Os objetivos desta pesquisa foram: compreender a perspectiva do profissional de saúde e do usuário hipertenso sobre a interação que ocorre entre eles no contexto da atenção em unidades públicas de saúde e analisar de que forma essa interação contribui para a não-adesão ao regime terapêutico. A metodologia aplicada para o desenvolvimento do estudo foi a Teoria Fundamentada nos Dados e o referencial teórico utilizado para a análise dos dados e interpretação dos resultados foi o Interacionismo Simbólico, além da literatura existente sobre o assunto. Ao todo, quinze profissionais de saúde e dez usuários fizeram parte da pesquisa. Ao final, foram encontradas seis categorias (duas delas, centrais) e outras subcategorias as quais, depois de um processo elaborado de comparações, relações e integração compuseram a proposição teórica que a autora fez sobre a interação entre o usuário e o profissional de saúde e da qual extraiu elementos para analisar a contribuição que essa interação tem para a não-adesão ao regime terapêutico. A autora concluiu que a interação, por ser pautada no modelo biomédico, centralizada no profissional de saúde, desigual, assimétrica e distanciada, tem elementos que podem estar contribuindo para a não- adesão do usuário ao regime terapêutico. Concluiu também que a principal ação que o profissional de saúde utiliza para promover a adesão do usuário ao regime terapêutico – a conscientização – tem sido ineficaz uma vez que se baseia no modelo tradicional de educação em saúde e no qual o usuário não é considerado como sujeito. Outra conclusão é a de que o usuário, por estar administrando o regime terapêutico à sua maneira, tem feito indicações ao profissional de saúde sobre sua forma de ver, entender e conviver com a hipertensão arterial e o regime terapêutico que nem sempre é congruente com o que o profissional de saúde quer e espera dele. Esta pesquisa aponta para a necessidade do profissional de saúde e outras instâncias políticas de decisão repensarem a interação profissional / usuário nos moldes que tem acontecido atualmente e para a necessidade de mudanças no modo de pensar e agir em relação ao usuário e com ele. / The aims of this research were to understand the perspective of the health professional and the hypertensive user about the interaction that occurs between them in the context of the service in health units and to analyze how this interaction contributes to the non-adherence to the therapeutic regime. The methodology applied for the development of the study was the Grounded Theory and the theoretical reference used for the analysis of the data and interpretation of the results was the Symbolic Interacionism, as well as existing literature on the subject. In all, fifteen health professionals and ten users were involved in the research. At the end, six categories were found (two of which were central) and other subcategories which, after an elaborated process of comparisons, relations and integration composed the theoretical proposal that the author made about the interaction between the user and the health professional and from which some elements were extracted in order to analyze the contribution that this interaction makes to the nonadherence to the therapeutic regime. The author concluded that the interaction, being based in the biomedical model, was centered in the health professional, was unequal, asymmetric and distant, and has elements that could be contributing to the user non-adherence to the therapeutic regime. It was also concluded that the main action that the health professional uses to make the user adhere to thetherapeutic regime – making the user aware of it – has been ineffective because it is based on the traditional model of health education in which the user is not considered individually. Another conclusion is that the user since he is managing the therapeutic regime in his own way has made indications to the health professional of his way of seeing, understanding and dealing with the arterial hypertension and the therapeutic regime that is not always congruent with what the health professional wants and expects of him. This research points to the necessity of the health professional and other policy-making forums to rethink the health professional/user interaction in the molds that have happened currently, and for the necessity of change in the way of thinking and of acting in relation to and with the user.

Introdução: A hipertensão arterial é de causa multifatorial, envolvendo hábitos de vida e estilos de vida inadequados como o consumo excessivo de bebida alcoólica que propiciam a elevação dos níveis pressóricos. Além disso, os sintomas relacionados ao transtorno mental comum também podem se associar ao estado de saúde, provocando mais danos ao sujeito com hipertensão arterial. Diante disso, o presente estudo teve como objetivo principal identificar associação entre a ocorrência de hipertensão arterial com o consumo de bebidas alcoólicas e a presença de transtorno mental comum em indígenas das aldeias Muras, residentes em região rural e urbana. Casuística e Métodos: Estudo transversal, de base populacional, com 455 indígenas Mura residentes no município de Autazes, Amazonas, Brasil. Foi aplicada a entrevista semi-estruturada com questões referentes aos dados socioeconômicos e educacionais, hábitos de vida, história clínica, histórico familiar, além dos questionários Alcohol Use Disorders Identification Test (AUDIT) e Self-Reporting Questonnaire (SRQ-20), para avaliar o consumo de álcool