Summary of the work<p>Abdominal aortic aneurysm (AAA) is a chronic degenerative disease that usually affects men over 65 years with an estimated prevalence of 5%. Aneurysm rupture represents a catastrophic event which carries a mortality rate of almost 90%. Current therapeutic options for AAAs measuring 5.5 cm in diameter or larger are based on prophylactic surgery, including conventional open reconstruction and endovascular stent-graft insertion. For patients with small asymptomatic AAAs (4.0 up to 5.5 cm in diameter), evidence from two recent large randomized controlled trials indicates no long-term survival benefit from immediate elective surgical repair as compared to imaging surveillance until aneurysm expands to 5.5 cm. This highlights the need for development of novel medical management strategies, including selective pharmacologic approaches, directed at preventing aneurysm expansion. In this regard, it is expected that a detailed knowledge of the pathobiology of human AAA lesion and a better understanding of pathophysiological mechanisms underlying initiation and progression of aneurysmal degeneration, particularly the specific involvement of T lymphocytes, will have special relevance to this challenging issue.<p>Inflammatory and helper T-cell responses in abdominal aortic aneurysm :controversial issues<p>Innate and inflammatory responses to endovascular versus open AAA repair. The occurrence of early acute systemic inflammatory responses after conventional open AAA repair is widely recognized and is thought to lead to the development of organ dysfunction and multiple organ failure, responsible for a large proportion of morbidity and mortality associated with aortic surgery. New therapeutic strategies designed to avoid ischemia-reperfusion injury related to aortic cross-clamping and to minimize the degree of tissue damage have thus been developed recently. Specifically, the advent of endovascular techniques has radically extended management options for patients with AAA. Although the method is believed to offer a clear short-term benefit over open repair, notably as regards restricted perioperative haemodynamic parameter fluctuations, reduced blood loss, briefer duration of surgery, shorter hospital stay, and lower 30-day mortality and complication rates, conflicting data are available regarding the exact nature and extent of the inflammatory events arising after such endoluminal procedures ;while several authors have indeed reported that endovascular AAA repair can determine a less intense and extensive inflammatory response, others have unexpectedly observed that the method may elicit a strong inflammatory response, the so-called « postimplantation syndrome ».<p>Adaptive cellular immune responses in human aneurysmal aortic lesion.<p>The inflammatory nature of AAA disease has long been suggested by the presence of a great number of CD4+ T lymphocytes in the outer media and adventitia of human AAA lesion. Interestingly, such infiltrating T-cell populations may have significant implications in the process of aneurysm dilation, since cytokines produced by T cells, notably IFN-gamma, have previously been shown to modulate production of matrix-degrading enzymes by resident macrophages and to induce apoptosis of medial SMCs. Through these key pathological mechanisms, T cells could potentially contribute to orchestrate aortic wall connective tissue disordered remodeling and degradation, and promote extensive disruption of elastic media, ultimately leading to aneurysmal degeneration. Nevertheless, despite their relative abundance in human AAA wall tissues, there is limited and controversial information as regards the functional profile of lesional lymphocytes, the exact nature of aortic wall adaptive cellular responses, and the etiologic role of T cells and their cytokines in initiation and progression of the aneurysmal process. Indeed, both Th1-type and Th2-type responses have been identified in human studies and experimental animal models of AAA.<p>Aims of the work<p>The main objectives of our work were to explore the innate and adaptive cellular immune responses in human AAA. In the first part of our work, we aimed to examine prospectively innate and inflammatory responses arising in a non-randomised cohort of patients undergoing endovascular versus open AAA repair. In the second part of our work, we focused our efforts on characterizing the nature of adaptive cellular immune responses and the phenotypic and functional repertoire of T cells in human AAA wall tissues obtained from a consecutive series of patients undergoing open AAA repair. Specifically, we sought to determine whether type 1 or type 2 responses occur predominantly in advanced AAA lesion.