The goal of this research is to contribute to the development of MARS spectral CT and to demonstrate the feasibility of molecular imaging using the technology. MARS is a newly developed micro CT scanner, incorporating the latest spectroscopic Medipix photon counting detector. I show that the scanner can identify both drug markers and stenosis of atherosclerosis labelled with non-toxic nanoparticles. I also show that spectral computed tomography using Medipix x-ray detectors can give quantitative measurements of concentrations of gold nanoparticles in phantoms, mice and excised atheroma. The characterisation of the Medipix2 assemblies with Si and CdTe x-ray sensors using poly-energetic x-ray sources has been performed. I measure the inhomogeneities within the sensors; individual pixel sensitivity response; and their saturation effects at higher photon fluxes. The effects of charge sharing on the performance of Medipix2 have been assessed, showing that it compromises energy resolution much more than spatial resolution. I have commissioned several MARS scanners incorporating several different Medipix2 and Medipix3 cameras. After the characterization of x-ray detectors and the geometrical assessment of MARS-CT, spectral CT data has been acquired, using x-ray energies that are appropriate for human imaging. The outcome shows that MARS scanner has the ability to discriminate among low atomic number materials, and from various concentrations of heavy atoms. This new imaging modality, used with functionalized gold nanoparticles, gives a new tool to assess plaque vulnerability. I demonstrated this by using gold nanoparticles, attached to antibodies, which targeted to thrombotic events in excised plaque. Likewise, the imaging modality can be used to track drugs labelled with any heavy atoms to assess how much drug gets into a target organ. Thus the methodology could be used to accelerate development of new drug treatments for cancers and inflammatory diseases.

Caractérisation des propriétés mécaniques de la plaque d'athérome à partir de données échographiques endovasculaires : La technique de palpographie revisitée. Ce travail de thèse a pour ambitions de créer des outils issus de la théorie de la mécanique des milieux continus dans le but de détecter et de caractériser les propriétés mécaniques des plaques d'athéromes vulnérables. Une première partie du travail a consisté à reformuler et à corriger une approche de palpographie permettant de détecter rapidement la présence de corps lipidiques au sein de la paroi vasculaire pathologique. Cette nouvelle technique, qui estime la compliance vasculaire, a été validée avec succès sur des données simulées ainsi que sur des images IVUS de modèles d'artère réalisés en PVA-c. Notons que cette technique a été brevetée. Le développement des nouvelles modalités d'imagerie telles que l'OCT, l'IVUS-HD ne permettent pas de mesurer les déformations sur la totalité d'une section d'artère. En effet, pour de telles techniques d'imagerie, le signal ne pénètre pas toute la paroi artérielle, mais simplement la couche endoluminale (appelée aussi domaine de palpographie). C'est pourquoi, dans la deuxième partie de mon travail, j'ai proposé une nouvelle approche - s'inspirant de travaux déjà effectués au laboratoire - permettant de reconstruire la cartographie du module d'Young du domaine de palpographie. De nombreux algorithmes tentent de déterminer les géométries ainsi que les propriétés mécaniques des plaques d'athéromes. Cependant, il reste difficile de valider les codes de calculs car il est rare de disposer à la fois: des images IVUS, des coupes anatomiques et des mesures de rigidité des différents constituants de la plaque. Afin d'obtenir ces jeux complets de données, j'ai créé un banc expérimental permettant la réalisation de mesures IVUS, AFM et histologiques ex-vivo. Les deux dernières parties de ce travail mettent en avant le nombre important de résultats expérimentaux obtenus sur des artères réalisées en PVA-c ainsi que sur des aortes pathologiques et saines de lapins Watanabe. La validation de mes deux techniques précédentes de caractérisation ont été effectuées à l'aide de ce banc expérimental mis en place en collaboration avec l'université de Montréal. / Estimation of mechanical properties of atherosclerosis plaque from endovascular echography data: Revisited palpography technic. The main aim of my works was to develop and propose biomechanical tools based on intravascular (IVUS) sequences to detect and characterize vulnerable coronary atherosclerosis plaques. In the first part of my PhD thesis, I revisited the palpography technique proposed by Céspedes et al. and initially published in Ultrasound in Medicine & Biology in 2000. Céspedes et al. developed the elasticity-palpography approach which allows a fast wall