Cardiovascular diseases (CVD) are the leading cause of death, and the underlying atherosclerotic process has its origin in youth. Physical activity lowers future CVD risk, however few adolescents achieve the recommended minimum amount of daily activity and interventions fail to meaningfully increase activity levels in this group. It is therefore essential to identify how small volumes of exercise can be optimised for the primary prevention of CVD. The purpose of this thesis is to identify the influence of exercise intensity on vascular health outcomes in adolescents, and to assess the efficacy of 2 weeks of low volume, high-intensity interval training on CVD risk factors in this population. Chapter 4 demonstrates that a single bout of high-intensity interval exercise (HIIE) performed one hour before a high fat meal elicits comparable reductions in postprandial lipaemia as a work-matched bout of moderate-intensity exercise (MIE) in girls. However, neither exercise attenuated postprandial lipaemia in the boys. Additionally, HIIE elicited a superior increase in postprandial fat oxidation and decrease in blood pressure, and this was sex independent. These findings are furthered in Chapter 5, which identified that accumulating HIIE, but not MIE, favourably modulates glycaemic control, postprandial blood pressure and fat oxidation in adolescents irrespective of sex. A high fat meal was included in Chapter 6 in order to impair vascular function via oxidative stress. Postprandial vascular function was preserved following MIE, but improved after HIIE, and these changes were not related to changes in postprandial lipaemia or total antioxidant status. Chapter 7 addressed the time course of the changes in vascular function post exercise, and identified that HIIE promotes superior changes in vascular function than MIE. Finally, Chapter 8 identified that 2 weeks of high-intensity interval training improved novel (endothelial function and heart rate variability), but not traditional CVD factors in adolescent boys and girls. However, most of these favourable changes were lost 3 days after training cessation. Thus, this thesis demonstrates that vascular health outcomes are positively associated with exercise intensity. Given that HIIE was perceived to be more enjoyable than MIE in Chapters 4, 6 and 7, performing HIIE appears to be an effectual and feasible alternative to MIE for the primary prevention of CVD.

The primary objective of this study is to evaluate the industry impact of a hypothetical Foot and Mouth Disease (FMD) outbreak in the Texas High Plains using alternative animal tracing levels. To accomplish this objective, an epidemiological disease spread model, AUSSPREAD, is used to simulate the FMD outbreak and an economic model is used to examine the impacts of different animal identification levels in cattle. The different levels of animal identification relate to the model?s ability to trace back the subsequent infected and/or dangerous contacts with which the initial outbreak herd has been in contact. The study examines direct disease management costs (slaughter, euthanasia, disposal, surveillance, and cleaning disinfection), forgone income, and other indirect costs (indemnity payments and welfare slaughter) for outbreaks originating from a large beef operation, a feedlot, and a saleyard across subsequent tracing periods from 1 to 10 days. Welfare slaughter and quarantine costs were estimated for the best and worst outbreaks from the feedlot operation. It is noteworthy that total direct costs of a FMD outbreak would be more extensive than the current study's calculations, which only analyzed the direct disease management costs. The increased days to trace dangerous contacts presented overall increases in outbreak losses over each outbreak scenario. Although outcome averages appear insensitive at times under the assumptions applied, the epidemiological model presented the possibility that traceability could reduce the risk of extreme outcomes in respect to the overall distribution of losses. For each cattle operation, the outbreaks stayed consistent or marginally increased with their respective average costs, but their maximum losses rose steadily, across the trace periods examined. The impact of increased traceability and decreased outbreak length can be justified in affecting FMD outbreak costs in a positive manner. The results provide the industry with estimations of different outbreak scenarios which can be used to inform the decision on the NAIS system. Longer tracing periods, larger simulations (by iteration), and further study of the model is necessary in order to more accurately imitate FMD outbreaks within the Texas High Plains and its detrimental effects.

