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Made available in DSpace on 2017-07-24T19:22:14Z (GMT). No. of bitstreams: 1 Ricelia Cecilia Possagno.pdf: 1935834 bytes, checksum: b8da96685dd93850721d2ac62bf78db5 (MD5) Previous issue date: 2010-02-25 / Fundação Araucária de Apoio ao Desenvolvimento Científico e Tecnológico do Paraná / Cardiovascular diseases are the leading cause of death almost in the whole world. Among these, the coronary atherosclerotic disease (CAD) is by far the most frequent cause of death. By through different studies, many researchers are trying show an association between periodontal disease and atherosclerosis. Therefore, it is necessary clarify what are the factors involved in this process. This study aimed to evaluate the oral health and periodontal status of patients undergoing catheterization examination. Subjects were divided into two groups: patients with atherosclerotic disease, comprising 67 individuals and patients without atherosclerotic disease consisted of 28 individuals. The results of catheterization examinations, biochemical and periodontal were related, trying find potential risk markers between periodontal disease and atherosclerosis. Can be verified statistically significant difference in the number of sites with presence of dental plaque (p <0.0001) and inflamed sites (p = 0.0003) between the group of patients with and without atherosclerotic disease, as well as the number of sites with bleeding (p <0.0001) and exudate (p <0.0001). Spearman correlation to the levels of urea in saliva versus serum levels in patients with coronary atherosclerosis was statistically significant (p = 0.0077). The data suggest a possible correlation between inflammatory periodontal disease and coronary atherosclerosis. / As doenças cardiovasculares são a principal causa de morte em quase todo o mundo. Entre essas, doença aterosclerótica coronariana (DAC) é de longe a causa mais freqüente de morte. Por meio de diferentes estudos, muitos pesquisadores estão tentando mostrar uma associação entre a doença periodontal e aterosclerose. Portanto, é necessário esclarecer quais são os fatores envolvidos neste processo. Este estudo teve como objetivo avaliar a saúde bucal e condição periodontal de pacientes submetidos a exame de cateterismo. Os pacientes foram divididos em dois grupos: pacientes com doença aterosclerótica, que inclui 67 indivíduos e pacientes sem doença aterosclerótica consistiu de 28 indivíduos. Os resultados dos exames de cateterismo, bioquímicos e periodontais foram relacionados, tentando encontrar marcadores de risco em potencial entre a doença periodontal e aterosclerose coronariana. Pode ser verificada diferença estatisticamente significante no número de sítios com presença de placa bacteriana (p <0.0001) e sítios inflamados (p = 0.0003) nas cavidades orais entre o grupo de pacientes com e sem doença aterosclerótica, bem como no número de sítios com sangramento ( p <0.0001) e exsudato (p <0.0001). Correlação de Spermann com os níveis de uréia na saliva versus níveis séricos em pacientes com doença aterosclerótica coronariana foi estatisticamente significativa (p = 0.0077). Os dados sugerem uma possível correlação entre a doença periodontal inflamatória e aterosclerose coronária.

A relação entre periodontite e doenças cardiovasculares (DCV) tem sido amplamente discutida, embora os mecanismos de interação não estejam claros. Foi sugerido que pacientes com periodontite apresentam inflamação sistêmica e um pequeno aumento no risco cardiovascular. Patógenos periodontais foram encontrados em placas de ateroma, mas a influência destes microrganismos na aterosclerose ainda não é compreendida. O objetivo primário deste estudo foi delinear o perfil inflamatório sistêmico de pacientes submetidos à endarterectomia carotídea. Os objetivos secundários foram associar o perfil inflamatório dos participantes à condição periodontal e à presença de patógenos orais encontrados na cavidade oral e em placas de ateroma. Trinta e cinco pacientes submetidos à endarterectomia carotídea foram incluídos neste estudo. Antes da cirurgia vascular, um exame clínico periodontal foi realizado e foram coletadas amostras de sangue, saliva e biofilme subgengival. Durante a endarterectomia, uma amostra da placa de ateroma foi coletada. As amostras de soro foram testadas com o ensaio imunoenzimático de alta sensibilidade Multiplex para dezessete marcadores de células Th17. Amostras de saliva, biofilme subgengival e placa de ateroma foram submetidas ao PCR quantitativo para avaliação de dez patógenos periodontais. Este estudo foi capaz de detectar vários marcadores inflamatórios circulantes, o que indica a presença de inflamação sistêmica como uma característica da população. T. forsythia foi o microrganismo mais frequentemente encontrado em amostras de ateroma (37% das amostras). Níveis de T. forsythia em amostras de ateroma foram positivamente correlacionados