La stéatose hépatique non-alcoolique (NAFLD) est une altération hépatique fréquente dans le diabète de type 2 (DT2) et est associée à diverses complications telles que la mortalité. L’établissement d’outils de prédiction non-invasifs de NAFLD est primordial. Mon projet de maîtrise avait pour objectif d’établir des marqueurs génétiques de NAFLD dans le DT2 via deux stratégies : 1) une sélection non-ciblée des marqueurs génétiques (SNPs) via la méthode LASSO et 2) une sélection ciblée de SNPs rapportés comme liés à la maladie ou à des altérations associées. Une population de 4098 patients avec DT2 d’origine caucasienne (ADVANCE) a été utilisée. Des données statistiques sommaires d’études pangénomiques ont été exploitées pour sélectionner, via LASSO, les marqueurs génétiques (SNPs) à inclure dans le score de risque polygénique (PRS). J’ai également développé un modèle de 3210 SNPs ajusté par des covariables capable de prédire les taux élevés de ALT (AUC=0,69) et la mortalité non-cardiovasculaire (AUC=0,66). Le criblage du locus candidat PNPLA3-SAMM50 a mis en avant une diversité des associations génétiques aux différentes altérations métaboliques comme les taux de ALT (substitut du diagnostic de NAFLD) (rs2294915, P = 1,83x10-7), à la mortalité non-cardiovasculaire (rs2294917, P = 3,9x10-4) et à l’efficacité de la thérapie intensive antidiabétique chez certains patients de la population (porteurs GG de rs16991236, P=0,007). Mes travaux ont permis de mieux comprendre le fond génétique de NAFLD dans le DT2 et laissent envisager l’établissement d’outils de diagnostic et de suivi de la maladie plus adéquats. / Non-alcoholic fatty liver disease (NAFLD) is a liver disorder more frequent in type 2 diabetes (T2D) and is associated with complications such as mortality. For this reason, establishing non-invasive tools for predicting NAFLD is crucial. My master’s project aimed to establish genetic markers for NAFLD in T2D using two strategies: 1) a non-targeted selection of genetic markers (SNPs) by the LASSO method and 2) a targeted selection of SNPs reported as associated with the disease or its related abnormalities. A population involving 4098 patients with T2D and Caucasian ancestry was used. Summary statistics data of pangenomic studies were exploited for the selection of SNPs to be involved in the polygenic risk score (PRS). I also designed a model of 3210 SNPs adjusted by covariates and able to predict the high rates of ALT (AUC=0.69) and non-cardiovascular death (AUC=0.66). Mapping of the candidate locus PNPLA3-SAMM50 allowed the observation of diversity in terms of genetic association with the metabolic abnormalities such as ALT (surrogate of NAFLD) (rs2294915, P = 1.83x10-7), non-cardiovascular death (rs2294917, P = 3.9x10-4) and the efficiency of the intensive antidiabetic therapy within a subgroup in the population (individuals with GG of rs16991236, P = 0.007). My studies allowed for a better understanding of the genetic background of NAFLD in T2D and open perspectives for establishing more adequate tools for diagnosis and follow-up of the disease.

No description available.

Introduction : La fibrillation auriculaire (FA) est l’arythmie la plus répandue au monde avec une prévalence estimée autour de 1-2% pour la population générale. Il s’agit d’une maladie complexe de causes multifactorielles, telles que la génétique, l’environnement et les habitudes de vie. Il est aussi important de prendre en compte que les risques de FA augmentent drastiquement avec l’âge. La fibrillation auriculaire post-opératoire (POAF) est la complication la plus commune à la suite d’une chirurgie cardiaque. Elle est associée avec une prolongation de la durée d’hospitalisation et à une augmentation du risque d’accident vasculaire cérébral (AVC) et de la mortalité. Il devient donc une priorité d’identifier les individus à risque de POAF et d’AVC causés par la FA, surtout en considérant l’existence d’interventions simples qui peuvent atténuer ces risques, comme certaines thérapies pharmacologiques. Hypothèse : L’hypothèse de ce projet est qu’un score polygénique (PGS) aurait un impact sur l’identification des individus à plus haut risque de FA à la suite d’une chirurgie cardiaque, mais aussi sur l’identification des individus à risque de récidive de FA lors d’un premier épisode de FA après une chirurgie. Objectifs : Ce projet se divise en 2 objectifs principaux. Dans un premier temps, nous cherchons à évaluer la capacité prédictive d’un PGS déjà validé (mais jamais utilisé pour la POAF) pour la POAF après une chirurgie cardiaque dans une population québécoise. Dans un second temps, nous cherchons à évaluer la capacité prédictive du même PGS au niveau de la récidive à distance de la FA chez le sous-groupe de personnes qui ont eu un épisode de POAF. Méthodes : Nous avons inclus 2340 participants de la Biobanque hospitalière de l’Institut de Cardiologie de Montréal (ICM) qui ont subi une chirurgie cardiaque entre 2005 et 2020 et qui n’avaient pas de FA diagnostiquée avant la chirurgie. La POAF a été définie comme une FA survenant jusqu’à 30 jours après la chirurgie. Le génotypage de la cohorte a été effectué à l’aide d’une puce de génotypage pangénomique, suivi d’une imputation avec l’aide du panel de référence TOPMed. Le PGS déjà validé et corrigé pour les principales composantes génétiques (PGS-AF) a été calculé à l’aide des poids d’un PGS publié (identifiant du PGS catalog : PGS000016). L’association entre le PGS-AF et la POAF a été évaluée par une régression logistique avec et sans la correction pour les facteurs de risque cliniques connus de la FA, y compris le score de risque clinique CHARGE-AF. Pour valider la valeur prédictive du PGS-AF indépendamment des prédicteurs cliniques, un indice de reclassement net (NRI) a été calculé. L’association entre le PGS-AF et le CHARGE-AF au niveau de la récidive de FA à distance, à plus de 30 jours après la chirurgie, au sein du sous-groupe de patients atteints de POAF a été évaluée avec un modèle de régression de Cox. Résultats : Sur les 2340 participants inclus dans l’étude rétrospective (80% d’hommes; âgés de 66 ans [59-71] au moment de la chirurgie cardiaque), 871 (37%) ont développé de la POAF. La POAF était plus fréquente après une chirurgie valvulaire que les autres chirurgies cardiaques (43% contre 32%, P<0,001) et avec une augmentation dans le score de risque clinique CHARGE-AF (P<0,001). Le PGS-AF était significativement associé à la POAF (P<0,001; augmentation du risque de POAF de 46% par augmentation de 1 écart-type du