<p>Main experimental findings<p>Limited inflammatory response after endovascular AAA repair. Serial peripheral venous blood samples were collected preoperatively, immediately after declamping or insertion of endograft, and after 1, 3, 6, 12, 24, 48, and 72 hours. We first examined the acute phase reaction and liberation of complement cascade products using turbidimetric method and nephelometry. We found that endovascular repair produced lower postoperative CRP, leucocytosis, neutrophilia, and C3d/C3 ratio as compared to open surgery. We next analyzed surface expression of activation markers on peripheral CD3+ T cells using flow cytometry. We observed a strong upregulation of CD38 after open but not endovascular repair. Analysis of CD69 and CD25 molecules revealed no perioperative fluctuations in any group. We then investigated release of various circulating soluble cell adhesion molecules, proinflammatory cytokines, and chemokines using enzyme-linked immunosorbent assays. We demonstrated that both procedures are characterized by similar increases in ICAM-1 and IL-6 levels. Finally, tendency towards high levels of TNF-alpha and IL-8 was detected in endovascular repair, but data failed to reach statistical significance.<p>Predominance of type 1 CD4+ T cells in human aneurysmal aortic lesion. We have developed a tissue enzymatic digestion and cell extraction procedure to isolate intact mononuclear cells from aortic wall segments. This original cell isolation protocol enabled us to examine ex vivo the presence, phenotype, and cytokine secretion profile of infiltrating T lymphocytes freshly isolated from human AAA tissues for comparison with their circulating counterparts using flow cytometry. We found that both populations of infiltrating CD4+ and CD8+ T cells display a unique activated memory phenotype, as assessed by an increased expression of CD69 and HLA-DR activation antigens, downregulation of CD62L molecule, and predominant expression of the CD45RO isoform characteristics of memory cells. In addition, we identified the presence in human aneurysmal aortic wall lesion of CD4+ T cells producing high levels of IFN-gamma but not IL-4, reflecting their type 1 nature. In an additional series of experiments, cytokine gene expression was determined in whole aneurysmal and non-diseased aortic samples using LightCycler-based quantitative real-time reverse transcription-polymerase chain reaction. The molecular basis of type 1 or type 2 dominant responses was further specified by analyzing mRNA levels of transcription factors specifically involved in Th1 or Th2 differentiation such as T-bet and GATA-3. We demonstrated that aneurysmal aortic specimens exhibit high transcript levels of IFN-gamma but not IL-4, and consistently overexpressed the IFN-g-promoting cytokine IL-12 and the type 1-restricted transcription factor T-bet, further establishing the prominent type 1 nature of aortic wall responses. Moreover, such selective tissue expression of IL-12 and T-bet in the vessel microenvironment points to a potential role for these signals in directing aortic wall responses towards a type 1 phenotype.<p>Conclusions<p>Our findings indicate that endovascular AAA repair is associated with a lesser degree of acute phase reaction, peripheral T-cell activation, and release of complement proteins as compared to conventional open surgery, suggesting that the innate and inflammatory responses to AAA repair are significantly attenuated by the endovascular approach as compared to the traditional open reconstruction. These results support the view that the endoluminal procedure represents an attractive alternative to open surgery for the treatment of large aneurysms. On the other hand, we have demonstrated that Th1 cell infiltrates predominate in human end-stage AAA lesion. These observations are relevant for helping clarify the pathobiology of human AAA tissues and defining prospects for the prevention of aneurysm expansion. Indeed, identification of such infiltrating populations of IFN-gamma-producing CD4+ T cells not only provide new insights into the pathogenesis of the disorder, but could also serve as a basis for the development of novel medical management strategies directed at preventing aneurysm formation and progression, including therapeutic approaches based on the modulation of aortic wall responses and designed to selectively target T-cell activation and cytokine production. In this respect, the present work provides experimental evidence in support of the emerging concept that, although multifactorial, aneurysm disease may be regarded as a Th1-driven immunopathological condition, and suggests that strategies targeting IFN-gamma could be a particularly exciting and fruitful avenue for further investigation. Ongoing clinical and basic research in these areas can be expected to yield design of promising pharmacologic approaches to control AAA expansion. From a clinical perspective, such efforts have the potential to dramatically influence both the outcome and management of this common and life threatening condition.<p> / Doctorat en sciences médicales / info:eu-repo/semantics/nonPublished

Abstract Endovascular aneurysm repair (EVAR) is a minimally invasive alternative to open surgery to exclude an abdominal aortic aneurysm from the circulation to avert a rupture. The aim of this thesis was to evaluate the early and mid-term results of EVAR using the Zenith® stent-graft (Cook Inc, Bloomington, IN, USA) in asymptomatic and symptomatic abdominal aortic aneurysm (AAA) patients in three Finnish university hospitals. Furthermore, the aim was to study whether preoperative embolization of the inferior mesenteric artery (IMA) before EVAR decreases the incidence of a type II endoleak or has an effect on the aneurysm sac shrinkage. Finally, the results after secondary interventions for a type II endoleak were evaluated. Two hundred six patients underwent elective endovascular repair of an intact AAA. The use of the Zenith® stent-graft was associated with good early and mid-term results. The thirty-day mortality rate (2.9%) was in accordance with other EVAR studies. Only one late aneurysm-related death occurred in this series, whilst no patients died of a late aneurysm rupture. No stent-graft migrations or fractures were observed. Endoleak, defined as persistent blood flow outside the graft and within the aneurysm sac, remains a long-term problem with EVAR. The overall endoleak incidence was 34.6%. A type II endoleak (retrograde perfusion via aortic side branches) occurred in 52 patients (25.4%). EVAR was performed for 14 patients with a symptomatic, unruptured AAA. The median delay from admission to intervention was 4 days. EVAR of a symptomatic, unruptured AAA was associated with a favourable outcome even in patients with a very high operative risk. There were no perioperative deaths. Altogether forty patients treated at Kuopio University Hospital had a patent IMA on preoperative computed tomography (CT) and were treated successfully with coil embolization before EVAR. Thirty-nine patients who underwent EVAR at Oulu University Hospital without preoperative embolization of a patent IMA served as a control group. Preoperative coil embolization of the IMA significantly reduced the incidence of type II endoleaks after EVAR, but the present study failed to show any influence on late postoperative aneurysm sac shrinkage. Overall, 14 patients underwent a secondary intervention to repair the type II endoleak. Ten patients had transarterial embolization and four patients had translumbar embolization. The results were unsatisfactory; clinical success after the first secondary intervention was achieved in only two patients in the transarterial embolization group and three patients in the translumbar embolization group. These results seem to favour direct translumbar embolization rather than transarterial embolization. In conclusion, EVAR with the Zenith® stent-graft is effective in excluding AAAs from the circulation and is associated with good mid-term results.

The diploma thesis deals with the assessment of the prediction of brain aneurysm rupture based on its geometrical and material properties. In the first part of the thesis there is a~detailed research study of cardiovascular systems with a focus on the cerebral artery and aneurysm occurring on their bifurcates. The second part of the thesis is focused on the creation of two models of arterial cerebral bifurcation with the presence of aneurysm and on obtaining their geometry in unloaded state. Emphasis is placed on the most realistic constitutive model of the artery wall material based on real data from uniaxial tensile tests and on a suitably chosen blood pressure load. This blood pressure may be step-changed, for example, in bungee jumping. In the work, a calculation of the increase in blood pressure during the step-change is performed, which is subsequently used in calculations of tension in the wall of the cerebral aneurysm. In conclusion, the risk of rupture is evaluated in two model idealized brain aneurysms and a discussion of the credibility of the results is given.

Background: Scoring models are widely established in the intensive care unit (ICU). However, the importance in patients with ruptured abdominal aortic aneurysm (RAAA) remains unclear. Our aim was to analyze scoring systems as predictors of survival in patients undergoing open surgical repair (OSR) for RAAA. Methods: This is a retrospective study in critically ill patients in a surgical ICU at a university hospital. Sixty-eight patients with RAAA were treated between February 2005 and June 2013. Serial measurements of Sequential Organ Failure Assessment score (SOFA), Simplified Acute Physiology Score II (SAPS II) and Simplified Therapeutic Intervention Scoring System-28 (TISS-28) were evaluated with respect to in-hospital mortality. Eleven patients had to be excluded from this study because 6 underwent endovascular repair and 5 died before they could be admitted to the ICU. Results: All patients underwent OSR. The initial, highest, and mean of SOFA and SAPS II scores correlated significant with in-hospital mortality. In contrast, TISS-28 was inferior and showed a smaller area under the receiver operating curve. The cut-off point for SOFA showed the best performance in terms of sensitivity and specificity. An initial SOFA score below 9 predicted an in-hospital mortality of 16.2% (95% CI, 4.3–28.1) and a score above 9 predicted an in-hospital mortality of 73.7% (95% CI, 53.8–93.5, p < 0.01). Trend analysis showed the largest effect on SAPS II. When the score increased or was unchanged within the first 48 h (score >45), the in-hospital mortality rate was 85.7% (95% CI, 67.4–100, p < 0.01) versus 31.6% (95% CI, 10.7–52.5, p = 0.01) when it decreased. On multiple regression analysis, only the mean of the SOFA score showed a significant predictive capacity with regards to mortality (odds ratio 1.77; 95% CI, 1.19–2.64; p < 0.01). Conclusion: SOFA and SAPS II scores were able to predict in-hospital mortality in RAAA within 48 h after OSR. According to cut-off points, an increase or decrease in SOFA and SAPS II scores improved sensitivity and specificity.

Das Aortenaneurysma ist eine häufige Erkrankung, welche mit der gravierenden Kompli-kation einer Aortenruptur einhergehen kann. In den letzten 20 Jahren konnten beachtliche kurative Fortschritte erzielt werden, welche u.a. auf die Ergänzung der rein operativen Therapie um endovaskuläre und Hybridverfahren zurückzuführen sind. Dennoch ist die Aneurysmaruptur mit einer außerordentlich hohen Mortalität assoziiert. Die Genese des Aortenaneurysmas ist multifaktoriell bedingt, sodass das Wachstumsverhalten der Aorta als Surrogat des realen Rupturrisikos schwer vorherzusagen ist. Im klinischen Alltag findet überwiegend der maximale Diameter als Größen- und Verlaufsparameter Anwendung, obwohl dadurch den heterogenen Veränderungen der Aorta möglicherweise nicht ausrei-chend Rechnung getragen wird. Ziel der Studie war es, anhand einer CT-gestützten Verlaufsquantifizierung von Aorten-veränderungen Prädiktoren für das Wachstum der Aorta abzuleiten und Wachstumsraten auf Basis unterschiedlicher morphologischer Ausgangsgrößen zu vergleichen. Zwischen den definierten Aortensegmenten konnten signifikante Unterschiede der erho-benen morphologischen Parameter wie beispielsweise der Größe, der Verteilung von Ge-fäßwand und –lumen, der Verkalkung und der Krümmung aufgezeigt werden. Diese Heterogenität ließ sich auch beim Vergleich von thorakalen/abdominalen, aneurysmati-schen/nicht aneurysmatischen und wachsenden/nicht wachsenden Segmenten bestätigen. So waren beispielweise wachsende Aortensegmente initial größer als nicht wachsende (Volumen 82 cm³ vs. 53 cm³, p < 0,00; Diameter 36 mm vs. 30 mm, p< 0,00), unterschie-den sich hingegen aber nicht hinsichtlich der Wandverkalkung (Calcium-Score 894 vs. 842, p = 0,77). Im Verlauf wiesen die wachsenden Segmente unter anderem eine stärkere Zunahme der maximalen Wandstärke (+15 % vs. +4 %, p > 0,00) und eine stärkere Elongationstendenz (Segmentlänge +3,6 % vs. -0,5 %, p < 0,00) auf. Insgesamt konnte gezeigt werden, dass im Verlauf eine Wachstumsdynamik beinahe aller erhobenen Größen bestand. Ein durchschnittliches Wachstum des Aortensegmentvolumens um 5,7 % pro Jahr gezeigt konnte werden. Unter den potentiellen Einflussfaktorenkonnten konnten als relevante Prädiktoren die ma-ximale Wandstärke, die Diameter-Längen-Ratio, die Exzentrizität der Außenzirkumferenz sowie die Risikofaktoren Rauchen und die Einnahme von Kortikoiden identifiziert wer-den. Der Vergleich morphologisch unterschiedlich basierter Wachstumsraten zeigte eine erhebliche Diskrepanz insbesondere zwischen dem Routineparameter maximaler Diameter und dem sensitiveren Volumen. Schlussfolgerung: CT-morphologisch bestimmbare Parameter wie die Wandstärke, das Proportionsmaß Diameter-Längen-Ratio und die Exzentrizität des Gefäßquerschnittes sind Prädiktoren überdurchschnittlichen Aortenwachstums. Die umfassenden routinemäßige Evaluation der Aorta mit Erhebung mehrerer morphologischer Parameter – insbesondere des Volumens – ist notwendig, um das heterogene und multifaktoriell bedingte Wachstum der Aorta suffizient zu erfassen.:Inhalt Inhalt I Bibliographische Beschreibung V Referat V Abbildungsverzeichnis VI Tabellenverzeichnis VII 1. Einführung 1 1.1. Zur Historie des Aneurysmas 1 1.1.1. Erste Erwähnungen und Altertum 1 1.1.2. Mittelalter und Renaissance– von außen nach innen 2 1.1.3. Neuzeit – Evolution pathogenetischer Erkenntnisse und suffizienter Therapien 3 1.2. Begriffsbestimmung 5 1.2.1. Aneurysma verum 5 1.2.2. Aneurysma dissecans 6 1.2.3. Aneurysma spurium 6 1.3. Ätiologie und Einflussfaktoren der Aneurysmaentstehung 6 1.3.1. Pathophysiologische Aspekte der Aneurysmagenese 7 1.3.2. Genetische Syndrome als Ursache von Aortenaneurysmen 9 1.3.3. Gefäßassoziierte Pathologien als Ursache für Aortenaneurysmen 11 1.3.4. Risikofaktoren für die Entstehung aortaler Aneurysmen 13 1.3.5. Medikamentöse Wechselwirkungen 15 