AAA disease remains a common and life threatening condition, predominantly affecting men of retirement age. Whilst clinical studies have done much to predict the course of this disease, understanding the pathogenesis has been complicated by both a multi-factorial aetiology as well as several poorly defined stages to the disease (formation, growth and rupture). Evidence points to a considerable inheritable component to this condition, but as yet, associations with identified genetic variants are few and weak. This thesis describes the current understanding of the molecular mechanisms behind AAA pathogenesis, concentrating on aneurysm formation and growth. A meta-analysis of published candidate gene studies identified three genes with small but significant effects on risk of developing AAA (ACE, MTHFR and MMP9) and none with a significant effect on AAA growth. Further examination of five genes connected the Renin-Angiotensin System, using three distinct case control series, demonstrated the strongest reported association to date with AAA disease risk, with AGTR1+1166A>C. (OR 1.55 [1.30-1.83, p=5x10-7]). An interest in the role of the TGF-β pathway in AAA formation and growth has developed from the recent illumination of the mechanism behind aneurysm aetiology in Marfan syndrome. Haplotype analysis was used to investigate five genes coding for TGF-β and its binding protein (LTBP). Variants in TGFB3 and LTBP4 were significantly associated with altered AAA growth. The importance of inflammatory process was also supported by observations made in a very large longitudinal data set of AAA growth. Anti-inflammatory drugs, together with anti-platelet drugs and drugs used in diabetes, were significantly associated with decreased AAA growth independent of confounding factors. In conclusion, this thesis demonstrates; a role for the RAS in AAA formation; TGF-β in AAA growth; and anti-inflammatory drugs as potentially disease modifying. In addition, observations have also been made concerning a two tier effect illuding to the nature AAA progression.

No description available.

Kollberg, S. Torbjörnsson, E. (2012). The lived experience in patients with screening-diagnosed abdominal aortic aneurysm (AAA).     ABSTRACT The aim of this study was to describe the patients’ experiences of living with the knowledge of having an abdominal aortic aneurysm (AAA) that was found during screening. Eleven patients from two different screening centers, with initially measured aneurysms of 40-46 mm, were invited to participate in the interview study. Three of the men declined to participate, so in total eight men were interviewed. The interviews were analyzed by qualitative content analysis.  Four categories were identified: the informant’s reasons for taking part in the screening program for abdominal aortic aneurysm, the experience of the screening, the experience of living with their abdominal aortic aneurysm and the thoughts on the present screening program. The result showed that the men joined the screening program (SCP) with very little knowledge of both aneurysms and the purpose of the screening. In connection with the ultrasound the men became upset over the information about them having an AAA. After they had received information about the diagnose from the vascular surgeon , all of the men felt soothed and understood that despite of their aneurysm, they could continue to live their life as they used to do. The men didn’t believe that the AAA affected their lives, though most of them had made changes in their way of living.   The result of this interview study shows that the men experience a lack of information between the ultrasound and the appointment with the physician. It could be of interest to investigate if an aortic nurse with the same function as the breast nurse in the mammography screening could be the solution of this problem.   Keywords: Abdominal Aortic Aneurysm, screening, information / Kollberg, S. Torbjörnsson, E. (2012). The lived experience in patients with screening-diagnosed abdominal aortic aneurysm (AAA).   SAMMANFATTNING Syftet med den här studien var att beskriva patienternas upplevelse av att leva med kunskapen av att ha en förstorad kroppspulsåder som är hittat via screening. Elva patienter från två olika screeningcenter, med en ursprunglig diameter på sin aorta uppmätt till 40 – 46 mm, bjöds in för deltagande i studien. Tre avböjde att delta, så totalt utfördes åtta intervjuer. Intervjuerna analyserades med kvalitativ innehållsanalys. Fyra kategorier identifierades: Informanternas anledning till att delta i screeningprogrammet, upplevelsen av screeningen, upplevelsen av att leva med AAA och patienternas tankar om det nuvarande screeningprogrammet. Resultatet visade att männen deltog i screeningsprogrammet (SCP) med en begränsad kunskap både om vad aneurysm är och vad syftet med screeningen är. I samband med ultraljudsundersökningen blev männen upprörda över beskedet att de har ett förstorat aneurysm, men efter besöket hos en kärlkirurg som gav information om diagnosen blev de lugnade och förstod att det går bra att fortsätta leva som vanligt trots deras diagnos. Männen i studien tyckte inte att diagnosen påverkade de i deras dagliga liv, trots att många av dem hade genomfört förändringar. Resultatet av den här studien visar att männen upplever en brist i informationen mellan ultraljudsundersökningen och besöket hos läkaren. Det skulle vara intressant att se om en aortasjuksköterska, med samma funktion som en bröstsjuksköterska inom mammografiscreeningen har, skulle kunna vara en lösning på problemet.   Nyckelord: Abdominellt aorta aneurysm, screening, information   Abstraktet är justerat efter instruktioner i Journal of Vascular Nursing

