Influence biomécanique de la géométrie des anévrismes de l'aorte abdominale sur la répartition des contraintes pariétales

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Influence biomécanique de la géométrie des anévrismes de l'aorte abdominale sur la répartition des contraintes pariétales

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Impact of calcification and intraluminal thrombus on the computed wall stresses of abdominal aortic aneurysm

Background: Increased biomechanical stresses within the abdominal aortic aneurysm (AAA) wall contribute to its rupture. Calcification and intraluminal thrombus can be commonly found in AAAs, but the relationship between calcification/intraluminal thrombus and AAA wall stress is not completely described. Methods: Patient-specific three-dimensional AAA geometries were reconstructed from computed tomographic images of 20 patients. Structural analysis was performed to calculate the wall stresses of the 20 AAA models and their altered models when calcification or intraluminal thrombus was not considered. A nonlinear large-strain finite element method was used to compute the wall stress distribution. The relationships between wall stresses and volumes of calcification and intraluminal thrombus were sought. Results: Maximum stress was not correlated with the percentage of calcification, and was negatively correlated with the percentage of intraluminal thrombus (r = -0.56; P = .011). Exclusion of calcification from analysis led to a significant decrease in maximum stress by a median of 14% (range, 2%-27%; P < .01). When intraluminal thrombus was eliminated, maximum stress increased significantly by a median of 24% (range, 5%-43%; P < .01). Conclusion: The presence of calcification increases AAA peak wall stress, suggesting that calcification decrease the biomechanical stability of AAA. In contrast, intraluminal thrombus reduces the maximum stress in AAA. Calcification and intraluminal thrombus should both be considered in the evaluation of wall stress for risk assessment of AAA rupture.

Automatic generation of models for abdominal aortic aneurysms and intraluminal thrombus based on hexahedral meshes

To propose an automated patient-specific algorithm for the creation of accurate and smooth meshes of the aortic anatomy, to be used for evaluating rupture risk factors of abdominal aortic aneurysms (AAA). Finite element (FE) analyses and simulations require meshes to be smooth and anatomically accurate, capturing both the artery wall and the intraluminal thrombus (ILT). The two main difficulties are the modeling of the arterial bifurcations, and of the ILT, which has an arbitrary shape that is conforming to the aortic wall.

Quantitative evaluation of patient-specific conforming hexahedral meshes of abdominal aortic aneurysms and intraluminal thrombus generated from MRI

A novel method for generating patient-specific high quality conforming hexahedral meshes is presented. The meshes are directly obtained from the segmentation of patient magnetic resonance (MR) images of abdominal aortic aneu-rysms (AAA). The MRI permits distinguishing between struc-tures of interest in soft tissue. Being so, the contours of the lumen, the aortic wall and the intraluminal thrombus (ILT) are available and thus the meshes represent the actual anato-my of the patient?s aneurysm, including the layered morpholo-gies of these structures. Most AAAs are located in the lower part of the aorta and the upper section of the iliac arteries, where the inherent tortuosity of the anatomy and the presence of the ILT makes the generation of high-quality elements at the bifurcation is a challenging task. In this work we propose a novel approach for building quadrilateral meshes for each surface of the sectioned geometry, and generating conforming hexahedral meshes by combining the quadrilateral meshes. Conforming hexahedral meshes are created for the wall and the ILT. The resulting elements are evaluated on four patients? datasets using the Scaled Jacobian metric. Hexahedral meshes of 25,000 elements with 94.8% of elements well-suited for FE analysis are generated.

Generación de modelos físicos personalizados y segmentación de la pared arterial y el trombo intraluminal en imágenes de aneurismas aórticos abdominales

