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Table S1 Search
Database Search
Cochrane (March 20, 2014)
EMBASE (1974-March 20, 2014)
MEDLINE (1948-March 20, 2014)
PubMed (March 20, 2014)
(sleep apnea or sleep apnoea or sleep apnea, obstructive or obstructive
sleep apnea or obstructive sleep apnoea) and (exhaled condensate
biomarker* or salivary biomarker* or urinary biomarker* or blood
biomarker* or serum biomarker* or biomarker*)
LILACS (March 20, 2014) "apnea" or "apneia" and "marcadores biologicos"
Google Scholar (March 20, 2014) “biomarkers and sleep apnea” (without patents or citations)
1
Table S2
Excluded articles and reasons for exclusion (n=26).
Author, year Reasons for
exclusion
Bratel et al 1999 15 6
Calvin et al 2010 16 1
Cholidou et al 2013 17 2
Culla et al 2010 18 2
El-Solh 2002 19 2
Gozal et al 2007 20 2
Gozal et al 2010 21 2
Khalyfa et al 2011 22 3
Kim et al 2012 23 2
Kishida et al 2014 24 8
Lin et al 2013 25 5
Loubaki et al 2008 26 7
Makino et al 2006 27 7
Osorio et al 2014 28 2
Oyama et al 2012 29 2
Patel et al 2009 30 4
Przybylowski et al 2006 31 5
Roche et al 2009 32 2
Rubinsztajn et al 2006 33 5
Salord 2014 34 2
Staats et al 35 4
Uysal et al 2014 36 2
2
Van Hoorenback 2012 37 6
Wang et al 2005 38 5
Wang et al 2010 39 2
Wang et al 2012 40 4
1-Central apnea, 2-OSA with morbidities, 3- Not OSA patients, 4-Different target condition, 5- Not English,
Spanish or Portuguese, 6-Not full overnight PSG, 7-Not biomarkers study, 8- Review.
3
Table S3
Complementary information regarding included pediatric articles (n=35).
Year Author Findings Main Conclusion
2002 Gozal et al 42 Serum VEGF concentrations of >100 pg/ml were weakly predictive of OSA. Circulating VEGF levels were frequently
elevated in OSA.
2004 Tauman et al 43 CRP levels were significantly higher in the OSA group. Plasma CRP levels were increased in OSA
and correlated with AHI.
2005 Kaditis et al 61 Insulin and HOMA index values were similar in children with AHI≥5 and with
AHI<5 (P>0.05).
Severity of OSA was not a significant
predictor of fasting insulin or HOMA index
values.
2005 Larkin et al 44 CRP levels varied with increasing BMI and OSA. AHI≥5 was associated with increasing
levels of CRP.
2006 Goldbart et al 45 LTB4 and cys-LT (LTC4/LTD4/LTE4) levels were elevated in OSA when
compared to mild OSA and control. PGE2 concentrations were similar among
the three groups.
Increases in leukotriene concentrations
may be a noninvasive tool in the clinical
assessment.
2006 Kheirandish-
Gozal et al 46
Mean initial CRP levels decreased after adenotonsillectomy (P < 0.05). OSA is frequently associated with increases
in CRP levels that are reversible upon
treatment.
2006 Krishna et al 47 Gelsolin, perlecan are differentially expressed in urine of OSA children. Increased expression of gelsolin and
4
perlecan in the urinary proteome of OSA
children could potentially serve as
biomarker.
2006 Li et al 66 Moderate to severe OSA group had significantly greater fasting insulin levels
and HOMA compared to the other two groups.
OSA is prevalent in obese children with HS
and insulin is independently associated with
the condition.
2006 Montgomery-
Downs et al 48
IsoP-m values were unrelated to any polysomnographic measures. Oxidative stress is not a significant feature
of pediatric OSA.
2006 O’Brien et al 49 P-selectin levels were significantly higher in the OSA group and the mild OSA
group when compared to control.
OSA children have plasma elevations of P-
selectin. Elevations in ICAM-1 are primarily
associated with obesity rather than OSA.
2006 Shah et al 50 Proteomic patterns were capable of diagnosing OSA with 93% sensitivity and
90%specificity.
Proteomic profiling of serum samples in
OSA children revealed differential
expression of circulating proteins that may
provide useful future diagnostic
approaches.
2007 Kaditis et al 62 Overnight change in cICAM-1 was similar in OSA children compared to those
with mild OSA or to children with an index less than or equal to 1 (P>0.05).
Overnight change in cICAM-1 levels was
not related with severity of OSA.
2007 Tauman et al 51 Log leptin concentrations were significantly lower in controls (P = 0.006) and
in children with SpO2 nadir ≥90% than children with SpO2 nadir <90%, even
OSA and associated hypoxemia may
5
after controlling for BMI z score (P<0.03). No significant differences were
found in log resistin levels as a function of obesity or AHI. Significant
correlations between log adiponectin levels and log Insulin/Glucose (I/G)
ratios (-0.28, P = 0.006) and between log leptin levels and log I/G ratios (r =
0.66, P<0.0001) emerged.
contribute to the elevation of leptin levels.
2008 Gozal et al 52 IL-6 levels were higher and IL-10 plasma levels were lower in OSA. They
returned to control levels after tonsillectomy and adenoidectomy surgery.
Systemic inflammation is a consequence of
OSA, even in the obesity absence, and is
reversible upon treatment.
2008 Li et al 68 Moderate OSA (OAI>5) had significantly higher CRP levels compared to non-
OSA (P=0.01). OAI was independently associated with CRP (P=0.001).
Sixteen children underwent treatment and there was significant reduction in
their serum CRP after intervention [P=0.033]. A significant correlation was
also demonstrated between change in CRP and change in OAI following
treatment for OSA.
OSA children may have associated
systemic inflammation as reflected by a
raised CRP that decreased significantly
following treatment.
2009 Gozal et al 53 Combinatorial approaches indicated that the presence of values beyond the
calculated cutoff concentrations for 3 or more of the proteins yielded a
sensitivity of 95%and a specificity of 100%.
Pediatric OSA is associated with specific
and consistent alterations in urinary
concentrations of specific proteins.
2009 Kaditis et al 63 Moderate-to severe OSA had higher log-transformed urine Cys-LTs levels
than those with mild OSA, PS, or control (P < 0.05).
Urine excretion of Cys-LTs is related to
pediatric OSA severity.
6
2009 Kaditis et al 64 Children with severe hypoxemia had significantly higher log-transformed
norepinephrine levels compared to those with moderate hypoxemia (P<0.05)
or compared to controls (P<0.05).
Severity of nocturnal hypoxemia in children
with intermittent upper airway obstruction
during sleep correlates with morning urine
levels of norepinephrine suggesting
increased sympathetic tone.
2010 Kim et al 54 Plasma log MRP8/14 levels showed AHI dose-dependent increases
regardless of obesity. Log MRP8/14 levels correlated with log AHI (P<0.001)
after controlling for age and body mass index Z-score, and with endothelial
function.
Plasma MRP8/14 levels were associated
with OSA.
2010 Li et al 67 OSA children did not have significantly different adiponectin and leptin
concentrations than non-OSA for both the obese and non-obese groups.
Systolic BP, age, high-density lipoprotein cholesterol, and BMI z -score were
independently associated with adiponectin, whereas diastolic BP, triglyceride,
height, and BMI z -score were independently associated with leptin
concentration.
BMI rather than OSA was the main
determinant of adipokines.
2011 Bhushan et al 55 Morning plasma FABP4 levels were increased in OSA children. Of the 11
SNPs tested, the frequency of rs1054135 (A/G) minor allele (A) was
significantly increased in OSA and obese subjects.
Childhood obesity and OSA are associated
with higher plasma FABP4 levels and thus
promote cardiometabolic risk.
2012 DeBoer et al 41 Sleep study parameters hsCRP or ΔhsCRP overnight. The degree of insulin resistance correlated
7
significantly with increased overnight
increase in hsCRP, while measures of
oxygen desaturation and AHI were not
correlated.
2012 Khalyfa et al 56 Morning plasma MIF levels were increased in OSA children. Of the 28 SNPs
tested, the frequency of rs10433310 minor allele was significantly decreased
in OSA. The minor allele frequency of all other 27 SNPs was similar in OSA
and non-OSA groups.
Pediatric OSA is associated with higher
plasma MIF, hsCRP, and fasting insulin
levels that promote cardiometabolic risk,
and the MIF gene SNP rs10433310 may
account for some of the variance in such
risk.
2012 Malakasioti et al
65
Children with moderate-to-severe OSA had higher log-transformed H2O2
concentrations compared to mild OSA, or to control. No significant
differences were demonstrated between the three study groups in terms of
EBC NOx levels.