Le principal objectif de cette thèse est de caractériser l'écoulement dans un anévrisme abdominal aortique (AAA) sous différentes conditions physiologiques et à différents stades de son développement. Cette étude est consacrée aux AAA axisymétriques, modélisés comme une dilatation de profil gaussien et de section circulaire. Ainsi, les résultats s'appliquent surtout aux étapes précoces du développement d'un AAA. Le modèle d'AAA est caractérisé par une hauteur maximale H et une largeur W, l'unité de mesure étant le diamètre d'entrée de l'artère. Pour commencer, la dynamique est étudiée pour les écoulements stationnaires. La stabilité globale de ces écoulements de base est analysée en calculant les valeurs propres et les fonctions propres pour des perturbations de faible amplitude. Pour comprendre les mécanismes d'instabilité, le transfer d'énergie entre l'écoulement de base et les perturbations est calculé. L'écoulement pour des AAA peu profonds (ou de grande longueur) se déstabilise par un mécanisme de ‘lift-up' et les perturbations amplifiées sont stationnaires. Des anévrismes plus localisés (ou plus profonds) deviennent instables pour des nombres de Reynolds plus élevés, sans doute par instabilité elliptique ; dans cette situation, les perturbations sont des modes oscillants. Dans le cas des écoulements pulsés, deux types de profil de débit physiologique ont été considérés dans cette étude, correspondant à une situation de repos ou d'exercice physique. Ces écoulements restent collés aux parois pendant la phase de systole et un écoulement décollé est généralement observé pendant la décélération après le maximum de systole. Dans cette phase, un vortex se forme à l'extrémité aval. Ce vortex s'agrandit au cours du temps et impacte l'extrémité aval de l'AAA, ce qui conduit à de forts gradients de contrainte pariétale, qui ne sont pas observés dans les cas sains. Il a été observé que les conditions d'écoulement varient significativement avec les nombre de Womersley (Wo) et de Reynolds (Re); l'écoulement reste attaché aux parois plus longtemps pour des nombres de Womersley croissants. Le principal effet d'une augmentation de Re est un renforcement du vortex primaire qui se forme après le maximum de systole. Les décollements de l'écoulement, l'impact de vortex au bord aval de l'AAA ou encore de faibles contraintes pariétales oscillantes (des caractéristiques importantes dans les cas d'anévrismes pathologiques) sont observés même pour des anévrismes de faible profondeur. Pour des anévrismes plus développés, des vortex multiples sont observés tout au long du cycle dans la cavité de l'AAA. Une analyse de stabilité de ces écoulements de base pulsés a montré que le maximum des perturbations se développe vers l'extérmité aval des AAA. Cependant, les perturbations ne sont pas complètement confinées dans la cavité de l'AAA et se développent aussi au-delà en aval. On en déduit qu'une fois qu'un AAA s'est développé, les perturbations affectent aussi les artères saines en aval de l'AAA. Enfin, en considérant deux profils équivalents d'AAA, de formes sinusoïdale et gaussienne, la sensibilité des résultats aux détails de la géométrie a pu être établie / The main objective of this thesis is to characterise the flow fields observed in an abdominal aortic aneurysm (AAA) under different physiological conditions during its progressive enlargement. An axisymmetric AAA, modeled as an inflation of Gaussian shape on a vessel of circular cross-section, is considered in the present study. This means that the results are more significant for the early stages of growth of an AAA. The model AAA is characterized by a maximum height H and width W, made dimensionless by the upstream vessel diameter. To begin with, the flow characteristics in AAAs are investigated using steady flows. The global linear stability of the base flows is analysed by determining the eigenfrequencies and eigenfunctions of small-amplitude perturbations. In order to understand the instability mechanisms, the energy transfer between the base flow and the perturbations is computed. The flow in relatively shallow aneurysms (of relatively large width) become unstable by the lift-up mechanism and have a perturbation flow which is characterized by stationary, growing modes. More localized aneurysms (with relatively small width) become unstable at larger Reynolds numbers, presumably by an elliptic instability mechanism; in this case the perturbation flow is characterized by oscillatory modes. For the case of pulsatile flows, two types of physiological flowrate waveforms are considered in our study, corresponding to rest and exercise conditions. The flows are observed to remain attached to the walls during the systolic phase, with flow separation generally observed during the deceleration after the peak systole. During this phase, the vorticity is found to roll-up into a vortex at the proximal end. This vortex enlarges with time and impinges at the downstream end of the AAA, resulting in large spatial gradients of wall shear stress (WSS) along the wall, which are not found in the healthy case. The flow conditions are observed to vary significantly with Womersley (Wo) and Reynolds (Re) numbers, with the flow remaining attached to the walls for longer times, as the Womersley number Wo increases. The principal effect of increasing Re is that the primary vortex formed after peak systole is stronger. Clinically relevant flow characteristics of aneurysmal flow, i.e. detachement of flow and impingement on the distal end, the presence of low oscillatory WSS within the AAA, are observed even for very shallow aneurysms. For deep aneurysms, multiple vortices are observed throughout the cycle within the AAA cavity. Stability analysis of pulsatile base flows reveals that the maximum values of the perturbations are observed near the distal end of the AAA. However, they are not entirely confined to the AAA cavity and extend downstream, implying that once an AAA is formed, the disturbed flow conditions spread even to the undeformed arterial walls downstream of the AAA. Finally, by considering two equivalent AAA shapes modeled by a sinusoidal and a gaussian function, the sensitivity

Abdominal aortic aneurysms (AAA) are a pathological dilation of the aorta greater than 2.5cm and affect more than 4% of the male population and 1% of women aged 60 years or older. Screening is recommended among men and women older than age 65, and is covered by Medicare for patients with a family history and men with a history of smoking. Due to its asymptomatic nature, AAA is usually found incidentally during another radiological investigation. Many factors are associated with AAA development, but it is most commonly found in conjunction with atherosclerosis. There is currently no pharmacological intervention specifically for AAA, though statin therapy has shown some promise. The aneurysm will invariably grow, with an average rate of expansion of less than 0.5cm per year. As the aneurysm grows larger the chance of the rupture increases significantly with this outcome carrying an extremely high rate of mortality. Surgical intervention is recommended once the diameter reaches 5.5cm in men or about 5cm in women. There are two approaches to the repair of the aorta: the open surgical approach and the endovascular approach. The open surgical procedure replaces the affected portion of the aorta with a graft. The endovascular procedure places an endograft within the intact aneurysm, effectively excluding the affected section of vessel. The endovascular method carries a lower perioperative mortality rate than the open procedure, but over time can require additional surgeries to prevent continued aneurysm expansion due to blood flow in the aneurysm sac. Additionally, lifetime surveillance of the endograft is required to monitor its integrity and effectiveness. Lifestyle changes and possible pharmacological interventions in patients with AAA should focus on cardiovascular health changes to improve overall health and minimize risk factors for continued development of the aneurysm. In patients who will require repair particular attention should be paid to individual risks and preferences. The open repair procedure may be preferable in patients with better overall health and a longer life expectancy, while endovascular repair may be beneficial for more elderly or frail patients. Research and technology in this area are developing quickly, particularly for endovascular procedures, and the near future may see important changes in the risk-benefit analysis of AAA surgical interventions.

no / Vascular inflammation is implicated in the pathogenesis of atherosclerosis and abdominal aortic aneurysm (AAA), and is thought to involve reactive species such as the nitric oxide-derived oxidant peroxynitrite. In the present study nitrotyrosine was measured as a stable marker of peroxynitrite production in vivo. Perioperative blood samples were obtained from patients undergoing elective open or endovascular repair of an AAA and from patients with intermittent claudication, smoking aged-matched controls, non-smoking aged-matched controls and non-smoking young healthy controls. Plasma nitrotyrosine was measured by an enzyme-linked immunosorbent assay. The median plasma nitrotyrosine concentration in patients with an AAA (0·46 nmol nitrated bovine serum albumin equivalents per mg protein) was significantly higher than that in patients with intermittent claudication (0·35 nmol; P = 0·002), smoking controls (0·36 nmol; P = 0·001), non-smoking controls (0·35 nmol; P = 0·002) and young healthy controls (0·27 nmol; P < 0·001). Nitrotyrosine concentrations increased during early reperfusion in open AAA repair, but not during endovascular repair. AAA exclusion from the circulation reduced levels to control values (P = 0·001). Patients with an AAA had raised levels of circulating nitrated proteins compared with patients with claudication and controls, suggesting a greater degree of ongoing inflammation that was not related to smoking. Copyright

The current study focuses on finding differential expression between circulating microRNAs in plasma from patients with abdominal aortic aneurysms compared to un-diseased individuals by using a qPCR-based array. In addition, we evaluated the expression of deregulated microRNAs in human tissue samples as well as microarray data from two independent mouse models of aneurysm development. Fifteen miRNAs were found to be significantly differentially expressed, with four of them surviving multiple testing. Interestingly all four of them were substantially different in murine aneurysm development.

Matrix metalloproteinase-2 (MMP-2, gelatinase A, type IV collagenase) is a member of a family of zinc-dependent metalloendopeptidases that functions in the degradation of elastin, collagens, and other components of extracellular matrix (ECM). Both secretion and activation of MMP-2 are elevated in human atherosclerotic lesions and abdominal aortic aneurysms (AAA). In this dissertation project, we sought to test the hypothesis that MMP-2 plays a critical role in both atherosclerosis and AAA. We also sought to determine the detailed mechanism. We first examined the atherosclerosis and AngII-induced AAAs development in MMP-2-/- x apolipoprotein (apoE)-/- mice in vivo. It was surprising that MMP-2 deficiency did not reduce the incidence of AngII-induced AAAs or the size of atherosclerosis in apoE-/- mice. However, the cellular and ECM content of atherosclerotic plaques were modified in MMP-2-/- x apoE-/- mice as compared to MMP-2+/+ x apoE-/- control mice. To explain the apparent paradox between this result and the hypothesis, we investigated the morphological characteristics of the aortic wall of MMP-2-/- mice. We detected an enhanced MMP-9 level in the aortic wall of MMP-2-/- x apoE-/- mice compared with MMP-2+/+ x apoE-/- mice. Interestingly, we also observed more branching of the elastin fibers in aortic wall of MMP-2-/- mice as compared with aorta of wild type mice. We also examined the behavior of macrophages from MMP-2-/- mice. Reduced adhesion, migration, and expression of integrin beta 3 were detected in MMP-2 deficient macrophages compared with wild type macrophages. Lastly, we examined whether MMP-2 deficiency in bone marrow-derived cells may influence AAAs and atherosclerosis using bone marrow transplantation technique. There was a significant reduction of both atherosclerosis development and AAAs formation in mice that were reconstituted MMP-2-/- bone marrow cells. In conclusion, the findings in this dissertation suggest that MMP-2 might play an important role in atherosclerosis and aneurysm through influencing inflammatory cell infiltration.

Endovascular aortic aneurysm repair (EVAR) is the procedure of choice in most patients with abdominal aortic aneurysm. The drawbacks of EVAR are a higher rate of complications and frequent need for reinterventions, requiring regular postoperative follow-up. Non-stratified follow-up may have a deleterious effect on patients and the health care system. The aim of this thesis is to develop strategies that can stratify the EVAR follow-up programme according to an individual patient´s risk profile. Study I, an international multicentre study of all abdominal aortic aneurysm (AAA) patients with EVAR in three centres (2000 to 2011) demonstrated a lower rate of late complications and reinterventions in patients with sac shrinkage during the first postoperative year, compared to the non-shrinkage group. Study II, an international multicentre study of patients treated for a ruptured aortic aneurysm with EVAR in three centres (2000 to 2012) demonstrated that ruptured EVAR (rEVAR) in patients with hostile anatomy is associated with a high rate of graft-related complications, reinterventions and increased overall mortality. Study III, a two-centre cohort study of 326 patients with EVAR (2001 to 2012), with first postoperative computerised tomographic angiography (CTA) within one year of the operation. Patients with adequate proximal and distal sealing zones and no endoleak in the first postoperative CTA had significantly lower risk for AAA-related complications and reinterventions up to five years postoperatively. Study IV, studied all complications and reinterventions in a two-centre cohort study of all EVAR patients (1998 to 2012), One-fourth of the patients in the study developed complications during a mean follow-up of five years. Most complications were asymptomatic imaging-detected. Ultrasound could detect most of the clinically significant complications.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20236号 / 医博第4195号 / 新制||医||1019(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 松原 和夫, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM