The risk of re-intervention after endovascular aortic aneurysm repair

This thesis studies survival analysis techniques dealing with censoring to produce predictive tools that predict the risk of endovascular aortic aneurysm repair (EVAR) re-intervention. Censoring indicates that some patients do not continue follow up, so their outcome class is unknown. Methods dealing with censoring have drawbacks and cannot handle the high censoring of the two EVAR datasets collected. Therefore, this thesis presents a new solution to high censoring by modifying an approach that was incapable of differentiating between risks groups of aortic complications. Feature selection (FS) becomes complicated with censoring. Most survival FS methods depends on Cox's model, however machine learning classifiers (MLC) are preferred. Few methods adopted MLC to perform survival FS, but they cannot be used with high censoring. This thesis proposes two FS methods which use MLC to evaluate features. The two FS methods use the new solution to deal with censoring. They combine factor analysis with greedy stepwise FS search which allows eliminated features to enter the FS process. The first FS method searches for the best neural networks' configuration and subset of features. The second approach combines support vector machines, neural networks, and K nearest neighbor classifiers using simple and weighted majority voting to construct a multiple classifier system (MCS) for improving the performance of individual classifiers. It presents a new hybrid FS process by using MCS as a wrapper method and merging it with the iterated feature ranking filter method to further reduce the features. The proposed techniques outperformed FS methods based on Cox's model such as; Akaike and Bayesian information criteria, and least absolute shrinkage and selector operator in the log-rank test's p-values, sensitivity, and concordance. This proves that the proposed techniques are more powerful in correctly predicting the risk of re-intervention. Consequently, they enable doctors to set patients’ appropriate future observation plan

Patient specific insights into thoracic aortic disease:Exploring male-female differences

There are clear differences between males and females with thoracic aortic aneurysms (TAA). For starters, thoracic aortic aneurysm (TAA) between is known to have a higher incidence in males. Furthermore, females seem to present with thoracic aortic aneurysm at an older age. However, little is known about possible differences between male and female TAA patients in presentation, management and outcomes. Worse outcomes in females after thoracic aortic dissection and elective thoracic aortic surgery have been reported, which lead to uncertainties about optimal timing of preventive thoracic aortic surgery in male and female patients. The mechanisms underlying these male-female differences in outcome remain unclear. As a result, there has been debate about the appropriateness of the use of absolute aortic diameter for the timing of surgery. Currently, sex and body size are not taken into account when timing preventive aortic surgery. However, male-female specific cut-off values for maximal aortic diameter might be helpful. Furthermore, the risk of aortic dissection causes stress and anxiety in TAA patients, which could impact quality of life. The effect of TAA on quality of life might be different in males and females, since male-female differences in emotional functioning, coping strategies and stress (i.e. anxiety/depression) are well known to exist in the general population. Moreover, limited information is available on the safety of daily activities, such as exercise and sports participation in both male and female patients with thoracic aortic disease. All these male-female differences have largely been neglected in patients with heart disease in general and aortic disease in particular. Therefore, research in all these aspects of aortic disease is essential. This thesis is part of the ‘Size Matters’ project, funded by ZonMW, aims to identify male-female differences and other patient specific insights into thoracic aortic aneurysm diagnosis, treatment and outcomes. More accurate identification of patients at risk for thoracic aortic dissection allows for better timing of intervention, and will hopefully contribute to better survival, as well as stress reduction and better quality of life

Patient specific insights into thoracic aortic disease:Exploring male-female differences

There are clear differences between males and females with thoracic aortic aneurysms (TAA). For starters, thoracic aortic aneurysm (TAA) between is known to have a higher incidence in males. Furthermore, females seem to present with thoracic aortic aneurysm at an older age. However, little is known about possible differences between male and female TAA patients in presentation, management and outcomes. Worse outcomes in females after thoracic aortic dissection and elective thoracic aortic surgery have been reported, which lead to uncertainties about optimal timing of preventive thoracic aortic surgery in male and female patients. The mechanisms underlying these male-female differences in outcome remain unclear. As a result, there has been debate about the appropriateness of the use of absolute aortic diameter for the timing of surgery. Currently, sex and body size are not taken into account when timing preventive aortic surgery. However, male-female specific cut-off values for maximal aortic diameter might be helpful. Furthermore, the risk of aortic dissection causes stress and anxiety in TAA patients, which could impact quality of life. The effect of TAA on quality of life might be different in males and females, since male-female differences in emotional functioning, coping strategies and stress (i.e. anxiety/depression) are well known to exist in the general population. Moreover, limited information is available on the safety of daily activities, such as exercise and sports participation in both male and female patients with thoracic aortic disease. All these male-female differences have largely been neglected in patients with heart disease in general and aortic disease in particular. Therefore, research in all these aspects of aortic disease is essential. This thesis is part of the ‘Size Matters’ project, funded by ZonMW, aims to identify male-female differences and other patient specific insights into thoracic aortic aneurysm diagnosis, treatment and outcomes. More accurate identification of patients at risk for thoracic aortic dissection allows for better timing of intervention, and will hopefully contribute to better survival, as well as stress reduction and better quality of life

Quantifying the Impact of Altered Hemodynamics and Vascular Biomechanics to Changes in Structure and Function in Native and Corrected Aortic Coarctation

Coarctation of the aorta (CoA) is associated with substantial cardiovascular morbidities despite successful treatment through surgical or catheter-based intervention. Although specific mechanisms leading to these morbidities remain elusive, abnormal hemodynamics and vascular biomechanics are implicated. We used a novel animal model that facilitates quantification of CoA-induced hemodynamic and vascular biomechanics alterations and their impact on vascular structure and function, independent of genetic or confounding factors. Rabbits underwent thoracic CoA at 10 weeks of age (~9 human years) to induce a 20 mmHg blood pressure (BP) gradient using permanent or dissolvable suture thereby replicating untreated and corrected CoA. Computational fluid dynamics (CFD) was performed using subject-specific imaging and BP data at 32 weeks to quantify velocity, strain, and wall shear stress (WSS). Vascular structure and function were evaluated at proximal and distal locations by histology, immunohistochemistry, and myograph analysis. Results revealed proximal systolic and mean BP was elevated in CoA compared to corrected and control rabbits leading to vascular remodeling, endothelial dysfunction proximally and distally, and increased stiffness and reduced active force response proximally. Corrected rabbits had reduced but significant medial thickening, endothelial dysfunction, and stiffening limited to the proximal region despite 12 weeks of alleviated systolic and mean BP (~4 human years) after the suture dissolved. Proximal arteries of CoA and corrected groups demonstrated increased non-muscle myosin expression and decreased myosin heavy chain expression, and this dedifferentiation may influence vascular remodeling and aortic stiffening. CFD analysis of untreated CoA rabbits demonstrated significantly reduced WSS proximal to CoA and markedly elevated WSS distally due to the presence of a stenotic velocity jet. Results from corrected rabbits indicate the velocity jet may have persistent effects on hemodynamics, as WSS remained significantly reduced. These hemodynamic and morphological observations are consistent with alterations in human patients. Using these coupled imaging and experimental results, we may determine changes in structure and function specific to CoA and correction and how they are influenced by hemodynamics and vascular biomechanics. We are now poised to augment clinical treatment of CoA through several methods, including investigation of specific cellular mechanisms causing morbidity in CoA and the development of therapies to improve endothelial function and restore vascular stiffness

In-vitro analysis of haemodynamics in stented arteries.

