[

Original Research Sleep Disorders

Endothelial Function in Children With OSA

and the Effects of Adenotonsillectomy
Kate C. C. Chan, MB; Chun T. Au, MPhil; Ping Chook, MD; Dennis L. Y. Lee, MB; Hugh S. Lam, MB;
Yun K. Wing, MB; and Albert Martin Li, MD

The association between childhood OSA and endothelial function as measured

by flow-mediated dilation (FMD) and its response to OSA treatment are uncertain. The objective of this study was to compare FMD in children with OSA with nonsnoring control subjects
and to examine its response to treatment.
BACKGROUND:

Index cases were children aged 6 to 18 years with habitual snoring and polysomnography (PSG)-confirmed OSA (obstructive apnea hypopnea index [OAHI] . 1 events/h).
Each case was paired with an age-, sex-, and BMI-matched nonsnoring control subject
recruited from our previous community growth survey. All subjects underwent FMD measurement in the morning after overnight PSG. Adenotonsillectomy (AT) was offered to subjects who satisfied predefined AT operation criteria. All cases underwent repeat PSG and FMD
assessment 6 months later.

METHODS:

A total of 63 case-control pairs were recruited. The OSA group had a significantly
higher OAHI (median, 5.3 events/h [interquartile range (IQR), 2.6-11.7] vs 0.2 events/h
[IQR, 0-0.5], P , .001) and lower FMD (mean SD, 7.9% 1.3% vs 8.3% 0.8%; P 5 .04)
than the control group. Thirty-two case subjects underwent AT. A significant reduction in
OAHI was documented in the AT group (28.8 events/h [IQR, 213.7 to 24.7]; P , .001)
accompanied by a significant increase in FMD (10.6% [IQR, 0.4-1.4]; P , .001), which was
not observed in subjects who did not undergo AT.
RESULTS:

CONCLUSIONS:

Children with OSA had reduced FMD, which was reversible with treatment.
CHEST 2015; 147(1):132-139

Manuscript received June 1, 2014; revision accepted September 8, 2014;

originally published Online First October 2, 2014.
ABBREVIATIONS: AT 5 adenotonsillectomy; FMD 5 flow-mediated
dilation; IQR 5 interquartile range; OAHI 5 obstructive apnea hypopnea
index; PSG 5 polysomnography
AFFILIATIONS: From the Department of Pediatrics (Drs Chan, Chook,
Lam, and Li, and Mr Au), the Department of Otorhinolaryngology Head and Neck Surgery (Dr Lee), and the Department of Psychiatry
(Dr Wing), Prince of Wales Hospital, The Chinese University of Hong
Kong, Shatin, Hong Kong.
Part of this article was presented in abstract form at the Annual Scientific
Meeting of the Hong Kong College of Pediatricians, December 7, 2013,
Hong Kong.

132 Original Research

FUNDING/SUPPORT: This study was supported by the Research Grants

Council of the Hong Kong Special Administrative Region, China
[CUHK4508/06M].
CORRESPONDENCE TO: Albert Martin Li, MD, Department of
Pediatrics, Prince of Wales Hospital, The Chinese University of Hong
Kong, 30-32 Ngan Shing St, Shatin, 000, Hong Kong; e-mail: albertmli@
cuhk.edu.hk
2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of
this article is prohibited without written permission from the American
College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.14-1307

147#1 CHEST JANUARY 2015

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

Childhood OSA is a common sleep disorder, affecting

around 5% of school-aged children.1,2 The condition is
characterized by prolonged partial and/or intermittent
complete upper airway obstruction. Repeated apneas
and hypopneas during sleep result in intermittent
hypoxemia and hypercapnia, cortical and sympathetic
nervous system arousals, and sleep fragmentation.2 In
adults, OSA is established as an important and independent risk factor for cardiovascular adverse events.3,4
However, the mechanisms underlying the association
are not well defined. One of the postulated mechanisms
is that OSA precipitates and/or accelerates atherosclerosis
mediated via endothelial dysfunction.3
Several studies have reported an association between
OSA and high BP in children.5-8 Intermittent hypoxia
and the resulting oxidative stress in OSA can reduce nitric
oxide bioavailability.9 A recent study showed that children
with OSA have more proinflammatory monocytes and
reduced nitric oxide production in circulating monocytes, which are closely linked to endothelial dysfunction.10 Furthermore, OSA results in sleep fragmentation
that causes systemic inflammation and sympathetic activation.9,11,12 All these intermediate processes can lead to
endothelial dysfunction, which has been shown to
precede the formation of plaque and atherosclerosis.3,9
Ultrasonographic assessment of endotheliumdependent flow-mediated dilation (FMD) of the