Esta tesis doctoral está encuadrada dentro del marco general de la ingeniería biomédica aplicada al tratamiento de las enfermedades cardiovasculares, enfermedades que provocan alrededor de 1.9 millones (40%) de muertes al año en la Unión Europea. En este contexto surge el proyecto europeo SCATh-Smart Catheterization, cuyo objetivo principal es mejorar los procedimientos de cateterismo aórtico introduciendo nuevas tecnologías de planificación y navegación quirúrgica y minimizando el uso de fluoroscopía. En particular, esta tesis aborda el modelado y diagnóstico de aneurismas aórticos abdominales (AAA) y del trombo intraluminal (TIL), allí donde esté presente, así como la segmentación de estas estructuras en imágenes preoperatorias de RM. Los modelos físicos específicos del paciente, construidos a partir de imágenes médicas preoperatorias, tienen múltiples usos, que van desde la evaluación preoperatoria de estructuras anatómicas a la planificación quirúrgica para el guiado de catéteres. En el diagnóstico y tratamiento de AAA, los modelos físicos son útiles a la hora de evaluar diversas variables biomecánicas y fisiológicas de las estructuras vasculares. Existen múltiples técnicas que requieren de la generación de modelos físicos que representen la anatomía vascular. Una de las principales aplicaciones de los modelos físicos es el análisis de elementos finitos (FE). Las simulaciones de FE para AAA pueden ser específicas para el paciente y permiten modelar estados de estrés complejos, incluyendo los efectos provocados por el TIL. La aplicación de métodos numéricos de análisis tiene como requisito previo la generación de una malla computacional que representa la geometría de interés mediante un conjunto de elementos poliédricos, siendo los hexaédricos los que presentan mejores resultados. En las estructuras vasculares, generar mallas hexaédricas es un proceso especialmente exigente debido a la compleja anatomía 3D ramificada. La mayoría de los AAA se encuentran situados en la bifurcación de la arteria aorta en las arterias iliacas y es necesario modelar de manera fiel dicha bifurcación. En el caso de que la sangre se estanque en el aneurisma provocando un TIL, éste forma una estructura adyacente a la pared aórtica. De este modo, el contorno externo del TIL es el mismo que el contorno interno de la pared, por lo que las mallas resultantes deben reflejar esta particularidad, lo que se denomina como "mallas conformadas". El fin último de este trabajo es modelar las estructuras vasculares de modo que proporcionen nuevas herramientas para un mejor diagnóstico clínico, facilitando medidas de riesgo de rotura de la arteria, presión sistólica o diastólica, etc. Por tanto, el primer objetivo de esta tesis es diseñar un método novedoso y robusto para generar mallas hexaédricas tanto de la pared aórtica como del trombo. Para la identificación de estas estructuras se utilizan imágenes de resonancia magnética (RM). Deben mantenerse sus propiedades de adyacencia utilizando elementos de alta calidad, prestando especial atención al modelado de la bifurcación y a que sean adecuadas para el análisis de FE. El método tiene en cuenta la evolución de la línea central del vaso en el espacio tridimensional y genera la malla directamente a partir de las imágenes segmentadas, sin necesidad de reconstruir superficies triangulares. Con el fin de reducir la intervención del usuario en el proceso de generación de las mallas, es también objetivo de esta tesis desarrollar un método de segmentación semiautomática de las distintas estructuras de interés. Las principales contribuciones de esta tesis doctoral son: 1. El diseño, implementación y evaluación de un algoritmo de generación de mallas hexaédricas conformadas de la pared y el TIL a partir de los contornos segmentados en imágenes de RM. Se ha llevado a cabo una evaluación de calidad que determine su aplicabilidad a métodos de FE. Los resultados demuestran que el algoritmo desarrollado genera mallas conformadas de alta calidad incluso en la región de la bifurcación, que son adecuadas para su uso en métodos de análisis de FE. 2. El diseño, implementación y evaluación de un método de segmentación automático de las estructuras de interés. La luz arterial se segmenta de manera semiautomática utilizando un software disponible a partir de imágenes de RM con contraste. Los resultados de este proceso sirven de inicialización para la segmentación automática de las caras interna y externa de la pared aórtica utilizando métodos basado en modelos de textura y forma a partir de imágenes de RM sin contraste. Los resultados demuestran que el algoritmo desarrollado proporciona segmentaciones fieles de las distintas estructuras de interés. En conclusión, el trabajo realizado en esta tesis doctoral corrobora las hipótesis de investigación postuladas, y pretende servir como aportación para futuros avances en la generación de modelos físicos de geometrías biológicas. ABSTRACT The frame of this PhD Thesis is the biomedical engineering applied to the treatment of cardiovascular diseases, which cause around 1.9 million deaths per year in the European Union and suppose about 40% of deaths per year. In this context appears the European project SCATh-Smart Catheterization. The main objective of this project is creating a platform which improves the navigation of catheters in aortic catheterization minimizing the use of fluoroscopy. In the framework of this project, the specific field of this PhD Thesis is the diagnosis and modeling of abdominal aortic aneurysm (AAAs) and the intraluminal thrombus (ILT) whenever it is present. Patient-specific physical models built from preoperative imaging are becoming increasingly important in the area of minimally invasive surgery. These models can be employed for different purposes, such as the preoperatory evaluation of anatomic structures or the surgical planning for catheter guidance. In the specific case of AAA diagnosis and treatment, physical models are especially useful for evaluating pressures over vascular structures. There are multiple techniques that require the generation of physical models which represent the target anatomy. Finite element (FE) analysis is one the principal applications for physical models. FE simulations for AAA may be patient-specific and allow modeling biomechanical and physiological variables including those produced by ILT, and also the segmentation of those anatomical structures in preoperative MR images. Applying numeric methods requires the generation of a proper computational mesh. These meshes represent the patient anatomy using a set of polyhedral elements, with hexahedral elements providing better results. In the specific case of vascular structures, generating hexahedral meshes is a challenging task due to the complex 3D branching anatomy. Each patient’s aneurysm is unique, characterized by its location and shape, and must be accurately represented for subsequent analyses to be meaningful. Most AAAs are located in the region where the aorta bifurcates into the iliac arteries and it is necessary to model this bifurcation precisely and reliably. If blood stagnates in the aneurysm and forms an ILT, it exists as a conforming structure with the aortic wall, i.e. the ILT’s outer contour is the same as the wall’s inner contour. Therefore, resulting meshes must also be conforming. The main objective of this PhD Thesis is designing a novel and robust method for generating conforming hexahedral meshes for the aortic wall and the thrombus. These meshes are built using largely high-quality elements, especially at the bifurcation, that are suitable for FE analysis of tissue stresses. The method accounts for the evolution of the vessel’s centerline which may develop outside a single plane, and generates the mesh directly from segmented images without the requirement to reconstruct triangular surfaces. In order to reduce the user intervention in the mesh generation process is also a goal of this PhD. Thesis to develop a semiautomatic segmentation method for the structures of interest. The segmentation is performed from magnetic resonance image (MRI) sequences that have tuned to provide high contrast for the arterial tissue against the surrounding soft tissue, so that we determine the required information reliably. The main contributions of this PhD Thesis are: 1. The design, implementation and evaluation of an algorithm for generating hexahedral conforming meshes of the arterial wall and the ILT from the segmented contours. A quality inspection has been applied to the meshes in order to determine their suitability for FE methods. Results show that the developed algorithm generates high quality conforming hexahedral meshes even at the bifurcation region. Thus, these meshes are suitable for FE analysis. 2. The design, implementation and evaluation of a semiautomatic segmentation method for the structures of interest. The lumen is segmented in a semiautomatic way from contrast filled MRI using an available software. The results obtained from this process are used to initialize the automatic segmentation of the internal and external faces of the aortic wall. These segmentations are performed by methods based on texture and shape models from MRI with no contrast. The results show that the algorithm provides faithful segmentations of the structures of interest requiring minimal user intervention. In conclusion, the work undertaken in this PhD. Thesis verifies the investigation hypotheses. It intends to serve as basis for future physical model generation of proper biological anatomies used by numerical methods.

High-quality conforming hexahedral meshes of patient-specific abdominal aortic aneurysms including their intraluminal thrombi

In order to perform finite element (FE) analyses of patient-specific abdominal aortic aneurysms, geometries derived from medical images must be meshed with suitable elements. We propose a semi-automatic method for generating conforming hexahedral meshes directly from contours segmented from medical images. Magnetic resonance images are generated using a protocol developed to give the abdominal aorta high contrast against the surrounding soft tissue. These data allow us to distinguish between the different structures of interest. We build novel quadrilateral meshes for each surface of the sectioned geometry and generate conforming hexahedral meshes by combining the quadrilateral meshes. The three-layered morphology of both the arterial wall and thrombus is incorporated using parameters determined from experiments. We demonstrate the quality of our patient-specific meshes using the element Scaled Jacobian. The method efficiently generates high-quality elements suitable for FE analysis, even in the bifurcation region of the aorta into the iliac arteries. For example, hexahedral meshes of up to 125,000 elements are generated in less than 130 s, with 94.8 % of elements well suited for FE analysis. We provide novel input for simulations by independently meshing both the arterial wall and intraluminal thrombus of the aneurysm, and their respective layered morphologies.

Flow pattern in chandler loop - the artificial thrombus formation

In this paper a hydrodynamic approach is used to analyse carefully the flow field inChandler loop--the artificial thrombus formation. The results obtained show that near thelower meniscus where the thrombus is formed, there is a back flow accompanied with asecondary flow and its mainflow is toward the meniscus, thus providing a favourable condi-tion for corpuscle aggregation. Our finding is valuable for studying the mechanism ofthrombus formation in artificial organ and in vivo.

In vivo relevance for platelet glycoprotein Ib alpha residue Tyr276 in thrombus formation

Background: Platelet glycoprotein (GP) Ib-IX-V supports platelet adhesion on damaged vascular walls by binding to von Willebrand factor (VWF). For several decades it has been recognized that the alpha-subunit of GP (GPIb alpha) also binds thrombin but the physiological relevance, if any, of this interaction was unknown. Previous studies have shown that a sulfated tyrosine 276 (Tyr276) is essential for thrombin binding to GPIb alpha.Objectives: This study investigated the in vivo relevance of GPIb alpha residue Tyr276 in hemostasis and thrombosis.Methods: Transgenic mouse colonies expressing the normal human GPIb alpha subunit or a mutant human GPIb alpha containing a Phe substitution for Tyr276 (hTg(Y276F)) were generated. Both colonies were bred to mice devoid of murine GPIb alpha.Results: Surface-expressed GPIb alpha levels and platelet counts were similar in both colonies. hTg(Y276F) platelets were significantly impaired in binding alpha-thrombin but displayed normal binding to type I fibrillar collagen and human VWF in the presence of ristocetin. In vivo thrombus formation as a result of chemical damage (FeCl3) demonstrated that hTg(Y276F) mice have a delayed time to occlusion followed by unstable blood flow indicative of embolization. In models of laser-induced injury, thrombi developing in hTg(Y276F) animals were also less stable.Conclusions: The results demonstrate that GPIb alpha residue Tyr276 is physiologically important, supporting stable thrombus formation in vivo.

Peripheral tachykinins and the neurokinin receptor NK1 are required for platelet thrombus formation

Platelets play an important role in hemostasis, with inappropriate platelet activation being a major contributor to debilitating and often fatal thrombosis by causing myocardial infarction and stroke. Although current antithrombotic treatment is generally well tolerated and effective, many patients still experience cardiovascular problems, which may reflect the existence of alternative underlying regulatory mechanisms in platelets to those targeted by existing drugs. In this study, we define a role for peripherally distributed members of the tachykinin family of peptides, namely substance P and the newly discovered endokinins A and B that are present in platelets, in the activation of platelet function and thrombus formation. We have reported previously that the preferred pharmacologically characterized receptor for these peptides, the NK1 receptor, is present on platelets. Inhibition or deficiency of the NK1 receptor, or SP agonist activity, resulted in substantially reduced thrombus formation in vitro under arterial flow conditions, increased bleeding time in mice, and a decrease in experimentally induced thromboembolism. Inhibition of the NK1 receptor may therefore provide benefit in patients vulnerable to thrombosis and may offer an alternative therapeutic target.

Platelet PECAM-1 inhibits thrombus formation in vivo

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a cell surface glycoprotein receptor expressed on a range of blood cells, including platelets, and on vascular endothelial cells. PECAM-1 possesses adhesive and signaling properties, the latter being mediated by immunoreceptor tyrosine-based inhibitory motifs present on the cytoplasmic tail of the protein. Recent studies in vitro have demonstrated that PECAM-1 signaling inhibits the aggregation of platelets. In the present study we have used PECAM-1-deficient mice and radiation chimeras to investigate the function of this receptor in the regulation of thrombus formation. Using intravital microscopy and laser-induced injury to cremaster muscle arterioles, we show that thrombi formed in PECAM-1-deficient mice were larger, formed more rapidly than in control mice, and were more stable. Larger thrombi were also formed in control mice that received transplants of PECAM-1-deficient bone marrow, in comparison to mice that received control transplants. A ferric chloride model of thrombosis was used to investigate thrombus formation in carotid arteries. In PECAM-1-deficient mice the time to 75% vessel occlusion was significantly shorter than in control mice. These data provide evidence for the involvement of platelet PECAM-1 in the negative regulation of thrombus formation.