1.4. Epidemiologie des Aortenaneurysmas 17 1.4.1. Angaben zur Prävalenz und Inzidenz 17 1.4.2. Rupturraten von thorakalen und abdominellen Aneurysmen 18 1.4.3. Angaben zu Wachstumsraten (GRy) aortaler Aneurysmen 19 1.5. Diagnostik und Bildgebung der Aorta 21 1.5.1. Nichtapparative Diagnostik 21 1.5.2. Konventionelles Röntgen und Angiografie 21 1.5.3. Ultraschall 21 1.5.4. Schnittbildgebung – Computer- und Magnetresonanztomografie (CT/MRT) 22 1.6. Therapeutische Optionen 23 1.6.1. Thorakale und thorakoabdominelle Aortenaneurysmen 23 1.6.2. Bauchaortenaneurysmen 23 2. Ziel der Studie 25 3. Materialien und Methoden 26 3.1. Studienkollektiv – Ein- und Ausschlusskriterien 26 3.2. Bildgebung 26 3.3. Bildverarbeitung und Messverfahren 27 3.3.1. Vorbereitung 27 3.3.2. Volumenberechnung 30 3.3.3. Messung von Diameter und Querschnittsfläche 30 3.3.4. Berechnung der Innen- und Außenfläche 31 3.3.5. Messung der minimalen und maximalen Wandstärke 32 3.3.6. Bestimmung der Segmentlänge 32 3.3.7. Winkelungs- und Krümmungsmessung 33 3.3.8. Exzentrizität des Gefäßquerschnittes 33 3.3.9. Vermessung der Gefäßwandverkalkung 34 3.4. Klinisch-anamnestische Faktoren 36 3.5. Berechnung der Wachstumsraten 36 3.6. Definition des Wachstumskriteriums 37 3.7. Gruppierung der Aortensegmente zur Auswertung 37 3.8. Statistische Auswertung 38 3.8.1. Mittelwertdifferenzen 38 3.8.2. Korrelation 38 3.8.3. Multiple Regressionsanalyse 38 3.8.4. Messmethodenvergleich 39 4. Ergebnisse 40 4.1. Charakteristika der Studienpopulation 40 4.1.1. Patientcharakteristika 40 4.1.2. Verteilung der klinischen Risikofaktoren 41 4.2. Quantifizierung der Aortenveränderungen anhand CT-morphologischer Parameter – initial und im Verlauf 43 4.2.1. Volumen 43 4.2.2. Diameter und Querschnittsfläche 47 4.2.3. Innen- und Außenfläche 48 4.2.4. Wandstärke 49 4.2.5. Länge, Proportion und Krümmung 52 4.2.6. Exzentrizität der Gefäßquerschnitte 55 4.2.7. Wandverkalkung 57 4.3. Einflussfaktoren des Aortenwachstums 62 4.3.1. Korrelationsanalyse der potentiellen Einflussfaktoren mit dem Wachstumskriterium 62 4.3.2. Prädiktoren des Aortenwachstums - Multiple Regressionsanalyse 67 4.4. Diskrepanzen zwischen unterschiedlich basierten Wachstumsraten 70 5. Diskussion 73 5.1. Wachstumsverhalten und Aortenmorphologie 73 5.1.1. Das Volumen als sensitiver Verlaufsparameter des Aortenwachstums 73 5.1.2. Etablierte Größen: Diameter und Querschnittsfläche 75 5.1.3. Alternative dreidimensionale Parameter: Innen- und Außenfläche 76 5.1.4. Die aortale Wandstärke als Surrogatparameter für intraluminalen Thrombus und atheromatöse Wandveränderungen 77 5.1.5. Die segementale Länge, Proportion und Krümmung als Korrelat longitudinalen Wachstums 78 5.1.6. Die Exzentrizität der Gefäßquerschnitte 79 5.1.7. Die aortale Wandverkalkung 80 5.2. Prädiktoren und Einflussfaktoren des Aortenwachstums 80 5.2.1. Initiale Größe 81 5.2.2. Gefäßwandveränderungen 82 5.2.3. Das Verhältnis von Proportion, Krümmung und Elongation der Aorten-segmente 84 5.2.4. Die Morphologie des Gefäßquerschnittes 86 5.2.5. Die Rolle der aortalen Wandverkalkung für das Aortenwachstum 87 5.2.6. Die Relevanz klinischer Risikofaktoren 87 5.3. Diskrepanzen der unterschiedlich basierten Wachstumsraten 89 5.4. Limitationen der Studie 91 5.5. Schlussfolgerung 92 6. Zusammenfassung der Arbeit 93 7. Literaturverzeichnis 95 8. Erklärung zur Dissertation 118 9. Curriculum Vitae 119 Persönliche Daten 119 Ausbildung 119 Praktische Erfahrungen und beruflicher Werdegang 119 10. Danksagung 121 / Purpose This study aims to identify clinical and CT-morphologic predictors of growth of the native aorta and aortic aneurysms. Material and methods Seventy-three patients (66 ±8.0 years) who underwent two subsequent computed tomography angiographies of the thoracic/thoracoabdominal/abdominal aorta for clinical reasons from 2002 - 2008 were retrospectively included. The mean interval between the CT scans was 1.8 ±0.8 years. The aortic anatomy was divided into 9 segments from sinotubular junction to iliac bifurcation. CT scans were obtained with 16- and 64-slice scanners, all series were analyzed on a commercially available workstation. Beside the collection of information about the past medical history, several morphologic parameters were measured for each segment such as aortic volume, maximum diameter, cross sectional area, surface area, calcification, tortuosity, wall thickness or cross sectional eccentricity. Annual growth rates were calculated for each parameter. Aortic total volume was considered as the standard of reference. Therefore, aortic growth was defined as a growth rate of total volume > 5 %. Multiple regression analysis was conducted to reveal predictors of aortic growth. Results For all segments, average volumes were 65.0 ± 59.0/44.7 ± 39.6/20.3 ± 27.9 cm³ (total/lumen/wall). The annual aortic growth rate of total volume was 5.7 % for all segments. All parameters that represent the initial size of the aortic segments (total and lumen volume, maximum diameter, cross sectional area, surface area) were approved as predictors of aortic growth. Further predictors were wall volume, maximum and minimum wall thickness, diameter length ratio, segmental length and tortuosity index. Among the clinical parameters, smoking, corticosteroid medication and peripheral artery disease were confirmed as aortic growth predictors. Conclusions In clinical routine, most therapeutic decisions a made based on the diameter measurement alone, which might be inappropriate. A comprehensive evaluation of aortic morphology is warranted in the presence of increased aortic size, wall thickness, cross sectional eccentricity, smoking and corticosteroid therapy.:Inhalt Inhalt I Bibliographische Beschreibung V Referat V Abbildungsverzeichnis VI Tabellenverzeichnis VII 1. Einführung 1 1.1. Zur Historie des Aneurysmas 1 1.1.1. Erste Erwähnungen und Altertum 1 1.1.2. Mittelalter und Renaissance– von außen nach innen 2 1.1.3. Neuzeit – Evolution pathogenetischer Erkenntnisse und suffizienter Therapien 3 1.2. Begriffsbestimmung 5 1.2.1. Aneurysma verum 5 1.2.2. Aneurysma dissecans 6 1.2.3. Aneurysma spurium 6 1.3. Ätiologie und Einflussfaktoren der Aneurysmaentstehung 6 1.3.1. Pathophysiologische Aspekte der Aneurysmagenese 7 1.3.2. Genetische Syndrome als Ursache von Aortenaneurysmen 9 1.3.3. Gefäßassoziierte Pathologien als Ursache für Aortenaneurysmen 11 1.3.4. Risikofaktoren für die Entstehung aortaler Aneurysmen 13 1.3.5. Medikamentöse Wechselwirkungen 15 1.4. Epidemiologie des Aortenaneurysmas 17 1.4.1. Angaben zur Prävalenz und Inzidenz 17 1.4.2. Rupturraten von thorakalen und abdominellen Aneurysmen 18 1.4.3. Angaben zu Wachstumsraten (GRy) aortaler Aneurysmen 19 1.5. Diagnostik und Bildgebung der Aorta 21 1.5.1. Nichtapparative Diagnostik 21 1.5.2. Konventionelles Röntgen und Angiografie 21 1.5.3. Ultraschall 21 1.5.4. Schnittbildgebung – Computer- und Magnetresonanztomografie (CT/MRT) 22 1.6. Therapeutische Optionen 23 1.6.1. Thorakale und thorakoabdominelle Aortenaneurysmen 23 1.6.2. Bauchaortenaneurysmen 23 2. Ziel der Studie 25 3. Materialien und Methoden 26 3.1. Studienkollektiv – Ein- und Ausschlusskriterien 26 3.2. Bildgebung 26 3.3. Bildverarbeitung und Messverfahren 27 3.3.1. Vorbereitung 27 3.3.2. Volumenberechnung 30 3.3.3. Messung von Diameter und Querschnittsfläche 30 3.3.4. Berechnung der Innen- und Außenfläche 31 3.3.5. Messung der minimalen und maximalen Wandstärke 32 3.3.6. Bestimmung der Segmentlänge 32 3.3.7. Winkelungs- und Krümmungsmessung 33 3.3.8. Exzentrizität des Gefäßquerschnittes 33 3.3.9. Vermessung der Gefäßwandverkalkung 34 3.4. Klinisch-anamnestische Faktoren 36 3.5. Berechnung der Wachstumsraten 36 3.6. Definition des Wachstumskriteriums 