Cardiovascular diseases (CVD) are the leading cause of death in the developed world. One of the most common management methods for CVD is through vascular implants such as stents to support arterial walls. However, determining the efficacy of stents can be difficult, particularly for high-risk stents, such as those used in the aorta. In-vitro modelling can provide safe insight into the haemodynamics changes within an artery due to specific stenting methods, without intrusive patient monitoring. The in-vitro studies presented in this thesis contribute to research on the haemodynamic changes within arteries using particle image velocimetry (PIV). In-vitro modelling can be used to investigate haemodynamics of arterial geometry and stent implants. However, in-vitro model fidelity is reliant on precise matching of in-vivo conditions. Flow distribution and wall shear stress depend on the Reynolds and Womersley numbers. This thesis reviewed currently published Reynolds and Womersley numbers for 14 major arteries in the human body. The results were presented both in a table and graphically for ease of understanding and future use. The results identified a paucity of information in smaller distal arteries compared to major arteries such as the aorta. Matching Reynolds and Womersley numbers for compliant in-vitro modelling may also be limited by model dimensional tolerances. A method for visualising the range of experimental conditions required for dynamic matching was developed and case studies for the ascending aorta and common carotid artery were presented. The assumed Sylgard 184 silicone would be used for phantom fabrication, and compared three working solutions: water/glycerine, water/glycerine/urea, and water/glycerine/sodium-iodide. To manufacture compliance matched silicone models of the ascending aorta and common carotid arteries, the models were scaled to 1.5x (ascending aorta) and 3x (common carotid) life scale, respectively. Modelling the ascending aorta with the comparatively high viscosity water/glycerine solution will lead to very high pump power demands. However, any of the working fluids considered could be dynamically matched with low pump demand for the common carotid model. The Frozen Elephant Trunk (FET) stent is a hybrid endovascular device that may be implemented in the event of an aneurysm or aortic dissection of the aortic arch or superior descending aorta. However, the FET stent is a high risk stent. In particular, the Type 1B endoleak can lead to intrasaccular flow due to an incomplete distal fit between the stent and artery during systole. Chapter 5 developed an in-vitro modelling technique to enable the investigation of the known failure. Recirculation zones and an asymmetric endoleak were identified distal to the surrogate stent graft. The endoleak developed at the peak of systole and was sustained until the onset of diastole. The endoleak geometry indicated a potential variation in the phantom artery wall thickness or stent alignment. Recirculation was identified on the posterior dorsal line during late systole which may induce an inflammatory response in an artery. The identification of the Type 1B endoleak proved that in-vitro modelling can be used to investigate complex compliance changes and wall motions. The kissing stent (KS) configuration is a low risk, stenting method often used to treat aorto-iliac occlusive disease (AIOD). However, long-term patency reduces by nearly 25% in the first five years potentially due to deleterious flow behaviour. The risk of harmful haemodynamics due to the KS configuration were investigated in-vitro. PIV experimentation identified peak proximal and distal velocity in-vitro was 0.71 m·s-1 and 1.90 m·s-1, respectively. A lumen wall collapse in the sagittal plane occurred during late systole to early diastole proximal the KS configuration. The collapse disturbed the flow proximal to the stented region producing potential recirculation zones and abnormal flow patterns. However, the systolic flow was as normal and undisturbed indicating the KS configuration is safe to use for repairing AIOD. The collapse had not been previously identified and would require further investigation. Thoracic extra-anatomic bypasses (EAB) are grafted stents that may be used to prophylactically revascularize supra-aortic arteries that may require blockage during thoracic endovascular aortic repair (TEVAR) methods. However, prophylactic use of EAB may introduce a risk of failure due to abnormally low or disrupted flow, known as competitive flow, within the bypasses. Competitive flow within the bypasses between supra-aortic arteries has not been captured previously. PIV was used to assess each model configuration for flow abnormalities and potential for flow competition. The investigation found potential for competitive flow in the bypasses when just the left subclavian artery (LSA), the left carotid artery (LCCA), or none of the arteries are blocked. In contrast, when the LSA and LCCA were both blocked, there was no evidence of competitive flow. Flow stagnated at the initiation of systole within the BC bypass in the 2 configurations with an unblocked LCCA, along with notable recirculation zones and reciprocating flow occurring throughout the rest of systolic flow. Flow stagnated in the CS bypass at early systole when only the LCCA was blocked. A large recirculation was identifiable in the CS bypass when just the LSA was blocked, particularly after peak systole. The potential of competitive flow indicated prophylactic used of EAB in the supra-aortic arteries may require location of proximal arteries to limit the number of pathways blood flow can take

Suivi par élastographie ultrasonore après réparation endovasculaire d’anévrisme aorto-iliaque : étude de faisabilité in vivo

Les maladies cardiovasculaires sont la première cause de mortalité dans le monde et les anévrismes de l’aorte abdominale (AAAs) font partie de ce lot déplorable. Un anévrisme est la dilatation d’une artère pouvant conduire à la mort. Une rupture d’AAA s’avère fatale près de 80% du temps. Un moyen de traiter les AAAs est l’insertion d’une endoprothèse (SG) dans l’aorte, communément appelée la réparation endovasculaire (EVAR), afin de réduire la pression exercée par le flux sanguin sur la paroi. L’efficacité de ce traitement est compromise par la survenue d’endofuites (flux sanguins entre la prothèse et le sac anévrismal) pouvant conduire à la rupture de l’anévrisme. Ces flux sanguins peuvent survenir à n’importe quel moment après le traitement EVAR. Une surveillance par tomodensitométrie (CT-scan) annuelle est donc requise, augmentant ainsi le coût du suivi post-EVAR et exposant le patient à la radiation ionisante et aux complications des contrastes iodés. L’endotension est le concept de dilatation de l’anévrisme sans la présence d’une endofuite apparente au CT-scan. Après le traitement EVAR, le sang dans le sac anévrismal coagule pour former un thrombus frais, qui deviendra progressivement un thrombus plus fibreux et plus organisé, donnant lieu à un rétrécissement de l’anévrisme. Il y a très peu de données dans la littérature pour étudier ce processus temporel et la relation entre le thrombus frais et l’endotension. L’étalon d’or du suivi post-EVAR, le CT-scan, ne peut pas détecter la présence de thrombus frais. Il y a donc un besoin d’investir dans une technique sécuritaire et moins coûteuse pour le suivi d’AAAs après EVAR. Une méthode récente, l’élastographie dynamique, mesure l’élasticité des tissus en temps réel. Le principe de cette technique repose sur la génération d’ondes de cisaillement et l’étude de leur propagation afin de remonter aux propriétés mécaniques du milieu étudié. Cette thèse vise l’application de l’élastographie dynamique pour la détection des endofuites ainsi que de la caractérisation mécanique des tissus du sac anévrismal après le traitement EVAR. Ce projet dévoile le potentiel de l’élastographie afin de réduire les dangers de la radiation, de l’utilisation d’agent de contraste ainsi que des coûts du post-EVAR des AAAs. L’élastographie dynamique utilisant le « Shear Wave Imaging » (SWI) est prometteuse. Cette modalité pourrait complémenter l’échographie-Doppler (DUS) déjà utilisée pour le suivi d’examen post-EVAR. Le SWI a le potentiel de fournir des informations sur l’organisation fibreuse du thrombus ainsi que sur la détection d’endofuites. Tout d’abord, le premier objectif de cette thèse consistait à tester le SWI sur des AAAs dans des modèles canins pour la détection d’endofuites et la caractérisation du thrombus. Des SGs furent implantées dans un groupe de 18 chiens avec un anévrisme créé au moyen de la veine jugulaire. 4 anévrismes avaient une endofuite de type I, 13 avaient une endofuite de type II et un anévrisme n’avait pas d’endofuite. Des examens échographiques, DUS et SWI ont été réalisés à l’implantation, puis 1 semaine, 1 mois, 3 mois et 6 mois après le traitement EVAR. Une angiographie, un CT-scan et des coupes macroscopiques ont été produits au sacrifice. Les régions d’endofuites, de thrombus frais et de thrombus organisé furent identifiées et segmentées. Les valeurs de rigidité données par le SWI des différentes régions furent comparées. Celles-ci furent différentes de façon significative (P < 0.001). Également, le SWI a pu détecter la présence d’endofuites où le CT-scan (1) et le DUS (3) ont échoué. Dans la continuité de ces travaux, le deuxième objectif de ce projet fut de caractériser l’évolution du thrombus dans le temps, de même que l’évolution des endofuites après embolisation dans des modèles canins. Dix-huit anévrismes furent créés dans les artères iliaques de neuf modèles