com os níveis séricos de IL-7, IL-6, IL-17, IL-13, IL-12p70, IFN-?, GCS-F (p<0,05) e IL-10 (p<0,01). Níveis séricos de IL-2 foram positivamente correlacionados com os concentrações salivares de P. intermedia, P. endodontalis (p<0,05) e T. denticola (p<0,01). Níveis séricos de TNF-? foram positivamente correlacionados com concentrações salivares de P. endodontalis (p<0,01). Concentrações de P. endodontalis em amostras subgengivais foram correlacionadas positivamente com IL-2 (p<0,05). A inflamação periodontal (PISA) foi positivamente correlacionada com IL-2 (p<0,05). A coexistência de patógenos periodontais comuns na cavidade oral e na placa de ateroma está associada a um estado inflamatório sistêmico, o que poderia ser relevante para a compreensão dos mecanismos que ligam periodontite com DCV. / The relationship between periodontitis and cardiovascular diseases (CVD) has been widely discussed, although the mechanisms of interaction are not clear. It has been suggested that patients with periodontitis exhibit systemic inflammation and mild increase in future cardiovascular risk. Periodontal pathogens have been found in atheromatous plaques, but their exact role in atherosclerosis are not yet undertstood. The primary aim of this study was to screen the systemic inflammation profile in patients undergoing carotid endarterectomy. The secondary aims were to associate participant\'s inflammatory profiles with periodontal status and the presence of periodontal pathogens found in oral cavity and atheromatous plaques. Thirty-five patients who underwent carotid endarterectomy were enrolled in this study. Prior to the vascular surgery, a clinical periodontal exam was conducted, and samples of blood, saliva and subgingival biofilm were collected. During endarterectomy, a sample of the atheromatous plaque was retrieved. Serum samples were assayed with high sensitivity Multiplex assay for seventeen Th17 biomarkers. Saliva, subgingival biofilm and atheromatous plaque samples were submited to quantitative PCR for ten periodontal pathogens. This study was able to detect several circulating inflammatory markers, indicating the systemic inflammatory burden as a characteristic of this population. T. forsythia was the more frequent microorganism found in atheromatous samples (37% of the samples). T. forsythia titres in atheromatous samples were positively correlated with serum levels of IL-7, IL-6, IL-17, IL-13, IL-12p70, IFN- ?, GCS-F (p<0.05) and IL-10 (p<0.01). Circulating levels of IL-2 were positively correlated with salivary titres of P. intermedia, P. endodontalis (p<0.05) and T. denticola (p<0.01). Circulating levels of TNF-? were positively correlated with salivary titres of P. endodontalis (p<0.01). Subgingival levels of P. endodontalis were positively correlated with IL-2 (p<0.05). Periodontal inflammation (PISA) was positively correlated with IL-2 (p<0.05). The co-existence of common periodontal pathogens in the oral cavity and in atheromatous plaque is associated with a systemic inflammatory state that could be relevant to understanding the mechanisms linking periodontitis to CVD.

O transtorno de humor bipolar (THB) é uma condição incapacitante e caracterizada pela presença de episódios de humor associados a alterações de cognição e de comportamento. Indivíduos com diagnóstico de THB estão particularmente propensos a múltiplas condições metabólicas. Em uma parcela dos pacientes acometidos pela doença observa-se a neuroprogressão do quadro, com alterações no campo da neuroimagem e de biomarcadores – citocinas inflamatórias, estresse oxidativo e neurotrofinas. Tais fatores parecem também relacionar-se ao aumento do risco cardiovascular (RCV) observado nessa população, visto que a doença cardiovascular (DCV) constitui a principal causa de morte em pacientes com THB. Mesmo conhecendo tal estatística, há escassez de literatura científica abordando avaliação cardiovascular em pacientes bipolares. Dessa forma, a presente tese tem o objetivo de melhorar o entendimento da associação entre neuroprogressão e doença cardiovascular. Para tal, inicialmente conduzimos uma revisão da literatura englobando variáveis associadas ao estadiamento e à neuroprogressão, sobretudo aspectos que se referem a biomarcadores, neuroimagem, cognição, funcionalidade e resposta ao tratamento. Em seguida, foi realizado estudo clínico com o objetivo de avaliar a prevalência de doença aterosclerótica coronariana através do uso do escore de cálcio coronariano (ECC) em pacientes ambulatoriais bipolares tipo 1. Os pacientes incluídos eram bipolares tipo 1, todos eutímicos e tendo assinado o termo de consentimento. Os escores de cálcio foram adquiridos utilizando um scanner Aquilion 64 CXL (Toshiba Medical Systems) e a quantificação realizada através do método de Agatston. Em nosso estudo verificou-se que pacientes com ECC positivo eram mais velhos (média 55.2 anos; p=0.001) e tinham uma média maior de internações psiquiátricas prévias (media 4.7; p=0.04) quando comparados ao grupo com ECC negativo, além de também haver uma associação positiva entre ECC e número de internações psiquiátricas prévias entre toda a amostra do estudo (p<0.001). Nossos resultados sugerem a associação entre idade e maiores escores coronarianos, além da relação entre cálcio coronariano e número de internacões psiquiátricas prévias. É possível que este achado relacione-se ao fato de que pacientes em estágios mais avançados da doença tenham maior carga inflamatória que, juntamente com os fatores de risco para DCV, justificaria o aumento do RCV, sugerindo um possível link entre neuroprogressão no THB e aterosclerose coronariana acelerada. / Bipolar disorder (BD) is a disabling condition characterized by the presence of mood episodes associated with changes in cognition and behavior. Individuals diagnosed with BD are particularly prone to multiple metabolic conditions. In a portion of the patients affected by the disease the neuroprogression is observed, with alterations in the field of neuroimaging and of biomarkers - inflammatory cytokines, oxidative stress and neurotrophins. These factors also seem to be related to the increased cardiovascular risk (CVR) observed in this population, since cardiovascular disease (CVD) is the main cause of death in patients with BD. Even knowing this statistic, there is a paucity of scientific literature addressing cardiovascular evaluation in bipolar patients. Thus, the present thesis aims to improve the understanding of the association between neuroprogression and cardiovascular disease. To this objective, we initially conducted a literature review encompassing variables associated with staging and neuroprogression, especially aspects that refer to biomarkers, neuroimaging, cognition, functionality and response to treatment. Afterwards, a clinical study was performed to evaluate the prevalence of coronary atherosclerotic disease through the use of coronary calcium score (CCS) in outpatient bipolar type 1 patients. The patients included were diagnosed as BD type 1, all of them euthymic and signed the consent form. Calcium scores were acquired using an Aquilion 64 CXL scanner (Toshiba Medical Systems) and quantification performed using the Agatston method. In our study, patients with CCS positive were older (mean 55.2 years; p = 0.001) and had a higher mean of previous psychiatric hospitalizations (mean 4.7, p = 0.04) when compared to the CCS negative group, and there was also a positive association between CCS and number of previous psychiatric hospitalizations among the entire study sample (p<0.001). Our results suggest the association between age and higher coronary scores, as well as the relationship between coronary calcium and the number of previous psychiatric hospitalizations. It is possible that this finding is related to the fact that patients in more advanced stages of the disease have a higher inflammatory load that, together with the risk factors for CVD, would justify the increase of CVR, suggesting a possible link between neuroprogression in BD and accelerated coronary atherosclerosis.

A relação entre periodontite e doenças cardiovasculares (DCV) tem sido amplamente discutida, embora os mecanismos de interação não estejam claros. Foi sugerido que pacientes com periodontite apresentam inflamação sistêmica e um pequeno aumento no risco cardiovascular. Patógenos periodontais foram encontrados em placas de ateroma, mas a influência destes microrganismos na aterosclerose ainda não é compreendida. O objetivo primário deste estudo foi delinear o perfil inflamatório sistêmico de pacientes submetidos à endarterectomia carotídea. Os objetivos secundários foram associar o perfil inflamatório dos participantes à condição periodontal e à presença de patógenos orais encontrados na cavidade oral e em placas de ateroma. Trinta e cinco pacientes submetidos à endarterectomia carotídea foram incluídos neste estudo. Antes da cirurgia vascular, um exame clínico periodontal foi realizado e foram coletadas amostras de sangue, saliva e biofilme subgengival. Durante a endarterectomia, uma amostra da placa de ateroma foi coletada. As amostras de soro foram testadas com o ensaio imunoenzimático de alta sensibilidade Multiplex para dezessete marcadores de células Th17. Amostras de saliva, biofilme subgengival e placa de ateroma foram submetidas ao PCR quantitativo para avaliação de dez patógenos periodontais. Este estudo foi capaz de detectar vários marcadores inflamatórios circulantes, o que indica a presença de inflamação sistêmica como uma característica da população. T. forsythia foi o microrganismo mais frequentemente encontrado em amostras de ateroma (37% das amostras). Níveis de T. forsythia em amostras de ateroma foram positivamente correlacionados com os níveis séricos de IL-7, IL-6, IL-17, IL-13, IL-12p70, IFN-?, GCS-F (p<0,05) e IL-10 (p<0,01). Níveis séricos de IL-2 foram positivamente correlacionados com os concentrações salivares de P. intermedia, P. endodontalis (p<0,05) e T. denticola (p<0,01). Níveis séricos de TNF-? foram positivamente correlacionados com concentrações salivares de P. endodontalis (p<0,01). Concentrações de P. endodontalis em amostras subgengivais foram correlacionadas positivamente com IL-2 (p<0,05). A inflamação periodontal (PISA) foi positivamente correlacionada com IL-2 (p<0,05). A coexistência de patógenos periodontais comuns na cavidade oral e na placa de ateroma está associada a um estado inflamatório sistêmico, o que poderia ser relevante para a compreensão dos mecanismos que ligam periodontite com DCV. / The relationship between periodontitis and cardiovascular diseases (CVD) has been widely discussed, although the mechanisms of interaction are not clear. It has been suggested that patients with periodontitis exhibit systemic inflammation and mild increase in future cardiovascular risk. Periodontal pathogens have been found in atheromatous plaques, but their exact role in atherosclerosis are not yet undertstood. The primary aim of this study was to screen the systemic inflammation profile in patients undergoing carotid endarterectomy. The secondary aims were to associate participant\'s inflammatory profiles with periodontal status and the presence of periodontal pathogens found in oral cavity and atheromatous plaques. Thirty-five patients who underwent carotid endarterectomy were enrolled in this study. Prior to the vascular surgery, a clinical periodontal exam was conducted, and samples of blood, saliva and subgingival biofilm were collected. During endarterectomy, a sample of the atheromatous plaque was retrieved. Serum samples were assayed with high sensitivity Multiplex assay for seventeen Th17 biomarkers. Saliva, subgingival biofilm and atheromatous plaque samples were submited to quantitative PCR for ten periodontal pathogens. This study was able to detect several circulating inflammatory markers, indicating the systemic inflammatory burden as a characteristic of this population. T. forsythia was the more frequent microorganism found in atheromatous samples (37% of the samples). T. forsythia titres in atheromatous samples were positively correlated with serum levels of IL-7, IL-6, IL-17, IL-13, IL-12p70, IFN- ?, GCS-F (p<0.05) and IL-10 (p<0.01). Circulating levels of IL-2 were positively correlated with salivary titres of P. intermedia, P. endodontalis (p<0.05) and T. denticola (p<0.01). Circulating levels of TNF-? were positively correlated with salivary titres of P. endodontalis (p<0.01). Subgingival levels of P. endodontalis were positively correlated with IL-2 (p<0.05). Periodontal inflammation (PISA) was positively correlated with IL-2 (p<0.05). The co-existence of common periodontal pathogens in the oral cavity and in atheromatous plaque is associated with a systemic inflammatory state that could be relevant to understanding the mechanisms linking periodontitis to CVD.

Introduction. L’Enquête Littoral Souffle Air Biologie Environnement (ELISABET) a pour objectif général l’étude de la santé respiratoire et cardiovasculaire dans les communautés urbaines de Lille (CUDL) et Dunkerque (CUD). Les objectifs spécifiques de cette thèse sont d’étudier : (i) la prévalence et le sous-diagnostic des troubles ventilatoires obstructifs (TVO), (ii) l’évolution de la prévalence des principaux facteurs de risque cardiovasculaire (FDRCV) dans la CUDL entre 1986 et 2013, (iii) les interactions entre deux biomarqueurs de l’asthme (fraction exhalée du monoxyde d’azote (FENO) et taux d’éosinophiles sanguin (S-eos)) et le statut tabagique, (iv) le rôle de médiateur de l’inflammation chronique de bas-grade dans la relation entre diabète et baisse de la fonction pulmonaire, et (v) l’impact à court terme de la pollution atmosphérique sur la fonction respiratoire.Méthodes. Les 3276 participants (âgés de 40 à 65 ans) à l’enquête transversale en ELISABET ont été sélectionnés à partir de listes électorales par échantillonnage aléatoire et inclus entre janvier 2011 et novembre 2013. Un questionnaire détaillé, des explorations fonctionnelles respiratoires et un prélèvement sanguin ont été effectués. (i) Les TVO ont été définis par un rapport du volume expiratoire maximal à la première seconde (VEMS) sur la capacité vitale forcée (CVF) inférieur à 0.70 ou à la limite inférieure de la normale calculée à partir des dernières équations de référence disponibles. (ii) La prévalence des principaux FDRCV a été estimée à partir d’échantillons représentatifs de la population de la CUDL issus des enquêtes MONICA1986-88, MONICA1995-96, MONALISA2005-07 et ELISABET2011-13. (iii) L’asthme allergique a été défini comme un asthme (auto-déclaration, et sifflements dans la poitrine dans les 12 derniers mois ou prise de traitement) avec terrain atopique. (iv) Le diabète était défini par la prise d’un traitement