37 3.7. Gruppierung der Aortensegmente zur Auswertung 37 3.8. Statistische Auswertung 38 3.8.1. Mittelwertdifferenzen 38 3.8.2. Korrelation 38 3.8.3. Multiple Regressionsanalyse 38 3.8.4. Messmethodenvergleich 39 4. Ergebnisse 40 4.1. Charakteristika der Studienpopulation 40 4.1.1. Patientcharakteristika 40 4.1.2. Verteilung der klinischen Risikofaktoren 41 4.2. Quantifizierung der Aortenveränderungen anhand CT-morphologischer Parameter – initial und im Verlauf 43 4.2.1. Volumen 43 4.2.2. Diameter und Querschnittsfläche 47 4.2.3. Innen- und Außenfläche 48 4.2.4. Wandstärke 49 4.2.5. Länge, Proportion und Krümmung 52 4.2.6. Exzentrizität der Gefäßquerschnitte 55 4.2.7. Wandverkalkung 57 4.3. Einflussfaktoren des Aortenwachstums 62 4.3.1. Korrelationsanalyse der potentiellen Einflussfaktoren mit dem Wachstumskriterium 62 4.3.2. Prädiktoren des Aortenwachstums - Multiple Regressionsanalyse 67 4.4. Diskrepanzen zwischen unterschiedlich basierten Wachstumsraten 70 5. Diskussion 73 5.1. Wachstumsverhalten und Aortenmorphologie 73 5.1.1. Das Volumen als sensitiver Verlaufsparameter des Aortenwachstums 73 5.1.2. Etablierte Größen: Diameter und Querschnittsfläche 75 5.1.3. Alternative dreidimensionale Parameter: Innen- und Außenfläche 76 5.1.4. Die aortale Wandstärke als Surrogatparameter für intraluminalen Thrombus und atheromatöse Wandveränderungen 77 5.1.5. Die segementale Länge, Proportion und Krümmung als Korrelat longitudinalen Wachstums 78 5.1.6. Die Exzentrizität der Gefäßquerschnitte 79 5.1.7. Die aortale Wandverkalkung 80 5.2. Prädiktoren und Einflussfaktoren des Aortenwachstums 80 5.2.1. Initiale Größe 81 5.2.2. Gefäßwandveränderungen 82 5.2.3. Das Verhältnis von Proportion, Krümmung und Elongation der Aorten-segmente 84 5.2.4. Die Morphologie des Gefäßquerschnittes 86 5.2.5. Die Rolle der aortalen Wandverkalkung für das Aortenwachstum 87 5.2.6. Die Relevanz klinischer Risikofaktoren 87 5.3. Diskrepanzen der unterschiedlich basierten Wachstumsraten 89 5.4. Limitationen der Studie 91 5.5. Schlussfolgerung 92 6. Zusammenfassung der Arbeit 93 7. Literaturverzeichnis 95 8. Erklärung zur Dissertation 118 9. Curriculum Vitae 119 Persönliche Daten 119 Ausbildung 119 Praktische Erfahrungen und beruflicher Werdegang 119 10. Danksagung 121

Tato práce se zabývá problematikou aneurysmat břišní aorty a možností využít konečnoprvkovou deformačně-napěťovou analýzu těchto aneurysmat ke stanovení rizika ruptury. První část práce je věnována úvodu do problematiky, popisu kardiovaskulární soustavy člověka s důrazem na abdominální aortu, anatomii, fyziologii a patologii stěny tepny s důrazem na procesy vedoucí ke vzniku aneurysmatu. Dále se práce věnuje rizikovým faktorům přispívajících ke vzniku aneurysmat spolu s analýzou současných klinických postupů ke stanovení rizika ruptury spolu se srovnáním navrhovaného kritéria maximálního napětí. Dominantní část této disertace je věnována identifikaci faktorů ovlivňujících napjatost a deformaci stěny aneurysmatu spolu s návrhem nových postupů, prezentací vlastních poznatků vedoucích ke zpřesnění určení rizika ruptury pomocí deformačně- napěťové analýzy a metody konečných prvků. Nejprve je analyzován vliv geometrie, vedoucí k závěru, že je nezbytné používání individuálních geometrií pacienta. Dále je pozornost zaměřena na odbočující tepny, které ve stěně působí jako koncentrátor napětí a mohou tedy ovlivňovat napjatost v ní. Jako další podstatný faktor byl identifikován vliv nezatížené geometrie a bylo napsáno makro pro její nalezení, které bylo opět zahrnuto jako standardní součást do výpočtového modelu. Mechanické vlastnosti jak stěny aneurysmatu, tak intraluminálního trombu jsou experimentálně testovány pomocí dvouosých zkoušek. Také je zde analyzován vliv modelu materiálu, kde je ukázáno, že srovnávání maximálních napětí u jednotlivých modelů materiálu není