Background: Acute Coronary Syndrome (ACS), whose main pathological substrate is atherosclerosis, is one of the main causes of morbidity and mortality in the modern world. Disorders related to sleep quality (DRS), which are highly prevalent in adults, are considered independent risk factors for cardiovascular disease (CVD). Objectives: to investigate the influence of sleep quality on the prognosis of patients with ACS. Method: This is an observational and cohort study, which included 254 consecutive patients with a diagnosis of ACS admitted at a cardiology hospital, from July 2014 to October 2016. All volunteers answered to the Pittsburgh Sleep Quality Index (PSQI), the Berlin Questionnaire (BQ), the Epworth Sleepiness Scale (ESS), Medical Outcomes Study 36-item Short Form (SF-36), and were followed for cardiovascular events (CVE) during hospitalization, based on a standardized evaluation, administered by the researcher, associated to medical records. Results: Patients were hospitalized with Unstable Angina (43.31%), AMI without SST (37.01%) and AMI with SST (19.69%). Only 88 (34.65%) presented good sleep quality and 166 (65.35%) patients presented poor sleep quality. The occurence of intra-hospital outcome was associated to AMI with SST diagnosis (OR=5.13; CI: 95% 2.14 – 12.79; p=0.0003) and systemic arterial hypertension (SAH) (OR=3.26; CI: 95% 1.26 – 9.71; p=0.0215). Conclusion: It was not possible to demonstrate the existence of association between poor sleep quality and worse intra-hospital evolution of ACS patients. It was verified a higher probability to the occurrence of intra-hospital outcome in AMI with SST and hypertensive patients. / Introdução: A Síndrome Coronariana Aguda (SCA), cujo principal substrato anatomopatológico é a aterosclerose, constitui uma das principais causas de morbimortalidade do mundo moderno. Os distúrbios relacionados à qualidade do sono (DRS), altamente prevalentes em adultos, são considerados fatores de risco independentes para o surgimento da doença cardiovascular (DCV). Objetivos: Investigar a influência da qualidade do sono no prognóstico de pacientes com SCA. Métodos: Trata-se de um estudo observacional e de coorte, utilizando-se 254 sujeitos admitidos, consecutivamente com diagnóstico de SCA em hospital de referência cardiológica, no período de julho de 2014 a outubro de 2016. Todos os voluntários responderam ao Índice de Qualidade de Sono de Pittsburgh (PSQI), ao Questionário de Berlim (QB), à Escala de Sonolência de Epworth (ESE), ao Questionário de Qualidade de Vida Relacionado à Saúde SF-36, e foram acompanhados quanto ao aparecimento de eventos cardiovasculares (ECV) durante o internamento, a partir de avaliação padronizada, administrada pelo pesquisador, corroborando dados do prontuário médico. Resultados: Os pacientes foram internados com o diagnóstico de: Angina Instável (43,3%), Infarto Agudo do Miocárdio (IAM) sem supra de ST (37,0%) e IAM com supra de ST (19,7%). Apenas 88 (34,65%) apresentaram boa qualidade do sono e 166 (65,35%) pacientes apresentaram qualidade do sono ruim, sendo que destes, 43 (16,92%) foram classificados como prováveis portadores de distúrbios do sono. Constatou-se que a ocorrência de desfecho intra-hospitalar esteve associada ao diagnóstico de IAM com supra ST (OR=5,13; IC: 95% 2,14 – 12,79; p=0,0003) e à hipertensão arterial sistêmica (HAS) (OR=3,26; IC: 95% 1,26 – 9,71; p=0,0215). Conclusão: Não foi demonstrado que existe associação entre qualidade do sono ruim e pior evolução clínica intra-hospitalar de pacientes com SCA. Verificou-se maior probabilidade de ocorrência de desfecho intra-hospitalar em pacientes com diagnóstico de IAM com supra de ST e hipertensos. / Aracaju, SE

O avançar da idade é reconhecidamente um fator de risco para a Síndrome da Apneia Obstrutiva do Sono (SAOS). O motivo dessa constatação está associado à diminuição do tônus da musculatura orofaringeana e à redução da Dimensão Vertical de Oclusão (DVO), esta última atribuída às perdas dentárias. A abordagem odontológica, no tratamento da SAOS, refere-se ao uso de Aparelho de Avanço Mandibular (AAM), que impede a obstrução, parcial ou total, da passagem do ar pela via respiratória alta, durante o sono. Os pacientes desdentados, no entanto, têm sido negligenciados, nos estudos atualmente realizados. Pelo exposto, este trabalho objetivou avaliar os efeitos do tratamento em variáveis polissonográficas, ronco, sonolência, qualidade do sono e ainda os efeitos colaterais pelo uso do AAM titulável, em pacientes idosos e desdentados portadadores de SAOS. A metodologia envolveu inicialmente, cinquenta pacientes, dos quais dezesseis realizaram polissonografia de noite inteira, com gravação do ronco, por meio de um Roncômetro, visando investigação objetiva do sono. Analisaram-se subjetivamente frequência e intensidade do ronco, por questionários. A Escala Visual Analógica de Ronco (EVAR), aplicada ao parceiro de quarto, permitiu, igualmente, que fosse avaliada a intensidade desse sintoma. A sonolência diurna foi quantificada pela Escala de Sonolência de Epworth e a qualidade do sono, pelo Índice de Qualidade do Sono de Pittsburgh. Confecção individualizada dos AAMs respeitou os princípios biológicos relativos à DVO. Durante uma semana após a instalação, os pacientes utilizavam o AMM sem qualquer avanço mandibular, visando redução de quaisquer desconfortos. Subsequentemente, o protocolo estabelecia titulação gradual e progressiva (30%, 50% e 70%) do aparelho. Transposta a etapa de adaptação, após um período superior a quinze dias, as avaliações iniciais foram repetidas Os efeitos colaterais pelo uso do AAM e adesão ao tratamento foram investigados, a partir de questionários. Doze pacientes completaram o estudo (83,3% mulheres), sendo a media de idade 68 anos e índice de massa corporal médio de 28,3 kg/m2. Os resultados permitiram observar reduções significantes no índice de dessaturação de O2 (17,710,1 eventos/h, p=0,05) e índice de apneia (3,10,9 eventos/h, p=0,02). O uso do AAM evidenciou também diminuições na latência do sono REM, movimentos períodicos de perna, saturação mínima de O2, índice de apneia e hipopneia, na posição supina (p>0,05). O estudo objetivo do ronco apontou redução de 49,522,6 eventos/h (p=0,07). Além do mais, as avaliações subjetivas de frequência (p=0,024) e intensidade (p=0,007) do ronco, EVAR (p=0,003), qualidade do sono (p=0,008), efeitos colaterais e adesão ao AAM foram estatisticamente significantes. Foi possível concluir pela eficácia do tratamento sobre algumas variáveis polissonográficas estudadas, parâmetros subjetivos do ronco e qualidade do sono. Ademais, os sintomas relatados, pelo uso do AAM, reduziram-se ao longo do tempo, o que permitiu, com vantagem, que houvesse maior adesão ao tratamento por parte dos pacientes inseridos nesta pesquisa. / Aging process is well known as a risky factor to Obstructive Sleep Apnea Syndrome (OSAS). Concomitant with this process, the reduction of orofacial and pharyngeal musculature tone, as well as the decrease of Vertical Occlusion Dimension (VOD), the latter attributed to tooth loss, have been considered as probable causal agents involved in OSAS pathogenesis. The Dentistry approach for OSAS treatment is commonly related to the use of Mandibular Advancement Devices (MAD), which could prevent partial or complete upper airway obstruction during sleep. However, this treatment has been scarcely used in toothless patients. The aim of this study was to assess the effects of a titratable MAD in polysomnographic (PSG) variables, snoring, sleepiness, sleep quality and side effects, in edentulous elderly patients with OSAS. Sixteen out of fifty patients assessed have been selected and have undergone an overnight polysomnographic study. Snoring was recorded by using suitable equipment, so that an objective assessment of sleep patterns could be made. The frequency and intensity of snoring have also been subjectively assessed by means of questionnaires. The Snoring Visual Analogic Scale (SVAS), posed to a bed partner, was also assessed to evaluate snoring intensity. Excessive daytime sleepiness and the quality of sleep have also been investigated by Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index, respectively. The patients went through the whole process for individually manufacturing of the MAD following the biological principles of the VDO. A week after using the MAD, at 0% of mandibular advancement, the patients were invited to return in order to undergo a new evaluation according to their adaptation to MAD. Subsequently, a titration protocol was gradually established at 30%, 50% and 70% for mandibular advancement. After a period of at least fifteen days, which should correspond to an adjustment of patients to their devices, the same initial assessment procedures were repeated. The MAD collateral effects as well as the treatment acceptance have been investigated through questionnaires. Twelve patients (83,3% females) completed the study, with an average age of 68 years, body mass index of 28,3 kg/m2. The results showed a significant reduction in O2 desaturation index (17,710,1 event/h, p=0,05) and also in AI (3,10,9 events/h, p=0,02). The use of the MAD also represented reductions in the latency to REM sleep, periodical leg movements, minimum O2 saturation, apnea and hypopnea index (AHI) in supine position (p>0,05). The objective assessment of snoring showed a reduction, with no statistical relevance of the Snoring Index (49,522,6 events per hour of recording, p=0,07). The subjective assessment of frequency (p=0,024) and intensity of snoring (p=0,007), EVAR (p=0,003), sleep quality (p=0,008) and the MAD collateral effects as well as the treatment acceptance were also statistically significant. We observed that the OSAS treatment with MAD was effective in some polysomnografic variables studied as well as in the subjective parameters of snoring and sleep quality in edentulous elderly patients. The reported symptoms due to MAD use decreased over the time.

A população idosa possui alta prevalência de edentulismo e, conseqüentemente, é afetada pelos problemas a ele associados. A perda da dimensão vertical de oclusão (DVO) é um destes problemas que compromete, entre outros fatores, o desempenho do sistema estomatognático. Logo, doenças relacionadas ao colapso da musculatura da via aérea superior (VAS), como a síndrome da apnéia obstrutiva do sono (SAOS), tornam-se enfermidades relevantes para pacientes nesta faixa etária. Sendo assim, medidas terapêuticas eficazes e de baixo custo, como a utilização de aparelhos intraorais (AIOs) para liberação do fluxo aéreo, podem ser empregadas contribuindo para a qualidade do sono destes pacientes. O objetivo deste estudo foi avaliar parâmetros subjetivos e objetivos do sono, em 10 pacientes idosos portadores de Próteses totais (PTs) bimaxilares, após a utilização de novas PTs confeccionadas no Programa Envelhecer Sorrindo e após o uso de dois AIOs: um dispositivo intraoral (DIO), especialmente desenvolvido para aumentar a DVO sem provocar avanço mandibular, e um aparelho de avanço mandibular (AAM). Para isso, questionários de rastreamento da qualidade do sono e polissonografias (PSGs) foram realizados, em quatro momentos distintos: sem as PTs, com as PTs, com o DIO e com o AAM. Foram realizadas, também, telerradiografias em norma lateral (TNL) dos pacientes com as PTs, com o DIO e com o AAM a fim de avaliar alterações no diâmetro da VAS e o posicionamento mandibular nesses três momentos. Concluiu-se que, o AAM testado promove maior porcentagem de sono no estágio 1, podendo contribuir para a melhora na qualidade subjetiva do sono dos pacientes, uma vez que ajudou a diminuir o tempo necessário para iniciar o sono, além de facilitar a manutenção do estado de vigília. / There is a high prevalence of edentulism and problems associated to it in the elderly population. A decrease in vertical dimension of occlusion (VDO) is one of these problems that may compromise the stomatognathic system. Therefore, it is important to investigate diseases related to upper airway (UA) musculature collapse, such as the syndrome of obstructive sleep apnea (OSAS). Therapeutic measures of low cost and high efficacy, such as intraoral appliances (IAs) to release the air flow may be employed, contributing to patients sleep quality. The aim of this study was to evaluate subjective and objective sleep parameters in 10 elderly patients who wore maxilar and mandibular complete dentures (CD). The analyses were performed after the use of a new pair of CD and after using two IAs: an intraoral device (ID), especially developed to increase the VDO without causing mandibular advance, and a mandibular advance device (MAD). For this purpose, questionnaires and polysomnography (PSG) were performed in four distinct stages: patients not wearing CD, wearing CD, wearing ID and wearing MAD. In addition, lateral cephalograms (LC) of patients wearing FD, wearing ID and wearing MAD were performed to assess changes in UAs diameter and in the mandibular positioning. It was concluded that the MAD tested promotes higher percentage of stage 1 sleep and and may contribute to the improvement in patients subjective sleep quality, as it helped to decrease the time needed to fall asleep, and facilitate the maintenance of wakefulness.

