Introdução: A prática de caminhada é recomendada como principal tratamento de indivíduos com claudicação intermitente (CI). Contudo, a realização da caminhada é acompanhada de dor. Tendo em vista que indivíduos com CI apresentam redução de força e massa musculares, é possível que o treinamento de força seja eficaz para o tratamento desses indivíduos. Objetivo: Verificar os efeitos do treinamento de força na aptidão física e em indicadores de qualidade de vida de indivíduos com CI. Métodos: Os indivíduos (n=42), recrutados no Ambulatório de Claudicação Intermitente do Hospital das Clínicas da Universidade de São Paulo, foram distribuídos em três grupos: treinamento de força (GTF), treinamento de caminhada (GCA) e controle (GCO); que foram submetidos a 12 semanas de treinamento físico. O GTF e o GCA realizaram treinamento supervisionado, em duas sessões semanais de 60 minutos cada. O GCO realizou treinamento não supervisionado. Antes e após o treinamento, foram mensurados componentes da aptidão física (massas gordurosa e magra, índice de massa muscular, distâncias de claudicação e total de caminhada, capacidade aeróbica, força muscular de membros inferiores, índice tornozelo braço, janela isquêmica, pressão arterial de braço, freqüência cardíaca e duplo produto) e indicadores da qualidade de vida (geral e capacidade de deambulação). Para os dados paramétricos foram utilizadas Análise de Variância e de Covariância, e para os dados não paramétricos, foram utilizados os testes de Wilcoxon e Kruskall- Wallis, com P<0,05. Resultados: O treinamento de força aumentou as distâncias de claudicação (+40,8%) e total de caminhada (+25,4%) e a força muscular dos membros inferiores, com maior, e menor índice tornozelo-braço (+9,5% e +10,5%, respectivamente). Foi observada redução da janela isquêmica (-46,9%), da freqüência cardíaca (-6,5%) e do duplo produto (- 15,9%) em repouso, e da pressão arterial de braço (-8,1%) e do duplo produto (-9,8%) em exercício sub-máximo. As modificações na aptidão física no GTF foram semelhantes aquelas observadas no GCA. Não foram observadas alterações nos indicadores de qualidade de vida após o treinamento de força. Conclusão: Os resultados deste estudo sugerem que o treinamento de força pode ser incorporado ao tratamento clínico dos indivíduos com CI, uma vez que promoveu melhoria nos componentes da aptidão física desta população. / Abstract Background: Walking exercise training has been recommended as the main treatment in persons with intermittent claudication (IC). However, walking is performed with pain. Once persons with IC present muscle atrophy and reduced leg strength, strength training programs could be successful in the treatment of these patients. Objective: To verify the effects of strength training on physical fitness and indicators of quality of life in persons with IC. Methods: Forty two subjects were recruited in the Intermittent Claudication Ambulatory of Clinics Hospital of the University of Sao Paulo. The subjects were allocated into three groups: strength training (ST), treadmill training (TT) and control (CO); which performed 12 weeks of exercise training. ST and TT performed supervised exercise, twice a week, in 60-minute sessions. CO performed unsupervised training. Before and after training, the components of physical fitness (fat and lean body mass, muscle mass index, claudication and total walking distances, leg strength, ankle brachial index, ischemic window, arm blood pressure, heart rate and rate pressure product) and quality of life indicators (general and related with ambulation capacity), were assessed. Analysis of Variance and Analysis of Covariance were used for parametric data; Wilcoxon and Kruskall-Wallis tests were used for non-parametric data, with P<0.05 Results: ST increased claudication (+40.8%) and total walking distances (+25.4%), and strength in the leg with higher and with lower ankle brachial index (+9.5 and +10.5%, respectively). There were a decrease in ischemic window (-46.9%), rest heart rate (-6.5%) and rate pressure product (-15.9%), and submaximal arm blood pressure (-8.1%) and rate pressure product (-9.8%). The changes in physical fitness were similar between ST and TT. There were no changes in the quality of life indicators after ST. Conclusions: The results of the present study suggest that ST could be used in the treatment of persons with IC, once it can improve the physical fitness in these patients.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-06-02T13:07:50Z No. of bitstreams: 2 Dissertação - Polliana Conceição Garcia - 2015.pdf: 2210434 bytes, checksum: 2904fb672abe80d906ef6e87a1f9d87d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-06-02T13:09:30Z (GMT) No. of bitstreams: 2 Dissertação - Polliana Conceição Garcia - 2015.pdf: 2210434 bytes, checksum: 2904fb672abe80d906ef6e87a1f9d87d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-06-02T13:09:30Z (GMT). No. of bitstreams: 2 Dissertação - Polliana Conceição Garcia - 2015.pdf: 2210434 bytes, checksum: 2904fb672abe80d906ef6e87a1f9d87d (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-12-18 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Several clinical and epidemiological studies have shown that the association between obesity and cardiovascular risk begins early in childhood, which makes crucial the identification and control of childhood obesity associated changes as strategies to prevent adult cardiovascular diseases. The present study aimed to evaluate the relationship between the degree of adiposity and the presence of cardiovascular risk factors in children. Additionally, we investigated possible associations between anthropometric variables and blood pressure values, lipid profile components, blood glucose levels and atherogenic index. The study was conducted with children of both sexes and aged 6 to 10 years, enrolled in a public educational institution in the city of Jataí-GO. We collected anthropometric measures, blood pressure values and blood samples for fasting glucose and lipid profile (enzymatic methods) determination. Children were distributed into 3 groups: control (n=51), overweight (n=29) and obese (n=36). The daily time devoted on sedentary activities was higher, while the time spent on physical activities was lower in obese children, when compared to the control group. obese children had also higher levels of triglycerides (TG), very low density lipoprotein cholesterol (VLDL-C), total cholesterol/ high-density lipoprotein cholesterol (CT/HDL-C) and TG/HDL, along with decreased HDL-C, when compared to children with normal weight. There was a positive association between anthropometric indicators (body mass índex, waist circumference, waist-to-height ratio e skinfold thicknesses) and the variables: systolic blood pressure, diastolic blood pressure, TGs, HDL-C, VLDL-C and atherogenic index. HDL-C correlated negatively with the anthropometric variables. We conclude that increased adiposity in childhood contributes to the occurrence of cardiovascular risk factors, including high blood pressure, changes in lipid profile and increase in atherogenic indexes. / Diversos estudos clínicos e epidemiológicos têm revelado que a associação existente entre obesidade e risco cardiovascular inicia-se durante a infância, o que torna imprescindível a identificação e o controle das alterações associadas à obesidade infantil como estratégia na prevenção de doenças cardiovasculares na fase adulta. O objetivo do presente estudo foi avaliar a relação entre o grau de adiposidade e a presença de fatores de risco cardiovasculares em crianças. Adicionalmente, investigamos possíveis associações entre variáveis antropométricas e valores de pressão arterial, componentes do perfil lipídico, níveis glicêmicos e índices aterogênicos. O estudo foi realizado com crianças de ambos os sexos e com idade entre 6 e 10 anos, matriculadas em uma instituição de ensino pública do município de Jataí-GO. Foram coletadas medidas antropométricas, valores de pressão arterial e amostras de sangue para testes de glicemia de jejum e perfil lipídico (métodos enzimáticos). As crianças foram distribuídas em 3 grupos: controle (n=51), sobrepeso (29) e obeso (n=36). Nossos resultados demonstraram que o tempo diário dedicado a atividades sedentárias foi maior, enquanto o tempo gasto em atividades físicas foi menor nas crianças obesas, quando comparadas ao grupo controle. As crianças obesas apresentaram ainda valores significativamente maiores de triglicérides (TG), colesterol de lipoproteínas de densidade muito baixa (VLDL-C), colesterol total/colesterol de lipoproteína de alta densidade (CT/HDL-C) e TG/HDL-C, além de diminuição do HDL-C em relação às crianças com peso normal. Houve associação positiva entre os indicadores antropométricos (índice de massa corporal, circunferência da cintura, razão cintura-estatura e dobras cutâneas) e as variáveis: pressão arterial sistólica, pressão arterial diastólica, TGs, HDL-C, VLDL-C e índices aterogênicos, enquanto o HDL-C correlacionou-se negativamente com as variáveis antropométricas. Concluímos que o excesso de tecido adiposo na infância contribui para a ocorrência de fatores de risco cardiovasculares, como a elevação da pressão arterial, o perfil lipídico inadequado e o aumento de índices aterogênicos.