Platelet adhesion signalling and the regulation of thrombus formation

Platelets perform a central role in haemostasis and thrombosis. They adhere to subendothelial collagens exposed at sites of blood vessel injury via the glycoprotein (GP) 1b-V-IX receptor complex, GPV1 and integrin alpha(2)beta(1)-These receptors perform distinct functions in the regulation of cell signalling involving non-receptor tyrosine kinases (e.g. Src, Fyn, Lyn, Syk and Btk), adaptor proteins, phospholipase C and lipid kinases such as phosphoinositide 3-kinase. They are also coupled to an increase in cytosolic calcium levels and protein kinase C activation, leading to the secretion of paracrine/autocrine platelet factors and an increase in integrin receptor affinities. Through the binding of plasma fibrinogen and von Willebrand Factor to integrin alphaIIbbeta(3), a platelet thrombus is formed. Although increasing evidence indicates that each of the adhesion receptors GPIb-V-IX and GPV1 and integrins alpha(2)beta(1) and alpha(IIb)beta(3) contribute to the signalling that regulates this process, the individual roles of each are only beginning to be dissected. By contrast, adhesion receptor signalling through platelet endothelial cell adhesion molecule 1 (PECAM-1) is implicated in the inhibition of platelet function and thrombus formation in the healthy circulation. Recent studies indicate that understanding of platelet adhesion signalling mechanisms might enable the development of new strategies to treat and prevent thrombosis.

Platelet protein disulfide isomerase is required for thrombus formation but not essential for hemostasis in mice

Protein disulfide isomerase (PDI) derived from intravascular cells is required for thrombus formation. However, it remains unclear whether platelet PDI contributes to the process. Using platelet-specific PDI-deficient mice, we demonstrate that PDI-null platelets have defects in aggregation and ATP secretion induced by thrombin, collagen, and ADP. Such defects were rescued by exogenously-added wild-type but not mutant PDI, indicating that the isomerase activity of platelet surface PDI is critical for the regulatory effect. PDI-deficient platelets expressed increased levels of intracellular ERp57 and ERp72. Platelet PDI regulated αIIbβ3 integrin activation but not P-selectin exposure, Ca2+ mobilization, β3-talin interaction, and platelet spreading on immobilized fibrinogen. Inhibition of ERp57 further diminished αIIbβ3 integrin activation, aggregation and ATP secretion of activated PDI-deficient platelets, suggesting distinct roles of PDI and ERp57 in platelet functions. We found that platelet PDI is important for thrombus formation on collagen-coated surfaces under arteriolar shear. Intravital microscopy demonstrates that platelet PDI is important for platelet accumulation but not initial adhesion and fibrin generation following laser-induced arteriolar injury. Tail bleeding time and blood loss in platelet-specific PDI-deficient mice were not significantly increased. Our results provide important evidence that platelet PDI is essential for thrombus formation but not for hemostasis in mice.

Staphylococcus aureus lipoteichoic acid inhibits platelet activation and thrombus formation via the Paf receptor

Impaired healing is common in wounds infected with the major human pathogen Staphylococcus aureus, although the underlying mechanisms are poorly understood. Here, we show that S.aureus lipoteichoic acid (LTA) inhibits platelet aggregation caused by physiological agonists and S. aureus and reduced platelet thrombus formation in vitro. The presence of D-alanine on LTA is necessary for the full inhibitory effect. Inhibition of aggregation was blocked using a monoclonal anti-platelet activating factor receptor (PafR) antibody and Ginkgolide B, a well-defined PafR antagonist, demonstrating that the LTA inhibitory signal occurs via PafR. Using a cyclic AMP (cAMP) assay and a western blot for phosphorylated VASP, we determined that cAMP levels increase upon platelet incubation with LTA, an effect which inhibits platelet activation. This was blocked when platelets were preincubated with Ginkgolide B. Furthermore, LTA reduced haemostasis in a mouse tail-bleed assay.

Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen

OBJECTIVE: Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. APPROACH AND RESULTS: By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbβ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. CONCLUSIONS: These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbβ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis.