Aortic infections are rare, life-threatening and constitute a major challenge in surgical management. This thesis aims to evaluate short – and long-term outcome of endovascular aortic repair (EVAR) for mycotic aortic aneurysms (MAA) and the subsequent risk of recurrent infections, changes in surgical practice over time for abdominal MAAs in Sweden and outcome for different treatment modalities, as well as the risk of secondary vascular infection after treatment with Open abdomen after aortic surgery. Paper I, a retrospective single centre study of patients with MAA treated with EVAR, demonstrated a good short-term outcome, 91% survival at 30-days, and acceptable mid-term survival, 73% at 1-year. Paper II, a retrospective international multicentre study of patients treated with EVAR for MAA, confirmed the results in paper I, and showed that EVAR is feasible and for most MAA patients a durable treatment option, 5-year survival was 55% and 10-year 41%. A total of 19% died from an infection-related complication, mostly during the first postoperative year. Non-Salmonella-positive culture was a predictor for late infection–related death. Paper III, a population-based cohort study on all abdominal MAAs operated on between 1994-2014 in Sweden. Overall survival was 86% at 3-months, 79% at 1-year and 59% at 5-years. The survival was significantly better after endovascular compared to open repair up to 1-year without increasing recurrence of infection or reoperation, thereafter there was no difference. After 2001 EVAR constituted 60 % of all repairs, thus indicating a paradigm shift in treatment for abdominal MAAs in Sweden. Paper IV, a prospective multicentre study of patients treated with open abdomen after aortic surgery. Infectious complications, such as graft infections, occurred after intestinal ischaemia and prolonged OA-treatment, and were often fatal.

Aneurismas e dissecções da aorta ascendente são caracterizados por degradação das fibras elásticas e de colágeno e diminuição de células musculares lisas, predominantemente em áreas mucóides, as quais são relacionadas ao acúmulo de glicosaminoglicanos ou proteoglicanos. Tendo em vistas tais alterações, estudamos a topologia das metaloproteases nestas doenças. Cortes de 5?m de aortas, fixadas em fomol e embebidas em parafina, foram submetidos a reações imuno-histoquímicas para MMP-3 (estromelisina), MMP-7 (matrilisina) e plasminogênio/plasmina na camada média. Em paralelo, cortes de aortas foram submetidos a coloração pela hematoxilina e eosina e azul de Alcian (para material mucóide). Aortas de 8 pacientes com aneurisma de aorta torácica e 10 com dissecções agudas foram analisadas. Adicionalmente, 9 aortas normais foram estudadas como controle. Em todos os casos, MMP-3 e, mais expressivamente, MMP-7 apresentaram marcação dentro dos acúmulos mucóides. Em contrapartida, a marcação para plasmina/plasminogênio situou-se ao redor deles. Fora dessas áreas, a MMP-3 mostrou distribuição intra e extracelular, a MMP-7 apresentou marcação intra e extracelular predominante na segunda metade da túnica média, e plasmina/plasminogênio teve co-localização com células musculares lisas. Considerando que matrilisina e estromelisina atuam sobre os proteoglicanos e sobre outros componentes da matriz extracelular, estas enzimas poderiam estar envolvidas diretamente na gênese dos aneurismas e dissecções da aorta ascendente, com possível modulação por plasminogênio/plasmina / In dissections and non-inflammatory aneurysms of the ascending aorta there is an increase in mucoid (proteoglycan) deposition. We analyzed by immunoperoxidase the distribution of stromelysin (MMP-7), matrilysin (MMP-3) and plasminogen/plasmin, enzymes that act on proteoglycans, in sections of human aortas with these diseases and in controls. In cases with any of these diseases MMP-7 and MMP-3 were accumulated in the areas of mucoid degeneration, and plasmin around them. Such enzymes could thus be involved in these diseases. We also evaluated by morphometry the amount of collagen in the two halves of the aortic media.