e presença de transtorno mental, respectivamente. A pressão arterial foi medida com aparelho automático de braço validado. Foram realizadas três medidas e usada a média das duas últimas medidas. Realizaram-se ainda, medida do peso, altura, circunferência do pescoço, circunferência da cintura, avaliação de bioimpedância; glicemia, triglicérides e colesterol com medida capilar. Na análise bivariada, foi testada a associação entre hipertensos, separadamente, com os dois desfechos: consumo de bebidas alcoólicas e a presença de transtorno mental comum explorando especialmente, os aspectos relacionados à hipertensão arterial. Foi ajustada a regressão de Poisson com variância robusta, para ambos os desfechos, com modelagem em stepwise backward automatizado, tendo como critério de entrada, p<0,20 e de significância no modelo final, p0,05. Utilizou-se como estimativa, as razões de prevalência e respectivos intervalos de confiança de 95%. Resultados: A maioria dos participantes era do sexo feminino (57,8%), com 42,10 (16,74) anos, vivendo com companheiro (74,7%) e cerca de quatro filhos por família, baixo nível de escolaridade Analfabeto/Fundamental incompleto (41,1%) e renda até dois salários mínimos (85,0%). A prevalência de hipertensão arterial foi de 26,6%, tabagismo (20,4%) e ser sedentário/irregularmente ativo (52,8%). O consumo de bebida alcoólica foi de 40,2%, sendo 13,4% classificados como alto risco para dependência alcoólica, e maior na área rural em comparação à urbana (57,3% vs 22,2%) p<0,001. Destacam-se os seguintes aspectos do uso abusivo de álcool: sentimento de culpa/remorso (45,9%); amnésia repentina por não lembrar o ocorrido na noite em que bebeu (31,7%); além de machucar-se ou sentir-se prejudicado por causa da bebida (29,6%); preocupação por parte de parentes, amigos ou profissionais de saúde, que aconselharam o entrevistado a interromper o consumo (51,5%). Não houve associação entre a presença e consumo de bebida alcoólica (23% e 26%). Os indígenas com diagnóstico de hipertensão referida, faziam menos uso de bebida alcoólica (14,2%vs 85,8%, p=0,009), porém nas ocasiões em que bebiam, ingeriam maior quantidade, comparado com os que não referiram hipertensão [55,3(72,2) vs 33,3(62,2) gramas de Etanol p=0,008]. A prevalência de transtorno mental comum foi de 45,7%, com destaque para os seguintes itens: referência de dores de cabeça frequentes (69,5%), sentir-se nervoso, tenso ou preocupado (66,2%), ter se sentido triste ultimamente (56,0%), dormir mal (55,2%) e ter sensações desagradáveis no estômago (42,9%). Além disso, destaca-se que 7,3% referiram ideia de acabar com a própria vida e 4,2% sentiram-se incapazes de desempenhar papel útil. Após análise ajustada a razão de prevalência após análise ajustada (Razão de prevalência, IC-95%), verificou-se associação positiva entre ingestão de bebida alcoólica e sexo masculino (2,72, IC-2,12-3,48), tabagismo (1,29, IC-1,06-1,56) e morar na zona rural (2,09, IC-1,61-2,72). Porém, a ação foi protetora para idade (0,98, IC-0,98-0,99), consumo de alimentos in natura (0,97, IC-0,95-0,99), e ausência de dislipidemias (0,75, IC-0,62-0,9). Entre os que apresentaram transtorno mental comum, a hipertensão arterial identificada esteve presente em 30,3% e o consumo de álcool uma vez ao mês em 22,1%. Após a análise ajustada (Razão de prevalência, IC-95%) verificou-se associação positiva entre o transtorno mental comum e a zona de moradia urbana (1.25, IC-1,02-1,54), não sabia que tinham antecedentes para diabetes (1.56, IC-1,24-1,96) e a ingestão de bebida alcoólica (1.01, IC-1,00-1,02). Porém, foi ação protetora não ter antecedentes pessoais de cardiopatia (0.59, IC-0,48-0,73). Conclusão: Observou-se que a presença de hipertensão arterial, consumo de bebida alcoólica e de transtorno mental comum foram elevados nos indígenas da etnia Mura. Esses achados podem ser decorrentes da aproximação e convivência entre indígenas e não indígenas favorecendo mudanças culturais, especialmente de hábitos e estilos de vida, com aumento do risco de doenças crônicas não transmissíveis. / Background: The arterial hypertension has a multifactorial disorder, including unappropriated habits and lifestyle as the excessive consumption of alcoholic beverages that may increase the blood pressure. Additionally, the symptoms related to the common mental disorder may be also associated with the health status, producing even more damages to the hypertensive subjects. Thus, this study aimed to identify the association of arterial hypertension occurrence with alcoholic beverages consumption and presence of common mental disorder in Indigenous from Mura villages, who live in rural and urban zones. Casuistic and Methods: Its a cross-sectional investigation, with demographic base, conducted with 455 Mura Indigenous from Autazes, Amazon, Brazil. Through a semi-structured interview, we gathered data about sociodemographic and educational profile, lifestyle, clinical records, family antecedents. In this occasion, the Alcohol Use Disorders Identification Test (AUDIT) and the Self-Reporting Questionnaire (SRQ-20) were applied to assess respectively the alcohol consumption and the presence of common mental disorder. The blood pressure was measured with an arm automatic device, validated for this goal, being three measures taken and, from the two last of them, a mean was obtained. Furthermore, we gathered weight, height, neck circumference, waist circumference, bioimpedance, glycemia, triglycerides and cholesterol, capillary measure for the last ones. In the bivariate analysis, we analyzed the association between hypertensive persons and the both outcomes- the alcohol consumption and the presence of common mental disorder, emphasizing the issues hypertension-related issues. The Poison regression, with robust variance, was adjusted for both outcomes, with a modelling in automatized stepwise backward, being p<0,20 the entrance criteria and p<0,05 the significance level for the final model. As estimative, we used the odds ratios and their respective confidence intervals of 95%. Results: Most were females (57,8%), with mean age of 42,2(16,74) years, living with a partner (74,7%), with about four children per family, poor educational level- Illiterate/Incomplete Basic (41,1%) and income of up two minimum wages (85,0%). 