antidiabétique ou une glycémie à jeun ≥ 1.26 g/L ou des valeurs d’hémoglobine A1c ≥ 6.5%. L’inflammation chronique a été mesurée par la Protéine C réactive ultra-sensible (CRPus). Une analyse de médiation a été conduite sur un échantillon de sujets sans pathologie respiratoire ou athérosclérotique. (v) Les valeurs des particules inférieures à 10 µm (PM10) et du dioxyde d'azote (NO2) ont été fournies par les stations de mesures ATMO des CUDL et CUD.Principaux résultats. (i) La prévalence des TVO s’étendait de 9.5% à 16% (dépendant du centre et de la définition utilisée) ; le taux de sous-diagnostic était élevé (environ 75 %). (ii) La prévalence des principaux FDRCV diminuait régulièrement sur une période de 25 ans, à l'exception de l'usage du tabac chez les femmes, du diabète chez les hommes (tous deux stables) et de la surcharge pondérale chez les hommes (augmentée). (iii) Une interaction positive entre le statut tabagique et l'asthme allergique a été observée dans les modèles expliquant le FENO (p = 0,003) et les S-eos (p = 0,001). Ainsi, les participants souffrant d'asthme allergique avaient (comparés à ceux n’en souffrant pas) des valeurs plus élevées de FENO (+ 63,4 %, IC95% = [39; 92]) et de S-eos (+ 63,2 % [38,2; 92,7]) chez les non-fumeurs, mais pas chez les fumeurs actuels. (iv) Le diabète était associé à une diminution des pourcentages prédits du VEMS (-3.5% [-5.8; -1.3]) et de la CVF (-3.6% [-5.9; -1.3]). La force de ces associations diminuait (-3.1% [-5.4; -0.9] pour les deux) après ajustement sur la CRPus. Ainsi, la part médiée de la CRPus valait 12% [2.4; 37] et 13% [3.7; 39.4] pour le VEMS et la CVF, respectivement. (v) Les mesures de PM10 et NO2 semblaient associées à une diminution du débit expiratoire maximal à 25 % de la CVF (résultat préliminaire).Conclusion. Les données de l’enquête ELISABET ont permis l’étude de la prévalence des TVO et des principaux FDRCV au sein de notre population d’étude. Elles ont également permis d’obtenir des résultats originaux à partir d’études cliniques et physiopathologiques. / Introduction. The general goal of the ELISABET (Enquête Littoral Souffle Air Biologie Environnement) survey is to study the respiratory and cardiovascular health in two urban areas in northern France (Lille and Dunkirk). The specific objectives of this thesis are to study: (i) the prevalence and underdiagnosis of airway obstruction (AO), (ii) long-term time trends in the prevalence of cardiovascular risk factors between 1986 and 2013 in the Lille urban area, (iii) the relationships between both the fractional exhaled nitric oxide (FENO) and the blood eosinophil count (B-eos) on one hand and asthma and atopy on the other, according to smoking status, (iv) whether low-grade systemic inflammation (as measured by the level of high sensitivity-C-reactive protein, hs-CRP) mediated the relationship between diabetes and lung function, and (v) the short-term impact of atmospheric pollution on lung function.Methods. The 3276 participants (aged from 40 to 64) in the 2011-2013 ELISABET cross-sectional survey were selected from electoral rolls by random sampling, and recruited between January 2011 and November 2013. A detailed questionnaire, lung function tests, and a blood sample collection were performed. (i) AO was defined by a forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) ratio below 0.70 or below the lower limit of normal calculated by the most recent reference equations of the Global Lung Initiative. (ii) The prevalence of the main cardiovascular risk factors was estimated from representative samples inhabitants of Lille urban area from MONICA1986-88, MONICA1995-96, MONALISA2005-07 and ELISABET2011-13 surveys. (iii) Allergic asthma was defined as asthma (a self-report of physician-diagnosed asthma, and wheezing in the previous 12 months or the use of asthma medications) with atopy. (iv) Diabetes mellitus was defined as ongoing diabetes treatment or a fasting blood glucose level ≥1.26 g/L or a hemoglobin A1c value ≥6.5%. A mediation analysis was performed to assess and quantify the hs-CRP level as a mediator of the relationship between diabetes and lung function from a sample of participants without self-reported pulmonary and atherosclerotic disease. (v) Measurements of particles less than 10 mm in diameter (PM10) and nitrogen dioxide (NO2) were provided by measuring stations ATMO in the two urban areas.Main results. (i) The prevalence of AO in northern France ranged from 9.5 to 16.0%, depending on the centre and definition used; the underdiagnosis rate was high (around 75%). (ii) A steady decline in the prevalence of cardiovascular risk factors over a 25-year period was observed, with the exception of tobacco use in women, prevalence of diabetes in men (both of which remained stable) and prevalence of overweight in men (which increased). (iii) A positive interaction between smoking status and allergic asthma was observed in multivariate models explaining FENO (p=0.003) and B-eos (p=0.001). Thus, compared to those without allergic asthma, participants with allergic asthma had higher FENO values (+63.4%, 95%CI=[39; 92]) and higher B-eos (+63.2% [38.2; 92.7]) in never and former smokers, but not in current smokers. (iv) Diabetes was associated with FEV1 (-3.5% [-5.8; -1.3]) and FVC (-3.6% [-5.9; -1.3]). Strength of both latter associations fell to -3.1% [-5.4; -0.9] after adjustment for hs-CRP. Hence, the proportion of the effect that is mediated by hs-CRP was 12% [2.4; 37] and 13% [3.7; 39.4] for FEV1 and FVC, respectively. (v) Measurements of PM10 and NO2 seemed to be associated with lower values of the expiratory flow at 25% of the FVC (preliminary result).Conclusion. Data from the ELISABET survey have allowed the study of the prevalence of AO and the main cardiovascular risk factors in our population. They also allowed obtaining original results from clinical and pathophysiological studies.

O transtorno de humor bipolar (THB) é uma condição incapacitante e caracterizada pela presença de episódios de humor associados a alterações de cognição e de comportamento. Indivíduos com diagnóstico de THB estão particularmente propensos a múltiplas condições metabólicas. Em uma parcela dos pacientes acometidos pela doença observa-se a neuroprogressão do quadro, com alterações no campo da neuroimagem e de biomarcadores – citocinas inflamatórias, estresse oxidativo e neurotrofinas. Tais fatores parecem também relacionar-se ao aumento do risco cardiovascular (RCV) observado nessa população, visto que a doença cardiovascular (DCV) constitui a principal causa de morte em pacientes com THB. Mesmo conhecendo tal estatística, há escassez de literatura científica abordando avaliação cardiovascular em pacientes bipolares. Dessa forma, a presente tese tem o objetivo de melhorar o entendimento da associação entre neuroprogressão e doença cardiovascular. Para tal, inicialmente conduzimos uma revisão da literatura englobando variáveis associadas ao estadiamento e à neuroprogressão, sobretudo aspectos que se referem a biomarcadores, neuroimagem, cognição, funcionalidade e resposta ao tratamento. Em seguida, foi realizado estudo clínico com o objetivo de avaliar a prevalência de doença aterosclerótica coronariana através do uso do escore de cálcio coronariano (ECC) em pacientes ambulatoriais bipolares tipo 1. Os pacientes incluídos eram bipolares tipo 1, todos eutímicos e tendo assinado o termo de consentimento. Os escores de cálcio foram adquiridos utilizando um scanner Aquilion 64 CXL (Toshiba Medical Systems) e a quantificação realizada através do método de Agatston. Em nosso estudo verificou-se que pacientes com ECC positivo eram mais velhos (média 55.2 anos; p=0.001) e tinham uma média maior de internações psiquiátricas prévias (media 4.7; p=0.04) quando comparados ao grupo com ECC negativo, além de também haver uma associação positiva entre ECC e número de internações psiquiátricas prévias entre toda a amostra do estudo (p<0.001). Nossos resultados sugerem a associação entre idade e maiores escores coronarianos, além da relação entre cálcio coronariano e número de internacões psiquiátricas prévias. É possível que este achado relacione-se ao fato de que pacientes em estágios mais avançados da doença tenham maior carga inflamatória que, juntamente com os fatores de risco para DCV, justificaria o aumento do RCV, sugerindo um possível link entre neuroprogressão no THB e aterosclerose coronariana acelerada. / Bipolar disorder (BD) is a disabling condition characterized by the presence of mood episodes associated with changes in cognition and behavior. Individuals diagnosed with BD are particularly prone to multiple metabolic conditions. In a portion of the patients affected by the disease the neuroprogression is observed, with alterations in the field of neuroimaging and of biomarkers - inflammatory cytokines, oxidative stress and neurotrophins. These factors also seem to be related to the increased cardiovascular risk (CVR) observed in this population, since cardiovascular disease (CVD) is the main cause of death in patients with BD. Even knowing this statistic, there is a paucity of scientific literature addressing cardiovascular evaluation in bipolar patients. Thus, the present thesis aims to improve the understanding of the association between neuroprogression and cardiovascular disease. To this objective, we initially conducted a literature review encompassing variables associated with staging and neuroprogression, especially aspects that refer to biomarkers, neuroimaging, cognition, functionality and response to treatment. Afterwards, a clinical study was performed to evaluate the prevalence of coronary atherosclerotic disease through the use of coronary calcium score (CCS) in outpatient bipolar type 1 patients. The patients included were diagnosed as BD type 1, all of them euthymic and signed the consent form. Calcium scores were acquired using an Aquilion 64 CXL scanner (Toshiba Medical Systems) and quantification performed using the Agatston method. In our study, patients with CCS positive were older (mean 55.2 years; p = 0.001) and had a higher mean of previous psychiatric hospitalizations (mean 4.7, p = 0.04) when compared to the CCS negative group, and there was also a positive association between CCS and number of previous psychiatric hospitalizations among the entire study sample (p<0.001). Our results suggest the association between age and higher coronary scores, as well as the relationship between coronary calcium and the number of previous psychiatric hospitalizations. It is possible that this finding is related to the fact that patients in more advanced stages of the disease have a higher inflammatory load that, together with the risk factors for CVD, would justify the increase of CVR, suggesting a possible link between neuroprogression in BD and accelerated coronary atherosclerosis.

O transtorno de humor bipolar (THB) é uma condição incapacitante e caracterizada pela presença de episódios de humor associados a alterações de cognição e de comportamento. Indivíduos com diagnóstico de THB estão particularmente propensos a múltiplas condições metabólicas. Em uma parcela dos pacientes acometidos pela doença observa-se a neuroprogressão do quadro, com alterações no campo da neuroimagem e de biomarcadores – citocinas inflamatórias, estresse oxidativo e neurotrofinas. Tais fatores parecem também relacionar-se ao aumento do risco cardiovascular (RCV) observado nessa população, visto que a doença cardiovascular (DCV) constitui a principal causa de morte em pacientes com THB. Mesmo conhecendo tal estatística, há escassez de literatura científica abordando avaliação cardiovascular em pacientes bipolares. Dessa forma, a presente tese tem o objetivo de melhorar o entendimento da associação entre neuroprogressão e doença cardiovascular. Para tal, inicialmente conduzimos uma revisão da literatura englobando variáveis associadas ao estadiamento e à neuroprogressão, sobretudo aspectos que se referem a biomarcadores, neuroimagem, cognição, funcionalidade e resposta ao tratamento. Em seguida, foi realizado estudo clínico com o objetivo de avaliar a prevalência de doença aterosclerótica coronariana através do uso do escore de cálcio coronariano (ECC) em pacientes ambulatoriais bipolares tipo 1. Os pacientes incluídos eram bipolares tipo 1, todos eutímicos e tendo assinado o termo de consentimento. Os escores de cálcio foram adquiridos utilizando um scanner Aquilion 64 CXL (Toshiba Medical Systems) e a quantificação realizada através do método de Agatston. Em nosso estudo verificou-se que pacientes com ECC positivo eram mais velhos (média 55.2 anos; p=0.001) e tinham uma média maior de internações psiquiátricas prévias (media 4.7; p=0.04) quando comparados ao grupo com ECC negativo, além de também haver uma associação positiva entre ECC e número de internações psiquiátricas prévias entre toda a amostra do estudo (p<0.001). Nossos resultados sugerem a associação entre idade e maiores escores coronarianos, além da relação entre cálcio coronariano e número de internacões psiquiátricas prévias. É possível que este achado relacione-se ao fato de que pacientes em estágios mais avançados da doença tenham maior carga inflamatória que, juntamente com os fatores de risco para DCV, justificaria o aumento do RCV, sugerindo um possível link entre neuroprogressão no THB e aterosclerose coronariana acelerada. / Bipolar disorder (BD) is a disabling condition characterized by the presence of mood episodes associated with changes in cognition and behavior. Individuals diagnosed with BD are particularly prone to multiple metabolic conditions. In a portion of the patients affected by the disease the neuroprogression is observed, with alterations in the field of neuroimaging and of biomarkers - inflammatory cytokines, oxidative stress and neurotrophins. These factors also seem to be related to the increased cardiovascular risk (CVR) observed in this population, since cardiovascular disease (CVD) is the main cause of death in patients with BD. Even knowing this statistic, there is a paucity of scientific literature addressing cardiovascular evaluation in bipolar patients. Thus, the present thesis aims to improve the understanding of the association between neuroprogression and cardiovascular disease. To this objective, we initially conducted a literature review encompassing variables associated with staging and neuroprogression, especially aspects that refer to biomarkers, neuroimaging, cognition, functionality and response to treatment. Afterwards, a clinical study was performed to evaluate the prevalence of coronary atherosclerotic disease through the use of coronary calcium score (CCS) in outpatient bipolar type 1 patients. The patients included were diagnosed as BD type 1, all of them euthymic and signed the consent form. Calcium scores were acquired using an Aquilion 64 CXL scanner (Toshiba Medical Systems) and quantification performed using the Agatston method. In our study, patients with CCS positive were older (mean 55.2 years; p = 0.001) and had a higher mean of previous psychiatric hospitalizations (mean 4.7, p = 0.04) when compared to the CCS negative group, and there was also a positive association between CCS and number of previous psychiatric hospitalizations among the entire study sample (p<0.001). Our results suggest the association between age and higher coronary scores, as well as the relationship between coronary calcium and the number of previous psychiatric hospitalizations. It is possible that this finding is related to the fact that patients in more advanced stages of the disease have a higher inflammatory load that, together with the risk factors for CVD, would justify the increase of CVR, suggesting a possible link between neuroprogression in BD and accelerated coronary atherosclerosis.

Vascular disease is the leading cause of death and disability worldwide. Incidence, risk factors, and outcome of coronary artery disease have been extensively studied, but there are fewer data on other forms of arterial disease, including carotid, aortic, visceral, and peripheral arterial disease. Although the burden of these diseases may be increasing due to the ageing population, we lack the most basic epidemiological data on which to base clinical decisions on individual patients (short and long-term prognosis); local service provision (current incidence and projected future burden); public health / screening initiatives (age and sex-specific incidence, risk factors, and outcome); and with which to assess current levels of primary prevention (pre-morbid risk factor control). Indeed, it is this lack of data, rather than a lack of treatments that is the greatest barrier to effective prevention. I have contributed to, cleaned, and analysed data from the Oxford Vascular Study, a prospective, population-based study (n=92,728) of all acute vascular events (2002-2012), and the Oxford Plaque Study, a carotid atherosclerosis biobank of over 1000 carotid plaques, in order to study these conditions. For acute aortic disease, I aimed to assess the risk factors associated with acute abdominal aortic aneurysms (AAA) and the population impact of the current UK AAA screening programme; and the incidence, risk factors, outcome, and projected future burden of acute aortic dissection. For acute peripheral arterial disease, I assessed the risk factors associated with premature onset and poor outcome, together with current levels of primary prevention. For symptomatic carotid artery disease, I studied the timing and benefits of surgical intervention in the current era; and went on to assess whether underlying carotid plaque morphology can be used to improve stroke risk stratification and help explain why ocular and cerebral stroke types have vast differences in future ipsilateral stroke risk. I found that compared with the current UK AAA screening strategy (one-off scan for men aged 65), screening of male smokers at 65 and all men at 75 would prevent nearly four-times as many deaths and three-times as many life-years lost with 21% fewer annual scans. I have also shown that incidence of acute aortic dissection is higher than previous estimates, a third of cases are out-of-hospital deaths, and uncontrolled hypertension is the most significant treatable risk factor for this condition. For acute peripheral arterial disease, the presence of multiple atherosclerotic risk factors are associated with premature onset, and severity of ischaemia, pre-morbid renal dysfunction, cardiac failure, and diabetes mellitus are predictive of future limb loss and survival. A significant proportion of acute peripheral events are AF-related in high risk patients who were not pre-morbidly anticoagulated despite having no contraindications and being at low risk of bleeding. Symptomatic carotid artery disease currently accounts for <10% of incident cerebrovascular events, and only 40% of these patients undergo surgical intervention. Due to improvements in medical therapy and on-going delays to intervention, little benefit is currently obtained from intervening in patients with <70% stenosis. Ipsilateral stroke risk is correlated with several carotid plaque features in a time-dependent manner, confirming the potential utility of plaque morphology in risk stratification. In addition, plaques from patients with cerebral events were significantly more unstable and inflammatory than from those with ocular events, helping explain differences in stroke risk between these groups. My findings advance the understanding of these conditions that form the backbone of modern vascular surgical practice, and I hope will improve prevention, clinical management, and outcome for patients with vascular disease.