Ca2+-activated potassium channels (KCa) and canonical transient receptor potential (TRPC) channels are essential to endothelial function. In ischemic heart disease, or in cardiac surgery, coronary endothelium is subjected to ischemia-reperfusion (I-R) / hypoxia-reoxygenation (H-R) injury. Hyperkalemic cardioplegic or organ preservation solutions used in cardiac surgery including heart transplantation also impair endothelial function. The present study was designed to mainly investigate whether endothelial dysfunction occurring in H-R or in hyperkalemic exposure is attributable to alterations of intermediate- and small-conductance KCa (IKCa and SKCa) channels, or TRPC channels, in particular, the TRPC3 channel. / Exposure to 60-min hypoxia followed by reoxygenation inhibited the vasorelaxant response of coronary arteries to IKCa / SKCa activator 1-EBIO. H-R reduced endothelial IKCa and SKCa currents and downregulated IKCa expression in PCECs. 1-EBIO enhanced endothelial K+ current that was blunted by H-R. / Exposure to hyperkalemic solutions decreased Ca2+ influx via TRPC3 in PCECs. The reduced Ca2+ influx in PCECs and the attenuated EDHF-mediated vasorelaxation in porcine coronary arteries, which were caused by hyperkalemic or cardioplegic / organ preservation solutions, were restored by OAG. / In PCECs, hypoxia for 60-min with reoxygenation reduced TRPC3 current and Ca2+ influx via TRPC3, which was accompanied by decreased NO release and endothelium-dependent vasorelaxation of porcine coronary arteries. The compromised endothelial function was restored by OAG. The translocation of TRPC3 to endothelial membrane was inhibited by H-R. / In TRPC3-overexpressing HEK293 cells, followed by reoxygenation, short-time hypoxia (10-min) enhanced, whereas prolonged hypoxia (60-min) reduced the current induced by TRPC3/6/7 activator OAG. / Our results indicate that: (1) Endothelial IKCa, SKCa and TRPC3 play an important role in regulating vascular tone; TRPC3 contributes to NO release from endothelial cells and is also involved in the function of EDHF. (2) H-R (60-30 min) reduces endothelial IKCa and SKCa currents with downregulation ofthe protein expression of IKCa. (3) H-R has dual effect on TRPC3 with short-time hypoxia (lO-min) enhancing whereas prolonged hypoxia (60-min) decreasing the electrophysiological activity of this channel. H-R (60-30 min) inhibits the translocation of TRPC3 to endothelial membrane. Furthermore, H-R inhibits Ca2+ influx via TRPC3 and such inhibition is associated with a decrease of NO production. (4) The activator of IKCa / SKCa or TRPC protects coronary endothelium against H-R injury. In coronary endothelium exposed to hyperkalemic or cardioplegic / organ preservation solutions, TRPC activator also exhibits protective effect. / The above findings are likely to have significant implications in ischemic heart disease and in modem cardiopulmonary surgery. / Whole-cell membrane currents of IKCa, SKCa, or TRPC3 were recorded by patch-clamp in primary cultured porcine coronary endothelial cells (PCECs). TRPC3 current was also studied in human embryonic kidney cells (HEK293 cells) transiently overexpressed with TRPC3 gene. Protein or mRNA expression of these channels was detected by Western blot or RT-PCR. Intracellular Ca2+ concentration was measured by Ca2+ imaging technique. Isometric force study was performed in a wire myograph and endothelial nitric oxide (NO) release was measured electrochemically by using a NO-specific microsensor in porcine coronary small arteries. / Huang, Junhao. / "December 2010." / Adviser: Qin Yang. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 138-165). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Wu Min. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 87-114). / Abstracts in English and Chinese. / Declaration --- p.i / Acknowledgement --- p.ii / Publication list --- p.iii / Abstract (English) --- p.xi / Abstract (Chinese) --- p.xiv / Abbreviations --- p.xvi / List of figures / tables --- p.xviii / Chapter Chapter 1. --- General Introduction --- p.1 / Chapter 1.1 --- Endothelial function in the regulation of vascular tone --- p.1 / Chapter 1.1.1 --- NO --- p.2 / Chapter 1.1.2 --- PGI2 --- p.5 / Chapter 1.1.3 --- EDHF --- p.6 / Chapter 1.2 --- Alteration of endothelial functions after preservation with cardioplegia /organ preservation solutions in the coronary and pulmonary microcirculations --- p.18 / Chapter 1.2.1 --- Cardioplegia/organ preservation solutions --- p.21 / Chapter 1.2.2 --- Effect of Cardioplegia/organ preservation solutions on endothelial function --- p.22 / Chapter 1.2.2.1 --- Effect of K+ on endothelial function --- p.23 / Chapter 1.2.2.2 --- Effect of other components on endothelial function --- p.24 / Chapter Chapter 2. --- Materials and Methods --- p.26 / Chapter 2.1 --- Isometric force study in coronary/pulmonary resistance arteries --- p.26 / Chapter 2.1.1 --- Preparation of vessels --- p.26 / Chapter 2.1.1.1 --- Preparation of porcine coronary small arteries --- p.26 / Chapter 2.1.1.2 --- Preparation of porcine pulmonary small arteries --- p.26 / Chapter 2.1.2 --- Technique of setting up --- p.29 / Chapter 2.1.2.1 --- Mounting of small vessels --- p.29 / Chapter 2.1.2.2 --- Normalization procedure for small vessels --- p.29 / Chapter 2.1.3 --- EDHF-mediated vasorelaxation --- p.30 / Chapter 2.1.3.1 --- Precontraction and stimuli of EDHF --- p.30 / Chapter 2.1.3.2 --- """True"" response of EDHF" --- p.31 / Chapter 2.1.4 --- Data acquisition and analysis --- p.32 / Chapter 2.2 --- Electrophysiological study --- p.32 / Chapter 2.2.1 --- Preparation of small porcine coronary/pulmonary arteries --- p.32 / Chapter 2.2.2 --- Preparation of microelectrode --- p.32 / Chapter 2.2.3 --- Impaling of microelectrode --- p.33 / Chapter 2.2.4 --- Recording of membrane potential --- p.33 / Chapter 2.3 --- Statistical analysis --- p.34 / Chapter 2.4 --- Chemicals --- p.34 / Chapter Chapter 3. --- Effects of Celsior Solution on Endothelial Function in Resistance Coronary Arteries Compared to St. Thomas' Hospital Solution --- p.37 / Chapter 3.1 --- Abstract --- p.37 / Chapter 3.2 --- Introduction --- p.38 / Chapter 3.3 --- Experimental design and analysis --- p.40 / Chapter 3.3.1 --- Vessel preparation --- p.40 / Chapter 3.3.2 --- Normalization --- p.40 / Chapter 3:3.3 --- "Relaxation study: BK-induced, EDHF-mediated relaxation" --- p.41 / Chapter 3.3.4 --- Cellular electrophysiological study: EDHF-mediated cellular hyperpolarization and associated relaxation --- p.41 / Chapter 3.3.5 --- Data analysis --- p.42 / Chapter 3.4 --- Results --- p.43 / Chapter 3.4.1 --- Relaxation study --- p.43 / Chapter 3.4.1.1 --- Resting force --- p.43 / Chapter 3.4.1.2 --- U46619-induced precontraction --- p.43 / Chapter 3.4.1.3 --- EDHF-mediated relaxation --- p.43 / Chapter 3.4.2 --- Electrophysiological studies --- p.44 / Chapter 3.4.2.1 --- Resting membrane potential --- p.44 / Chapter 3.4.2.2 --- EDHF-mediated cellular hyperpolarization --- p.45 / Chapter 3.4.2.3 --- Cellular hyperpolarization-associated relaxation --- p.45 / Chapter 3.5 --- Discussion --- p.46 / Chapter 3.5.1 --- Effects of Celsior solution on endothelial function --- p.47 / Chapter 3.5.2 --- Effects of ST solution on EDHF-mediated function --- p.48 / Chapter 3.5.3 --- Comparison between Celsior and ST solutions on EDHF-mediated function --- p.48 / Chapter 3.5.4 --- Clinical implications --- p.49 / Chapter Chapter 4. --- Effects of Perfadex and Celsior Solution on Endothelial Function in Resistance Pulmonary Arteries --- p.57 / Chapter 4.1 --- Abstract --- p.57 / Chapter 4.2 --- Introduction --- p.58 / Chapter 4.3 --- Experimental design and analysis --- p.59 / Chapter 4.3.1 --- Vessel Preparation --- p.59 / Chapter 4.3.2 --- Normalization --- p.60 / Chapter 4.3.3 --- Isometric force study --- p.60 / Chapter 4.3.4 --- Electrophysiological studies --- p.61 / Chapter 4.3.5 --- Data analysis --- p.61 / Chapter 4.4 --- Results --- p.62 / Chapter 4.4.1 --- Relaxation study: EDHF-mediated relaxation --- p.62 / Chapter 4.4.1.1 --- Resting force --- p.62 / Chapter 4.4.1.2 --- U46619-induced precontraction --- p.62 / Chapter 4.4.1.3 --- EDHF-mediated relaxation --- p.62 / Chapter 4.4.2 --- Electrophysiological studies --- p.63 / Chapter 4.4.2.1 --- Resting membrane potential --- p.63 / Chapter 4.4.2.2 --- EDHF-mediated cellular hyperpolarization --- p.64 / Chapter 4.4.2.3 --- Cellular hyperpolarization-associated relaxation --- p.64 / Chapter 4.5 --- Discussion --- p.65 / Chapter 4.5.1 --- Effects of Celsior solution on endothelial function during cardiopulmonary surgery --- p.65 / Chapter 4.5.2 --- Effects of Perfadex solution on EDHF-mediated endothelial function --- p.66 / Chapter 4.5.3 --- Comparison between Celsior and Perfadex solutions on EDHF-mediated function --- p.66 / Chapter 4.5.4 --- Clinical implications --- p.67 / Chapter Chapter 5. --- Exploration of the Nature of EDHF - the Effect of H2O2 on the Membrane Potential in the Rat Small Mesenteric Arteries --- p.73 / Chapter Chapter 6. --- General Discussion --- p.75 / Chapter 6.1 --- EDHF-mediated endothelial function in porcine coronary and pulmonary circulation --- p.75 / Chapter 6.1.1 --- Role of EDHF in the regulation of porcine coronary arterial tone --- p.75 / Chapter 6.1.2 --- Role of EDHF in the regulation of porcine pulmonary arterial tone --- p.76 / Chapter 6.2 --- Alteration of EDHF-mediated endothelial functions after exposure to organ preservation solutions --- p.77 / Chapter 6.2.1 --- Effects of hyperkalemic solution on EDHF-mediated endothelial function in coronary and pulmonary circulation --- p.78 / Chapter 6.2.2 --- Effects of low-potassium-based preservation solution on EDHF-mediated endothelial function in pulmonary circulation --- p.79 / Chapter 6.2.3 --- Comparison between hyperkalemic solution and low-potassium-based preservation solution on EDHF-mediated endothelial function --- p.80 / Chapter 6.2.4 --- Effects of other component of organ preservation solutions on EDHF-mediated endothelial function --- p.81 / Chapter 6.3 --- Clinical implications --- p.82 / Chapter 6.4 --- The effect of H202 on the membrane potential in rat small mesenteric arteries --- p.83 / Chapter 6.5 --- Limitation of the study --- p.84 / Chapter 6.6 --- Future investigations --- p.85 / Chapter 6.7 --- Conclusions --- p.85 / References --- p.87

Com os avanços tecnológicos das últimas décadas, a ecocardiografia surgiu como uma alternativa de diagnóstico por imagem de relativo baixo custo, que não faz uso de energia ionizante ou radioativa. Recentemente, o advento dos agentes de contraste por microbolhas e dos transdutores matriciais tornou possível a visualização tridimensional da anatomia das artérias coronárias. Neste projeto, é proposta a avaliação de métodos de segmentação capazes de visibilizar as artérias coronárias epicárdicas em Imagens de ecocardiografias tridimensionais com contraste de microbolhas. Esse é o primeiro passo para o desenvolvimento de ferramentas computacionais eficazes e eficientes na assistência não invasiva ao acompanhamento do quadro clínico de pacientes, do diagnóstico ao pós-operatório. Propõe-se, uma metodologia que facilite o acesso às coronárias a partir de imagens de ecocardiografia tridimensionais com aplicação de contraste por microbolhas. Dentre as metodologias estudadas, as técnicas baseadas na teoria Fuzzy Connectedness (FC) foram identificadas como as mais promissoras. Estudou-se, portanto, seis abordagens baseadas nessa teoria, três delas são descritas na literatura (Generalized FC GFC; Relative FC RFC; Dynamic Weighted FC DyWFC) e três proposições originais (Area of Search FC ASFC; Ultrasound-k FC USFC; Guided FC GuFC). Para avaliar a acurácia desses algoritmos, confeccionou-se um conjunto de imagens simuladas, composto por 360 imagens, e selecionou-se um conjunto de imagens de exames reais, composto de 10 imagens reais de pacientes com quadro de Cardiomiopatia Hipertrópica. Para as imagens simuladas, os métodos da literatura alcançaram acurácia de 85,5% para GFC, 89,5% para RFC e 92,0% para DyWFC. Enquanto isso, os métodos propostos alcançaram acurácia de 88,9% para ASFC, 91,7 % para USkFC e 95,2% para GuFC. Para as imagens reais, os métodos convergiram para uma segmentação satisfatória quanto à usabilidade na clínica médica. Esses resultados demonstraram, ainda, o melhor desempenho do método proposto GuFC ante os demais. Dessa forma, ele se torna um candidato para ingressar na etapa de segmentação de uma ferramenta computacional para visibilização das coronárias epicárdicas no futuro / With the technological advances of recent decades, echocardiography has emerged as a relatively low cost imaging diagnostic alternative, that does not use ionizing or radioactive energy. Lately, the advent of microbubble-based contrast agents and array transducers turned possible the visualization of three-dimensional coronary arteries anatomy. The present project proposes to evaluate segmentation methods able to deal with the visualization of the epicardial coronary arteries in microbubble-based three-dimensional echocardiography images. This is the first step towards the development of effective and efficient computational tools for diagnosis and prognosis assistance of cardiac pacient. We propose a methodology to facilitate the access to epicardial coronary arteries in tridimensional echocardiographic images. Among the studied approaches, Fuzzy Connectednessbased segmentation methods were identified as being the most promising. We studied six approaches based on this theory, three of them are described in the literature (Generalized FC GFC; Relative FC RFC; Dynamic Weighted FC DyWFC) and three original contributions (Area of Search FC ASFC; Ultrasound-k FC USFC; Guided FC GuFC). To evaluate the accuracy of these algorithms, a set composed of 360 simulated images were created. We also selected a set of 10 real images, composed of hypertrophic cardiomyopathy patients. For simulated images set, the methods of literature achieved accuracy of 85.5% for GFC, 89,5% for RFC and 92,0% for DyWFC, meanwhile, the proposed method achieved accuracy of 88.9% for ASFC, 91,7 % for USkFC and 95,2% for GuFC. Using the real images set, the methods converged to good results for clinical purposes. These results demonstrate that the proposed method GuFC has shown a better performance than the others, becoming a candidate to the segmentation step in a computational tool for coronary arteries visualization in the future

Hemodynamic factors play a role in atherogenesis and the localization of atherosclerotic plaques. The human aorta and coronary arteries are susceptible to arterial disease, and there have been many studies of flows in models of these vessels. However, previous work has been limited in that investigations have not modeled both the geometry and flow conditions in specific individuals. The first aim of the research was to develop a methodology that combined computational fluid dynamics (CFD) and magnetic resonance imaging (MRI) to simulate the blood flow patterns found in the human aorta. The methodology included MR image processing, 3D model reconstruction and flow simulation using in vivo velocity boundary conditions obtained from phase contrast (PC)-MRI scanning. The CFD simulations successfully reproduce the unusual right-hand helical flow pattern that has been reported in the ascending aorta, giving confidence in the accuracy of the methodology. The second aim was to investigate the causes of the right-hand helical flow. It was found that the correct flow dynamics could only be produced by including the specific aortic motion caused by the beating heart; and it is concluded that this is a significant factor in producing the observed in vivo helical flow patterns. The entrance flows of coronary arteries are expected to be affected by flow in the aortic root, and the third aim was to explore these effects using models that include aorta and coronary arteries. The simulation results demonstrate that a pair of axial vortexes with different rotating directions exists in the entrance segments of the right and left coronary arteries during systole and early diastole, producing asymmetrical wall shear stress (WSS) distributions. The last aim of the research was to examine possible relationships between WSS distributions induced by the entry flow patterns and the frequency distributions of atherosclerosis in the proximal segments of coronary arteries reported in the clinical literature. A close correspondence between low WSS and higher frequency of plaque occurrence was observed. The tools developed in this study provide a promising avenue for future study of cardiovascular disease because of the ability to investigate phenomena in individual human subjects.

At present, cardiovascular diseases cause ca. 30 of deaths worldwide, and are the most common cause of death and disability (The World Health Report 2002; Pearson 1999). Coronary artery disease (CAD) accounts for nearly 50 of all deaths caused by cardiovascular diseases. In 2002, 7.2 million people died of CAD worldwide, and 5.8 million new cases were diagnosed. In 2000, the number of people with CAD around the world amounted to ca. 40 millions (Mackay 2004). The modern understanding of the pathophysiology of atherosclerosis and the concept of “cardiovascular risk factors” started forming in 1950s, when the first findings of the Framingham study were published (Wilson et al. 1998, D’Agostino et al. 2000). Information accumulated during scientific research on atherosclerosis allowed for a significant reduction of CAD-related mortality in the developed countries during the last 20 years, but a more profound analysis showed that the mortality mostly decreased in males, whereas in females it continues to grow. Nearly two-thirds of suddenly deceased women previously showed no clinical symptoms of CAD (AHA 2002). This most probably was influenced by a still predominant erroneous opinion that women, especially of younger age, very rarely have CAD and atherosclerosis of peripheral arteries. Epidemiological studies showed that cardiovascular diseases induced by atherosclerosis are equally frequent cause of death in both males and females. Of all patients who in 2000 in the U.S. died... [to full text]

Effet de l’atorvastatine sur la dysfonction endothéliale des artères coronaires épicardiques associée à l’hypertrophie ventriculaire gauche dans un modèle porcin Forcillo J, Aubin MC, Horn A, Shi YF, Carrier M, Tardif JC, Perrault LP Introduction: L’atorvastatine par ses effets pléiotropiques pourrait limiter la dysfonction endothéliale associée au développement de l’HVG. Méthodologie : Un cerclage de l’aorte ascendante pendant 2 mois entraîne le développement d’HVG et les groupes ont été traités avec atorvastatine 40 ou 80 mg de 60 à 90 jours. L’HVG est confirmée par échographie. La réactivité vasculaire est évaluée en chambres d’organe, la fonction endothéliale par la quantification de la GMPc et des nitrites/nitrates plasmatiques. Le stress oxydant est mesuré par les niveaux d’ANG II et de la carbonylation des protéines. Résultats : Après 60 et 90 j de cerclage, l’HVG est observée chez tous ces groupes. Les courbes concentrations-réponse des anneaux des artères coronaires épicardiques des groupes traités avec l’atorvastatine 40 et 80 mg pour 30 et 60 jours n’ont démontré aucune amélioration des relaxations dépendantes de l’endothélium. Une exacerbation significative de la dysfonction endothéliale a été observée. Les niveaux vasculaires de GMPc sont significativement diminués dans le groupe sans cerclage traité 60 d et ceux d’ANG II sont fortement augmentés chez ce dernier groupe ainsi que le groupe traité avec 80 mg pour 30 jours par rapport aux contrôles. L’expression de la carbonylation des protéines est augmentée dans le groupe témoin traité avec atorvastatine 80 mg, reflétant une augmentation du stress oxydant. Conclusion : L’administration d’atorvastatine ne prévient pas le développement de l’HVG ni la dysfonction endothéliale dans notre modèle. Au contraire l’atorvastatine à haute dose a un effet toxique sur les artères coronaires épicardiques en augmentant la dysfonction endothéliale. / Effect of atorvastatin on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy in a porcine model. Forcillo J, Aubin MC, Horn A, Shi YF, Carrier M, Tardif JC, Perrault LP Background: Atorvastatin, through pleiotropic effects, may prevent or reverse the endothelial dysfunction associated with LVH. Methods: After performing a banding of the ascending aorta for 2 months leading to the development of LVH, groups have been treated with atorvastatin 40 or 80 mg for 60 and 90 day periods. LVH was evaluated by echocardiographic studies. Vascular reactivity studies were performed in organ chambers. In vitro endothelial function was evaluated by plasmatic nitrites/nitrates, the degradations products of nitric oxide, and cGMP quantification. To quantify and qualify oxidative stress, protein carbonyl and angiotensin II levels were assessed. Results: Following 60 and 90 days of aortic banding, the development of LVH was observed in these groups. Concentration-response curves from rings of epicardial coronary arteries of groups treated with atorvastatin 40 and 80 mg for 30 and 60 days showed a significant decrease of endothelium-dependent relaxations with worsening of the endothelial dysfunction. Levels of cGMP were significantly decreased in the 60 days treated sham group and levels of ANG II were increased in the latter and also in the 90 days banded groups treated with 80 mg for 30 days compared to controls. The expression of protein carbonyl increased in the sham group treated with atorvastatin 80 mg compatible with an increase in oxidative stress. Conclusion: The administration of atorvastatin does not limit the development of LVH nor the endothelial dysfunction in our model. On the opposite, atorvastatin at a high dose has a toxic effect on epicardial coronary arteries by exacerbating the endothelial dysfunction.

To aid diagnosis, treatment planning, and patient education, clinicians require tools to anal- yse and explore the increasingly large three-dimensional (3-D) datasets generated by modern medical scanners. Direct volume rendering is one such tool finding favour with radiologists and surgeons for its photorealistic representation. More recently, volume illustration — or non-photorealistic rendering (NPR) — has begun to move beyond the mere depiction of data, borrowing concepts from illustrators to visually enhance desired information and suppress un- wanted clutter. Direct volume rendering generates images by accumulating pixel values along rays cast into a 3-D image. Transfer functions allow users to interactively assign material properties such as colour and opacity (a process known as classification). To achieve real-time framerates, the rendering must be accelerated using a technique such as 3-D texture mapping on commod- ity graphics processing units (GPUs). Unfortunately, current methods do not allow users to intuitively enhance regions of interest or suppress occluding structures. Furthermore, addi- tional scalar images describing clinically relevant measures have not been integrated into the direct rendering method. These tasks are essential for the effective exploration, analysis, and presentation of 3-D images. This body of work seeks to address the aforementioned limitations. First, to facilitate the research program, a flexible architecture for prototyping volume illustration methods is pro- posed. This program unifies a number of existing techniques into a single framework based on 3-D texture mapping, while also providing for the rapid experimentation of novel methods. Next, the prototyping environment is employed to improve an existing method—called tagged volume rendering — which restricts transfer functions to given spatial regions using a number of binary segmentations (tags). An efficient method for implementing binary tagged volume rendering is presented, along with various technical considerations for improving the classifi- cation. Finally, the concept of greyscale tags is proposed, leading to a number of novel volume visualisation techniques including position modulated classification and dynamic exploration. The novel methods proposed in this work are generic and can be employed to solve a wide range of problems. However, to demonstrate their usefulness, they are applied to a specific case study. Ischaemic heart disease, caused by narrowed coronary arteries, is a leading healthconcern in many countries including Australia. Computed tomography angiography (CTA) is an imaging modality which has the potential to allow clinicians to visualise diseased coronary arteries in their natural 3-D environment. To apply tagged volume rendering for this case study, an active contour method and minimal path extraction technique are proposed to segment the heart and arteries respectively. The resultant images provide new insight and possibilities for diagnosing and treating ischaemic heart disease.

Com os avanços tecnológicos das últimas décadas, a ecocardiografia surgiu como uma alternativa de diagnóstico por imagem de relativo baixo custo, que não faz uso de energia ionizante ou radioativa. Recentemente, o advento dos agentes de contraste por microbolhas e dos transdutores matriciais tornou possível a visualização tridimensional da anatomia das artérias coronárias. Neste projeto, é proposta a avaliação de métodos de segmentação capazes de visibilizar as artérias coronárias epicárdicas em Imagens de ecocardiografias tridimensionais com contraste de microbolhas. Esse é o primeiro passo para o desenvolvimento de ferramentas computacionais eficazes e eficientes na assistência não invasiva ao acompanhamento do quadro clínico de pacientes, do diagnóstico ao pós-operatório. Propõe-se, uma metodologia que facilite o acesso às coronárias a partir de imagens de ecocardiografia tridimensionais com aplicação de contraste por microbolhas. Dentre as metodologias estudadas, as técnicas baseadas na teoria Fuzzy Connectedness (FC) foram identificadas como as mais promissoras. Estudou-se, portanto, seis abordagens baseadas nessa teoria, três delas são descritas na literatura (Generalized FC GFC; Relative FC RFC; Dynamic Weighted FC DyWFC) e três proposições originais (Area of Search FC ASFC; Ultrasound-k FC USFC; Guided FC GuFC). Para avaliar a acurácia desses algoritmos, confeccionou-se um conjunto de imagens simuladas, composto por 360 imagens, e selecionou-se um conjunto de imagens de exames reais, composto de 10 imagens reais de pacientes com quadro de Cardiomiopatia Hipertrópica. Para as imagens simuladas, os métodos da literatura alcançaram acurácia de 85,5% para GFC, 89,5% para RFC e 92,0% para DyWFC. Enquanto isso, os métodos propostos alcançaram acurácia de 88,9% para ASFC, 91,7 % para USkFC e 95,2% para GuFC. Para as imagens reais, os métodos convergiram para uma segmentação satisfatória quanto à usabilidade na clínica médica. Esses resultados demonstraram, ainda, o melhor desempenho do método proposto GuFC ante os demais. Dessa forma, ele se torna um candidato para ingressar na etapa de segmentação de uma ferramenta computacional para visibilização das coronárias epicárdicas no futuro / With the technological advances of recent decades, echocardiography has emerged as a relatively low cost imaging diagnostic alternative, that does not use ionizing or radioactive energy. Lately, the advent of microbubble-based contrast agents and array transducers turned possible the visualization of three-dimensional coronary arteries anatomy. The present project proposes to evaluate segmentation methods able to deal with the visualization of the epicardial coronary arteries in microbubble-based three-dimensional echocardiography images. This is the first step towards the development of effective and efficient computational tools for diagnosis and prognosis assistance of cardiac pacient. We propose a methodology to facilitate the access to epicardial coronary arteries in tridimensional echocardiographic images. Among the studied approaches, Fuzzy Connectednessbased segmentation methods were identified as being the most promising. We studied six approaches based on this theory, three of them are described in the literature (Generalized FC GFC; Relative FC RFC; Dynamic Weighted FC DyWFC) and three original contributions (Area of Search FC ASFC; Ultrasound-k FC USFC; Guided FC GuFC). To evaluate the accuracy of these algorithms, a set composed of 360 simulated images were created. We also selected a set of 10 real images, composed of hypertrophic cardiomyopathy patients. For simulated images set, the methods of literature achieved accuracy of 85.5% for GFC, 89,5% for RFC and 92,0% for DyWFC, meanwhile, the proposed method achieved accuracy of 88.9% for ASFC, 91,7 % for USkFC and 95,2% for GuFC. Using the real images set, the methods converged to good results for clinical purposes. These results demonstrate that the proposed method GuFC has shown a better performance than the others, becoming a candidate to the segmentation step in a computational tool for coronary arteries visualization in the future

Les maladies coronariennes constituent l'ensemble des troubles affectant les artères coronaires. Elles sont la première cause mondiale de mortalité. Par conséquent, la détection précoce de ces maladies en utilisant des techniques peu invasives fournit un meilleur résultat thérapeutique, et permet de réduire les coûts et les risques liés à une approche interventionniste. Des études récentes ont montré que la tomodensitométrie peut être utilisée comme une alternative non invasive et fiable pour localiser et quantifier ces lésions. Cependant, l'analyse de ces examens, basée sur l'inspection des sections du vaisseau, reste une tâche longue et fastidieuse. Une haute précision est nécessaire, et donc seulement les cliniciens hautement expérimentés sont en mesure d'analyser et d'interpréter de telles données pour établir un diagnostic. Les outils informatiques sont essentiels pour réduire les temps de traitement et assurer la qualité du diagnostic. L'objectif de cette thèse est de fournir des outils automatisés de traitement d'angiographie CT, pour la visualisation et l'analyse des artères coronaires d'une manière non invasive. Ces outils permettent aux pathologistes de diagnostiquer et évaluer efficacement les risques associés aux maladies cardio-vasculaires tout en améliorant la qualité de l'évaluation d'un niveau purement qualitatif à un niveau quantitatif. Le premier objectif de ce travail est de concevoir, analyser et valider un ensemble d'algorithmes automatisés utiles pour la détection et la quantification de sténoses des artères coronaires. Nous proposons un nombre de techniques couvrant les différentes étapes de la chaîne de traitement vers une analyse entièrement automatisée des artères coronaires. Premièrement, nous présentons un algorithme dédié à l'extraction du cœur. L'approche extrait le cœur comme un seul objet, qui peut être utilisé comme un masque d'entrée pour l'extraction automatisée des coronaires. Ce travail élimine l'étape longue et fastidieuse de la segmentation manuelle du cœur et offre rapidement une vue claire des coronaires. Cette approche utilise un modèle géométrique du cœur ajusté aux données de l'image. La validation de l'approche sur un ensemble de 133 examens montre l'efficacité et la précision de cette approche. Deuxièmement, nous nous sommes intéressés au problème de la segmentation des coronaires. Dans ce contexte, nous avons conçu une nouvelle approche pour l'extraction de ces vaisseaux, qui combine ouvertures par chemin robustes et filtrage sur l'arbre des composantes connexes. L'approche a montré des résultats prometteurs sur un ensemble de 11 examens CT. Pour une détection et quantification robuste de la sténose, une segmentation précise de la lumière du vaisseau est cruciale. Par conséquent, nous avons consacré une partie de notre travail à l'amélioration de l'étape de segmentation de la lumière, basée sur des statistiques propres au vaisseau. La validation avec l'outil d'évaluation en ligne du challenge de Rotterdam sur la segmentation des coronaires, a montré que cette approche présente les mêmes performances que les techniques de l'état de l'art. Enfin, le cœur de cette thèse est consacré à la problématique de la détection et la quantification des sténoses. Deux approches sont conçues et évaluées en utilisant l'outil d'évaluation en ligne de l'équipe de Rotterdam. La première approche se base sur l'utilisation de la segmentation de la lumière avec des caractéristiques géométriques et d'intensité pour extraire les sténoses coronaires. La seconde utilise une approche basée sur l'apprentissage. Durant cette thèse, un prototype pour l'analyse automatisée des artères coronaires et la détection et quantification des sténoses a été développé. L'évaluation qualitative et quantitative sur différents bases d'examens cardiaques montre qu'il atteint le niveau de performances requis pour une utilisation clinique / Coronary heart diseases are the group of disorders that affect the coronary artery vessels. They are the world's leading cause of mortality. Therefore, early detection of these diseases using less invasive techniques provides better therapeutic outcome, as well as reduces costs and risks, compared to an interventionist approach. Recent studies showed that X-ray computed tomography (CT) may be used as an alternative to accurately locate and grade heart lesions in a non invasive way. However, analysis of cardiac CT exam for coronaries lesions inspection remains a tedious and time consuming task, as it is based on the manual analysis of the vessel cross sections. High accuracy is required, and thus only highly experienced clinicians are able to analyze and interpret the data for diagnosis. Computerized tools are critical to reduce processing time and ensure quality of diagnostics. The goal of this thesis is to provide automated coronaries analysis tools to help in non-invasive CT angiography examination. Such tools allow pathologists to efficiently diagnose and evaluate risks associated with CVDs, and to raise the quality of the assessment from a purely qualitative level to a quantitative level. The first objective of our work is to design, analyze and validate a set of automated algorithms for coronary arteries analysis with the final purpose of automated stenoses detection and quantification. We propose different algorithms covering different processing steps towards a fully automated analysis of the coronary arteries. Our contribution covers the three major blocks of the whole processing chain and deals with different image processing fields. First, we present an algorithm dedicated to heart volume extraction. The approach extracts the heart as one single object that can be used as an input masque for automated coronary arteries segmentation. This work eliminates the tedious and time consuming step of manual removing obscuring structures around the heart (lungs, ribs, sternum, liver...) and quickly provides a clear and well defined view of the coronaries. This approach uses a geometric model of the heart that is fitted and adapted to the image data. Quantitative and qualitative analysis of results obtained on a 114 exam database shows the efficiency and the accuracy of this approach. Second, we were interested to the problem of coronary arteries enhancement and segmentation. In this context, we first designed a novel approach for coronaries enhancement that combines robust path openings and component tree filtering. The approach showed promising results on a set of 11 CT exam compared to a Hessian based approach. For a robust stenoses detection and quantification, a precise and accurate lumen segmentation is crucial. Therefore, we have dedicated a part of our work to the improvement of lumen segmentation step based on vessel statistics. Validation on the Rotterdam Coronary Challenge showed that this approach provides state of the art performances. Finally, the major core of this thesis is dedicated to the issue of stenosis detection and quantification. Two different approaches are designed and evaluated using the Rotterdam online evaluation framework. The first approach get uses of the lumen segmentation with some geometric and intensity features to extract the coronary stenosis. The second is using a learning based approach for stenosis detection and stenosis. The second approach outperforms some of the state of the art works with reference to some metrics. This thesis results in a prototype for automated coronary arteries analysis and stenosis detection and quantification that meets the level of required performances for a clinical use. The prototype was qualitatively and quantitatively validated on different sets of cardiac CT exams

Indiana University-Purdue University Indianapolis (IUPUI) / Factors released from coronary perivascular adipose tissue (PVAT), which surrounds large coronary arteries, have been implicated in the development of coronary disease. However, the precise contribution of coronary PVAT-derived factors to the initiation and progression of coronary vascular dysfunction remains ill defined. Accordingly, this investigation was designed to delineate the mechanisms by which PVAT-derived factors influence obesity-induced coronary smooth muscle dysfunction. Isometric tension studies of coronary arteries from lean and obese swine demonstrated that both lean and obese coronary PVAT attenuate vasodilation via inhibitory effects on smooth muscle K+ channels. Specifically, lean coronary PVAT attenuated KCa and KV7 channel-mediated dilation, whereas obese coronary PVAT impaired KATP channel-mediated dilation. Importantly, these effects were independent of alterations in underlying smooth muscle function in obese arteries. The PVAT-derived factor calpastatin impaired adenosine dilation in lean but not obese arteries, suggesting that alterations in specific factors may contribute to the development of smooth muscle dysfunction. Further studies tested the hypothesis that leptin, which is expressed in coronary PVAT and is upregulated in obesity, acts as an upstream mediator of coronary smooth muscle dysfunction. Long-term administration (3 day culture) of obese concentrations of leptin markedly altered the coronary artery proteome, favoring pathways associated with calcium signaling and cellular proliferation. Isometric tension studies demonstrated that short-term (30 min) exposure to leptin potentiated depolarization-induced contraction of coronary arteries and that this effect was augmented following longer-term leptin administration (3 days). Inhibition of Rho kinase reduced leptin-mediated increases in coronary artery contractions. Acute treatment was associated with increased Rho kinase activity, whereas longer-term exposure was associated with increases in Rho kinase protein abundance. Alterations in Rho kinase signaling were also associated with leptin-mediated increases in coronary vascular smooth muscle proliferation. These findings provide novel mechanistic evidence linking coronary PVAT with vascular dysfunction and further support a role for coronary PVAT in the pathogenesis of coronary disease.