PGS-AF; statistique C = 0,61). L’incidence de la POAF était significativement plus élevée chez les patients avec PGS-AF au-dessus du 95e percentile (62%) comparativement aux patients avec PGS-AF en dessous du 95% percentile (36%; ratio de cote 2.3, intervalle de confiance 95% 1.6-3.4; P<0,001). Dans un modèle combinant le PGS-AF avec des prédicteurs cliniques (CHARGE-AF et chirurgie valvulaire), l’association du PGS-AF avec la POAF reste significative (P<0,001). De plus, par rapport à la prédiction clinique uniquement, l’ajout du PGS-AF entraine une amélioration significative du modèle (statistique C de 0,68 contre 0,65; test du rapport de vraisemblance P<0,001; NRI = 35%). Parmi les patients atteints de POAF, 235 (27%) ont développé de la FA au cours d’un suivi médian de 4,4 ans. Le PGS-AF et le CHARGE-AF étaient à la fois associés de manière significative et indépendante à la récidive de FA à distance (P<0,05), où chaque augmentation d’écart-type du PGS-AF augmente le risque de récidive de FA de 19%. Discussion et conclusion : Un score de risque polygénique précédemment validé pour la fibrillation auriculaire (PGS-AF) est significativement associé à la FA survenant comme une complication de la chirurgie cardiaque, indépendamment des prédicteurs de risque cliniques. Bien que la capacité discriminative soit modeste globalement, le PGS-AF permet d’identifier 5% de la population de patients avec risque de POAF 2,3 fois plus élevé, une magnitude d’effet de pertinence clinique. Le PGS-AF est également associé à la récidive à distance de la FA et, s’il est validé, pourrait aider à identifier les patients plus susceptibles de bénéficier d’une anticoagulation à long terme pour prévenir les AVC. Plus globalement, ces données impliquent le risque polygénique pour expliquer la variance de scénarios cliniques complexes tels que les complications chirurgicales. / Introduction: Atrial fibrillation (AF) is the most common arrhythmia in the world with an estimated prevalence of around 1-2% of the general population. It is a complex disease with multifactorial causes, such as genetics, environment, and lifestyle. It is also important to consider that the risk of AF increases drastically with age. Postoperative atrial fibrillation (POAF) is the most common complication following cardiac surgery. It is associated with a prolonged hospital stay length and an increased risk of cerebrovascular accident (CVA) and mortality. It therefore becomes a priority to identify individuals at higher risk of POAF and stroke caused by AF, especially considering the existence of simple interventions that can mitigate these risks, such as certain pharmacological therapies. Hypothesis: The project hypothesis is that a polygenic score (PGS) would have an impact on the identification of individuals at higher risk of AF following cardiac surgery, but also on the identification of individuals at higher risk of recurrence of AF within the subgroup of patients who had a first episode of AF after surgery. Aims: This project is divided into 2 main objectives. First, we seek to assess the predictive ability of an already validated PGS (but never used before for POAF) for POAF after cardiac surgery in a Quebec population. In a second step, we seek to assess the predictive capacity of the same PGS for distant recurrence of AF within the subgroup of people who have had an episode of POAF. Methods: We included 2,340 participants from the Montreal Heart Institute (MHI) hospital Biobank who underwent heart surgery from 2005 to 2020 and did not have an AF diagnosis before surgery. POAF was defined as AF occurring in up to 30 days after surgery. Cohort genotyping was performed using a genome-wide genotyping array, followed by imputation using the TOPMed reference panel. The PGS already validated and corrected for the main genetic components (PGS-AF) was calculated using weights of a published PGS (PGS catalog ID: PGS000016). The association between PGS-AF and POAF was assessed by logistic regression with and without correction for known AF clinical risk factors, including the CHARGE-AF clinical score. To validate the predictive ability of PGS-AF independently of clinical predictors, a net reclassification index (NRI) was calculated. The association between PGS-AF and CHARGE-AF in remote AF recurrence, more than 30 days after cardiac surgery, within the subgroup of patients with POAF was assessed using a Cox Proportional Hazards Model. Results: Of the 2,340 participants included in the retrospective study (80% males; aged 66 years old [59-71] at the time of cardiac surgery), 871 (37%) developed POAF. POAF was more common after valve surgery than other cardiac surgeries (43% vs 32%, P<0.001) and with an increase in the CHARGE-AF clinical risk score (P<0.001). PGS-AF was significantly associated with POAF (P<0.001; POAF risk increased by 46% per each standard deviation increase in PGS-AF; C-statistic = 0.61). The incidence of POAF was significantly higher in patients with PGS-AF above the 95th percentile (62%) compared to patients with PGS-AF below the 95% percentile (36%; odds ratio 2.3, range 95% confidence interval 1.6-3.4; P<0.001). In a model combining PGS-AF with clinical predictors (CHARGE-AF and valve surgery), the association of PGS-AF with POAF remains significant (P<0.001). Moreover, compared to the clinical predictors only, the addition of PGS-AF leads to a significant improvement in the model (C-statistic of 0.68 vs 0.65; likelihood ratio test P<0.001; NRI = 35%). Among patients with POAF, 235 (27%) developed AF during a median follow-up of 4.4 years. PGS-AF and CHARGE-AF were both significantly and independently associated with distant recurrence of AF (P<0.05 for both), where each standard deviation increase in PGS-AF increases the risk of distant AF recurrence by 19%. Discussion and conclusion: A previously validated polygenic risk score for atrial fibrillation (PGS-AF) is significantly associated with AF occurring as a complication of cardiac surgery, independently of clinical risk predictors. Although the discriminative ability is modest overall, the PGS-AF identifies 5% of the patient population with a 2.3 times higher risk of POAF, an effect size of clinical relevance. PGS-AF is also associated with distant recurrence of AF and, if validated, could help identify patients who could most likely benefit from long-term anticoagulation to prevent stroke. More broadly, these data implicate polygenic risk to explain the variance of complex clinical scenarios such as surgical complications.

Introduction: There are no economic evaluations to determine the value of PRSs. The objective of this study was to determine if the addition of a PRS to traditional risk factors to guide statin therapy is a cost-effective intervention for the prevention of primary MI cases in the Ontario healthcare payer perspective. Methods: A PRS cost-effectiveness model was constructed to produce various statin prescription strategies in conjunction with the FRS. Upper PRS thresholds (between 25% to 70%) were set such that individuals falling into them would be eligible for statins while those in lower PRS thresholds (between 1% to 25%) were deemed protected and removed from consideration. The model determined number of incident MIs saved or not saved by statins, costs, quality of life, and the effect of statins on preventing MIs over a 10-year time horizon, discounted at 1.5% annually. One-way sensitivity analysis and a PSA were performed by varying all model parameters. Non-related participants of white British descent from 96,736 participants in the UK Biobank at intermediate risk for cardiovascular disease, determined using the Canadian Cardiovascular Society dyslipidemia guidelines of 2016, were used for the study. Results: The optimal clinical and economic strategy was one whereby the top 70% PRS individuals are eligible for statins, with the lower 5% PRS excluded. A base-case analysis at a PRS cost of $70 produced an ICER of $747,184.10/QALY, ranging from $525,678.90/QALY to $930,144.40/QALY in a one-way sensitivity analysis. In the PSA, the intervention has approximately a 50% probability of being cost-effective at $750,000/QALY. At a genotyping cost of $0, statin strategies guided by PRS dominated standard care when at least 12% of the lower PRS individuals were withheld from statins. When the predictive performance of the PRS is increased, the ICER drops drastically depending on the cost of genotyping and statin strategy. Conclusion: The cost-effectiveness model considers MI cases exclusively and a short, 10-year time horizon which likely overestimate the ICER. However, this study elucidates that the PRS has the potential to be extremely cost-effective in the future. / Thesis / Master of Science (MSc) / Approximately 1 in 3 Canadians live with at least one genetically linked chronic disease. Together, these diseases constitute a large economic burden on the healthcare system and well-being of individuals. Recent advancements in genetics allow risk prediction of developing complex, but common chronic diseases such as cardiovascular disease. Termed as polygenic risk scores, they have the potential to carry beneficial clinical outcomes such as an improved quality of life. However, the economics is not yet understood. This study determined that when targeting heart attacks, approximately $750,000 is required to gain an additional life-year for an adult. Although this may seem high, the result is closer to an upper-limit estimate than the true cost since polygenic risk scores have more benefits than solely for heart attacks. In the future, when accounting for their entire potential, the cost per life-year is likely to be lower, and perhaps even a money-returning investment.

Background The number of liver resections is constantly rising over the last decades. Despite the reduction of overall mortality and morbidity in liver surgery, biliary leakage is still a relevant postoperative complication that can lead to a fatal postoperative course. Aim of this analysis is the identification of specific risk factors for postoperative biliary complications after liver resections and the development of a predictive biliary leakage risk score. Methods A single-center, retrospective analysis of 844 liver resections performed in the Department of Visceral, Thoracic and Vascular Surgery, Technische Universität Dresden, between 1/2013 and 12/2019 is conducted to identify risk factors for postoperative biliary leakage and a risk score for biliary leakage after hepatectomy is established based on multivariate regression. The score has been validated by an independent validation cohort consisting of 142 patients. Results Overall morbidity is 43.1% with 36% surgical complications and an overall mortality of 4.3%. Biliary leakage occurred in 15.8% of patients. A predictive score for postoperative biliary leakage based on age, major resection, pretreatment with FOLFOX/cetuximab and operating time is created. Patients are stratified to low (< 15%) and high (> 15%) risk with a sensitivity of 67.4% and a specificity of 70.7% in development cohort and a specificity of 68.2% and sensitivity of 75.8% in validation cohort. Conclusions The presented score is robust and has been validated in an independent patient cohort. Depending on the calculated risk, prevention or early treatment can be initiated to avoid bile leakage and to improve postoperative course.

Os profissionais da área da saúde que atuam no serviço de atendimento pré-hospitalar podem estar sujeitos a fatores de risco cardiovasculares em razão do estilo de vida adotado e das características do trabalho. O objetivo principal do estudo foi avaliar a influência do plantão de 24 horas sobre a pressão arterial e os fatores de risco para afecções cardiovasculares nesses profissionais. Casuística e Método: Estudo transversal com 154 profissionais (90 enfermeiros, 41 médicos, 23 auxiliares de enfermagem) que atuavam no serviço de atendimento pré-hospitalar: Grupo de Atendimento Médico de Urgência (GRAU-193), Serviço Móvel de Urgência (SAMU-192) e Samu-Vale do Ribeira. Realizou-se medida da pressão arterial casual com aparelho automático validado e considerou-se hipertenso pressão 140/90mmHg e/ou uso de anti-hipertensivos. Procedeu-se a Monitorização Ambulatorial da Pressão Arterial (MAPA), durante o plantão no pré-hospitalar e em dia usual de atividade. Foram analisados o índice de massa corpórea (IMC), a circunferência abdominal (CA), a glicemia, o perfil lipídico e a proteína C reativa. O risco cardiovascular foi calculado pelo Escore de Risco de Framingham (ERF) e avaliada a presença da Síndrome Metabólica. Foram utilizados os instrumentos: Índice de Qualidade de Sono de Pittsburg, Self Report Questionnaire, Inventário de Depressão de Beck, Escala de Estresse no Trabalho e Malasch Burnout Inventory. O nível de significância adotado foi p<0,05, utilizou-se análise univariada e regressão logística para as variáveis significativas. Resultados: As características dos participantes foram: idade 40,9±7,8 anos. Sedentarismo 64,9%, CA alterado 70,2% e IMC sobrepeso/obeso de 65,6%. Alteração de glicose em 11%, colesterol elevado em 11%, LDL-c alto 7,8%, HDL-c alto 11% e triglicérides em 16,2%, proteína C reativa 40,3% nos quartis mais altos. A prevalência da hipertensão arterial pela medida casual no pré-hospitalar foi 33,1% e em dia usual de atividade 13,6%. Na MAPA de 24h no pré-hospitalar 29,3%, dia usual de atividade 22,6%; MAPA da vigília no pré-hospitalar 26,6%, dia usual de atividade 18,5%; MAPA no sono pré-hospitalar 63,0%, dia usual de atividade 42,5%. Houve diferenças significativas nos níveis pressóricos pré-hospitalares em relação ao dia usual de atividade para medida casual sistólica e diastólica (124,9±15,1mmHg/79,0±10,8 mmHg vs. 122,1±14,5mmHg/76,7±10,5mmHg) e na MAPA no período de sono, para a pressão diastólica (110,5±11,5mmHg/72,6±9,5mmHg vs. 111,8±10,8mmHg/67,6±7,9 mmHg). Os fatores associados à hipertensão foram a pela medida casual: HDL-c > 40 mg/dL (Odds Ratio (OR) 0,257; intervalo de confiança (IC) 95%: 0,0810,813) e ERF > 10% (OD: 23,159; IC 95%: 2,029264,378). b) pela MAPA: no período de 24 horas: sexo masculino (OR: 2,717; IC 95%: 1,206-6,122); trabalhar cansado raramente/nunca (OR: 0,197; IC 95%: 0,061-0,638) e às vezes (OR: 0,174; IC 95%: 0,050-0,614); glicemia > 100 mg/dL (OR: 9,983; IC 95%: 1,560-63,881). Para MAPA da vigília: sexo masculino (OR: 3,245; IC 95%: 1,385-7,606); trabalhar cansado raramente/nunca (OR: 0,142; IC 95%: 0,042-0,481); e às vezes (OR: 0,163; IC 95%: 0,045-0,590); glicemia > 100 mg/dL (OR:11,1809; IC 95%: 1,632-76,60) e IMC > 25kg/m2 (OR: 1,101; IC 95%: 1,006-1,206). Para MAPA do sono: IMC > 25kg/m2 (OR: 1,119; IC 95%: 1,021-1,226) e presença de sono diurno (OR: 0,140; IC 95%: 0,065-0,300). O Escore de Risco de Framingham foi médio/alto em 10,6%; Síndrome Metabólica presente em 28,6%, má qualidade de sono em 41,6%, transtornos mentais comuns em 16,2%, depressão em 7,8%, média de estresse no trabalho em 50,1% e Burnout em 29%. Conclusão: houve diferenças pressóricas durante o plantão no serviço pré-hospitalar em relação a um dia usual de atividade, e os profissionais estudados estavam expostos a fatores de risco modificáveis, sendo necessárias mudanças no estilo de vida / Professionals that work in pre-hospital assistance might be subject to the cardiovascular risk factors due to their adopted lifestyle and specific characteristics of their occupation. Casuistic and Method: Transversal study with 154 professionals (90 nurses, 41 physicians, 23 nurse auxiliaries) that work in prehospital: Grupo de Atendimento Médico de Urgência [Group of Emergency Medical Assistance] (GRAU-193), Serviço Móvel de Urgência [Emergency Rescue Service] (SAMU-192) and Samu-Vale do Ribeira. Measures were performed regarding casual blood pressure; it was considered arterial hypertensive pressure (HA) 140/90mmHg and/or use of antihypertensives. The Ambulatorial Monitoring of Blood Pressure (ABPM) was performed during the duty on prehospital and also on casual day of activities. The Body Mass Index (IMC), Abdominal Circumference (CA), glucose, lipids profile and C-reactive protein were analyzed. The cardiovascular risk was used Framingham Risk Score (ERF), Metabolic Syndrome were analyzed. The used tools were: Pittsburg Sleep Quality Index, Self Report Questionnaire, Beck Depression Inventory, Job Stress Scale and Malasch Burnout Inventory. Data were processed on SPSS System v.7.5. The level of significance adopted was p <0,05, univariate analysis was used and the logistic regression was performed for remarkable variables. Results: Age of 40,9 ± 7,8 years. Sedentary lifestyle 64,9%, CA altered 70,2% and IMC overweight/obese of 65,6%. Glucose alteration in 11%, elevated cholesterol in 11%, high LDL-c in 7,8%, high HDL-c in 11% and triglycerides in 16,2%, C-reactive protein in 40,3% on higher quartiles. The prevalence of prehospital HA: 33,1% and casual day of activities 13,6%. ABPM: 24h prehospital 29,3%, casual day of activities 22,6%; ABPM: daytime prehospital 26,6%, casual day of activities 18,5%; ABPM: nighttime prehospital 63,0%, casual day of activities 42,5%. There were significant differences on pressoric levels of prehospital in comparison with casual day of activities for casual measure of systolic and diastolic pressures (124,9±15,1 mmHg/79,0±10,8 mmHg vs. 122,1±14,5 mmHg; /76,7±10,5mmHg), and on ABPM of nighttime period for diastolic pressure (110,5 ± 11,5 mmHg/72,6±9,5 mmHg vs. 111,8±10,8 mmHg/67,6±7,9 mmHg). Factors related with casual HA: HDL-c > 40 mg/dL (Odds Ratio (OR) 0,257; confidence interval (IC) 95%: 0,0810,813) and ERF >10% (OD: 23,159; IC 95%: 2,029264,378). The HA measured by