Submitted by Franciele Moreira (francielemoreyra@gmail.com) on 2017-11-21T17:24:03Z No. of bitstreams: 2 Tese - Max Weyler Nery - 2013.pdf: 3823648 bytes, checksum: 45da627ca3fc33274b6ed62abbaf86f2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-11-22T10:12:26Z (GMT) No. of bitstreams: 2 Tese - Max Weyler Nery - 2013.pdf: 3823648 bytes, checksum: 45da627ca3fc33274b6ed62abbaf86f2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-11-22T10:12:26Z (GMT). No. of bitstreams: 2 Tese - Max Weyler Nery - 2013.pdf: 3823648 bytes, checksum: 45da627ca3fc33274b6ed62abbaf86f2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2013-05-16 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / A highly active antiretroviral therapy (HAART) has significantly reduced the morbidity and mortality of HIV infection. The greatest survival, chronic inflammation and metabolic changes resulting from HAART are associated with increased cardiovascular disease (CVD). Objectives: To evaluate the correlation between CVD risk scores; estimate the frequency of evaluating the metabolic and obtaining lipid targets in HIV-positive patients. Method: Cohort of seropositive individuals recruited at a referral center for HIV, in Goiás, 2009-2011. 294 participants aged >19 years were followed with clinical and laboratory evaluations performed at baseline, after 3 and 6 months. We analyzed the correlation between Framingham with and without aggravating factors; PROCAM and DAD (Kappa). We estimated the frequency of metabolic changes and obtaining lipid targets, post-intervention, according to Guidelines of the Brazilian Society of Cardiology. According to clinical and laboratory criteria, patients received rosuvastina and/or ciprofibrate. The level of significance was set at p<5%. SPSS 18.0 software was used. Results: predominantly male population (76.9%); with a mean age of 36.8 years (SD=10.3); 66.3% on HAART, of whom 50.0% for less than two years. High risk of CVD ranged from 0.4 to 5.7%. Intermediate risk for CVD was seen in 3.2, according to the Framingham score and 39.9% of the participants, considering the presence of aggravating factors. At baseline, 72.8% of participants had some type of dyslipidemia. There was a significant reduction in the percentage of individuals with mixed dyslipidemia and low HDL, post-deployment lipid targets (p<0.05). Conclusions: Framingham with aggravating factors seems to overestimate cardiovascular risk in HIV positive patients. One third of patients with dyslipidemia reached lipid treatment targets in six months. Further studies are needed to assess the predictive power of different risk scores, as well as to assess the benefits of medium and long-term use of statins in this population. / A terapia antirretroviral (TARV) potente reduziu de forma significativa a morbidade e a mortalidade da infecção pelo HIV. A maior sobrevida, o processo inflamatório crônico e as alterações metabólicas decorrentes da TARV estão associados a um aumento de doenças cardiovasculares (DCV). Objetivos: Avaliar a concordância entre escores de risco para DCV; estimar a frequência de alterações metabólicas e avaliar a obtenção de metas lipídicas, em pacientes HIV positivos. Método: Coorte de indivíduos soropositivos recrutados em centro de referência para HIV, em Goiás, de 2009 a 2011. Foram acompanhados 294 participantes com idade > 19 anos, sendo realizadas avaliações clínicas e laboratoriais na admissão, após 3 e 6 meses. Analisou-se a concordância entre: Framingham, com e sem fatores agravantes; PROCAM e DAD (Kappa). Estimou-se a frequência de alterações metabólicas e de obtenção de metas lipídicas, pós-intervenção, segundo a IV Diretriz da Sociedade Brasileira de Cardiologia. De acordo com critérios clínicos e laboratoriais, os pacientes receberam rosuvastina e/ou ciprofibrato. O nível de significância foi estabelecido em p<5%. Utilizou-se o programa SPSS 18.0. Resultados: População predominantemente masculina (76,9%); com média de idade de 36,8 anos (desvio padrão=10,3); 66,3% em uso de TARV, dos quais 50,0% há menos de dois anos. Alto risco para DCV variou de 0,4 a 5,7%. Risco intermediário para DCV foi evidenciado em 3,2, segundo o escore de Framingham e em 39,9% dos participantes, considerando a presença de fatores agravantes. Na avaliação inicial, 72,8% dos participantes apresentavam algum tipo de dislipidemia. Observou-se uma redução significativa do percentual de indivíduos com dislipidemias mistas e com HDL-baixo, pós-implantação de metas lipídicas (p<0,05). Conclusões: Framingham com fatores agravantes parece superestimar o risco cardiovascular em pacientes HIV positivos. Um terço dos pacientes com dislipidemias alcançou as metas terapêuticas lipídicas, em seis meses. Novos estudos são necessários para avaliar o poder de predição dos diferentes escores de risco, bem como para avaliar os benefícios à médio e longo prazo do uso de hipolipemiantes, nessa população.

INTRODUÇÃO: As doenças cardiovasculares (DCV) são a principal causa de morte no mundo, sendo muitos dos fatores de risco passíveis de prevenção e controle. Embora as DCV sejam complexas em sua etiologia e desenvolvimento, a concentração elevada de LDL-c e baixa de HDL-c constituem os fatores de risco modificáveis mais monitorados na prática clínica, embora não sejam capazes de explicar todos os eventos cardiovasculares. Portanto, investigar como intervenções farmacológicas e nutricionais podem modular parâmetros oxidativos, físicos e estruturais das lipoproteínas pode fornecer estimativa adicional ao risco cardiovascular. Dentre os diversos nutrientes e compostos bioativos relacionados às DCV, os lipídeos representam os mais investigados e descritos na literatura. Nesse contexto, os ácidos graxos insaturados (ômega-3, ômega-6 e ômega-9) têm sido foco de inúmeros estudos. OBJETIVOS: Avaliar o efeito da suplementação com ômega-3, ômega-6 e ômega-9 sobre os parâmetros cardiometabólicos em indivíduos adultos com múltiplos fatores de risco e sem evento cardiovascular prévio. MATERIAL E MÉTODOS: Estudo clínico, randomizado, duplo-cego, baseado em intervenção nutricional (3,0 g/dia de ácidos graxos) sob a fórmula de cápsulas contendo: ômega-3 (37 por cento de EPA e 23 por cento de DHA) ou ômega-6 (65 por cento de ácido linoleico) ou ômega-9 (72 por cento de ácido oleico). A amostra foi composta por indivíduos de ambos os sexos, com idade entre 30 e 74 anos, apresentando pelo menos um dos seguintes fatores de risco: Dislipidemia, Diabetes Mellitus, Obesidade e Hipertensão Arterial Sistêmica. Após aprovação do Comitê de Ética, os indivíduos foram distribuídos nos três grupos de intervenção. No momento basal, os indivíduos foram caracterizados quanto aos aspectos demográficos (sexo, idade e etnia) e clínicos (medicamentos, doenças atuais e antecedentes familiares). Nos momentos basal e após 8 semanas de intervenção, amostras de sangue foram coletadas após 12h de jejum. A partir do plasma foram analisados: perfil lipídico (CT, LDL-c, HDL-c, TG), apolipoproteínas AI e B, ácidos graxos não esterificados, atividade da PON1, LDL(-) e auto-anticorpos, ácidos graxos, glicose, insulina, tamanho e distribuição percentual da LDL (7 subfrações e fenótipo A e não-A) e HDL (10 subfrações). O efeito do tempo, da intervenção e associações entre os ácidos graxos e aspectos qualitativos das lipoproteínas foram testados (SPSS versão 20.0, p <0,05). RESULTADOS: Uma primeira análise dos resultados baseada em um corte transversal demonstrou, por meio da análise de tendência linear ajustada pelo nível de risco cardiovascular, que o maior tercil plasmático de DHA se associou positivamente com HDL-c, HDLGRANDE e tamanho de LDL e negativamente com HDLPEQUENA e TG. Observou-se também que o maior tercil plasmático de ácido linoleico se associou positivamente com HDLGRANDE e tamanho de LDL e negativamente com HDLPEQUENA e TG. Esse perfil de associação não foi observado quando foram avaliados os parâmetros dietéticos. Avaliando uma subamostra que incluiu indivíduos tabagistas suplementados com ômega-6 e ômega-3, observou-se que ômega-3 modificou positivamente o perfil lipídico e as subfrações da HDL. Nos modelos de regressão linear ajustados pela idade, sexo e hipertensão, o DHA plasmático apresentou associações negativas com a HDLPEQUENA. Quando se avaliou exclusivamente o efeito do ômega-3 em indivíduos tabagistas e não tabagistas, observou-se que fumantes, do sexo masculino, acima de 60 anos de idade, apresentando baixo percentual plasmático de EPA e DHA (<8 por cento ), com excesso de peso e gordura corporal elevada, apresentam maior probabilidade de ter um perfil de subfrações de HDL mais aterogênicas. Tendo por base os resultados acima, foi comparado o efeito do ômega-3, ômega-6 e ômega-9 sobre os parâmetros cardiometabólicos. O ômega-3 promoveu redução no TG, aumento do percentual de HDLGRANDE e redução de HDLPEQUENA. O papel cardioprotetor do ômega-3 foi reforçado pelo aumento na incorporação de EPA e DHA, no qual indivíduos com EPA e DHA acima de 8 por cento apresentaram maior probabilidade de ter HDLGRANDE e menor de ter HDLPEQUENA. Em adição, observou-se também que o elevado percentual plasmático de ômega-9 se associou com partículas de LDL menos aterogênicas (fenótipo A). CONCLUSÃO: Ácidos graxos plasmáticos, mas não dietéticos, se correlacionam com parâmetros cardiometabólicos. A suplementação com ômega-3, presente no óleo de peixe, promoveu redução no TG e melhoria nos parâmetros qualitativos da HDL (mais HDLGRANDE e menos HDLPEQUENA). Os benefícios do ômega-3 foram particularmente relevantes nos indivíduos tabagistas e naqueles com menor conteúdo basal de EPA e DHA plasmáticos. Observou-se ainda que o ômega-9 plasmático, presente no azeite de oliva, exerceu impacto positivo no tamanho e subfrações da LDL. / INTRODUCTION: Cardiovascular diseases (CVD) are the leading cause of death worldwide and many of the risk factors are likely to prevention and control. While CVD are complex in their etiology and development, a high concentration of LDL-c and low HDL-c are the most investigated modifiable risk factors in clinical practice, although they are not able to explain all cardiovascular events. So investigate how nutritional and pharmacological interventions can modulate oxidative, physical and structural parameters of lipoproteins can provide additional estimate for cardiovascular risk. Among the many nutrients and bioactive compounds related to CVD, lipids represent the most investigated and described in the literature. In this context, the unsaturated fatty acids (omega-3, omega-6 and omega-9) have been focus of numerous studies. OBJECTIVES: To evaluate the effect of supplementation with omega-3, omega-6 and omega-9 on cardiometabolic parameters in adults with multiple risk factors and without previous cardiovascular event. MATERIAL AND METHODS: Clinical trial, randomized, double-blind, based on nutritional intervention (3.0 g/day of fatty acids) containing: omega-3 (37 per cent EPA and 23 per cent DHA) or omega-6 (65 per cent linoleic acid) or omega-9 (72 per cent of oleic acid). Subjects of both sexes, aged between 30 and 74 years old, with at least one of the following risk factors: hyperlipidemia, diabetes mellitus, obesity and hypertension were included. After Ethics Committee approval, the subjects were distributed on the three intervention groups. At baseline the demographic (gender, age and ethnicity) and clinical (medications, current diseases and family history) data were evaluated. At baseline and after 8 weeks of intervention, blood samples were collected after 12 hours of fasting. From the plasma were analyzed: lipid profile (TC, LDLc, HDL-c, TG), apolipoproteins AI and B, non esterified fatty acid, PON1 activity, LDL (-) and autoantibodies, fatty acids, glucose, insulin, size and distribution of LDL (7 subfractions and phenotype) and HDL (10 subfractions). The effect of time, intervention and associations between fatty acids and qualitative aspects of lipoproteins were evaluated (SPSS version 20.0, p <0.05). RESULTS: A first analysis of the results based on a cross sectional study showed through the linear trend analysis, adjusted by the level of cardiovascular risk, that the highest tertile of plasma DHA was positively associated with HDL-c, HDLLARGE and LDL size and inversely with HDLSMALL and TG. The highest tertile of plasma linoleic acid was positively associated with HDLLARGE and LDL size and negatively with HDLSMALL and TG. This association was not observed when we evaluated the dietary parameters. A sample including smokers supplemented with omega-6 and omega-3 showed that omega-3 positively modify the lipid profile and HDL subfractions. In linear regression models adjusted for age, sex and hypertension, plasma DHA showed negative associations with HDLSMALL. When only assessed the effect of omega-3 in smokers and non-smokers, the results showed that smokers, male, over 60 years old, with low percentage of EPA and DHA (<8 per cent ), overweight and/or obese and high body fat have an increased chance to have HDL subfractions profile less cardioprotective. Based on the above results, we compared the effect of omega-3, omega-6 and omega-9 on cardiometabolic parameters. The omega-3 decreased TG, increase the percentage of HDLLARGE and decrease HDLSMALL. The cardioprotective role of the omega-3 was enhanced by increasing the incorporation of EPA and DHA, in which subjects with more than 8 per cent of EPA and DHA were more likely to have HDLLARGE and lower HDLSMALL. In addition, it was also observed that higher omega-9 plasma levels was associated with less atherogenic LDL particles (phenotype A). CONCLUSION: Plasma fatty acids, but not dietary, correlate with cardiometabolic parameters. Supplementation with omega-3, present in fish oil, promoted reduction in TG and improved the qualitative parameters of HDL (more HDLARGE and less HDLSMALL). The benefits of omega-3 were particularly significant in smokers and those with lower baseline content of EPA and DHA. It was also observed that omega-9, present in olive oil, had a positive impact on the size of LDL.