Materials and Methods

Subjects and Study Design
Children aged 6 to 18 years with habitual snoring ( 3 nights per week)
were recruited from our sleep disorder clinic. Nonsnoring control subjects were recruited from participants in a community growth survey.
Written informed consent and assent were obtained from parents and
subjects, respectively. The exclusion criteria included previous treatment of OSA; presence of structural heart disease; medical history of
hypertension, dyslipidemia, diabetes mellitus, genetic syndrome, craniofacial anomalies, congenital or acquired neuromuscular disease,
premature birth, or intrauterine growth retardation; active smoking;
and acute illness within 4 weeks of recruitment.
Weight, height, and BP of the subjects were measured on the day of
the polysomnography (PSG). BP was measured using the oscillometric
method (Datascope Accutorr Plus; Datascope Corp) after sitting for
5 min. Two readings were taken at 5-min intervals on the nondominant
arm at the heart level with the proper-sized cuff chosen according to
the length and circumference of the arm. The average of two readings
was used for analysis. BMI was converted to BMI z score according
to local reference.24 Overweight was defined as a BMI z score . 1.036
(ie, . 85th percentile), and obesity was defined as a BMI z score . 1.645
(ie, . 95th percentile).
All subjects underwent overnight PSG. A blood sample for fasting lipid
profile was taken the next morning, followed by FMD evaluation.
Index cases were subjects with habitual snoring and PSG-confirmed
OSA with an obstructive apnea hypopnea index (OAHI) of . 1 event/h.

brachial artery is the gold standard in assessing endothelial function.13,14 FMD is predominately a result of
endothelial nitric oxide release, and FMD of the
brachial artery correlates well with both coronary
endothelial function and the extent of coronary artery
atherosclerosis.15-17
The few studies that have investigated the association
between childhood OSA and impaired endothelial function have documented positive results.18-22 In one study
that assessed the effects of treatment, endothelial dysfunction improved after adenotonsillectomy (AT).18 However,
these studies were limited by their methodology, namely
unmatched cases and control subjects, and the gold
standard of measuring FMD induced by hyperemia was
not used.18-21 A publication that assessed FMD by hyperemia yielded negative results; the authors failed to document a significant difference in FMD between children
with a desaturation index of . 10/h and those with a
desaturation index of 10/h.23 Therefore, whether endothelial dysfunction is associated with childhood OSA
remains unclear.
In this study, we aimed to evaluate (1) FMD in children
with OSA compared with normal control subjects and
(2) its response to OSA treatment. We hypothesized
that children with OSA would have lower FMD when
compared with control subjects, and that the impairment would improve following AT.

Each index case was paired with an age-, sex-, and BMI-matched control subject. For the control group, there was no parental report of
snoring. All control subjects had a normal PSG (OAHI 1 event/h)
and did not snore on the night of the PSG.
All subjects found to have OSA were referred for upper airway assessment by an otorhinolaryngologist. AT was offered to those with large
tonsils (Brodsky grading 2) and/or large adenoids (adenoids 25%
of the postnasal space, as examined by nasoendoscopy).25 For those
who refused surgical intervention, or in cases in which surgery was
not indicated based on predefined criteria, intranasal corticosteroids
(Mometasone, 100 mg/day for 6 months) or CPAP therapy were offered.
All OSA cases were invited to have a reassessment 6 months later. This
study was conducted with the approval of the Joint Chinese University
of Hong Kong-New Territories East Cluster Clinical Research Ethics
Committee (reference number 2005.356).
Polysomnography
An overnight PSG was performed on each subject using the Siesta
ProFusion II PSG monitor (Compumedics Telemed PTY Ltd) to record
the following parameters: EEG from four leads (C3/A2, C4/A1),
bilateral electrooculogram, and electromyogram of mentalis activity
and bilateral anterior tibialis. Respiratory movements of the rib cage
and abdomen were detected by piezo-based effort belts. ECG and heart
rate were recorded continuously from two anterior chest leads. Arterial
oxyhemoglobin saturation was monitored by an oximeter (Ohmeda
Biox 3900 Pulse Oximeter; Datex-Ohmeda). Respiratory airflow pressure signals were measured at the anterior nares and connected to a
pressure transducer. An oronasal thermal sensor was also used to

journal.publications.chestnet.org

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

133

detect the absence of airflow. Snoring was assessed by a snoring

microphone placed near the throat. Body position was recorded by a
body position sensor.26 Computerized sleep data were edited visually by
an experienced PSG technologist according to standardized criteria.27
An obstructive apnea was defined as an absence of airflow with persistent respiratory effort lasting at least two baseline breaths, irrespective of arterial oxygen saturation changes. An obstructive hypopnea
was defined as a reduction of 50% in the amplitude of the pressuretransduced airflow signal, with persistent respiratory effort lasting at
least two baseline breaths, accompanied by an oxygen desaturation of
at least 3% and/or an arousal. The OAHI was defined as the total number
of obstructive apneas and hypopneas per hour of total sleep time. The
oxygen desaturation index was defined as the total number of dips in
arterial oxygen saturation of at least 3% per hour of sleep. Arousal
was defined as an abrupt shift in EEG frequency during sleep, which
may have included u, a, and/or frequencies . 16 Hz but not spindles,
with 3 to 15 s in duration. In rapid eye movement sleep, arousals were
scored only when accompanied by concurrent increases in submental
electromyogram amplitude. The arousal index was defined as the total
number of arousals per hour of total sleep time.
Assessment of Endothelial Function
The assessment was carried out within 3 h after awakening in a quiet,
temperature-controlled room. All subjects abstained from food, including
caffeine, for at least 6 h before the study. The diameter of the brachial
artery was measured on B-mode ultrasound images (1) at rest and (2) in
response to reactive hyperemia, which was induced by inflation of a
BP cuff placed around the lower arm to a pressure of 220 mm Hg for
4 to 5 min, followed by rapid deflation, using a linear array transducer
(L10-5 median frequency, 7.5 MHz) and the Advanced Technology
Laboratories 3000 ultrasound system. To minimize variability, all

Results
Endothelial Function in Children With OSA

A total of 63 sex-, age-, and BMI-matched case-control

pairs were recruited (Table 1). The mean ages in the
OSA and control groups were 10.3 2.9 years and
10.4 2.7 years, respectively. Thirty subjects in each
group were overweight or obese. None of the
recruited children had hypertension. There were no
statistically significant differences in the baseline BP
and fasting lipid profiles between the two groups. The
OSA group had a significantly higher OAHI (median,
5.3 events/h [IQR, 2.6-11.7 events/h] vs 0.2 events/h
[IQR, 0-0.5 events/h]; P , .001) and lower FMD
(mean, 7.9% 1.3% vs 8.3% 0.8%; P 5 .04) than the
control group (Table 1).
Responses to AT

Forty-six out of 63 OSA cases were candidates for AT

according to the predefined criteria, of whom 32 agreed
to receive the operation. Of the 31 children who did not
have AT, none agreed to use CPAP, 10 received 6-month
intranasal corticosteroids therapy, and the remaining
21 subjects refused any treatment. Comparisons between
groups are shown in Table 2. Children who underwent
surgical intervention had significantly higher OAHI at

134 Original Research

measurements were taken at end diastole identified by the R wave on

electrocardiogram, and the average of three measurements taken along
the vessel was calculated. The full procedure was described in detail
previously.28
FMD was defined as the percentage increase in vessel diameter from
baseline in response to reactive hyperemia. In arteries lined by healthy
endothelium, increased flow causes dilatation of the vessel via release
of the endothelium-derived relaxing factor and, therefore, FMD is
endothelium dependent. Hyperemia was calculated as the percentage
increase in blood flow after cuff deflation, compared with baseline. The
whole procedure produced minimal discomfort and was well tolerated
by the children.28-30 All ultrasonographic scans were performed by
the same investigator, who was blinded to the identity and clinical
characteristics of the subjects. The accuracy, reproducibility, and low
interobserver error for this measurement have been demonstrated
previously.28,30-32
Statistical Analysis
Data were expressed as mean SD for normally distributed data and
median (interquartile range [IQR]) for nonnormally distributed data,
unless otherwise specified. Case-control comparisons were tested by
independent Student t tests and Mann-Whitney U tests for normally
distributed and nonnormally distributed data, respectively. The withingroup changes over time for the AT and non-AT groups were tested by
paired Student t tests and Wilcoxon signed-rank tests for normally
distributed and nonnormally distributed data, respectively. Two-way
repeated-measures analysis of variance was used to assess the differences in the changes in FMD between the AT and non-AT groups. All the
statistical analyses were performed with SPSS 13.0 for Windows (IBM),
and a two-tailed P value , .05 was considered statistically significant.

baseline when compared with those who did not

undergo AT (10.5 events/h [IQR, 6.0-15.4 events/h]
vs 3.3 events/h [IQR, 1.8-4.1 events/h]; P , .001) (Table 2).
No significant differences in age, BMI, BP, FMD, hyperemia, or fasting lipid profiles were found between groups
at baseline. At baseline, those who received nasal spray
(n 5 10) had milder disease than did those who had
AT (n 5 32) (2.1 events/h [IQR, 1.6-3.5 events/h]
vs 10.5 events/h [IQR, 6.0-15.4 events/h]; P , .001), and
there was no significant difference in FMD (8.3% 1.1%
vs 7.7% 1.5%; P 5 .26).
In the group that had undergone AT, a significant reduction
in OAHI (28.8 events/h [IQR, 213.7 to 24.7 events/h];
P , .001) and a significant decrease in arousal index
(26 events/h [215.0 to 0.5 events/h]; P , .001) were
observed. The amount of time in stage 1 also significantly
decreased after AT (20.6% [23.3% to 0.2%]; P 5 .01).
The improvements were accompanied by a significant
increase in FMD (10.6% [IQR, 0.4% to 1.4%]; P , .001).
There was a significant difference in the change in FMD
between the two groups even after adjustment for age,
sex, BMI z score, and brachial artery diameter at rest
(P , .001). Moreover, FMD after AT was also found to
be comparable with that of the non-OSA control subjects (8.5% 1.2% vs 8.3% 0.8%; P 5 .26). On the

