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Déterminants de la progression et de la réponse myocardique dans le rétrécissement aortique calcifié / Determinants of progression and myocardial response in calcipic aortic stenosisArangalage, Dimitri 17 September 2018 (has links)
Le rétrécissement aortique calcifié (RAC) est une maladie calcifiante de la valve aortique caractérisée par un remodelage fibro-calcique lentement progressif des feuillets valvulaires, et par un remodelage du ventricule gauche (VG). Il n’existe à ce jour aucun traitement pharmacologique capable de prévenir la maladie, et le seul traitement consiste en un remplacement valvulaire chirurgical ou percutané. Les objectifs de cette thèse étaient d’identifier des déterminants de la progression du RAC et du remodelage VG, d’étudier une nouvelle modalité d’évaluation de la sévérité du RAC, et d’analyser par une approche expérimentale les mécanismes initiateurs de la calcification valvulaire aortique. Les résultats de ce travail peuvent être résumés comme suit : - Le taux plasmatique de galectine-3 n’était pas associé au degré de sévérité du RAC ou au statut fonctionnel des patients. La galectine-3 n’avait pas de valeur pronostique sur la survenue d'événements liés au RAC. Les résultats observés sont en défaveur de l'utilisation de ce biomarqueur au cours de la prise en charge des patients ayant un RAC asymptomatique. - Dans une cohorte prospective de patients ayant un RAC au moins minime, le volume de graisse épicardique était indépendamment associé à un remodelage péjoratif du VG. Ce résultat suggère que la graisse épicardique pourrait être un déterminant du remodelage pathologique du VG via une interaction locale. - L’utilisation de l’imagerie de fusion a entrainé une augmentation du taux de discordance entre les paramètres de sévérité du RAC. Ce résultat était plus marqué chez les patients ayant une valve aortique bicuspide. Au regard de la classification et des seuils définissant actuellement la sévérité du RAC, et du fait de leur valeur pronostique bien démontrée, les résultats de cette étude sont en défaveur de l'utilisation de l’imagerie de fusion pour évaluer la sévérité du RAC. - L’accumulation dans le feuillet valvulaire aortique d’érythrocytes sénescents, suite à la survenue de lésions endothéliales non cicatrisées, constitue une situation délétère favorisant la différenciation des cellules valvulaires interstitielles vers un phénotype ostéoblastique et in fine le dépôt de calcium conduisant au RAC. La physiopathologie d’initiation des calcifications valvulaires et de progression du RAC est complexe et multifactorielle. La découverte de cibles thérapeutiques potentielles et l’optimisation de la prise en charge des patients ayant un RAC nécessite de combiner des études cliniques pour identifier les déterminants de la progression et de la réponse myocardique au cours du RAC, et une approche fondamentale pour caractériser les mécanismes impliqués dans la maladie. / Calcific aortic stenosis (AS) is characterized by a slowly progressive fibrocalcific remodeling of aortic valve leaflets, and by a left ventricular (LV) remodeling. There is currently no effective medical treatment capable of preventing disease progression, and the only treatment is surgical or percutaneous valve replacement. The objectives of this thesis were to identify determinants of AS progression and LV remodeling, to study a new modality of evaluation of AS severity, and to analyze through an experimental approach the initiating mechanisms of valve calcification. The results of this work can be summarized as follows: - The plasmatic level of galectin-3 was not associated with the degree of AS severity or the functional status of patients. Galectin-3 had no prognostic value for the occurrence of AS-related events. The results observed are not in favor of the use of this biomarker for the management of patients with asymptomatic AS. - In a prospective cohort of patients with at least mild AS, epicardial fat volume was independently associated with an adverse remodeling of the LV. This result suggests that epicardial fat may be a determinant of pathological LV remodeling through a local interaction. - The use of fusion imaging increased the rate of discordant AS severity parameters. This result was more pronounced in patients with a bicuspid aortic valve. Considering current classification and thresholds defining AS severity, and their well-proven prognostic value, the results of this study do not favor the use of fusion imaging to assess AS severity. - The accumulation of senescent erythrocytes in aortic valve leaflets, consecutive to unhealed endothelial injury, is a noxious condition that promotes the differentiation of valvular interstitial cells towards an osteoblastic phenotype and favor calcium deposition leading to AS. The pathophysiology of initiation of valvular calcification and AS progression is complex and multifactorial. The discovery of potential therapeutic targets and the optimization of the management of patients with AS require the combination of clinical studies to identify the determinants of AS progression and myocardial response, and a fundamental approach to characterize mechanisms involved in the disease.
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Purification and Characterization of Proteoglycan from Bovine Aortic Endothelial Cells Conditioned Media, and its Interaction with Basic Fibroblast Growth Factor (bFGF)Wang, Ningling III 22 September 1997 (has links)
Cultured bovine aortic endothelial (BAE) cells were found to synthesize and secrete heparan sulfate proteoglycans (HSPG), which bound basic fibrobalst growth factor (bFGF). bFGF is a known mitogen for vascular smooth muscle cells, and is indicated to have a role in some proliferative vascular disorders. In the present study, we have purified proteoglycans from BAE cells conditioned media (BAE PG), and further separated the PG into two fractions, PG-I and PG-II, by ion exchange chromatography on a Q-Sepharose column using a linear salt gradient (0.15 M to 1.2 M). PG-I and PG-II elute at 0.85M salt and 0.1M salt respectively. BAE PG is primarily composed of heparan sulfate, which is accessible to the digestion of Heparinase I/III and nitrous acid treatment; and a small amount of chondroitin sulfate, which can be digested by Chondroitinase ABC. Gel filtration chromatography (Sepharose CL-2B and CL-4B columns) showed that BAE PG consisted of two different sized peaks, and had an average molecular weight of approximately 5 x 10⁵ Da. SDS-PAGE with silver staining indicated that BAE PG had two core proteins with estimated sizes of 300kDa and 320kDa, which corresponded to the core protein of PG-I and PG-II respectively. Western blotting with anti-perlecan primary antibody recognized the core proteins of BAE PG. Size exclusion chromatography (Sepharose CL-6B column) following β-elimination showed that BAE PG had GAG chains with an estimated size less than 2 x 10⁵ Da.
A protocol to investigate the cell free binding of bFGF with purified BAE PG was established using the BioRad Bio-Dot apparatus - the cationic filtration assay (CAFAS). Using a simple monovalent binding model, we obtained values for the equilibrium dissociation constant, K<sub>D</sub>, of (1.6 ± 0.8) x 10⁻¹⁰ M; the dissociation rate constant, k<sub>r</sub>, of 0.01 min⁻¹; the association rate constant, k<sub>f</sub>, of 6.2 x 10⁷ M⁻¹min⁻¹ and the total binding sites of the proteoglycan, R<sub>T</sub>, of 0.1~0.2 (# of site)/(molecule of PG). The comparison of experimental data with model predictions indicates that when the number of binding sites provided by the PG is similar or greater than that of bFGF, the monovalent binding model is valid. When the number of binding sites is less than that of bFGF, one possibility is that the binding might not be the described simple monovalent reaction, and bFGF might bind to the PG as dimers or oligomers. In addition, a model is proposed for BAE PG, in which 5 ~ 10 BAE PG molecules form a high affinity binding site for bFGF. Experimentally we find that exogenous heparan sulfate competes with BAE PG for binding with bFGF, while chondroitin sulfate seems to facilitate the binding. This result may be a useful consideration when we want to design possible pharmaceutical compounds. / Master of Science
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Exacerbation of Intracranial Aneurysm and Aortic Dissection in Hypertensive Rat Treated With the Prostaglandin F-Receptor Antagonist AS604872 / プロスタグランジンF受容体選択的阻害薬AS604872は高血圧ラットにおいて脳動脈瘤と大動脈解離を増悪させるFukuda, Miyuki 25 January 2016 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19397号 / 医博第4048号 / 新制||医||1012(附属図書館) / 32422 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 小泉 昭夫, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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The tumor suppressor Reck is critical for vascular patterning and stabilization in mice / マウス血管のパターン形成と安定化におけるがん抑制遺伝子Reckの重要性Glicia, Maria De Almeida 23 March 2016 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第19865号 / 生博第346号 / 新制||生||46(附属図書館) / 32901 / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 渡邊 直樹, 教授 松田 道行, 教授 根岸 学 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM
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Prevention of abdominal aortic aneurysm progression by oral administration of green tea polyphenol in a rat model / 緑茶ポリフェノール経口投与によるラット腹部大動脈瘤進展抑制効果Setozaki, Shuji 23 March 2017 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20236号 / 医博第4195号 / 新制||医||1019(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 松原 和夫, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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The Influence of Cyclic Pressure and Angiotensin II on the Biomechanical Properties of Aortic Heart ValvesMyles, Valtresa Shena 11 May 2013 (has links)
Hypertension, a risk factor for aortic valve stenosis, increases transvalvular load and can elicit extracellular matrix (ECM) remodeling. Elevated cyclic pressure and the vasoactive agent angiotensin II (Ang II) both promote collagen synthesis, an early hallmark of aortic sclerosis. It was hypothesized that increased collagen production induced by elevated pressure conditions or the presence of Ang II would affect the mechanical properties of leaflet tissue by decreasing extensibility. Porcine aortic valve leaflets were exposed to pressure conditions of increasing magnitude with and without Ang II. Biaxial mechanical testing was performed to determine peak stretch. Collagen content was determined using a quantitative dye-binding method. The results demonstrated Ang II and elevated pressure decrease the extensibility of leaflet tissue and increase the collagen content in the ECM. In conclusion, the results demonstrated that both elevated pressure and Ang II play a role in altering the biomechanical properties of aortic valve leaflets.
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Analysis of Acute Type A Aortic Dissection in Japan Registry of Aortic Dissection (JRAD) / JRAD データベースを用いたStanford A型急性大動脈解離の解析Inoue, Yosuke 25 July 2022 (has links)
京都大学 / 新制・論文博士 / 博士(医学) / 乙第13494号 / 論医博第2259号 / 新制||医||1060(附属図書館) / (主査)教授 石見 拓, 教授 大鶴 繁, 教授 近藤 尚己 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Inhibition of microRNA-33b specifically ameliorates abdominal aortic aneurysm formation via suppression of inflammatory pathways / マイクロRNA-33bの阻害は、炎症経路の抑制を介して腹部大動脈瘤形成を特異的に改善するYamasaki, Tomohiro 23 March 2023 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第24484号 / 医博第4926号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森信 暁雄, 教授 YOUSSEFIAN Shohab, 教授 齊藤 博英 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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A Comparative Study for the Effect of Tissure Anisotropy on the Behavior of a Single Cardiac Pressure Cycle for a Symmetric Tri-Leaflet ValveThomas, Vineet Sunny 13 December 2010 (has links)
No description available.
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Mechanical Studies on the Porcine Aortic Valve Part I: Geometrical Asymmetry, Material Inhomogeneity and Anisotropy in the Porcine Aortic ValveChong, Ming 12 1900 (has links)
<p> Various areas of studies on the natural and the prosthetic aortic valves are reviewed. </p> <p> A microtensile technique devised to investigate the inhomogeneous and anisotropic material properties of a porcine aortic valve's leaflets is described. Also, the theory and apparatus of a new stereophotogrammetric technique to define points in space by their Cartesian coordinates is introduced. The technique is used to investigate the local surface strains and curvatures of a porcine aortic valve's leaflets from 0 to 120 mm. Hg. in-vitro. </p> <p> It is found that the valve leaflets display marked inhomogeneity and anisotropy (orthotropy is assumed) in the elastic moduli and transition strains. For the non-coronary leaflet, the radial post-transition moduli vary from 42 to 215 gm/mm² with a mean of 111 gm/mm² (s.d. = 43 gm/mm²); and the radial transition strains vary from 30% to 70% with a mean of 58% (s.d. = 7%). Areas nearer the leaflet's coaptation edge tend to exhibit lower radial transition strains than the annulus edge. The central region of the leaflet is found to be the stiffest. For the same non-coronary leaflet, the circumferential post-transition moduli vary from 220 to 590 gm/mm² with a mean of 342 gm/mm² (s.d. = 118 gm/mm²); and the circumferential transition strains vary from 22% to 47% with a mean of 33% (s.d. = 3%). </p> <p> Inhomogeneity between leaflets is also observed; preliminary results seem to suggest that the non-coronary leaflet is the stiffest in the radial direction and the least stiff in the circumferential direction. In comparison, the right coronary leaflet exhibits the largest radial transition strains (~80% ) and the smallest circumferential transition strains (~25%). </p> <p> For the diastolic valve in-vitro, the circumferential strains are less than 10% at all pressures; therefore , this suggests pre-transition behaviour during diastole which is contrary to the general belief. Radial strains at diastole vary from 10% to well over 100% and show a definite tendency to increase from the sinus-annulus edge to the coaptation edge. The non-coronary leaflet is the least strained of the leaflets (10% to 60% at diastole). </p> <p> The determination of pre-or post-transition state at diastole is discussed and the implications of the results on stress analyses and trileaflet valve designs are noted. </p> / Thesis / Master of Engineering (ME)
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