Introdução: A obesidade é um importante problema de Saúde Pública e, segundo a Organização Mundial da Saúde, representa uma epidemia global. É considerada uma doença crônica, multifatorial, que depende não só de fatores genéticos e fisiopatológicos, mas também de variáveis culturais, sociais e psicológicas associadas à quantidade e a qualidade da alimentação. Nesse contexto, os adolescentes como foco de mudanças fisiológicas, anatômicas e sociais se tornam um grupo com elevada frequência de fatores de risco associados à obesidade. Objetivo: Avaliar o papel da lipoproteína de baixa densidade eletronegativa [LDL(-)], da proteína transportadora de éster de colesterol (CETP) e da resistência à insulina (RI) no risco cardiometabólico de adolescentes. Métodos: Foram recrutados adolescentes de ambos os sexos, com faixa etária de 10 a 19 anos e, regularmente matriculados em escolas da cidade de São Paulo. Medidas antropométricas, tais como, peso, altura, circunferência da cintura (CC) e composição corporal foram avaliadas, e classificadas considerando sexo e idade. Após jejum (12-15h), foi coletada uma amostra de sangue e a partir do plasma foram realizadas as seguintes análises: glicose, insulina e cálculo do HOMA, perfil lipídico, apolipoproteína A-I e B, atividade da paraoxonase 1 (PON1), ácidos graxos livres (AGL), atividade da CETP e LDL(-). Os resultados obtidos foram analisados por meio dos testes qui-quadrado, Kappa, Kolmogorov-Smirnov, t-student, ANOVA, Mann-Whitney, Kruskal-Wallis, Bonferroni e de tendência linear, com valor de significância de p< 0,05. Resultados: Os adolescentes eutróficos apresentaram menor atividade de CETP e conteúdo de LDL(-) em relação àqueles com excesso de peso. O IMC apresentou associação positiva e linear com o CT/HDL-C, TG/HDL-C, ApoB/ApoA-I, LDL(-) e LDL(-)/CT. Perfil inverso foi observado para HDL-C e ApoA-I. A CC mostrou associação positiva com TG, CT/HDL-C, LDL-C/HDL-C, TG/HDL-C, ApoB/ApoA-I, LDL(-), LDL(-)/CT e CETP. Associação negativa foi observada entre CC e HDL-C e ApoA-I. Após o ajuste pela atividade da CETP, associações entre o HDL-C, LDL-C/HDL-C, CT/HDLC e LDL(-)/LDL-C com o IMC ou CC foram modificadas. Ao ajustarmos pela concentração de LDL(-), nenhuma associação sofreu alteração, o que sugere um mecanismo independente para a regulação dessa partícula durante a obesidade.Ao analisarmos os adolescentes segundo CC, verificamos que os adolescentes com CCALTA apresentaram elevado IMC, por cento de gordura corporal, pressão arterial sistólica, conteúdo de insulina, HOMA, TG, TG/HDL-C, CT/HDL-C, LDL-C/HDL-C, ApoB/ApoA-I, AGL, LDL(-), LDL(-)/CT e atividade da CETP, quando comparados aqueles com CCBAIXA. Perfil inverso foi observado para por cento de massa magra, HDL-C, ApoA-I, HDL/ApoA-I e PON-1. Quando classificados segundo HOMA (resistente à insulina - RI e sensível à insulina - SI), os adolescentes RI mostraram um impacto negativo sobre o IMC, CC, por cento de gordura corporal, pressão arterial, TG e TG/HDL-C, e resultado inverso para por cento de massa magra e PON1. O índice de risco cardiovascular proposto mostrou que o grupo CCALTA-RI = CCALTA-SI > CCBAIXA-RI = CCBAIXASI. Conclusões: Portanto, a concentração de LDL(-) e a atividade da CETP associada à obesidade, principalmente abdominal, alteram o risco cardiometabólico de adolescentes / Introduction: Obesity is a major public health problem and, according to World Health Organization, represents a global epidemic. It is considered a chronic, multifactorial disease, which depends not only of genetic and pathophysiology factors, but also of cultural, social and psychological associated with diet profile variables. In this context, adolescents as the focus of physiological, anatomical and social changes become a group with high frequency of risk factor for obesity. Objective: To evaluate the role of the electronegative low-density lipoprotein [LDL(-)] concentration, cholesteryl ester transfer protein (CETP) activity and insulin resistance on cardiometabolic risk of adolescents. Methods: We recruited adolescents of both sexes, aged 10 to 19 years and enrolled in schools in the city of São Paulo. Anthropometric measurements such as weight, height, waist circumference (WC) and body composition were evaluated and classified according to sex and age. After fasting (12-15h) was analyzed from plasma: glucose, insulin and HOMA, lipid profile, apolipoprotein A-I and B, paraoxonase 1 activity (PON1), non-esterified fatty acids (NEFA), CETP activity and LDL(-). The results were analyzed by chi-square, Kappa, Kolmogorov-Smirnov, t-student, ANOVA, Mann-Whitney, Kruskal-Wallis, Bonferroni and linear tendency test, with p< 0.05. Results: The subjects with normal weight had lower CETP activity and content of LDL(-) than excess weight adolescents. BMI showed positive and linear association with TC/HDL-C, TG/HDL-C, ApoB/ApoA-I, LDL(-) and LDL(-)/TC. Profile opposite was observed for HDL-C and ApoA-I. The WC was positively associated with TG, TC/HDL-C, LDL-C/HDL-C, TG/HDL-C, ApoB/ApoA-I, LDL(-), LDL(-)/CT and CETP. Negative association was observed between WC and HDL-C and ApoA-I. After adjustment for CETP, associations between HDL-C, LDL-C/HDL-C, TC/HDL-C and LDL(-)/LDL-C with BMI or WC were modified. Adjustment for LDL(-) content was not able to change these associations, suggesting an independent mechanism for regulation of the levels of this particle during obesity. Analysis second WC, it was found that adolescents 10 with WCHIGH showed higher BMI, per cent body fat, systolic blood pressure, insulin, HOMA, TG, TG/HDL-C, TC/HDL-C, LDL-C/HDL-C, ApoB/ApoA-I, NEFA, LDL(-), LDL(-)/TC and CETP activity than WCLOW group. Profile opposite was observed for per cent lean body mass, HDL-C, ApoA-I, HDL/ApoA-I and PON-1. When it classified according to HOMA (insulin resistant IR and insulin sensitive IS), IR group showed a negative impact on BMI, WC, per cent body fat, blood pressure, TG and TG/HDL-C, and contrary result for per cent mass lean and PON1. The cardiovascular risk index propose showed that WCHIGH IR = WCHIGH IS > WCLOW IR = WCLOW IS group. Conclusions: Therefore, LDL(-) content and CETP activity associated with obesity, mainly abdominal, alter the cardiometabolic risk of adolescents

Background: The Framingham Study from 1988 showed a heavy impact of diabetes mellitus (DM) on the risk and prognosis of cardiovascular disease (CVD). Several other studies have confirmed that DM is an independent risk factor for coronary heart disease (CHD) and that patients with DM have a poor prognosis. However, the strength of DM as a risk factor is debated. Some studies indicate that DM, as a risk factor for a coronary event, is comparable to already known or established CHD. Also, mechanisms of how diabetes increases the CVD risk are under intensive research. A novel risk factor such as altered fibrinolysis is one of the potential mechanisms explaining the heavy cardiovascular burden in diabetes. Hypofibrinolytic changes can be seen in individuals with metabolic syndrome, insulin resistance, and obesity as well as in patients with manifest diabetes or manifest CHD. Methods: This dissertation is divided in three parts; epidemiological, etiological and interventional. Papers I and II are epidemiological, population based retrospective studies which compare time trends in myocardial infarction and stroke morbidity and mortality between patients with or without diabetes. Papers III and IV have an etiological approach to the fibrinolytic system and CVD risk both in patients with or without diabetes. Paper V is the interventional part of this thesis studying if intensive insulin treatment can improve fibrinolysis in patients with high CVD risk. Results: The incidence