26,6% of the sample had hypertension, 20,4% were smokers and 52,8% were sedentary/irregularly active. Alcohol consumption was of 40,2%, with 13,4% showed high risk for alcohol addiction, and the consumption was higher in rural area in comparison with the urban one (57,3% vs 22,2%) p<0,001. We emphasize the following aspects of alcohol abuse: feeling of guilty and remorse (45,9%); abrupt amnesia for not remembering what happened in the night that they had drunk (31,7%); feeling hurt or impaired due to the drink consumption (29,6%); concerns from relatives, friends or healthcare professionals who advised the interviewed to interrupt the consumption (51,5%). There was not association between presence and alcoholic beverages consumption (23% and 26%). Indigenous diagnosed with referred arterial hypertension drank less alcoholic beverages (14,2%vs 85,8% p=0,009), but, when they drank, they had a larger amount than those with referred hypertension [55,3(72,2) vs 33,3(62,2) grams of Ethanol p=0,008]. The common mental disorder was identified in 45,7% of the individuals, being highlighted the following items: reporting of frequent headaches (69,5%), feeling nervous, anxious or worried (66,2%), feeling sad in the last days (56,0%), sleeping badly (55,2%) and having upset stomach (42,9%). Additionally, 7.3% reported the idea of committing suicide, and 4,2% felt themselves unable to play a useful role. We verified positive association between alcoholic beverage consumption and male gender (2.72, CI-2,12-3,48); smoking (1.29, CI-1.06-1.56); and living in rural area (2.09, CI-1.61-2.72). However, the action was protective for the age (0.98, CI-0,98-0,99), intake of natural foods (0.97, CI-0,95-0,99), and absence of dyslipidemias (0.75, CI-0,62-0,9). Among those diagnosed with common mental disorder, the arterial hypertension was found in 30,3% and the alcohol consumption once a month in 22,1%. We observed a positive association of common mental disorder and: living in the urban area (1.25, CI-1,02-1,54); unknowing the antecedents for diabetes (1.56, CI-1,24-1,96); and the alcohol consumption (1.01,CI-1,00-1,02). However, the absence of personal background of heart diseases was not protective (0.59, CI-0,48-0,73). Conclusion: We observed that the presence of arterial hypertension, alcoholic beverages consumption and common mental disorder were high in the Mura ethnicity. This finding may be explained for the approach and interaction among Indigenous and non-Indigenous, which favors cultural changes, especially in habits and lifestyle, increasing the risk of non-transferable chronic diseases.

A homocisteína plasmática é considerada marcador de risco para doenças cardiovasculares e sua associação com a hipertensão arterial essencial parece ser importante no agravamento desta doença. O exercício físico tem mostrado eficácia na redução da pressão arterial e o ácido fólico suplementar a dieta como a melhor conduta para a redução da homocisteinemia. O objetivo deste trabalho foi verificar o efeito da suplementação de ácido fólico e/ou do exercício físico sobre as concentrações plasmáticas de homocisteína em hipertensos essenciais medicados. Para tanto foram estudados 69 hipertensos (57&#177;10 anos), sendo 22 do sexo masculino e 47 do sexo feminino, divididos em dois grupos: grupo 1 medicado com diurético e grupo 2 medicado sem diurético, sendo o tiazídico o diurético mais utilizado (80%). Foram realizadas avaliações médica, antropométrica, dietética, pressórica, bioquímica e o teste de aptidão cardiorrespiratória. Os indivíduos receberam suplementação com 500 &#181;g/dia de ácido fólico, em estudo do tipo cruzado, e foram submetidos a treinamento com exercícios físicos supervisionados, sendo reavaliados a cada dois meses até o final do estudo. Os grupos foram homogêneos em relação a todas as variáveis estudadas exceto a homocisteína plasmática que foi maior significativamente no grupo 1. Não houve diferença significativa entre os sexos para todas as variáveis estudadas. Os hipertensos eram em sua maioria (62%) não controlados e portadores de síndrome metabólica (77%). O exercício físico apresentou efeito benéfico na reclassificação dos hipertensos leves e moderados para a classe de limítrofes sem normalizar a pressão arterial. Não houve efeito do exercício na composição corporal e na homocisteinemia. A suplementação de ácido fólico reduziu a hiperhomocisteinemia em 11% no grupo 1 e 19% no grupo 2 frente a aumentos similares na folacemia. Em relação à pressão arterial houve normalização da homocisteinemia apenas nos hipertensos com pressão arterial normalizada. Os hipertensos limítrofes e leves apresentaram reclassificação da hiperhomocisteinemia limítrofe para moderada. A presença