Endovascular aortic repair (EVAR) is a minimally invasive alternative to open surgery for the treatment of aortic aneurysms (AA). However, standard EVAR is not applicable to complex AA with involvement of vital branches, which could be occluded by the endograft. As an emerging technique, the concept of multiple overlapping uncovered stents (MOUS) have been proposed to manage complex lesions. MOUS was used to modulate the flow pattern inside the aneurysm sac, and promote the thrombus formation followed by the aneurysm shrinkage. In this dissertation, we sought to investigate the mechanism of MOUS-induced flow modulation and key factors associated with the success of this novel technique: - The mechanical behaviour of AA was characterised by uniaxial material tests (Chapter 4). A Bayesian framework was proposed for material constants identification. They were found correlated to the microstructure of tissue fibre network and were capable in differentiating tissue types. - Solid-to-solid interaction and one-way fluid-solid interaction (FSI) analysis was performed based on patient-specific computer tomography angiography (Chapters 5&6). Structural stress concentrations were observed within the landing zones, which increased with the number of stents deployed. In the parameter studies (Chapter 6), the overall porosity was identified as the dominant factor of the flow-diverting outcome, while cross-stent structures of MOUS had limited influence. - The pathological effect of structural stress concentration induced by an implanted device was further studied in rabbit models (Chapter 7). The wall structural stress and fluid shear stress were obtained from FSI analysis based on magnetic resonance imaging (MRI), and correlated to plaque characteristics. Both high structural stress and low fluid shear stress were found correlated to plaque initialisation and increased inflammation. Overall, MOUS modulates the blood flow with robust performance under different overlapping patterns. Image-based biomechanical analysis can optimise MOUS design and can contribute to personalised pre-surgery planning.

An intracranial aneurysm is a local dilation of an artery in the cerebral circulation. While the etiology of intracranial aneurysms is unknown, they likely result from a combination of factors including the weakening and degeneration of the collagen fibers and the internal elastic lamina comprising the arterial wall, as well as hemodynamic-associated stress resulting from blood pulsation inside the aneurysm sac. Intracranial aneurysm rupture leads to a devastating sequela, as 50% of patients die. In the U.S. alone there are approximately 30,000 cases of subarachnoid hemorrhage annually, a prevalence which has pushed practitioners to aggressively treat the aneurysm disease. Traditionally, intracranial aneurysms were managed with open craniotomy and microsurgical clipping; however, these treatment modalities carry relatively high morbidity and mortality depending upon the aneurysm location and surgical experience. In 2002 the International Subarachnoid Hemorrhage Aneurysm Trial established the superiority of the endovascular coiling of intracranial aneurysms compared to microsurgical clipping. This trial led to a paradigm shift in treating intracranial aneurysms with marked use of intracranial stenting, including devices used to assist endovascular coiling and stand-alone flow diverting devices. However, the placement of intracranial devices in the cerebral circulation mandates the adjunctive application of dual anti-platelet pharmaceuticals to minimize thromboembolic events, despite being associated with increased patient risk. This dissertation proposes a novel multilayer, nanometer-scale coating technology suitable for commercially available intracranial stents and flow diverting devices to minimize the use of dual anti-platelet therapy in the elective setting and expand the use of intracranial devices in the acute setting of ruptured intracranial aneurysms. A combination of qualitative and quantitative chemical characterization techniques was used to assess the composition, uniformity, and thickness of each coating layer on commercially available flow diverting devices; overall the coating was found to be relatively uniform and conformal to the device wires. Furthermore, in-vitro and in-vivo testing on commercially available intracranial devices suggest some hemocompatible and antithrombotic properties. Finally, the proposed coating technology can be modified for use as a platform for the attachment of FDA-approved molecules. With further optimization and testing this technology has the potential to minimize the adjunctive use of dual-antiplatelet therapy in the endovascular treatment of intracranial aneurysms.

Abdominal aortic aneurysms (AAAs), a permanent dilation in the abdominal region of the aorta, is a highly sexually dimorphic disease. AAAs prevalence is ranging from 4-10 fold higher in males than females. Defining the mechanistic basis for reduced (in females) or increased (in males) AAA formation and progression may uncover potential therapeutic targets. The majority of studies examining sexual dimorphism focus on the role of sex hormones. However, genes residing on sex chromosomes, in addition to sex hormones, may contribute to sexual dimorphism of AAAs. For example, the X chromosome contains about 5% of the whole genome, but the role of sex chromosomes genes to sexual dimorphism of cardiovascular diseases such as AAAs is largely unknown. The purpose of this study was to determine the role of sex chromosomes as mediators of sex differences for angiotensin II (AngII)-induced AAAs in hypercholesterolemic mice. We used the four core genotype murine model, which enables the creation of phenotypically normal male and female mice with an XX versus XY sex chromosome complement, to test the hypothesis that an XY sex chromosome complement promotes AngII-induced AAAs. Transgenic male mice expressing the Sry gene on an autosome, but not on the Y-chromosome, were bred to female low-density lipoprotein receptor deficient mice to create male and female mice with an XX or an XY sex chromosome complement. In females, an XY sex chromosome complement doubled the incidence and markedly increased the severity of AngII-induced AAAs. To define mechanisms, we examined gene expression patterns in abdominal aortas and demonstrated elevated expression of inflammatory genes that were linked to increased MMP activity and oxidative stress in aortas from XY females. Moreover, administration of testosterone to XY females, to mimic males, resulted in a striking level of aneurysm rupture. In males, transcriptional profiling of abdominal aortas revealed 450 genes that were influenced by sex chromosomes. Infusion of AngII to XY males resulted in diffuse pathology along the length of the aorta, while XX males developed focal AAAs, with pathology reduced by orchiectomy in both genotypes. Thoracic aortas of XY males exhibited adventitial thickening which was not exist in thoracic aortas from XX males. Following a prolonged period (3 months) of AngII infusions XY males had AAAs with expanded aortic walls, while XX males had thin walled dilated AAAs. In summary, our findings demonstrate a remarkable effect of sex chromosome complement to regulate aortic vasculature and disease development. Aside from demonstrating mechanisms of sexual dimorphism of aortic diseases, these findings indicate that chronic sex hormone therapy in the aging and transgender population may have cardiovascular ramifications. Moreover, identification of targets influenced by sex chromosomes and/or sex hormones in a manner that predicts disease development may identify sex-specific approaches to cardiovascular therapy.

Objective: To assess neck angulation and endograft oversizing as factors contributing to folding. Endograft folding will then be assessed on its role in endograft fixation strength. Methods: Bench top flow loop experiments were performed with barbless Gore Excluder endovascular grafts (EVG) that were deployed into silicone aorta-AAA models with neck angles of 0, 30, and 60. A total of five oversizings were tested: -7%, 2%, 12%, 24%, and 38% with N= 3 for each oversizing at each neck angle for a total of 45 experiments. Photographs of the stent apex to apex distances were taken for the entire circumference of the device for a total of 8 photos per experiment. Measurements of the apex to apex distance were taken for the top three stent layers and variance for each stent layer was calculated. Variances for all three stent layers were summed to represent the folding metric. The silicone model was then removed from the flow loop and placed on the uniaxial extension tester to for pull out testing to assess impact on attachment strength. Results: Neck angle and oversizing increases folding risk at oversizing ≥12% for 0° and 30° neck angles, and ≥ 2% oversizing for a 60° neck angle. Folding metric comparison between 0° vs. 30° and 0° vs. 60° across all oversizings had statistical significance (Mann-Whitney U, p

Rupture of abdominal aortic aneurysm (AAA) is a catastrophic event that leads to high mortality and morbidity in patients. The primary causes associated with aneurysm rupture remain poorly understood despite rigorous investigations. Reports have shown that AAA that went on to rupture or present ruptured had higher peak wall tension (stress resultant) than those that did not go on to rupture or present ruptured. Studies investigating the material strength of ruptured AAA and unruptured AAA revealed that the uniaxial failure strength in ruptured AAA is no different on average than unruptured AAA. However, it is poorly understood whether uniaxial failure properties are reliable as they are not indicative of the manner in which failure occurs in biological soft tissues. Multi-axial failure properties using a bubble inflation test (BIT) have been implemented by various groups but have not been directly compared against uniaxial failure properties. The current study seeks to develop a BIT apparatus, to compare multi-axial and uniaxial failure properties of fibrous anisotropic biological soft tissues (bovine aorta) and non-fibrous isotropic molded silicon, and to perform a survey of computational indices at the rupture sites of four ruptured AAA. Two versions of the BIT apparatus were developed: a manual that was developed allows for a large amount of failure properties to be extracted that can identify localized weaknesses. It was found that circumferentially oriented multi-axial failure was correlated with longitudinally oriented uniaxial failure properties, however, for oblique oriented multi-axial failure the correlation decreased. Utilizing the insights gained from the multi-axial experiments it was determined that the failure properties used in the computational study with the data from Raghavan et al. were appropriate for use in retrospective assessment of the rupture site in four ruptured AAA computational models. Although the study was inconclusive in finding causation, the rupture line of each aneurysm had indices ranging between the third quartile and peak values for tension to failure tension ratio, nodal displacement magnitude, strain energy per unit volume and strain energy per unit surface area. This study provides a framework for interrogating failure properties at a higher density of measurement and a heterogeneous computational model that has the potential to predict AAA rupture in the future.

<p>Even if popliteal artery aneurysm (PAA) is the most common peripheral aneurysm, no single surgeon or institution has enough patients to study this disease with appropriate scientific methods, and no population-based investigation exists. </p><p>PAA epidemiology, treatment, management, and outcome were studied in a population-based study of 571 patients (717 legs) primarily operated on for PAAs and 100 episodes of preoperative thrombolysis in Sweden between 1987 and 2002. Patients were identified in the Swedish Vascular Registry and case-records were reviewed. Information on amputation and survival was obtained for all patients, and 190 patients were re-examined with ultrasound, after mean 7.2 years (range 2-18)</p><p>Median age was 71 years; 5.8% were women. Patients with unilateral PAA had AAA in 28%, increasing to 38% when PAAs were bilateral. Crude survival was 91.4% at one and 70% at five years, significantly lower than among age and sex matched controls. The cumulative incidence for operation of PAA in Sweden was estimated to 8.3/million person year. One-year amputation-rate was 8.8 %, increasing to 11% after follow-up (7.2 years). Independent risk factors for amputation within one year were poor run-off, age, emergency procedure, and prosthetic graft. Run-off was improved by preoperative thrombolysis among 87% of legs, when acute ischemia. After surgical repair with a medial approach the risk of late expansion of the aneurysm was 33%, with a posterior approach 8% , p=0.014. Among 190 re-examined patients, 108 (57%) had at least one additional aneurysm at index-operation, increasing to 131 (68%) at re-examination, the total number of aneurysms increasing by 42% (from 244 to 346).</p><p>Conclusions: Multiple aneurysms are common among patients operated on for PAA. Preoperative thrombolysis improves run-off and decreases the amputation-rate in PAAs with acute ischemia. Vein grafts do better than prosthetic grafts, especially when a long bypass is needed. Posterior approach, when possible, reduces the risk of late expansion. A complete examination of the aorto-iliac and femoro-popliteal arteries is warranted at the time of surgery. All patients should be kept under life-long surveillance in order to detect and treat newly developed aneurysms timely. Normal arterial segments should be re-examined after three years.</p>

Even if popliteal artery aneurysm (PAA) is the most common peripheral aneurysm, no single surgeon or institution has enough patients to study this disease with appropriate scientific methods, and no population-based investigation exists. PAA epidemiology, treatment, management, and outcome were studied in a population-based study of 571 patients (717 legs) primarily operated on for PAAs and 100 episodes of preoperative thrombolysis in Sweden between 1987 and 2002. Patients were identified in the Swedish Vascular Registry and case-records were reviewed. Information on amputation and survival was obtained for all patients, and 190 patients were re-examined with ultrasound, after mean 7.2 years (range 2-18) Median age was 71 years; 5.8% were women. Patients with unilateral PAA had AAA in 28%, increasing to 38% when PAAs were bilateral. Crude survival was 91.4% at one and 70% at five years, significantly lower than among age and sex matched controls. The cumulative incidence for operation of PAA in Sweden was estimated to 8.3/million person year. One-year amputation-rate was 8.8 %, increasing to 11% after follow-up (7.2 years). Independent risk factors for amputation within one year were poor run-off, age, emergency procedure, and prosthetic graft. Run-off was improved by preoperative thrombolysis among 87% of legs, when acute ischemia. After surgical repair with a medial approach the risk of late expansion of the aneurysm was 33%, with a posterior approach 8% , p=0.014. Among 190 re-examined patients, 108 (57%) had at least one additional aneurysm at index-operation, increasing to 131 (68%) at re-examination, the total number of aneurysms increasing by 42% (from 244 to 346). Conclusions: Multiple aneurysms are common among patients operated on for PAA. Preoperative thrombolysis improves run-off and decreases the amputation-rate in PAAs with acute ischemia. Vein grafts do better than prosthetic grafts, especially when a long bypass is needed. Posterior approach, when possible, reduces the risk of late expansion. A complete examination of the aorto-iliac and femoro-popliteal arteries is warranted at the time of surgery. All patients should be kept under life-long surveillance in order to detect and treat newly developed aneurysms timely. Normal arterial segments should be re-examined after three years.