and mortality from myocardial infarction and stroke have declined in the counties of Västerbotten and Norrbotten in Northern Sweden. Unfortunately, the subgroup with patients with diabetes and myocardial infarction (MI) in Paper I did not benefit from these favorable trends over the study period. For stroke, this is for the first time declining incidence has been reported in this population. Incidence of first-ever stroke decreased for non-diabetic men with a yearly change of -0.8 percent (p-value  &lt;0.001), and for diabetic women with a yearly change of -1.5 percent (p-value=0.012). Recurrent stroke incidence declined highly significant, p-value  &lt;0.001, for non-diabetic men and women and for diabetic women with a yearly change of -1.5, -2.7, and -5.4 percent, respectively. For diabetic men a non-significant decline of -1.0 percent (p-value=0.28) in stroke incidence was seen. Paper II showed that women with diabetes had decreased incidence for stroke but not men with diabetes. Also, reduced mortality from stroke was found in all patients except for diabetic women with first ever stroke. Patients with diabetes have altered fibrinolysis compared to individuals with normal glucose metabolism. Also, patients with prior MI manifest a hypofibrinolytic stage with low tissue-type plasminogen activator (tPA) activity and high levels of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Paper III showed a significant association between decreased tPA activity and increased fibrinogen levels in patients with a first MI when examined 3 months after the event. The results persisted even after adjustment for traditional risk factors and variables mirroring the insulin resistance syndrome and were significant in the whole study group of subjects with MI as well as for men alone. Paper IV, a 10 year follow-up study, showed that in patients with diabetes, tPA-activity significantly predicted the presence of sign(s) of lower extremity arterial disease (LEAD) at the baseline and at the 10-year follow-up. In addition, tPA-mass at the 10-year follow-up was associated with signs of LEAD. Baseline age, hypertension, and HbA1c were independently associated with sign(s) of LEAD at 10 years. This long-term study supports previous findings of a significant association between asymptomatic LEAD and tPA-activity. Thus, tPA-activity may be an early marker of LEAD, although the mechanism of this relationship remains unclear. Several studies report conflicting results regarding benefits and disadvantages of intensive insulin treatment. ORIGIN trial was an international multicenter trial studying effects of intensive insulin treatment on CVD. This thesis reports a Swedish sub-study of ORIGIN trial examining effects of insulin treatment on fibrinolysis. The allocation to insulin treatment did not significantly affect the studied fibrinolytic markers or von Willebrand factor (VWF) compared to the standard treatment. Log mean delta values between baseline and end of study increased significantly for tissue plasminogen activator activity (tPAact) and tPA/PAI-1 complex. For plasminogen activator inhibitor-1 (PAI-1), tPA antigen (tPAag) and VWF no significant differences were found. Within-group analysis during the whole study period revealed significant changes for tPA/PAI-1 complex, tPA antigen, and VWF in the insulin treatment group but no significant changes in the standard treatment group. The hypothesis that allocation to insulin treatment would improve the levels of markers of fibrinolysis or VWF compared to standard glucose lowering treatment could not be verified.   Conclusion: This dissertation shows that patients with diabetes still have a heavy cardiovascular disease burden with increased risk for MI and stroke compared to individuals with normal glucose metabolism. This cardiovascular burden also includes increased morbidity, mortality, and poorer long-term prognosis. The fibrinolytic system has an impact on cardiovascular disease and this thesis has shown that patients with diabetes have unfavorable changes in their fibrinolysis and that alterations in fibrinolysis can predict future peripheral artery disease. However, intensive insulin therapy did not appear to affect this system to the extent of resulting in reduced cardiovascular morbidity. / Diabetes bakgrund: Diabetes Mellitus är en av de vanligaste kroniska sjukdomarna i världen. Diabetesförekomsten har ökat påtagligt de senaste årtiondena. Ökningen beror på ökat insjuknande på grund av livsstilsförändringar med minskat fysisk aktivitet och ökad övervikt och även på grund av förbättrad diagnostik. Även förbättrad sjukvård med ökad överlevnad hos patienter med diabetes samt fler andel äldre ökar andelen diabetes patienter i befolkningen. Enligt WHO har antalet patienter med diabetes stigit från 30 miljoner år 1985 till 171 miljoner år 2000 då uppskattningsvis 4,6 % av vuxenbefolkning har diabetessjukdomen. Majoriteten, ca 80 % har diabetes typ 2. WHO:s prognos visar fortsatt kraftig ökning av diabetes med ca 550 miljoner drabbade år 2030. Majoriteten av denna förändring förklaras av diabetes typ 2 som i framtiden beräknas utgöra 90-95% av all diabetes. Diabetes är fortsatt den viktigaste bakomliggande orsaken till terminal njursvikt i industriländer och en av de vanligaste orsakerna till blindhet i världen. Diabetes innebär en kraftigt ökad risk för hjärt- och kärlsjukdomar. Patienter med diabetes som drabbats av hjärt- och kärlsjukdom såsom hjärtinfarkt eller stroke har ofta sämre prognos, både akut och på långsiktigt, jämfört med patienter utan diabetes. På grund av att diabetes är en kronisk sjukdom med många, ofta svåra och kostsamma, komplikationer står diabetesrelaterade sjukvårdskostnader för en betydande del av totala de sjukvårdskostnaderna i världen varierande mellan 2,5 – 25 % av olika länders sjukvårdsbudget. Diabetes och risk för hjärt- och kärlsjukdomar: De klassiska risk-faktorerna för hjärt- och kärlsjukdomar är ålder, rökning, högt blodtryck, högt kolesterol, låg fysisk aktivitet/övervikt och ärftlighet. Lägger man till diabetes till dessa riskfaktorer får man påtagligt ökad risk för kärlsjukdomar som hjärtinfarkt, stroke och perifer kärlsjukdom. Mekanismerna bakom denna överrisk av diabetes är fortfarande åtminstone till viss del oklara och aktuella för intensiv forskning och debatt. Sannolikt har tiden före diabetesdiagnosen, prediabetes, betydelse då vi vet att vid tidpunkt för diagnos har patienterna med typ 2 diabetes haft störd sockeromsättning varierande länge, oftast sannolikt flera år. Andra tänkbara diabetesrelaterade orsaker för ökad hjärt- och kärlsjuklighet kan vara kronisk inflammation, blodets störda levringsfunktion (hypofibrinolys), nedsatt funktion i blodkärlen (endoteldysfunktion), ogynnsam blodfetts-profil, kroniskt höga insulinnivåer och även sannolikt direkt skadlig effekt av det höga sockret på flertal celler och organ i kroppen. Framtidens behandlingsmöjligheter: Aktuella behandlingsriktlinjer betonar vikten av att betrakta individer med diabetes som högriskpersoner avseende hjärt- och kärlsjukdomar oavsett förekomst av känd kärlsjukdom. Sjukvården ska primärpreventivt intensivbehandla de traditionella riskfaktorerna hos individer med diabetes. Det är dock uppenbart att personer även med helt optimalt behandlade riskfaktorer som blodtryck och kolesterol och även optimal sockerkontroll har fortsatt högre risk för hjärt- och kärlsjukdomar, så kallad residual risk, jämfört med personer utan diabetes. Det är viktigt att i framtiden försöka klargöra vilka faktorer som utgör denna residual risk och utveckla behandlingsmöjligheter mot dessa faktorer. Det är sannolikt av största vikt att tidigt identifiera individer med störd sockeromsättning och risk för utveckling av diabetes. Sjukvården bör sträva efter att minimera de negativa effekterna av prediabetes och förebygga progress till manifest diabetes. Avhandlingens syfte: Att kartlägga hur effektiv den traditionella riskfaktorbehandlingen har varit i att förebygga hjärt- och kärlsjukdomar, särskilt hjärtinfarkt och stroke, hos patienter med diabetes. I avhandlingen  studeras närmare en av de icke traditionella riskfaktorerna nämligen i det blodproppsupplösande systemet, fibrinolysen. Det är numera välkänt att diabetes i sig påverkar fibrinolyssystemet ogynnsamt och att vissa diabetesläkemedel kan påverka fibrinolysen gynnsamt. Vi har studerat om förändringar i fibrinolysen kan prediktera perifer kärlsjukdom hos patienter med diabetes och om intensiv insulinbehandling kan påverka detta fibrinolyssystem. Resultat: Avhandlingen visar att insjuknandet och dödlighet i hjärtinfarkt och stroke har minskat i Västerbotten och i Norrbotten. För stroke var det första gången ett minskat insjuknande kunde rapporteras för denna population. Tyvärr har inte patienter med diabetes och hjärtinfarkt fått ta del av dessa gynnsamma trender under studerad tid. För stroke har kvinnor med diabetes fått minskat insjuknande men inte män med diabetes. Strokestudien kunde också redovisa minskat dödlighet i stroke för alla patienter utom kvinnor med diabetes med en förstagångs insjuknande i stroke. Patienter med diabetes har påverkad fibrinolys jämfört med personer med normal glukosmetabolism. Även patienter med tidigare hjärtinfarkt uppvisar ett hypofibrinolytisk tillstånd med låg tPA-aktivitet och höga nivåer av PAI-1 och fibrinogen. Arbete III visade en association mellan låg tPA-aktivitet och höga nivåer av fibrinogen hos patienter med förstagångs hjärtinfarkt. Detta samband kvarstod även efter justering med traditionella riskfaktorer. Arbete IV, en 10 års uppföljning visade hos patienter med diabetes att tPA-aktivitet kan prediktera förekomsten perifer kärlsjukdom vid baslinjen och även vid 10-års uppföljning. Dessutom var tPA-mass vid 10-års uppföljning associerad med perifer kärlsjukdom. Av de traditionella riskfaktorerna var ålder, hypertension och HbA1c vid studiestart oberoende associerade med förekomst av perifer kärlsjukdom vid 10 års uppföljning. Denna långtidsstudie stöder tidigare fynd av ett signifikant samband mellan asymtomatisk perifer kärlsjukdom och tPA-aktivitet. Sålunda kan tPA-aktivitet vara en tidig markör av perifer kärlsjukdom, även om, den bakom liggande mekanismen för detta är fortfarande oklart. Flera större studier rapporterar motstridiga resultat beträffande för- och nackdelarna med intensiv insulinbehandling. ORIGIN studien var en internationell multicenterstudie som undersökte effekterna av intensiv insulinbehandling på hjärt- och kärlsjukdomar. I arbete V med ORIGIN-studiens svenska kohort undersöktes effekterna av insulinbehandling på fibrinolys. Randomisering till insulinbehandling hade ingen signifikant effekt på de studerade fibrinolytiska markörerna eller von Willebrand faktorn VWF jämfört med standardbehandling. Logaritmerade medeldeltavärden mellan baslinjen och studie slutet ökade signifikant för tPA-aktivitet och tPA/PAI-1-komplexet. För PAI-1, tPA-antigen och för VWF kunde inga signifikanta skillnader visas. Inom-gruppsanalys över hela studieperioden visade signifikanta förändringar för tPA/PAI-1-komplexet, tPA-antigen och VWF i insulingrupp men inga signifikanta förändringar för patienter med standardbehandling. Hypotesen att randomisering till insulinbehandling skulle förbättra nivåerna av fibrinolysfaktorer eller VWF jämfört med standardbehandling kunde inte verifieras Konklusion: Denna avhandling visar att patienter med diabetes har fortsatt ökad risk för hjärtinfarkt och stroke jämfört med individer med normal sockeromsättning. Denna överrisk betyder för patienter med diabetes en ökad risk för insjuknande, svårare sjukdomstillstånd och sämre prognos med ökad risk för återinsjuknande samt även högre dödlighet både på kort och lång sikt. Även andra aktuella studier rapporterar en fortsatt hjärt- och kärlrelaterad överrisk hos patienter med diabetes. Fibrinolyssystemet har betydelse för hjärt- och kärlsjukdomar och denna avhandling visar att patienter med diabetes har ogynnsamma förändringar i sin fibrinolys, så kallad hypofibrinolys. Intensiv insulinbehandling förefaller inte påverka fibrinolysen till den grad att minskad hjärt- och kärlsjuklighet kan ses.

La santé est une construction dynamique et multifactorielle qui a une dimension individuelle et une dimension sociale. Cette dernière peut avoir un effet direct ou indirect sur les comportements des individus et sur leurs choix de vie. L’étude de Framingham a révélé que le risque cardiovasculaire était multifactoriel et donc son estimation devait être globale. Mais les méthodes d’estimation du risque cardiovasculaire ne prennent pas en compte l’environnement de vie des individus qui favoriserait le développement des facteurs de risque modifiables. A travers ce travail, nous mettons en lumière les caractéristiques de l'environnement de diffusion des facteurs de risque cardiovasculaires modifiables : métaboliques et comportementales. Depuis des décennies, la région Nord enregistre pour les maladies cardiovasculaires des taux élevés de mortalité globale et prématurée. Nous nous sommes interrogés sur les déterminants de cette situation de la région Nord, en la comparant aux autres régions françaises, et en explorant le lien entre un risque cardiovasculaire élevé et une situation économique défavorable. Dans ce but, nous avons étudié le lien entre la distribution du risque cardiovasculaire et la distribution du revenu, en employant des critères normatifs basés sur la notion de dominance sociale en termes de pauvreté.Ce travail permet d’analyser les connaissances en rapport avec l’environnement de vie des individus et ainsi une meilleure compréhension des mécanismes de diffusion des facteurs de risque modifiables, ce qui s’inscrit dans une double perspective, réduire l’incidence et la prévalence des maladies cardiovasculaires et diminuer les inégalités sociales de santé. / Health is a dynamic and multifactor construction which has both an individual and a social dimension. The latter may have a direct or indirect effect on the behaviour of individuals and their life choices. The Framingham study has revealed that cardiovascular risk is multifactorial and, as such, its estimate should be global. However, the assessment of global cardiovascular risk methods do not take into account the living environment of individuals, which would factor the development of modifiable risk factors. Through this work, we highlight the characteristics of the environment of dissemination of modifiable cardiovascular risk factors: metabolic and behavioural. Since decades, the North region of France has, for cardiovascular diseases, a high level of global and premature mortality. We are asked about the determinants of the situation of this region, by comparing it to other French regions and by exploring the link between a high cardiovascular risk and an unfavourable economic situation. Thus, we are interested in the link between the distribution of cardiovascular risk and the distribution of income, using normative criteria based on the concept of expected social dominance in terms of poverty. Shedding a light on factors favouring the occurrence of cardiovascular problems and analyzing the knowledge about the individual’s life environment allows a better understanding of the mechanisms of diffusion of the modifiable risk factors, with a double objective to lower the incidence and prevalence of cardiovascular diseases and to reduce the social inequalities in health.

