Oscar Sans Capdevila

Metabolic Alterations and Systemic Inflammation in Obstructive Sleep Apnea among Nonobese and Obese Prepubertal Children

RATIONALE Obstructive sleep apnea (OSA) has been associated with a higher prevalence and severity of the metabolic syndrome in adult patients, even after controlling for obesity. In contrast, OSA in prepubertal children does not appear to correlate with the magnitude of such metabolic derangements. OBJECTIVES To further establish the potential mechanistic role of OSA in metabolic regulation in prepubertal children. METHODS Fasting glucose, insulin, C-reactive protein, apolipoprotein B, and serum lipid concentrations were determined during the initial polysomnographic diagnosis of OSA and 6-12 months after adenotonsillectomy in both obese and nonobese children. MEASUREMENTS AND MAIN RESULTS Sixty-two children with OSA (37 obese and 25 nonobese), age 7.40 +/- 2.6 years (mean +/- SD) completed the study. After adenotonsillectomy, significant improvements in apnea-hypopnea index and sleep fragmentation occurred, particularly among nonobese children. In nonobese children, adenotonsillectomy was associated with mild increases in body mass index z scores, no changes in either fasting glucose or insulin, significant increases in high-density lipoprotein and reciprocal decreases in low-density lipoprotein, and reductions in plasma C-reactive protein and apolipoprotein B levels. In obese children, adenotonsillectomy did not result in body mass index or glucose changes, but was associated with marked improvements in all other measures. CONCLUSIONS OSA does not appear to induce insulin resistance in nonobese pediatric patients but seems to play a significant role in obese patients. The significant improvements in lipid profiles, C-reactive protein, and apolipoprotein B after adenotonsillectomy in the two groups suggest a pathogenic role for OSA in lipid homeostasis and systemic inflammation independent of the degree of adiposity.

Pediatric Obstructive Sleep Apnea: Complications, Management, and Long-term Outcomes

Obstructive sleep apnea (OSA) in children has emerged not only as a relatively prevalent condition but also as a disease that imposes a large array of morbidities, some of which may have long-term implications, well into adulthood. The major consequences of pediatric OSA involve neurobehavioral, cardiovascular, and endocrine and metabolic systems. The underlying pathophysiological mechanisms of OSA-induced end-organ injury are now being unraveled, and clearly involve oxidative and inflammatory pathways. However, the roles of individual susceptibility (as dictated by single-nucleotide polymorphisms), and of environmental and lifestyle conditions (such as diet, physical, and intellectual activity), may account for a substantial component of the variance in phenotype. Moreover, the clinical prototypic pediatric patient of the early 1990s has been insidiously replaced by a different phenotypic presentation that strikingly resembles that of adults afflicted by the disease. As such, analogous to diabetes, the terms type I and type II pediatric OSA have been proposed. The different manifestations of these two entities and their clinical course and approaches to management are reviewed.

Obstructive Sleep Apnea and Endothelial Function in School-Aged Nonobese Children Effect of Adenotonsillectomy

Background— Obstructive sleep apnea (OSA) in children is associated with cardiovascular morbidity such as systemic and pulmonary hypertension. However, it remains unclear whether endothelial dysfunction occurs in pediatric OSA and whether it is reversible on effective treatment of OSA. Methods and Results— Consecutive nonobese children (aged 6 to 11 years) who were diagnosed with OSA after overnight polysomnography and control children matched on the basis of age, gender, ethnicity, and body mass index underwent blood draw the next morning for soluble CD40 ligand, asymmetric dimethylarginine (ADMA), and nitrotyrosine levels, as well as 2 iterations of 60-second cuff-occlusion tests for assessment of endothelial function. These tests were repeated 4 to 6 months after adenotonsillectomy. OSA children showed blunted reperfusion kinetics after release of occlusion, which completely normalized in 20 of 26 patients after adenotonsillectomy. All 6 children in whom no improvements occurred had a strong family history of cardiovascular disease (versus 2 of the remaining 20 patients; P<0.04). Plasma nitrotyrosine and ADMA levels were similar in OSA and control children; however, soluble CD40 ligand levels were higher in OSA children and were reduced after treatment, particularly in those with normalized hyperemic responses. Conclusions— Postocclusive hyperemia is consistently blunted in children with OSA, and such altered endothelial function is reversible 4 to 6 months after treatment, particularly if a family history of cardiovascular disease is not present. Although no evidence for either nitric oxide–dependent oxidative/nitrosative stress or for the increased presence of the circulating nitric oxide synthase inhibitor ADMA was found in children with OSA, soluble CD40 ligand levels were increased in OSA and reflected the changes in endothelial function after treatment.

Obstructive Sleep Apnea in Children: Relative Contributions of Body Mass Index and Adenotonsillar Hypertrophy

BACKGROUND The obesity epidemic has prompted remarkable changes in the proportion of obese children who are referred for habitual snoring. However, the contribution of obesity to adenotonsillar hypertrophy remains undefined. METHODS In our study, 206 nonobese habitually snoring children with polysomnographically diagnosed obstructive sleep apnea (OSA) were matched for age, gender, ethnicity, and obstructive apnea-hypopnea index (OAHI) to 206 obese children. Size estimates of tonsils and adenoids, and Mallampati class scores were obtained, and allowed for the assessment of potential relationships between anatomic factors and obesity in pediatric OSA. RESULTS The mean OAHI for the two groups was approximately 10.0 episodes/h total sleep time. There was a modest association between adenotonsillar size and OAHI in nonobese children (r = 0.22; p < 0.001) but not in obese children. The mean (+/- SEM) adenotonsillar size was larger in nonobese children (3.85 +/- 0.16 vs 3.01 +/- 0.14, respectively; p < 0.0001), and conversely Mallampati class scores were significantly higher in obese children (p < 0.0001). CONCLUSION The magnitude of adenotonsillar hypertrophy required for any given magnitude of OAHI is more likely to be smaller in obese children compared to nonobese children. Increased Mallampati scores in obese children suggest that soft-tissue changes and potentially fat deposition in the upper airway may play a significant role in the global differences in tonsillar and adenoidal size among obese and nonobese children with OSA.

APOE ε4 allele, cognitive dysfunction, and obstructive sleep apnea in children

Background: Obstructive sleep apnea (OSA) in children is associated with severity-dependent changes in neurocognitive functioning. However, the severity of OSA accounts for only approximately 40% of the variance in cognitive performance. Thus, genetic determinants of individual susceptibility may also contribute to the morbidity of OSA. Considering the unique susceptibility of apolipoprotein E (ApoE) knock-out mice to an experimental model of OSA, we examined whether the APOE ε4 allele contributes to increased neurocognitive morbidity in pediatric OSA. Methods: Consecutive habitually snoring and nonsnoring 5- to 7-year-old children underwent overnight polysomnography, neurocognitive testing, and a blood draw the next morning. Children were divided into OSA or no OSA, and OSA children were further subdivided into those with ≥2 abnormal cognitive subtest scores and those with normal cognitive scores. The presence of the APOE ε4 allele was determined from blood genomic DNA. Results: Among all children without OSA, APOE ε4 was present in 3 of 199 children, whereas in those with OSA, APOE ε4 was found in 16 of 146 children (p < 0.0002). Furthermore, 16 of 74 children with OSA and cognitive scores <85% had the APOE ε4 allele compared with 3 of 72 children with OSA with abnormal cognitive scores (p < 0.002). Conclusions: APOE ε4 allele is more frequent in children with obstructive sleep apnea and particularly in those who develop neurocognitive deficits, suggesting that the APOE ε4 allele is associated with not only increased odds of having sleep-disordered breathing, but also with an increased risk for neurocognitive dysfunction.

Elevated Serum Aminotransferase Levels in Children at Risk for Obstructive Sleep Apnea

BACKGROUND Fatty liver disease (FLD) is a highly prevalent condition in obese (Ob) children, who are at increased risk for obstructive sleep apnea (OSA). However, the contribution of OSA to FLD remains unknown. DESIGN Prospective study. SETTING Polysomnographic evaluation and assessment of plasma levels of insulin, glucose, and lipids, and liver function tests. PARTICIPANTS A total of 518 consecutive snoring children 4 to 17 years of age who were being evaluated for habitual snoring and suspected OSA. RESULTS A total of 376 children had body mass index z score of < 1.20 (non-Ob children), 3 children (<1%) had elevated serum aminotransferase (LFT) levels, and 248 had OSA (65.9%). Among the 142 overweight/Ob children, 46 had elevated LFT levels (32.4%); of these children, 42 had OSA (91.3%). In contrast, OSA was present in only 71.8% of Ob children without elevated LFT level (p < 0.01). Insulin resistance and hyperlipidemia were more likely to occur in children with FLD. Furthermore, FLD was improved after treatment of OSA in 32 of 42 Ob children (p < 0.0001). CONCLUSION Increased liver enzyme levels are frequently found in Ob snoring children, particularly among those with OSA and/or metabolic dysfunction. Effective treatment of OSA results in improved liver function test results in the vast majority of these patients.

Two-Dimensional Differential In-Gel Electrophoresis Proteomic Approaches Reveal Urine Candidate Biomarkers in Pediatric Obstructive Sleep Apnea

RATIONALE Sleep studies are laborious, expensive, inaccessible, and inconvenient for diagnosing obstructive sleep apnea (OSA) in children. OBJECTIVES To examine whether the urinary proteome uncovers specific clusters that are differentially expressed in the urine of children with OSA. METHODS Two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry proteomics followed by validation with western blot of ELISA. MEASUREMENTS AND MAIN RESULTS Morning urine proteins from 60 children with polysomnographically confirmed OSA and from matched children with primary snoring (n = 30) and control subjects (n = 30) were assessed. A total of 16 proteins that are differentially expressed in OSA were identified, and 7 were confirmed by either immunoblots or ELISA. Among the latter, receiver-operator curve analyses of urinary concentrations of uromodulin, urocortin-3, orosomucoid-1, and kallikrein assigned favorable predictive properties to these proteins. Furthermore, combinatorial approaches indicated that the presence of values beyond the calculated cutoff concentrations for three or more of the proteins yielded a sensitivity of 95% and a specificity of 100%. CONCLUSIONS Proteomic approaches reveal that pediatric OSA is associated with specific and consistent alterations in urinary concentrations of specific protein clusters. Future studies aiming to validate this approach as a screening method of habitually snoring children appears warranted.

Increased Morning Brain Natriuretic Peptide Levels in Children With Nocturnal Enuresis and Sleep- Disordered Breathing: A Community-Based Study

INTRODUCTION. Habitual snoring and obstructive sleep apnea have been associated with bed-wetting in children, and effective obstructive sleep apnea treatment may improve enuresis. OBJECTIVES. The purpose of this work was to assess whether habitual snoring is associated with increased incidence of enuresis and whether severity of obstructive sleep apnea correlates with enuretic frequency and to evaluate brain natriuretic peptide levels. METHODS. Parental surveys of 5- to 7-year-old children were reviewed for habitual snoring and enuresis. Enuresis was also assessed in a cohort of 378 children with habitual snoring undergoing overnight polysomnographic evaluation, and brain natriuretic peptide plasma levels were determined in 20 children with obstructive sleep apnea, 20 with habitual snoring without obstructive sleep apnea, and 20 nonsnoring children, matched for enuresis. RESULTS. There were 17646 surveys completed (50.6% boys; 18.3% black). A total of 1976 (11.2%) of these children were habitual snoring (53% boys; 25.2% black). A total of 531 habitual snoring children also had enuresis (26.9%), with a predominant representation of boys (472 boys [87.5%]). Among the 15670 nonsnoring children, enuresis was reported in 1821 children (11.6%), of whom 88.8% were boys. However, enuresis among 378 children with habitual snoring did not correlate with the magnitude of sleep respiratory disturbances. Indeed, enuresis was reported in 33 of 149 children with obstructive sleep apnea (obstructive apnea hypopnea index: >2 per hour of total sleep time; 53% boys) as compared with 36 habitual snoring children with enuresis (62% boys) and obstructive apnea hypopnea index <2 per hour of total sleep time. Brain natriuretic peptide levels were elevated among children with enuresis and were marginally increased among children with obstructive sleep apnea. CONCLUSIONS. Habitual snoring is associated with increased prevalence of enuresis, and brain natriuretic peptide levels are increased in enuretic children with further increases with obstructive sleep apnea. However, the prevalence of enuresis is not modified by severity of sleep disturbance. Even mild increases in sleep pressure because of habitual snoring may raise the arousal threshold and promote enuresis, particularly among prone children, that is, those with elevated brain natriuretic peptide levels.

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity and Obstructive Sleep Apnea

BACKGROUND Endothelial dysfunction can develop in the context of both obesity and obstructive sleep apnea (OSA) in children. However, the potential interactions between OSA and obesity have not been defined. METHODS Children who were prepubertal and nonhypertensive were recruited. Endothelial function was assessed in a morning fasted state, using a modified hyperemic test involving cuff-induced occlusion of the radial and ulnar arteries, and blood was drawn for assessment of myeloid-related protein 8/14 (MRP8/14) levels using a commercial enzyme-linked immunosorbent assay. Overnight polysomnography defined the presence of OSA or absence of OSA (NOSA) in subjects investigated for sleep-disordered breathing. Anthropometric measurements were performed to assign subjects to obese (OB) and nonobese (NOB) categories. RESULTS Fifty-four children with OSA who were obese and nonobese (mean age, 7.90 ± 0.26 years; mean BMI z-score, 1.70 ± 0.3; obstructive apnea-hypopnea index [OAHI], 7.36 ± 1.09) were compared with 54 children without OSA who were obese and nonobese (mean age, 8.26 ± 0.24 years; mean BMI z-score, 1.41 ± 0.18; OAHI, 0.86 ± 0.07). Of those subjects, 62.5% of the OB-OSA category, 38.7% of the OB-NOSA category, and 20.0% of the NOB-OSA category had evidence of endothelial dysfunction, compared with 0.0% of the NOB-NOSA category (P < .01). The degree of endothelial dysfunction in all groups was associated with circulating MRP8/14 levels (r = 0.343, P < .001). CONCLUSIONS Both obesity and OSA can independently increase the risk for endothelial dysfunction, and the concurrent presence of both markedly increases such risk. Although the mechanisms underlying endothelial dysfunction remain unclear, a potential role for MRP8/14 as an inflammatory biomarker of endothelial dysfunction is suggested.

DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea

BACKGROUND Pediatric obstructive sleep apnea (OSA) leads to multiple end-organ morbidities that are mediated by the cumulative burden of oxidative stress and inflammation. Because not all children with OSA exhibit increased systemic inflammation, genetic and environmental factors may be affecting patterns of DNA methylation in genes subserving inflammatory functions. METHODS DNA from matched children with OSA with and without high levels of high-sensitivity C-reactive protein (hsCRP) were assessed for DNA methylation levels of 24 inflammatory-related genes. Primer-based polymerase chain reaction assays in a case-control setting involving 47 OSA cases and 31 control subjects were conducted to confirm the findings; hsCRP and myeloid-related protein (MRP) 8/14 levels were also assayed. MEASUREMENTS AND MAIN RESULTS Forkhead box P3 (FOXP3) and interferon regulatory factor 1 (IRF1) showed higher methylation in six children with OSA and high hsCRP levels compared with matched children with OSA and low hsCRP levels (P < 0.05). In the case-control cohort, children with OSA and high CRP levels had higher log FOXP3 DNA methylation levels compared with children with OSA and low CRP levels and control subjects. IRF1 did not exhibit significant differences. FOXP3 DNA methylation levels correlated with hsCRP and MRP 8/14 levels and with apnea-hypopnea index (AHI), BMI z score, and apolipoprotein B levels. A stepwise multiple regression model showed that AHI was independently associated with FOXP3 DNA methylation levels (P < 0.03). CONCLUSIONS The FOXP3 gene, which regulates expression of T regulatory lymphocytes, is more likely to display increased methylation among children with OSA who exhibit increased systemic inflammatory responses. Thus, epigenetic modifications may constitute an important determinant of inflammatory phenotype in OSA, and FOXP3 DNA methylation levels may provide a potential biomarker for end-organ vulnerability.