147#1 CHEST JANUARY 2015

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

TABLE 1

] Comparisons Between OSA Case Subjects and Control Subjects

Characteristic

Case Subjects (n 5 63)

Age, y

10.3 2.9

Male, No. (%)

Overweight, No. (%)

41 (65.1)
30 (47.6)

Control Subjects (n 5 63)

10.4 2.7

P Value
.71

41 (65.1)

1.00

30 (47.6)

1.00

BMI, kg/m2

20.6 5.9

20.3 5.8

.72

BMI z score

0.89 1.26

0.84 1.09

.81

Sleep eciency, %

88.8 8.6

85.7 9.8

.07

Total sleep time, min

492 60

473 75

.12

REM sleep, %

21.5 (18.8-25.0)

19.5 (16.6-21.9)

.01

Stage 1 sleep, %

6.0 (3.3-7.9)

4.0 (1.2-7.3)

Stage 2 sleep, %

38.3 (32.7-41.9)

40.5 (34.3-45.8)

Slow-wave sleep, %

33.5 (29.0-40.8)

34.4 (27.3-41.7)

.02
.09
.70

OAHI, events/h

5.3 (2.6-11.7)

0.2 (0-0.5)

ODI, events/h

3.7 (1.1-11.0)

0.5 (0.1-1.0)

, .001

94 (93- 95)

, .001

SpO2 nadir, %

90 (85-93)

Arousal index, events/h

16.4 (12.9-21.8)

Systolic BP, mm Hg

108 12

Diastolic BP, mm Hg

65 9

9.5 (6.6-13.2)

, .001

, .001

107 11

.61

64 10

.43

FMD, %

7.9 1.3

8.3 0.8

.04

Hyperemia, %

508 141

527 116

.41

TC, mM

4.3 0.6

4.3 0.8

.85

LDL, mM

2.3 0.5

2.3 0.7

.86

HDL, mM

1.5 0.4

1.6 0.4

.33

TG, mM

1.2 0.8

1.0 0.5

.11

Data are presented as mean SD or median (interquartile range) unless indicated otherwise. FMD 5 ow-mediated dilation; HDL 5 high-density
lipoprotein; LDL 5 low-density lipoprotein; OAHI 5 obstructive apnea hypopnea index; ODI 5 oxygen desaturation index; REM 5 rapid eye movement;
SpO2 5 oxygen saturation; TC 5 total cholesterol; TG 5 triglyceride.

other hand, treatment with nasal spray did not result in

significant improvement in OAHI and FMD (baseline
OAHI, 2.1 events/h [IQR, 1.6-3.5 events/h]; posttreatment OAHI, 2.2 events/h [IQR, 1.6-7.0 events/h],
P 5 .72; baseline FMD, 8.3% 1.1%; post-treatment
FMD, 8.4% 0.6%; P 5 .59).

Discussion
Our study showed that children with OSA had impaired
endothelial function, as demonstrated by their significantly lower FMD compared with nonsnoring control
subjects, and in those with moderate to severe OSA,
AT was able to reverse the impaired endothelial function. These results provided robust evidence to support
an association between childhood OSA and endothelial
dysfunction.
Our results were consistent with those of previous
studies showing impaired endothelial function in children with OSA, although the methods adopted for
assessing endothelial function were different.18-22 Most

of the previous studies measured the degree of vessel

dilation in response to reactive hyperemia. The association between reactive hyperemia and FMD was not
linear and was dependent on several between-subject
factors, including structural and genetic differences.33
Children with OSA in our study had significantly
reduced FMD compared with the control subjects, but
significant differences in hyperemia between the groups
were not observed. Similarly, a significant increase in
FMD in the AT group was not accompanied by a significant increase in hyperemia. In other words, effective
treatment of OSA could increase the FMD response
independent of the change in the magnitude of reactive
hyperemia. Therefore, measuring reactive hyperemia
solely, as carried out in previous studies, would not
provide an accurate assessment of endothelial function.
Although these studies demonstrated the blunted postocclusive hyperemia in children with OSA and its reversibility with AT, our results further consolidated the
association between childhood OSA and endothelial

journal.publications.chestnet.org

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

135

136 Original Research

147#1 CHEST JANUARY 2015

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

90.5 8.1
502 60

89.2 8.3
506 47
19.2 (16.2-22.2)

Sleep eciency, %

Total sleep time, min

REM sleep, %

33.8 (27.2-40.0)
10.5 (6.0-15.4)
8.0 (2.4-13.5)b
89 (83-94)

Slow-wave sleep, %

OAHI, events/h

ODI, events /h

.07

8.5 1.2
513 119
4.2 0.9
2.2 0.7
1.5 0.4
1.3 0.7

7.7 1.5
496 148
4.1 0.6
2.2 0.5
1.5 0.4
1.2 0.9

Hyperemia, %

TC, mM

LDL, mM

HDL, mM

TG, mM

65 9

65 9

Diastolic BP, mm Hg

FMD, %

111 15

107 11

Systolic BP, mm Hg

.35

.98

.82

.53

.57

, .001

.80

.22

, .001
, .001

94 (92-95)

