Orientador: Beatriz B. Matsubara / Resumo: Placa de aterosclerose em aorta torácica é uma importante causa de acidente vascular cerebral (AVC) e ataque isquêmico transitório (AIT). Sua gênese estaria relacionada com migração, para a circulação cerebral, de trombos e cristais de colesterol que se desprenderiam de placas complexas, localizadas na aorta torácica proximal. Existem várias semelhanças entre a fisiopatologia do desenvolvimento da placa de aterosclerose e a remodelação miocárdica. Por causa disso, formulou-se a hipótese de que a avaliação de pacientes com AVC e AIT, por meio do ecocardiograma transtorácico ((ETT), pode identificar características associadas com risco aumentado de placa de aterosclerose em aorta. Os objetivos desse estudo foram: 1) avaliar a incidência de placa de aterosclerose em aorta torácica de pacientes com história de AVC e AIT prévios, por meio do ecocardiograma transesofágico (ETE); 2) avaliar se existe associação entre a presença dessas placas e sinais de remodelação ventricular, observados por meio do ETT; e, finalmente, 3) analisar os níveis séricos de proteína C reativa de alta sensibilidade (PCRas), nesses pacientes... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Atherosclerosis plaque in the thoracic aorta is an important cause of acute cerebrovascular events. It would be caused by migration of thrombi and cholesterol cristals released from complex plaques, located at the proximalis thoracic aorta, to the cerebral circulation. Because there are several similarities between the physiopathology of atherosclerosis plaque development and myocardial remodeling. We hypothesized that patients with cerebrovascular events, and atherosclerosis plaque have cardiac morpho-functional alterations. The objectives of the present study were: 1) to evaluate the incidence of thoracic aorta artherosclerosis plaques in patients with a previous cerebrovascular events history, by transesophageal echocardiogram (TEE); 2) to evaluate if there is an association between the presence of plaques and signs of ventricular remodeling, observed by means of transthoracic echocardiogram; and, 3) to analyze the high sensitivity C-reactive protein (hs-CRP) seric levels, in those patients. One hundred and sixteen patients (79 male) with a previous... (Complete abstract click electronic address below) / Doutor

Made available in DSpace on 2014-06-11T19:31:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2004Bitstream added on 2014-06-13T18:41:27Z : No. of bitstreams: 1 hueb_jc_dr_botfm.pdf: 402586 bytes, checksum: 0363aade5dace29841c7485277d2b0f8 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Placa de aterosclerose em aorta torácica é uma importante causa de acidente vascular cerebral (AVC) e ataque isquêmico transitório (AIT). Sua gênese estaria relacionada com migração, para a circulação cerebral, de trombos e cristais de colesterol que se desprenderiam de placas complexas, localizadas na aorta torácica proximal. Existem várias semelhanças entre a fisiopatologia do desenvolvimento da placa de aterosclerose e a remodelação miocárdica. Por causa disso, formulou-se a hipótese de que a avaliação de pacientes com AVC e AIT, por meio do ecocardiograma transtorácico ((ETT), pode identificar características associadas com risco aumentado de placa de aterosclerose em aorta. Os objetivos desse estudo foram: 1) avaliar a incidência de placa de aterosclerose em aorta torácica de pacientes com história de AVC e AIT prévios, por meio do ecocardiograma transesofágico (ETE); 2) avaliar se existe associação entre a presença dessas placas e sinais de remodelação ventricular, observados por meio do ETT; e, finalmente, 3) analisar os níveis séricos de proteína C reativa de alta sensibilidade (PCRas), nesses pacientes... / Atherosclerosis plaque in the thoracic aorta is an important cause of acute cerebrovascular events. It would be caused by migration of thrombi and cholesterol cristals released from complex plaques, located at the proximalis thoracic aorta, to the cerebral circulation. Because there are several similarities between the physiopathology of atherosclerosis plaque development and myocardial remodeling. We hypothesized that patients with cerebrovascular events, and atherosclerosis plaque have cardiac morpho-functional alterations. The objectives of the present study were: 1) to evaluate the incidence of thoracic aorta artherosclerosis plaques in patients with a previous cerebrovascular events history, by transesophageal echocardiogram (TEE); 2) to evaluate if there is an association between the presence of plaques and signs of ventricular remodeling, observed by means of transthoracic echocardiogram; and, 3) to analyze the high sensitivity C-reactive protein (hs-CRP) seric levels, in those patients. One hundred and sixteen patients (79 male) with a previous... (Complete abstract click electronic address below)

