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Descripción
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| The coronary microvasculature comprises the smallest blood vessels of the cardiac tissue. It continuously adapts in response to physiological and pathophysiological conditions to meet tissue demands. Quantitative assessment of the dynamic changes taking place in the coronary microvasculature is therefore crucial in enhancing our knowledge regarding the impact of cardiovascular disease on tissue perfusion and on developing efficient angiotherapies. This thesis focuses on deciphering the structural and functional changes that occur at the microvascular level, at various stages after myocardial infarction (1, 3, and 7 days following damage). Towards this aim, we have adopted an interdisciplinary approach which combines confocal microscopy, fully automated 3D image analysis and mathematical modelling. We used thick cardiac tissue sections labelled for nuclei, endothelial cell junctions and smooth muscle cells and we imaged them by confocal microscopy. Firstly, we developed a novel method for the segmentation of labelled structures from confocal images as well as an innovative approach for the accurate 3D reconstruction of the microvasculature based on endothelial cell junction and smooth muscle actin staining. Subsequently, we designed a fully automated image analysis pipeline to extract parameters that quantify all major features of the microvasculature, its relation to smooth muscle actin-positive cells and capillary diffusion regions. The novel pipeline was applied to the analysis of the coronary microvascu-lature from healthy tissue and also tissue at various stages after myocardial infarction. We used the pig animal model, whose coronary vasculature closely resembles that of human tissue. We discovered alterations in the microvasculature, particularly structural changes and angioadaptation resulting in altered capacity for oxygen diffusion in the aftermath of myocardial infarction. In addition, we evaluated the extracted knowledge?s potential in terms of predicting the pathophysiological condition of the tissue. The high accuracy achieved in this respect, demonstrates the ability of our approach not only to quantify and identify pathology-related changes of microvascular beds, but also to predict complex and dynamic microvascular patterns. Lastly, the anatomical data obtained regarding the microvasculature were used to feed a continuum perfusion model in order to calculate physiologically mean-ingful permeability tensors. By using this theoretical blood flow modelling approach, we were able to obtain insights into tissue perfusion and to demonstrate the functional effect of the structural changes occurring as a result of myocardial infarction. Overall, this work is a step forward towards increasing our understanding of microvas-cular alterations after myocardial infarction, modelling microcirculation at different stages after tissue damage and it also provides an unbiased means for the evaluation of potential treatments. | |
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Internacional
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Si |
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ISBN
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Tipo de Tesis
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Doctoral |
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Calificación
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Sobresaliente cum laude |
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Fecha
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26/09/2018 |