Children with moderate-to-severe OSA
have increased H2O2 levels in morning
EBC, an indirect index of altered redox
status in the respiratory tract.
2012 Stefanini et al 74 Hemoglobin, hematocrit, and HDL were all significantly higher in the Snore
group when compared to the OSA group. VLDL levels were higher in the
OSA group. There was no statistical difference between the groups based on
OSA severity.
Non-obese OSA children present no
significant alterations in metabolic tests or
BP levels.
2013 Benedek et al 75 EBC pattern of OSA was discriminated from control (P = 0.03) EBC biomarker pattern can be
8
distinguished in OSA from HS.
2013 Gozal et al 57 OSA children and abnormal endothelial function had significantly lower
adropin concentrations compared with controls (P < 0.001) and OSA children
and normal endothelial function (P < 0.001). Individual adropin concentrations
were not significantly correlated with age, BMI z-score, obstructive AHI, or
nadir oxygen saturation. Mean adropin concentration measured after
adenotonsillectomy in a subset of OSA children showed an increase in the
OSA+/ EF+ group (P < 0.01), but essentially no change in the OSA+EF-
group (P > 0.05).
Plasma adropin concentrations are reduced
in pediatric OSA when endothelial
dysfunction is present, and return to within
normal values after adenotonsillectomy.
Assessment of circulating adropin
concentrations may provide a reliable
indicator of vascular injury.
2013 Kheirandish-
Gozal et al 58
Overnight increases in epinephrine, norepinephrine, and GABA levels
emerged in children with OSA; taurine levels decreased. Using combinatorial
approaches and cutoff values for overnight changes of these four
neurotransmitters enabled prediction of OSA (p< .0001). GABA and taurine
alterations, as well as overnight reductions in phenylethylamine, were more
prominent in OSA children.
Increases in GABA levels and decreases in
taurine levels could underlie mechanisms of
neuronal excitotoxicity and dysfunction.
Combinatorial approaches using defined
cutoffs in overnight changes in
concentrations of selected
neurotransmitters in urine may predict OSA.
2013 Kim et al 59 OSA children had significantly higher TREM-1 and pentraxin-3 levels versus
controls: P< 0.01, P< 0.05, respectively).
Plasma TREM-1 and pentraxin-3 levels are
elevated in pediatric OSA.
2013 Park et al 69 m-sCor significantly decreased with OSA severity. This decrease resulted in
a r-sCor that was significantly different between the control group and the two
Salivary cortisol may be a useful biomarker
9
OSA subgroups. n-sCor did not show a significant change with OSA severity of OSA.
2014 Jeong et al 70 Postoperative m-sCor, the difference of cortisol level (sub-sCor: m-sCor
minus n-sCor), and the ratio of cortisol level (r-sCor: m-sCor/n-sCor) showed
significant difference postoperatively.
Tonsil and adenoid surgery can normalize
disturbed cortisol secretion. Assessment of
salivary cortisol in OSA children may be a
useful tool for postoperative management
planning and follow-up.
2014 Kheirandish-
Gozal 60
Non-obese controls had the lowest levels of LBP, and the presence of obesity
without OSA was associated with significant LBP increases. Non-obese
children with OSA exhibited increased LBP levels, with obese children with
OSA demonstrating the highest LBP levels of all four groups.
Systemic low-level endotoxemia and
resultant systemic inflammation is present
in children who are either obese or suffer
from OSA and is particularly prominent
when both conditions are present.
Disrupted sleep and other factors facilitating
obesity such as a high-fat diet may disrupt
the gut microbiome and lead to increased
systemic LPS levels with resultant
inflammation, promoting downstream
metabolic dysfunction.
2014 Park et al 71 The sAA subtraction and ratio (P = 0.014 and P < 0.001, respectively) were
significantly higher in severe OSAS than in the mild/moderate and control
Screening test of sAA in children suspicious
of having sleep disorderd breathing may be
10
groups. Although ODI and AHI were significantly associated with sAA, sAA in
the OSAS group was not related to lowest oxygen saturation or
adenotonsillar hypertrophy
used as a helpful tool to identify those with
OSA, when PSG cannot be available.
2014 Patacchioli et al
72
Compared with controls, both mild and moderate to severe OSA children
showed: increased salivary cortisol diurnal production, and no changes in a-
amylase diurnal trajectory and production. Morning salivary cortisol
concentrations were negatively associated with the disease severity in the
moderate to severe OSA group.
Pediatric OSA is associated with
dysregulation of the HPA axis activity.
2014 Villa et al 73 Urinary 8-isoprostane levels were significantly higher in the group with AHI of
≥5 than in the group with AHI of <5 (P<0.01).
Urinary 8-isoprostane may be used as a
specific inflammatory marker to predict
OSA severity.
* All terms that mean obstructive sleep apnea (SDB, SRDB, OSAS) were standardized as OSA.
Abbreviations
AHI=apnea/hypopnea index, BMI=body mass index, BP=blood pressure, cICAM-1=circulating intercellular adhesion molecule 1, CRP=C reactive protein, Cys-
LTs=cysteinyl leukotrienes, EBC=exhaled breath condensate, FABP4=fatty acid binding protein 4, GABA=y–aminobutyric acid, H2O2=hydrogen peroxide,
HDL=high density lipoprotein, HOMA=homeostatic model assessment, HPA=hypothalamic-pituitary-adrenal axis, HS=habitual snoring, hsCRP=high-sensitivity C-
reactive protein, ICAM-1=intercellular adhesion molecule-1, IL-10=interleukin-10, IL-6=interleukin-6, IsoP-m=isoprostane metabolites, LBP=lipopolysaccharide-
binding protein, LPS= lipopolysaccharide, LTB4=leukotriene B4, LTC4=leukotriene C4, LTD4=leukotriene D4, LTE4= leukotriene E4, m-sCor=salivary cortisol after
PSG, MIF=macrophage migration inhibitory factor, MRP8=myeloid-related protein-8, n-sCor=salivary cortisol before PSG, NOx=nitrate mono-nitrogen oxides,
11
OAI=obstructive apnea index, ODI=oxygen desaturation index, OSA=obstructive sleep apnea, PGE2=prostaglandin E2, PSG=polysomnography, r-sCor=salivary
cortisol ratio, sAA=salivary alpha amylase, SNPs=single nucleotide polymorphisms, SpO2=peripheral capillary oxygen saturation, sub-sCor=subtract salivary
cortisol, TREM-1=triggering receptor expressed on myeloid cells-1, VEGF=vascular endothelial growth factor, VLDL=very-low-density lipoprotein.
12
Table S4
Complementary information regarding adults selected studies.*
Year Author Findings Main Conclusion
2000 Chin et al 99 Soluble E-selectin level had decreased after 3 to 4 days of nasal CPAP therapy,
(P =0.002) and after 1 month (P = 0.02). After 6 months, soluble vascular cell
adhesion molecule-1 levels had not changed significantly, while the mean soluble
intercellular adhesion molecule-1 level had decreased further (P=0.02). Before
treatment, soluble intercellular adhesion molecule-1 levels and the apnea and
hypopnea index were correlated (r = 0.43, P = 0.04).
OSA and hypopnea have a significant
adverse effect on serum soluble cell
adhesion molecule-1 levels that may
be reduced by nasal CPAP treatment.
2002 Carpagnano
et al 149
Higher concentrations of IL-6 were found in OSA patients (8.7 ± 0.3 pg/mL) than
in healthy control (1.6 ± 0.1 pg/mL; p < 0.0001). Obese subjects also had higher
levels than healthy control subjects, but lower levels than OSA patients (2.1 ±0.2
pg/mL, P < 0.05 and p < 0.0001 respectively). 8-isoprostane levels were found to
be higher in OSA patients (7.4 ±0.7 pg/mL) than in obese subjects (5 ± 0.3
pg/mL; P =0.4) and healthy subjects (4.5 _±0.5 pg/mL; P < 0.005)..
The inflammation and oxidative stress
are characteristic in the airway of OSA
patients and their levels depend on the
severity of the OSA. The measurement
of IL-6 and 8-isoprostane levels may
prove to be useful in screening and
monitoring obese patients who have a
high risk of developing OSA.
2002 Gozal et al 42 Serum VEGF levels were significantly higher in adults when compared to those
with mild or no disease (p<0.0001).
Circulating VEGF levels are frequently
elevated in OSA patients, and may
13
play a role in the regulation of tissue
oxygen delivery.
2002 Lavie et al
Study 1 110
AHI was found to be a significant independent predictor of morning VEGF
concentrations.
VEGF may contribute to the long-term
adaptation of OSA to recurrent
nocturnal hypoxia.
2002 Lavie et al
Study 2 110
VEGF concentrations were found to be significantly higher in OSA patients
comparing with control 1 and control 2. (P<0.007)
VEGF may contribute to the long-term
adaptation of OSA to recurrent
nocturnal hypoxia.
2002 Lavie et al
Study 3 110
A significant decrease in VEGF concentrations was found only in patients in
whom nocturnal hypoxia improved after treatment. (P<0.01)
VEGF may contribute to the long-term
adaptation of OSA to recurrent
nocturnal hypoxia.
2002 Schulz et al
114
Group A had significantly (P <0.01) increased VEGF serum levels when
compared with Group B and Group C (mean ±SEM: 410 ±77 pg/ml versus 224
±38 pg/ml and 245 ±61 pg/ml). The degree of nocturnal oxygen desaturation in
OSA significantly correlated with the VEGF concentrations (r =0.67, P <0.01).
Serum levels of VEGF are elevated in
severely hypoxic patients with OSA
and are related to the degree of
nocturnal oxygen desaturation.
2002 Shamsuzzam
an et al 88
Plasma CRP levels were significantly higher in patients with OSA than in controls
(P<0.0003). In multivariate analysis, CRP levels were independently associated
with OSA severity (F=6.8, P=0.032).
OSA is associated with elevated levels
of CRP. The severity of OSA is
proportional to the CRP level.
2003 Carpagnano Higher concentrations of 8-isoprostane were found in the EBC (9.5 ±1.9 pg/mL) Systemic and local oxidative stress are
14
et al 155 and plasma (9.7± 1.5 pg/mL) of OSA patients compared to controls (p < 0.0001).
Significant reduction of 8-isoprostane was seen after CPAP therapy (p < 0.005).
A positive correlation was found between morning exhaled 8-isoprostane levels
and the AHI (r =0.8; P < 0.0001).
increased in OSA patients, and that
they are higher after nocturnal apnea
and reduced by CPAP therapy.
2003 Christou et al
113
The measurement of antioxidant capacity did not differ between the OSA patients
and healthy sample. Patients with severe had linearly negative correlation
between antioxidant capacity in their blood samples and AHI (R =2 0:551,
P=0:041).
Reduced antioxidant capacity in serum
is an index of excessive oxidative
stress. Patients with severe OSA have
reduced values of antioxidant capacity.
2003 Ohga et al 100 nCPAP decreased apnea, desaturation, and the circulating ICAM-1 and IL-8
levels in OSA patients. The circulating levels of ICAM-1, IL-8, and MCP-1 in
untreated OSA patients were significantly greater than those in the controls.
nCPAP therapy could reduce OSA-
induced hypoxia and generation of
inflammatory mediators.
2003 Yokoe et al 101 Levels of CRP and IL-6 were significantly higher in patients with OSA than in
controls (CRP P<0.001, IL-6 P<0.05). IL-6 production by monocytes was also
higher in patients with OSA than in controls (P<0.01).
nCPAP significantly decreased levels of both CRP (P<0.0001) and IL-6
(P<0.001) and spontaneous IL-6 production by monocytes (P<0.01).
Levels of CRP and IL-6 and
spontaneous production of IL-6 by
monocytes are elevated in patients
with OSA but are decreased by
nCPAP.
2004 Guilleminault
et al 89
Analysis of variance indicated a significant difference between the groups for
diastolic BP, RDI, lowest SaO2, and BMI. The mean serum CRP level was normal
in all 3 groups.
Obesity is a risk factor for high serum
CRP levels in OSA patients, as in the
general population.
2004 Imagawa et al No significant increase in IL-6 or TNF-α was detected in the present study cohort. The elevation in VEGF is not directly
15
102 related to IL-6 or TNF-α · levels.
2005 Alzoghaibi et
al 115
Mean SOD and lipid peroxidation concentrations of patients were not significantly
different from those of control subjects (0.29±0.015 vs 0.31±0.01 U/ml and
4.64±0.57 vs 4.62±0.54 mmol/ml, respectively). Higher concentrations of IL-8 and
GCP-2 were found in OSA patients (198.8±4.76 vs 180.83±3.38 and
383.34±46.19 vs 218±13.16 pg/ml, respectively, P<0.005).
There is a significant increase in
neutrophil chemokines IL-8 and CGP-2
in serum f OSA adults.
2005 Sukegawa et
al 103
During the CPAP treatment, both 24-h urinary adrenaline and noradrenaline were
significantly lower compared with natural sleep. CPAP significantly decreased the
AHI, DSI, % stage 1, and arousal index and significantly increased the lowest
SpO2. There were no significant differences in % stage 2, % stage 3/4, and %
REM between before and during CPAP treatment. Multiple analysis of covariance
tests revealed that lowest SpO2was the most important factor for increasing 24-h
urinary noradrenaline levels (F = 4.75, p = 0.048).
One night CPAP treatment could
improve autonomic dysfunction.
2005 Yamauchi et
al 104
Urinary 8-OHdG excretion was significantly higher in the severe OSA group (p
=0.03). Urinary 8-OHdG excretion was significantly correlated with parameters of
OSA. Only ODI was significantly correlated with urinary 8-OHdG excretion after
adjustment for confounding factors that are considered to be related to oxidative
stress.
The severity of OSA is independently
associated with oxidative stress.
Among various OSA parameters, ODI
is most closely related to oxidative
stress.
16
2006 Braga et al 116 S100B was higher in OSA (0.15 ± 0.09 mg/l) than in the control group (0.08 ±
0.06 mg/l; P<0.01). Serum NSE was similar in both groups (17.5 ± 12.2 vs. 15.8
± 6.8 ng/ml).
There is an elevated serum S100B
levels in OSA adults compared to
controls.
2006 Htoo et al 90 The degree of NF-κB activation was positively correlated with indices of apnea
severity. In five severe OSA patients, 1 month of CPAP therapy decreased
neutrophil NF-κB activation to control levels. sEselectin and sVCAM
concentrations were reduced by CPAP in four of these five subjects. OSA leads
to NF-κB activation, which may constitute an important pathway linking OSA with
systemic inflammation and cardiovascular disease.
Activation of NF-kB may play a central
role linking the pathophysiological
features of OSA with adverse
cardiovascular consequences.
2006 Lentini et al
117
The mean baseline CK level was significantly higher in patients with severe OSA
compared to those with mild-to-moderate OSA and controls. ROC analysis
identified an optimal cutoff value of > 148 U/L (r =0.660) for CK, which yielded a
PPV of 99%, a sensitivity of 43%, and a specificity of 95% for the diagnosis of
OSA. CPAP treatment resulted in a significant decline of CK levels both in
patients with mild-to-moderate OSA (P < 0.001) and in patients with severe OSA
(P < 0.001).
One third of the sample showed a
mild-to-moderate elevation in CK level,
which was highly predictive of OSA.
The application of CPAP therapy in
OSA patients resulted in a significant
decrease in CK level.
2006 Mehra et al 91 Linear regression analysis showed that after adjustment for subject
characteristics, waist circumference, and comorbidities, OSA was not significantly
associated with morning IL-6 levels. In contrast, linear regression analyses
showed that, compared with the participants without OSA, those with OSA had
Morning sIL-6R levels demonstrated
stronger associations with moderate to
severe OSA than morning IL-6 levels.
Associations with OSA and morning
17
significantly higher morning sIL-6R levels (mean±SD, 4.60±1.42 ng/mL
[P=0.001]), even after adjustment for subject characteristics, waist circumference,
and comorbidities, which persisted after adjustment of evening sIL-6R levels.
sIL-6R levels persisted even after
adjustment for waist circumference,
cardiovascular disease, and evening
sIL-6R levels, suggesting the potential
utility of sIL-6R as a marker for
measuring overnight OSA stresses.
2007 Peled et al 118 There was no association of VEGF or VEGF/platelets with the severity of OSA..
Age was the only parameter to significantly predict VEGF and VEGF/platelets on
multivariate analysis (R 2 = 0.713, P = 0.001 and R 2 = 0.844, P= 0.001,
respectively).
The elevation of serum VEGF in OSA
is not associated with the severity of
the disease, but it is associated with
patient age.
2007 Phillips et al
151
Compared with baseline on CPAP, withdrawal from therapy resulted in an
immediate return of OSA with an increase in RDI to 26.7 ±5.2 and 39.0 ± 5.9
events per hour after one and seven nights without CPAP, respectively (both P <
0.0001). This was accompanied by a concomitant rise in daytime urinary
noradrenaline (P < 0.0001) after seven nights CPAP withdrawal that was
positively associated with the severity of hypoxaemia. In contrast, withdrawal
from CPAP therapy was not accompanied by any change in measured cytokines
or VEGF (all P > 0.1).
One week of CPAP withdrawal was
associated with a return of OSA and a
marked increase in sympathetic
activity without a concomitant elevation
of vascular inflammatory markers.
2007 Punjabi et al
92
A strong association was found between degree of OSA and serum levels of
CRP, with or without adjustment for age and several measures of adiposity.
Mechanisms other than adiposity per
se could contribute to the inflammatory
18
state seen in OSA adults.
2007 Ryan et al 119 CRP levels were similar in groups 1, 2 and 3 (p = 0.727), but were significantly
higher in group 4 than in the other groups (p<0.05 by individual group
comparisons). There was no difference in homocysteine levels between all four
groups (p = 0.1). CPAP did not alter CRP (P = 0.145) or homocysteine levels (P
= 0.381).
CRP and homocysteine levels are not
associated with OSA severity in men.
2007 Ursavas et al
120
Circulating levels of both ICAM-1 (480.1 ±216.7 vs. 303.4 ± 98.6 ng/ml, p !
0.0001) and VCAM-1 (1,156.6 ±79.8 vs. 878.8 ±71.1 ng/ml, p = 0.002) were
significantly increased in the OSA group compared to the control group. For an
ICAM-1 cutoff level of 375 ng/ml, predictive sensitivity and specificity for OSA
were 69.2% (95% confidence interval, CI: 52.4–83.0%) and 82.4% (95% CI:
65.5–93.2%), respectively. For a VCAM-1 cutoff level of 859 ng/ml, predictive
sensitivity and specificity for OSA were 74.4% (95% CI: 57.9–86.9%) and 64.7%
(95% CI: 46.5–80.2%), respectively.
OSA can independently increase
circulating levels of adhesion
molecules.
2007 Ye et al 76 Serum concentrations of CRP and MMP-9 were significantly higher in OSA
patients than in controls. Levels of CRP and MMP-9 were significantly higher in
patients with moderate to severe OSA than in patients with mild OSA or in obese
control subjects. A positive correlation was found between levels of CRP and
MMP-9 in OSA patients.
AHI, mirroring the frequency of IHR,
was a predictor of enhanced circulating
CVD biomarkers MMP-9 and CRP.
IHR contributes to the upregulation of
the inflammatory factors in OSA
patients
19
2008 Antonopoulou
et al 156
An increased level of leptin and respective increase of inflammatory variables
was found. No significant association was observed between parameters of EBC
and plasma leptin levels. A part of the parameters of disease severity is
significantly associated with pH and 8- isoprostane. Smoking did not seem to be
a critical confounding factor for evaluation of the above measurements.
There is no significant association
between the increased levels of leptin
and increased airway inflammation in
OSA.
2008 Arias et al 152 Nocturnal urinary levels of norepinephrine, epinephrine and sTNFR-1 (1,053±269
versus 820±166 pg.mL-1) were significantly higher in OSA patients. There were
no significant differences in plasma levels of IL-6, LTB4, or TNF-α between the
two study groups. There were no significant differences in BP, urinary
catecholamine levels, or plasma IL-6, LTB4 and TNF-a levels after both treatment
modalities. After 3 months of effective CPAP usage, sTNFR-1 levels were
significantly reduced (1,053±269 vs 899±254 pgmL-1).
OSA patients have higher levels of
sTNFR-1 than Non-OSA individuals.
sTNFR-1 levels are lowered by CPAP
therapy.
2008 Burioka et al
105
Serum IL-6 levels were significantly reduced after CPAP therapy by 46% (p
<0.005). No significant 24 h variation of serum IL-6 in severe OSA patients was
found before CPAP; however, a significant 24 h variation of serum IL-6 was
found after CPAP.
Intermittent hypoxia during sleep may
contribute to systemic inflammation
and result in an elevation of serum IL-6
in severe OSA patients.
2008 Constantinidis
et al 121
Production of TNF-a and IL-6 were significantly elevated in OSA patients and
obese controls compared with overweighted control subjects (p < 0.05). Serum
levels of IL-1β did not differ among the study groups. Preoperative cytokine
values were significantly correlated with the preoperative BMI and the AHI in
Surgical management of mild to
moderate OSA is indicated for the
reduction of pro-inflammatory
cytokines.
20
OSA patients. Surgery resulted a significant reduction in the TNF-α and IL-6
values of the study group. Decrease in cytokine level was strongly correlated with
the AHI decrease. The postoperative relative percentage change of IL-6 values
was significantly higher than this of TNF-α (P < 0.001). Surgical management of
mild to moderate OSA leads to a significant reduction in TNF-α and IL-6 values.
2008 Kanbay et al
122
There was a significant negative correlation between plasma TNF- α and
adiponectin levels in OSA group. Compared with the non-obese OSA group,
subjects with obesity and OSA had lower adiponectin levels and SpO2 <90%, and
higher TNF- α levels. Obese OSA patients had higher rates of CVD with lower
plasma adiponectin levels when compared with obese control subjects.
Serum adiponectin is significantly
lower in OSA patients and it is
independent of obesity.
2008 Li et al 157 IL-6 and TNF-α in EBC and serum gave the highest correlation coefficients (r =
0.62 and r = 0.71 in EBC; r = 0.58 and r = 0.66 in serum, respectively) as well as
the lowest AIC values (63.87, 68.97; 62.65, 70.64, respectively).
IL-6 and TNF-α measurements may be
used in OSA treatment follow-ups,
when PSG is not available.
2008 Norman et al
93
Markers of hypoxia (lowest oxygen saturation level and %T<90), correlated
significantly with AST and ALT levels (Pearson’s r = -0.31 to -0.38, P <0.003),
while AHI, BMI, BP, fasting glucose, triglyceride, and cholesterol levels did not.
Hierarchical linear regression was then done to determine the best predictors of
aminotransferase levels. Markers of metabolic syndrome were entered as one
block and markers of sleep apnea as another. Regression analyses explained
16.3% of the variance in AST and 18.9% of the variance in ALT, with %T<90
In OSA patients serum ami-
notransferase levels are better
predicted by markers of oxygen de-
saturation than by factors traditionally
associated with the metabolic
syndrome.
21
playing the largest role.
2008 Petrosyan et
al 150
The levels of eNO and eCO were higher in OSA patients than in control subjects
(P<0.05). Nasal NO was higher in OSA patients than in obese controls (P<0.01).
The level of H2O2, 8-isoprostane, LTB4, and nitrates were elevated in OSA
patients in comparison with obese subjects (P<0.01). pH was lower in OSA
patients than in non-apneic controls (P<0.01). One month of CPAP therapy
increased pH (P<0.05) and reduced eNO (P<0.001) and nNO (P<0.05). AHI was
positively correlated with 8-isoprostane (r=0.42; P<0.05), LTB4 (r=0.35; P<0.05),
nitrates (r=0.54; p<0.001), and H2O2 (r=0.42; P<0.05).
Airway inflammation and oxidative
stress are present in the airway of
OSA patients in contrast to non-apneic
subjects. Exhaled breath markers are
positively correlated with the severity
of OSA. One-month administration of
CPAP improved airway inflammation
and oxidative stress.
2008 Takahashi et
al 106
The TRX level was significantly higher (p =0.02) and the adiponectin level was
significantly lower (P= 0.02) in the OSA group than in the non-OSA group. After 1
month of nCPAP (n =27), the TRX level significantly decreased (P =0.03), and
the adiponectin level significantly increased (p =0.03). Among the 14 patients
with untreated OSA, the TRX and adiponectin levels did not significantly change
over a 1-month interval. Among the 53 (41 OSA =12 non-OSA) subjects, the TRX
level was positively correlated with the respiratory disturbance index (p =0.001)
and percentage of time with SaO2 <90% (p =0.0002). The adiponectin level, but
not the TRX level, was correlated with the BMI (n =53; P =0.02).
Plasma TRX may be a unique marker
for evaluating oxidative stress and
monitoring the effectiveness of nCPAP
in OSA patients.
2008 Zamarron et
al 123
OSA patients presented significantly higher circulating levels of PAI-1 compared
with the control group, and the difference was even more marked in patients with
OSA patients presented higher
circulating levels of PAI than controls
22
both OSA and hypertension. OSA patients presented a significant inverse
correlation between PAI-1 levels and AHI (r = -0.71, P<0.001).
group, which was even greater when
patients had associated hypertension.
2009 Kim et al 124 Multiple regression analysis showed that haptoglobin and apolipoprotein M levels
are independently related to AHI (P < 0.01).