ABPM: on 24 hours period: male gender (OR: 2,717; IC 95%: 1,206-6,122); never/occasionally work tired (OR: 0,197; IC 95%: 0,061-0,638) and sometimes (OR: 0,174; IC 95%: 0,050-0,614); glucose > 100mg/dL (OR: 9,983; IC 95%: 1,560-63,881). For daytime: male gender (OR: 3,245; IC 95%: 1,385-7,606); never/occasionally work tired (OR: 0,142; IC 95%: 0,042-0,481); and sometimes (OR: 0,163; IC 95%: 0,045-0,590); glucose > 100mg/dL (OR: 11,1809; IC 95%: 1,632-76,60) and IMC > 25kg/m2 (OR: 1,101; IC 95%: 1,006-1,206). For nighttime period: IMC > 25kg/m2 (OR: 1,119; IC 95%: 1,021-1,226) and presence of somnolence during day (OR: 0,140; IC 95%: 0,065-0,300). Prevalence of Metabolic Syndrome: 28,6%; Framingham Risk Score: medium/high: 10,6%; poor quality of sleeping 41,6%, common mental disorders: 16,2%, depression: 7,8%, average job stress: 50,1% and Burnout 29%. It might be concluded: that there were pressoric differences during duty on prehospital in comparison with a casual day of activities, and that these professionals are exposed to the modifiable risk factor and need changes in their lifestyles.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / O diabetes mellitus(DM) e as disfunções tireoidianas(DT) são as duas desordens endocrinológicas mais comuns na prática clínica. A DT não reconhecida pode interferir no controle metabólico e adicionar mais risco a um cenário predisponente à doença cardiovascular. O objetivo deste estudo foi avaliar a prevalência da DT em pacientes com diabetes mellitus tipo 1 e tipo 2 (DM1 e DM2) e avaliar o risco cardiovascular em pacientes com DM2 com e sem DT utilizando parâmetros clínicos e laboratoriais. Trata-se de um estudo observacional de corte transversal. Foram avaliados 304 pacientes com DM2 e 82 pacientes com DM1. Os pacientes foram submetidos a um inquérito clínico-demográfico e avaliação laboratorial para determinação do perfil lipídico, glicídico e da função tireoidiana. Os pacientes com DM2 tiveram seus escores de risco cardiovascular em 10 anos determinados pelas equações de Framingham e do UKPDS risk engine. A frequência de disfunção tireoidiana entre os 386 pacientes foi de 14,7%, sendo de 13% nos que não possuíam disfunção prévia. A disfunção mais frequente encontrada foi de hipotireoidismo subclínico, com 13% no DM1 e de 12% no DM2. A prevalência de anticorpos anti-tireoperoxidase (TPO) positivos foi de 10,8%, sendo de14,6% em pacientes com DM1.Foram diagnosticados 44 (11,2%) novos casos de disfunção tireoidiana em pacientes que negavam ou desconheciam terem DT prévia.Destes novos casos, 12,8% em DM1 e 13,1% em DM2.Dos 49 pacientes com DT prévia, 50% dos DM1e 76% dos DM2 estavam compensados. Não foi observada diferença entre as médias do escore de risco de Framingham entre os pacientes DM2 com eutireoidismo e com hipotireoidismo subclínico. Observou-se uma associação entre o hipotireoidismo subclínico e risco cardiovascular nos pacientes com DM2 demonstrado pela diferença estatisticamente significativa entre as médias do escore UKPDS para doença coronariana não-fatal e fatal, acidente vascular cerebral fatal entre os dois grupos (p=0,007; 0,005;0,027 respectivamente). As demais funções tireodianas (hipotireoidismo clínico, hipertireoidismo clínico e subclínico) encontradas não foram analisadas devido ao pequeno número de pacientes em cada grupo.Concluímos que o rastreio da doença tireoidiana entre os pacientes com diabetes mellitus deve ser realizado rotineiramente considerando-se a prevalência de novos casos de DT diagnosticados e o fato de que os pacientes com DM2 e com hipotireoidismo subclínico avaliados possuírem um risco cardiovascular maior. Todavia, concluímos que estudos prospectivos e com maior número de pacientes são necessários para o esclarecimento do impacto da doença tireoidiana no risco cardiovascular do paciente com DM. / Diabetes mellitus and thyroid dysfunction (TD) are the two most common endocrine disorders in clinical practice. The unrecognized TD may adversely affect the metabolic control and add more risk to an already predisposing scenario for cardiovascular diseases. The objective of this study was to evaluate the prevalence of TD in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM) and to evaluate the cardiovascular risk of patients with T2DM with and without thyroid dysfunction using clinical and laboratory parameters. This is an observational cross-sectional study. We evaluated 304 patients with T2DM and 82 patients with T1DM. The patients underwent a clinical-demographic survey and laboratory evaluation to determine the lipid and glycemic profile and thyroid function. Patients with T2DM had their 10 years cardiovascular risk scores determined by Framingham equations and the UKPDS risk engine. The frequency of TD among the 386 patients was 14.7% and 13% who denied previous TD. The most frequently TD was subclinical hypothyroidism, in 13% of patients with T1DM and in 12% of patients with T2DM.The prevalence of anti-TPO antibodies was 10.8%, being more frequently among patients with T1DM (14.6%). Forty-four (11.2%) new cases of TD were diagnosed during the study in patients who denied or were unaware of this clinical condition. Of the 49 patients with prior TD,50% of the T1DM and 76% of T2DM were compensated. No differencies were observed between the mean scores of the Framingham risk among patients with T2DM who had normal thyroid function compared to those with subclinical hypothyroidism. An association between subclinical hypothyroidism and cardiovascular risk in T2DM patients was found by statistically significant difference between the mean UKPDS scores for non-fatal and fatal CHD and fatal stroke between the two groups (p = 0,007;0,005;0027; respectively). The other TD (clinical hypothyroidism, clinical and subclinical hyperthyroidism) found were not analyzed due to the small number of patients in each group.We conclude that screening for thyroid disease among patients with diabetes mellitus should be routinely performed considering the prevalence of new cases diagnosed and the fact that patients with DM2 and subclinical hypothyroidism evaluated had a higher cardiovascular risk. However, prospective studies and with more patients are warranted to determine the impact of thyroid dysfunction in the cardiovascular risk of patients with diabetes.