Le syndrome d’apnées obstructives du sommeil (SAOS) est une pathologie caractérisée par des épisodes d’hypoxie intermittente (HI) nocturnes et 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 épisodes d’HI est considérée comme le facteur principal responsable de cette morbidité cardiovasculaire dont l’athérosclérose fait partie. Le traitement de référence du SAOS par la pression positive continue présente dans certains cas une efficacité limitée, en particulier sur les conséquences cardiovasculaires qui nécessitent d’autres thérapeutiques plus spécifiques. Les mécanismes reliant SAOS et athérosclérose ne sont pas encore totalement connus. Cependant, des perturbations du métabolisme des acides gras (AG) en lien avec le processus athéromateux ont déjà été rapportées au cours du SAOS. Elles concernent en particulier le métabolisme de l’acide arachidonique (AG n-6) avec une augmentation d’eicosanoïdes pro-inflammatoires. Par ailleurs, les AG n-3 peuvent avoir une influence sur le développement et la progression des maladies cardiovasculaires, notamment grâce à une modification de la balance AG n-6 / AG n-3. Ainsi l’objectif de ce travail a donc été dans un premier temps de caractériser expérimentalement l’effet d’une supplémentation en AG n-3 sur le développement de l’athérosclérose dans le contexte d’HIC, et d’évaluer cliniquement la distribution AG n-6 / AG n-3 au niveau érythrocytaire chez des patients atteints d’un SAOS. Nous avons démontré que la supplémentation en AG n-3 permet de prévenir l’accélération de l’athérosclérose dans le contexte de l’HIC et est associée à une modulation de l’expression de certains médiateurs inflammatoires. Ces résultats prometteurs incitent à envisager une étude interventionnelle chez les patients SAOS. Dans un second temps, nous nous sommes intéressés au métabolisme des AG, via la β-oxydation mitochondriale, et aux métabolites intermédiaires produits, les acylcarnitines (ACs). Ces métabolites sont de plus en plus étudiés dans le contexte des pathologies cardiovasculaires. Nous avons étudié l’impact du SAOS sur la β-oxydation et ses conséquences sur la fonction vasculaire. L’étude de ces métabolites semble prometteuse et permettra peut-être l’émergence de marqueurs biologiques en relation avec l’état cardiovasculaire des patients. / Obstructive sleep apnea (OSA) syndrome is a disease characterized by recurrent episodes of nocturnal intermittent hypoxia (IH). OSA is a major public health problem due to its frequency in general population (5 to 20%) and its numerous metabolic and cardiovascular complications. Repetitive apneas lead to IH which is responsible of early atherosclerosis and cardiovascular complications. Gold standard treatment of OSA, that is to say continuous positive airway pressure, has poor effects on OSA cardiovascular consequences in some patients, underlining the need of alternative therapeutic strategies. Underlying mechanisms linking OSA to atherosclerosis are still poorly understood. Nevertheless, a link between polyunsaturated fatty acids (PUFAs) metabolism changes and atheromatous process has already been report during OSA syndrome. Arachidonic acid (n-6 PUFA) metabolism leads to increased biosynthesis of pro-inflammatory eicosanoids during OSA. Moreover, n-3 PUFAs influence cardiovascular complications progression especially by modifying n-6 FA / n-3 FA balance. The aim of this work was first to evaluate the influence of n-3 PUFAs supplementation on a CIH induced atherosclerosis progression model, and to clinically evaluate erythrocyte n-6 PUFA / n-3 PUFA distribution in OSA patients. We have shown that n-3 PUFAs supplementation prevents atherosclerosis acceleration in CIH exposed mice and is associated with a modulation of inflammatory mediators. These promising results encourage us to consider an interventional clinical study in OSA patients. In a second time, we have studied FA mitochondrial β-oxidation metabolism via acylcarnitines (ACs) metabolites. These ACs are increasingly studied especially in cardiovascular diseases context. OSA impact on β-oxidation metabolism and its vascular function consequences have been evaluated. ACs study is promising and will perhaps allow biological markers emergence in relation to cardiovascular pattern.

Introdução: A correta localização do sítio de obstrução nas vias aéreas superiores (VAS) possibilita melhores resultados de tratamento para os pacientes com Síndrome da Apneia Obstrutiva do Sono (SAOS). A endoscopia com sono induzido (DISE) com propofol permite esta avaliação, mas o sono induzido pelo propofol altera a arquitetura do sono, abolindo a presença do sono REM (rapid eye movement). Objetivos: Avaliar as alterações promovidas pelo propofol nos principais parâmetros respiratórios por meio do exame de polissonografia (PSG) nos pacientes portadores de SAOS com predomínio no sono REM (SAOS-R). Descrever os achados da DISE nesses pacientes, comparando-os aos achados da manobra de Müller e às descrições na literatura. Casuística e Métodos: Foram estudados 12 indivíduos não obesos com SAOS-R (confirmado por PSG noturna diagnóstica recente), submetidos a dois exames polissonográficos diurnos, com e sem indução do sono com propofol. O propofol foi utilizado via endovenosa em infusão contínua e controlada por bomba de infusão alvocontrolada (Diprifusor®). Os parâmetros comparados entre os exames foram: IAH (índice de apneia e hipopneia), IA (índice de apneia), IH (índice de hipopneia) e saturação de oxi-hemoglobina (SaO2) mínima e média. Além desses parâmetros, os sítios de obstrução das VAS encontrados na DISE foram comparados com os observados na avaliação ambulatorial com os indivíduos em estado de vigília. Resultados: Não foi evidenciado sono REM em nenhum exame realizado com propofol. O IAH, IA e IH do exame com propofol não apresentaram diferença estatística quando comparados com os exames diurnos sem indução e PSG noturna. A SaO2 média apresentou diferença estatística entre os três exames, sendo menor nas PSGs com indução do sono utilizando propofol, tanto em relação ao exame sem sedação (p<0,0001) quanto ao noturno (p=0,004). A SaO2 mínima foi semelhante entre as PSGs com sedação e noturnas, mas foi significativamente menor nos exames com sedação em relação aos sem sedação diurnos (p=0,011). Quando houve diferença significativa, esta ocorreu em torno de 2 a 3%. A análise de concordância para a classificação de VOTE (velum, oropharynx, tongue base and epiglottis) na avaliação ambulatorial e na DISE não demonstrou nenhuma concordância para todas as estruturas avaliadas (Kappa = - 0,029 em palato, 0,1 em orofaringe, 0,16 em base da língua e 0,0 em epiglote). Os resultados demonstraram que, apesar de o propofol influenciar a arquitetura do sono, abolindo o sono REM, os principais parâmetros utilizados na avaliação dos pacientes com SAOS-R, permaneceram inalterados, ou foram clinicamente irrelevantes. Conclusão: Assim, quando utilizado por infusão contínua, o propofol demonstrou ser uma droga segura na avaliação endoscópica dos indivíduos com SAOS-R para a determinação dos sítios de obstrução, acrescentando informações importantes para o correto tratamento. Ainda, a PSG sob sono induzido com propofol manteve os principais parâmetros ventilatórios em comparação à PSG sob sono espontâneo. / Introduction: The correct localization of upper airway obstruction induces the patients with obstructive sleep apnea syndrome (OSAS) to present better treatment results. Drug induced sleep endoscopy (DISE) with propofol allows this evaluation, but changes the sleep architecture, abolishing the presence of REM sleep. Objecives: To evaluate the changes promoted by propofol on the main respiratory parameters of polysomnography (PSG) in patients with REM-related OSAS (REM-OSAS). To describe the endoscopic findings in these patients, and to compare them to the outpatient Müller\'s maneuver and to the findings described in literature. Casuistic and Methods: In this study, 12 non-obese subjects with REM-OSAS (confirmed by recent nocturnal PSG) underwent two polysomnographic examinations during the day, with and without sleep induction with propofol. Propofol was used intravenously in continuous infusion controlled by target-controlled infusion pump (Diprifusor®). The parameters compared between the examinations were: AHI (apnea-hypopnea index), AI (apnea index), HI (hypopnea index) and both minimal and mean oxihemoglobin saturation (SaO2). Besides these parameters the sites of upper airway obstruction found in DISE were compared with those found in awake outpatient evaluation. Results: REM sleep was not achieved in any moment, in any patient, when propofol was infused. The AHI, AI and HI during infusion with propofol showed no statistical difference when compared with both diurnal test without propofol and diagnostic nocturnal PSG. Mean SaO2 showed statistical difference between the 3 tests, being lower in PSG with sleep induction with propofol, both for the exam without sedation (p<0.0001) as for and the diagnostic PSG (p=0.004). Minimum SaO2 was similar between examinations with sedation and diagnostic nocturnal PSG, but it was significantly lower in tests with propofol infusion compared with the diurnal exam without sedation (p=0,011). Mean difference, when significant, was about 2 to 3%. The analysis of agreement for the VOTE classification by patient evaluation and DISE showed no agreement in any measured structure (kappa = -0.029 for velum, 0,1 for oropharynx, 0,16 for tongue base and 0,0 for epiglottis). The results demonstrate that although propofol influences sleep architecture, abolishing REM sleep, the main respiratory parameters remained unchanged in patients with REMOSAS. Conclusions: Thus, target-controlled infusion of propofol is a safe method for endoscopic evaluation of patients with REM-OSAS, in order to determine the sites of obstruction, and it adds important information for proper treatment. Yet, PSG during DISE with propofol was related to manteinance of the most important ventilatory parameters when compared with PSG under spontaneous sleep.

No description available.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Le syndrome d’apnées obstructives du sommeil (SAOS) est associé à de nombreuses co-morbidités métaboliques et cardiovasculaires. L’hypoxie intermittente chronique, une des composantes du SAOS, induit des mécanismes intermédiaires délétères tels que stress oxydatif, inflammation, insulino-résistance ou encore dyslipidémie, à l’origine de ces comorbidités. Ces mécanismes intermédiaires sont également communs à d’autres pathologies respiratoires chroniques telles que la bronchopneumopathie chronique obstructive (BPCO) et le syndrome d’obésité hypoventilation (SOH).L’hypoxie intermittente et les mécanismes intermédiaires associés sont aussi à l’origine de l’existence et de la progression de la stéatopathie métabolique (« non alcoholic fatty liver disease »). Ce lien entre pathologies respiratoires chroniques et atteinte hépatique est un mécanisme essentiel mais plus récemment étudié des co-morbidités dans le SAOS et la BPCO. Différents biomarqueurs cardiométaboliques ont donc été étudiés dans ces pathologies respiratoires chroniques à la fois pour caractériser les co-morbidités et l’atteinte systémique et pour apprécier l’impact de différentes thérapeutiques. La première partie de cette thèse sera consacrée à une revue systématique des différents biomarqueurs cardio-métaboliques liés à chacune de ces 3 pathologies respiratoires chroniques : SAOS, BPCO et SOH.Le traitement du SAOS par pression positive continue (PPC) a un effet bénéfique sur les symptômes fonctionnels liés à cette pathologie. Cependant, l’impact de la PPC sur d’autres conséquences cardio-métaboliques délétères du SAOS reste encore à démontrer par des essais randomisés contrôlés, notamment sur l’atteinte hépatique.Dans la seconde partie de cette thèse, nous détaillerons l’impact de la PPC sur les différents marqueurs cardiométaboliques du SAOS à l’aide d’une revue systématique puis d’une étude randomisée contrôlée sur l’impact de la PPC sur les marqueurs d’atteinte hépatique.Par ailleurs, les patients atteints de SAOS, BPCO ou SOH reçoivent du fait de leur polypathologie (multimorbidité) des traitements médicamenteux multiples qui visent à contrôler au mieux les co-morbidités. Il est donc primordial de considérer la prise en charge globale de ces patients du point de vue de leurs traitements instrumentaux (PPC et ventilation non invasive) mais aussi en considérant l’impact des traitements médicamenteux associés. En effet, les traitements médicamenteux peuvent interférer avec la sévérité de la pathologie elle-même et impacter les biomarqueurs liés aux comorbidités associées. La troisième partie de cette thèse sera consacrée à l’étude d’un antihypertenseur chez le patient SAOS et envisagera l’influence des médicaments sur la pertinence de l’usage des bicarbonates comme marqueurs diagnostiques du SOH.En conclusion, nous insisterons sur la nécessité d’une prise en charge intégrée multi systémique et d’une prise en charge personnalisée de ces patients. / Obstructive sleep apnea (OSA) is associated with related metabolic and cardiovascular comorbidities. Chronic intermittent hypoxia the hallmark of OSA induces deleterious intermediary mechanisms such as oxidative stress, systemic inflammation, insulin resistance and dyslipidemia. Cardiovascular and metabolic comorbidities are also key features of other chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS). Chronic hypoxia and deleterious intermediary mechanisms also trigger occurrence and progression of non alcoholic fatty liver disease. This link between chronic respiratory diseases and liver injury is observed through modifications of specific liver biomarkers in OSA and COPD. A variety of cardiometabolic biomarkers have been studied for stratification of cardio-metabolic risk and assessing treatment impact in chronic respiratory diseases. The first part of this PhD thesis is a systematic review of cardio-metabolic biomarkers in 3 respiratory diseases: OSA, COPD and OHS.Continuous positive airway pressure (CPAP) the first line therapy for OSA improves symptoms and quality of life. However, CPAP effects on cardio-metabolic consequences remains still debated. In the second part of the PhD thesis, we will address CPAP impact on different cardiometabolic biomarkers and more specifically in markers of liver injury by reporting original results of a randomized controlled trial (RCT).Polypharmacy is usual in patients with OSA, COPD or OHS. Beyond CPAP or non invasive ventilation treatment, it is essential address the contribution of associated medications. Indeed, pharmacological treatments can interfere with the severity of the disease and control of associated comorbidities. The third part of the thesis will present a RCT evaluating Bosentan in hypertensive OSA patients and will present how medications for comorbidities decrease bicarbonate diagnosis value for OHS.We will conclude by underlining the crucial importance of personalized medicine and integrated care in chronic respiratory diseases.

Le syndrome d’apnées obstructives du sommeil (SAOS) est associé à la survenue de neuropathies optiques, en particulier la neuropathie optique ischémique antérieure aigue non artéritique (NOIAA-NA). Parmi les mécanismes d’apparition de cette neuropathie et potentiellement associés au SAOS, la dysrégulation et l’inflammation vasculaires pourraient jouer un rôle. Il n’existe aucune donnée dans la littérature sur l’effet de l’hypoxie intermittente (HI) chronique sur la fonction vasculaire de l’œil.Le but de ce travail était de développer des techniques d’évaluation de la fonction vasculaire oculaire chez le rat et de les appliquer à l’étude des conséquences vasculaires oculaires de l’HI. Ainsi, deux approches complémentaires ont été développées : 1) un prototype de fluxmètre laser Doppler (LDF) adapté au rongeur pour l’évaluation in vivo de la perfusion sanguine rétinienne et de la tête du nerf optique (TNO) et 2) le modèle d’étude de l’artère ophtalmique (AO) du rat par myographie vasculaire, in vitro.La mise au point du LDF chez le rat sain a permis de valider la pertinence du signal provenant des artères rétiniennes. A l’inverse, nos données invalident l’intérêt de la mesure au niveau de la TNO. En réponse à l’inhalation d’oxygène pur, nous observons une diminution de 17,0 ± 13,7 % de la vélocité artérielle rétinienne (VelART). Nous n’observons pas de variation significative de VelART lors d’injection intra-carotidienne d’endothéline 1 (ET-1) malgré une forte vasoconstriction des vaisseaux rétiniens. Les perspectives consistent à associer une caméra de haute résolution à un système bidirectionnel de LDF. L’étude de la réactivité de l’AO par myographie chez le rat soumis à 14 jours d’HI a mis en évidence une augmentation de la contraction à l’ET-1, associée à une augmentation de la réponse médiée par les récepteurs de type A (ETRA)et à une surexpression des ETRA au sein de l’AO. La relaxation NO-dépendante était diminuée chez le rat HI, et associée à un effet prédominant des produits vasoconstricteurs du cytochrome P450. Ces réponses étaient associées à une augmentation de la présence d’anions superoxyde dans la paroi de l’AO. Des études complémentaires sont nécessaires pour explorer les mécanismes à l’origine des ces altérations vasculaires, en particulier le rôle du stress oxydant. / Obstructive sleep apnea (OSA) has recently been associated with the occurrence of optic neuropathies, especially acute non-arteritic anterior ischemic optic neuropathy (NAION). Among the mechanisms of NAION onset potentially associated with OSA, vascular dysregulation and inflammation may play a role. There is still no data on the effect of chronic intermittent hypoxia (IH) on vascular function of the eye. The purpose of this work was to develop techniques for assessing rat ocular vascular function and apply them to the study of the ocular vascular consequences of IH. Thus, two complementary models have been developed: 1) a laser Doppler flowmeter (LDF) prototype adapted for rodents, to evaluate in vivo retinal and optic nerve head (ONH) blood perfusion and 2) in vitro model of rat ophthalmic artery (OA) study by myography. Preliminary work on healthy rat enabled us to validate the relevance of retinal arteries LDF signal, but not that of the ONH. Retinal blood velocity (VelART) dropped by 17.0 ± 13.7% in response to pure oxygen inhalation. We did not observe any significant change in VelART signal after intracarotidian endothelin 1 (ET -1) injection, despite strong vasoconstriction of retinal vessels. OA reactivity study by myography in rats exposed to a 14-day IH showed increased contraction to ET-1, associated with an increased endothelin receptor A-mediated (ETRA) response and ETRA overexpression within the AO. NO-dependent relaxation is reduced in IH rats, and associated with a shift towards vasoconstrictive effects of cytochrome P450 products. These responses were associated with an increase in superoxide anions in the OA wall. Further studies are needed to explore the underlying mechanisms of these vascular changes, particularly the role of oxidative stress. Understanding of the LDF signal is partial and should be further explored to permit application to the study of IH rat.

Introdução: A correta localização do sítio de obstrução nas vias aéreas superiores (VAS) possibilita melhores resultados de tratamento para os pacientes com Síndrome da Apneia Obstrutiva do Sono (SAOS). A endoscopia com sono induzido (DISE) com propofol permite esta avaliação, mas o sono induzido pelo propofol altera a arquitetura do sono, abolindo a presença do sono REM (rapid eye movement). Objetivos: Avaliar as alterações promovidas pelo propofol nos principais parâmetros respiratórios por meio do exame de polissonografia (PSG) nos pacientes portadores de SAOS com predomínio no sono REM (SAOS-R). Descrever os achados da DISE nesses pacientes, comparando-os aos achados da manobra de Müller e às descrições na literatura. Casuística e Métodos: Foram estudados 12 indivíduos não obesos com SAOS-R (confirmado por PSG noturna diagnóstica recente), submetidos a dois exames polissonográficos diurnos, com e sem indução do sono com propofol. O propofol foi utilizado via endovenosa em infusão contínua e controlada por bomba de infusão alvocontrolada (Diprifusor®). Os parâmetros comparados entre os exames foram: IAH (índice de apneia e hipopneia), IA (índice de apneia), IH (índice de hipopneia) e saturação de oxi-hemoglobina (SaO2) mínima e média. Além desses parâmetros, os sítios de obstrução das VAS encontrados na DISE foram comparados com os observados na avaliação ambulatorial com os indivíduos em estado de vigília. Resultados: Não foi evidenciado sono REM em nenhum exame realizado com propofol. O IAH, IA e IH do exame com propofol não apresentaram diferença estatística quando comparados com os exames diurnos sem indução e PSG noturna. A SaO2 média apresentou diferença estatística entre os três exames, sendo menor nas PSGs com indução do sono utilizando propofol, tanto em relação ao exame sem sedação (p<0,0001) quanto ao noturno (p=0,004). A SaO2 mínima foi semelhante entre as PSGs com sedação e noturnas, mas foi significativamente menor nos exames com sedação em relação aos sem sedação diurnos (p=0,011). Quando houve diferença significativa, esta ocorreu em torno de 2 a 3%. A análise de concordância para a classificação de VOTE (velum, oropharynx, tongue base and epiglottis) na avaliação ambulatorial e na DISE não demonstrou nenhuma concordância para todas as estruturas avaliadas (Kappa = - 0,029 em palato, 0,1 em orofaringe, 0,16 em base da língua e 0,0 em epiglote). Os resultados demonstraram que, apesar de o propofol influenciar a arquitetura do sono, abolindo o sono REM, os principais parâmetros utilizados na avaliação dos pacientes com SAOS-R, permaneceram inalterados, ou foram clinicamente irrelevantes. Conclusão: Assim, quando utilizado por infusão contínua, o propofol demonstrou ser uma droga segura na avaliação endoscópica dos indivíduos com SAOS-R para a determinação dos sítios de obstrução, acrescentando informações importantes para o correto tratamento. Ainda, a PSG sob sono induzido com propofol manteve os principais parâmetros ventilatórios em comparação à PSG sob sono espontâneo. / Introduction: The correct localization of upper airway obstruction induces the patients with obstructive sleep apnea syndrome (OSAS) to present better treatment results. Drug induced sleep endoscopy (DISE) with propofol allows this evaluation, but changes the sleep architecture, abolishing the presence of REM sleep. Objecives: To evaluate the changes promoted by propofol on the main respiratory parameters of polysomnography (PSG) in patients with REM-related OSAS (REM-OSAS). To describe the endoscopic findings in these patients, and to compare them to the outpatient Müller\'s maneuver and to the findings described in literature. Casuistic and Methods: In this study, 12 non-obese subjects with REM-OSAS (confirmed by recent nocturnal PSG) underwent two polysomnographic examinations during the day, with and without sleep induction with propofol. Propofol was used intravenously in continuous infusion controlled by target-controlled infusion pump (Diprifusor®). The parameters compared between the examinations were: AHI (apnea-hypopnea index), AI (apnea index), HI (hypopnea index) and both minimal and mean oxihemoglobin saturation (SaO2). Besides these parameters the sites of upper airway obstruction found in DISE were compared with those found in awake outpatient evaluation. Results: REM sleep was not achieved in any moment, in any patient, when propofol was infused. The AHI, AI and HI during infusion with propofol showed no statistical difference when compared with both diurnal test without propofol and diagnostic nocturnal PSG. Mean SaO2 showed statistical difference between the 3 tests, being lower in PSG with sleep induction with propofol, both for the exam without sedation (p<0.0001) as for and the diagnostic PSG (p=0.004). Minimum SaO2 was similar between examinations with sedation and diagnostic nocturnal PSG, but it was significantly lower in tests with propofol infusion compared with the diurnal exam without sedation (p=0,011). Mean difference, when significant, was about 2 to 3%. The analysis of agreement for the VOTE classification by patient evaluation and DISE showed no agreement in any measured structure (kappa = -0.029 for velum, 0,1 for oropharynx, 0,16 for tongue base and 0,0 for epiglottis). The results demonstrate that although propofol influences sleep architecture, abolishing REM sleep, the main respiratory parameters remained unchanged in patients with REMOSAS. Conclusions: Thus, target-controlled infusion of propofol is a safe method for endoscopic evaluation of patients with REM-OSAS, in order to determine the sites of obstruction, and it adds important information for proper treatment. Yet, PSG during DISE with propofol was related to manteinance of the most important ventilatory parameters when compared with PSG under spontaneous sleep.