[pt] Este estudo apresenta a validação de um modelo físico/numérico para prever o escoamento na aorta ascendente de um paciente saudável, com o objetivo de estender sua aplicação para analisar outros pacientes, especificamente, com aneurisma da aorta ascendente (AAoA). Aplicando o conceito paciente-específico (PSM), os resultados fornecidos pela técnica de Ressonância Magnética Quadridimensional (4D-Flow MRI) foram utilizados na simulação empregando a abordagem de Dinâmica dos Fluidos Computacional (CFD) com um modelo de turbulência capaz de prever transições entre regimes laminar/turbulento durante o ciclo cardíaco. Condição de contorno baseada na vazão medida foi imposta na entrada da aorta. Nas saídas, foram considerados os percentuais da vazão de entrada correspondentes à cada saída, bem como o modelo Windkessel de três elementos para estabelecer uma aproximação mais precisa da relação pressão-vazão. Os resultados favoráveis obtidos dos perfis de pressão, vazão e tensão de cisalhamento em várias posições ao longo da aorta e ao longo do ciclo cardíaco validaram a aplicação potencial do PSM a outros pacientes, em particular, pacientes com AAoA. O AAoA é uma doença silenciosa com alta mortalidade, e os fatores associados ao pior prognóstico ainda não são totalmente conhecidos. Com o objetivo de relacionar características da dinâmica do escoamento com a doença, modelos anatômicos personalizados foram obtidos a partir de angiotomografias de 30 pacientes em dois anos diferentes (com intervalos de um a três anos entre eles). Com base na diferença de volume da aorta ascendente de um ano para outro, dois grupos foram definidos: um com crescimento do aneurisma e outro sem crescimento. O escoamento durante o ciclo cardíaco e a geometria correspondente a cada grupo foram comparados para encontrar padrões que possam indicar o crescimento do aneurisma a partir do primeiro exame. Embora não tenha havido uma tendência clara entre os dois grupos de pacientes, foram observados valores mais altos da pressão média- temporal ( ) em pacientes com crescimento do aneurisma, bem como períodos mais longos durante o ciclo com a aorta submetida a altos valores de tensão de cisalhamento. O presente estudo explorou o processo de remodelação de pacientes com aneurisma e como a geometria pode impactar em seu crescimento, contribuindo para uma melhor compreensão da fisiopatologia aórtica. / [en] This study presents the validation of a physical/numerical model designed to predict the ascending aorta flow in a healthy patient, aiming to extend its application to analyze other patients, specifically, with ascending aortic aneurysm (AAoA). Applying the patient-specific model (PSM) concept, the results provided by the Four-dimensional Flow Magnetic Resonance Imaging (4D-Flow MRI) technique were used in the simulation employing the Computational Fluid Dynamics (CFD) approach, with a turbulence model capable of predicting laminar/turbulent regime transitions during the cardiac cycle. Boundary condition based on measured flow rate was imposed at the aorta s inlet. At the outlets, the physiological percentages of inlet flow rate corresponding to each output were considered, as well as the three-element Windkessel model to establish a more accurate approximation of the pressure-flow relationship. The favorable results obtained on pressure, flow rate and shear stress profiles at various positions along the aorta and throughout the cardiac cycle, validated the potential application of PSM to other patients, in particular patients with AAoA. AAoA is a silent disease with high mortality, and factors associated with a worse prognosis are not yet fully known. Aiming to relate flow dynamics characteristics with the disease, personalized anatomic models were obtained from angiotomography scans of 30 patients in two different years (with intervals of one to three years between them). Based on the volume difference of the ascending aorta from one year to another, two groups were defined: one with aneurysm growth and another without growth. The flow field during the cardiac cycle and the geometry corresponding to each group were compared to find patterns that may indicate the aneurysm growth from the first exam. Although there was no clear trend between the two patient groups, higher time-averaged pressure ( ) values were observed in patients with aneurysm growth, as well as longer time periods during the cycle with the aorta subjected to high values of shear stress. The present study explored the remodeling process of patients with aneurysm and how the geometry and flow pattern can impact its growth, contributing to a better understanding of aortic pathophysiology.