stiffness quantification based on the arterial strain and blood pressure measurements. However, this technique suffers of major limitations since it has been developed for homogeneous, isotropic, quasi incompressible, circular and concentric atherosclerotic plaques, only. Therefore in the current study, the native palpography technique was successfully revisited and improved to account for complex plaque and arbitrary palpography domain geometries. The revisited elasticity-palpography technique was successfully applied to six coronary lesions of patients imaged in vivo with intravascular ultrasound (IVUS). Validation of this method was conducted on simulated data and on IVUS sequences performed on PVA-c phantoms. This new IVUS technique, which successfully estimates the vessel compliance, has been patented. One major limitation of the elasticity reconstruction method proposed recently by our collaborative laboratories (Le Floch et al., Ultrasound Med Bio 2012) is the need to quantify accurately the strain field in the entire lesion. Such global strain-elastogram may be often difficult to extract when using intravascular imaging techniques (as OCT or HD-IVUS ) with limited depth penetration signals or due to the fact that the amplitude of the original signal becomes attenuated as the depth of penetration increases. Therefore, in the second part of my PhD manuscript I revisited and improved our previous approach to reconstruct the Young's modulus map (i.e. modulogram) from strain-elastogram estimated in the limited endoluminal plaque region. This improved approach was successfully tested on IVUS sequences obtained in patients with stable angina and scheduled to undergo percutaneous coronary intervention (PCI) at the Hôpital Cardiologique et Pneumologique of Lyon. The robustness and performance of the new approach was investigated with regard to noise which may affect prediction of plaque morphology and elasticity. This study demonstrates the potential of the new IVUS modulography technique based on the proposed elasticity reconstruction method to detect vulnerable plaques in vivo. In the last part of my PhD thesis I described the animal protocol developed in our laboratory to analyze the performance of the proposed new morphology and elasticity IVUS reconstruction techniques. A complete set of data (plaque morphology and elasticity) was acquired ex vivo using atherosclerotic aorta of Watanabe rabbits. Several IVUS, histology, AFM and µacoustic measurements were performed on such artery sections. This protocol is detailed and the preliminary data and elasticity reconstruction maps are presented.

Made available in DSpace on 2014-06-11T19:23:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-07-23Bitstream added on 2014-06-13T18:51:20Z : No. of bitstreams: 1 castro_kf_me_jabo.pdf: 1173046 bytes, checksum: 3f548cfd5539d25d90bbd19c032374f5 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A aterosclerose é uma doença multifatorial, lenta e progressiva e a hiperlipidemia um dos fatores potenciais no desenvolvimento de doenças cardíacas ateroscleróticas. As vantagens da indução das dislipidemias experimentais são a produção de lesões ateromatosas em curto espaço de tempo; adequado controle dietético e fatores ambientais; a possibilidade de estudos sobre a reversibilidade de lesões ateroscleróticas e ensaios pré clínicos de substâncias hipolipidêmicas. Este estudo visou avaliar a capacidade do surfactante na indução aterogênica na região do arco aórtico de ratos por meio de estudos morfológico e morfométrico das túnicas íntima, média e adventícia da aorta, bem como analisar o perfil lipídico sérico. Foram utilizados 28 ratos Wistar, machos, albinos, adultos e hígidos. Estes foram distribuídos em quatro grupos experimentais formados por sete animais cada, a saber: Grupo I – (controle); Grupo II – tratado com tyloxapol, na dose de 500 mg/Kg de peso corporal, via intraperitoneal a cada 48 horas, durante duas semanas; Grupo III – tratado com tyloxapol na dose de 500 mg/Kg de peso corporal, via intraperitoneal a cada 48 horas, durante três semanas; Grupo IV – tratado com tyloxapol na dose de 500 mg/Kg de peso corporal, via intraperitoneal a cada 48 horas, durante quatro semanas. A análise morfológica do arco aórtico dos animais dos grupos II, III e IV evidenciou características histológicas semelhantes às do grupo I nas túnicas íntima, média e adventícia. No estudo morfométrico, os valores da espessura, em μm, da túnica íntima indicaram que o grupo III diferiu significativamente dos grupos I, II e IV. Os valores da espessura, em μm, encontrados para a túnica média e adventícia revelaram que não houve diferença significativa entre os grupos I, II, III e IV. Na avaliação do perfil lipídico os valores de colesterol total... / Atherosclerosis is a multifactorial, progressive and slow disease, and hyperlipidaemia is one of the potential factors in the development of atherosclerotic cardiac diseases. The experimental dyslipidaemia carrying out advantages are the production of atheromatous lesions in a short period of time, an adequate dietetic control and environmental factors, the possibility of studies concerning reversibility of atherosclerotic lesions, and pre-clinic experiments with hypolipidaemic substances. This study aims at evaluating tyloxapol ability in atherogenic inducing, in the rats’ aortic arch region, through morphologic morphometric studies, in intima, media and adventitia tunicas of the aortic arch, as well as analyzing serum lipid levels. Twenty-eight healthy Wistar adults’ albino male rats, weighing an average of 200 g were utilized. They were distributed into four experimental groups with seven animals each, as follows: Group I – (control); Group II – treated with tyloxapol at a dose of 500mg/Kg of body weight, through intraperitoneal via each 48 hours, for two weeks; Group III - treated with tyloxapol at a dose of 500mg/Kg of body weight, through intraperitoneal via each 48 hours, for three weeks; Group IV - treated with tyloxapol at a dose of 500mg/Kg of body weight, through intraperitoneal via each 48 hours, for four weeks. Morphological analysis of the aortic arch of the animals from groups II, III and IV, showed similar histological characteristics to group I at intima, media and adventitia tunicas. The intima tunica values at the morphometric study indicated that group III has significant differed from groups I, II and IV. The media and adventitia tunicas values revealed that there were no significant differences between groups I, II, III, and IV. As lipid profile evaluation is concerned, the values of total cholesterol, triglycerides and HDL have indicated... (Complete abstract click electronic access below)

FUNDAMENTO: O suco de laranja (Citrus sinensis) é rico em vitami-na C, folatos e seu principal flavonóide, a hesperidina, cuja conformação es-pacial é semelhante à genisteína de soja que tem ação favorável sobre o aparelho cardiovascular. A vitamina C é conhecida como potente inibidor da peroxidação lipídica. Mas sua capacidade por possuir efeitos terapêuticos no tratamento da aterosclerose é pouco estudada. OBJETIVO: O presente tra-balho visa a determinar se o suco de laranja pode ter efeito aditivo no trata-mento com estatinas e fibratos, reduzindo placas ateroscleróticas e a quanti-dade de LDL Oxidado (LDL ox). MÉTODOS: Análise do efeito do suco nas dimensões de cortes histológicos e na quantidade de anticorpos anti LDL oxidado (antiLDLox) em lesões ateroscleróticas na aorta de coelhos. RE-SULTADOS: O suco de laranja potencializou a redução de área de placas ateroscleróticas e a quantidade de LDL(ox) em relação às reduções obtidas com rosuvastatina e gemfibrozil. CONCLUSÕES: O suco de laranja tem efei-to sinérgico ao tratamento convencional da aterosclerose de coelhos / Statins and fibrates have been used as anti-atherosclerotic drugs. However, a high number of treated patients still present acute events and death by atherosclerotic complications. Flavonoid ingestion has been associ-ated with lower risk of death, lower incidence of coronary artery disease and more preserved endothelial function in atherosclerotic patients. Orange juice is rich in C vitamine, a well known potent inhibitor of lipidic peroxidation, and in flavonoids, mainly the hesperidine that seems the soy bean genisteine, which is associated with decrease LDL and increase HDL. Objective: In this work we studied if orange juice has addictive effect to statin and gemfibrozil in the treatment of rabbit atherosclerosis, reducing plaque area and oxidate LDL (LDLox). Methods: Five group of atherosclerotic rabbits, fed with 1% cholesterol enriched diet during 12 weeks, were analyzed: GI - received no treatment, GII Gemfibrozil 600mg/day, GIII treated with Gemfibrozil 600mg/day + orange juice, GIV - rosuvastatin/10mg / day and GV - rosu-vastatin/10mg / day + orange juice. The most severe atherosclerotic cross section in ascendant aorta was analyzed in H&E and anti-oxidated LDL (oxLDL) immunostained slides, obtaining intimal area, total vessel area, % luminal obstruction and % oxLDL area in intima. Results: The means (stan-dard deviations) of plaque area and % plaque area of oxLDL in GI were 1.05 (0.91) and 0.12 (0.13), with no significant difference with GII animals, respec- tively 3.85 (5.27) and 0.18 (0.22), but significantly reduced in GIII, 0.64 (1.56) and 0.03 (0.05). Similar data were seen in GIV, 2.11 (2.77) and 0.19 (0.25), compared with GV, 0.04 (0.09) and 0.00 (0.00). Conclusion: This work de-monstrates that orange juice has a potential synergistic action with statin and fibrates in reducing atherosclerosis and the mechanism seems to involve in-hibition of oxLDL concentration and migration of smooth muscle cells in the subendothelial space

Resumo: A aterosclerose é uma doença multifatorial, lenta e progressiva e a hiperlipidemia um dos fatores potenciais no desenvolvimento de doenças cardíacas ateroscleróticas. As vantagens da indução das dislipidemias experimentais são a produção de lesões ateromatosas em curto espaço de tempo; adequado controle dietético e fatores ambientais; a possibilidade de estudos sobre a reversibilidade de lesões ateroscleróticas e ensaios pré clínicos de substâncias hipolipidêmicas. Este estudo visou avaliar a capacidade do surfactante na indução aterogênica na região do arco aórtico de ratos por meio de estudos morfológico e morfométrico das túnicas íntima, média e adventícia da aorta, bem como analisar o perfil lipídico sérico. Foram utilizados 28 ratos Wistar, machos, albinos, adultos e hígidos. Estes foram distribuídos em quatro grupos experimentais formados por sete animais cada, a saber: Grupo I - (controle); Grupo II - tratado com tyloxapol, na dose de 500 mg/Kg de peso corporal, via intraperitoneal a cada 48 horas, durante duas semanas; Grupo III - tratado com tyloxapol na dose de 500 mg/Kg de peso corporal, via intraperitoneal a cada 48 horas, durante três semanas; Grupo IV - tratado com tyloxapol na dose de 500 mg/Kg de peso corporal, via intraperitoneal a cada 48 horas, durante quatro semanas. A análise morfológica do arco aórtico dos animais dos grupos II, III e IV evidenciou características histológicas semelhantes às do grupo I nas túnicas íntima, média e adventícia. No estudo morfométrico, os valores da espessura, em μm, da túnica íntima indicaram que o grupo III diferiu significativamente dos grupos I, II e IV. Os valores da espessura, em μm, encontrados para a túnica média e adventícia revelaram que não houve diferença significativa entre os grupos I, II, III e IV. Na avaliação do perfil lipídico os valores de colesterol total... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Atherosclerosis is a multifactorial, progressive and slow disease, and hyperlipidaemia is one of the potential factors in the development of atherosclerotic cardiac diseases. The experimental dyslipidaemia carrying out advantages are the production of atheromatous lesions in a short period of time, an adequate dietetic control and environmental factors, the possibility of studies concerning reversibility of atherosclerotic lesions, and pre-clinic experiments with hypolipidaemic substances. This study aims at evaluating tyloxapol ability in atherogenic inducing, in the rats' aortic arch region, through morphologic morphometric studies, in intima, media and adventitia tunicas of the aortic arch, as well as analyzing serum lipid levels. Twenty-eight healthy Wistar adults' albino male rats, weighing an average of 200 g were utilized. They were distributed into four experimental groups with seven animals each, as follows: Group I - (control); Group II - treated with tyloxapol at a dose of 500mg/Kg of body weight, through intraperitoneal via each 48 hours, for two weeks; Group III - treated with tyloxapol at a dose of 500mg/Kg of body weight, through intraperitoneal via each 48 hours, for three weeks; Group IV - treated with tyloxapol at a dose of 500mg/Kg of body weight, through intraperitoneal via each 48 hours, for four weeks. Morphological analysis of the aortic arch of the animals from groups II, III and IV, showed similar histological characteristics to group I at intima, media and adventitia tunicas. The intima tunica values at the morphometric study indicated that group III has significant differed from groups I, II and IV. The media and adventitia tunicas values revealed that there were no significant differences between groups I, II, III, and IV. As lipid profile evaluation is concerned, the values of total cholesterol, triglycerides and HDL have indicated... (Complete abstract click electronic access below) / Orientadora: Maria Rita Pacheco / Coorientador: Silvana Martinez Baraldi Artoni / Banca: Lucia Helena Vasques / Banca: Mirela Tinucci Costa / Mestre

This master thesis analyses stress and strain of iliac artery with atheroma. Model of artery is created as 2D and symmetric about the y-axis. The first part of the thesis deals with a research, which includes obtaining information from medicine, which is necessary fort the right solution of the task. Next part dedicates to nonlinear mechanics, constitutive modeling from the view of biomechanice and computational modeling of arteries. In the next part is made analysis for load on artery by physiological and also by high blood pressure. In the end were specified uncertainties of the used model and evaluated chance of atherosclerotic plaque rupture.