% (log-transformed before analysis), minimum O2 saturation (logit-transformed before analysis), total cholesterol, LDL, high-density lipoprotein (log-transformed before analysis), and triglyceride levels.

In the matched control analysis, 32 pairs of subjects matched in MRI visceral fat volume were identified. Apart from visceral fat volume, there was also no significant difference between the two groups in age, BMI, waist circumference, and smoking status, but CRP levels were significantly higher in the group with AHI ≥ 15 events/h (p = 0.001) [Fig 2, Table 3].

Figure Jump LinkFigure 2 High-sensitivity CRP (hsCRP) in subjects with no or mild OSA (AHI, 15 events/h) and moderate-to-severe OSA (AHI, 15 events/h). The two groups were matched in MRI visceral fat volume. Boxes represent values within the interquartile range, whiskers represent the data range, and lines across the boxes represent the median values.Grahic Jump Location
Table Graphic Jump Location
Table 3 A Matched Comparison of Two Groups with AHI ≥ 15 and AHI < 15*

*Values are given as the mean (SD) or median (interquartile range). T90 = duration of O2 saturation < 90%. See Table 1 for abbreviations not used in the text.

†The groups were compared using the t test.

‡Log-transformed before analysis.

§Logit-transformed before analysis.

‖Square root transformed before analysis.

Our study demonstrates that CRP was elevated in men with moderate-to-severe OSA, independent of known confounders. CRP levels were linearly correlated with the severity of OSA as indicated by the frequency of apnea/hypopnea and arousals as well as the severity of O2 desaturation; AHI, waist circumference, and triglycerides levels were independent predictors of CRP levels.

Existing evidence indicate that atherosclerosis represents a chronic inflammatory process.2,3,43 CRP level is elevated in atherosclerosis as it is in other inflammatory diseases, although for large part in a much lower range (< 1 mg/L).13 In a cohort of 22,000 middle-aged men with no clinical evidence of disease, those with baseline levels of high-sensitivity CRP in the highest quartile (0.38 to 1.5 mg/dL) had a twofold increase in risk of stroke or peripheral vascular disease and a threefold increase in risk of myocardial infarction.9,44 In addition to being a cardiovascular prognostic marker, it is believed that CRP has a direct role in promoting atherosclerotic processes and endothelial dysfunction.4,5

Of note, the level of CRP is affected by various factors such as age, smoking, gender, and atherosclerotic disease and its risk factors.3,1720 The hepatic production of CRP is stimulated by interleukin-6, which is produced by adipose tissue.2126 Visceral adipocytes produce numerous cytokines that impose detrimental effects on vasculature. Hence, visceral obesity was most closely related to cardiovascular diseases and metabolic syndrome.2426 With the common occurrence of central obesity in OSA subjects, visceral obesity becomes an important confounder in the analysis of the independent association between OSA and CRP. Quantification of visceral fat volume by MRI will be complementary to the one-dimensional waist circumference measurement and allow more adequate adjustment of the effect of obesity on CRP level.

The literature regarding CRP levels in OSA has been controversial. A careful perusal of the literature has shown that a number of the studies3439 have included subjects with comorbidities that may give rise to elevated CRP, and there was usually inadequate quantification of obesity status. A cross-sectional study34 with > 200 subjects recruited from the community did not find any association between CRP and severity of OSA after adjustment for obesity (BMI), but the CRP assay had a range 1 to 120 mg/L, and no adjustments for hypertension or smoking were performed. Another study35 that did not adjust for hypertension or smoking reported that CRP was positively correlated with AHI, but the relationship became insignificant after adjustment for BMI. A case-control study38 with approximately 30 subjects in each group found no significant difference in CRP levels among the non-OSA group, the mild-to-moderate OSA group, and the severe OSA group, although it did find a correlation between CRP level and AHI. The negative findings could be due to underpowering in the sample size. The prospective cohort study39 carried out in India did not take measures of central obesity into analytical consideration.

A number of previous works2733 have demonstrated an independent relationship between OSA and an elevated CRP, including several studies using matched case-control analysis. It was first reported with positive findings in a study31 of 22 otherwise healthy OSA subjects, with significantly elevated CRP levels as compared to 20 healthy control subjects matching for age and BMI. In a study32 comparing OSA subjects with obese controls, CRP and interleukin-6 levels were found to be elevated in patients with OSA, and both markers were decreased by continuous positive airway pressure. In this study, patients with mild OSA and moderate-to-severe OSA were compared with similarly obese control subjects, but the inclusion of patients with hypertension, diabetes mellitus, and cardiovascular diseases had complicated the interpretation of the results. Recently, another positive study27 recruited a group of male subjects free of prevalent medical diseases. Cautious statistical manipulation was undertaken to ameliorate the effects of confounders including age, BMI, waist circumference, percentage body fat, and total sleep time. The major limitations of the study were the inclusion of relatively obese subjects (mean BMI, 31.2 kg/m2; range, 20.3 to 51.9 kg/m2) and the lack of precise quantification of visceral fat, which could both render adjustment of the confounding effects from obesity incomplete. In our study, those with extreme obesity (BMI > 35 kg/m2) were excluded, and visceral obesity quantified by MRI was meticulously included in the analysis.

The relationship between CRP and OSA has also been investigated in pediatric subjects, where the issue of coexistent adiposity is less problematic. One study45 found no difference in CRP between nonsnoring children, snoring children without OSA, and children with OSA of differing degrees of severity. Another study,46 which recruited > 1,000 children living in the community, reported that CRP level was elevated in those with OSA, which was associated with neurocognitive deficits. A recent prospective cohort study47 demonstrated a reduction of CRP in both obese and nonobese prepubertal children with OSA after adenotonsillectomy. However, the controversy continues because CRP levels in children may be confounded by the common presence of inflamed tonsils.

Our study is limited by its cross-sectional nature, and the potential causal relationship between OSA and elevated CRP level cannot be concluded. The effects of treatment of OSA on CRP levels have been investigated in a few open studies,33,40,48,49 and results again were conflicting. A randomized controlled trial50 in 2007 demonstrated an improvement in signs of atherosclerosis including CRP after continuous positive airway pressure treatment for 4 months. The demonstration of decrement of CRP levels after effective treatment of OSA can certainly consolidate the contributing role of OSA to an elevated CRP level, but the finding may not be always consistent because adverse cardiovascular complications due to OSA may not be fully reversible. Furthermore, our findings cannot be generalized to women. Previous studies13 have shown that gender affects the relationship between CRP and anthropometric variables, and large-scale epidemiologic studies in the United States have reported that a given level of CRP is translated into a different relative risk of cardiovascular morbidity in men as compared to women. Thus, the inclusion of solely male subjects in our study simplifies the interpretation of the results, at the expense that it may not be applicable to women.

Our finding of elevation of CRP levels in apparently healthy OSA subjects may indicate the risk of developing cardiovascular disease or the presence of subclinical atherosclerosis, both of which may benefit from timely effective treatment of OSA. The clinical utility of CRP assay for cardiovascular risk stratification in OSA patients and its potential use to guide treatment of OSA are important areas requiring further rigorous research.

AHI

apnea-hypopnea index

BMI

body mass index

CRP

C-reactive protein

ESS

Epworth sleepiness scale

LDL

low-density lipoprotein

OSA

obstructive sleep apnea

PSG

polysomnography

VAT

visceral adipose tissue

The authors would like to thank Ms. Agnes Lai for project coordination and statistical assistance, Ms. Pui Pui Ku for manual scoring of polysomnograms, and Messrs. Mark Yeung and Samuel Tang for management of MRI data and overall data entry.

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Gozal D, Capdevila OS, Kheirandish-Gozal L. Metabolic alterations and systemic inflammation in obstructive sleep apnea among nonobese and obese prepubertal children. Am J Respir Crit Care Med. 2008;177:1142-1149. [PubMed]
 
Akashiba T, Akahoshi T, Kawahara S, et al. Effects of long-term nasal continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea syndrome. Intern Med. 2005;44:899-900. [PubMed]
 
Steiropoulos P, Tsara V, Nena E, et al. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest. 2007;132:843-851. [PubMed]
 
Drager LF, Bortolotto LA, Figueiredo AC, et al. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;176:706-712. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Log transformed CRP vs square-root AHI with adjustment for age, BMI, waist circumference, smoking, and sleep efficiency.Grahic Jump Location
Figure Jump LinkFigure 2 High-sensitivity CRP (hsCRP) in subjects with no or mild OSA (AHI, 15 events/h) and moderate-to-severe OSA (AHI, 15 events/h). The two groups were matched in MRI visceral fat volume. Boxes represent values within the interquartile range, whiskers represent the data range, and lines across the boxes represent the median values.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Characteristics of Recruited Subjects by OSA Severity*

*Values represent mean (SD) or median (interquartile range) depending on the data distribution. HDL = high-density lipoprotein; SBP = systolic BP; DBP = diastolic BP. The groups were compared using one-way analysis of variance.

†p < 0.001.

Table Graphic Jump Location
Table 2 Stepwise Multiple Regression Models of CRP*

*Independent variables considered: age, waist circumference, BMI, MRI visceral fat volume, MRI total fat volume, smoking status, sleep efficiency (logit-transformed before analysis), AHI (square root transformed before analysis), arousal index (log-transformed before analysis), duration of O2 saturation < 90% (log-transformed before analysis), minimum O2 saturation (logit-transformed before analysis), total cholesterol, LDL, high-density lipoprotein (log-transformed before analysis), and triglyceride levels.

Table Graphic Jump Location
Table 3 A Matched Comparison of Two Groups with AHI ≥ 15 and AHI < 15*

*Values are given as the mean (SD) or median (interquartile range). T90 = duration of O2 saturation < 90%. See Table 1 for abbreviations not used in the text.

†The groups were compared using the t test.

‡Log-transformed before analysis.

§Logit-transformed before analysis.

‖Square root transformed before analysis.

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Akashiba T, Akahoshi T, Kawahara S, et al. Effects of long-term nasal continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea syndrome. Intern Med. 2005;44:899-900. [PubMed]
 
Steiropoulos P, Tsara V, Nena E, et al. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest. 2007;132:843-851. [PubMed]
 
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