de diurético potencializou a normalização da pressão pelo exercício físico e indiretamente influenciou, nesses casos, a normalização da homocisteína. Entretanto, a maior redução das concentrações médias de homocisteína ocorreu coma oferta de ácido fólico na ausência de diurético. Desta forma, recomenda-se a adequação dietética do folato como adjuvante terapêutico da hipertensão arterial associadamente ao exercício físico e/ou medicamentos / The plasma homocysteine is considered to be a risk indicator for cardiovascular diseases and its association with essential hypertension seems to be important to the worsening of this disease. Physical exercises are efficient to reduce blood pressure and the dietary supplements of folic acid are considered the best way to decrease homocysteine. The aim of this study was investigate the effect of acid folic supplementation and physical exercises on plasmatic levels of homocysteine in essential hypertensive medicated individuals. In order to that, 69 hypertensive subjects were studied (22 men and 47 women) divided in two groups: group 1 medicated with diuretic and group 2 medicated without diuretic. Medical, anthropometrical, dietetic, blood pressure, biochemistry and cardio-respiratory capacity evaluations were performed. These individuals received 500 &#181;g/dia of folic acid supplementation in a cross-over design and were submitted to daily supervisioned physical exercise. They were evaluated every two months until the end of the study. The groups were similar for all variables except for the homocysteine which was significantly greater in the group 1. There were no difference for the gender to all variables. The high blood pressure was not controlled (62%) and 77% of the patients showed metabolic syndrome. The physical exercise showed benefit on the reclassification of slight and moderated hypertensives to border-line hypertension, however, it did not normalize the blood pressure. There were no effects on the body composition and on homocysteine values . Folic acid supplementation decreased 11% of hyperhomocysteinemia in the group 1 and 19% in group 2 face to similar increases in folate. Regarding to high blood pressure subjects the homocysteine normalization occurred only in hypertensive subjects with normalized blood pressure. The border and slightly hypertensive individuals had border-line hyperhomocysteine wich were reclassificated to moderated c1ass. The use of diuretic enhanced blood pressure normalization with the physical exercise and indirectly influenced the plasma homocysteine normalization. However the greater decreasing mean homocysteine concentration occurred with folic acid but in the diuretic absence. So we strong recommend an adequate folate intake as a terapheutical adjuvant to arterial hypertension treatments either with physical exercise and/or antihipertensive drugs.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-09-19T13:56:14Z No. of bitstreams: 1 caiocesarbatistaandrade.pdf: 1594203 bytes, checksum: a677299f50f290066e643c085468364f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-09-22T15:02:37Z (GMT) No. of bitstreams: 1 caiocesarbatistaandrade.pdf: 1594203 bytes, checksum: a677299f50f290066e643c085468364f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-09-22T15:02:49Z (GMT) No. of bitstreams: 1 caiocesarbatistaandrade.pdf: 1594203 bytes, checksum: a677299f50f290066e643c085468364f (MD5) / Made available in DSpace on 2017-09-22T15:02:49Z (GMT). No. of bitstreams: 1 caiocesarbatistaandrade.pdf: 1594203 bytes, checksum: a677299f50f290066e643c085468364f (MD5) Previous issue date: 2017-08-03 / A hipertensão arterial é considerada um mal silencioso e a doença cardiovascular mais prevalente no Brasil. Considerada como um problema de saúde pública dentro das Doenças Crônicas não Transmissíveis,é responsável pelo grande aumento de morbimortalidade da comunidade. Alterações no estilo de vida são fundamentais para um progresso terapêutico e para a prevenção da doença, como a prática regular de atividade física, o consumo reduzido de sal, o abandono do uso do tabaco e o uso restrito de álcool.O objetivo geral deste estudo foi: analisar a associação da hipertensão arterial com os fatores ocupacionais e o estilo de vida entre os Agentes Comunitários de Saúde do município de Juiz de Fora - MG; os específicos são: descrever o perfil sociodemográfico, os fatores ocupacionais e o estilo de vida dos Agentes Comunitários de Saúde; identificar a prevalência da hipertensão arterialentre estes profissionais.Trata-se de estudo seccionalseccionalseccional seccionalseccional, recortede uma pesquisa denominada “Trabalhadores da Atenção Primária à Saúde: Condições de Trabalho e de Vida'', no qual participaram 400 Agentes Comunitários de Saúde. A coleta de dados se deu por meio de questionário-entrevista aplicado por entrevistadoresno período de julho a outubro de 2015 e outubro de 2016 a fevereiro de 2017. Os resultados mostram que a população de estudo foi composta, em sua maioria, por mulheres (91,2%), sendo a média de idade de 46 anos; 46,3% se autodeclaram brancos, 65,3% possuíam até o Ensino Médio Completo e 57,5% eram casados ou viviam em união estável. Sobre ahipertensão arterial, 70,8% dos trabalhadores relatam não ter o diagnóstico médico dessa patologia. Em relação aos hábitos de vida e saúde, 43,6% foram considerados muito ativos, 89,8% tinham um baixo consumo de álcool e 94,3% apresentavam muito baixo grau de dependência do tabaco. Já relacionado ao estresse psicossocial, 