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Original Research: Sleep Disorders |

Endothelial Function in Children With OSA and the Effects of AdenotonsillectomyEndothelial Function in Children With OSA FREE TO VIEW

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; Albert Martin Li, MD
Author and Funding Information

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.

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


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.

FUNDING/SUPPORT: This study was supported by the Research Grants Council of the Hong Kong Special Administrative Region, China [CUHK4508/06M].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(1):132-139. doi:10.1378/chest.14-1307
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BACKGROUND:  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.

METHODS:  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.

RESULTS:  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 = .04) than the control group. Thirty-two case subjects underwent AT. A significant reduction in OAHI was documented in the AT group (−8.8 events/h [IQR, −13.7 to −4.7]; P < .001) accompanied by a significant increase in FMD (+0.6% [IQR, 0.4-1.4]; P < .001), which was not observed in subjects who did not undergo AT.

CONCLUSIONS:  Children with OSA had reduced FMD, which was reversible with treatment.

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.58 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 endothelium-dependent flow-mediated dilation (FMD) of the 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.1517

The few studies that have investigated the association between childhood OSA and impaired endothelial function have documented positive results.1822 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.1821 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.

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. 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 μg/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 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 pressure-transduced 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 θ, α, 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 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.2830 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.28,3032

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 within-group 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.

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 = .04) than the control group (Table 1).

Table Graphic Jump Location
TABLE 1 ]  Comparisons Between OSA Case Subjects and Control Subjects

Data are presented as mean ± SD or median (interquartile range) unless indicated otherwise. FMD = flow-mediated dilation; HDL = high-density lipoprotein; LDL = low-density lipoprotein; OAHI = obstructive apnea hypopnea index; ODI = oxygen desaturation index; REM = rapid eye movement; Spo2 = oxygen saturation; TC = total cholesterol; TG = triglyceride.

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 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 = 10) had milder disease than did those who had AT (n = 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 = .26).

Table Graphic Jump Location
TABLE 2 ]  Comparisons Between AT and Non-AT Groups at Baseline and Reassessment

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.

a 

P values were obtained from paired t tests and Wilcoxon signed rank tests for normally distributed and nonnormally distributed data, respectively.

b 

Significant differences between the pretreatment data of the two groups.

In the group that had undergone AT, a significant reduction in OAHI (−8.8 events/h [IQR, −13.7 to −4.7 events/h]; P < .001) and a significant decrease in arousal index (−6 events/h [−15.0 to 0.5 events/h]; P < .001) were observed. The amount of time in stage 1 also significantly decreased after AT (−0.6% [−3.3% to 0.2%]; P = .01). The improvements were accompanied by a significant increase in FMD (+0.6% [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 = .26). On the 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 = .72; baseline FMD, 8.3% ± 1.1%; post-treatment FMD, 8.4% ± 0.6%; P = .59).

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.1822 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 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.5,9,3437 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 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.

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.

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.

AT

adenotonsillectomy

FMD

flow-mediated dilation

IQR

interquartile range

OAHI

obstructive apnea hypopnea index

PSG

polysomnography

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Widlansky ME. Shear stress and flow-mediated dilation: all shear responses are not created equally. Am J Physiol Heart Circ Physiol. 2009;296(1):H31-H32. [CrossRef] [PubMed]
 
Kheirandish-Gozal L, Bhattacharjee R, Gozal D. Autonomic alterations and endothelial dysfunction in pediatric obstructive sleep apnea. Sleep Med. 2010;11(7):714-720. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [PubMed]
 
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. [CrossRef] [PubMed]
 
Kim J, Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, Gozal D. Circulating microparticles in children with sleep disordered breathing. Chest. 2011;140(2):408-417. [CrossRef] [PubMed]
 
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285-1295. [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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 nicotinamide-adenine dinucleotide phosphate oxidase. Pediatrics. 2008;122(3):e648-e655. [CrossRef] [PubMed]
 
Reneman RS, Arts T, Hoeks AP. Wall shear stress—an important determinant of endothelial cell function and structure—in the arterial system in vivo. Discrepancies with theory. J Vasc Res. 2006;43(3):251-269. [CrossRef] [PubMed]
 
Green DJ, Dawson EA, Groenewoud HM, Jones H, Thijssen DH. Is flow-mediated dilation nitric oxide mediated?: A meta-analysis. Hypertension. 2014;63(2):376-382. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
TABLE 1 ]  Comparisons Between OSA Case Subjects and Control Subjects

Data are presented as mean ± SD or median (interquartile range) unless indicated otherwise. FMD = flow-mediated dilation; HDL = high-density lipoprotein; LDL = low-density lipoprotein; OAHI = obstructive apnea hypopnea index; ODI = oxygen desaturation index; REM = rapid eye movement; Spo2 = oxygen saturation; TC = total cholesterol; TG = triglyceride.

Table Graphic Jump Location
TABLE 2 ]  Comparisons Between AT and Non-AT Groups at Baseline and Reassessment

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.

a 

P values were obtained from paired t tests and Wilcoxon signed rank tests for normally distributed and nonnormally distributed data, respectively.

b 

Significant differences between the pretreatment data of the two groups.

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Widlansky ME. Shear stress and flow-mediated dilation: all shear responses are not created equally. Am J Physiol Heart Circ Physiol. 2009;296(1):H31-H32. [CrossRef] [PubMed]
 
Kheirandish-Gozal L, Bhattacharjee R, Gozal D. Autonomic alterations and endothelial dysfunction in pediatric obstructive sleep apnea. Sleep Med. 2010;11(7):714-720. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [PubMed]
 
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. [CrossRef] [PubMed]
 
Kim J, Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, Gozal D. Circulating microparticles in children with sleep disordered breathing. Chest. 2011;140(2):408-417. [CrossRef] [PubMed]
 
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285-1295. [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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 nicotinamide-adenine dinucleotide phosphate oxidase. Pediatrics. 2008;122(3):e648-e655. [CrossRef] [PubMed]
 
Reneman RS, Arts T, Hoeks AP. Wall shear stress—an important determinant of endothelial cell function and structure—in the arterial system in vivo. Discrepancies with theory. J Vasc Res. 2006;43(3):251-269. [CrossRef] [PubMed]
 
Green DJ, Dawson EA, Groenewoud HM, Jones H, Thijssen DH. Is flow-mediated dilation nitric oxide mediated?: A meta-analysis. Hypertension. 2014;63(2):376-382. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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