Abstract The research focus for smoking and public health has typically been on serious smoking diseases such as cancer and coronary thrombosis, which typically require treatment in a hospital setting at an older age. In this thesis, primary health care utilisation and cardiovascular risk factors according to smoking status were studied in a younger cohort: at age 46 in the Northern Finland Birth Cohort of 1966. Primary health care costs of smokers vs. never-smokers were 28% higher for men and 21% higher for women. Signs of elevated risk of metabolic syndrome and cardiovascular disease were visible: smokers had 20% higher triglycerides, slightly larger waist-to-hip ratio, and type 2 diabetes prevalence was twice as high among smokers than never-smokers after adjustment for covariates. The calculated ten-year risk of a cardiovascular event was twice as high for smokers vs. either never-smokers, former smokers or recent quitters. These results should be seen as early warning signals in primary health care, and cost-effective actions should be taken to prevent later multimorbidity – smoking cessation aid by a physician is very cost effective. Only a minority of smokers receive cessation support from a physician, even though the majority of them wish to quit. In order to understand this discrepancy, a survey was conducted on physicians and smoking cessation. Physicians thought it was their responsibility to try to get the patient to quit, but practical measures to treat smoking dependence were rare. The most commonly reported restrictions for smoking cessation work – lack of time and functional treatment paths – could be addressed by administration and management. The attitudes and experiences of Finnish physicians were in line with the WHO recommendation to improve smoking cessation services and integrate them into health care: 80% were in favour of more resources being directed to smoking cessation services, and less than one third thought that smoking cessation was even somewhat well organised in the Finnish health care system. / Tiivistelmä Tupakoinnin terveys- ja talousvaikutusten tarkastelu keskittyy usein myöhemmällä iällä sairaalahoitoa vaativiin tupakkasairauksiin kuten syöpään ja sepelvaltimotautiin. Tässä väitöskirjassa tarkastellaan tupakoinnin ja perusterveydenhuollon käytön sekä sydän- ja verisuonitautien riskitekijöiden yhteyttä nuoremmassa otoksessa: 46 vuoden iässä Pohjois-Suomen vuoden 1966 syntymäkohortissa. Perusterveydenhuollon vuosittaiset kustannukset olivat tupakoivilla korkeammat kuin tupakoimattomilla: miehillä 28% ja naisilla 21%. Merkkejä kohonneesta metabolisen oireyhtymän ja sydän- ja verisuonitautien riskistä oli havaittavissa: tupakoivien triglyseridit olivat 20% korkeammat, heidän lantio-vyötärösuhteensa oli hieman suurempi kuin tupakoimattomilla, ja tyypin 2 diabetes oli heillä kaksi kertaa yleisempää taustamuuttujien vakioinnin jälkeen. Arvioitu riski saada vakava sydän- tai verisuonitapahtuma seuraavan kymmenen vuoden kuluessa oli tupakoivilla kaksi kertaa suurempi kuin heillä, jotka joko eivät olleet ikinä tupakoineet, olivat aiemmin tupakoineet, tai jotka olivat hiljattain lopettaneet. Perusterveydenhuollon tulisi nähdä nämä ilmiöt varhaisina varoitussignaaleina ja ryhtyä kustannusvaikuttaviin toimenpiteisiin myöhemmän multimorbiditeetin ehkäisemiseksi – lääkärin antama tuki tupakoinnin lopettamisessa on erittäin kustannusvaikuttavaa. Vaikka suurin osa tupakoitsijoista haluaa lopettaa, vain vähemmistö saa siihen tukea lääkäriltä. Tämän epäsuhdan ymmärtämiseksi tehtiin kyselytutkimus lääkäreille tupakastavieroituksesta. Lääkärit näkivät velvollisuudekseen yrittää saada tupakoiva potilas lopettamaan, mutta käytännön toimet tupakkariippuvuuden hoitamiseksi olivat harvinaisia. Yleisimmin raportoidut esteet vieroitustyölle – aikapula ja puutteelliset hoitopolut – olivat hallinnon ja johdon ratkaistavissa. WHO:n mukaan Suomella on parantamisen varaa lopettamisen tukipalveluissa ja tupakkariippuvuuden hoidon integroimisessa terveydenhuoltojärjestelmään. Tästä väitöskirjasta käy ilmi, että suomalaisten lääkäreiden asenteet ja kokemukset ovat linjassa WHO:n ohjeistuksen kanssa: 80% kannatti lisäresurssien ohjaamista lopettamispalveluihin ja alle kolmanneksen mielestä tupakastavieroitus toteutui edes jokseenkin hyvin suomalaisessa terveydenhuoltojärjestelmässä.

Les troubles métaboliques caractéristiques d’une alimentation de type « Western diet », sont à l’origine de pathologies cardiovasculaires, première cause de mortalité dans le monde. Il apparait nécessaire d’améliorer la compréhension des mécanismes impliqués dans l’installation des dysfonctions cardiovasculaires afin de pouvoir proposer des stratégies thérapeutiques ou préventives adaptées. Ainsi, le premier objectif de la thèse a été d’évaluer les effets d’une boisson sucrée sur la fonction vasculaire macro- et micro-circulatoire chez des sujets sains, par une approche translationnelle allant de la clinique humaine à un modèle expérimental de rongeur. Nos résultats montrent une altération de la fonction endothéliale en réponse à une prise de boisson sucrée, dans l’ensemble des lits vasculaires. L’exploration des mécanismes sous-jacents ces altérations nous a permis d’identifier l’implication du couple stress-oxydant/voie du NO. Un second objectif de thèse, a été d’étudier l’impact d’un stress métabolique chronique sur la fonction vasculaire et son incidence sur la régulation de la pression artérielle. Comme observé chez certains sujets souffrant de syndrome métabolique, notre modèle de rat ne présentait pas d’hypertension artérielle, malgré une hyperactivité du système sympathique. Ceci semble être expliqué par une compensation endothéliale eNOS-dépendant, qui permet de garantir le maintien d’une pression artérielle normale en dépit de l’effet vasopresseur adrénergique élevé. Le troisième objectif de thèse a porté sur un nouvel élément participant au maintien de l’homéostasie vasculaire et impacté par les situations pathologiques : le tissu adipeux périvasculaire (PVAT). Nos travaux démontrent dans le contexte du SMet, une altération de la voie adiponectine/eNOS dans le PVAT, en parallèle d’une augmentation de la production d’espèces oxygénées réactives.La pratique régulière d’un exercice physique est aujourd’hui reconnue comme une stratégie non-pharmacologique permettant d’impacter à la fois les désordres métaboliques et cardiovasculaires, notamment via une amélioration de la voie du NO. Nos résultats démontrent une limitation de l’apparition des dysfonctions endothéliales causée par une hyperglycémie aigue lorsqu’un protocole d’exercice physique chronique est réalisé. Enfin, l’exercice physique permet également de prévenir les modifications des propriétés vaso-actives du PVAT dans un modèle de rat SMet. Ce phénomène pourrait être expliqué par une amélioration du statut oxydant de la paroi artérielle, et à une potentialisation de la voie adiponectine/eNOS par l’exercice physique / The globalization of the western diet has mediated prevalence in cardiovascular disease related mortality, the single leading cause of death worldwide. Considering this, it is imperative that the underlying mechanisms of cardiovascular dysfunctions are continually investigated to establish a greater understanding of its pathogenesis from a healthy state to the presence of cardiometabolic diseases; and to improve upon current treatment and preventative strategies. Therefore, the first aim of this research was to identify vascular impact of acute hyperglycaemic stress induced by sweet sugar beverage consumption, with a translational approach. The results of this study demonstrated that consumption of a single commercially available sugar-sweetened beverage (SSB) induced transient micro- and macrovascular endothelial dysfunction, even in a healthy population. Further exploration into the underlying mechanisms of SSB-mediated endothelial dysfunction indicated that an increase in oxidative stress disrupts normal function of the nitric oxide pathway. Although disturbances in cardiovascular function may initially be transient, repetitive acute metabolic stress may translate to chronic cardiometabolic disease. Therefore, the second aim of this research was to assess the impact of a chronic metabolic disorder, metabolic syndrome (MetS), on vascular function in a rat model. Despite increasing sympathetic activity, the MetS rats didn’t present elevated arterial pressure. Such findings may be explained by a compensatory adaptation of endothelial function that increases production of nitric oxide in response to α-adrenergic agonist and, thus, regulates arterial pressure despite sympathetic hyperactivity. Considering this, the third aim of this research evaluated the impact of perivascular adipose tissue (PVAT) on vascular fucntion in MetS rats; demonstrating that MetS altered the adiponectin-endothelial nitric oxide synthase pathway in PVAT, in an oxidative stress-dependant manner.Exercise training is well recognized as a non-pharmacological strategy that has a beneficial impact on both metabolic and cardiovascular disorders via an improvement in function of the nitric oxide pathway. Considering this, research also assessed the efficacy of this approach to prevent vascular injury induced by acute hyperglycaemia in a healthy population and by PVAT in those with MetS. It was demonstrated that exercise attenuated acute hyperglycemia-mediated endothelial dysfunction; and restored endothelium-dependent vascular reactivity in rats with MetS, due to an improvement in the biocommunication between PVAT and arterial tissue and a notable enhancement of the adiponectine-endothelial nitric oxide synthase pathway.

Contexte : En France, le cancer de la prostate est une maladie fréquente de l’homme âgé et la première cause de cancer. Il est associé à une survie de 70 % à 10 ans. Différentes options thérapeutiques sont recommandées dans la prise en charge de ce cancer, parmi lesquelles l’hormonothérapie (ou thérapie par déprivation d’androgène, ADT). Le profil de sécurité de l’hormonothérapie et des différentes modalités qui la composent est remis en question depuis le milieu des années 2000 avec plusieurs auteurs ayant évoqué un sur-risque cardiovasculaire comparativement aux patients non traités. Les résultats de ces études étant discordants, l’hypothèse d’une hétérogénéité entre les différentes modalités d’ADT a été évoquée mais n’a pas été directement investiguée. Objectif : L’objet de ce travail a été d’évaluer l’hypothèse d’une hétérogénéité qualitative entre les différentes modalités d’ADT indiquées dans le cancer de la prostate. Méthodes : De façon originale par rapport aux études précédemment publiées, une méta-analyse des essais cliniques randomisés et des études observationnelles, « METADTCR », a été réalisée comparant la morbidité et mortalité cardiovasculaire ischémique ainsi que la mortalité toutes causes au sein des différentes modalités d’ADT. Dans un second temps, une étude observationnelle, « ADTCR », utilisant la base de données de l’Assurance Maladie couplée aux données de remboursement hospitalières, a été réalisée afin de suivre spécifiquement, sur une cohorte nationale de patients avec un cancer de la prostate initiant une hormonothérapie, l’apparition d’évènements ischémiques (accidents vasculaires cérébraux ischémiques et infarctus du myocarde). Résultats - Conclusion : Concernant METADTCR, les essais cliniques se sont révélés extrêmement peu contributifs quant au risque de morbidité et mortalité cardiovasculaire ; la méta-analyse des études observationnelles souffrant d’une hétérogénéité substantielle au niveau des différentes comparaisons étudiées, la question du risque de morbidité et mortalité cardiovasculaire subsistait. Concernant ADTCR, une hétérogénéité du risque d’évènements ischémiques a été constatée entre les différentes modalités d’ADT : comparativement aux agonistes GnRH, un sur-risque d’évènements ischémiques a été identifié avec le blocage androgénique complet et une diminution du risque observée avec les anti-androgènes. La comparaison d’intérêt pour les cliniciens concernait celle avec l’antagoniste GnRH : aucune différence statistiquement significative n’a été observée. La plausibilité pharmacologique expliquant un potentiel sur-risque d’évènements ischémiques entre ces deux modalités n’a par ailleurs pas emporté la conviction et nous conforte dans l’hypothèse de l’absence de différence de risque. Ces résultats viennent compléter les recommandations françaises et européennes de prise en charge du cancer de la prostate quant à la différence de profil de sécurité de certaines modalités d’ADT en matière d’évènements ischémiques à court terme (< 2 ans). / Context: In France, prostate cancer is a frequent disease in elderly men, and the first cause of cancer. It is associated with a 70 % survival at 10 years. Different therapeutics options are recommended in prostate cancer management, including hormonotherapy (or androgen deprivation therapy, ADT). Safety of ADT modalities is challenged since mid of 2000’s when some authors evoked an increased cardiovascular risk in ADT-treated patients compared to non-treated patients. Results of these studies appeared conflicting, and heterogeneity of cardiovascular risk across ADT modalities was evoked but not directly investigated. Objective: Our aim was to assess the hypothesis of qualitative heterogeneity across the different ADT modalities used for prostate cancer. Methods: Through a new approach compared to previously published studies, we firstly conducted a direct and network meta-analysis of both randomized controlled trials and observational studies, “METADTCR”, comparing ischemic cardiovascular morbidity, mortality and overall death across the different ADT modalities. Secondly, we set up a population-based cohort study, “ADTCR”, using French Health Insurance database (SNIIRAM/DCIR) linked to hospital reimbursement data (PMSI), including men with prostate cancer who initiated an ADT, and measuring the occurrence of ischemic diseases (myocardial infarction or ischemic stroke). Results – Conclusion: As regards METADTCR, randomized controlled trials gave too few data related to cardiovascular morbidity and mortality; observational studies meta-analysis suffered from substantial inconsistency and eventually the question of cardiovascular risk morbidity and mortality remained. In ADTCR, a heterogeneous risk of ischemic events was observed across ADT modalities: compared to GnRH agonists, an increased risk of ischemic events was identified with combined androgen blockade, and a decrease risk with anti-androgen alone. The most interesting comparison concerned GnRH antagonist: no statistically significant difference was observed. Pharmacological plausibility for a potential increased risk of ischemic events between GnRH agonists and antagonist is not convincing to date and the hypothesis of no risk difference might be true. These results add valuable information to the French and European guidelines for prostate cancer management as regards the safety profile of the different ADT modalities in term of short term ischemic events onset (< 2 years).