32,5% se encontravam na categoria de alta exigência no trabalho, que é considerada a mais prejudicial para a saúde do trabalhador. Em relação ao trabalho, encontrou-se poder de significância quanto ao turno diurno e ao tempo de trabalhona Atenção Primária à Saúde. Aqueles que declararam trabalhar somente no turno diurno e os que têm mais tempo de trabalho na Atenção Primária à Saúde são os trabalhadores mais predisponentes àhipertensão arterial. Não houve diferença estatisticamente significativa entre as variáveis sociodemográficas, os hábitos de vida e saúde e a hipertensão arterial. / Hypertension is considered a silent disease and the most prevalent cardiovascular disease in Brazil. Considered to be a public health problem within non communicable chronic diseases, it is responsible for the large increase in community morbidity and mortality. Lifestyle changes are critical to therapeutic progress and disease prevention, such as regular physical activity, reduced salt consumption, cessation of tobacco use, and restricted use of alcohol. The general objective of this study was to analyze the association of arterial hypertension with occupational factors and lifestyle among the Community Health Agents of the city of Juiz de Fora - MG; The specific ones are: to describe the sociodemographic profile, the occupational factors and the lifestyle of the Community Health Agents; To identify the prevalence of hypertension among these professionals. This is a cross-sectional study, a study of "Primary Health Care Workers: Working and Living Conditions", in which 400 community health agents participated. Data collection was done through a questionnaire-interview Applied by interviewers from July to October 2015 and from October 2016 to February 2017. The results show that the study population was composed mostly of women (91,2%), the mean age being 46 years; 46,3% declared themselves white, 65,3% had completed high school and 57,5% were married or lived in a stable union. Regarding arterial hypertension, 70,8% of the workers report not having the medical diagnosis of this pathology. Regarding life and health habits, 43,6% were considered very active, 89,8% had a low alcohol consumption and 94,3% had a very low degree of dependence on tobacco. Already related to psychosocial stress, 32,5% were in the category of high labor demand, which is considered to be the most harmful to the health of the worker. Regarding work, we found a power of significance regarding day shift and working time in Primary Health Care. Those who declared that they only work during the day shift and those who have the most working time in Primary Health Care are workers More predisposing to hypertension. There was no statistically significant difference between sociodemographic variables, life and health habits, and arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease that results in increased pulmonary vasculature resistance, causing right ventricular (RV) remodeling, which eventually progresses into right heart failure and mortality. New and emerging therapeutic strategies involve regenerative approaches to repair the underlying vascular pathology using regenerative cell therapy and methods to alleviate RV dysfunction in the setting of fixed RV afterload. In the first section of the thesis, we investigated the role of EPC paracrine mechanisms in the treatment of PAH. We characterized the paracrine function of EPCs by demonstrating that EPC conditioned medium enhances endothelial cell migration, survival and angiogenesis in vitro. We further examined the role of secreted extracellular vesicles in the paracrine function of EPCs, which played a minor role in promoting wound healing. However, using the monocrotaline rat model of PAH, we did not demonstrate a consistent benefit on RV pressures or remodeling with EPCs or EPC conditioned medium. The lack of effect may be related to the advanced phenotype observed in our model of PAH. Survival in severe pulmonary arterial hypertension (PAH) is related to the ability of the right ventricle (RV) to adapt to increased afterload. Therefore, we explored the effect of genetic background on right ventricular adaptation and survival in a rat model of severe (PAH). Compared to the conventional Sprague-Dawley rat strain, we observed high mortality in the Fischer SUHx model of severe PAH. This was related to a strain-dependent failure of RV adaptation, as evidenced by RV dilatation, RV contractile dysfunction, decreased cardiac ouptut and decreased exercise capacity. Further analysis by gene expression microarrays and fluorescence microangiography demonstrate that failure of RV adaptation is due at least in part due to lack of adequate microvascular angiogenesis in the hypertrophied RV. This work lays the foundation for the section on RV-specific therapy that follows. Using the Fischer model of maladaptive RV remodeling, we tested whether cardiotrophin-1 (CT-1), a pro-angiogenic and cardioprotective cytokine, could improve RV adaptation. We demonstrated that as a rescue treatment, CT-1 reduced RV dilatation and function without influencing RV afterload, which suggests improved RV adaptation. These changes were associated with an increase in RV capillary density. As an early-stage preventative treatment, in addition to improving RV remodeling, CT-1 also reduced pulmonary pressures. These hemodynamic changes suggest that CT-1 may also have a direct impact on vascular tone or the underlying pulmonary vascular pathology.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Diabetes mellitus (DM) is a disorder of the metabolism of carbohydrates, lipids and proteins characterized by hyperglycemia, which in type 2 diabetes (T2DM) involves the production deficiency and / or insulin action. Diabetic subjects exhibit high levels of oxidative stress due to chronic and persistent hyperglycemia, which impairs the activity of the antioxidant defense system and promotes the generation of free radicals. This level of oxidative stress can cause renal, neurological, ocular and cardiovascular complications, such as systemic arterial hypertension (HAS). The enzyme δ-aminolevulinate dehydratase (δ-ALA-D) is a sulfhydryl enzyme, which participates in the synthesis of pyrrole compounds and has been linked to several diseases, including DM. The aim of this study was to evaluate the oxidative status of patients with DM2 and its relationship with the activity of the enzyme δ-ALA-D, lipid profile, body fat distribution besides the role of hypertension in the parameters analyzed. The results showed a decreased activity of the enzyme δ-ALA-D as well as an increase in its reactivation index in patients (n = 63) compared to controls (n = 63). It was also observed, in the T2DM group, an increased level of thiobarbituric acid reactive species (TBARS) and a smaller amount of antioxidants as vitamin C plasma protein thiol groups (P-SH) in plasma and nonprotein (NP-SH) in erythrocytes, as well as a reduction in activity of the enzyme catalase in erythrocytes. Patients who had DM2 plus hypertension (n = 30) showed a more pronounced decrease in the activity of δ-ALA-D than patients with type 2 diabetes only (n = 23) compared to healthy subjects (n = 30), along with an increased rate of reactivation. Also, patients DM2/HAS showed a greater depletion of NP-SH. Correlations among activity of δ-ALA-D and its reactivation index with oxidative stress markers, such as NP-SH and carbonyl groups, as well as lipid profile of patients were also observed. Further, correlations were found between the level of TBARS and triglycerides, as well as between vitamin C, plasma glucose and HbA1c as well as P-SH and body mass index. Therefore, patients with DM2 have changes in lipid profile and body fat distribution, and a situation of oxidative stress that can lead to changes in key molecules as the enzyme δ-ALA-D. This enzyme was effective in reflecting the level of oxidative stress of patients can be considered an interesting biomarker for assessment of damage in chronic metabolic processes such as DM. Furthermore, hypertension appears to be a synergistic factor to the metabolic condition of patients with type 2 diabetes, contributing to the development of its complications. / O Diabetes mellitus (DM) é uma desordem do metabolismo de carboidratos, lipídeos e proteínas caracterizado pela hiperglicemia, que no tipo 2 da doença (DM2) envolve a deficiência da produção e/ou ação da insulina. Indivíduos diabéticos exibem alto nível de estresse oxidativo devido à hiperglicemia crônica e persistente, que prejudica a atividade do sistema de defesa antioxidante e promove a geração de radicais livres. Esse nível de estresse oxidativo pode acarretar complicações renais, neurológicas, oculares e cardiovasculares, como a hipertensão arterial sistêmica (HAS). A enzima δ-Aminolevulinato desidratase (δ-ALA-D) é uma enzima sulfidrílica, que participa da síntese de compostos pirrólicos e vem sendo relacionada a diversas patologias, inclusive o DM. O objetivo deste estudo foi avaliar o status oxidativo de pacientes portadores de DM2 e sua relação com a atividade da enzima δ-ALA-D, perfil lipídico, distribuição de gordura corporal assim como o papel da HAS nos parâmetros analisados. Os resultados demonstraram uma diminuição da atividade da enzima δ-ALA-D assim como um aumento de seu índice de reativação nos pacientes (n=63) em relação aos controles (n=63). Observou-se também, no grupo DM2, um aumentado índice de espécies reativas ao ácido tiobarbitúrico (TBARS) e uma menor quantidade de antioxidantes como vitamina C plasmática, grupamentos tióis protéicos (PSH) em plasma e não protéicos (NP-SH) em eritrócitos, assim como uma redução na atividade da enzima catalase em eritrócitos. Os pacientes que além de DM2 apresentavam HAS (n=30) demonstraram uma diminuição mais pronunciada na atividade da δ-ALA-D do que os pacientes somente com DM2 (n=23) em relação a indivíduos saudáveis (n=30), juntamente com um aumentado índice de reativação. Também, os pacientes DM2/HAS apresentaram uma maior depleção de NP-SH. Correlações entre atividade da δ-ALA-D e seu índice de reativação com marcadores de estresse oxidativo, como NP-SH e grupamentos carbonílicos, bem como com o perfil lipídico dos pacientes também foram observadas. Ainda foram encontradas correlações entre o nível de TBARS e triglicerídeos, bem como entre vitamina C, glicose plasmática e HbA1c além de P-SH e índice de massa corporal. Portanto, os pacientes com DM2 apresentam alterações no perfil lipídico e na distribuição de gordura corporal, além de uma situação de estresse oxidativo que pode levar a alterações de moléculas importantes como a enzima δ-ALA-D. Tal enzima se mostrou efetiva em refletir o nível de estresse oxidativo dos pacientes podendo ser considerada um interessante biomarcador para avaliação de danos em processos metabólicos crônicos como o DM. Ainda a HAS parece ser um fator sinérgico à condição metabólica do paciente com DM2 podendo contribuir para o desenvolvimento de suas complicações.

La décompensation cardiaque se manifeste par une symptomatologie de dyspnée et de fatigue, et par une diminution de l’aptitude aérobie. La décompensation cardiaque peut être globale ou gauche (DCG), ou droite comme dans le cas de l’hypertension artérielle pulmonaire (HTAP). Les mesures fonctionnelles de repos (fonction ventriculaire gauche ou pression artérielle pulmonaire moyenne) sont peu corrélées à l’aptitude aérobie, qui est cependant un élément important de la mise au point et du suivi clinique des patients atteints de DCG ou d’HTAP. <p>\ / Doctorat en Sciences de la motricité / info:eu-repo/semantics/nonPublished

L’hypertension artérielle pulmonaire (HTAP) est une pathologie affectant les artères pulmonaires de petit calibre entraînant une augmentation des résistances artérielles pulmonaires aboutissant à une défaillance cardiaque droite. La vasoconstriction, le remodelage des artères pulmonaires distales, l’inflammation et le stress oxydant sont de facteurs clés de la pathogénèse de l'HTAP. Nous avons testé les potentiels de la formulation EPA:DHA 6:1 à prévenir l’hypertension pulmonaire et les altérations cardiovasculaires et pulmonaires induites par l’injection de monocrotaline chez le rat. Le traitement des rats monocrotaline avec l’EPA:DHA 6:1 (500 mg/kg/j, p.o) prévient significativement l’élévation de la pression artérielle pulmonaire moyenne, la pression systolique du ventricule droit, diminue le débit cardiaque, l’hypertrophie et la dilatation du ventricule droit. L’EPA:DHA 6:1 réduit également les résistances vasculaires pulmonaires, le remodelage des artérioles pulmonaires et les infiltrations lymphocytaires et macrophagiques. De plus, l’EPA:DHA 6:1 inhibe la production des espèces réactives de l’oxygène, diminue la surexpression des sous-unités p22phox et p47phox de la NADPH oxydase, des cyclooxygénases 1 et 2, des récepteurs ETA et ETB de l’endothéline-1, de la eNOS découplée et améliore la dysfonction endothéliale des artères pulmonaires. L’EPA:DHA 6:1 exercent des effets anti-inflammatoires, antioxydants et vasoprotecteurs et prévient le développement de l’HTAP induite par l’injection de monocrotaline chez le rat. / Pulmonary arterial hypertension (PAH) is characterized by remodeling of the small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure. Pulmonary endothelial dysfunction, inflammation and oxidative stress promote the development of pulmonary hypertension. Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) have been shown to protect the cardiovascular system and reduce inflammation and oxidative stress. The present study evaluate the potential of EPA:DHA 6:1 to prevent monocrotaline-induced PAH in rats. EPA:DHA 6:1 treatment (500 mg/kg/d, p.o) prevented the MCT-induced mean pulmonary arterial pressure, right ventricular systolic pressure and decreased cardiac output. EPA:DHA 6:1 also attenuated right ventricular hypertrophy by reducing Fulton’s index and pulmonary arterial remodeling, decreased lymphocytes T and macrophages infiltration. EPA:DHA 6:1 treatment significantly reduced MCT-induced vascular oxidative stress and improved endothelial function in pulmonary arteries. The protective effect of EPA:DHA 6:1 was associated with the prevention of the MCT-induced upregulation of NADPH oxidase subunits (p22phox and p47phox), COX-1 and COX-2, endothelin A and B receptors and uncoupled eNOS in pulmonary arterioles. Our studies show that the EPA:DHA 6:1 formulation exerts anti-inflammatory, anti-oxidant and has a protective vascular effect in the pulmonary arteries, which may contribute to prevent and potentially cure pulmonary hypertension induced by MCT in rat.

Ce travail a eu pour but (1) de comparer les différentes méthodes d'évaluation de la balance sympatho-vagale (BSV) actuellement utilisées chez le rat, et (2) d'évaluer les effets d'une altération de la BSV en faveur d'une prédominance vagale sur l'instabilité électrique atriale spontanée chez le rat spontanément hypertendu (SHR) vieillissant. L'électrocardiogramme a été mesuré chez les rats éveillés grâce à une sonde télémétrique chroniquement implantée. La méthode de référence pour l'estimation de la BSV repose sur le calcul du rapport de la fréquence cardiaque (FC) de repos à la FC intrinsèque. Selon que l'index est supérieur ou inférieur à 1, on peut conclure respectivement à une prédominance sympathique ou à une prédominance vagale. La FC intrinsèque est obtenue par l'administration combinée d'antagonistes sélectifs des deux branches du système nerveux autonome, c'est-à-dire un bloqueur β-adrénergique (aténolol) et un antagoniste des récepteurs muscariniques (méthylatropine). Les autres méthodes (mesure séparée des tonus autonomes, index extraits de l'analyse de la variabilité sinusale) fournissent des résultats incohérents ou contradictoires. L'administration chronique d'un inhibiteur de l'acétylcholinestérase (pyridostigmine) chez des rats SHR vieillissants induit une hypertonie vagale relative (BSV=0,81±0,02) par rapport aux rats non traités (BSV=1,06±0,01) qui s'accompagne d'une bradycardie sinusale et d'une augmentation de la fréquence et de la durée des épisodes de tachyarythmie atriale. Ces études démontrent l'intérêt de la méthode de référence pour l'estimation de la BSV chez le rat éveillé. La potentialisation de l'activité vagale endogène aggrave l'instabilité électrique atriale chez le rat SHR vieillissant, ce qui confirme le rôle pathogénique du système nerveux parasympathique dans ce modèle / The aim of the present work was (1) to compare the different methods currently used to assess sympathovagal balance (SVB) in rats, and (2) to assess SVB alterations towards vagal predominance on atrial electrical instability in aging spontaneously hypertensive rats (SHR). The electrocardiogram was measured in conscious rats using chronically implanted telemetric probes. The reference method to estimate