Of these nine proteins, haptoglobin,
paraoxonase and apoliprotein M were
quantified in 74 subjects.
2009 Kuramoto et
al 107
Serum level of SAA (P<0.05), brachial-ankle PWV (P<0.05) and BP (P<0.005)
were significantly higher in Group 3 than in Group 1.
Markers of inflammation and
autonomic dysfunction are increased in
patients with OSA, and nCPAP might
help to reduce risk factors for
cardiovascular disease.
2009 Lam et al 124 Urinary catecholamines were positively correlated with severity of sleep apnea,
independent of obesity. BP measurements correlated with age, obesity, severity
of sleep apnea, and urinary catecholamines. Regression analysis showed that
sleep indices and urinary catecholamines were independent determinants of
morning systolic and diastolic BP, respectively, while total cholesterol and waist
circumference were respective additional factors. Urinary catecholamines and
waist circumference were determinants of evening BP, with morning cortisol
being an additional determinant for diastolic BP.
OSA and related sympathetic activity
contributed significantly to the
determination of daytime BP in
overweight middle-aged men without
overt cardiometabolic diseases, and
other contributing factors include
abdominal obesity, total cholesterol,
and cortisol levels.
2009 Lederer et al Median plasma KL-6 levels were higher in patients with OSA compared with
controls: 317 (232–506) UmL-1 versus 226 (179–257) UmL-1, respectively. Higher
Circulating KL-6 levels are elevated in
some patients with OSA, possibly
23
94 plasma KL-6 levels were associated with greater time spent asleep with an
oxyhaemoglobin saturation <90%, lower nadir saturation, more frequent
desaturation of >4% during sleep and lower brachial artery flow-mediated
dilation. Adjustment for nadir saturation or flow-mediated dilation attenuated the
association between plasma KL-6 levels and OSA.
reflecting increased alveolar wall
permeability.
2009 Li et al 78 Biomarker levels, in both EBC and serum, differed significantly across the four
groups. Classification by LDA using IL-10 in EBC showed the highest agreement
with AHI classification (kappa = 0.88). Logistic regression distinguished moderate
and severe OSA from mild OSA and non-OSA perfectly using IL-6 in EBC and
almost perfectly using IL-10 in EBC (area under the ROC curve = 0.997). The
levels of biomarkers among smokers overlapped with mild to severe OSA
patients.
EBC IL-6 and IL-10 have potential to
predict severity of OSA in non-smoker
OSA suspects.
2009 Lui et al 79 After adjustment for age, smoking, BMI, waist circumference, and sleep
efficiency, CRP correlated positively with the 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 magnetic
resonance image 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
In healthy middle-aged men, elevated
CRP level is associated with OSA
independent of visceral obesity.
24
=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 magnetic resonance image 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).
2009 Ting et al 111 BMI, neck circumference, waistline circumference, respiratory disturbance index,
arousal index, lowest oxygen saturation, duration of SaO2 < 90%, blood glucose,
hs-CRP, and metabolic syndrome score in Morning Surge and Constant High
were significantly greater than those in Constant Low. Except metabolic
syndrome score, all other parameters in Morning Drop were similar to those in
Constant Low.
OSA patients whose post- to pre-
overnight SSBPs were elevated or
maintained a constant high have more
sleep respiratory disturbance, more
pro-inflammatory state, and higher
metabolic syndrome indices than the
rest. Without subdividing into Constant
Low, Morning Drop, Constant High,
and Morning Surge, the important
pathophysiologic points of OSA
patients will possibly be missed.
2009 Ucar et al 125 Morning lactate was significantly higher in the OSA group than the Non-OSA
group (1.65 ±0.48 and 1.35 ±0.57 mmol/L, respectively) (P =0.003). Lactate
levels at night and the change overnight in lactate levels were not significantly
As a marker of tissue hypoxia, arterial
lactate may be used to assess the
severity of OSA.
25
different between groups. After an adjustment for age, gender, and BMI, lactate
levels before PSG were related to the AHI (beta: 0.004, 95% CI: 0.000–0.008)
and the rate of sleep-time spent under 90% oxygen saturation (T90%). The
following morning lactate level was correlated with the T90% (beta: 0.005, 95%
CI: 0.000–0.010). After an adjustment for lactate levels before PSG, lactate in the
morning was correlated with T90% (beta: 0.004, 95% CI: 0.000–0.008).
2010 Lee et al 126 Twenty-three percent of the overall patients had significantly elevated serum
levels of hs-CRP. The increase of hs-CRP correlated fairly with BMI, AHI, tonsil
size, and ESS (r =0.450, 0.398, 0.393, and 0.300, respectively; all P ≤0.05) after
adjustment for conventional coronary heart disease risk factors. Only the AHI
could predict for significantly elevated hs-CRP after stepwise multiple linear
regression (R2 =0.251, P <0.001).
Patients in this study with hs-CRP≥ 3
mg/L were more prevalent in the
severe OSA group. This observation
suggests that the severe OSA patients
need to have their cardiovascular
statuses evaluated by use of an hs-
CRP screening test.
2010 Pallayova et
al 95
Both increases in AHI and the presence of prediabetes/diabetes were associated
with reductions in HOMA-IS in the entire cohort even after adjustment for sex,
race, age, and BMI (P = 0.003). In subjects with NGM (n = 30), OSA severity was
associated with significantly increased HOMA-B (a trend towards decreased
HOMA-IS) independent of sex and adiposity. OSA-related oxyhemoglobin
desaturations correlated with TNF-α (r=-0.76; P = 0.001) in women with NGM
and with IL-6 (rho=-0.55; P = 0.035) in women with IGM (n = 15) matched
OSA is independently associated with
altered glucose homeostasis and
increased basal beta cell function in
severely obese adults with NGM.
Moderate to severe OSA imposes an
excessive functional demand on
pancreatic beta-cells, which may lead
26
individually for age, adiposity, and AHI. to their exhaustion and impaired
secretory capacity over time. The two
distinct biomarker profiles linking sleep
apnea with NGM and IGM via TNF-a
and IL-6 have been discerned in our
study to suggest that sleep apnea and
particularly nocturnal oxyhemoglobin
desaturations are associated with
chronic metabolic fluxes and specific
cytokine stressors that reflect links
between sleep apnea and glucose
metabolism.
2010 Steiropoulos
et al 127
OSA patients had significantly higher TNF-α levels (P < .001) while no other
difference in the examined inflammation markers was recorded between groups.
Overall, TNF-α levels were correlated with neck circumference (P < .001), AHI (P
= .002), and Oxygen Desaturation Index (P = .002).
Obese OSA patients have elevated
TNF-α levels compared to BMI
matched controls, suggesting a role of
OSA in promoting inflammation,
possibly mediated by TNF- α.
2010 Ye et al 80 Serum DNA, IL-6, and MDA concentrations were measured and were
significantly higher in patients with moderate and severe OSA groups than those
in the mild OSA and control groups (p< 0.05). Univariate analysis showed that
The increasing concentration of serum
DNA in patients with OSA was
positively correlated with disease
27
serum DNA correlated positively with AHI, ODI, IL-6, and MDA, and negatively
correlated with minimal oxygen saturation (miniSaO2) (all p<0.05). In stepwise
multiple regression analysis, only MDA and miniSaO2 were suggested as
significant independent predictors for the serum DNA concentrations. After 6
months of nCPAP therapy, serum concentrations of DNA, IL-6, and MDA were
significantly decreased (P<0.05).
severity. Serum DNA may become an
important parameter for monitoring the
severity of OSA and effectiveness of
therapy.
2011 Akinnusi et al
96
pLOX-1 levels were higher in subjects with OSA than in control (326.9 ±267.1
pg/mL and 141.1 ± 138.6 g/mL, respectively; P = 0.004).
Patients with OSA showed a threefold increase in baseline endothelial
expression of LOX-1 relative to control subjects.
CPAP therapy resulted in a significant decrease in endothelial LOX-1 expression
only in CPAP-adherent patients.
Circulating apoptotic endothelial cells correlated directly with baseline expression
of LOX-1 (R 2 =0.32, P = 0.01) after adjustment for age, BMI, and waist to hip
ratio.
The increased burden of circulating
apoptotic endothelial cells in OSA
adults is associated with upregulation
of LOX-1 expression on vascular
endothelium. Adherence to CPAP
therapy ameliorates these
derangements and pay reverse the
long-term cardiovascular complications
of OSA.
2011 Cintra et al 128 The cysteine plasma levels were higher in patients with OSA compared with
control (490.16 ± 67.00 m mol/L vs 439.81 ± 76.12 m mol/L, respectively, P
<0.01). The homocysteine plasma levels did not differ between groups. Cysteine
plasma levels were higher in the OSA lean subgroup when compared with lean
control (484.21 ± 71.99 μmol/L vs 412.01 ±70.73 μmol/L, respectively, P =0.009).
Cysteine is a potential biomarker of
OSA and is reduced after effective
OSA treatment.
28
There was a significant decrease of cysteine plasma levels after 6 months of
CPAP effective therapy.
2011 Jurado-
Gamez et al
130
The OSA patients showed a significant worsening of morning IRH, and a
significant increase in malondialdehyde and 8-hydroxydeoxyguanosine levels.
Only the oxygen desaturation index independently explained morning IRH, while
malondialdehyde levels showed a weak effect on IRH. In severe OSA patients,
IRH improved significantly after CPAP treatment, as did malondialdehyde, 8-
hydroxydeoxyguanosine and protein carbonyl levels.
In OSA patients, endothelial
dysfunction and oxidative stress were
observed, and IRH worsened after
sleep. The increase in oxidative stress
was not associated with IRH, while
intermittent hypoxia was strongly
associated with IRH. In severe OSA
patients, CPAP treatment improved
oxidative stress and endothelial
function.
2011 Kohler et al
153
CPAP withdrawal led to a recurrence of OSA within a few days and a return of
subjective sleepiness, however was not associated with significant deterioration
of psychomotor performance within 2 weeks. Endothelial function decreased
significantly in the CPAP withdrawal group compared with therapeutic CPAP
(mean difference in change, –3.2%; 95% CI, –4.5, –1.9%; P <0.001). Compared
with continuing CPAP, 2 weeks of CPAP withdrawal was associated with a
significant increase in morning systolic BP (mean difference in change, +8.5 mm
Hg; 95% CI,+1.7,+15.3mmHg; P=0.016), morning diastolic BP (mean difference
CPAP withdrawal usually leads to a
rapid recurrence of OSA, a return of
subjective sleepiness, and is
associated with impaired endothelial
function, increased urinary
catecholamines, BP, and heart rate.
29
in change, +6.9 mm Hg; 95% CI, +1.9, +11.9 mm Hg; P =0.008), and morning
heart rate (mean difference in change, +6.3 bpm, 95% CI,10.4,+12.2 bpm; P=0.
0.035). CPAP withdrawal was associated with an increase in urinary
catecholamines but did not lead to an increase in markers of systemic
inflammation, insulin resistance, or blood lipids.
2011 Ladesich et al
97
After controlling for age, sex, race, smoking, BMI, alcohol intake, fish intake, and
omega-3 supplementation, RBC DHA was inversely related with OSA severity.
For each 1-SD increase in DHA levels, a patient was about 50% less likely to be
classified with severe OSA. The OR (95% CI) was 0.47 (0.28 to 0.80) and 0.55
(0.31 to 0.99) for being in the severe group versus the none/mild or moderate
groups, respectively.
Disordered membrane fatty acid
patterns may play a causal role in OSA
and that the assessment of RBC DHA
levels might help in the diagnosis of
OSA. The effects of DHA
supplementation on OSA should be
explored.
2011 Pallayova et
al 98
Surgical weight loss resulted in significant decreases in BMI (16.7±5.97
kg/m2/median 365 days), AHI, CRP, IL-6, sTNFαR1, sTNFαR2, and leptin levels,
while ghrelin, adiponectin, and soluble leptin receptor concentrations increased
significantly. Utilizing an AHI cutoff of 15 events/h, significantly elevated levels of
baseline sTNFαR2 and greater post-WL sTNFαR2 decreases were found in
subjects with baseline AHI ≥15 events/h compared to those with AHI <15
events/h despite no significant differences in baseline BMI, age, and BMI. In a
multivariable linear regression model adjusting for sex, age, impaired glucose
Of all the biomarkers, the decrease in
sTNFα R2 was independently
determined by the amelioration of
sleep apnea achieved by bariatric
surgery. The results suggest that
sTNFαR2 may be a specific sleep
apnea biomarker across a wide range
of body weight.
30
metabolism, BMI, and follow-up period, the post- weight loss decreases in AHI
were an independent predictor of the decreases in sTNFαR2 and altogether
accounted for 46% of the variance of sTNFαR2 (P=0.011) in the entire cohort.
2011 Zamarron et
al 132
OSA patients presented higher circulating levels of ICAM-1, endothelin-1 and
PAI-1 than the control group. No differences were found in E-selectin and vWF.
After 1 year of CPAP treatment, there was a significant decrease in circulating
levels of ICAM-1 and PAI-1. No differences were found in endothelin-1, E-
selectin and vWF.
OSA is associated with elevated levels
of ICAM-1 and PAI-1 and these levels
normalize after treatment with CPAP.
2012 Duru et al 133 Median serum S100B protein level was 133.7 pg/mL (range 20.97-230.70 pg/mL)
in OSA patients and 16.1 pg/mL (range 10.1-22.9 pg/mL) in control group
(p<0.005). Serum 100B protein level did not correlate with any studied variable
(p>0.05 for each correlation coefficient).
Serum S100B protein level is
increased in OSA patients and may be
a useful maker for OSA.
2012 Feng et al 81 Serum chemerin levels were significantly elevated in OSA patients (120.93 ±
25.84 μg/L vs. 107.51 ±20.41 μg/L). Multivariable logistic regression analysis
revealed that serum chemerin levels were an independent determinant of the
presence of OSA (OR 1.030, 95% CI 1.016–1.045; P < 0.001). Serum chemerin
levels in severe OSA patients were significantly higher compared with those in
mild and moderate OSA patients (P= 0.015 and P=0.020, respectively).
Spearman correlation analysis indicated that serum chemerin levels were
correlated with the severity of OSA (r = 0.210, P=0.016). Serum chemerin were
Elevated serum chemerin levels could
be an independent predicting marker
for OSA.
31
positively correlated with waist circumference (r = 0.164, P=0.008), BMI (r =
0.158, P=0.014), systolic BP (r = 0.135, P=0.037), homeostasis model
assessment of insulin resistance (r = 0.140, p = 0.031), CRP (r = 0.202,
P=0.002), and AHI (r = 0.152, P=0.022).
2012 Guven et al
134
The serum hs-CRP levels were significantly higher in the OSA group (4.03±3.58
mg/L) than in the control group (2.41±1.95 mg/L) (P=0.013). This high level was
positively correlated with BMI (r=0.376, P=0.001) and with AHI (r=0.280,
P=0.014). In multiple regression analysis, elevated hs-CRP levels were
associated with AHI (F=3.293, P=0.033), which was independent of obesity.
OSA severity is responsible for the
elevation of hs-CRP. OSA patients
have elevated serum levels of hs-CRP,
a marker for inflammation and an
independent risk predictor for
cardiovascular morbidity.
2012 Hira et al 129 Both before and after sleep uric acid levels of patients with OSA were found to be
significantly higher (P=0.001 and 0.002, respectively) as compared to UA levels
of controls. A statistically significant (P=0.02) overnight (after sleep) rise was
observed in the serum lactate level of OSA patients. The correlation between
serum uric acid values and %TSTs below 95% SaO2 (P=0.02) was statistically
significant. The correlation was positive with %TSTs below 90% SaO2, whereas it
was found negative with normal basal oxygen. No significant correlation was
observed between serum uric acid and the AHI. Polysomnographic variables
failed to show significant correlation with serum UA on respective multiple
regression models controlling for age, BMI, and waist-hip ratio.
The measurement of serum lactate
level was a better marker of oxidative
stress among OSA patients.
32
2012 Jurado-
Gamez et al
135
The severe desaturation group showed significantly higher values in the AHI,
MDA, ICAM-1 and P-selectin (p<0.005), as well as a worsening of IRH (p=0.001).
Only ICAM-1 (p=0.019) and P-selectin (p=0.033) were independently associated
with IRH in a multiple-linear regression model.
Patients with OSA and greater
intermittent hypoxia showed worse
endothelial function, and higher levels
of MDA, ICAM-1 and P-selectin.
Nevertheless, ICAM-1 and P-selectin
rather than MDA were independently
associated with IRH.
2012 Lee et al 136 There was no significant difference in either oxidative stress or antioxidant status
markers among the three groups. There was no significant correlation between
the oxidative stress markers and the OSA variables. There were correlations
between WHR–oxLDL (r=0.424), WHR–GPX (r=0.318), WHR–TAS (r=−0.317),
and WHR–SOD (r=−0.338). In multiple regression analysis, WHR was a
significant independent variable of oxLDL, GPX, TAS, and SOD.
The oxidative stress in OSA was
related to central obesity rather than
intermittent hypoxia or respiratory
disturbances.
2012 Mancuso et al
137
OSA patients showed increased protein oxidative damage and impaired
antioxidant defenses. Patients with more severe OSA had a lower total
antioxidant capability. Preliminary data on a subgroup of patients (n = 7) treated
with CPAP show a significant increment of the FRAP values
(P < 0.005).
Oxidative stress markers may be
useful to detect and monitor redox
imbalance in OSA. FRAP might be a
new useful biomarker to monitor in vivo
the oxidative response to CPAP
therapy.
2012 Papaioannou The group median dim light melatonin onset did not differ in OSA patients The circadian phase is the same in
33
et al 112 compared to healthy subjects (OSA patients: 90 [60–150] min; healthy subjects:
135 [90–150] min, p = 0.19).
OSA patients and healthy subjects.
2012 Simiakakis et
al 138
The levels of d-ROMS were significantly higher (p = 0.005) in the control group
but the levels of antioxidant capacity were significantly lower (p = 0.004) in OSA
patients. The most important factors predicting the variance of oxidative stress
were obesity, smoking habit, and sex. Parameters of sleep apnea severity were
not associated with oxidative stress. Minimal oxygen desaturation and smoking
habit were the most important predicting factors of BAP levels.
Obesity, smoking, and sex are the
most important determinants of
oxidative stress in OSA subjects.
2012 Sokucu et al
139
RDW increased significantly with increased severity of OSA (P = 0.046) and was
positively correlated with the AHI (P = 0.002, r = 0.300), even in the non-anemic
group (P = 0.013, r = 0.291). The AHI was significantly higher in the group with
high RDW (> 15; P = 0.046). RDW was negatively correlated with sleep time (p =
0.028, r = 0.217), average oxygen saturation of hemoglobin (P = 0.003, r = -
0.239), and minimum desaturation value (P = 0.016, r = -0.235).
In patients with a clinical diagnosis of
OSA, RDW may be a marker for the
severity of the condition.
2012 Svensson et
al 131
The levels of CRP, IL-6 and lysozyme were significantly higher in subjects with
AHI ≥15 compared with women with lower AHI. All inflammatory markers except
MPO correlated to AHI and oxygen desaturation measures, and to waist
For women from the general
population there is an independent
correlation between OSA and
34
circumference. In multiple linear regressions adjusting for age, waist
circumference and smoking, independent correlations between ODI and
inflammation were found for IL-6 (P=0.03 for % sleep time with saturation <90%)
and TNF-α (P=0.03 for ODI 3%). No significant correlations were found between
AHI and inflammation.
inflammation, even after adjusting for
obesity. The results indicate that
intermittent hypoxia, and not the AHI,
is related to systemic inflammation
seen in OSA.
2013 Aihara et al
108
Each measured serum biomarker (leptin, IL-6, IL-8, TNF-α, and VEGF) was
significantly correlated with waist circumference or fat area determined by
computed tomography.
Regarding airway inflammation, sputum IL-6, IL-8, TNF-α, and VEGF were
significantly correlated with OSA severity as indicated by the respiratory
disturbance index or oxygen desaturation indices. Sputum IL-6, IL-8, TNF-α, and
VEGF were significantly related to sputum neutrophil number, and sputum IL-8
and TNF-α were related to proximal airway resistance independently of BMI.
There were no significant associations between the same biomarkers in serum
and induced sputum.
Systemic and airway inflammation in
OSA might be differently regulated by
OSA itself and comorbid obesity,
depending on the type of cytokine.
2013 Chung et al
140
In the derivation cohort, with a STOP-Bang score ≥3, the specificity for all OSA,
moderate/ severe OSA, and severe OSA was 37.0%, 30.4%, and 27.7%,
respectively. HCO3 - level of 28 mmol/L was selected as a cutoff for analysis. With
the addition of HCO3 2 level ≥28 mmol/L to the STOP-Bang score ≥3, the
specificity for all OSA, moderate/severe OSA, and severe OSA improved to
Serum HCO3 level increases the
specificity of STOP-Bang screening in
predicting moderate/severe OSA. The
authors proposed a two-step screening
process. The first using STOP-Bang
35
85.2%, 81.7%, and 79.7%, respectively. Similar improvement was observed in
the validation cohort.
score, and the second using HCO3
level.
2013 Cofta et al 141 There was a progressive increase in the concentrations of all three selectins with
the severity of OSA.
The level of plasma adhesion
molecules may be indicative of OSA
and may contribute to cardiovascular
sequelae.
2013 Ferrarini et al
142
Putative identification of 14 statistically significant features was obtained and
changes that can be related to the episodes of hypoxia/reoxygenation
(inflammation) have been highlighted.
The patterns of variation of platelet
activating factor and
lysophospholipids, together with some
compounds related to differential
activity of the gut microflora (bile
pigments and pipecolic acid) open new
lines of research that will benefit our
understanding of the alterations,
offering new possibilities or adequate
monitoring of the stage of the disease.
2013 Guo et al 82 The plasma TRX level in severe group was increased (8.62±2.14, 13.33±5.60,
14.71±5.53, and 16.10±7.34 ng/ml; P<0.05). The TRX positively related to AHI
Plasma TRX level is associated with
OSA severity and may be used as a
36
(r=0.313; p<0.05), while negatively related to the lowest O2 saturation (r=0.266;
P<0.037). The OSA patients associated with hypertension showed elevated TRX
level (17.70±6.98 vs. 13.43±5.83 ng/ml; t=2.434, P<0.018). The cutoff value of
TRX for identifying OSA was 9.39 ng/ml (sensitivity 91 %, specificity 78 %), and
its cutoff value for differentiating moderate–severe OSA from mild OSA was
11.79 ng/ml (sensitivity 75 %, specificity 65 %).
severity indicator of OSA.
2013 Hirotsu et al
143
Uric acid levels were correlated with most important risk factors for OSA, such as
AHI, desaturation time and index, SpO2, BP, cholesterol, BMI, triglycerides and
arousal, and with OSA itself. Uric acid was increased in OSA volunteers even
after controlling for all confounders. Hyperuricemic volunteers presented lower
mean and minimum SpO2 and increased desaturation index. Minimum SpO2 was
a significant predictor of uric acid levels, which in turn was considered an
independent predictor for OSA in the binary logistic model. ROC curve analysis
for establishing cut-off points for uric acid levels as a biomarker of OSA revealed
moderate sensitivity and specificity.
A strong association was found
between uric acid levels and OSA.
2013 Kurt et al 144 Hemoglobin, platelet, CRP, MPV, and RDW values did not differ between AHI
groups. PDW was significantly higher in group D (mean value 14.4±1.8) than in
group A (13.2±0.5) (P<0.001). When the four groups were compared, group D
had the lowest minimum SpO2 value [group A (89.4±3.0), B (86.7±4.2), C
(81.2±6.4), and D (68.2±13.0)]. There was a statistically significant correlation
The severity of OSA was not
correlated with CRP, MPV, and RDW.
PDW might be related markers of OSA
severity.
37
between AHI and age (r=0.35, P<0.001), BMI (r=0.31, P=0.003), PDW (r=0.28,
P=0.006), and Epworth sleepiness scale (r=0.29, P=0.007). AHI was not
correlated with CRP, MPV, and RDW. PDW is higher in severe OSA and is
correlated with different parameters of breathing function during sleep.
2013 Murase et al
109
The Ngal level correlated significantly with OSA severity as determined by the
AHI (r = 0.24, p = 0.01) and 4% ODI (r = 0.26, p = 0.01). Multiple regression
analysis showed that the Ngal level was associated with 4%ODI independently of
other clinical variables. Although the OSA (4% ODI: 33.1±16.7 to 1.1±1.9/h,
P<0.01) had significantly improved in those with good compliance, the Ngal
levels were not significantly changed (60.5±18.1 before CPAP vs 64.2±13.9
ng/ml after CPAP, P=0.27).
Plasma Ngal levels were positively
associated with the severity of OSA. It
does not seem reasonable to use the
Ngal level as a specific biomarker of
OSA in clinical practice.
2013 Ntalapascha
et al 145
The overnight change (%) of GSH/GSSG ratio and GSH was significantly
different between OSA and controls (p=0.03 and p=0.048, respectively). Plasma
protein carbonyls, erythrocyte catalase activity, 8- isoprostane, SOD, TBARS,
and TAC plasma values were not different between OSA and controls (p>0.05).
No significant correlation was found between changes in the levels of biomarkers
and AHI, arousal, or desaturation index.
OSA per se might be associated with
increased oxidative burden possibly
via GSH/GSSG pathway.
2013 Ozben et al
146
Patients with OSA had a higher incidence of hypertension and BMI but lower
serum copeptin level (P=0.007) compared with the healthy controls. There was
no significant difference regarding to serum copeptin levels between the
Copeptin levels in OSA patients could
be valuable to demonstrate impairment
in ADH regulation.
38
moderate and severe OSA patients (P=0.409).
2013 Pinto et al 154 At baseline, NOx levels showed a significant decrease during the night in both
groups (P<0.001). U-NE level and BP were significantly higher in the severe OSA
group. After 1 month of CPAP, there was a significant increase in NOx levels and
a reduction in U-NE level and BP only in patients with severe OSA.
One month of CPAP results in
significant improvements in NOx
levels, 24-h U-NE level and BP in
patients with severe OSA, but not in
patients with mild-moderate OSA.
2013 Shi et al 83 Serum S100A12 levels were significantly higher in the OSA group than in the
control group (132.17 (range 101.86 to 174.49) ng/ml vs. 78.40 (range 58.35 to
129.44) ng/ml, P<0.01). Multivariate logistic regression demonstrated that
S100A12 was the only significant and independent predictor of OSA (OD 1.012,
95 % CI 1.006 to 1.017; P<0.01). Serum S100A12 levels elevated with the
increase in the severity of OSA (S100A12 levels of 106.04 (range 83.92 to
135.13) ng/ml in mild OSA group, 133.51 (range 109.64 to 208.95) ng/ml in
moderate OSA group, and 173.04 (range 131.88 to 275.77) ng/ml in severe OSA
group; P<0.001). Serum S100A12 levels were independently correlated with AHI
scores (r=0.324, P<0.001)
Serum S100A12 levels were
independently associated with the
presence and severity of OSA. Serum
S100A12 level could be a potential
biomarker for OSA.
2013 Wang et al 85 Plasma fractalkine levels were significantly higher in patients with OSA than in
controls (463.15±110.78 versus 364.67±64.81 pg/mL, F=2.58, P=0.004).
Fractalkine were associated with AHI (r=0.756, P<0.0001), lowest oxygen
OSA is associated with elevated levels
of fractalkine. The severity of OSA is
proportional to the fractalkine level.
39
saturation (r=−0.466, P=0.005), and mean oxygen saturation (r=−0.344,
P=0.043). Plasma fractalkine levels were significantly decreased in patients with
OSA after four nights nCPAP (463.15±110.78 versus 416.75± 97.67 pg/mL,
P=0.001).
2013 Wang et al 84 Serum omentin-1 levels were significantly decreased in OSA patients compared
with healthy controls. Multivariable logistic regression analysis revealed that
serum omentin-1 levels were inversely associated with the presence of OSA
(OR= 0.520, 95% confidence interval 0.433 to 0.623; P<0.001). Severe OSA
patients had significantly lower serum omentin-1 levels compared with mild and
moderate OSA patients.
Decreased serum omentin-1 levels
could be considered as an marker of
OSA.
2013 Zhang et al 86 Compared with the control group, patients with severe OSA presented
significantly higher levels of hsCRP (1.10±0.28 vs. 0.88±0.20 mg/l) and serum
cystatin C (0.87±0.12 vs. 0.74±0.10 mg/l) (p<0.05 for all comparisons). After
adjustment for confounding factors, AHI was significantly and positively
associated with serum cystatin C levels (β00.284, P=0.007).
Serum cystatin C was associated with
the severity of OSA in younger men.
2014 Tual-Chalot et
al 147
VEGF content carried by circulating microparticles from OSA patients was
increased when compared with microparticles from non-OSA patients. Circulating
microparticles from OSA patients induced an increase of angiogenesis that was
abolished in the presence of the antagonist of endothelin-1 receptor type B.
Endothelin-1 secretion was increased in human endothelial cells treated by OSA
Circulating microparticles from OSA
patients can modify the secretome of
endothelial cells leading to
angiogenesis.
40
microparticles.
2014 Vavougios et
al 148
Statistically significant correlations were detected between DJ-1’s levels and AHI
(P=0.04), Desaturation Index (P=0.012), and LDL (P=0.042).
DJ-1 may be a useful biomarker in
OSA.
2014 Wang et al 87 Serum YKL-40 concentrations were significantly elevated in OSA patients than in
controls. Multivariate logistic regression including all variables revealed that YKL-
40 was the significant and independent predictor for the present of OSA. There is
a significant positive correlation between increments in serum YKL-40
concentrations and severity of OSA. Serum YKL-40 concentrations were
independently and significantly correlated with AHI scores.
YKL-40 could be used as a potential
biomarker for predicting OSA.
* All terms that mean obstructive sleep apnea (SDB, SRDB, OSAS) were standardized as OSA.
Abbreviations
8-OHdG=8-hydroxy-2’-deoxyguanosine, ADH=antidiuretic hormone, AHI=apnea/hypopnea index, AIC=akaike information criterion, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, BMI=body mass index, BP=blood pressure, CI=confidence interval, CK=creatine phosphokinase, CPAP=continuous positive
airway pressure, CRP=C-reactive protein, CVD=cardiovascular disease, DHA=omega-3 fatty acid docosahexaenoic acid, d-ROMs= derivatives of reactive oxygen
metabolites, DJ-1=gene that is involved in tumorigenesis and in maintaining mitochondrial homeostasis, DSI=desaturation index, EBC= exhaled breath
condensate, eCO=exhaled carbon monoxide, eNO=exhaled nitric oxide, ESS=epworth sleepiness scale, FRAP=ferric reducing antioxidant power, GCP-
2=granulocyte chemotactic peptide-2, GPX=glutathione peroxidase, GSH=reduced glutathione, GSSG=oxidized glutathione, H2O2= hydrogen peroxide, HCO 3
=bicarbonate, HOMA-B= Homeostasis Model Assessment- β-cell function, HOMA-IS=homeostasis model assessment estimates of insulin sensitivity, hs-CRP=high
41
sensitivity C-reactive protein, ICAM-1=intercellular adhesion molecule-1, IGM=immunoglobulin M, IHR=intermittent hypoxia/reoxygenation, IL-6=interleukin-6, IL-
8=interleukin-8, IL-10=interleukin-10, IQR=interquartile range, IRH=ischemic reactive hyperemia, KL-6=Krebs von den Lungen-6, LDA=linear discriminant analysis,
LDL=low-density lipoprotein, LOX-1=oxidized low-density lipoprotein receptor-1, LTB4=leukotriene B4, MCP-1=monocyte chemoattractant protein-1,
MDA=malondialdehyde, MMP-9=matrix metallopeptidase-9, MPO=myeloperoxidase, MPV=mean platelet volume, nCPAP=nasal continuous positive airway
pressure, NF-kB=proinflamatory transcription nuclear factor kappa B, Ngal=neutrophil gelatinase-associated lipocalin, NGM=normal glucose metabolism,
nNO=nasal nitric oxide, NOx=reduced plasma nitrate mono-nitrogen oxides, NSE=neuron-specific enolase, ODI=oxygen desaturation index, OR=odds ratio,
OSA=obstructive sleep apnea, oxLDL=oxidized low-density lipoprotein, PAI-1=plasminogen activator inhibitor-1, PDW=platelet distribution width, pLOX-1=plasma
LOX-1, PPVs=positive predictive values, PSG=polysomnography, PWV=pulse wave velocity, RBC=red blood cell, RDI=respiratory disturbance index, RDW=red
cell distribution width, ROC=receiver operating characteristic, SAA= serum amyloid, SaO2=oxygen saturation, S100B=S100 Calcium Binding Protein B, sIL-
6R=soluble interleukin-6 receptor, SOD=superoxide dysmutase, SpO2=peripheral capillary oxygen saturation, SSBP=sleep systolic blood pressure, sTNFR-
1=soluble tumor necrosis factor receptor-1, svCAM=soluble vascular cell adhesion molecule, TAC=total antioxidant capacity, TAS=total antioxidant status, TBARS
=thiobarbituric acid-reactive substances, TNF-α R2=tumor necrose factor alpha receptor 2, TNF-α=tumor necrose factor alpha, TRX=thioredoxin, TSH=thyroid
stimulating hormone, TSTs=percentage of total sleep time spent, U-NE=urinary norepinephrine, VCAM=vascular cell adhesion molecule, VCAM-1=vascular cell
adhesion molecule-1, VEGF=vascular endothelial growth factor, vWF=von Willebrand factor, WHR=waist-to-hip ratio, WL=weight loss, YKL-40=human cartilage
glycoprotein-39.
42