, .001

0.4 (0.1-0.9)

13.1 (8.8-17.6)

, .001

0.6 (0.2-1.6)

18.0 (14.8-25.7)b

.18

.08

.01

37.1 (31.2-42.4)

39.5 (34.3-43.3)

2.4 (1.1-3.5)

Arousal index, events /h

SpO2 nadir, %

42.7 (36.5-46.6)

Stage 2 sleep, %

3.7 (1.0- 6.7)

Stage 1 sleep, %

.72

.46

.06

.003

, .001

P Value
a

20 (64.5)

1.6 0.5
1.1 0.5

1.2 0.7

2.4 0.5

4.5 0.7

537 133

8.1 0.9

63 9

108 16

15.8 (12.5-20.9)

91 (87-94)

2.2 (1.1-5.5)

3.5 (1.7-8.0)

32.0 (26.5-40.8)

39.3 (33.1-44.5)

4.5 (1.5-8.5)

22.2 (18.5-23.9)

492 64

89.2 9.0

1.01 1.33

21.8 6.1

11.3 2.9

Reassessment

1.6 0.4

2.4 0.5

4.5 0.5

521 134

8.1 1.1

65 10

109 12

14.4 (12.5-18.1)b

91 (86-93)

1.7 (0.8-4.7)b

3.3 (1.8-4.1)

35.5 (27.3-43.4)

38.1 (33.7-45.5)

4.0 (1.8-9.1)

20.2 (17.2-21.9)

478 68

88.3 9.0

1.09 1.30

21.8 6.3

10.6 3.1

Baseline

Non-AT (n 5 31)

.87

.51

.34

.68

.71

.71

.25

.58

.38

.12

.89

.85

.19

.72

.66

.03

.29

.62

.14

.78

, .001

P Valuea

Data are presented as mean SD for normally distributed data and median (interquartile range) for nonnormally distributed data, unless indicated otherwise. See Table 1 legend for expansion of abbreviations.
P values were obtained from paired t tests and Wilcoxon signed rank tests for normally distributed and nonnormally distributed data, respectively.
bSignicant dierences between the pretreatment data of the two groups.

0.85 1.15

21.6 (18.0-25.1)

20.5 5.5

BMI, kg/m
0.71 1.20

21 (65.6)

10.7 2.6

19.6 5.3

9.9 2.6

Reassessment

BMI z score

Male, No. (%)

Age, y

Baseline

AT (n 5 32)

] Comparisons Between AT and Non-AT Groups at Baseline and Reassessment

Characteristic

TABLE 2

dysfunction with the use of the gold standard FMD

measurement.
The evidence linking childhood OSA to cardiovascular
morbidities has been growing, and endothelial dysfunction has been consistently found to be associated with
OSA.34 The mechanisms leading to cardiovascular morbidities in patients with OSA were likely secondary to
the complications associated with sleep-disordered
breathing, namely disrupted sleep architecture, intermittent hypoxia, oxidative stress, hypertension, systemic
inflammation, maladaptive autonomic responses, metabolic imbalance, and so forth.5,9,34-37 All these factors
interacted and may also have placed an adverse influence
on endothelial function, platelets, and inflammatory
cells.37,38 Endothelial homeostasis played a significant
role in determining the risk of a cardiovascular event.
With disturbances to the normal homeostasis, the endothelium would lose its ability to prevent abnormal vasoconstriction, platelet aggregation, and smooth muscle
cell proliferation.39 Endothelial dysfunction has indeed
been shown to be an early risk marker preceding the
process of atherogenesis.3,4 FMD was an endothelial
nitric oxide synthase-dependent response. Basically, the
ultrasonographic assessment of FMD was a measurement of the compliance and the capacity of the blood
vessels to respond to an increase in blood flow by vasodilation.13 In adults, abnormal FMD predicted cardiovascular morbidity independently of traditional
cardiovascular risk factors, and interventions to reduce
cardiovascular risk were accompanied by a parallel
improvement in FMD.14,40 FMD of the brachial artery
correlated well with coronary artery endothelial function, the impairment of which preceded the development of overt atherosclerosis and coronary artery
disease.16 Thus, FMD of the brachial artery was a useful
surrogate reflecting the risk of coronary artery atherosclerosis.17 This has signified the importance of our findings that reduced FMD of brachial artery in the subjects
with OSA might predict future cardiovascular morbidities and timely intervention might be able to reverse
this risk factor.
AT remains the first-line treatment of children with
moderate to severe OSA, yet the therapy for mild OSA
is still controversial. In our study, only children with
more severe disease underwent surgical treatment.
Nevertheless, a reversal of endothelial dysfunction following surgical intervention was demonstrated. For those
who had mild disease and refused surgery, a course of
nasal spray corticosteroids was shown not to be effective
in reversing endothelial dysfunction. All children with

OSA were assessed by an otorhinolaryngologist, and

those who satisfied the predefined criteria for surgery
were offered such intervention; however, only the parents of those with moderate to severe disease accepted
surgery. Despite a thorough explanation of the possible
complications associated with childhood OSA and our
experience of likely progression to more severe disease
in children with mild OSA and enlarged tonsils, most
of the parents of children with mild disease refused
surgery.41 This was not unexpected because the acceptance of surgery among Chinese parents is generally low.
Similar to the experience of other centers, the acceptance of and compliance with home noninvasive ventilation is also low in our locality; in fact, none of the
subjects in our cohort with moderate to severe disease
received noninvasive ventilation.
Hyperlipidemia and obesity are both important,
independent determining factors of endothelial
dysfunction.22,28,29,42 Therefore, BMI-matched control
subjects were recruited in this study to minimize the
cofounding effects of body weight. Moreover, there were
no significant differences in fasting lipid profile between
the OSA and control groups or between children who
received AT and those who did not. In the AT group, the
fasting lipid profiles were similar before and after AT.
This further supports the finding that the impairment of
endothelial function and its reversibility were associated
with OSA and AT, respectively.
Our study had several limitations. FMD has been demonstrated not to be entirely nitric oxide mediated, but
affected by a complex interplay of vasodilator and
vasoconstrictor stimuli.43,44 Factors including other
vasoactive substances, wall shear stress, and the
activity of the sympathetic nervous system also contribute to the total FMD response.43,44 Potential biased
interference on endothelial function by the scaling
properties of the FMD index is another concern.45
However, to date, the methodology adopted in our
study remains the most widely accepted standard assessment of endothelial function. We successfully demonstrated the association between childhood OSA and
endothelial dysfunction; however, whether this would
contribute to the development of cardiovascular complications in adulthood remained uncertain. However,
it has been found that the disease process of atherosclerosis could begin as early as the first decade of life.14,28,29
Impairment of the endothelial function in early life
may initiate abnormal reactions among the vessel wall,
platelets, neutrophils, and macrophages, and may
result in atherogenesis. Further prospective study

journal.publications.chestnet.org

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

137

would be needed to clarify the long-term implications

of endothelial dysfunction in children. In our study,
only selected subjects in the cohort underwent AT;
therefore, our results were more applicable to those
with moderate to severe disease. Further studies are
needed to confirm whether a reversal of impaired
endothelial function could also be seen with treatment
in children with milder disease.

Acknowledgments
Author contributions: Dr Chan is the
guarantor of the manuscript and takes
responsibility for the integrity of the data and
the accuracy of the data analysis. K. C. C. C.,
C. T. A., and A. M. L. contributed to the
project planning and data interpretation;
C. T. A. contributed to the interpretation
of PSG; K. C. C. C. and A. M. L. contributed
to the recruitment of subjects; C. T. A.
contributed to the data analysis; K. C. C. C.
contributed to the preparation of the
manuscript; P. C. contributed to the assessment
of endothelial function; D. L. Y. L. contributed
to the upper airway assessment and surgical
treatment of the subjects; and K. C. C. C.,
C. T. A., P. C., D. L. Y. L., H. S. L., Y. K. W.,
and A. M. L. contributed to the revision and
approval of the final manuscript.
Financial/nonfinancial disclosures: The
authors have reported to CHEST the following
conflicts of interest: Dr Wing has received
honoraria for serving as a part-time consultant
for Renascence Therapeutics Ltd. Drs Chan,
Chook, Lee, Lam, and Li and Mr Au have
reported that no potential conflicts of interest
exist with any companies/organizations
whose products or services may be discussed
in this article.
Role of sponsors: The design, execution,
data collection, and analysis of the study
were carried out solely by the research team
without the involvement of the funding
body.
Other contributions: This work was
performed at the Department of Pediatrics,
Prince of Wales Hospital, The Chinese
University of Hong Kong, Shatin, Hong Kong.
We are grateful for the cooperation and
participation of all the children and their
parents.

References
1. Li AM, So HK, Au CT, et al. Epidemiology
of obstructive sleep apnoea syndrome in
Chinese children: a two-phase community
study. Thorax. 2010;65(11):991-997.
2. Marcus CL, Brooks LJ, Draper KA, et al;
American Academy of Pediatrics.
Diagnosis and management of childhood
obstructive sleep apnea syndrome.
Pediatrics. 2012;130(3):576-584.
3. Kato M, Adachi T, Koshino Y, Somers
VK. Obstructive sleep apnea and cardiovascular disease. Circ J. 2009;73(8):
1363-1370.

138 Original Research

Conclusions
Our study supported an association between childhood
OSA and endothelial dysfunction as reflected by
reduced FMD. The impairment in the endothelial function was reversible with AT. These results suggest that
childhood OSA exerts a significant adverse effect on the
endothelial function and therefore, early diagnosis of
childhood OSA and timely intervention are vital.

4. Snchez-de-la-Torre M, CamposRodriguez F, Barb F. Obstructive sleep

apnoea and cardiovascular disease.
Lancet Respir Med. 2013;1(1):61-72.
5. Li AM, Au CT, Sung RY, et al. Ambulatory
blood pressure in children with obstructive sleep apnoea: a community based
study. Thorax. 2008;63(9):803-809.
6. Amin R, Somers VK, McConnell K, et al.
Activity-adjusted 24-hour ambulatory
blood pressure and cardiac remodeling in
children with sleep disordered breathing.
Hypertension. 2008;51(1):84-91.
7. Bixler EO, Vgontzas AN, Lin HM, et al.
Blood pressure associated with sleepdisordered breathing in a population
sample of children. Hypertension. 2008;
52(5):841-846.
8. Nisbet LC, Yiallourou SR, Biggs SN, et al.
Preschool children with obstructive sleep
apnea: the beginnings of elevated blood
pressure? Sleep. 2013;36(8):1219-1226.
9. Jelic S, Padeletti M, Kawut SM, et al.
Inflammation, oxidative stress, and repair
capacity of the vascular endothelium
in obstructive sleep apnea. Circulation.
2008;117(17):2270-2278.
10. Kheirandish-Gozal L, Wang Y, Duggan
RC, et al. Nitric oxide production by
monocytes in children with OSA and
endothelial dysfunction. Clin Sci (Lond).
2014;127(5):323-330.
11. Hakim F, Gozal D, Kheirandish-Gozal L.
Sympathetic and catecholaminergic
alterations in sleep apnea with particular
emphasis on children. Front Neurol.
2012;3.
12. Kim J, Hakim F, Kheirandish-Gozal L,
Gozal D. Inflammatory pathways in children with insufficient or disordered sleep.
Respir Physiol Neurobiol. 2011;178(3):
465-474.
13. Corretti MC, Anderson TJ, Benjamin
EJ, et al; International Brachial Artery
Reactivity Task Force. Guidelines for the
ultrasound assessment of endothelialdependent flow-mediated vasodilation
of the brachial artery: a report of the
International Brachial Artery Reactivity
Task Force. J Am Coll Cardiol. 2002;
39(2):257-265.
14. Urbina EM, Williams RV, Alpert BS,
et al; American Heart Association
Atherosclerosis, Hypertension, and
Obesity in Youth Committee of the
Council on Cardiovascular Disease in
the Young. Noninvasive assessment of
subclinical atherosclerosis in children
and adolescents: recommendations for

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

standard assessment for clinical research:

a scientific statement from the American
Heart Association. Hypertension. 2009;
54(5):919-950.
Joannides R, Haefeli WE, Linder L, et al.
Nitric oxide is responsible for flowdependent dilatation of human peripheral conduit arteries in vivo. Circulation.
1995;91(5):1314-1319.
Anderson TJ, Uehata A, Gerhard MD,
et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;
26(5):1235-1241.
Schroeder S, Enderle MD, Ossen R,
et al. Noninvasive determination of
endothelium-mediated vasodilation as a
screening test for coronary artery disease:
pilot study to assess the predictive value
in comparison with angina pectoris,
exercise electrocardiography, and myocardial perfusion imaging. Am Heart J.
1999;138(4 pt 1):731-739.
Gozal D, Kheirandish-Gozal L, Serpero LD,
Sans Capdevila O, Dayyat E. Obstructive
sleep apnea and endothelial function in
school-aged nonobese children: effect of
adenotonsillectomy. Circulation. 2007;
116(20):2307-2314.
Kheirandish-Gozal L, Bhattacharjee R,
Kim J, Clair HB, Gozal D. Endothelial
progenitor cells and vascular dysfunction in children with obstructive sleep
apnea. Am J Respir Crit Care Med.
2010;182(1):92-97.
Kim J, Bhattacharjee R, Snow AB,
Capdevila OS, Kheirandish-Gozal L,
Gozal D. Myeloid-related protein 8/14
levels in children with obstructive sleep
apnoea. Eur Respir J. 2010;35(4):843-850.
Brunetti L, Francavilla R, Scicchitano P,
et al. Impact of sleep respiratory disorders on endothelial function in children.
Scientific World Journal. 2013:719456.
Bhattacharjee R, Kim J, Alotaibi WH,
Kheirandish-Gozal L, Capdevila OS,
Gozal D. Endothelial dysfunction in
children without hypertension: potential
contributions of obesity and obstructive
sleep apnea. Chest. 2012;141(3):682-691.
Dubern B, Aggoun Y, Boul M, Fauroux B,
Bonnet D, Tounian P. Arterial alterations
in severely obese children with obstructive sleep apnoea. Int J Pediatr Obes.
2010;5(3):230-236.
Leung SS, Cole TJ, Tse LY, Lau JT. Body
mass index reference curves for Chinese
children. Ann Hum Biol. 1998;25(2):
169-174.

