La bicuspidie aortique représente la malformation cardiaque congénitale la plus fréquente, affectant environ 2% de la population. Paradoxalement, le mécanisme de dégénérescence accélérée d’une valve bicuspide n’est pas encore élucidé. Ce travail s’appuie sur l’analyse de modèles animaux et sur l’analyse d’une cohorte prospective de 300 patients porteurs d’une valve aortique bicuspide.Notre cohorte de 300 patients nous a permis de chercher à identifier de nouveaux gènes impliqués dans la bicuspidie aortique par des approches de séquençage nouvelle génération, mais aussi par une approche de gène candidat. La comparaison des données cliniques et échographiques des patients porteurs de bicuspidie aortique avec et sans dysfonctionnement nous a permis d’établir une corrélation entre le phénotype de la bicuspidie et fonction valvulaire.Ce travail a eu pour objectif d’améliorer la compréhension de la physiopathologie de la bicuspidie aortique en identifiant de nouveaux gènes candidats et d’acquérir une meilleure connaissance du processus de dégénérescence valvulaire accélérée par le biais de modèles murins et d’études cliniques. / Bicuspid Aortic Valve (BAV) is the most common congenital heart defect, affecting about 2% of the population. BAV is a heritable trait, but the genetic basis underlying this defect remains unclear. BAV is associated with an excess of morbidity and mortality related to several complications such as accelerated valve degeneration that required earlier and more frequent referral for surgery. Despite its burden, the mechanism underlying BAV degeneration has not been elucidated. Aortic valve replacement constitutes a late response to a disease whose diagnosis is often carried out earlier, at the stage of non-severity. My thesis aims to identify the pathophysiology of BAV and to investigate the mechanisms involved in BAV degeneration. Thus, this study was based on the analysis of animal models and on the examination of a prospective cohort of 300 patients with BAV. Three hundred patients with BAV were prospectively included in our cohort to identify new genes involved in BAV by next generation sequencing and candidate-gene approach. The objective of this thesis was to improve our understanding of the pathophysiology of BAV and to assess the mechanisms underlying BAV degeneration by analyzing animal and clinical models.

Made available in DSpace on 2014-06-11T19:22:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2003Bitstream added on 2014-06-13T19:08:21Z : No. of bitstreams: 1 mello_fmc_me_botfm.pdf: 590394 bytes, checksum: 6bd49179dbdb5496cc2a8f6a9ebad2ed (MD5) / Com o objetivo de avaliar a ocorrência de aneurisma da aorta abdominal infra-renal (AAAIR), estudou-se uma amostra da população masculina do Município de Marília, com idade igual ou acima de 50 anos, no período de 2000 a 2002. Foram avaliados 240 homens por meio da ultrasonografia abdominal (USAb), com média de idade de 65,1 anos (±9,8 anos). A aorta abdominal foi medida no sentido ânteroposterior (AP) e látero-lateral (LL) aproximadamente a 2cm abaixo da artéria mesentérica superior (AMS) e 2cm acima de sua bifurcação. O critério utilizado para considerar aneurisma foi o maior diâmetro encontrado igual ou maior que 3,1cm. Também por questionário, foram avaliados os fatores de risco (tabagismo, sedentarismo, alimentação) e as doenças associadas (HAS, DPOC, IM, DM, AOP ou hiperlipidemia). Nos 240 homens, foram encontrados 11 aneurismas, sendo, portanto, a freqüência de 4,6%. Desses 11 aneurismas, 8 mediam entre 3,1 e 4cm (72,7%) e 3, entre 4,1 e 5cm (27,3%). O maior diâmetro da aorta aneurismática foi de 5 cm (sentido AP a 2cm abaixo da AMS). Foi encontrada uma associação significativa entre aneurisma e AOP e DM, não ocorrendo o mesmo com os demais fatores de risco ou outras doenças associadas. A freqüência de aneurisma encontrada em nossa amostra não foi diferente da referida nos estudos populacionais publicados na literatura, o que mostra a importância da doença em nosso meio, e os indivíduos com AOP e DM têm risco maior