A febre aftosa é causada por um vírus do gênero Aphtovirus, cujas proteínas não estruturais (PNE) estão relacionadas diretamente a replicação viral e são comuns a todos os sorotipos e, portanto, são mais adequadas à pesquisa de anticorpos contra este vírus. Métodos de diagnóstico capazes de diferenciar animais infectados de vacinados aliados ao uso de vacinas purificadas quanto à PNE são imprescindíveis na estratégia para comprovação de ausência de transmissão viral. Através da Instrução Normativa nº 50/2008, o Brasil passou a realizar o controle oficial da pureza nas vacinas contra a febre aftosa. O objetivo deste trabalho foi avaliar se as chances de encontrar bovinos reativos aos testes sorológicos serão maiores antes da implantação do controle oficial, tanto nos resultados do controle oficial das vacinas, quanto nos inquéritos. Para isto, foram utilizados modelos de regressão logística com efeitos aleatórios, interações e controle de possíveis confundidores. Os resultados demonstraram que no realizado em laboratório oficial em 1016 partidas de vacinas, observou-se que a chance de ocorrência de resultados reativos antes da implantação da norma utilizando o método de triagem ELISA 3ABC NCPanaftosa foi 2,86 (IC95%,1,92-4,14) vezes a chance de ocorrência nos testes de vacina feitos após a norma, utilizando-se o mesmo método de triagem. Já a chance de resultados reativos antes da norma, utilizando-se o método NCPanaftosa, foi 19,70 (IC 95%,8,55- 45,37) vezes a chance de ocorrência após a norma com o uso do método PrioCHECK como triagem Já, a partir da comparação entre inquéritos soroepidemiológicos, foi possível observar que antes da implantação da IN50/2008 a chance de ocorrência de resultados reativos em bovinos que receberam uma dose de vacina foi 2,22 (IC 95%, 1,22-4,06) vezes a chance da ocorrência em bovinos não vacinados. Já, a chance de ocorrência de resultados reativos em bovinos que receberam duas ou três vacinas foi 5,94 (IC 95%, 3,25-10,87) vezes a de bovinos não vacinados. Nas estimativas modeladas para os inquéritos soroepidemiológicos realizados após a implantação da norma, independentemente do método de triagem utilizado, não houve associação significativa entre diferentes doses de vacinas e a ocorrência de animais reativos. Os resultados obtidos sugerem que há uma associação do controle oficial com a melhoria da produção de vacinas no que diz respeito a purificação do antígeno, assim como, indicam que a melhoria na pureza está associada à diminuição na chance de ocorrência de bovinos reativos em inquéritos soroepidemiológicos, ou seja, redução nos falso-positivos a campo. / Foot and mouth disease (FMD) is a highly contagious disease caused by an Aphtovirus. Non-structural proteins (NSP) of this virus are directly related to viral replication and are common to all serotypes. Therefore, are more suitable for antibodies-based serological diagnosis. Diagnostic methods capable of differentiating infected from vaccinated animals (DIVA) are important surveillance tools; however, strategies should be in step with the development of vaccines. Since January 2009, the Brazilian government has been conducting an official control to evaluate NSP purity in vaccines production through the Normative Instruction No. 50 from 2008. This paper evaluates the situation of the vaccines produced in Brazil regarding NSP purification based on the results of the official control carried out by MAPA, as well as the adequacy of the surveillance system based on seroepidemiological surveys. Logistic regression with random effects, interactions and control for potential confounders were the chosen models. For the data obtained from the control of vaccines carried out in the official laboratory, the model estimated that the chance of occurrence of seroreactive results before the application of the official control using the 3ABC NCPanaftosa ELISA as screening method was 2.86 (95% CI, 1.92-4.14) times the chance of occurrence in the vaccine tests made after the standard, using the same method. The chance of seroreactive results before the official control, using the NCPanaftosa method as screening, was 19.70 (95% CI, 8.55 to 45.37) times the chance of occurrence after the official control with the use of the PrioCHECK method Comparing the seroepidemiological surveys results, the model indicated that, before the official control of vaccine purity, the chance of occurrence of reactive results in cattle receiving a single dose of vaccine was 2.22 (95% CI, 1.22 -4.06) times the chance of occurrence in unvaccinated animals. Furthermore, the chance of occurrence of reactive results in animals receiving two or three vaccines was 5.94 (95% CI, 3.25-10.87) times that of unvaccinated animals. Despite that, there was no significant difference in the estimates of the odds ratio between different doses of vaccines regardless of the screening method used for the seroepidemiological surveys performed after the official control of vaccines purity,. The present study suggests that there is an association of the implementation of Normative Instruction No. 50 from 2008 with the improvement of the NSP purity of vaccines, as well as indicates that this improvement is associated with a decrease in chance of occurrence of reactive animals in seroepidemiological surveys, i.e., reduction of false-positives in field monitoring.

A febre aftosa é causada por um vírus do gênero Aphtovirus, cujas proteínas não estruturais (PNE) estão relacionadas diretamente a replicação viral e são comuns a todos os sorotipos e, portanto, são mais adequadas à pesquisa de anticorpos contra este vírus. Métodos de diagnóstico capazes de diferenciar animais infectados de vacinados aliados ao uso de vacinas purificadas quanto à PNE são imprescindíveis na estratégia para comprovação de ausência de transmissão viral. Através da Instrução Normativa nº 50/2008, o Brasil passou a realizar o controle oficial da pureza nas vacinas contra a febre aftosa. O objetivo deste trabalho foi avaliar se as chances de encontrar bovinos reativos aos testes sorológicos serão maiores antes da implantação do controle oficial, tanto nos resultados do controle oficial das vacinas, quanto nos inquéritos. Para isto, foram utilizados modelos de regressão logística com efeitos aleatórios, interações e controle de possíveis confundidores. Os resultados demonstraram que no realizado em laboratório oficial em 1016 partidas de vacinas, observou-se que a chance de ocorrência de resultados reativos antes da implantação da norma utilizando o método de triagem ELISA 3ABC NCPanaftosa foi 2,86 (IC95%,1,92-4,14) vezes a chance de ocorrência nos testes de vacina feitos após a norma, utilizando-se o mesmo método de triagem. Já a chance de resultados reativos antes da norma, utilizando-se o método NCPanaftosa, foi 19,70 (IC 95%,8,55- 45,37) vezes a chance de ocorrência após a norma com o uso do método PrioCHECK como triagem Já, a partir da comparação entre inquéritos soroepidemiológicos, foi possível observar que antes da implantação da IN50/2008 a chance de ocorrência de resultados reativos em bovinos que receberam uma dose de vacina foi 2,22 (IC 95%, 1,22-4,06) vezes a chance da ocorrência em bovinos não vacinados. Já, a chance de ocorrência de resultados reativos em bovinos que receberam duas ou três vacinas foi 5,94 (IC 95%, 3,25-10,87) vezes a de bovinos não vacinados. Nas estimativas modeladas para os inquéritos soroepidemiológicos realizados após a implantação da norma, independentemente do método de triagem utilizado, não houve associação significativa entre diferentes doses de vacinas e a ocorrência de animais reativos. Os resultados obtidos sugerem que há uma associação do controle oficial com a melhoria da produção de vacinas no que diz respeito a purificação do antígeno, assim como, indicam que a melhoria na pureza está associada à diminuição na chance de ocorrência de bovinos reativos em inquéritos soroepidemiológicos, ou seja, redução nos falso-positivos a campo. / Foot and mouth disease (FMD) is a highly contagious disease caused by an Aphtovirus. Non-structural proteins (NSP) of this virus are directly related to viral replication and are common to all serotypes. Therefore, are more suitable for antibodies-based serological diagnosis. Diagnostic methods capable of differentiating infected from vaccinated animals (DIVA) are important surveillance tools; however, strategies should be in step with the development of vaccines. Since January 2009, the Brazilian government has been conducting an official control to evaluate NSP purity in vaccines production through the Normative Instruction No. 50 from 2008. This paper evaluates the situation of the vaccines produced in Brazil regarding NSP purification based on the results of the official control carried out by MAPA, as well as the adequacy of the surveillance system based on seroepidemiological surveys. Logistic regression with random effects, interactions and control for potential confounders were the chosen models. For the data obtained from the control of vaccines carried out in the official laboratory, the model estimated that the chance of occurrence of seroreactive results before the application of the official control using the 3ABC NCPanaftosa ELISA as screening method was 2.86 (95% CI, 1.92-4.14) times the chance of occurrence in the vaccine tests made after the standard, using the same method. The chance of seroreactive results before the official control, using the NCPanaftosa method as screening, was 19.70 (95% CI, 8.55 to 45.37) times the chance of occurrence after the official control with the use of the PrioCHECK method Comparing the seroepidemiological surveys results, the model indicated that, before the official control of vaccine purity, the chance of occurrence of reactive results in cattle receiving a single dose of vaccine was 2.22 (95% CI, 1.22 -4.06) times the chance of occurrence in unvaccinated animals. Furthermore, the chance of occurrence of reactive results in animals receiving two or three vaccines was 5.94 (95% CI, 3.25-10.87) times that of unvaccinated animals. Despite that, there was no significant difference in the estimates of the odds ratio between different doses of vaccines regardless of the screening method used for the seroepidemiological surveys performed after the official control of vaccines purity,. The present study suggests that there is an association of the implementation of Normative Instruction No. 50 from 2008 with the improvement of the NSP purity of vaccines, as well as indicates that this improvement is associated with a decrease in chance of occurrence of reactive animals in seroepidemiological surveys, i.e., reduction of false-positives in field monitoring.

Patients with chronic inflammatory conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) experience premature cardiovascular mortality and morbidity compared with the general population. The increased risk of cardiovascular disease (CVD) may in part, result from an interaction between traditional and non-traditional risk factors, modulated by chronic inflammation. The aim of this project was to look at lipid associated biomarkers in patients with SLE/RA and the association between these markers and cardiovascular disease outcomes. We also aimed to study the effect of inflammation reduction on vascular biomarkers. In the first study we examined 168 SLE patients median (IQR) age was 53 (46-61) years and median disease duration 13 (7, 23) years and 56 healthy controls median age 50 (39-60) years. We demonstrated elevated level of oxidised-LDLin SLE patients compared with healthy controls (76 (57, 99) U/l vs 56 (42, 88)U/l P= 0.02). We further explored the association between oxidant stress and premature atherosclerosis as measured by carotid intima media thickness (cIMT) and plaque. In addition to age and systolic blood pressure, oxidised-LDL and urinary 8-isoprostane were significantly and independently associated with cIMTin SLE patients _ coefficient 95%CI [0.00007 (5.29−6, 0.0001) and 0.003 (0.0008,0.004)], respectively. In healthy controls, age was the only independent variable. In the Norfolk Arthritis Register, 1266 patients with early inflammatory polyarthritis (IP) were studied. A linear regression analysis revealed a significant negative association between CRP and lipid profile namely TC, LDL, TG and ApoA-1. During a median (IQR) follow up = 5.5 (3.7-7.7) years 100 (7%) patients died (all causes) of which 33% (33) deaths were attributed to CVD. Forward stepwise regression analysis demonstrated that a low total cholesterol was independently associated with all cause mortality HR (95%CI) 0.75 (0.61, 0.91) and CVD mortality HR (95%CI) 0.49 (0.29, 0.85). In a small cohort 27 SLE patients and 15 healthy controls. We measured endothelial function using flow mediated dilatation of the brachial artery. At baseline we found a significant increase in TG level [1.36 (0.9, 1.87) mmol/l vs0.88 (0.64, 1) mmol/l P= 0.009] and a significant impaired endothelial function in SLE patients compared to the healthy controls [2.86 (0.6, 5.3) vs 6.81 (3.46,8.57), P= 0.03]. After treatment, there was a trend towards reduced TG level and improved endothelial function. Oxidised-LDL did not change significantly. In conclusion, oxidant stress is increased in SLE patients and relates to some measures of subclinical atherosclerosis. Control of inflammation may not be sufficient to completely control this in routine practice. In early RA, active inflammationmay mask any tendency to hyperlipidemia in this population. Low total cholesterol may be the best biomarker of the overall metabolic and inflammatory status of the patients as well as indicating a group with increased risk of future mortality.

A febre aftosa é causada por um vírus do gênero Aphtovirus, cujas proteínas não estruturais (PNE) estão relacionadas diretamente a replicação viral e são comuns a todos os sorotipos e, portanto, são mais adequadas à pesquisa de anticorpos contra este vírus. Métodos de diagnóstico capazes de diferenciar animais infectados de vacinados aliados ao uso de vacinas purificadas quanto à PNE são imprescindíveis na estratégia para comprovação de ausência de transmissão viral. Através da Instrução Normativa nº 50/2008, o Brasil passou a realizar o controle oficial da pureza nas vacinas contra a febre aftosa. O objetivo deste trabalho foi avaliar se as chances de encontrar bovinos reativos aos testes sorológicos serão maiores antes da implantação do controle oficial, tanto nos resultados do controle oficial das vacinas, quanto nos inquéritos. Para isto, foram utilizados modelos de regressão logística com efeitos aleatórios, interações e controle de possíveis confundidores. Os resultados demonstraram que no realizado em laboratório oficial em 1016 partidas de vacinas, observou-se que a chance de ocorrência de resultados reativos antes da implantação da norma utilizando o método de triagem ELISA 3ABC NCPanaftosa foi 2,86 (IC95%,1,92-4,14) vezes a chance de ocorrência nos testes de vacina feitos após a norma, utilizando-se o mesmo método de triagem. Já a chance de resultados reativos antes da norma, utilizando-se o método NCPanaftosa, foi 19,70 (IC 95%,8,55- 45,37) vezes a chance de ocorrência após a norma com o uso do método PrioCHECK como triagem Já, a partir da comparação entre inquéritos soroepidemiológicos, foi possível observar que antes da implantação da IN50/2008 a chance de ocorrência de resultados reativos em bovinos que receberam uma dose de vacina foi 2,22 (IC 95%, 1,22-4,06) vezes a chance da ocorrência em bovinos não vacinados. Já, a chance de ocorrência de resultados reativos em bovinos que receberam duas ou três vacinas foi 5,94 (IC 95%, 3,25-10,87) vezes a de bovinos não vacinados. Nas estimativas modeladas para os inquéritos soroepidemiológicos realizados após a implantação da norma, independentemente do método de triagem utilizado, não houve associação significativa entre diferentes doses de vacinas e a ocorrência de animais reativos. Os resultados obtidos sugerem que há uma associação do controle oficial com a melhoria da produção de vacinas no que diz respeito a purificação do antígeno, assim como, indicam que a melhoria na pureza está associada à diminuição na chance de ocorrência de bovinos reativos em inquéritos soroepidemiológicos, ou seja, redução nos falso-positivos a campo. / Foot and mouth disease (FMD) is a highly contagious disease caused by an Aphtovirus. Non-structural proteins (NSP) of this virus are directly related to viral replication and are common to all serotypes. Therefore, are more suitable for antibodies-based serological diagnosis. Diagnostic methods capable of differentiating infected from vaccinated animals (DIVA) are important surveillance tools; however, strategies should be in step with the development of vaccines. Since January 2009, the Brazilian government has been conducting an official control to evaluate NSP purity in vaccines production through the Normative Instruction No. 50 from 2008. This paper evaluates the situation of the vaccines produced in Brazil regarding NSP purification based on the results of the official control carried out by MAPA, as well as the adequacy of the surveillance system based on seroepidemiological surveys. Logistic regression with random effects, interactions and control for potential confounders were the chosen models. For the data obtained from the control of vaccines carried out in the official laboratory, the model estimated that the chance of occurrence of seroreactive results before the application of the official control using the 3ABC NCPanaftosa ELISA as screening method was 2.86 (95% CI, 1.92-4.14) times the chance of occurrence in the vaccine tests made after the standard, using the same method. The chance of seroreactive results before the official control, using the NCPanaftosa method as screening, was 19.70 (95% CI, 8.55 to 45.37) times the chance of occurrence after the official control with the use of the PrioCHECK method Comparing the seroepidemiological surveys results, the model indicated that, before the official control of vaccine purity, the chance of occurrence of reactive results in cattle receiving a single dose of vaccine was 2.22 (95% CI, 1.22 -4.06) times the chance of occurrence in unvaccinated animals. Furthermore, the chance of occurrence of reactive results in animals receiving two or three vaccines was 5.94 (95% CI, 3.25-10.87) times that of unvaccinated animals. Despite that, there was no significant difference in the estimates of the odds ratio between different doses of vaccines regardless of the screening method used for the seroepidemiological surveys performed after the official control of vaccines purity,. The present study suggests that there is an association of the implementation of Normative Instruction No. 50 from 2008 with the improvement of the NSP purity of vaccines, as well as indicates that this improvement is associated with a decrease in chance of occurrence of reactive animals in seroepidemiological surveys, i.e., reduction of false-positives in field monitoring.

<p>The fluid dynamics of blood in the systemic circulation modulates production of nitric oxide (NO), a potent vasodilator. Non-invasive techniques such as the flow-mediated dilation (FMD) test and physiologic phenomena associated with autonomic stress induce hyperemia and subsequently higher levels of wall shear stress (WSS), stimulating endothelial nitric oxide synthase (eNOS) expression. In the current clinical practice, WSS–a key regulator of endothelial function–is commonly estimated assuming a parabolic velocity distribution, despite the evidence that the temporal changes of pulsatile blood flow over the cardiac cycle modulate vasodilation in mammals. This work investigates the effect of cardiovascular stress on local WSS distributions and the potential for near-wall accumulation of nitrite, the vasoactive storage form of NO in the bloodstream. The specific aims of the project are therefore as follows: 1) develop a reduced-order model of the major systemic vasculature at rest, during a flight-or-flight response, and under moderate levels of aerobic exercise; 2) derive a velocity-driven Womersley solution for pulsatile flow to support accurate estimation of pulsatile WSS in the clinical setting; and 3) quantify cumulative transport of nitrite in a multiscale model of bifurcating vasculature utilizing computational fluid dynamics (CFD). Development of these open-source, translatable methods enable accurate quantification of hemodynamics and species transport during cardiovascular stress. Results detailed herein extend our knowledge about regulation of regional blood flow during autonomic stress, suggest a convergent evolutionary theory for having a complete circle of Willis, and potentially clarify reproducibility concerns associated with the FMD test. </p>

CHDS State/Local / Approved for public release, distribution is unlimited / Threatened with the loss of federal funding for Homeland Security and emergency management preparedness programs, state and local entities must implement the National Response Plan and the National Incident Management System, which includes the Incident Command System, Unified Command, and the Multiagency Coordination System. Although mandated by Congress and implemented by Homeland Security Presidential Directive 5, underdeveloped areas of Indian country and small towns, especially farming and ranching communities and agriculturally-based counties are likely to find that they do not have the capacity to fully implement these mandated federal response programs. A theoretical terrorist-induced multistate Foot and Mouth Disease (FMD) outbreak is used to examine the impact of implementing newly established federally mandated response management programs on rural and tribal communities in agrarian states. Recovering from such an agroterrorism bioattack would require a coordinated multi-disciplinary response that is heavily dependent on local, tribal, state, and private sector personnel. However, because the United States has not experienced an outbreak of FMD since 1929, many of the skills required to quickly diagnose and respond may no longer exist. This thesis identifies potential methods for obtaining and deploying the FMD virus in a coordinated bioattack on the U.S. economy. / Director, Idaho Bureau of Disaster Services

<p dir="ltr">Fibromuscular Dysplasia (FMD) is a non-inflammatory, non-atherosclerotic blood vessel disorder characterized by a series of narrowed and dilated regions of vasculature. These patients are prescribed blood thinners or anti-platelet therapeutics as treatment to this systemic disease. Current image-based diagnostic methods cannot reliably predict a patient’s risk of stroke in order to properly manage medication. There are also challenges in distinguishing FMD from other diseases that can cause arterial obstructions, like atherosclerosis or vasculitis.</p><p dir="ltr">The ultimate goal of this research is to develop a methodology for evaluating the risk of mechanical platelet activation based on medical imaging. Our hypothesis is that subject-specific assessment of platelet activation due to hemodynamic stress can improve risk stratification of FMD patients. The aims of the projects were therefore to 1) Develop a CFD-based methodology for estimating platelet activation state, and 2) Test this methodology on a small cohort of subjects with FMD, carotid artery stenosis, and healthy controls. A modeling workflow was developed, combining Eulerian and Lagrangian approaches to compute flow fields and evaluate shear stress history of particles advected through the vascular geometries. From this stress history, predictive estimates of mechanical platelet activation can be calculated utilizing a platelet activation state (PAS) metric. We applied this modeling workflow to assess platelet activation in segments of carotid arteries of patients with Fibromuscular Dysplasia, Carotid Artery Stenosis, and healthy controls for comparison against experiments performed at the Cleveland Clinic assessing mechanical platelet activation in patients with each of these conditions. This work supports the development of a patient-specific determination of these same metrics, in order to more precisely assess patient risk of stroke.</p>

La dysplasie fibromusculaire artérielle (DFM) est un groupe de pathologies vasculaires non inflammatoires, et non athéromateuses de la paroi artérielle. Elle est caractérisée par la sténose, l'occlusion, l’anévrisme ou la dissection des artères de petit et moyen calibres, en particulier les artères rénales et le tronc supra-aortique. La DFM est un facteur de risque de l’hypertension et de l’accident vasculaire cérébral. Elle touche essentiellement les femmes (80% des cas) de moins de 50 ans. La prévalence en population générale est inconnue et les estimations varient de 0.4% pour les formes cliniques à 4% dans une cohorte de donneurs de reins. Une agrégation familiale a été démontrée et une composante génétique suggérée. L'objectif de mon travail de thèse était de caractériser les bases génétiques la DFM. Dans la première partie, nous avons analysé des variants génétiques rares générés par séquençage d'exomes chez 16 cas apparentés de DFM issus de 7 fratries. Aucun gène majeur n’était muté pour l’ensemble des fratries ou pour au moins 3 fratries sur 7. Cependant, nous avons pu mettre en évidence puis validé un enrichissement en variants rares à fort potentiel fonctionnel de quatre gènes candidats pour la DFM (MYLK, OBSCN, DYNC2H1, RNF213) en combinant l’approche de séquençage d’exomes et l’étude d’association gène entier de 62767 variants rares (MAF < 5%) générés par génotypage avec la puce Exome-chip chez 249 cas non apparentés de DFM et 689 témoins. Cependant, l’implication de ces gènes dans la DFM doit être confirmée dans d’autres familles, et par des études de validations