canins, suivis d’une endofuite de type I après EVAR. Deux gels embolisants (Chitosan (Chi) ou Chitosan-Sodium-Tetradecyl-Sulfate (Chi-STS)) furent injectés dans le sac anévrismal pour promouvoir la guérison. Des examens échographiques, DUS et SWI ont été effectués à l’implantation et après 1 semaine, 1 mois, 3 mois et 6 mois. Une angiographie, un CT-scan et un examen histologique ont été réalisés au sacrifice afin d’évaluer la présence, le type et la grosseur de l’endofuite. Les valeurs du module d’élasticité des régions d’intérêts ont été identifiées et segmentées sur les données pathologiques. Les régions d’endofuites et de thrombus frais furent différentes de façon significative comparativement aux autres régions (P < 0.001). Les valeurs d’élasticité du thrombus frais à 1 semaine et à 3 mois indiquent que le SWI peut évaluer la maturation du thrombus, de même que caractériser l’évolution et la dégradation des gels embolisants dans le temps. Le SWI a pu détecter des endofuites où le DUS a échoué (2) et, contrairement au CT-scan, détecter la présence de thrombus frais. Finalement, la dernière étape du projet doctoral consistait à appliquer le SWI dans une phase clinique, avec des patients humains ayant déjà un AAA, pour la détection d’endofuite et la caractérisation de l’élasticité des tissus. 25 patients furent sélectionnés pour participer à l’étude. Une comparaison d’imagerie a été produite entre le SWI, le CT-scan et le DUS. Les valeurs de rigidité données par le SWI des différentes régions (endofuite, thrombus) furent identifiées et segmentées. Celles-ci étaient distinctes de façon significative (P < 0.001). Le SWI a détecté 5 endofuites sur 6 (sensibilité de 83.3%) et a eu 6 faux positifs (spécificité de 76%). Le SWI a pu détecter la présence d’endofuites où le CT-scan (2) ainsi que le DUS (2) ont échoué. Il n’y avait pas de différence statistique notable entre la rigidité du thrombus pour un AAA avec endofuite et un AAA sans endofuite. Aucune corrélation n’a pu être établie de façon significative entre les diamètres des AAAs ainsi que leurs variations et l’élasticité du thrombus. Le SWI a le potentiel de détecter les endofuites et caractériser le thrombus selon leurs propriétés mécaniques. Cette technique pourrait être combinée au suivi des AAAs post-EVAR, complémentant ainsi l’imagerie DUS et réduisant le coût et l’exposition à la radiation ionisante et aux agents de contrastes néphrotoxiques.Cardiovascular diseases are the leading cause of death worldwide. Abdominal aortic aneurysms (AAAs) are part of these horrible diseases. An aneurysm is a dilatation of an artery that can lead to death. A rupture of an AAA can lead to death nearly 80% of the time. One way to treat AAAs is the insertion of a stent-graft (SG) in the aorta in order to reduce the pressure on the wall, commonly known as endovascular repair (EVAR). Endoleak, defined as persistent blood flow within the aneurysm sac and outside the SG, is the main complication of EVAR. This phenomenon increases the risk of rupture and can develop at any time after EVAR. A life-long surveillance follow-up with computed tomography (CT-scan) is required to detect endoleak, increasing the cost of EVAR, exposing patient to ionizing radiation and nephrotoxic contrast agent. Aneurysm growth without evidence of endoleak on CT-scan is called endotension. After SG delivery, the blood is trapped between the SG and aneurysm wall. If there is no residual flow (endoleak), the blood will coagulate to form fresh thrombus that will progressively organize to become a fibrous thrombus leading to aneurysm shrinkage. There is little data in the literature to study the timing of this process and the relationship between thrombus organization and aneurysm shrinkage. The gold-standard of post-EVAR surveillance, the CT-scan, cannot detect the presence of fresh thrombus. There is a clear need to invest in a safe and cost effective technique for post-EVAR surveillance. A recent method, dynamic elastography, measures the elasticity of tissues in real time. The principle of this technique is based on the generation of shear waves and studies their propagations for the determination of elastic properties (stiffness) of tissues. This thesis aims the application of dynamic elastography for the detection of endoleak and to characterize mechanical properties of AAAs tissues after EVAR. This project reveals the potential of elastography to reduce costs, exposure to ionizing radiation and nephrotoxic contrast agents in CT-scan follow-up of AAAs post-EVAR. Dynamic elastography using the shear wave imaging (SWI) is promising and can complement the Doppler ultrasound (DUS), which is already used in post-EVAR follow-up. SWI has the potential to get information from thrombus organization and to detect endoleak. The first objective of this thesis was to test the SWI on AAAs in canines models for the detection of endoleak and the characterization of thrombus. SGs were implanted in 18 dogs after surgical creation of type I endoleaks (4 AAAs), type II endoleaks (13 AAAs) and no endoleaks (1 AAA). DUS and SWI were engaged before (baseline) and 7, 30, 90 and 180 days (sacrifice) after SG implantation. Digital subtraction angiography, CT-scan and macroscopic tissue sections were analyzed at sacrifice. Endoleak and thrombus areas were identified and segmented. Elasticity (Young's) moduli were measured in different regions of interest (endoleaks, fresh and organized thrombi) after registration of pathological findings. Rigidity values of the regions of interest were significantly different (P < 0.001). SWI was able to detect endoleaks where CT-scan (1) and DUS (3) failed. The second objective of this project was to characterize the evolution of the thrombus in time, also as the endotension after endoleak embolization in canines models. EVAR was done with creation of type I endoleak in 18 aneurysms created in nine dogs (common iliacs arteries). Two embolization gels (Chitosan (Chi) or Chitosan-Sodium-Tetradecyl-Sulfate (Chi-STS)) were injected in the sac to seal the endoleak and promote healing. SWI and DUS were performed at baseline (implantation, 1 week, 1 month, 3 months) whereas angiography and CT-scan were performed at sacrifice to evaluate the presence and type of the endoleak. Macroscopic and histopathological analyses were processed to identify and segment five different regions of interest (ROIs) (endoleak, fresh or organized thrombus, Chi or Chi-STS). Elasticity values of endoleak and fresh thrombus areas were significantly lower than organized thrombus, Chi and Chi-STS areas (P < 0.001). Elasticity values of fresh thrombus at 1 week and at 3 months indicated that SWI can evaluate thrombus maturation. It can also characterize embolization agents degradation. SWI was able to detect endoleak where DUS failed (2) and distinguish fresh thrombi which cannot be detected on CT-scan. Finally, the last step of the doctoral project was to apply the SWI in a clinical phase with humans with an AAA for the detection of endoleak and characterizing elasticity of tissues. 25 patients were selected to participate in the study. Comparison of SWI, CT-scan and DUS images was conducted. Rigidity values by SWI of regions of interest (endoleak, thrombus) were identified and segmented. These were significantly different (P < 0.001). SWI detected 5 endoleaks on 6 (sensitivity of 83.3%) and had 6 false positives (specificity of 76%). SWI detected endoleaks where CT-scan (2) and DUS (2) failed. No statistical difference was found in elasticity between thrombus with an AAA with endoleak and thrombus with an AAA without endoleak. Also, no correlation was found between AAA diameter or its variation over time and thrombus elasticity. SWI has the potential to detect endoleaks and characterize thrombus. The approach could be combined with DUS surveillance of AAAs after EVAR, which is currently widely practiced to reduce the cost of AAA follow-up and exposure to ionizing radiation and contrast agents