de desenvolver a doença. / In order to evaluate the occurrence of Infra-Renal Abdominal Aortic Aneurysm (AAAIR), a sample of the male population in the city of Marília aged 50 years or older was studied from 2000 to 2002. A group of 240 men with mean age of 65,1 years (±9,8 years) was evaluated through abdominal ultra-sonography examination. The abdominal aorta was measured in the anteroposterior (AP) and in the latero-lateral directions (LL) approximately 2cm below the superior mesenteric artery and 2cm above its bifurcation. The largest diameter equal or larger than 3.1cm found was the criterion used for aneurysm. Risk factors such as smoking, eating, and exercise habits and associated diseases (systemic arterial hypertension, chronic obstructive pulmonary disease, myocardial infarction, diabetes mellitus, occlusive peripheral arterial disease, or hyperlipidemia) were also evaluated through questionnaires. Eleven aneurysms were found in the 240 men, which meant a frequency of 4,6%. Out of these 11 aneurysms, 8 measured from 3.1 to 4cm (72,7%) and 3 measured from 4.1 to 5cm (27,3%). The largest diameter of the aneurysmatic aorta was 5cm (AP direction approximately 2cm of the superior mesenteric artery). A significant association between aneurysm and peripheral vascular disease and diabetes mellitus was found. The same did not occur with the other risk factors or other associated diseases. The frequency of aneurysm found in our sample was not different from the frequency mentioned in population studies published in the literature, which shows the importance of the disease in our environment and that patients with peripheral vascular disease and diabetes mellitus have a higher risk to develop the disease.

Abstract Fibrillar type I and III collagens are the major constituents of the extracellular matrix, providing the tissue with tensile strength and influencing cell attachment and migration. The amount of type III collagen and the extent of its processing and cross-link maturation were studied in human atherosclerotic plaques, abdominal aortic aneurysms, colon and ovarian cancer, and finally, colon diverticulosis, using a novel radioimmunoassay for the cross-linked aminoterminal telopeptide of type III collagen. In addition, immunoassays for different structural domains of type I and type III collagens, together with immunohistochemical methods, were applied. In atherosclerotic plaques, the fully cross-linked type III collagen was the major collagen type. Type III collagen was completely processed, since the amount of type III pN-collagen was negligible. The amounts of free type I and III procollagen propeptides in the soluble fraction were small, indicating a low rate of collagen turnover. The proportion of type III collagen was lower in abdominal aortic aneurysms than in atherosclerotic aortic control samples. Furthermore, the amount of type III pN-collagen was significantly increased in aneurysms. Type I and III collagens were also maturely cross-linked in colon diverticulosis, the only difference from normal colon tissue being the increased amount of the aminoterminal propeptide of type III procollagen in the soluble tissue extract, indicating a slightly increased metabolic activity of type III collagen. In malignant ovarian tumors, the cross-linking of type I and III collagens was defective. A similar trend was also seen for type I collagen in colon cancer. Even though procollagen synthesis was increased in these malignancies, the total collagen content and the amounts of cross-linked collagens were decreased. The amount of type III pN-collagen was increased in malignant ovarian tumors, whereas no such tendency was seen in colon cancer. These findings suggest a wide variety of changes in the metabolism of type I and III collagens in diseases. Defective processing and cross-link maturation of these collagen types might result in impaired fibril formation or increased susceptibility of collagens to proteolytic attack - both of them processes with a potential role in the pathogenesis of diseases.

No description available.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, for the degree of Doctor of Philosophy. Johannesburg, South Africa September 2017. / Although brachial blood pressure (BP) is a well-recognized risk factor for predicting cardiovascular events, aspects of aortic BP may enhance risk prediction. Pulse pressure (PP) is amplified from the aorta to peripheral arteries and variations in differences between brachial and aortic PP (PP amplification) are determined by factors that influence either the aortic forward (Pf) or backward (Pb)(reflected) pressure waves. Although aortic Pb may be more important than Pf in mediating cardiovascular risk, the best approach to assessing backward wave function (augmentation pressures [Pa] and index [AIx] or wave separation analysis); the relative impact of aortic Pb versus Pf on cardiovascular damage; and whether the ability of aortic-to-brachial PP amplification (PPamp) to add to risk prediction reflects backward or forward wave effects, is uncertain. In the present thesis I therefore first assessed in 808 community participants whether gender influences relations between Pa or AIx and left ventricular mass (LVM), a well-accepted end-organ measure. Aortic haemodynamics were determined using radial applanation tonometry and SphygmoCor software and LVM from echocardiography. In men, both AIx derived from Pa/central aortic PP (Pa/PPc) (p<0.01) and AIx derived from the second peak/first peak (P2/P1) of the aortic pulse wave (p<0.0005) were associated with LVM. In contrast, in women neither AIx derived from Pa/PPc (p=0.08) nor AIx derived from P2/P1 (p=0.17) were associated with LVM. Both the strength of the correlations (p<0.001 and p<0.0005) and the slope of the AIx-LVM relationships (p=0.001 and p<0.0005) were greater in men as compared to women. Therefore, in the present study I show that AIx is independently associated with LVMI in men, but not in women. I subsequently evaluated whether in women, measures of aortic systolic pressure augmentation (Pa or AIx) underestimate the effects of reflected waves on cardiovascular risk or whether Pb plays little role in cardiovascular risk prediction. In the same community sample I therefore evaluated sex-specific contributions of reflected (Pb and the reflection index [RI]) versus augmented (Pa and AIx) pressure wave indices to iii variations in PPc (n=1185, 65.0% women), and LVM (n=793, 64.9% women). Aortic Pb and Pf were determined using wave separation analysis. In both women and in men, independent of confounders, RI and Pb contributed more than Pf, whilst Pa and AIx contributed less than incident wave pressure (Pi) to variations in PPc (p<0.0001 for comparison of partial r values). In both men and in women Pb contributed more than Pf (p<0.05) to variations in LVM. Although in men Pa (partial r=0.33, p<0.0001) contributed to a similar extent as Pi ((partial r=0.34, p<0.0001) to variations in LVMI, in women Pa (partial r=0.05, p=0.36) failed to contribute to LVM, whilst Pi was significantly associated with LVM (partial r=0.30, p<0.0001). Similar results were obtained with AIx as opposed to Pa in the regression models. Therefore, in both women and in men, Pb is more closely associated with PPc and LVM than Pf, but indices of aortic pressure augmentation markedly underestimate these effects, particularly in women. As the relative impact of aortic Pb as compared to Pf on cardiovascular damage independent of brachial BP is uncertain, in 1174 participants from a community sample I subsequently assessed the relative impact of Pb and Pf on variations in LVM (n=786), aortic pulse wave velocity (PWV)(n=1019), carotid intima-media thickness (IMT)(n=578), transmitral early-to-late LV diastolic velocity (E/A)(n=779) and estimated glomerular filtration rate (eGFR)(n=1174). Independent of mean arterial pressure and confounders, PPc and both Pb and Pf were associated with end-organ measures or damage (p<0.05 to <0.0001). With adjustments for brachial PP and confounders, Pb remained directly associated with LVM (partial r=0.10, p<0.01), PWV (partial r=0.28, p<0.0001), and IMT (partial r=0.28, p<0.0001), and inversely associated with E/A (partial r=-0.31, p<0.0001) and eGFR (partial r=-0.14, p<0.0001). Similar relations were noted with the presence of end-organ damage (p<0.05 to <0.0001). In contrast, with adjustments for brachial PP and confounders, Pf no longer retained direct relations with LVM, PWV, and IMT or inverse relations with E/A and eGFR. Adjustments for Pb, but not Pf diminished brachial PP-independent relationships between PPc and end-organ measures. Thus, although both Pf and Pb contribute to end-organ measures and damage, independent of brachial iv BP, the impact of aortic BP is accounted for largely by Pb. PPamp is independently associated with cardiovascular outcomes. However, the aortic functional change most likely to account for this effect is uncertain. In 706 community participants I subsequently aimed to identify the aortic functional change that accounts for relations between PPamp and LVM. In multivariate models with the inclusion of brachial PP, 1/PPamp (partial r=0.12, p<0.005), Pb (partial r=0,09, p<0.05), and aortic PWV (partial r=0.09, p<0.05) were independently associated with LVMI. Similarly, in multivariate models with the inclusion of brachial PP, 1/PPamp (p<0.005), Pb (p<0.01), and aortic PWV (p<0.01) were independently associated with LV hypertrophy (LVH). With adjustments for Pb, the brachial PP-independent relationships between 1/PPamp and LVMI or LVH were abolished (p>0.08 for both). However, adjustments for PWV failed to modify brachial PP-independent relations between 1/PPamp and LVMI or LVH. Hence, independent relations between PPamp and LVM or LVH are largely accounted for by Pb. In conclusion, in the present thesis I show that the use of augmented pressures underestimates the impact of reflected pressure wave effects on end-organs, particularly in women; that brachial BP-independent relations between aortic BP and end organs is determined largely by Pb and that relations between PPamp and end organ measures is largely accounted for by Pb. These findings add to our understanding of the adverse effects of aortic functional changes on the cardiovascular system and suggest cost-effective approaches to add to risk prediction. / LG2018

In calcific aortic valve disease, the early sclerotic valve lesion is similar to the atherosclerotic arterial plaque, but at the later stage calcification prevails. Our aim was to assess the association of several new potential risk factors, eg. systemic inflammation, neurohormonal activation and altered calcium metabolism with aortic stenosis (AS) in patients with significant coronary artery disease..

Symptomatic aortic stenosis (AS) is an increasing phenomenon as more adults live longer. The gold standard for treating AS is surgical aortic valve replacement (SAVR). Frequently, as older individuals with AS often have multiple comorbidities, a SAVR is determined to be too high risk. Therefore, a less invasive treatment option is available, namely a transcatheter aortic valve implantation (TAVI) or transcatheter aortic valve replacement (TAVR). Such biomedical procedures have encouraged life extension and the decision to intervene commonplace with the aging population. Without an intervention, significant debilitating symptoms affect a person's quality of life (QoL). Multiple quantitative studies evaluating QoL before and after a TAVI have been performed. However QoL has multiple attributes and is not a single construct. By limiting practice to these defined QoL measures, we exclude the human experience and what values individuals describe as important to them. The dilemma in the present medical model is influenced by two paradigms, evidence based medicine and patient centered medicine. Some people opt not to have a TAVI. This study aims to understand what it is like living with aortic stenosis as perceived by the participant and to gain a more meaningful understanding of why some individuals with AS choose not to have this procedure performed. Using a convenience sample of patients who declined a TAVI, a telephone interview with the person focused on their perceived QoL and the implications determining not to pursue a TAVI. In this qualitative phenomenological design, open-ended questions included: 1) What is it like to live with Aortic Stenosis. 2) Why did you choose not to have the TAVI? Interviews will explore emerging themes. Advanced practice nurses are in ideal positions for performing research to gain greater insight on the complexity of people's health choices. As the incidence of AS occurs more frequently in the increasing aged population, TAVI offers a treatment option for those patients who are symptomatic with AS and are not surgical candidates. However, health care providers should focus on the illness, not the disease, and explore the patients' biopsychosocial values with their medical needs. The information gathered in this study will help guide heath care providers with offering holistic health care incorporating both paradigms of evidence based practice and patient centered medicine options on treatment for people with symptomatic AS.

Diss. Linköping : Linköpings universitet, 2008.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13399号 / 論医博第2223号 / 新制||医||1051(附属図書館) / (主査)教授 今中 雄一, 教授 佐藤 俊哉, 教授 福田 和彦 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM