Metabolic Syndrome Osa

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Metabolic syndrome, insulin resistance,fibrinogen, homocysteine, leptin, and C-reactiveprotein in obese patients with obstructive sleep

apnea syndromeOzen K. Basoglu, Fulden Sarac,1Sefa Sarac,2Hatice Uluer,3andCandeger Yilmaz!ut"or information #!rticle notes #Co$%rig"t and &icense information #'"is article "as (eencited (%ot"er articles in )*C.

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AbstractOBJEC!"E#

The prevalence of obstructive sleep apnea syndrome (OSAS)

and metabolic syndrome is increasing worldwide, in part linked

to epidemic of obesity. The purposes of this study were to

establish the rate of metabolic syndrome and to compare

fibrinogen, homocysteine, highsensitivity !reactive protein

(hs!"#), leptin levels, and homeostasis model assessment

insulin resistance ($O%A&") in the obese patients with and

without OSAS.

ME$O%

The study population included ' consecutive obese patients

with OSAS (' males* mean age, +. -/.0 years), and '1

obese patients without OSAS (0 males* mean age, 1/.0-.

years) were enrolled as control group. %etabolic syndrome was

investigated* fibrinogen, homocysteine, !"#, and leptin levels

were measured, and &" was assessed.

'E&()

%etabolic syndrome was found in 0 (10.2) obese OSAS

patients, whereas only /.12 of obese sub3ects had metabolic

syndrome (P4 .+). Obese patients with OSAS had

significantly higher mean levels of triglyceride (P5 .),

totalcholesterol (P6 .'), lowdensity lipoproteincholesterol

(P6 .), fasting glucose (P6 .), $O%A&" (P5.),

thyroidstimulating hormone (P6 .'), fibrinogen (P5 .'),
http://www.ncbi.nlm.nih.gov/pubmed/?term=Basoglu%20OK%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Sarac%20F%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Sarac%20S%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Uluer%20H%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Yilmaz%20C%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131753/citedby/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131753/citedby/http://www.ncbi.nlm.nih.gov/pubmed/?term=Sarac%20F%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Sarac%20S%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Uluer%20H%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/?term=Yilmaz%20C%5Bauth%5Dhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131753/citedby/http://www.ncbi.nlm.nih.gov/pubmed/?term=Basoglu%20OK%5Bauth%5D


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hs!"# (P5.), and leptin (P6 .') than control group .

7esides, leptin level was positively correlated with waist (r6

.+,P6 .') and neck circumferences (r6 .+10,P6 .'),

and fasting glucose (r6 .10,P6 .1) in OSAS patients, but

not in obese sub3ects.

CO*C)(&!O*#

This study demonstrated that obese OSAS patients may have an

increased rate of metabolic syndrome and higher levels of serum

lipids, fasting glucose, &", leptin, fibrinogen, and hs!"# than

obese sub3ects without sleep apnea. Thus, clinicians should be

encouraged to systematically evaluate the presence of metabolic

abnormalities in OSAS and vice versa.

Keywords: !reactive protein, fibrinogen, homocysteine,

insulin resistance, leptin, metabolic syndrome, obesity,

obstructive sleep apnea syndrome

Obstructive sleep apnea syndrome (OSAS) is a common

disorder that has a ma3or impact on public health.891: #atients

with obstructive sleep apnea (OSA) have abnormalities in each

of the components of the metabolic syndrome;high bloodpressure, high fasting glucose, increased waist circumference,

low highdensity lipoprotein ($


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protein (hs!"#) with OSAS show conflicting results. Some

studies have reported significant relationship,8@9: whereas

others have not.8'9+: &n one study, the very severe OSAS

group had significantly higher homeostasis model assessment of

&" ($O%A&") and $O%A betacell function than other OSAS

groups and the control group.8: The relationship of OSAS

with &" may be the pathway that leads to increased risk for the

development of cardiovascular disease in these patients. The

mechanisms involved in the association between OSAS and

cardiovascular diseases are actually comple> and very diverse.

These also include episodic hypo>iareo>ygenation, tonic

elevation of sympathetic neural activity, and endothelial

dysfunction as well as hypercoagulability, o>idative stress, and

inflammation. $ypercoagulability resulting from imbalance

between coagulation and fibrinolysis is associated with an

increased risk for cardiovascular disease. A variety of findings

support the e>istence of a relation between hypercoagulability,

OSAS, and cardiovascular disease. #atients with OSAS have

elevated plasma fibrinogen levels, e>aggerated platelet activity,

and reduced fibrinolytic capacity. Although not consistently

shown, severity of OSA and plasma epinephrine wereindependent predictors of platelet activity, and average minimal

o>ygen saturation was an independent predictor of fibrinogen.

These findings suggest that severity of intermittent nocturnal

hypo>emia may contribute to procoagulant disturbances in

OSA. &n some studies, treatment with continuous positive

airway pressure decreased platelet activity, plasma fibrinogen

levels, and activity of clotting factor &&.80,@: !onversely,

Steiropoulos et al.8/: failed to demonstrate a difference infibrinogen levels between obese individuals with or without

OSAS, suggesting that the presence of OSAS probably does not

play an important role in the upregulation of fibrinogen levels.

$omocysteine levels are also associated with an increased

cardiovascular risk and may be a predictor of longterm

prognosis following premature myocardial infarction.

$omocysteine levels have previously been reported to be raised

in patients with OSA, but only in patients with associated


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ischemic heart disease andBor hypertension, and severe OSAS.

89: 7esides, it has been observed that OSAS patients have

increased leptin and !"# levels and &",8': indicating a

possible role in the pathogenesis of cardiovascular morbidity.

There were no much studies related to the incidence of

metabolic syndrome and levels of fibrinogen, homocysteine,

hs!"#, leptin, and &" in obese patients with OSAS and obese

patients without sleepdisordered breathing. $owever,

identifying possible risk factors involved in cardiovascular

morbidity is of great clinical importance in OSA. The

measurement of circulating cardiovascular risk factors

(including several new phenotypic markers of cardiovascular

disease) enables a more accurate prediction of cardiovascular

risk to be made, as there are clearly established relationships

between levels of various circulating haemostatic risk factors

and a subseCuent cardiovascular event. Therefore, the purposes

of this study were to assess the rate of metabolic syndrome and

its related components, and to compare the fibrinogen,

homocysteine, hs!"#, and leptin levels and &" in obese patients

with and without OSAS.

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MethodsThe study population consisted of ' consecutive obese patients

with OSAS (' males* mean age, +. - /.0 years 81+0

years:). Thirtyfour obese patients without OSAS (0 males*

mean age, 1/.0 - . years 811/ years:) were enrolled as a

control group. 7ody mass inde> (7%&) of the patients in the

study and control groups were similar (''.+ - +.0 kgBmand'1.+ - ./ kgBm, respectively,P6 .'). The study and control

groups were matched for age, gender, and 7%&. The sub3ects of

the control group were selected among patients who were

admitted to The &nternal %edicine Outpatient !linic for various

reasons and matched randomly to OSAS patients using a

computed techniCue. They were all Cuestioned in details by the

same doctor who was e>perienced in sleep medicine (OD7), and

none of them had symptoms related to OSAS. Obese patientswith any symptoms of OSAS were e>cluded from the control


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group of the study. The local ethics committee approved the

study and all sub3ects gave informed consent. %etabolic

syndrome was defined as in AT# &&&.81:

Anthropometric measurements were evaluated in all groups.$abitual alcohol consumption for each sub3ect was ascertained

based on the following two CuestionsE Fygen saturation.

Thoracoabdominal plethysmograph, oronasal temperature

thermistor and nasalcannulapressure transducer system were

used to identify apneas and hypopneas. Transcutaneous finger

pulse o>imeter was used to measure o>ygen saturation. Sleep

was recorded and scored according to the standard method.80:


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An apnea was defined as a total cessation of airflow for N

seconds. $ypopnea was defined as a reduction in airflow with a

+2 from baseline for at least seconds, a '2 drop in o>ygen

saturation from the preceding stable saturation, andBor arousal.

Apneahypopnea inde> (A$&) was the sum of the number of

apneas and hypopneas per hour of sleep. OSAS was defined as

an A$& of + eventsBh and the presence of clinical symptoms,

e.g., e>cessive daytime sleepiness, loud snoring, witnessed

apneas, and nocturnal choking or A$& of + eventsBh without

any OSAS symptoms.8@: 7esides, an A$& of 5+ eventsBh

considered within normal limits, and numbers of ++, +',

and 4' representing mild, moderate, and severe OSAS,

respectively.

Biochemical analysis

Serum concentrations of glucose, triglyceride, total and $


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('.) packaged software. Iumerical variables were

summariLed with mean - ST< deviation. 7aseline data were

compared using oneway analysis of variance (AIOA).

ariables with skewed distribution were transformed into

logarithms before all analyses. #earson correlation coefficients

were calculated to identify associations of clinical variables. The

correlations among the groups were e>amined using the

stepwise regression analysis. A value ofP5 .+ was considered

significant for all statistical analysis.

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'esults

The characteristics and clinical findings of the study and controlgroups are shown in Table . Obese patients with OSAS had

higher mean systolic and diastolic blood pressure, and neck

circumference compared with obese without OSAS (P5 .,

P6 .,P6 .', respectively).

Table

!haracteristics and clinical findings of obese patients with

and without OSAS

Among OSAS patients, '.2 were smokers and @@./2

informed alcohol consumption, whereas +.2 of obese patients

without OSAS were smokers and only +.2 of them consumed

alcohol (P6 .1,P6 .). Of ' OSAS patients, + ('./2)

had a history of cardiovascular disease, @ (+.2) had

dyslipidemia, (+.+2) had stroke, 1 ('@./2) had hypertension,

and 0 (/.12) had diabetes mellitus. &n control group, ' (@.@2)

had family history of cardiovascular disease, 0 (.2) had

dyslipidemia, / (.+2) had hypertension, and ' (@.@2) had

glucose metabolism disorders.

#ulmonary function tests, arterial blood gas analysis, andpolysomnography were evaluated in OSAS patients and are
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131753/table/T1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131753/table/T1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131753/table/T1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131753/table/T1/


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shown in Table . The mean MSS was significantly higher in

OSAS patients than the control group (./ - . vs 1. - ./,P

6 .).

Table

Spirometry, bloo

and polysomnogr

of OSAS patients

%etabolic syndrome was found in 0 (10.2) obese patients

with OSAS, whereas only (/.12) obese sub3ects had

metabolic syndrome. $owever, the difference between groups

was not statistically significant. The biochemical analyses of

two groups were compared with each other. Obese patients with

OSAS had significantly higher mean levels of triglyceride (P5

.), totalcholesterol (P6 .'), lowdensity lipoprotein

(=


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7lood profiles of obese patients with and without OSAS&n obese

patients with OSAS, waist circumference was positively

correlated with mean levels of $O%A (r6 .@0',P6 .), and

neck circumference was negatively correlated with $


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in the metabolic syndrome and OSAS are similar. The

pathogenesis of cardiovascular disease in OSAS is not

completely understood but likely to be multifactorial, involving

a diverse range of mechanisms including sympathetic nervous

system overactivity, o>idative stress, selective activation of

inflammatory molecular pathways, endothelial dysfunction,

abnormal coagulation, and metabolic dysregulation, the latter

particularly involving &" and disordered lipid metabolism. The

factors that may contribute to metabolic dysregulation in OSAS

also include sleep fragmentation, increased sympathetic activity,

and intermittent hypo>ia.8': &n addition, dyslipidemia and

adipose tissue dysfunction caused by &" and obesity also

contribute to the development of vascular risk factors and

cardiovascular disease in metabolic syndrome.8': The patients

with OSAS appear to suffer from the disorders which

characteriLe the metabolic syndrome, and have hypertension,

high fasting blood glucose levels, increased waist

circumference, low $


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respiratory events with &" was entirely dependent on body mass.

&p et al.8': showed that in sub3ects with OSAS, obesity was the

primary determinant of &" and noted that sleep apnea had an

independent but smaller effect. Rhang et al.8'0: found that after

ad3ustment for age, 7%&, and waisttohip ratio, OSAS group

was more insulin resistant, as indicated by the higher levels of

A$& and $O%A&". &n our study, mean level of $O%A&" in

obese OSAS patients was higher than obese sub3ects without

sleep apnea, but A$& was not associated with $O%A. Also, in

patients with OSAS, waist circumference was positively

correlated with mean levels of $O%A.

=eptin is a multiplefunction adipocytederived cytokineinvolved in the pathogenesis of obesity and increased

cardiovascular risk. #reviously, leptin levels in OSAS were

investigated in many studies.8,,': &t was shown that leptin

was significantly higher in OSAS patients compared with those

in nonOSAS control sub3ects with similar 7%&, age, and

gender. Serum leptin levels were positively correlated with 7%&,

skinfold thickness, A$&, and percentage of sleep time with SaO

5 /2.8'@: Krsavas et al.8'/: also found a positive correlationbetween serum leptin levels and 7%& in OSAS patients. &n the

present study, leptin levels were significantly higher in OSAS

patients than obese sub3ects. 7esides, leptin was positively

correlated with fasting glucose, waist and neck circumferences

in OSAS patients, but not in the control group.

Although the e>act cause that links OSA with cardiovascular

disease is unknown, there is evidence that OSA is associated

with a group of proinflammatory and prothrombotic factors that

have been identified as important in the development of

atherosclerosis. #resence of high !"# and fibrinogen levels

were associated with increased risk of cardiovascular and

cerebrovascular mortality in OSAS patients. !"# is a sensitive

marker for systemic inflammation. An elevated plasma level of

this acutephase reactant indicates heightened activity of

inflammation in human beings. Also, it is a surrogate marker of

lowgrade inflammation linked to obesity. &n many studies,


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obesity is correlated with elevated serum !"#.8191: Hokoe et

al.81': found that !"# was significantly higher in ' patients

with newly diagnosed OSA than 1 obese sub3ects and there was

a relationship between OSAS severity and !"# levels.

Similarly, ShamsuLLaman et al.811: showed that !"# levels

were higher in OSAS patients when compared with

control sub3ects. The groups were matched for age, and

importantly, 7%&. Similarly, in our study, mean levels of hs!"#

were significantly higher in OSAS patients than the control

group. 7esides, we found a significant increase in terms of mean

levels of fibrinogen in sleep apnea patients, which was

compatible with the literature.8@,1+:

The role of plasma homocysteine levels in OSAS is unclear,

with some studies reporting higher levels only in OSAS patients

suffering from pree>isting cardiac disease and other reports

identifying homocysteine levels to be independently associated

with OSAS.8191@: HavuL et al.8: suggested that

homocysteine might be an important factor for the development

of cardiovascular disease in patients with OSAS. $owever, we

did not find any difference related to homocysteine levelsbetween obese patients with and without OSAS.

Our study had limitations which warrant discussion. irst, the

numbers of sub3ects in the study and control groups were

somehow small. %etabolic syndrome was higher in OSAS

patients, but the difference was not significant probably because

of sample siLe. Second, obese patients without OSAS did not

undergo polysomnography as the waiting list of our sleep

laboratory was Cuite long and it was very difficult to perform

polysomnography even to the patients with obvious OSAS

symptoms. $owever, they were all Cuestioned in details and

none of them had symptoms related to OSAS and no e>cessive

daytime sleepiness measured by MSS. inally, it would be better

to include obese patients without any comorbidity in the study in

order not to confound the effects of these diseases. $owever, it

should be noted that it is really very difficult to find obese

sub3ects without any diseases.


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&n conclusion, the present study demonstrated an increased rate

of metabolic syndrome in obese OSAS patients when compared

with obese sub3ects without OSAS. &t was also shown that

patients with OSAS had higher levels of serum lipids, fasting

glucose, &", leptin, fibrinogen, and hs!"# than obese without

sleep apnea. The prevalence of both OSAS and metabolic

syndrome is increasing worldwide, in part linked to the

epidemic of obesity. 7eyond their epidemiologic relationship,

growing evidence suggests that OSAS may be causally related

to metabolic syndrome. Thus, clinicians should be encouraged

to systematically evaluate the presence of metabolic

abnormalities in OSAS and vice versa.

Metabolic Syndrome Osa

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