Os profissionais da área da saúde que atuam no serviço de atendimento pré-hospitalar podem estar sujeitos a fatores de risco cardiovasculares em razão do estilo de vida adotado e das características do trabalho. O objetivo principal do estudo foi avaliar a influência do plantão de 24 horas sobre a pressão arterial e os fatores de risco para afecções cardiovasculares nesses profissionais. Casuística e Método: Estudo transversal com 154 profissionais (90 enfermeiros, 41 médicos, 23 auxiliares de enfermagem) que atuavam no serviço de atendimento pré-hospitalar: Grupo de Atendimento Médico de Urgência (GRAU-193), Serviço Móvel de Urgência (SAMU-192) e Samu-Vale do Ribeira. Realizou-se medida da pressão arterial casual com aparelho automático validado e considerou-se hipertenso pressão 140/90mmHg e/ou uso de anti-hipertensivos. Procedeu-se a Monitorização Ambulatorial da Pressão Arterial (MAPA), durante o plantão no pré-hospitalar e em dia usual de atividade. Foram analisados o índice de massa corpórea (IMC), a circunferência abdominal (CA), a glicemia, o perfil lipídico e a proteína C reativa. O risco cardiovascular foi calculado pelo Escore de Risco de Framingham (ERF) e avaliada a presença da Síndrome Metabólica. Foram utilizados os instrumentos: Índice de Qualidade de Sono de Pittsburg, Self Report Questionnaire, Inventário de Depressão de Beck, Escala de Estresse no Trabalho e Malasch Burnout Inventory. O nível de significância adotado foi p<0,05, utilizou-se análise univariada e regressão logística para as variáveis significativas. Resultados: As características dos participantes foram: idade 40,9±7,8 anos. Sedentarismo 64,9%, CA alterado 70,2% e IMC sobrepeso/obeso de 65,6%. Alteração de glicose em 11%, colesterol elevado em 11%, LDL-c alto 7,8%, HDL-c alto 11% e triglicérides em 16,2%, proteína C reativa 40,3% nos quartis mais altos. A prevalência da hipertensão arterial pela medida casual no pré-hospitalar foi 33,1% e em dia usual de atividade 13,6%. Na MAPA de 24h no pré-hospitalar 29,3%, dia usual de atividade 22,6%; MAPA da vigília no pré-hospitalar 26,6%, dia usual de atividade 18,5%; MAPA no sono pré-hospitalar 63,0%, dia usual de atividade 42,5%. Houve diferenças significativas nos níveis pressóricos pré-hospitalares em relação ao dia usual de atividade para medida casual sistólica e diastólica (124,9±15,1mmHg/79,0±10,8 mmHg vs. 122,1±14,5mmHg/76,7±10,5mmHg) e na MAPA no período de sono, para a pressão diastólica (110,5±11,5mmHg/72,6±9,5mmHg vs. 111,8±10,8mmHg/67,6±7,9 mmHg). Os fatores associados à hipertensão foram a pela medida casual: HDL-c > 40 mg/dL (Odds Ratio (OR) 0,257; intervalo de confiança (IC) 95%: 0,0810,813) e ERF > 10% (OD: 23,159; IC 95%: 2,029264,378). b) pela MAPA: no período de 24 horas: sexo masculino (OR: 2,717; IC 95%: 1,206-6,122); trabalhar cansado raramente/nunca (OR: 0,197; IC 95%: 0,061-0,638) e às vezes (OR: 0,174; IC 95%: 0,050-0,614); glicemia > 100 mg/dL (OR: 9,983; IC 95%: 1,560-63,881). Para MAPA da vigília: sexo masculino (OR: 3,245; IC 95%: 1,385-7,606); trabalhar cansado raramente/nunca (OR: 0,142; IC 95%: 0,042-0,481); e às vezes (OR: 0,163; IC 95%: 0,045-0,590); glicemia > 100 mg/dL (OR:11,1809; IC 95%: 1,632-76,60) e IMC > 25kg/m2 (OR: 1,101; IC 95%: 1,006-1,206). Para MAPA do sono: IMC > 25kg/m2 (OR: 1,119; IC 95%: 1,021-1,226) e presença de sono diurno (OR: 0,140; IC 95%: 0,065-0,300). O Escore de Risco de Framingham foi médio/alto em 10,6%; Síndrome Metabólica presente em 28,6%, má qualidade de sono em 41,6%, transtornos mentais comuns em 16,2%, depressão em 7,8%, média de estresse no trabalho em 50,1% e Burnout em 29%. Conclusão: houve diferenças pressóricas durante o plantão no serviço pré-hospitalar em relação a um dia usual de atividade, e os profissionais estudados estavam expostos a fatores de risco modificáveis, sendo necessárias mudanças no estilo de vida / Professionals that work in pre-hospital assistance might be subject to the cardiovascular risk factors due to their adopted lifestyle and specific characteristics of their occupation. Casuistic and Method: Transversal study with 154 professionals (90 nurses, 41 physicians, 23 nurse auxiliaries) that work in prehospital: Grupo de Atendimento Médico de Urgência [Group of Emergency Medical Assistance] (GRAU-193), Serviço Móvel de Urgência [Emergency Rescue Service] (SAMU-192) and Samu-Vale do Ribeira. Measures were performed regarding casual blood pressure; it was considered arterial hypertensive pressure (HA) 140/90mmHg and/or use of antihypertensives. The Ambulatorial Monitoring of Blood Pressure (ABPM) was performed during the duty on prehospital and also on casual day of activities. The Body Mass Index (IMC), Abdominal Circumference (CA), glucose, lipids profile and C-reactive protein were analyzed. The cardiovascular risk was used Framingham Risk Score (ERF), Metabolic Syndrome were analyzed. The used tools were: Pittsburg Sleep Quality Index, Self Report Questionnaire, Beck Depression Inventory, Job Stress Scale and Malasch Burnout Inventory. Data were processed on SPSS System v.7.5. The level of significance adopted was p <0,05, univariate analysis was used and the logistic regression was performed for remarkable variables. Results: Age of 40,9 ± 7,8 years. Sedentary lifestyle 64,9%, CA altered 70,2% and IMC overweight/obese of 65,6%. Glucose alteration in 11%, elevated cholesterol in 11%, high LDL-c in 7,8%, high HDL-c in 11% and triglycerides in 16,2%, C-reactive protein in 40,3% on higher quartiles. The prevalence of prehospital HA: 33,1% and casual day of activities 13,6%. ABPM: 24h prehospital 29,3%, casual day of activities 22,6%; ABPM: daytime prehospital 26,6%, casual day of activities 18,5%; ABPM: nighttime prehospital 63,0%, casual day of activities 42,5%. There were significant differences on pressoric levels of prehospital in comparison with casual day of activities for casual measure of systolic and diastolic pressures (124,9±15,1 mmHg/79,0±10,8 mmHg vs. 122,1±14,5 mmHg; /76,7±10,5mmHg), and on ABPM of nighttime period for diastolic pressure (110,5 ± 11,5 mmHg/72,6±9,5 mmHg vs. 111,8±10,8 mmHg/67,6±7,9 mmHg). Factors related with casual HA: HDL-c > 40 mg/dL (Odds Ratio (OR) 0,257; confidence interval (IC) 95%: 0,0810,813) and ERF >10% (OD: 23,159; IC 95%: 2,029264,378). The HA measured by ABPM: on 24 hours period: male gender (OR: 2,717; IC 95%: 1,206-6,122); never/occasionally work tired (OR: 0,197; IC 95%: 0,061-0,638) and sometimes (OR: 0,174; IC 95%: 0,050-0,614); glucose > 100mg/dL (OR: 9,983; IC 95%: 1,560-63,881). For daytime: male gender (OR: 3,245; IC 95%: 1,385-7,606); never/occasionally work tired (OR: 0,142; IC 95%: 0,042-0,481); and sometimes (OR: 0,163; IC 95%: 0,045-0,590); glucose > 100mg/dL (OR: 11,1809; IC 95%: 1,632-76,60) and IMC > 25kg/m2 (OR: 1,101; IC 95%: 1,006-1,206). For nighttime period: IMC > 25kg/m2 (OR: 1,119; IC 95%: 1,021-1,226) and presence of somnolence during day (OR: 0,140; IC 95%: 0,065-0,300). Prevalence of Metabolic Syndrome: 28,6%; Framingham Risk Score: medium/high: 10,6%; poor quality of sleeping 41,6%, common mental disorders: 16,2%, depression: 7,8%, average job stress: 50,1% and Burnout 29%. It might be concluded: that there were pressoric differences during duty on prehospital in comparison with a casual day of activities, and that these professionals are exposed to the modifiable risk factor and need changes in their lifestyles.

Le diabète de type 2 (DT2) est devenu de plus en plus une maladie métabolique chronique fréquente, associée à de nombreuses complications micro et macro-vasculaires. Les patients diabétiques ont environ deux fois plus de risque de mort subite d'origine cardiaque (MSC) que ceux normaux. Les interventions pharmacologiques (anti-plaquettaires, anti-hypertenseurs, anti-diabétiques et hypolépimiants) nous semblent les candidats les plus efficaces, accessibles et économiques pour prévenir cet événement à long terme, par contre leurs effets sur la MSC n'ont pas été bien connus. Nous visons à estimer leur impact sur la santé publique et à optimiser leur utilisation chez les DT2, grâce à des études d'analyse, de synthèse et de modélisation.Ce travail inclut trois étapes: premièrement, de construire un score de risque permettant de prédire le risque de MSC dans le DT2 en utilisant les bases de données INDANA. Deuxièmement, d'effectuer des méta-analyses/revues systématiques de différentes stratégies thérapeutiques afin d'estimer leurs effets sur le risque de MSC. Enfin, de simuler différentes stratégies sur une population virtuelle réaliste (PVR) des diabétiques français et d'intégrés les résultats obtenus sur cette plate-forme pour estimer le risque de MSC avec et sans traitements. Cette simulation permet d'estimer leurs bénéfices absolus, par le nombre d'événements prévus (Number of Events Prevented, NEP) et le nombre de patients à traiter pour prévenir une MSC (Number Needed to Treat, NNT). Nous avons construit un score incluant 7 facteurs de risque de MSC chez les patients atteints d'hypertension artérielle (+/- diabète) et collecté les meilleures estimations sur l'effet des médicaments. Notre simulation sur la PVR générée a suggéré que chez 10% des patients ayant le risque de MSC prédit le plus haut, la co-prescription de l'inhibiteurs de l'enzyme de conversion-l'aspirine-l'empagliflozine permettait de prévenir une MSC sur 57 individus traités dans les 5 ans. Le chiffre correspondant pour toute la PVR était 135. Nous concluons que cette approche pourrait aider à mieux transposer les résultats des essais cliniques à la pratique ; et à faciliter la décision clinique aux niveaux populationnel et individuel / Type 2 diabetes (T2D) has increasingly become a common metabolic condition, associated with numerous micro and macro-vascular complications. Diabetic patients are at about two-time higher risk of sudden cardiac death (SCD), compared to non-diabetic ones. Pharmacologic intervention (anti-platelet, anti-hypertensive, lipid lowering, and to a lesser extent, anti-diabetic agents) appear to be the most efficient and economic candidate to prevent this event at long term, yet treatment effects have not well addressed. We aimed to optimize their use and estimate their impact on public health via analysis, synthesis and modeling studies.This work engaged three phases: First, to construct a risk score to predict SCD risk in T2D from the INDANA database. Second, to perform the meta-analyses/systematic reviews of different therapeutic strategies in order to estimate their effects on SCD risk. Finally, to simulate therapeutic strategies on a generated French diabetic realistic virtual population (RVP) of T2D, by estimating the occurrence of SCD with and without treatments, thus their absolute benefits, through the Number of Events Prevented (NEP) due to treatment, and the Number of patients Needed to be Treated to prevent one SCD (NNT).We built a 7-risk factor to predict 5-year risk of SCD in patients with hypertension (+/-diabetes) and collected the best evidence on drugs’ effects. Integrating and simulating altogether on a generated French diabetic RVP suggested that for every 57 individuals of the 10% highest predicted SCD risk, the co-prescription of angiotensin converting enzyme inhibitor-aspirin-empagliflozin could prevent one SCD in 5 years. For the whole population, the corresponding number was 135. In perspectives, this approach could help better transposing clinical trial results into practice and facilitating clinical decision at both public health and individual levels

The main expansion of the discovery of genetic variants associated with complex diseases has occurred during the last decade. This expansion has been accompanied, and in some sense motivated, by the desire to use this information to improve the predictive capacity of many diseases with an unidentified familial component, including coronary heart disease (CHD), with the aim of translating this genetic knowledge into clinical practice. This doctoral thesis is structured in two lines of investigation that address distinct aspects of this issue, first to evaluate the possible role of genetic variation in a candidate gene in modulating CHD risk, and second to evaluate whether genetic information can be used to improve risk assessment tools used in clinical practice. In the first research line (described in Part I), we investigate the contribution of genetic variation in one of the most widely-studied genes in cardiovascular genetics, ESR1, which encodes the Oestrogen receptor α protein. We provide a solid meta-analysis of evidence regarding the most widely-studied variant in this gene and we further explore the role of a broad range of common and uncommon variants in this gene in CHD risk. Using these approaches, we find no evidence of association between the genetic variants studied and CHD risk. However, although we can confidently accept that common genetic polymorphisms are not associated with cardiovascular disease, we cannot discard the possibility that other types of variation in this gene (for instance epigenetic variation) could modify susceptibility to cardiovascular disease, or that other elements of this pathway are associated with an increased risk of CHD. In this research I have provided a reliable answer to this long running unanswered question in cardiovascular genetics, allowing research to re-focus on other elements of this system or other pathways. In the second line, we explored the possible utility of genetic information obtained from genome-wide association studies (GWAS) in prediction of 10-year risk of CHD events by adding this information to cardiovascular risk functions. We have followed the recommendations proposed by the American Heart Association for evaluating the utility of novel biomarkers in clinical practice, and have demonstrated that although the magnitudes of the effects of these genetic variants on CHD risk are modest, there is a tendency towards improvement in the capacity of the risk functions to predict future CHD events. The translation of genetic information into clinical practice was one of the main motivations for the investment in genome-wide association studies, and my research represents one of the first efforts to explore this possibility. / L’expansió principal pel que fa al descobriment de variants genètiques associades amb malalties complexes s’ha dut a terme durant la última dècada. Aquesta expansió ha estat acompanyada, i d’alguna forma motivada, pel desig d’usar aquesta informació per millorar la capacitat de predicció d’aquelles malalties on hi és present un cert component familiar però en les que no es coneixien les variants que conferien un major risc de patir la malaltia, entre elles la cardiopatia isquèmica (CI). La present tesis doctoral està estructurada en dues línies d’investigació que avaluen el possible rol d’un gen candidat en la susceptibilitat de la CI i també avalua la millora en la capacitat de predicció d’un esdeveniment coronari de les eines usades habitualment en la pràctica clínica mitjançant la inclusió d’informació genètica. Més concretament, la primera línea d’investigació es centra en la contribució de la variació genètica en un dels gens més estudiats en relació amb CI: el gen que codifica pel receptor d’estrogens alfa (ESR1). En aquesta línea hem proveït un sòlid meta-anàlisis entre la variant més àmpliament estudiada d’aquest gen i risc coronari i també hem explorat el paper de la majoria de les variants comunes descrites en aquest gen i risc de CI. Mitjançant cap dels anàlisis hem trobat evidència d’associació entre les variants genètiques en aquest gen i el risc de CI. No obstant això, i encara que podem acceptar que les variants genètiques comunes d’aquest gen no estan associades amb esdeveniments coronaris, no podem descartar que altres tipus de variació en aquest gen (com per exemple variació epigenètica) pugui estar modificant la susceptibilitat a patir un esdeveniment coronari, ni tampoc que altres elements de la mateixa cadena de senyalització estiguin associats amb la malaltia. En la segona línea d’investigació, hem explorat el possible paper de les variants genètiques, obtingudes mitjançant estudis d’associació global del genoma (GWAS), en la millora de la capacitat de predicció a 10 anys dels esdeveniments coronaris, mitjançant la seva addició en les funcions de risc cardiovascular clàssiques. Hem seguit les recomanacions proposades per la American Heart Association per l’avaluació en la pràctica clínica de nous biomarcadors, i hem demostrat que, tot i que la magnitud de l’associació d’aquestes variants és modesta, hi ha una tendència cap a la millora de la capacitat de predicció de les funcions de risc.