147#1 CHEST JANUARY 2015

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

25. Ng SK, Lee DL, Li AM, Wing YK, Tong

MC. Reproducibility of clinical grading
of tonsillar size. Arch Otolaryngol Head
Neck Surg. 2010;136(2):159-162.
26. Li AM, Ng C, Ng SK, et al. Adipokines
in children with obstructive sleep apnea
and the effects of treatment. Chest.
2010;137(3):529-535.
27. Iber C, Ancoli-Israel S, Chesson AL Jr,
Quan SF; for the American Academy of
Sleep Medicine. The AASM Manual for the
Scoring of Sleep and Associated Events: Rules,
Terminology and Technical Specifications.
1st ed. Westchester, IL: American Academy
of Sleep Medicine; 2007.
28. Celermajer DS, Sorensen KE, Gooch
VM, et al. Non-invasive detection of
endothelial dysfunction in children and
adults at risk of atherosclerosis. Lancet.
1992;340(8828):1111-1115.
29. Woo KS, Chook P, Yu CW, et al.
Overweight in children is associated with
arterial endothelial dysfunction and
intima-media thickening. Int J Obes Relat
Metab Disord. 2004;28(7):852-857.
30. Woo KS, Chook P, Yu CW, et al. Effects
of diet and exercise on obesity-related
vascular dysfunction in children.
Circulation. 2004;109(16):1981-1986.
31. Sorensen KE, Celermajer DS,
Spiegelhalter DJ, et al. Non-invasive
measurement of human endothelium
dependent arterial responses: accuracy
and reproducibility. Br Heart J. 1995;
74(3):247-253.
32. Woo KS, Chook P, Lolin YI, Sanderson
JE, Metreweli C, Celermajer DS. Folic

acid improves arterial endothelial

function in adults with hyperhomocystinemia. J Am Coll Cardiol. 1999;34(7):
2002-2006.

40.

33. Widlansky ME. Shear stress and flowmediated dilation: all shear responses are
not created equally. Am J Physiol Heart
Circ Physiol. 2009;296(1):H31-H32.
34. Kheirandish-Gozal L, Bhattacharjee R,
Gozal D. Autonomic alterations and
endothelial dysfunction in pediatric
obstructive sleep apnea. Sleep Med.
2010;11(7):714-720.
35. Chan JY, Li AM, Au CT, et al. Cardiac
remodelling and dysfunction in children
with obstructive sleep apnoea: a community based study. Thorax. 2009;64(3):
233-239.
36. Kheirandish-Gozal L, Capdevila OS,
Tauman R, Gozal D. Plasma C-reactive
protein in nonobese children with
obstructive sleep apnea before and after
adenotonsillectomy. J Clin Sleep Med.
2006;2(3):301-304.
37. Gozal D, Kheirandish-Gozal L.
Cardiovascular morbidity in obstructive
sleep apnea: oxidative stress, inflammation, and much more. Am J Respir Crit
Care Med. 2008;177(4):369-375.
38. Kim J, Bhattacharjee R, KheirandishGozal L, Spruyt K, Gozal D. Circulating
microparticles in children with sleep
disordered breathing. Chest. 2011;140(2):
408-417.
39. Deanfield JE, Halcox JP, Rabelink TJ.
Endothelial function and dysfunction:

journal.publications.chestnet.org

Downloaded From: http://journal.publications.chestnet.org/ by a Addenbrookes Hospital User on 08/13/2015

41.

42.

43.

44.

45.

testing and clinical relevance. Circulation.

2007;115(10):1285-1295.
Chan SY, Mancini GB, Kuramoto L,
Schulzer M, Frohlich J, Ignaszewski A.
The prognostic importance of endothelial dysfunction and carotid atheroma
burden in patients with coronary artery
disease. J Am Coll Cardiol. 2003;42(6):
1037-1043.
Li AM, Au CT, Ng SK, et al. Natural
history and predictors for progression of
mild childhood obstructive sleep apnoea.
Thorax. 2010;65(1):27-31.
Martino F, Loffredo L, Carnevale R, et al.
Oxidative stress is associated with arterial
dysfunction and enhanced intima-media
thickness in children with hypercholesterolemia: the potential role of nicotinamideadenine dinucleotide phosphate oxidase.
Pediatrics. 2008;122(3):e648-e655.
Reneman RS, Arts T, Hoeks AP. Wall
shear stressan important determinant of endothelial cell function and
structurein the arterial system in vivo.
Discrepancies with theory. J Vasc Res.
2006;43(3):251-269.
Green DJ, Dawson EA, Groenewoud HM,
Jones H, Thijssen DH. Is flow-mediated
dilation nitric oxide mediated?: A metaanalysis. Hypertension. 2014;63(2):
376-382.
Atkinson G, Batterham AM. The percentage flow-mediated dilation index: a
large-sample investigation of its appropriateness, potential for bias and causal
nexus in vascular medicine. Vasc Med.
2013;18(6):354-365.

139