OBJECTIVES: The association between bicuspid aortic valves and aortic aneurysms has been well documented. In order to better understand this association, this study sought to accomplish two goals. The first was to determine if there was any correlation between specific bicuspid aortic valve phenotypes and aortic aneurysms. The second goal was to determine if the association between bicuspid aortic valve disease and aortic aneurysms has a genetic or hemodynamic cause. METHODS: For the non-genetic portion of the study, we used echocardiogram and surgical records to classify the phenotypes of the aortic valve and the aorta of 434 patients. We then evaluated the correlation between valve morphotype and aortic aneurysm phenotype. For the genetic portion, we used a genome wide association study on 452 patients to find genes that could potentially be responsible for aortic aneurysms. These were then compared with genes suspected of causing bicuspid aortic valve to determine if there is a common genetic link between the two disorders. RESULTS: We observed a significant association between bicuspid aortic valve and aortic aneurysms; however we did not find any significant association between the different bicuspid aortic valve phenotypes and aortic aneurysm phenotypes. For the genome wide association study, we identified genes that could potentially be responsible for causing aortic aneurysms; however, none of the suspected markers were considered statistically significant. Also none of the identified genes matched to the genes suspected of causing bicuspid aortic valve. CONCLUSION: While the results were not as expected, the study provided us with information to better understand the relationship between bicuspid aortic valves and aortic aneurysms. According to the results of the current study, patients with bicuspid aortic valve are more likely to develop an aortic aneurysm but specific phenotype has no effect on where the aneurysm occurs in the aorta. The increased frequency of aortic aneurysms in bicuspid valve patients is most probably due to a combination of altered hemodynamics and genetic effects. In order for this information to be useful in the clinical setting, the methods of this study should be repeated in a larger cohort to make sure the results are accurate.

Cerebral aneurysm is a pathology of the circulatory system in the brain in which an arterial wall balloons into a blood-filled sac. If the aneurysm ruptures, stroke can occur and has a high probability of causing permanent disability or death. Aneurysm surgery carries a high rate of morbidity and mortality compared to the natural rate of aneurysm rupture, so physicians must take care in recommending surgery for an aneurysm patient. However, very little is known about the etiology of brain aneurysm rupture and what prognostics exist. The International Study for Intracranial Aneurysms suggested that large aneurysm size and posterior location are important factors in identifying high rupture risk. However, many small aneurysms and aneurysms in other portions of the circulation still rupture. Many studies have assessed morphological traits, identified from aneurysm appearance on diagnostic medical images, and found such traits to be different in aneurysms that ruptured and aneurysms that did not rupture. In fact, more than 50 such morphological indices have been introduced in the literature, and many of them redundantly quantify particular morphological characteristics. In order to demonstrate the prognostic ability of morphology as an indicator of rupture risk, however, a large longitudinal cohort study must be carried out. A study such as this is time-consuming and expensive, and each additional hypothesis that a particular morphological index is predictive of rupture risk would require increasing the study population size in order to fulfill the necessary statistical power requirements for a rigorous test. Thus, a minimal set of physically meaningful, independent metrics that fully describe the aneurysm morphology is needed. In this dissertation an automated protocol was developed to process segmented medical images and extract an exhaustive set of morphological indices that quantify all relevant morphological features. Each morphological index was then analyzed for robustness to inter-user variability and for sensitivity to the particular morphological characteristic that it was designed to quantify. A factor analysis was then performed using the most robust, sensitive metrics on a population of unruptured aneurysms from five data centers and 276 patient-specific aneurysms. The results from the factor analysis were utilized to ascertain what morphological features those metrics truly described, if there were any redundancies in definition, and the variance each morphological trait described in the population. Four underlying morphological constructs were uncovered through the factor analysis. The first factor, sac size, was highly aligned with morphological indices that measured volume and one-dimensional size measurements. Sac size described 50% of the variance in the data set. The second factor, sac irregularity, was highly aligned with morphological indices that described various aspects of irregular shape. A set of variables that all were implicated in causing irregular shape, but in reality measured sac-neck size relation, also merited inclusion of a second metric to describe the variance seen in the second factor. Sac irregularity described 20% of the variance in the data set. The third factor, sac ellipticity, aligned highly with morphological indices that described the overarching ellipticity of the aneurysm sac independent of other non-spherical characteristics. Sac ellipticity described 13% of the variance in the data set. The fourth factor, sac-vessel size relation, aligned highly with morphological indices that described the size of the aneurysm sac in relation to its parent vessel. Sac-vessel size relation described 7% of the variance in the data set. All four of these factors in combination described 91% of the variance in the data set. Five morphological indices – non-planar isolation sac volume (Vnp), Voronoi diagram core evolution irregularity index (IRRvdc), tissue stretch ratio (TSR), Voronoi diagram core evolution ellipticity index (EIvdc) and size ratio (SRang) were determined to be the key indices for describing aneurysm morphology. Finally, the proposed metrics were used to test the hypothesis that aneurysms that are chosen for untreated observation are morphologically different than those that are treated – commonly referred to as selection bias. Study population was 27 patient-specific aneurysms that were placed on untreated observation (observation group) and 27 patient specific aneurysms that were size- and location-matched but were chosen for treatment (treated group). A significant difference was found in the morphological index that measured ellipticity between the two groups, indicating that physicians already commonly select highly elliptical aneurysms for treatment. This result may give insight into physicians’ choices, and merits further investigation with a larger data set for confirmation. Additionally, because the same result was replicated in both of the metrics chosen to quantify ellipticity (for both manual and automated methods), this highlighted the use of the morphological factors in determining an minimal set of independent, robust morphological indices.

Abdominal aortic aneurysms are a focal dilation of the aorta which can be potentially life threatening if left untreated. Endovascular aneurysm repair (EVAR) is a noninvasive treatment that can reduce the mortality rate when compared to the standard open repair. Yet, EVAR is associated with other complications that can arise such as migration, endoleaks, or device related failures. These complications drive the need for reinterventions which have been shown to occur more frequently with EVAR than with open repair. The long term fixation and sealing characteristics of these devices is likely related to the nature of its apposition to the aortic wall. Currently there is little understanding of these mechanics and factors in how the device performs at the time of deployment. A computational model that reflects the compressive nature of an endovascular graft is beneficial in investigating these mechanics. The aims of the study are; 1) formulate an experimental methodology that captures the radial compressive nature of the stent graft, 2) develop a parameterized finite element model of the stent structure, and 3) compare the compressive behavior this model against the acquired experimental data. A 2 mil polyethylene sleeve was used to transfer a compressive vacuum pressure from the sleeve onto 10 independent stent grafts. The loading-unloading pressure was cycled from 0 to -50 mmHg (complete collapse) over 5 minutes. A pressure transducer and optical micrometer were used to capture the vacuum pressure and diameter relationship. All ten grafts compressed in a similar elliptical shape configuration. Commercial software was leveraged to construct a parameterized model of the stent geometry. All crest and trough vertex locations of the sinusoidal stent structure were validated within 1 mm of a measured value. A dynamic quasi-static computational simulation was completed that included large deformations and contact between the sleeve and stent as well as self-contact in the sleeve. Our results show that the model is representative of the experiments and can be used to interrogate how a stent graft will perform during certain stages of deployment and immediately after deployment with some caution in regard to the stated limitations.

Abdominal Aortic Aneurysms (AAA) are amongst the top ten most common cause of death in those over 55 years of age. The disease is usually asymptomatic, often being diagnosed incidentally. Once diagnosed, elective repair of an AAA results in excellent long-term survival with a 3-5% operative mortality. However, up to one half of patients present with ruptured aneurysms, a complication that carries an 80% mortality in the community, and of those reaching hospital, a 50% mortality. Clearly early diagnosis and treatment results in improved survival. Screening for AAA, with ultrasound, would detect aneurysms early, prior to rupture. However, debate continues over the cost effectiveness of population based screening programmes. The identification of a sub-population at a higher risk of developing AAA would increase the yield of a screening prograrmne. A number of populations have been examined, none of which have received international acceptance. About 20% of patients with an AAA have a family history of an aneurysm. The disease is also considered to be a disease of Caucasians, both facts suggesting a strong genetic component to the disease. Perhaps a genetically identified sub-population at a high risk of developing an AAA would prove to be an ideal population for screening. This thesis examines the incidence of aneurysms and the family histories of patients with AAA in the Otago region of New Zealand. Almost twenty percent of the population has a family history of AAA. DNA was collected from each of these patients for genetic analysis. The population was divided into familial AAA and non-familial AAA for the purpose of genetic analysis and compared to a control population. AAA is believed to be a disease of Caucasians; a non-Caucasian population with a low incidence of AAA may prove to be a good control population for genetic studies. A literature review demonstrated a higher incidence of AAA in Caucasians than other ethnic groups and within Caucasians a higher incidence in patients of Northern European origin. The incidence was low in Asian communities, even in studies involving of migrant Asian populations. The New Zealand Maori are believed to have originated from South East Asia, therefore could be expected to have a low incidence of AAA and would make an ideal control population for genetic studies. A pilot study was undertaken to examine the incidence of AAA in the New Zealand Maori. The age standardised incidence of AAA proved to be at least equal in Maori to non-Maori, with a more aggressive form of the disease in Maori, manifesting with a younger age at presentation and a higher incidence of ruptured aneurysms at diagnosis. It is well known that at the time of surgery, an AAA is at the end stage in its life. At this time, inflammation and matrix metalloproteinases (MMP) enzymes are prevalent within the aneurysm wall and have destroyed the wall of the aorta. One of the most important genetic pathways regulating these enzymes is the plasminogen activator inhibiter 1-Tissue plasminogen activator-plasmin pathway. Genetic analysis of this pathway demonstrated an association of the 4G5G polymorphism in the promoter of the PAl-1 gene with familial AAA. In this insertion:deletion polymorphism, the 5G variant binds an activator and repressor, resulting in reduced PAI-1 expression and ultimately increased MMP activation. This allele was associated with familial aneurysms, 47% versus 62% non-familial AAA and 61% controls (p=0.024). A polymorphism within the tissue plasminogen activator gene was also examined and no association was found with AAA. Another way the MMPs expression could be increased is from mutations or polymorphisms in their own genetic structure. Stromelysin 3 is itself a MMP capable of destroying the aortic wall and it has a role in activating other MMPs. A 5A6A insertion:deletion polymorphism exists in the promoter of this gene. The 5A allele variant results in increased stromelysin expression and is associated with AAA 46% versus 33% in controls p=0. 0006. The actions of the MMPs are themselves inhibited by the tissue inhibitors of matrix metalloproteinases. The TIMP genes have been sequenced; two polymorphisms have been identified in the non-coding promoter area of the TIMP 1 gene. Further studies are necessary to examine the effect of these polymorphisms. Inflammation has been implicated in aneurysm progression. One of the roles of the inflammatory cells found in an aneurysm is to deliver the MMP�s to the AAA. The HLA system is integral in controlling this inflammation and was therefore examined. From this series of studies it is concluded that there is a genetic component to AAA. This thesis presents the first genetic polymorphism associated with familial AAA and explores the role of a genetic pathway in the formation of AAA.

According to the American Heart Association about 795,000 people suffer a stroke each year. Of those strokes almost 140,000 are fatal; this makes Stroke the third leading cause of death in the United States behind coronary heart disease and cancer. Hemorrhagic strokes are caused when an artery in the brain ruptures, such as a ruptured aneurysm. One possible treatment for cerebral aneurysm is a porous tubular structure, similar to a stent, called a flow diverter. A flow diverter can be placed across the neck of a cerebral aneurysm to induce the cessation of flow and initiate the formation of an intra-aneurysmal thrombosis. This excludes the aneurysm from the parent artery and returns the flow of blood to normal. The process of flow diversion alone has been shown to take months to fully exclude the aneurysm. It is possible however with an adjuvant therapy called photothrombosis to accelerate this process so that the aneurysm is excluded within minutes. Previous flow diverting devices have been analyzed to determine optimal characteristics, such as braiding angle and wire diameter. From this information a new optimized device was designed and is now in the process of being tested. In order to evaluate the effect of the device, a model must be created. One such model is the rabbit elastase induced aneurysm, which was characterized so that elastomer models could be created for in vitro studies. Particle Image Velocimetry (PIV) is a method of analysis that utilizes very small glass spheres (between 8 mu m and 12 mu m in diameter) to determine the velocity vectors of fluid flow in an in vitro model. These velocities can be used to calculate hydrodynamic circulation and kinetic energy inside an elastomer model of the elastase induced aneurysm. By comparing these values inside the aneurysm with values for previously developed diverters and a control without a diverter, it can be shown that despite changes in the braiding angle and individual wire thickness that the behavior of the devices is not significantly different (P > 0.05). Flow diversion is also being used in concert with photothrombosis. A flow diverter is used to exclude the neck remnant from the parent vessel and to provide a scaffold for the remodeling of the neck. This combination of techniques allows for very fast and near complete occlusion of the aneurysm thereby excluding the aneurysm from the parent vessel and eliminating the risk of a rupture.

published_or_final_version / Surgery / Master / Master of Philosophy

Abdominal Aortic Aneurysms (AAA) are amongst the top ten most common cause of death in those over 55 years of age. The disease is usually asymptomatic, often being diagnosed incidentally. Once diagnosed, elective repair of an AAA results in excellent long-term survival with a 3-5% operative mortality. However, up to one half of patients present with ruptured aneurysms, a complication that carries an 80% mortality in the community, and of those reaching hospital, a 50% mortality. Clearly early diagnosis and treatment results in improved survival. Screening for AAA, with ultrasound, would detect aneurysms early, prior to rupture. However, debate continues over the cost effectiveness of population based screening programmes. The identification of a sub-population at a higher risk of developing AAA would increase the yield of a screening prograrmne. A number of populations have been examined, none of which have received international acceptance. About 20% of patients with an AAA have a family history of an aneurysm. The disease is also considered to be a disease of Caucasians, both facts suggesting a strong genetic component to the disease. Perhaps a genetically identified sub-population at a high risk of developing an AAA would prove to be an ideal population for screening. This thesis examines the incidence of aneurysms and the family histories of patients with AAA in the Otago region of New Zealand. Almost twenty percent of the population has a family history of AAA. DNA was collected from each of these patients for genetic analysis. The population was divided into familial AAA and non-familial AAA for the purpose of genetic analysis and compared to a control population. AAA is believed to be a disease of Caucasians; a non-Caucasian population with a low incidence of AAA may prove to be a good control population for genetic studies. A literature review demonstrated a higher incidence of AAA in Caucasians than other ethnic groups and within Caucasians a higher incidence in patients of Northern European origin. The incidence was low in Asian communities, even in studies involving of migrant Asian populations. The New Zealand Maori are believed to have originated from South East Asia, therefore could be expected to have a low incidence of AAA and would make an ideal control population for genetic studies. A pilot study was undertaken to examine the incidence of AAA in the New Zealand Maori. The age standardised incidence of AAA proved to be at least equal in Maori to non-Maori, with a more aggressive form of the disease in Maori, manifesting with a younger age at presentation and a higher incidence of ruptured aneurysms at diagnosis. It is well known that at the time of surgery, an AAA is at the end stage in its life. At this time, inflammation and matrix metalloproteinases (MMP) enzymes are prevalent within the aneurysm wall and have destroyed the wall of the aorta. One of the most important genetic pathways regulating these enzymes is the plasminogen activator inhibiter 1-Tissue plasminogen activator-plasmin pathway. Genetic analysis of this pathway demonstrated an association of the 4G5G polymorphism in the promoter of the PAl-1 gene with familial AAA. In this insertion:deletion polymorphism, the 5G variant binds an activator and repressor, resulting in reduced PAI-1 expression and ultimately increased MMP activation. This allele was associated with familial aneurysms, 47% versus 62% non-familial AAA and 61% controls (p=0.024). A polymorphism within the tissue plasminogen activator gene was also examined and no association was found with AAA. Another way the MMPs expression could be increased is from mutations or polymorphisms in their own genetic structure. Stromelysin 3 is itself a MMP capable of destroying the aortic wall and it has a role in activating other MMPs. A 5A6A insertion:deletion polymorphism exists in the promoter of this gene. The 5A allele variant results in increased stromelysin expression and is associated with AAA 46% versus 33% in controls p=0. 0006. The actions of the MMPs are themselves inhibited by the tissue inhibitors of matrix metalloproteinases. The TIMP genes have been sequenced; two polymorphisms have been identified in the non-coding promoter area of the TIMP 1 gene. Further studies are necessary to examine the effect of these polymorphisms. Inflammation has been implicated in aneurysm progression. One of the roles of the inflammatory cells found in an aneurysm is to deliver the MMP�s to the AAA. The HLA system is integral in controlling this inflammation and was therefore examined. From this series of studies it is concluded that there is a genetic component to AAA. This thesis presents the first genetic polymorphism associated with familial AAA and explores the role of a genetic pathway in the formation of AAA.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.