O objetivo deste estudo foi investigar os efeitos do hipotiroidismo experimental sobre o leito vascular da aorta torácica. Para a análise histológica foram realizadas colorações de hematoxilina-eosina, picrosirius e Weigert. Na análise de expressão proteica, foram realizadas as quantificações para colágeno I e III, elastina, MMP-9 e MMP-2, TIMP-1 e TIMP-2. As análises histológicas demonstraram uma diminuição da AST das aortas dos animais hipo e juntamente a esta alteração, foi constatada a diminuição da expressão proteica de colágeno do tipo I. Em relação à elastina, foi possível observar aumento da expressão deste elemento nas aortas dos animais hipotiroideos. Na avaliação da expressão proteica para MMP-9, foi possível verificar uma redução desta proteína no grupo hipotiroideo, assim como um aumento da expressão de TIMP-2. Frente aos presentes resultados, é possível sugerir que o estado hipometabólico desencadeado pelo hipotiroidismo afeta as CMLVs comprometendo mecanismos de síntese/degradação, alterando o importante arranjo da MEC presente na aorta torácica. / The aim of this study was to investigate hypothyroidism effects on thoracic aorta wall. For histological analyses were performed stains like hematoxilin-eosin, picrosirius and Weigert. In the protein expression assays were performed quantification for collagen I and III, elastin, MMP-9, MMP-2, TIMP-1 and TIMP-2. The histological analyses showed a decrease in aortas CSA and also a decrease in protein expression of collagen I in the hypo group. As regards to elastin, was possible to see an increase of this protein expression in hypo animals. In the evaluation for MMP-9 expression, was found a decrease in this protein and for TIMP-2 an increase in hypothyroidism group. Facing to these results, is possible to suggest that the hypometabolic state triggered by hypothyroidism, affects the VSMCs compromising mechanisms of synthesis/degradation and changing the important constitution of thoracic aorta ECM.

O objetivo deste estudo foi investigar os efeitos do hipotiroidismo experimental sobre o leito vascular da aorta torácica. Para a análise histológica foram realizadas colorações de hematoxilina-eosina, picrosirius e Weigert. Na análise de expressão proteica, foram realizadas as quantificações para colágeno I e III, elastina, MMP-9 e MMP-2, TIMP-1 e TIMP-2. As análises histológicas demonstraram uma diminuição da AST das aortas dos animais hipo e juntamente a esta alteração, foi constatada a diminuição da expressão proteica de colágeno do tipo I. Em relação à elastina, foi possível observar aumento da expressão deste elemento nas aortas dos animais hipotiroideos. Na avaliação da expressão proteica para MMP-9, foi possível verificar uma redução desta proteína no grupo hipotiroideo, assim como um aumento da expressão de TIMP-2. Frente aos presentes resultados, é possível sugerir que o estado hipometabólico desencadeado pelo hipotiroidismo afeta as CMLVs comprometendo mecanismos de síntese/degradação, alterando o importante arranjo da MEC presente na aorta torácica. / The aim of this study was to investigate hypothyroidism effects on thoracic aorta wall. For histological analyses were performed stains like hematoxilin-eosin, picrosirius and Weigert. In the protein expression assays were performed quantification for collagen I and III, elastin, MMP-9, MMP-2, TIMP-1 and TIMP-2. The histological analyses showed a decrease in aortas CSA and also a decrease in protein expression of collagen I in the hypo group. As regards to elastin, was possible to see an increase of this protein expression in hypo animals. In the evaluation for MMP-9 expression, was found a decrease in this protein and for TIMP-2 an increase in hypothyroidism group. Facing to these results, is possible to suggest that the hypometabolic state triggered by hypothyroidism, affects the VSMCs compromising mechanisms of synthesis/degradation and changing the important constitution of thoracic aorta ECM.

Amyloidoses are a group of protein misfolding diseases characterized by deposits of insoluble fibrillar protein aggregates. Medin amyloid, which is the focus of this thesis, appears in the media of the thoracic aorta in nearly all individuals over 50 years. The fibrils are derived from a 50 amino acid residue fragment of the precursor protein lactadherin. How medin amyloid arises is unknown, but in paper I we demonstrated, with immunohistochemical and in vitro binding experiments, that both lactadherin and medin interact with elastin, implying that the elastic fibre is central in amyloid formation. In paper II, we further showed that the last 18-19 amino acid residues constitute the amyloid-promoting region. In paper III, the consequence of medin deposition was investigated. Aortic specimens from patients with thoracic aorta aneurysm and dissection were examined for medin content. The tissue findings indicated that the two disease groups contained more medin oligomers than normal aortas. Interestingly, recent reports demonstrate that the toxicity of amyloid proteins is attributed to prefibrillar oligomeric aggregates rather than to mature fibrils. In support of this finding, we observed that prefibrillar medin, in contrast to medin fibrils, was toxic in cell culture. Amyloid formation is a nucleation-dependent process. Addition of preformed fibrils to an amyloid protein solution dramatically accelerates fibrillation, a phenomenon called seeding. In paper IV, serum amyloid A-derived (AA) amyloid was found co-localized with medin deposits in the aorta. In vitro, medin fibrils enhanced the formation of AA fibrils, indicative of a seeding mechanism. The data are of great importance as they suggest that one type of amyloid is capable of inducing fibrillation and deposition of another amyloid type. In conclusion, the results of this thesis shed light on how medin is formed, the function of lactadherin and the consequences of medin deposition for aortic pathology.

Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention. Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers. Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age. Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p<0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10. Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI. Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers. Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.

Thesis (Ph. D.)--University of Missouri-Columbia, 2006. / Title from title screen of research.pdf file (viewed on December 22, 2006). The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "May 2006" Includes bibliographical references.

L’épidémiologie des anévrismes de l’aorte est un problème de santé publique majeur dans les pays industrialisés. Cette pathologie peut engendrer la mort du patient en cas de rupture de l’anévrisme. Actuellement les critères d’intervention chirurgicale sont basés sur la morphologie de l’anévrisme et il existe des difficultés à évaluer correctement le risque de rupture pour chaque patient. L’objectif de cette thèse était de développer une méthode d’identification des propriétés mécaniques de la paroi artérielle de manière personnalisée permettant d’affiner les critères d’intervention chirurgicale. Des essais de gonflement utilisant des mesures de champs et le développement d’une méthodologie d’analyse ont permis de quantifier la distribution des contraintes des anévrismes de manière expérimentale et de mettre en évidence l’apparition des affaiblissements ponctuels dans la paroi afin de prédire la localisation de la rupture de l’anévrisme. Ensuite, une méthode d’identification de propriétés mécaniques a été mise en place pour mettre en évidence l’hétérogénéité du tissu artériel et pour localiser les endroits à l’origine de la rupture du tissu. L’identification des lois de comportement à partir de données expérimentales issues de patients permettra d’améliorer les modèles numériques artériels utilisées aujourd’hui. De plus, la méthodologie créée pour l’analyse de la rupture d’anévrismes pendant cette thèse ouvre la porte à une étape qui vise à développer la caractérisation mécanique in-vivo par l’utilisation de l’imagerie médicale. L’objectif final sera d’évaluer le risque de rupture de l’anévrisme de chaque patient de manière non-invasive. / Epidemiology of aortic aneurysms is a major public health issue that affects a significant proportion of the population in industrialized countries and can cause the death of the patient in case of rupture of the aneurysm.Currently the only criteria for surgery are based on the morphology of the aneurysm, and there are problems to accurately assess the risk of rupture for each patient.The aim of this thesis was to develop a method to identify the mechanical properties of the arterial wall in a personalized way to refine the criteria for surgery.Inflation tests, full-field measurements and a methodology developed were used in order to quantify experimentally the stress distribution of aneurysms. It was possible to highlight the appearance of localized weakening in the wall which will let us predict the location of the rupture on the aneurysm. Then a method was developed to identify the mechanical properties of the aortic tissue. It was possible to highlight the heterogeneity of arterial tissue and locate the places where the rupture of the tissue may occur.The identification of the aneurysm’s mechanical properties from experimental data will improved arterial numerical models used today. In addition, the methodology developed for the analysis of the rupture of aneurysms during this thesis opens the door to a step that aims to develop the in vivo mechanical characterization by the use of medical imaging. The ultimate goal will be to assess the risk of rupture of the aneurysm of each patient in a noninvasive manner.

Background: Effects of cardiovascular (CV) risk factors on the diameter of the thoracic aorta have not been fully studied. This study examined the associations between CV risk factors and diameter of thoracic aorta. Materials and Methods: Study population comprised of 1273 asymptomatic adults aged ≥18 years from Central Appalachia region of the United States who participated in a coronary artery screening between January 2014 and December 2016. Descriptive statistics and multiple linear regression analyses were performed to examine associations between multiple CV risk factors and diameters of the thoracic aorta. Results: Mean (±SD) age of participants was 57.9±9.7 years; that of body mass index (BMI) was 29.4±5.9. The mean aortic sinus, ascending aorta, and descending aorta diameter were 34.1±4.4 mm, 33.8±4.4 mm, and 26.0±3.6 mm, respectively. Increasing age, being male, and having a higher BMI were associated with wider aortic sinus, ascending aorta, and descending aorta diameters. Hypertension (p < 0.05) and obesity (p < 0.0001) were significantly associated with wider diameter for all measured aortic diameters. Participants with diabetes had wider descending aorta compared to those without (26.6±3.9 mm vs. 25.9±3.5 mm, P = 0.012). Participants who had ever smoked a cigarette had significantly wider descending aorta diameter compared to never smokers (26.3±3.6 mm vs. 25.9±3.5 mm, p = 0.031). Conclusions: The study results suggest that decreasing BMI and management of CV risk factors such as hypertension and modifying behavioral risk factors such as smoking are likely to be emphasized in order to decrease the rate of aortic dilatation and subsequent aortic dissection, if aortic dilatation is detected during a CT scan.

INTRODUÇÃO: O tratamento endovascular das doenças da aorta é modalidade consagrada atualmente, sendo realizado em indivíduos jovens e idosos, tanto na aorta torácica quanto na abdominal. Esta terapia baseia-se numa interação adequada entre a endoprótese e a parede aórtica. Neste sentido, o conhecimento do comportamento biomecânico da aorta é fundamental. A aorta humana é uma estrutura complexa, com comportamento biomecânico diferente de acordo com a idade, a região e a presença de doenças. Estudos com biomecânica da aorta humana não aneurismática são escassos. OBJETIVOS: Analisar os parâmetros biomecânicos de falência e as características histológicas da aorta torácica e abdominal humana, correlacionando-os com idade e gênero. MÉTODO: Testes destrutivos uniaxiais de espécimes removidos de 26 aortas frescas de cadáveres foram realizados num aparelho de tração universal. Os parâmetros biomecânicos de falência avaliados foram: força, tensão, estresse, deformação e energia de deformação. Foi realizado estudo histológico do tecido aórtico para quantificação de fibras colágenas, musculares e elásticas. RESULTADOS: Foram analisados os testes biomecânicos válidos de 153 espécimes, sendo 95 da aorta torácica e 58 da aorta abdominal. Na comparação entre aorta torácica e abdominal, realizada por análise de variância, foi observado que diâmetro (30,45 versus 23,99 mm; p < 0,001), espessura (1,69 versus 1,44 mm; p < 0,001), força máxima (6,18 versus 4,85 N; p = 0,001), tensão de falência (19,88 versus 14,53 N/cm; p = 0,001), deformação de falência (0,66 versus 0,49; p = 0,003) e a percentagem de fibras elásticas (19,39 versus 14,06 %; p = 0,011) foram maiores, com significância, na aorta torácica. As correlações de Spearman entre idade e força máxima, estresse de falência, tensão de falência, deformação de falência e energia de deformação foram negativas e significativas na aorta torácica e abdominal. As aortas do sexo masculino, através do teste t de Student, apresentaram maior força máxima e tensão de falência. Não houve diferença na composição histológica entre os gêneros. CONCLUSÕES: A aorta torácica é mais resistente e elástica que a aorta abdominal. O conteúdo de fibras elásticas é maior na aorta torácica. Os idosos apresentam aortas menos resistentes e mais rígidas que os jovens. A aorta do sexo masculino é mais resistente / INTRODUCTION: The endovascular repair of aortic diseases is currently widely performed among young and elderly patients, in both the thoracic and abdominal aorta. This treatment is based on an appropriate interaction between the stent graft and the aortic wall. Thus, it is essential to understand the biomechanical behavior of the aorta. The human aorta is a complex vessel with different biomechanical behaviors according to age, location and diseases. There are few biomechanical studies of the human nonaneurysmal aorta. OBJECTIVES: To analyze the biomechanical properties and histological composition of the human aorta according to age and gender. METHODS: Twenty-six human aortas were harvested whole from fresh cadavers during their autopsies. Each aorta was cut into strips for mechanical testing. Uniaxial tensile tests were performed on a tensile-testing machine. The failure load, failure stress, failure tension, failure strain and strain energy were calculated. A histological study was performed to measure the amount of collagen, elastin and smooth muscle cells in the aortic wall. RESULTS: A total of 153 strips were studied (95 from the thoracic aorta and 58 from the abdominal aorta). The diameter (30.45 versus 23.99 mm; p < 0.001), thickness (1.69 versus 1.44 mm; p < 0.001), failure load (6.18 versus 4.85 N; p = 0.001), failure tension (19.88 versus 14.53 N/cm; p = 0.001), failure strain (0.66 versus 0.49; p = 0.003) and elastin amount (19.39 versus 14.06 %; p = 0.011) were all significantly higher for the thoracic aorta than for the abdominal aorta. There was a significant negative Spearman\'s correlation between age and failure load, failure stress, failure tension, failure strain and strain energy. Male aortas had a higher failure load and failure tension than female aortas. No difference in the histological composition was found between the genders. CONCLUSIONS: The thoracic aorta has a higher strength and elasticity than the abdominal aorta. The elastin amount is higher in the thoracic aorta than in the abdominal aorta. The elderly have weaker and stiffer aortas than the young. Male aortas have a higher strength than female aortas