Amyloidoses are a group of protein misfolding diseases characterized by deposits of insoluble fibrillar protein aggregates. Medin amyloid, which is the focus of this thesis, appears in the media of the thoracic aorta in nearly all individuals over 50 years. The fibrils are derived from a 50 amino acid residue fragment of the precursor protein lactadherin. How medin amyloid arises is unknown, but in paper I we demonstrated, with immunohistochemical and in vitro binding experiments, that both lactadherin and medin interact with elastin, implying that the elastic fibre is central in amyloid formation. In paper II, we further showed that the last 18-19 amino acid residues constitute the amyloid-promoting region. In paper III, the consequence of medin deposition was investigated. Aortic specimens from patients with thoracic aorta aneurysm and dissection were examined for medin content. The tissue findings indicated that the two disease groups contained more medin oligomers than normal aortas. Interestingly, recent reports demonstrate that the toxicity of amyloid proteins is attributed to prefibrillar oligomeric aggregates rather than to mature fibrils. In support of this finding, we observed that prefibrillar medin, in contrast to medin fibrils, was toxic in cell culture. Amyloid formation is a nucleation-dependent process. Addition of preformed fibrils to an amyloid protein solution dramatically accelerates fibrillation, a phenomenon called seeding. In paper IV, serum amyloid A-derived (AA) amyloid was found co-localized with medin deposits in the aorta. In vitro, medin fibrils enhanced the formation of AA fibrils, indicative of a seeding mechanism. The data are of great importance as they suggest that one type of amyloid is capable of inducing fibrillation and deposition of another amyloid type. In conclusion, the results of this thesis shed light on how medin is formed, the function of lactadherin and the consequences of medin deposition for aortic pathology.

Abdominal aortic aneurysm (AAA) is a common disease that develops gradually over several years and is characterised by weakening and dilatation of the aortic wall. AAAs also demonstrates a marked inflammatory infiltrate throughout the aortic wall. Chlamydophila pneumoniae (C. pneumoniae), is a common bacterium. About 50% of the population has been infected in adolescence. Thirteen studies report the presence of either C. pneumoniae or its antigens in 35-100% of AAA specimens. The overall aim of this thesis was to evaluate the possible role of C. pneumoniae in inflammatory response and expansion of AAA from a clinical point of view. In paper I, viable C. pneumoniae was detected in a majority of 26 patients with AAA having open surgery. Patients operated for AAA had higher C. pneumoniae antibodies titers than controls. In paper II, 247 patients were randomised in a double-blind trial, to evaluate the effect of azithromycin on the expansion of small AAAs. No such effect was seen and there was no correlation between C. pneumoniae antibody titers and AAA expansion. In paper III, 42 patients with AAA were compared to 100 age- and sex matched controls with normal aortas. C. pneumoniae antibodies were analysed in plasma samples obtained at screening, and in samples from a study conducted 5-15 (mean 12) years previously on the same population. There was no significant difference between the groups. In paper IV, were 211 patients were analysed, we could not find an association between levels in plasma of three markers of inflammation (IL-6, MMP-9 and CRP) and AAA expansion. A significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins. In conclusion, viable C. pneumoniae is found at the scene of the crime, but we were unable to reverse or halt expansion of AAA with antibiotic treatment. C. pneumoniae antibody titers cannot be used, to detect small AAA, or to evaluate AAA expansion. From a clinical point of view, based on the methods and analyses used in this thesis, the role of C. pneumoniae in the inflammatory response and expansion of abdominal aortic aneurysms is limited.

Subarachnoid hemorrhage (SAH) is a disease with high risk of mortality and morbidity. Elderly patients have an even higher risk of poor outcome. The incidence of SAH increases with age and the elderly constitute a substantial and increasing proportion of the population. Thus, the management of elderly SAH patients is an imminent clinical challenge. Time trends in clinical management and outcome were investigated in 281 SAH patients aged ≥65 years admitted over an 18-year period. The volume of elderly patients, especially patients ≥70 years and patients in worse clinical condition increased over time. The proportion of patients with favorable outcome increased over time, without an increase in severely disabled patients. Technical results and clinical outcome of endovascular aneurysm treatment (EVT) was investigated in 62 elderly SAH patients. EVT can be performed in elderly SAH patients with high technical success, acceptable aneurysm occlusion degree, acceptable procedural complication rate, and fair outcome results. EVT was compared to neurosurgical clipping (NST) in 278 elderly SAH patients in the International Subarachnoid Aneurysm Trial. In good grade elderly SAH patients, EVT should probably be the favored treatment for internal carotid and posterior communicating artery aneurysms, while elderly patients with middle cerebral artery aneurysms appear to benefit from NST. Occurrence of secondary insults and their impact on clinical deterioration were studied in 99 patients with severe SAH. High intracranial pressure increased and high cerebral perfusion pressure decreased the risk of clinical deterioration. Elderly patients had less intracranial hypertension insults and more hypertensive, hypotensive and hypoxemic insults. Good outcome was achieved in 24% of elderly patients with severe SAH, and the proportion of severe disability was similar to that of younger patients. Patient age was not a significant predictor for vasospasm in 413 SAH patients when admission and treatment variables were adjusted for with multiple logistic regression.