Introdução: A apnéia obstrutiva do sono é um problema de saúde pública dada sua alta prevalência e morbidade. O tratamento de escolha para casos graves é o uso de máscara ligado à pressão positiva contínua na via aérea (CPAP). Nos casos de apnéia obstrutiva do sono moderada, a adesão ao CPAP é variável, e outras formas alternativas de tratamento são necessárias. A disfunção da musculatura de via aérea superior participa na gênese da apnéia obstrutiva do sono. Exercícios orofaríngeos (terapia miofuncional) são derivados da terapia fonoaudiológica dentro da especialidade de motricidade orofacial, e foram desenvolvidos para o tratamento da apnéia obstrutiva do sono. A terapia miofuncional consiste em exercícios isométricos e isotônicos dirigidos para a língua, palato mole e paredes laterais faríngeas, incluindo a adequação das funções de sucção, deglutição, mastigação, respiração e fala. Objetivo: Testar a hipótese de que a terapia miofuncional reduz a gravidade da apnéia obstrutiva do sono. Métodos: Pacientes com apnéia obstrutiva do sono moderada, determinada através de polissonografia (índice de apnéia-hipopnéia entre 15 e 30 eventos/hora) foram sorteados para 3 meses de medidas gerais incluindo lavagem nasal, orientação da mastigação bilateral alternada e exercícios de inspiração e expiração nasal na posição sentado (grupo controle), ou tratamento com terapia miofuncional. Além das orientações recebidas pelo grupo controle, a terapia miofuncional incluiu exercícios orofaríngeos diários sem supervisão e sob supervisão uma vez por semana (sessões de 20 minutos). Foram realizadas na entrada e final do estudo medidas antropométricas, questionários avaliando a freqüência e intensidade do ronco, sonolência subjetiva diurna (Epworth), qualidade do sono (Pittsburgh) e polissonografia completa. Resultados: Foram incluídos no estudo 45 pacientes; 8 foram excluídos por falta de adesão ao protocolo. O grupo final se constituiu de 37 pacientes com idade (média ± desvio padrão) = 51±9 anos, índice de massa corpórea = 30±4 Kg/m2 e índice de apnéia e hipopnéia = 23±5 apnéias/hora, sendo 17 do grupo controle e 20 do grupo tratamento. O grupo controle não teve mudança significativa em todos os parâmetros. Em contraste, os pacientes tratados com terapia miofuncional apresentaram melhora significante (p<0.05) na circunferência cervical (39.5±3.4 vs. 38.3±3.7 cm), na sonolência diurna (13.2±5.4 vs. 8.2±6.0), na qualidade do sono (10.3±3.5 vs. 7.1±2.3), na freqüência do ronco (3.9±0.5 vs. 2.7±1.1), na intensidade do ronco (3.4±0.5 vs. 1.8±0.9) e no índice de apnéia e hipopnéia (23.2±4.8 vs. 14.6±8.1 eventos/hora; p<0.01). Considerando todo o grupo, as mudanças na circunferência cervical se correlacionaram com as mudanças no índice de apnéia e hipopneia (r=0.55; p<0.001). Conclusões: A terapia miofuncional por 3 meses reduz os sintomas e a gravidade da apnéia obstrutiva do sono moderada. A melhora da apnéia se correlaciona com a diminuição do diâmetro cervical, sugerindo que o tônus da musculatura da via aérea superior durante a vigília se correlaciona com a gravidade da apnéia obstrutiva do sono e pode ser modificada com a terapia miofuncional. / Introduction: Obstructive sleep apnea is a public health problem due to the high prevalence and high morbidity. Continuous positive airway pressure (CPAP) is the treatment of choice for severe cases. However, adherence to CPAP is variable among moderate obstructive sleep apnea patients and alternative treatments are necessary. Upper airway muscle weakness plays an important role in the genesis of obstructive sleep apnea. Oropharyngeal exercises (myofunctional therapy) are derived from phonoaudiological therapy within orofacial motricity specialty, and were developed for the treatment of sleep obstructive apnea. The myofunctional therapy consists of isometric and isotonic exercises directed to tongue, soft palate and lateral pharyngeal wall, including adequate functioning of suction, swallowing, chewing, breathing and speech. Objective: To test the hypothesis that myofunctional therapy will attenuate obstructive sleep apnea syndrome severity. Methods: We included 37 moderate obstructive sleep apnea patients apnea-hypopnea index (AHI) between 15 and 30 events/hour that were randomized to 3 months of general measures, including nasal lavage, orientation of alternated bilateral chewing and exercises of inspiration and expiration in the seated position (control group). The treatment with myofunctional therapy consisted of oropharyngeal exercises performed without supervision daily and under supervision once a week (20 minutes), in adition to the orientations given to the control group. Anthropometric measurements, questionnaires evaluating snoring frequency and intensity (Berlin), daytime subjective sleepiness (Epworth), sleep quality (Pittsburgh) and full polysomnography were performed at baseline and in the end of the study. Results: 45 patients were included in the study, 8 were excluded because they failed to return regularly. The final group consisted of 37 patients age (mean ± SD) = 51±9 years, body mass index = 30±4 Kg/m2 and apnea hypopnea index = 23±5 apneas/hour), seventeen were randomized to the control group and twenty to the treatment group. The control group did not changes in all parameters along the study. In contrast, the patients treated with myofunctional therapy presented a significant decrease (p<0.05) in neck circumference (39.5±3.4 vs. 38.3±3.7 cm), daytime somnolence (13.2±5.4 vs. 8.2±6.0), sleep quality (10.3±3.5 vs. 7.1±2.3), snoring frequency (3.9±0.5 vs. 2.7±1.1), snoring intensity (3.4±0.5 vs. 1.8±0.9) and apnea hypopnea index (23.2±4.8 vs. 14.6±8.1 events/hour; p<0.01). Considering the entire group, changes in neck circumference correlated with the changes in AHI (r=0.55; p <0.001). Conclusions: Myofunctional therapy, over 3 months, reduce symptons and severity of moderate obstructive sleep apnea. The improvement correlates with the decrease of cervical diameter, suggesting that the musculature tonus of upper airway while awake correlates with the severity of obstructive sleep apnea and can be modified with myofunctional therapy.

Objetivo: O estudo avaliou, cefalometricamente, crianças na faixa etária de sete a dez anos, entre as diferentes estratificações da SAOS e o grupo controle, com relação às alterações esqueléticas e faciais e o posicionamento do osso hioide. Casuística e Método: Foram avaliadas 76 crianças, com idades entre sete e dez anos, em fase de dentição mista, sem histórico de tratamento ortodôntico, fonoaudiológico ou cirúrgico otorrinolaringológico. Todas as crianças foram submetidas à avaliação otorrinolaringológica e polissonográfica em laboratório do sono, além da realização do exame cefalométrico. Os participantes foram, também subdivididos em grupos, de acordo com a gravidade da SAOS. Das 76 crianças, 14 constituíram o grupo controle; 62 apresentavam SAOS, sendo 46 classificadas como SAOS leve e 16 SAOS moderada ou grave. Todas as crianças foram submetidas à cefalometria lateral para obtenção de medidas lineares craniofaciais e medidas específicas do osso hioide. Essas medidas foram comparadas entre si dentro dos diferentes grupos pelo teste t de Student (correlação de Welch) e correlacionadas com o valor do Índice de apneias obstrutivas + hiponeias (IAOH) do paciente por meio do teste de correlação de Pearson. O nível de significância estabelecido foi p<0,05. Resultados: Observouse maior distância do osso hioide em relação ao plano mandibular no grupo SAOS, quando comparado ao controle (p=0,03). Entre os dois subgrupos da SAOS, os pacientes com doença moderada ou grave apresentaram significativa menor distância horizontal entre o hioide e a parede posterior da faringe (p=0,03), quando comparados aos com SAOS leve. Na correlação entre as medidas cefalométricas e o IAOH, essas mesmas duas medidas apresentaram relação significativa, sendo a correlação positiva para distância do hioide para o plano mandibular (p=0,04) e negativa para distância horizontal do hioide com a faringe (p=0,006). Para as variáveis cefalométricas faciais, não se observou diferença significativa entre os grupos. Conclusão: A posição do osso hioide, em crianças de sete a dez anos, foi caracterizada pela inferiorização naquelas com a doença e posteriorização em pacientes com maior gravidade da SAOS. Para as medidas craniofaciais lineares não houve diferença estatística / Objective: The study evaluated cephalometric children aged 7-10 years between the different strata of OSA and control groups, with the skeletal and facial changes and the position of the hyoid bone. Casuistic and Method: This study included 76 children, aged between 7 and 10 years in mixed dentition phase, with no history of orthodontic treatment, speech therapy or surgical otorhinolaryngological. All children were submitted to otorhinolaryngological examination and polysomnography in a sleep laboratory, as well as holding the cephalometric examination. The participants were then divided into groups according to the severity of OSA. Of the 76 children of research, 14 constitute the control group; 62 children are affected of OSAS, 46 classified as mild OSA and 16 moderate or severe OSA. All children underwent lateral cephalometric, to obtain craniofacial linear measurements and specific measurements of the hyoid bone. The measurements were compared to each other within the different groups by Student\'s t-test (Welch correlation) and correlated with the OAHI value of the patient through the Pearson correlation test. The level of significance was set at p<0.05. Results: There was a greater distance from the hyoid bone to the mandibular plane in the OSA group when compared to control (p = 0.03). Between the two subgroups of OSAS, patients with moderate or severe impairment had significant lower horizontal distance between the hyoid and the posterior pharyngeal wall (p=0.03) when compared to patients with mild OSA. The correlation between the cephalometric and OAHI measures, these same two measures had a significant relationship with the positive correlation to distance from the hyoid to the mandibular plane (p=0.04) and negative for the horizontal distance from the hyoid to the throat (p=0.006). For facial cephalometric variables, there was no significant difference between groups. Conclusion: The position of the hyoid bone in children 7-10 years was characterized by inferiority in children with the disease and posteriorization in patients with more gravity of OSA. For craniofacial linear measurements showed no statistical difference

INTRODUÇÃO: A Síndrome de Prader-Willi (SPW) é uma doença multigênica causada pela perda de expressão de genes na região 15q11- q13. As principais características incluem hipotonia e disfunção hipotalâmica, que pode ser responsável pela hiperfagia levando a obesidade durante a infância, por controle ventilatório anormal e deficiência do Hormônio de Crescimento (GH). O objetivo deste estudo foi descrever e comparar o sono dos pacientes com SPW, descrever o IGF-I e correlacionar o IAH com IGF-I. MÉTODOS: Foram realizadas polissonografias em 17 pacientes (idade entre 3 anos e 18 anos) com SPW divididos em dois grupos, GH+ (n=9) e GH- (n=8). Trata-se de um estudo prospectivo realizado com pacientes do ambulatório de Endocrinologia do Instituto da Criança da Universidade de São Paulo, tendo sido obtido de seus prontuários resultados de IGF-I sérico anterior à realização do exame. RESULTADOS: Os grupos GH+ e GHforam homogêneos. Quatorze (82,3%) dos pacientes eram obesos, 8 (88,9%) GH+. Todos os pacientes apresentaram Índice de Apneia e Hipopneia (AH) 1. 88,2% dos pacientes apresentaram ronco. A eficiência do sono foi menor em 7 (41,2%) pacientes, sendo 6 (85,7%) do grupo GH+. 23,5% dos pacientes apresentaram porcentagem diminuída do sono de ondas lentas e 29,4% dos pacientes de sono REM. Cinco (29,5%) pacientes apresentaram latência de sono REM diminuída, sendo 2 (40%) paciente GH+ e 4 (23,6%) pacientes latência de sono aumentada, sendo 2 (50%) GH+. Todos os pacientes apresentaram fragmentação do sono. Os eventos mais comuns foram as hipopneias e as apneias obstrutivas. Três (17,7%) pacientes, sendo 1 (11,1%) GH+ apresentaram episódios de dessaturação importantes com mínima 65% e média 85%. Não foram encontradas correlação entre o IAH e IGF-I (p = 0,606). Não houve diferença estatisticamente significante entre os dados polissonográficos de ambos os grupos. CONCLUSÕES: Todos os pacientes apresentaram IAH 1, dessaturação de oxigênio com predomínio em sono REM e fragmentação do sono. Não foram encontradas diferenças na correlação do IGF-1 com IAH. Não foram encontradas diferenças entre os grupos GH+ e GH- em relação aos dados antropométricos e polissonográficos / BACKGROUND: Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of expression of genes in the 15q11-q13 region. The main features include hypotonia and hypothalamic dysfunction that may be responsible for hyperphagia leading to obesity during childhood, abnormal ventilatory control and Growth Hormone (GH) deficiency. The aim of this study is to describe and compare the sleep of patients with PWS, describe the IGF-I and correlate IGF-I with AHI. METHODS: All polysomnographic (PSG) studies were performed in 17 patients (aged between 3 years and 18 years) with PWS divided in 2 groups, as follows: GH + (n = 9) and GH- (n = 8). This prospective study was conducted at the Endocrinologic Outpatient Clinic (Children\'s Hospital, University of São Paulo) and results of IGF-I serum were obtained from their medical records prior to the PSG. RESULTS: The groups GH + and GH-were homogeneous. 82,3% patients were obese, 8 (88.9%) GH +. All patients had AHI 1. 88,2% patients presented snoring. The sleep efficiency was lower in 7 (41.2%) patients, 6 (85.7%) GH +. 23,5% patients showed reduced percentage of slow wave sleep and 29,4% patients showed reduced percentage of REM sleep . Five (29.5%) patients had reduced REM latency, 2 (40%) GH + and 4 (23.6%) patients had increased REM latency, 2 (50%) GH+. All patients had sleep fragmentation. The most common events were hypopneas and obstructive apneas. Three (17.7%) patients, 1 (11.1%) GH+ had important desaturation (SatO2 minimum 65% and SatO2 average 85%. No correlation was found between the AHI and IGF-I (p = 0.606). There were no statistically significant differences between polysomnographic data from both groups. CONCLUSIONS: All patients had AHI 1, oxygen desaturation predominating in REM sleep and sleep fragmentation. No differences were found in the correlation of IGF-1 with IAH. No differences were found between groups GH + and GH- in relation to anthropometric and polysomnographic data

Introdução: A apnéia obstrutiva do sono é um problema de saúde pública dada sua alta prevalência e morbidade. O tratamento de escolha para casos graves é o uso de máscara ligado à pressão positiva contínua na via aérea (CPAP). Nos casos de apnéia obstrutiva do sono moderada, a adesão ao CPAP é variável, e outras formas alternativas de tratamento são necessárias. A disfunção da musculatura de via aérea superior participa na gênese da apnéia obstrutiva do sono. Exercícios orofaríngeos (terapia miofuncional) são derivados da terapia fonoaudiológica dentro da especialidade de motricidade orofacial, e foram desenvolvidos para o tratamento da apnéia obstrutiva do sono. A terapia miofuncional consiste em exercícios isométricos e isotônicos dirigidos para a língua, palato mole e paredes laterais faríngeas, incluindo a adequação das funções de sucção, deglutição, mastigação, respiração e fala. Objetivo: Testar a hipótese de que a terapia miofuncional reduz a gravidade da apnéia obstrutiva do sono. Métodos: Pacientes com apnéia obstrutiva do sono moderada, determinada através de polissonografia (índice de apnéia-hipopnéia entre 15 e 30 eventos/hora) foram sorteados para 3 meses de medidas gerais incluindo lavagem nasal, orientação da mastigação bilateral alternada e exercícios de inspiração e expiração nasal na posição sentado (grupo controle), ou tratamento com terapia miofuncional. Além das orientações recebidas pelo grupo controle, a terapia miofuncional incluiu exercícios orofaríngeos diários sem supervisão e sob supervisão uma vez por semana (sessões de 20 minutos). Foram realizadas na entrada e final do estudo medidas antropométricas, questionários avaliando a freqüência e intensidade do ronco, sonolência subjetiva diurna (Epworth), qualidade do sono (Pittsburgh) e polissonografia completa. Resultados: Foram incluídos no estudo 45 pacientes; 8 foram excluídos por falta de adesão ao protocolo. O grupo final se constituiu de 37 pacientes com idade (média ± desvio padrão) = 51±9 anos, índice de massa corpórea = 30±4 Kg/m2 e índice de apnéia e hipopnéia = 23±5 apnéias/hora, sendo 17 do grupo controle e 20 do grupo tratamento. O grupo controle não teve mudança significativa em todos os parâmetros. Em contraste, os pacientes tratados com terapia miofuncional apresentaram melhora significante (p<0.05) na circunferência cervical (39.5±3.4 vs. 38.3±3.7 cm), na sonolência diurna (13.2±5.4 vs. 8.2±6.0), na qualidade do sono (10.3±3.5 vs. 7.1±2.3), na freqüência do ronco (3.9±0.5 vs. 2.7±1.1), na intensidade do ronco (3.4±0.5 vs. 1.8±0.9) e no índice de apnéia e hipopnéia (23.2±4.8 vs. 14.6±8.1 eventos/hora; p<0.01). Considerando todo o grupo, as mudanças na circunferência cervical se correlacionaram com as mudanças no índice de apnéia e hipopneia (r=0.55; p<0.001). Conclusões: A terapia miofuncional por 3 meses reduz os sintomas e a gravidade da apnéia obstrutiva do sono moderada. A melhora da apnéia se correlaciona com a diminuição do diâmetro cervical, sugerindo que o tônus da musculatura da via aérea superior durante a vigília se correlaciona com a gravidade da apnéia obstrutiva do sono e pode ser modificada com a terapia miofuncional. / Introduction: Obstructive sleep apnea is a public health problem due to the high prevalence and high morbidity. Continuous positive airway pressure (CPAP) is the treatment of choice for severe cases. However, adherence to CPAP is variable among moderate obstructive sleep apnea patients and alternative treatments are necessary. Upper airway muscle weakness plays an important role in the genesis of obstructive sleep apnea. Oropharyngeal exercises (myofunctional therapy) are derived from phonoaudiological therapy within orofacial motricity specialty, and were developed for the treatment of sleep obstructive apnea. The myofunctional therapy consists of isometric and isotonic exercises directed to tongue, soft palate and lateral pharyngeal wall, including adequate functioning of suction, swallowing, chewing, breathing and speech. Objective: To test the hypothesis that myofunctional therapy will attenuate obstructive sleep apnea syndrome severity. Methods: We included 37 moderate obstructive sleep apnea patients apnea-hypopnea index (AHI) between 15 and 30 events/hour that were randomized to 3 months of general measures, including nasal lavage, orientation of alternated bilateral chewing and exercises of inspiration and expiration in the seated position (control group). The treatment with myofunctional therapy consisted of oropharyngeal exercises performed without supervision daily and under supervision once a week (20 minutes), in adition to the orientations given to the control group. Anthropometric measurements, questionnaires evaluating snoring frequency and intensity (Berlin), daytime subjective sleepiness (Epworth), sleep quality (Pittsburgh) and full polysomnography were performed at baseline and in the end of the study. Results: 45 patients were included in the study, 8 were excluded because they failed to return regularly. The final group consisted of 37 patients age (mean ± SD) = 51±9 years, body mass index = 30±4 Kg/m2 and apnea hypopnea index = 23±5 apneas/hour), seventeen were randomized to the control group and twenty to the treatment group. The control group did not changes in all parameters along the study. In contrast, the patients treated with myofunctional therapy presented a significant decrease (p<0.05) in neck circumference (39.5±3.4 vs. 38.3±3.7 cm), daytime somnolence (13.2±5.4 vs. 8.2±6.0), sleep quality (10.3±3.5 vs. 7.1±2.3), snoring frequency (3.9±0.5 vs. 2.7±1.1), snoring intensity (3.4±0.5 vs. 1.8±0.9) and apnea hypopnea index (23.2±4.8 vs. 14.6±8.1 events/hour; p<0.01). Considering the entire group, changes in neck circumference correlated with the changes in AHI (r=0.55; p <0.001). Conclusions: Myofunctional therapy, over 3 months, reduce symptons and severity of moderate obstructive sleep apnea. The improvement correlates with the decrease of cervical diameter, suggesting that the musculature tonus of upper airway while awake correlates with the severity of obstructive sleep apnea and can be modified with myofunctional therapy.

L'hypoxie intermittente (HI), induite par les apnées du sommeil, conduit à des altérations de la sensibilité à l'insuline et de l'homéostasie glucidique mais les mécanismes impliqués restent mal connus. L'objectif de ce travail était d'étudier les effets et les mécanismes sous jacents d'une exposition chronique à l'HI sur l'homéostasie glucidique. L'HI induit une résistance à l'insuline à la fois systémique et tissulaire, ainsi qu'une amélioration de la tolérance au glucose associée à une activation de l'AMPK musculaire. L'HI cause également des altérations du foie et du tissu adipeux associées à un changement du pattern d'expression des gènes dans ces tissus et à un risque accru de développement de pathologies vasculaires comme l'athérosclérose. Enfin, la délétion de PHD1, une des protéines régulatrices de HIF-1, entraîne une résistance à l'insuline associée une stéatose hépatique, faisant de HIF-1 une cible potentielle impliquée dans les altérations metaboliques induites par l'HI. / Intermittent hypoxia (IH), induced by sleep apnea, leads to alterations in insulin sensitivity and glucose homeostasis but the mechanisms involved remains poorly understood. The objective of this work was to study the effects and the underlying mechanisms of chronic exposure to IH on glucose homeostasis. IH induces both systemic and tissue-specific insulin resistance , as well as improved glucose tolerance associated with an activation of muscle AMPK. IH also causes a change in the pattern of gene expression in liver and adipose tissue and an increased risk of vascular pathologies such as atherosclerosis development. Finally, the deletion of PHD1, a regulatory protein of HIF-1, leads to insulin resistance associated with hepatic steatosis, making HIF-1 a possible target involved in the metabolic changes induced by IH.

Chez l'homme, l'hypoxie correspond à une inadéquation entre les besoins tissulaires et les apports en oxygène. Cet état est une caractéristique commune à l'exposition à l'altitude et au syndrome d'apnées obstructives du sommeil (SAOS), bien que celle-ci soit continue dans le premier cas et intermittente et nocturne dans le second.L'hypoxie d'altitude entraine une altération des performances cognitives et motrices. La réduction de la performance à l'exercice en altitude a longtemps été attribuée à une altération du métabolisme musculaire du fait d'une réduction de l'apport en oxygène. Les perturbations cérébrales induites par l'hypoxie pourraient également avoir un rôle majeur dans cette limitation.Le SAOS, véritable enjeu de santé publique, est associé à des troubles cognitifs pouvant ainsi influencer le fonctionnement quotidien des patients souffrant de ce syndrome et résulter en une somnolence diurne excessive, une baisse de la qualité de vie ou encore une réduction de la productivité au travail et des performances scolaires. Le fait que ces altérations cérébrales puissent influencer les capacités motrices et à l'effort des patients atteints d’apnées obstructives du sommeil reste en revanche à investiguer.Au cours de ce travail de thèse, nous nous sommes intéressés à deux modèles d’exposition hypoxique et à leurs conséquences cérébrales et neuromusculaires. Nous avons tout d’abord étudié l'effet d'une exposition à l'hypoxie d'altitude aigue (quelques heures) et prolongée (plusieurs jours) sur la fonction neuromusculaire et ses répercussions à l'exercice chez le sujet sain. Nous avons ensuite étudié l'influence du modèle d'hypoxie intermittente associé au SAOS sur la fonction neuromusculaire et la tolérance à l'exercice de ces patients. Nous avons ainsi cherché à caractériser les altérations cérébrales à l'exercice en lien avec ce syndrome et leur réversibilité suite à un traitement en ventilation par pression positive continue.Chez le sujet sain, nous avons démontré que la performance à l'exercice impliquant une masse musculaire réduite (fléchisseurs du coude) n'était pas limitée par une fatigue centrale accrue après 1 et 5 jours d'exposition à une altitude de 4350 m. Nous avons mis en évidence que la dysfonction musculaire (force et endurance réduites) observée chez le patient SAOS est associée à un déficit d'activation supraspinal et une augmentation de l'inhibition intracorticale. De plus, nos résultats suggèrent qu'une altération de la réponse cérébrovasculaire à l'exercice puissent impacter négativement la tolérance à l'exercice des patients souffrant d'un SAOS sévère. Ces altérations neuromusculaires et cérébrovasculaires n'étaient pas corrigées après un traitement de huit semaines par ventilation nocturne en pression positive continue soulignant la nature persistante de ces altérations cérébrales. / In humans, hypoxia is defined as the mismatch between tissue requirement and oxygen delivery. This condition is a common feature between high-altitude exposure and obstructive sleep apnea syndrome (OSA), although it is continuous in the first instance and intermittent and nocturnal in the second one.High-altitude exposure causes an impairment in cognitive and motor performance. The reduction in exercise performance observed under hypoxic condition has been mainly attributed to altered muscle metabolism due to impaired oxygen delivery. However, hypoxia-induced cerebral perturbations may also play a major role in exercise limitation.OSA, a major public health concern, is associated with cognitive impairment that can alter patients' daytime functioning and result in excessive daytime sleepiness, reduced quality of life and lowered work productivity and school performance. The fact that these cerebral alterations can influence motor and exercise performance in patients with obstructive sleep apnea remains to be investigated.In this thesis, we investigated two different models of hypoxic exposure and their cerebral and neuromuscular consequences. First, we assessed the effect of acute (several hours) and prolonged (several days) high-altitude exposure on the neuromuscular function and its repercussions during exercise in healthy subject. Then, we then investigated the model of intermittent hypoxia associated with OSA and its influence on the neuromuscular function and exercise tolerance in these patients. We seeked to characterize cerebral alterations during exercise associated with this syndrome and their reversibility following continuous positive airway pressure treatment.In healthy subject, we showed that exercise performance involving a small muscle mass (elbow flexors) was not limited by an exacerbated amount of central fatigue after 1 and 5 days of high-altitude exposure (4,350 m). We highlighted that muscle dysfunction (reduced strength and endurance) was associated with a supraspinal activation deficit and an increase in intracortical inhibition. Moreover, our results suggest that an alteration in cerebrovascular response during exercise may contribute to reduced exercise tolerance observed in patients with severe OSA syndrome. The neuromuscular and cerebrovascular abnormalities were not reversed following an eight-week continuous positive airway pressure treatment, highlighting the persistent nature of the cerebral alterations.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O tratamento para a Síndrome da Apnéia Obstrutiva do Sono (SAOS) mostra-se necessário devido às co-morbidades associadas ao quadro da síndrome. Fatores como problemas cardiovasculares, e aumento das chances de acidentes automobilísticos e de trabalho, além da diminuição da qualidade de vida, fazem dessa condição um sério problema a ser tratado. Dentre os tratamentos clínicos têm recebido especial atenção os aparelhos intra-orais por se tratar de um método simples e não invasivo. Os objetivos deste trabalho foram avaliar através dos índices polissinográficos as melhoras produzidas por um aparelho experimental e um aparelho placebo, e através de radiografias cefalométricas analisar fatores anatômicos relacionados com a severidade inicial do quadro e com as alterações do quadro da síndrome decorrentes do uso do aparelho experimental (Twin Block). Dezenove pacientes participaram deste estudo que foi prospectivo, com acompanhamento médio de 10,5 meses, cruzado, randomizado e duplo-cego. Foram feitas polissonografias iniciais e em uso dos aparelhos, após em média 6,47 (d.p.=2,01) meses do uso do Twin Block e 3,8 (d.p.=0,84) meses do uso do placebo e radiografias cefalométricas inicial e com o aparelho Twin Block em posição. Os dados pareados foram avaliados pelo teste de Wilcoxon, os não pareados pelos testes t de Student e Mann-Whitney e a comparação de proporções com o teste z, todos com 5% de significância (p<0.05). Os resultados mostraram tendências, embora não comprovadas estatisticamente, nas quais o grupo com SAOS moderada apresentou medidas de faringe menores e posição do osso hióide menos caudal quando comparados com o grupo com SAOS leve; que houve melhor resposta à terapia com o Twin-Block do que com o placebo, considerando-se o índice de apnéias mais hipopnéias por hora de sono (IAH), o índice de apnéias por hora de sono (IA), e a percentagem de sono REM; que a posição do osso hióide vertical diminuiu mais nos pacientes que melhoraram, tanto para o IAH quanto para o IA, que a maioria das medidas de faringe sofreram maior aumento nos pacientes que melhoraram em comparação com os que não melhoraram.Também foi possível estabelecer-se correlação positiva entre hipofaringe (HF) e os pacientes que melhoraram (avaliando pelo IAH), entre distância do osso hióide a terceira vértebra cervical (DHTV), faringe na altura do plano oclusal [NF(2)], largura do palato mole (PM) e os pacientes que melhoraram (avaliando pelo IA), além de entre NF (2) e os pacientes que não melhoraram (avaliando pelo IA). Conclui-se que o Twin Block mostrou-se clinicamente mais efetivo que o aparelho placebo no controle da SAOS, que algumas medições cefalométricas podem estar relacionadas com a severidade da síndrome medida inicialmente e que há variações de alterações anatômicas entre os pacientes que responderam e não responderam à terapia com aparelho intra-oral. / The treatment for the Obstructive Sleep Apnea Syndrome (OSAS) is necessary due to the co-morbidities associated with the syndrome. Factors such as cardiovascular problems, higher risk of automobile and work accidents, in addition to the decreased quality of life, makes the condition a serious problem to be treated. Among the treatments, clinicians have given special attention to the intra-oral appliances because it is simple and noninvasive. The objectives of this study were to evaluate by polysomnographyc indexes the improvements produced by both experimental and placebo units, and by cephalometric radiographs examine anatomical factors related with the initial severity of the syndrome and with the changes resulting from the use of the experimental appliance (Twin Block). Nineteen patients participated in this crossover, randomized, double-blind and prospective study, with monitoring average of 10.5 months. Polysomnographys were made in the initial use of the devices, after an average of 6.47 months (s.d. = 2.01) of Twin Block use and 3.8 months (s.d. = 0.84) of placebo use, along with cephalometric radiographs taken initially and with the Twin Block in position. Paired data were analyzed by the Wilcoxon test, non-paired by the Student t test and Mann-Whitney and compared proportions with the test z, all with 5% of significance (p <0.05). The results showed trends, though not statistically proven, that the group with moderate OSAS presented lower measures for the pharynx and higher hyoid bone position when compared to the group with mild OSAS; that the patients were more responsive to therapy with Twin-Block than with placebo, considering the index of more apnea hypopnea per hour of sleep (AHI), the index of sleep apnea per hour (AI), and the percentage of REM sleep; that the position of the vertical hyoid bone decreased more in patients who improved, both for the AHI and for the AI; that most pharyngeal measures suffered greater increase in patients who improved in comparison with those who did not get better. It could also be established a positive correlation between hypopharynx (HF) and patients who improved (by assessing AHI), distance between the hyoid bone and the third cervical vertebra (DHTV), pharynx in the occlusal plain [NF (2)], the width of the soft palate (PM) and patients that improved (by assessing AI), and between NF (2) and patients who had not improved (by assessing AI). It is concluded that the Twin Block was clinically more effective than the placebo unit in the control of OSAS, that some cephalometric measurements may be related to the severity of the syndrome measure initially and that there are variations in anatomic changes among patients who responded and not responded to therapy with intra-oral device.

Le Syndrome d'Apnées Obstructives du Sommeil (SAOS) est défini par la survenue durant le sommeil d'épisodes fréquents d'obstruction complète ou partielle des voies aériennes supérieures, responsables d'apnées/hypopnées. L'hypoxie intermittente (HI) qui en résulte est responsable, à long terme, d'une augmentation de la morbi-mortalité cardiovasculaire (CV) dans un contexte de forte prévalence de syndrome métabolique, d'obésité et d'insulinorésistance. Certains patients SAOS obèses présentent une hypoventilation/hypercapnie, caractérisant le syndrome d'obésité hypoventilation (SOH) dont la morbi-mortalité CV est encore plus sévère que le SAOS seul. Le stress oxydant, l'inflammation de bas grade et la dérégulation du métabolisme glucido-lipidique et hormonal sont parmi les mécanismes clés responsables de la dysfonction endothéliale et in fine de l'augmentation du risque CV chez ces patients. Cependant, si ces mécanismes délétères sont démontrés par de nombreuses études fondamentales, leur mise en évidence en clinique est moins évidente, notamment du fait des multiples facteurs de co-morbidité. La première partie clinico-biologique de ce travail a été consacrée à la mise en évidence, chez des patients porteurs d'un SAOS ou d'un SOH, des déséquilibres métaboliques et hormonaux impliquant le stress oxydant, en lien avec la sévérité de ces syndromes et leurs conséquences CV. Nous avons ainsi montré chez des patients SOH les plus sévères une altération de la fonction somatotrope proportionnelle à la dysfonction respiratoire et à l'hypertriglycéridémie. Nous avons ensuite mis en évidence, chez des patients SAOS non obèses, l'implication du stress oxydant lipidique dans l'athérosclérose précoce associée à la sévérité du SAOS. Enfin, nous nous sommes intéressés à l'homocystéinémie, facteur de risque cardio-vasculaire connu, chez des patients porteurs d'un syndrome métabolique présentant ou non un SAOS. Nous avons observé une majoration de l'homocystéinémie chez les patients souffrant d'un SAOS par rapport aux patients SMet non SAOS, en lien avec la sévérité des apnées/hypopnées, avec l'athérosclérose précoce, ainsi qu'avec un déséquilibre de la balance pro/antioxydante. Dans une seconde partie fondamentale, nous avons étudié les effets de l'endothéline-1 (ET-1), peptide vasoconstricteur d'origine endothéliale dont la sécrétion est majorée par l'HI, sur le métabolisme d'adipocytes en culture. Nous avons montré que ce peptide majore la lipolyse adipocytaire via les récepteur ET-1 de type A, tend à diminuer l'incorporation du glucose, et ce de manière opposée et additionnelle aux effets de l'insuline. Chez le rat Wistar exposé 14 jours à l'HI, nous avons observé une activation du système endothéline associée à un remodelage du tissu adipeux avec diminution de taille adipocytaire. Au-delà de ses effets vasoconstricteurs, ET-1 déséquilibre donc le métabolisme glucido-lipidique adipocytaire, et pourrait ainsi participer activement à l'insulinorésistance des patients SAOS obèses. Le rôle du système endothéline au niveau du métabolisme énergétique et son impact sur le tissu adipeux constituent donc des pistes sérieuses à explorer dans ce contexte. Mots-clés : Syndrome d'apnées obstructives du sommeil, syndrome d'obésité hypoventilation, stress oxydant, hypoxie intermittente, endothéline-1, insulinorésistance, lipolyse, adipocyte et tissu adipeux. / Obstructive Sleep Apnea Syndrome (OSAS) is defined by recurrent complete (apnea) or partial (hypopnea) upper airway obstructions during sleep. The resulting intermittent hypoxia (IH) is responsible for a long-term increase in cardiovascular (CV) morbi-mortality in a context of strong prevalence of metabolic syndrome, obesity and insulin resistance. Some obese OSAS patients present with Obesity Hypoventilation Syndrome (OHS) characterized by hypoventilation/hypercapnia and an even higher risk of cardiovascular morbi-mortality. Oxidative stress, low-grade inflammation, gluco-lipidic and hormonal alterations are among the key mechanisms leading to endothelial dysfunction and in fine to increased CV risk in OSAS. However, these various mechanisms have been identified by fundamental studies and their relevance in clinical research is less evident, in particular because of the presence of multiple comorbidity factors. The clinicobiological part of this work was devoted to the exploration of the oxidative stress-related metabolic and hormonal changes in OSAS and OHS patients, in relation with the severity of these diseases and their associated CV consequences. In the most severe OHS patients, we showed an impairment of the somatotropic axis linked to respiratory dysfunction and increase in triglycerides. We then highlighted, in non-obese OSAS patients, the involvement of lipid oxidative stress in early atherosclerosis and its association with OSAS severity. Finally, we investigated homocysteine, a well-known CV risk factor, in patients suffering from metabolic syndrome (MS) with or without OSAS. We observed an increase in homocysteinemia in OSAS+MS patients compared to non-OSAS+MS patients, linked to the severity of sleep apnea, to early atherosclerosis, as well as to pro/antioxidative imbalance. In the experimental part, we investigated the effects of the hypoxia-released vasoconstrictor peptide endothelin-1 (ET-1) on the metabolism of 3T3-L1 adipocytes in vitro. We showed that through its type-A receptor, ET-1 increases adipocyte lipolysis, tends to decrease glucose uptake and significantly inhibits the effects of insulin. Moreover, ET-1 stimulates its own expression, and expression of its ET-A receptor in 3T3-L1 cells. In parallel, in Wistar rats exposed to 14 days of IH, we observed an activation of the endothelin system associated with a remodelling of adipose tissue characterized by a decrease in adipocyte size. In conclusion, beyond its vasoconstrictor effects, ET-1 can modify glucose and lipid metabolism of adipocytes, and could thus actively participate in the insulin resistance and dyslipidemia observed in OSAS obese patient. The role of the endothelin system in energetic metabolism and its impact on adipose tissue thus represent promising avenues to be investigated in OSAS. Keywords: obstructive sleep apnea syndrome, obesity hypoventilation syndrome, oxidative stress, intermittent hypoxia, endothelin-1, insulin resistance, lipolysis, adipocyte and adipose tissue.

Le syndrome d'apnées obstructives du sommeil (SAOS) est un problème de santé publique par sa prévalence dans la population générale (5-20%) et ses nombreuses complications métaboliques et cardiovasculaires. La répétition des apnées génère une hypoxie intermittente (HI) considérée comme le facteur principal responsable de cette morbidité cardiovasculaire dont l'athérosclérose. Cependant les mécanismes physiopathologiques sont peu connus. De nombreux arguments évoquent l'implication de la graisse blanche viscérale notamment via la sécrétion de médiateurs inflammatoires. Les objectifs de notre travail ont été d'étudier les altérations du tissu adipeux viscéral induites par l'HI, et leurs relations avec les atteintes métaboliques et vasculaires causées par l'HI à l'aide d'un modèle animal d'apnées du sommeil (modèle murin d'HI). Nos travaux confirment l'effet délétère de l'HI dans les atteintes métaboliques et vasculaires pré-athérosclérotique et athéroclérotique, notamment à travers une inflammation impliquant les récepteurs TLR-4. En dehors de toute obésité, l'HI entraîne des modifications majeures du tissu adipeux viscéral (remodelages morphologique et inflammatoire, redistribution territoriale) qui contribuent à l'inflammation et aux atteintes métaboliques et vasculaires causées par l'HI. Ainsi nos résultats précisent les mécanismes physiopathologiques des conséquences associées au SAOS, et suggèrent que la correction de l'inflammation pourrait constituer une approche thérapeutique supplémentaire pour les patients apnéiques. / Obstructive sleep apna syndrome (OSAS) is a public health problem due to its frequency in general population (5 to 20%) and its numerous metabolic and cardiovascular complications. Repetitive apneas lead to intermittent hypoxia (IH), which is the determinant factor for the OSAS-related cardiovascular morbidity, including atherosclerosis. However the pathophysiology mechanisms are unclear. There are growing evidences suggesting a role for visceral white adipose tissue, in particular through the inflammatory mediator secretion. This project aimed to assess the IH-induced alterations of visceral adipose tissue, and to study the causal relationship of these fat alterations with the IH-induced metabolic dysfunctions and vascular remodeling thanks to an animal model of OSAS (murine model of IH). These results confirm the deleterious effects of IH on pre-atheroclerotic and atherosclerotic vascular remodeling, especially through inflammation involving TLR-4. Without any obesity, IH induces both important structural and functional changes of visceral adipose tissue that are, in part, involved in inflammation and in IH-related metabolic and vascular alterations. These results bring new insight into the pathophysiology of OSAS-associated consequences, and suggest that correcting visceral adipose tissue inflammation could provide further therapeutic options for OSA patients.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O tratamento para a Síndrome da Apnéia Obstrutiva do Sono (SAOS) mostra-se necessário devido às co-morbidades associadas ao quadro da síndrome. Fatores como problemas cardiovasculares, e aumento das chances de acidentes automobilísticos e de trabalho, além da diminuição da qualidade de vida, fazem dessa condição um sério problema a ser tratado. Dentre os tratamentos clínicos têm recebido especial atenção os aparelhos intra-orais por se tratar de um método simples e não invasivo. Os objetivos deste trabalho foram avaliar através dos índices polissinográficos as melhoras produzidas por um aparelho experimental e um aparelho placebo, e através de radiografias cefalométricas analisar fatores anatômicos relacionados com a severidade inicial do quadro e com as alterações do quadro da síndrome decorrentes do uso do aparelho experimental (Twin Block). Dezenove pacientes participaram deste estudo que foi prospectivo, com acompanhamento médio de 10,5 meses, cruzado, randomizado e duplo-cego. Foram feitas polissonografias iniciais e em uso dos aparelhos, após em média 6,47 (d.p.=2,01) meses do uso do Twin Block e 3,8 (d.p.=0,84) meses do uso do placebo e radiografias cefalométricas inicial e com o aparelho Twin Block em posição. Os dados pareados foram avaliados pelo teste de Wilcoxon, os não pareados pelos testes t de Student e Mann-Whitney e a comparação de proporções com o teste z, todos com 5% de significância (p<0.05). Os resultados mostraram tendências, embora não comprovadas estatisticamente, nas quais o grupo com SAOS moderada apresentou medidas de faringe menores e posição do osso hióide menos caudal quando comparados com o grupo com SAOS leve; que houve melhor resposta à terapia com o Twin-Block do que com o placebo, considerando-se o índice de apnéias mais hipopnéias por hora de sono (IAH), o índice de apnéias por hora de sono (IA), e a percentagem de sono REM; que a posição do osso hióide vertical diminuiu mais nos pacientes que melhoraram, tanto para o IAH quanto para o IA, que a maioria das medidas de faringe sofreram maior aumento nos pacientes que melhoraram em comparação com os que não melhoraram.Também foi possível estabelecer-se correlação positiva entre hipofaringe (HF) e os pacientes que melhoraram (avaliando pelo IAH), entre distância do osso hióide a terceira vértebra cervical (DHTV), faringe na altura do plano oclusal [NF(2)], largura do palato mole (PM) e os pacientes que melhoraram (avaliando pelo IA), além de entre NF (2) e os pacientes que não melhoraram (avaliando pelo IA). Conclui-se que o Twin Block mostrou-se clinicamente mais efetivo que o aparelho placebo no controle da SAOS, que algumas medições cefalométricas podem estar relacionadas com a severidade da síndrome medida inicialmente e que há variações de alterações anatômicas entre os pacientes que responderam e não responderam à terapia com aparelho intra-oral. / The treatment for the Obstructive Sleep Apnea Syndrome (OSAS) is necessary due to the co-morbidities associated with the syndrome. Factors such as cardiovascular problems, higher risk of automobile and work accidents, in addition to the decreased quality of life, makes the condition a serious problem to be treated. Among the treatments, clinicians have given special attention to the intra-oral appliances because it is simple and noninvasive. The objectives of this study were to evaluate by polysomnographyc indexes the improvements produced by both experimental and placebo units, and by cephalometric radiographs examine anatomical factors related with the initial severity of the syndrome and with the changes resulting from the use of the experimental appliance (Twin Block). Nineteen patients participated in this crossover, randomized, double-blind and prospective study, with monitoring average of 10.5 months. Polysomnographys were made in the initial use of the devices, after an average of 6.47 months (s.d. = 2.01) of Twin Block use and 3.8 months (s.d. = 0.84) of placebo use, along with cephalometric radiographs taken initially and with the Twin Block in position. Paired data were analyzed by the Wilcoxon test, non-paired by the Student t test and Mann-Whitney and compared proportions with the test z, all with 5% of significance (p <0.05). The results showed trends, though not statistically proven, that the group with moderate OSAS presented lower measures for the pharynx and higher hyoid bone position when compared to the group with mild OSAS; that the patients were more responsive to therapy with Twin-Block than with placebo, considering the index of more apnea hypopnea per hour of sleep (AHI), the index of sleep apnea per hour (AI), and the percentage of REM sleep; that the position of the vertical hyoid bone decreased more in patients who improved, both for the AHI and for the AI; that most pharyngeal measures suffered greater increase in patients who improved in comparison with those who did not get better. It could also be established a positive correlation between hypopharynx (HF) and patients who improved (by assessing AHI), distance between the hyoid bone and the third cervical vertebra (DHTV), pharynx in the occlusal plain [NF (2)], the width of the soft palate (PM) and patients that improved (by assessing AI), and between NF (2) and patients who had not improved (by assessing AI). It is concluded that the Twin Block was clinically more effective than the placebo unit in the control of OSAS, that some cephalometric measurements may be related to the severity of the syndrome measure initially and that there are variations in anatomic changes among patients who responded and not responded to therapy with intra-oral device.