fonctionnelles. Dans la seconde partie, nous avons étudié l'association avec la DFM de 25606 variants fréquents (MAF ≥ 5%) de l’Exome-chip. Les résultats majeurs obtenus ont été répliqués dans une première étude (402 cas de DFM et 2537 témoins) puis dans 3 autres études incluant 512 cas de DFM et 669 témoins. La méta-analyse de l’ensemble a permis d’associer à la DFM le polymorphisme rs9349379-A situé dans l’intron du gène PHACTR1 (OR=1,39 [1,39-1,54] ; P=7,36 ×10-10). Ce variant est aussi un facteur de risque pour la maladie coronaire, la migraine et la dissection de l’artère cervicale. Des études complémentaires conduites chez 2458 volontaires non malades ont permis de montrer que l’allèle à risque pour la DFM, rs9349379-A est associé avec une augmentation de l’épaisseur intima média (P=1,97×10-4) et du rapport de la paroi sur la lumière artérielle (P=0,002), deux paramètres décrits comme augmentés chez les cas de DFM dans des études antérieures. Ensuite, PHACTR1 a été détecté par immunohistochimie dans l’endothélium et les cellules musculaires lisses de carotides dysplasiques et non dysplasiques avec une expression augmentée de PHACTR1 pour les porteurs de l’allèle à risque de DFM dans des cultures primaires de fibroblastes humains (N=86, P=0,003). Enfin, l’invalidation de Phactr1 chez le poisson zèbre conduit à une dilatation des vaisseaux indiquant un défaut du développement vasculaire. Ce travail confirme le caractère multifactoriel et hétérogène de la DFM et ouvre de nouvelles perspectives pour évaluer l’ensemble de la variabilité génomique des patients de DFM par des approches massives de génétique épidémiologique. / Fibromuscular dysplasia (FMD) is a group of nonatherosclerotic and noninflammatory vascular diseases leading to stenosis, aneurysm, dissection and/or occlusion of medium-sized arteries, in particular the renal and extracranial cervical arteries. Clinical manifestations of FMD are hypertension, dizziness, pulsatile tinnitus, transient ischemic attack or stroke, according to the involved arterial beds. FMD occurs predominantly (80% of cases) in females under 50 years with a variable prevalence estimation from 0.4% for asymptomatic clinical relevant forms to 4% in potential renal donors. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation. The aim of my thesis work was to characterize genetic basis of FMD. In the first part of this thesis, we analyzed whole exome sequencing data in 16 related FMD cases from seven families. No gene harbors variants that were shared by all affected members in at least three out seven families. Using combined strategy of whole exome sequencing and gene based association study of 62,767 rare variants (MAF < 5%) generated by Exome‐chip arrays in 249 unrelated FMD cases and 689 controls, we have identified and validated an enrichment of rare and putatively functional variants in four candidates genes (MYLK, OBSCN, DYNC2H1 and RNF213). This results need to be validated in other FMD families and by functional analysis. In the second part, we analyzed 25,606 common variants (MAF ≥ 5%) generated by Exome‐chip array. Top loci were replicated in first replication study (402 cases and 2,537 controls) and in 3 others studies (512 cases and 669 controls). Meta-analysis of all including 1,154 unrelated FMD cases and 3,895 controls allowed identification of association between FMD and rs9349379-A (OR=1.39 [1.39-1.54]; P=7.4×10‐10). rs9349379 is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from 2,458 healthy volunteers indicated higher intima media thickness (P = 1.97×10‐4) and wall to lumen ratio (P = 0.002) in rs9349379‐A carriers, suggesting indices of carotid hypertrophy as previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379‐A carriers (N=86, P=0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impairment of vascular development. This work confirms the multifactorial and heterogeneous genetic architecture of the FMD and opens new opportunities to evaluate all of genomic variability of FMD patients with massive genetic epidemiology approaches.