SVB is based on the calculation of the ratio of intrinsic heart rate (HR) to resting HR. Depending on whether the index is greater or lower than 1, one can conclude to sympathetic or vagal predominance, respectively. Intrinsic HR is obtained after the combined administration of selective antagonists of both branches of the autonomic nervous system, i.e. β- adrenergic blocker (atenolol) and muscarinic receptor antagonist (methylatropine). Other methods (autonomic tones measured separately, calculation of indices derived from heart rate variability analysis) provide inconsistent or conflicting results. The chronic infusion of an acetylcholinesterase inhibitor (pyridostigmine) in aging SHRs induced relative vagal hypertonia (SVB=0.81±0.02) in comparison with untreated rats (SVB=1.06±0.01) along with sinus bradycardia and increased frequency and duration of atrial tachyarrhythmia episodes. These studies highlight the value of the reference method for evaluating SVB in conscious rats. Potentiation of endogenous vagal activity aggravates atrial electrical instability in aging SHRs, consistent with a pathogenic role of the parasympathetic nervous system in this model

La maladie rénale chronique (MRC) affecte environ 10% de la population adulte et est associée à un risque élevé de progression vers l’insuffisance rénale terminale (IRT), d’événements cardiovasculaires et de décès précoce. Des mesures sont recommandées pour prévenir la progression et les complications de la MRC, mais elles sont souvent basées sur un niveau de preuve faible ou sur la seule opinion d’experts. Dans cette thèse, nous avons utilisé des données observationnelles pour évaluer les pratiques cliniques dans deux domaines clés de la MRC : les abords artérioveineux (AV) en hémodialyse et le contrôle de l’hypertension artérielle (HTA) dans la MRC non terminale. Avec le registre national REIN des traitements de suppléance de l'IRT, nous avons montré que seuls 56% des 53 092 patients adultes incidents en hémodialyse de 2005 à 2013 avaient une voie d’abord AV (fistule ou pontage) créée, telle que recommandée, avant le démarrage de la dialyse, dont 16% étaient non fonctionnelles, nécessitant l'utilisation d'un cathéter associé à une sur-mortalité. La conversion en abord AV fonctionnel était associée à un meilleur pronostic, mais concernait dans les trois premières années de dialyse moins de deux patients sur trois ayant démarré sur cathéter. Dans l’étude de cohorte CKD-REIN, chez 1658 patients avec une MRC modérée à sévère, nous avons mis en évidence un moins bon contrôle de l'HTA et des niveaux de pression artérielle systolique plus élevés en lien avec des apports élevés en sodium, mais pas avec des apports faibles en potassium, évalués sur échantillon urinaire ponctuel. Le ratio sodium/potassium urinaire n'était pas plus discriminant que le sodium seul. Enfin, grâce au réseau International Network of Chronic Kidney Disease cohorts (iNET-CKD), qui inclut 17 cohortes sur 4 continents (N=34 602 patients avec un débit de filtration glomérulaire estimé < 60 mL/min/1,73 m2) nous avons mis en lumière le contrôle médiocre de l’HTA en général dans la MRC au regard des recommandations, avec d'importantes variations entre pays (27 à 61% de pression artérielle ≥140/90 mm Hg) expliquées en partie par les caractéristiques des patients et associées à des profils de traitements antihypertenseurs très différents. En conclusion, cette thèse pointe des écarts importants aux recommandations dans la prise en charge de la MRC en vie réelle et des pistes de prévention des complications liées aux abords AV et un meilleur contrôle de l'HTA. / Chronic kidney disease (CKD) affects about 10% of the adult population and is associated with high risk of end-stage kidney disease (ESKD), cardiovascular complications, and premature death. Guidelines recommend a number of measures for the prevention of CKD progression and complications, but these recommendations are often based on low evidence or expert opinion. In this thesis, we used observational data to assess clinical practices in two key areas of CKD: arteriovenous (AV) access for hemodialysis, and hypertension control in moderate to severe CKD. Using data from the French REIN registry of renal replacement therapy for ESKD, we showed that only 56% of the 53,092 adult incident patients on hemodialysis from 2005 through 2013 had an AV access (either fistulae or grafts) created at hemodialysis initiation as recommended, of which 16% were nonfunctional, requiring catheter use associated with high mortality risk. Conversion into functional AV access was associated with better outcome, but less than two out of three patients starting hemodialysis with a catheter experienced this conversion within 3 years after dialysis start. In the CKD-REIN cohort study, among 1658 patients with moderate to severe CKD, we found less hypertension control and higher systolic blood pressure to be associated with higher sodium intake assessed from spot urine, but not with lower potassium intake. Spot urinary sodium/potassium ratio did not appear to add value than sodium alone for patient monitoring. Finally, using data from the International Network of Chronic Kidney Disease cohorts (iNET-CKD), including 17 cohort studies over 4 continents (N=34,602 patients with an estimated glomerular filtration rate < 60 mL/min/1.73 m2), we highlighted a global poor hypertension control in CKD with regards to recommendations, with large variations across countries (from 27 to 61% blood pressure ≥140/90 mm Hg). These variations are partly explained by patients’ characteristics, and associated with very different antihypertensive treatment profiles. In conclusion, this thesis points out major gaps between guideline recommendations and CKD management in real life, and provide clues for the prevention of AV access-related complications and better hypertension control.