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Apneia obstrutiva do sono : marcadores de gravidade e de resposta à terapêutica
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RESUMO: A síndrome de apneia obstrutiva do sono (SAOS) é um distúrbio respiratório do sono. Consiste num conjunto de sintomas e sinais que resulta dos episódios recorrentes de obstrução intermitente da via aérea superior, que ocorrem apesar da existência de esforço respiratório. Estima-se que esta síndrome seja muito frequente. No entanto, desconhece-se a sua verdadeira prevalência, uma vez que se encontra sub-diagnosticada. A SAOS é considerada uma doença sistémica à qual se associam várias consequências, nomeadamente doenças cardiovasculares e metabólicas, o que a torna num problema de saúde pública. As complicações cardiovasculares, pelo seu impacto individual, social e económico, são talvez as consequências mais bem estudadas da SAOS. Também os distúrbios metabólicos têm merecido especial atenção, não só pela relação bidirecional com a SAOS, mas também pela sua contribuição a nível do risco cardiovascular. A polissonografia (PSG) é o exame de eleição para o diagnóstico da SAOS. No entanto, o facto de ser um exame moroso e exigente em termos de recursos, acaba por contribuir para o sub-diagnóstico desta patologia. O tratamento de primeira linha da SAOS consiste no uso noturno de dispositivos de pressão positiva da via aérea (PAP). No entanto, os efeitos a nível clínico e fisiopatológico desta terapêutica são ainda tema de
debate. Globalmente, estas razões têm sido responsáveis pela procura de métodos alternativos e que possam ser usados no diagnóstico, na avaliação do prognóstico e/ou da resposta à terapêutica. Estudos recentes têm incidido, principalmente, na procura direcionada de biomarcadores metabólicos, de inflamação e de stress oxidativo da SAOS e das patologias que lhes estão associadas. Apesar de vários candidatos a biomarcadores terem emergido nos últimos anos, nenhum foi considerado como biomarcador adequado para o diagnóstico. Este facto deve-se provavelmente à diversidade clínica e à complexidade fisiopatológica da SAOS. Assim, justifica-se trabalho adicional na pesquisa de biomarcadores, com enfoque no prognóstico e na resposta à terapêutica. Para além dos parâmetros metabólicos, especial atenção tem sido dada à homocisteína, bem como aos parâmetros do hemograma, como o red blood cell distribution width (RDW) e alguns índices plaquetários, como biomarcadores associados à morbilidade/mortalidade cardiovascular. No entanto, persistem dúvidas acerca da relação entre estes diversos parâmetros e a gravidade da SAOS, bem como quanto ao seu comportamento sob terapêutica com PAP. Adicionalmente, na procura de biomarcadores da SAOS, tem sido dado especial destaque ao stress oxidativo, por ser considerado o paradigma unificador da morbilidade cardiovascular e dos distúrbios metabólicos que lhe estão associados. Presentemente, sabe-se que os glóbulos vermelhos (GV) são os principais efetores do sistema anti-oxidante vascular. No entanto, permanece por estudar, nos doentes com SAOS, se proteínas eritrocitárias, pertencentes às vias de stress oxidativo, poderão servir de biomarcadores de gravidade e/ou de resposta à terapêutica com PAP. Assim, em alternativa à pesquisa convencional ou direcionada de biomarcadores, tem ganho expressão a pesquisa exploratória de proteínas. Neste campo, a proteómica tem sido uma ferramenta fundamental, pois permite a pesquisa simultânea de inúmeras proteínas, passíveis de serem potenciais biomarcadores de várias doenças, incluindo da SAOS. Apesar disso, até ao momento, existem poucos estudos de proteómica na SAOS e nenhum usando os GV como meio biológico. O primeiro artigo, publicado no âmbito desta tese, consistiu numa revisão acerca do estado da arte sobre a proteómica aplicada na SAOS. Neste artigo foi feita uma revisão dos estudos proteómicos realizados na população pediátrica e adulta, levados a cabo com o objetivo de identificar
potenciais biomarcadores aplicados ao diagnóstico/tratamento desta entidade clínica. A presente dissertação teve como objetivo geral investigar, numa amostra de doentes com SAOS, a existência de biomarcadores de gravidade e de resposta à terapêutica, através da pesquisa direcionada tradicional (convencional) e da pesquisa exploratória (proteómica). Definiram-se como objetivos específicos avaliar, nos doentes com SAOS, o comportamento de marcadores de inflamação, metabólicos e de stress oxidativo. Em concreto, pela via convencional pretendeu-se avaliar o comportamento da homocisteína, dos parâmetros glicídicos, lipídicos e do hemograma, e pela via exploratória (proteómica) as proteínas eritrocitárias diferencialmente expressas e
pertencentes às vias de stress oxidativo. Para a operacionalização destes objetivos foram desenvolvidos três estudos, para os quais se procedeu ao recrutamento sequencial de indivíduos a partir da Consulta de Patologia do Sono do Centro Hospitalar Lisboa Norte, EPE. Foram recolhidos dados demográficos, polissonográficos e analíticos, com base nos quais se desenvolveu uma base de dados e criou-se um biobanco de amostras biológicas. No período de 24 meses foi selecionada uma população de 103 doentes do género masculino, com idades compreendidas entre os 25 e os 60 anos, que realizaram PSG e avaliação analítica (sangue e urina). Excluíram-se doentes do género femininos, assim como portadores de outras doenças do sono, diabetes mellitus tipo I, dislipidemia familiar e doença aguda/grave. A partir dos 103 doentes estabeleceu-se um grupo de estudo com 73 doentes com SAOS e um de controlo com 30 roncadores sem SAOS. Os grupos eram comparáveis em termos de características demográficas e história clínica, exceto a maior prevalência de dislipidémia e de obesidade nos doentes com SAOS. A partir desta população foram selecionadas amostras para investigação de biomarcadores pela via direcionada, ou convencional, e pela via
exploratória, ou proteómica. O primeiro estudo avaliou a homocisteína e os perfis glicémico e lipídico nos roncadores (n=30) e nos doentes com SAOS (n=73), de diferentes gravidades (46=63% eram ligeiros/moderados e os restantes eram graves). O referido estudo demonstrou que os doentes com SAOS grave podem exibir alterações do perfil glicémico mesmo na ausência de diabetes conhecida, com repercussão na glicémia, hemoglobina glicosilada (HbA1c), insulina e resistência à insulina. Estes parâmetros
estiveram relacionados com a gravidade da doença. Adicionalmente, a homocisteína, os perfis glicémico e lipídico alteraram-se significativamente após 6 meses de tratamento com PAP nos doentes com SAOS grave, sugerindo o efeito protetor cardiovascular e metabólico da PAP. Concluiu-se, assim, que a homocisteína, os perfis glicémico e lipídico são parâmetros acessíveis e económicos, que podem complementar a abordagem diagnóstica e de seguimento dos doentes com SAOS. O segundo estudo avaliou os parâmetros do hemograma nos doentes com SAOS (n=73) de diferentes gravidades (em que 36 =49,3% eram ligeiros, 10 =13,7% eram moderados e 27 =37% eram graves). O estudo demonstrou uma associação positiva entre os valores do RDW e a gravidade da SAOS. Adicionalmente, foi avaliado um subgrupo de 48 doentes após 6 meses de tratamento com PAP. Verificou-se que a contagem de GV, a hemoglobina, o hematócrito e a contagem de plaquetas diminuíram de forma significativa após este período de terapêutica. Considerando a gravidade da SAOS, estes parâmeros também diminuíram de forma significativa nos doentes ligeiros mas apenas a hemoglobina, o hematócrito e a contagem das plaquetas diminuíram significativamente nos doentes
graves. Estes resultados também suportam o efeito protetor cardiovascular da PAP. Concluiu-se que o RDW pode tornar-se um biomarcador sanguíneo acessível e financeiramente atrativo, potencialmente útil no estabelecimento de prioridade nos doentes com suspeita de SAOS a aguardar PSG, sendo os parâmetros eritrocitários e plaquetários vantajosos no seguimento dos doentes com SAOS sob tratamento com PAP. Para o terceiro estudo, a partir da amostra inicial e após a exclusão de diabetes tipo 2 e doença cerebrovascular, foi selecionada uma outra amostra para análise proteómica exploratória e que decorreu em duas fases, designadas de fase de descoberta e fase de validação. Na fase de descoberta, foi selecionada uma amostra de 12 roncadores e de 12 doentes com SAOS (moderados/graves). A análise proteómica foi realizada nos GV através da técnica de 2-DIGE (Difference Gel Electrophoresis) associada a espectometria de massa (mass spectrometry - MS) antes (noite) e após (manhã) a PSG, a fim de serem analisadas as variações do proteoma entre estes dois tempos. As proteínas desreguladas pertenceram ao grupo das enzimas catalíticas, de resposta ao stress e reguladores redox, como é o caso da peroxirredoxina 2 (PRDX2). Na fase de validação, foi selecionada uma outra amostra, agora de 10 roncadores e de 10 doentes com SAOS (ligeiros, moderados e graves). Verificou-se que nos GV dos doentes com SAOS, as formas monoméricas/diméricas da PRDX2 estavam mais sobreoxidadas no período da manhã comparativamente com o período da noite. Verificou-se, ainda, que os níveis matinais de PRDX2 sobreoxidada estavam correlacionados com o índice de despertar e parâmetros metabólicos (HbA1c, insulina, resistência à insulina), enquanto os níveis noturnos dos dímeros dissulfido, associados à atividade peroxidase da PRDX2, estavam relacionados com parâmetros polissonográficos (índice de distúrbio respiratório, % tempo com saturação <90% e índice de dessaturação de oxigénio). Após 6 meses de tratamento com PAP, ocorreu uma diminuição desta sobreoxidação e foram geradas formas sobreoxidadas multiméricas da PRDX 2, que se sabe apresentarem atividade de chaperone/transdução da sinalização. Após tratamento, os multímeros matinais da PRDX 2 estavam correlacionados negativamente com a glucose em jejum e os níveis de dopamina urinária. Globalmente, estes resultados apontam para a existência de stress oxidativo grave e alteração da homeostasia anti-oxidante nos GV dos doentes com SAOS ocorrendo sobretudo pela manhã, mas com consequências até à noite. O tratamento com PAP apresentou um efeito benéfico na modulação do estado redox/oligomérico da PRDX2, cujo mecanismo e funções associadas de chaperone/transdução da sinalização justificam mais investigação. A PRDX2 eritrocitária poderá ser um biomarcador promissor da gravidade da SAOS e da monitorização do seu tratamento. Em conclusão, os resultados desta tese reforçam o uso da homocisteína, dos perfis glicémico e
lipídico e do hemograma como parâmetros complementares da abordagem diagnóstica e de seguimento dos doentes com SAOS. Os resultados apontam, também, para o uso do RDW como biomarcador sanguíneo de estabelecimento de prioridade nos doentes com suspeita de SAOS a aguardar PSG, e ainda que a PRDX2 eritrocitária poderá ser um biomarcador promissor da gravidade da SAOS e da monitorização do tratamento.
ABSTRACT: Obstructive sleep apnea syndrome (OSAS) is a sleep-related disorder characterized by symptoms and signs due to intermittent episodes of upper airway obstruction, despite ongoing inspiratory efforts. It is estimated that this disorder is common but the real prevalence is unknown since this syndrome is under-diagnosed. OSAS is considered as a systemic disease associated with several consequences, notably cardiovascular and metabolic, making OSAS a public health concern. Cardiovascular consequences bring individual, social, and economic impact, and for that are, perhaps, the most studied OSAS’s consequences. In addition, systematic attention has been given to metabolic disturbances. These disturbances are related to OSAS in a bidirectional way and they also contribute to cardiovascular OSAS associated diseases. Polysomnography (PSG) is a very complete exam, being the gold standard for OSAS diagnosis. However, this exam needs several resources and there is a waiting list to perform it, contributing to OSAS’s under diagnosis. The OSAS first line treatment is the use of positive airway pressure (PAP) devices during sleep. However, their clinical and pathophysiological effects are not consensual. Altogether, these reasons have justified the scientific concern to find alternative methods to help diagnosis, prognosis or treatment evaluation. Recent studies have been focusing on metabolic, inflammatory and oxidative stress specific markers, for OSAS disease and its associated consequences. Although there have been several candidates, none was considered as a diagnostic biomarker. This fact is probably due to clinical OSAS diversity and pathophysiological complexity. As a result, additional work is required in biomarker research focusing on prognosis and treatment response. Besides metabolic parameters, consideration has been given to homocysteine and hemogram data, such as the Red blood cell distribution width (RDW) and some platelet indices, as cardiovascular morbidity/mortality biomarkers. However, limited data is available on the association between these parameters and OSAS´s severity and their behavior on PAP therapy. In addition, several studies have explored pathophysiological mechanisms of OSAS and its associated diseases. Special attention has been paid to oxidative stress, due the fact that it has been considered to be the unified paradigm of OSAS cardiovascular morbidity and its metabolic underlying disturbances. Nowadays, red boold cells (RBC) are considered to be the main effectors of anti-oxidant vascular system. Nevertheless, further research on OSAS’s RBC is needed, to evaluate the expression of proteins belonging to oxidative stress processes, which could become markers of prognosis and response to PAP therapy. Thus, in alternative to conventional biomarker investigation, exploratory investigation has gained more expression. The advanced high-throughput proteomics-based technologies have become a fundamental approach to simultaneously explore several disease mediators for many diseases, including OSAS. Conversely, there are few studies concerning the use of proteomics in OSAS and neither of them used RBC as biological sample. In this thesis, the first paper included a review about the state-of-the-art proteomics in OSAS. In this paper the authors reviewed proteomic studies in children and adults with OSAS, undertaken to find potential diagnostic and treatment markers. The current research aims to evaluate in OSAS patients’ biomarkers of prognosis and response to treatment, in two different ways, by means of conventional and exploratory (proteomic) research. In terms of specific objectives, this research intended to evaluate metabolic, inflammatory, and oxidative stress markers behaviour in OSAS patients. In specific terms, homocysteine, glicidic, lipidic, and hemogram paramaters were evaluated by using a conventional approach, and RBC proteins differentially expressed and belonging to oxidative stress, by using an exploratory (proteomic) approach. Accordingly, three studies were performed. The study patients, who were male individuals from a Sleep Clinic of Centro Hospitalar Lisboa Norte, EPE, were consecutively recruited to participate. Demographic, polysomnographic, and analytical parameters were analysed. A database was developed to store this information and, associated with it, a biobank for biological samples was created. During 24 months, a total of 103 male patients, aged 25-60 years old were selected to perform PSG and blood and urinary analysis. The exclusion criteria were female patients, other sleep disorders, type I diabetes mellitus, familiar dyslipidemia, and acute/severe disease. One-hundred and three patients were included, where 73 (71%) were OSAS patients and the remainder were snorers. OSAS patients were similar to snorers concerning demographics and medical information except for the existence of known dyslipidemia and higher body mass index (BMI). From this population, different samples were selected for conventional and proteomic evaluation. The first study analysed homocysteine, glycemic, and lipidic profiles in snorers (n=30) and OSAS patients (n=73) of different severities (46 (63%)) were mild/moderate and the remainder were severe). The present study demonstrated that severe OSAS patients may exhibit changes in glycemic profile, even in absence of known diabetes, with compromise of glycemia, HbA1c, insulin, and insulin resistance, and these were correlated with OSAS severity. Moreover, homocysteine, glycemic, and lipidic profiles changed significantly after 6 months of PAP therapy in severe OSAS patients, supporting cardiovascular and metabolic protective effect of PAP. To conclude, homocysteine, glycemic, and lipidic profiles are accessible and inexpensive blood parameters, which should complement diagnostic and follow-up approach of OSAS patients. The second study analised hemogram parameters in OSAS patients (n=73) of different severities (36 were mild (49.3%), 10 moderate (13.7%), and 27 severe (37%)). This study reported a positive association between RDW values and OSAS severity. Additionally, a subgroup of 48 patients underwent six months of PAP treatment. After this period, red blood cell count, haemoglobin, haematocrit, and platelet count showed a significant decrease. Concerning the severity of OSAS, these parameters have also significantly decreased in mild patients but only haemoglobin, haematocrit, and platelet count decreased in severe patients. These results support a cardiovascular protective effect of PAP. RDW may become an accessible/inexpensive blood biomarker, making it useful in prioritizing OSAS patients’ awaiting for polysomnography, and red cell and platelet parameters could be useful in PAP follow-up. In the third study, and after exclusion of type 2 diabetes and cerebrovascular disease, a sample of patients was selected for proteomic analysis. This analysis was performed in two stages: the discovery and the validation stages. In the discovery stage, a sample of 12 snorers and 12 OSAS patients (moderate/severe) were selected. The proteomic evaluation in RBC was performed through 2-DIGE (Difference Gel Electrophoresis) associated with mass spectrometry (MS) at pre- (evening) and post- (morning) PSG so that proteome variations between these time points could be also assessed. Dysregulated proteins mainly fell in the group of catalytic enzymes, stress response, and redox regulators, such as peroxiredoxin 2 (PRDX2). In the validation stage, a sample of 10 snorers and 10 OSAs patients (mild, moderate and severe) were selected and validation assays confirmed that in the morning the monomeric/dimeric forms of PRDX2 were more overoxidized in OSAS RBC when compared to evening samples. Morning levels of overoxidized PRDX2 correlated with arousal index and metabolic parameters (HbA1c, insulin, insulin resistance), whereas the evening level of disulfide-linked dimer associated with peroxidase activity of PRDX2 correlated with PSG parameters (respiratory disturbance índex, % of time with saturation under 90% and oxygen desaturation índex). Six months of PAP treatment decreased this overoxidation and generated multimeric overoxidized forms associated with chaperone/transduction signaling activity of PRDX2. After treatment, morning multimer of PRDX2 was negatively correlated with fasting glucose and urinary dopamine levels. Overall, these data point toward severe oxidative stress and altered antioxidant homeostasis in OSAS RBC occurring mainly at morning time but with consequences till the evening. The beneficial effect of PAP involves modulation of the redox/oligomeric state of PRDX2, whose mechanism and associated chaperone/transduction signaling functions deserves further investigation. RBC PRDX2 is a promising biomarker for OSAS severity and treatment monitoring. In conclusion, the results of this thesis reinforce the use of homocysteine, glycemic and lipidic profiles, and hemogram as complementary parameters in diagnosis and follow-up approach of OSAS patients. The results point to the use of RDW as a useful biomarker in prioritizing OSAS patients awaiting for polysomnography and PRDX2 as a promising biomarker for OSAS severity and treatment monitoring.
ABSTRACT: Obstructive sleep apnea syndrome (OSAS) is a sleep-related disorder characterized by symptoms and signs due to intermittent episodes of upper airway obstruction, despite ongoing inspiratory efforts. It is estimated that this disorder is common but the real prevalence is unknown since this syndrome is under-diagnosed. OSAS is considered as a systemic disease associated with several consequences, notably cardiovascular and metabolic, making OSAS a public health concern. Cardiovascular consequences bring individual, social, and economic impact, and for that are, perhaps, the most studied OSAS’s consequences. In addition, systematic attention has been given to metabolic disturbances. These disturbances are related to OSAS in a bidirectional way and they also contribute to cardiovascular OSAS associated diseases. Polysomnography (PSG) is a very complete exam, being the gold standard for OSAS diagnosis. However, this exam needs several resources and there is a waiting list to perform it, contributing to OSAS’s under diagnosis. The OSAS first line treatment is the use of positive airway pressure (PAP) devices during sleep. However, their clinical and pathophysiological effects are not consensual. Altogether, these reasons have justified the scientific concern to find alternative methods to help diagnosis, prognosis or treatment evaluation. Recent studies have been focusing on metabolic, inflammatory and oxidative stress specific markers, for OSAS disease and its associated consequences. Although there have been several candidates, none was considered as a diagnostic biomarker. This fact is probably due to clinical OSAS diversity and pathophysiological complexity. As a result, additional work is required in biomarker research focusing on prognosis and treatment response. Besides metabolic parameters, consideration has been given to homocysteine and hemogram data, such as the Red blood cell distribution width (RDW) and some platelet indices, as cardiovascular morbidity/mortality biomarkers. However, limited data is available on the association between these parameters and OSAS´s severity and their behavior on PAP therapy. In addition, several studies have explored pathophysiological mechanisms of OSAS and its associated diseases. Special attention has been paid to oxidative stress, due the fact that it has been considered to be the unified paradigm of OSAS cardiovascular morbidity and its metabolic underlying disturbances. Nowadays, red boold cells (RBC) are considered to be the main effectors of anti-oxidant vascular system. Nevertheless, further research on OSAS’s RBC is needed, to evaluate the expression of proteins belonging to oxidative stress processes, which could become markers of prognosis and response to PAP therapy. Thus, in alternative to conventional biomarker investigation, exploratory investigation has gained more expression. The advanced high-throughput proteomics-based technologies have become a fundamental approach to simultaneously explore several disease mediators for many diseases, including OSAS. Conversely, there are few studies concerning the use of proteomics in OSAS and neither of them used RBC as biological sample. In this thesis, the first paper included a review about the state-of-the-art proteomics in OSAS. In this paper the authors reviewed proteomic studies in children and adults with OSAS, undertaken to find potential diagnostic and treatment markers. The current research aims to evaluate in OSAS patients’ biomarkers of prognosis and response to treatment, in two different ways, by means of conventional and exploratory (proteomic) research. In terms of specific objectives, this research intended to evaluate metabolic, inflammatory, and oxidative stress markers behaviour in OSAS patients. In specific terms, homocysteine, glicidic, lipidic, and hemogram paramaters were evaluated by using a conventional approach, and RBC proteins differentially expressed and belonging to oxidative stress, by using an exploratory (proteomic) approach. Accordingly, three studies were performed. The study patients, who were male individuals from a Sleep Clinic of Centro Hospitalar Lisboa Norte, EPE, were consecutively recruited to participate. Demographic, polysomnographic, and analytical parameters were analysed. A database was developed to store this information and, associated with it, a biobank for biological samples was created. During 24 months, a total of 103 male patients, aged 25-60 years old were selected to perform PSG and blood and urinary analysis. The exclusion criteria were female patients, other sleep disorders, type I diabetes mellitus, familiar dyslipidemia, and acute/severe disease. One-hundred and three patients were included, where 73 (71%) were OSAS patients and the remainder were snorers. OSAS patients were similar to snorers concerning demographics and medical information except for the existence of known dyslipidemia and higher body mass index (BMI). From this population, different samples were selected for conventional and proteomic evaluation. The first study analysed homocysteine, glycemic, and lipidic profiles in snorers (n=30) and OSAS patients (n=73) of different severities (46 (63%)) were mild/moderate and the remainder were severe). The present study demonstrated that severe OSAS patients may exhibit changes in glycemic profile, even in absence of known diabetes, with compromise of glycemia, HbA1c, insulin, and insulin resistance, and these were correlated with OSAS severity. Moreover, homocysteine, glycemic, and lipidic profiles changed significantly after 6 months of PAP therapy in severe OSAS patients, supporting cardiovascular and metabolic protective effect of PAP. To conclude, homocysteine, glycemic, and lipidic profiles are accessible and inexpensive blood parameters, which should complement diagnostic and follow-up approach of OSAS patients. The second study analised hemogram parameters in OSAS patients (n=73) of different severities (36 were mild (49.3%), 10 moderate (13.7%), and 27 severe (37%)). This study reported a positive association between RDW values and OSAS severity. Additionally, a subgroup of 48 patients underwent six months of PAP treatment. After this period, red blood cell count, haemoglobin, haematocrit, and platelet count showed a significant decrease. Concerning the severity of OSAS, these parameters have also significantly decreased in mild patients but only haemoglobin, haematocrit, and platelet count decreased in severe patients. These results support a cardiovascular protective effect of PAP. RDW may become an accessible/inexpensive blood biomarker, making it useful in prioritizing OSAS patients’ awaiting for polysomnography, and red cell and platelet parameters could be useful in PAP follow-up. In the third study, and after exclusion of type 2 diabetes and cerebrovascular disease, a sample of patients was selected for proteomic analysis. This analysis was performed in two stages: the discovery and the validation stages. In the discovery stage, a sample of 12 snorers and 12 OSAS patients (moderate/severe) were selected. The proteomic evaluation in RBC was performed through 2-DIGE (Difference Gel Electrophoresis) associated with mass spectrometry (MS) at pre- (evening) and post- (morning) PSG so that proteome variations between these time points could be also assessed. Dysregulated proteins mainly fell in the group of catalytic enzymes, stress response, and redox regulators, such as peroxiredoxin 2 (PRDX2). In the validation stage, a sample of 10 snorers and 10 OSAs patients (mild, moderate and severe) were selected and validation assays confirmed that in the morning the monomeric/dimeric forms of PRDX2 were more overoxidized in OSAS RBC when compared to evening samples. Morning levels of overoxidized PRDX2 correlated with arousal index and metabolic parameters (HbA1c, insulin, insulin resistance), whereas the evening level of disulfide-linked dimer associated with peroxidase activity of PRDX2 correlated with PSG parameters (respiratory disturbance índex, % of time with saturation under 90% and oxygen desaturation índex). Six months of PAP treatment decreased this overoxidation and generated multimeric overoxidized forms associated with chaperone/transduction signaling activity of PRDX2. After treatment, morning multimer of PRDX2 was negatively correlated with fasting glucose and urinary dopamine levels. Overall, these data point toward severe oxidative stress and altered antioxidant homeostasis in OSAS RBC occurring mainly at morning time but with consequences till the evening. The beneficial effect of PAP involves modulation of the redox/oligomeric state of PRDX2, whose mechanism and associated chaperone/transduction signaling functions deserves further investigation. RBC PRDX2 is a promising biomarker for OSAS severity and treatment monitoring. In conclusion, the results of this thesis reinforce the use of homocysteine, glycemic and lipidic profiles, and hemogram as complementary parameters in diagnosis and follow-up approach of OSAS patients. The results point to the use of RDW as a useful biomarker in prioritizing OSAS patients awaiting for polysomnography and PRDX2 as a promising biomarker for OSAS severity and treatment monitoring.
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Palavras-chave
Apneia obstrutiva do sono Doença metabólica Doença cardiovascular Biomarcadores Obstructive sleep apnea Metabolic disease Cardiovascular disease Biomarkers