The general purpose of this thesis is to establish the ability of Speckle Tracking Echocardiography (STE) in assessing left atrial (LA) response to pressure and volume overload respectively in aortic stenosis (AS) and mitral regurgitation (MR), and to evaluate its accuracy in predicting LA and right ventricular (RV) fibrosis in patients with end-stage heart failure (HF) undergoing heart transplantation (HTx). I demonstrated that assessment of left ventricular (LV) long axis systolic velocity and amplitude of excursion is more sensitive than simple determination of ejection fraction (EF) for revealing the beneficial impact of MR surgery on overall LV systolic performance. Severe symptomatic AS is associated with LA enlargement and compromised mechanical function with a high incidence of peri-operative atrial fibrillation (AF). Valve replacement reverses these abnormalities and regains normal atrial function, a behaviour which is directly related to the severity of pre-operative LV outflow tract obstruction. Early identification of LA size and function disturbances, as shown by myocardial strain measurements might contribute to better patient’s recruitment for a safe valve replacement. In late stage HF patients, the right ventricle is enlarged, with reduced systolic function due to significant myocardial fibrosis. RV free wall myocardial deformation is the most accurate function measure that correlates with the extent of RV myocardial fibrosis and functional capacity. In patients with preserved EF, severe MR masks LV and LA myocardial dysfunction and correlates with symptoms and post-operative cavity function instability. Three months after MVR, the underlying myocardial disturbances are unmasked suggesting that most pre-operative measurements are subject to loading conditions. Finally LA volume and PALS remain the main predictors of post-operative AF, thus should be used for stratifying surgical risk. STE has been shown to accurately determine the severity of impairment of LA myocardial function shown by suppressed PALS which was the strongest predictor of the presence and extent of fibrosis, over and above other structure and function parameters. These findings may assist in better stratifying patients with end stage HF and identifying particularly those requiring HTx.

This thesis consists of four self-contained papers. Essay I (with Linuz Aggeborn): Fluoridation of the drinking water is a public policy whose aim is to improve dental health. Although the evidence is clear that fluoride is good for dental health, concerns have been raised regarding potential negative effects on cognitive development. We study the effects of fluoride exposure through the drinking water in early life on cognitive and non-cognitive ability, education and labor market outcomes in a large-scale setting. We use a rich Swedish register dataset for the cohorts born 1985-1992, together with drinking water fluoride data. To estimate the effects, we exploit intra-municipality variation of fluoride, stemming from an exogenous variation in the bedrock. First, we investigate and confirm the long-established positive relationship between fluoride and dental health. Second, we find precisely estimated zero-effects on cognitive ability, non-cognitive ability and education for fluoride levels below 1.5 mg/l. Third, we find evidence that fluoride improves later labor market outcomes, which indicates that good dental health is a positive factor on the labor market. Essay II: I study the associations between cognitive and non-cognitive abilities and mortality using a population-wide dataset of almost 700,000 Swedish men born between 1950 and 1965. The abilities were measured at the Swedish military enlistment at age 18-20. In addition, I investigate if income and education are good proxies for the abilities. The results suggest that both cognitive and non-cognitive abilities are strongly associated with mortality, but that non-cognitive ability is a stronger predictor. The associations are only partly mediated through income and education. For middle and high income earners and individuals with a college education there are no associations with mortality. However, for low income earners and individuals without a college education, both abilities are strongly associated with mortality. The associations are mainly driven by the bottom of the distributions. Essay III (with Matz Dahlberg, Kevin Mani and Anders Wanhainen): We examine how health information affects individuals' well-being using a regression discontinuity design on data from a screening program for an asymptomatic disease, abdominal aortic aneurysm (AAA). The information provided to the individuals is guided by the measured aorta size and its relation to pre-determined levels. When comparing individuals that receive information that they are healthy with those that receive information that they are in the risk zone for AAA, we find no effects. However, when comparing those that receive information that they have a small AAA, and will be under increased surveillance, with those who receive information that they are in the risk zone, we find a weak positive effect on well-being. This indicates that the positive information about increased surveillance may outweigh the negative information about worse health. Essay IV: I estimate the effect of SSRI antidepressants on the risk of mortality for myocardial infarction (MI) patients using Propensity Score Matching on individual health variables such as pharmaceutical drug prescription, patient history and severity of the MI. The effect of antidepressants on mortality is a heavily debated topic. MI patients have an elevated risk of developing depression, and antidepressants are among the most common treatments for depression and anxiety. However, there are indications that some classes of antidepressants may have drug-induced cardiovascular effects and could be harmful for individuals with heart problems, but there is a lack of large-scale studies using credible identification strategies. My findings indicate no increased risk of two-year mortality for MI patients using SSRI. The results are stable for several specifications and robustness checks.

Preeclampsia is one of the leading causes of maternal and fetal mortality and morbidity. Furthermore, women who have had preeclampsia have an increased risk of cardiovascular events over the next 10-15 years. Indeed, preeclampsia is associated with a four-fold increase in the risk of hypertension and double the risk of fatal and non fatal ischaemic heart disease and stroke. In addition, offspring born to preeclampsia are more likely to have higher blood pressure from childhood and stroke in later life. The risk to mother and offspring is greatest when preeclampsia is diagnosed at an earlier gestation, suggesting a more severe form of preeclampsia. As the long term cardiovascular risk to both mother and child is known from delivery, the main interest of my research was to identify key phenotypic variations in mothers and children during the years between the episode of preeclampsia and emergence of established cardiovascular disease, which might explain the link between the two conditions. This information could then be used to devise ways to identify subjects at greatest risk of later cardiovascular disease and to establish intermediate endpoints for future preventative interventions. Therefore, in a case control study, women diagnosed with preeclampsia between 1998 and 2003 and their offspring were recruited and underwent comprehensive cardiovascular and metabolic phenotyping. Furthermore, young adults born preterm to hypertensive pregnancy were also investigated in their twenties. The research demonstrates that early-onset preeclampsia, diagnosed before 34 weeks gestation, is associated with blood pressure patterns in mothers 6-13 years after pregnancy that are distinct from those seen following later-onset disease. Furthermore, there is evidence of distinct differences in cardiac, vascular and metabolic profiles in these individuals with women having evidence of increased arterial stiffness, changes in cardiac function and reduced capillary density. Preterm offspring of hypertensive pregnancies similarly have higher blood pressure than seen in those born following late-onset disease and, in young adult life, have reduced endothelial function and changes in cardiac size proportional to this dysfunction. This research demonstrates adverse cardiac and vascular remodelling after preeclampsia in mothers and offspring that are evident before the development of clinical cardiovascular disease. The identified differences in cardiac and vascular function may be useful as surrogate endpoints in future preventive trials.

La sténose valvulaire aortique (SVA) est une pathologie associée au vieillissement et aux facteurs de risque cardiovasculaire. Afin d’étudier la SVA et d’explorer de nouvelles thérapies, plusieurs modèles animaux ont été récemment développés, mais la plupart de ces modèles ciblent les mécanismes de développement de la SVA reliés à l’hypercholestérolémie. Le syndrome de Werner (WS) est une maladie caractérisée par un vieillissement prématuré. Récemment, il a été découvert que des souris mutantes ayant une délétion du domaine hélicase du gène Werner, responsable du WS, démontraient un profile hémodynamique typique de la SVA. De ce fait, nous avons émis l’hypothèse que ces souris pourraient développer une SVA plus rapidement que des souris de type sauvage. Nous avons donc étudié les effets cette mutation chez des souris WrnΔhel/Δhel, en comparant le taux de progression d’une SVA entre des souris WrnΔhel/Δhel (WrnΔhel) et des souris de type sauvage comme groupe contrôle. À la suite d’une diète riche en sucre et en gras sur une période de 24 semaines, les souris WrnΔhel ont démontré une diminution plus prononcée de leur aire de valve aortique (mesures échocardiographiques) que les souris contrôles, supportée par les analyses histologiques concernant la fibrose des valves aortiques. Les souris n’ont toutefois développé aucun signe évident d’athérosclérose comme l’infiltration de lipides ou l’inflammation, bien que certaines caractéristiques liées à la dysfonction endothéliale semblent être augmentées chez les souris WrnΔhel. D’autres mesures échocardiographiques indiquant une SVA, comme une hypertrophie du ventricule gauche dans le groupe WrnΔhel, ont été obtenues. Nous avons aussi observé des indices de vieillissement plus marqués quant aux analyses sanguines et de la moelle osseuse des souris WrnΔhel en comparaison avec les souris contrôles. Par conséquent, ce modèle expérimental de vieillissement pourrait être utilisé pour les études futures sur la SVA sans les principaux effets athérogéniques des autres modèles expérimentaux. / Aortic valve stenosis (AVS) is associated with aging and classical cardiovascular risk factors. Different animal models were recently developed to study AVS and explore new therapies, however, most of these models rely almost exclusively on hypercholesterolemia-related mechanisms for AVS development. Werner syndrome (WS) is a disorder characterized by premature aging. It was recently demonstrated that mutant mice with a deletion of the helicase domain of the Werner gene, the gene responsible for WS, showed hemodynamic profile typical of AVS. We therefore hypothesized that mice with the WrnΔhel deletion could develop AVS earlier than wild-type (WT) mice. We studied the effect of the WrnΔhel mutation by comparing the rate of progression of AVS in homozygous mutant versus WT mice. By twenty-four weeks on a high-fat/high-carbohydrate diet, WrnΔhel/Δhel (WrnΔhel) mice showed a stronger decrease of the aortic valve area measured by serial echocardiography than WT mice, supported by histological analyses of valve fibrosis but without developing major signs of atherosclerosis such as lipid infiltration or increased inflammation. Some features linked to endothelial dysfunction also appeared to be increased in WrnΔhel mice. Other echocardiographic measurements were typical of AVS, such as left ventricle hypertrophy in the WrnΔhel group. We also observed stronger aging properties from WrnΔhel mice bone marrow and blood analyses compared to the WT group. Consequently, this experimental aging model could be used for AVS research without the major confounding atherogenic effects of other experimental models.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Les anévrysmes de l'aorte abdominale (AAAs) sont des dilatations artérielles qui exposent le patient au décès par rupture. Ils sont caractérisés notamment par la perte de la monocouche de cellules endothéliales et son remplacement par un épais thrombus mural. Cependant, le lienentre l'accroissement du diamètre anévrysmal, la présence d'un thrombus et la perte en cellules endothéliales reste inexploré. Notre hypothèse est que la perte de l'endothélium contribue au développement des AAAs et que sa restauration par thérapie cellulaire permettrait de stabiliser les AAAs. In vivo, la réparation endothéliale implique le recrutement des cellules endothéliales adjacentes mais également des cellules progénitrices endothéliales (EPCs). Chez l'homme, le nombre et l’activité fonctionnelle des EPCs sont inversement corrélés aux facteurs de risque cardiovasculaire, et très peu de données sont disponibles sur l’activité fonctionnelle des EPCs issues de patients porteurs d'AAA. La présence du thrombus pourrait ainsi diminuer le nombre et les propriétés cicatricielles des EPCs issues de patients porteurs d'AAA. / Summary not transmitted

Tato práce se zabývá problematikou aneurysmat břišní aorty a možností využít konečnoprvkovou deformačně-napěťovou analýzu těchto aneurysmat ke stanovení rizika ruptury. První část práce je věnována úvodu do problematiky, popisu kardiovaskulární soustavy člověka s důrazem na abdominální aortu, anatomii, fyziologii a patologii stěny tepny s důrazem na procesy vedoucí ke vzniku aneurysmatu. Dále se práce věnuje rizikovým faktorům přispívajících ke vzniku aneurysmat spolu s analýzou současných klinických postupů ke stanovení rizika ruptury spolu se srovnáním navrhovaného kritéria maximálního napětí. Dominantní část této disertace je věnována identifikaci faktorů ovlivňujících napjatost a deformaci stěny aneurysmatu spolu s návrhem nových postupů, prezentací vlastních poznatků vedoucích ke zpřesnění určení rizika ruptury pomocí deformačně- napěťové analýzy a metody konečných prvků. Nejprve je analyzován vliv geometrie, vedoucí k závěru, že je nezbytné používání individuálních geometrií pacienta. Dále je pozornost zaměřena na odbočující tepny, které ve stěně působí jako koncentrátor napětí a mohou tedy ovlivňovat napjatost v ní. Jako další podstatný faktor byl identifikován vliv nezatížené geometrie a bylo napsáno makro pro její nalezení, které bylo opět zahrnuto jako standardní součást do výpočtového modelu. Mechanické vlastnosti jak stěny aneurysmatu, tak intraluminálního trombu jsou experimentálně testovány pomocí dvouosých zkoušek. Také je zde analyzován vliv modelu materiálu, kde je ukázáno, že srovnávání maximálních napětí u jednotlivých modelů materiálu není vhodné díky zcela rozdílným gradientům napětí ve stěně aneurysmatu. Dále je zdůrazněna potřeba znalosti distribuce kolagenních vláken ve stěně a navržen program k jejímu získání. Intraluminální trombus je analyzován ve dvou souvislostech. Jednak je ukázán vliv jeho ruptury na napětí ve stěně a jednak je analyzován vliv jeho poroelastické struktury na totéž. Posledním identifikovaným podstatným faktorem je zbytková napjatost ve stěně. Její významnost je demonstrována na několika aneurysmatech a i tato je zahrnuta jako integrální součást do našeho výpočtového modelu.Na závěr jsou pak navrženy další možné směry výzkumu.

(v AJ) Introduction to the topic and importance of the topic: Aortic valve disease is the third most frequent cardiovascular disease and also the most frequently operated valvular disease in adulthood. The natural process of the disease is unfavorable, almost half of the patients suffer from symptoms of heart failure (Branny et al. 2012). This is the reason why I focused my thesis on the assessment of the quality of life of patients diagnosed of aortic stenosis. Aim of the thesis and research questions: The aim of my thesis is to evaluate the quality of life patients with diagnosed aortic valve disease, within one month before the planned surgery and in the postoperative period when patients will be checked at a cardiac surgery clinic. The partial objective at the same time was to compare the quality of life and health status of patients with aortic valve disease who have completed a spa therapy with those who have rejected it. Methodology (method, research sample): The research work will be carried out as a quantitative research in a group of 29 respondents. The HRQoL construct it means questionnaire SF-36 were used to obtain the data. The questionnaire was anonymous. For the completed questionnaires, a closed box was set up, which I didn't open until the poll was complete. The survey was...

Introdução: O istmo aórtico (IAo) fetal é um pequeno segmento vascular localizado entre a origem da artéria subclávia esquerda e a extremidade aórtica do canal arterial, que reflete o equilíbrio entre a impedância ao fluxo no território cerebral e na circulação fetal periférica. Considerado o único shunt arterial verdadeiro entre os sistemas vasculares direito e esquerdo, seu fluxo alterado se associa a resultados perinatais adversos, incluindo aumento da mortalidade fetal e morbidade neurológica, especialmente em fetos com insuficiência placentária e restrição de crescimento. Justificativa: Não há protocolo mundial estabelecido definindo conduta clínica baseada na avaliação Doppler do istmo aórtico fetal, havendo espaço para que sua análise seja incorporada como justificativa para indicação do parto e proteção contra injúrias perinatais. Entretanto, implementar novas medidas à prática clínica requer a demonstração de quão confiáveis e reprodutíveis são os resultados obtidos, o que contribui para a garantia de qualidade em sua utilização. Objetivos: Estimar a reprodutibilidade intra e interobservador do índice de pulsatilidade do istmo da aorta fetal (IAo-IP) no terceiro trimestre de gestação (32 a 36+6 semanas), e determinar qual das aquisições, longitudinal ou transversal, produz medidas com melhores confiabilidade e concordância. Métodos: Estudo observacional (transversal) para o qual foram convidadas a participar gestantes no terceiro trimestre de gestação (32 a 36+6 semanas) que preenchiam os critérios de elegibilidade. O IAo-IP foi obtido por dois observadores, que utilizaram os planos longitudinal e transversal para as aquisições, realizadas de forma completamente independente, sem que tivessem conhecimento dos valores das próprias medidas, tampouco das medidas do outro observador. Os dados foram apresentados como média ± DP (desvio-padrão), mediana, mínimo e máximo; A reprodutibilidade foi avaliada pelo coeficiente de correlação intraclasse (ICC). Resultados: As principais características das 49 gestantes foram: média de idade de 26.3 ± 4.7 anos, variando entre 18 e 40 anos, com média da idade gestacional de 33.6 ± 1.5 semanas e índice de massa corporal de 27.9 ± 4.5 Kg/m2. Os resultados dos IP obtidos do estudo Doppler espectral do istmo aórtico fetal pela via longitudinal, demonstraram uma média de 2.75 ± 0.46 para o observador A, 2.53 ± 0.38 para o observador B, e 2.74 ± 0.58 para a segunda medida do observador A. Para a via transversal, as médias foram de 2.75 ± 0.46 para o observador A, 2.53 ± 0.38 para o observador B, e 2.74 ± 0.58 para a segunda medida do observador A. A avaliação Doppler do istmo aórtico fetal no plano longitudinal apresentou ICC de 0.25 na comparação entre os observadores (interobservador), e de 0.42 para a análise intraobservador. No plano transversal, os coeficientes obtidos foram de 0.18 e 0.43 respectivamente para as análises inter-observador e intraobservador. Conclusões: Embora o papel do istmo aórtico na hemodinâmica fetal esteja bem estabelecido, o presente estudo demonstrou que sua reprodutibilidade no terceirotrimestre (32 a 36+6 semanas) é fraca, logo, a medida do IAo-IP deve ser interpretada com cautela, desencorajando seu emprego na prática clínica. Os estudos que examinam aperfeiçoamentos técnicos para melhorar a sua reprodutibilidade devem ser incentivados / Introduction: The fetal aortic isthmus (AoI) is a small vessel located between the origin of the left subclavian artery and the aortic extremity of the arterial ductus, which reflects the balance between the impedance of the brain and systemic circulation of the fetus. Known as the only arterial shunt regarding both right and left vascular systems, its abnormal flow is associated to adverse perinatal outcomes, including high fetal mortality and neurological morbidity, especially among placental insufficiency and growth-restricted fetuses. Rationale: There is no established global protocol defining clinical management based on the Doppler evaluation of the fetal aortic isthmus, allowing its analysis to be incorporated as a reason to indicate delivery and protection against perinatal injury. However, implementation of new methods to clinical practice requires demonstration of how reliable and reproducible the results are, which contributes to quality assurance in their use. Objectives: To estimate the intra and interobserver reproducibility of the fetal aortic isthmus pulsatility index (IAo-PI) in the third trimester of gestation (32 to 36+6 weeks), and to determine which of both longitudinal and transversal acquisitions show better reliability and agreement. Methods: Observational (cross-sectional) study in which were invited to participate pregnant women in the third trimester of gestation (32 to 36+6 weeks) who met the eligibility criteria. The AoI-PI was obtained by two observers, who used the longitudinal and transverse plans for the acquisitions, performing independent acquisitions and blinded analysis. Data were presented as mean ± SD (standard deviation), median, minimum and maximum. The reproducibility was evaluated by the intraclass correlation coefficient (ICC). Results: The main characteristics of the 49 pregnant women were: mean age of 26.3 ± 4.7 years, ranging from 18 to 40 years, with mean gestational age of 33.6 ± 1.5 weeks and body mass index of 27.9 ± 4.5 kg/m2. The results of the PI obtained from the spectral Doppler evaluation of the fetal aortic isthmus, regarding the longitudinal plane, have demonstrated an average of 2.75 ± 0.46 for observer A, 2.53 ± 0.38 for observer B, and 2.74 ± 0.58 for the second measurement of observer A. For the transversal plane the mean values were 2.75 ± 0.46 for the observer A, 2.53 ± 0.38 for the observer B, and 2.74 ± 0.58 for the second measurement of the observer A. The Doppler evaluation of the fetal aortic isthmus in the longitudinal plane has shown a ICC of 0.25 in the comparison between the observers (interobserver), and 0.42 for the intraobserver analysis. In the transversal plane, the coefficients obtained were 0.18 and 0.43 respectively for the interobserver and intraobserver analysis. Conclusions: Although the role of the aortic isthmus in fetal hemodynamics is well established, the present study have reported that its reproducibility in the third trimester (32 to 36+6 weeks) is very poor, so the measurement of the AoI-PI should be interpreted with caution, discouraging its use in clinical practice. Studiesexamining technical amendments to improve its reproducibility should be encouraged