vhodné díky zcela rozdílným gradientům napětí ve stěně aneurysmatu. Dále je zdůrazněna potřeba znalosti distribuce kolagenních vláken ve stěně a navržen program k jejímu získání. Intraluminální trombus je analyzován ve dvou souvislostech. Jednak je ukázán vliv jeho ruptury na napětí ve stěně a jednak je analyzován vliv jeho poroelastické struktury na totéž. Posledním identifikovaným podstatným faktorem je zbytková napjatost ve stěně. Její významnost je demonstrována na několika aneurysmatech a i tato je zahrnuta jako integrální součást do našeho výpočtového modelu.Na závěr jsou pak navrženy další možné směry výzkumu.

Abdominal aortic aneurysm (AAA) disease involves a dilation of the aorta below the renal arteries. If the aneurysm becomes sufficiently dilated and tissue strength is less than vascular pressure, rupture of the aorta occurs entailing a high mortality rate. Despite improvements in surgical technique, the mortality rate for emergency repair remains high and so an accurate predictor of rupture risk is required. Inflammation and the associated recruitment of monocytes into the aortic wall are critical in the pathology of AAA disease, stimulating the degradation and remodeling of the vessel wall. Areas with high concentrations of macrophages may experience an increase in tissue degradation and therefore an increased risk of rupture. Determining the magnitude and distribution of monocyte recruitment can help us understand the pathology of AAA disease and add spatial accuracy to the existing rupture risk prediction models. In this study finite element computational fluid dynamics simulations of AAA haemodynamics are seeded with monocytes to elucidate patterns of cell deposition and probability of recruitment. Haemodynamics are first simulated in simplified AAA geometries of varying diameters with a patient averaged flow waveform inlet boundary condition. This allows a comparison with previous experimental investigations as well as determining trends in monocyte adhesion with aneurysm progression. Previous experimental investigations show a transition to turbulent flow occurring during the deceleration phase of the cardiac cycle. There has thus far been no investigation into the accuracy of turbulence models in simulating AAA haemodynamics and so simulations are compared using RNG κ − ε, κ − ω and LES turbulence models. The RNG κ − ε model is insufficient to model secondary flows in AAA and LES models are sensitive to inlet turbulence intensity. The probability of monocyte adhesion and recruitment depends on cell residence time and local wall shear stress. A near wall particle residence time (NWPRT)model is created incorporating a wall shear stress-limiter based on in vitro experimental data. Simulated haemodynamics show qualitative agreement with experimental results. Peaks of maximum NWPRT move downstream in successively larger geometries, correlating with vortex behaviour. Average NWPRT rises sharply in models above a critical maximum diameter. These techniques are then applied to patient-specific AAAs. Geometries are created from CT slices and velocity boundary conditions taken from Phase Contrast-MRI (PC-MRI) data for 3 patients. There is no gold standard for inlet boundary conditions and so simulations using 3 velocity components, 1 velocity component and parabolic flow profiles at the inlet are compared with each other and with PC-MRI data at the AAA midsection. The general trends in flow and wall shear stress are similar between simulations with 3 and 1 components of inlet velocity despite differences in the nature and complexity of secondary flow. Applying parabolic velocity profiles, however, can cause significant deviations in haemodynamics. Axial velocities show average to good correlation with PC-MRI data though the lower magnitude radial velocities produce high levels of noise in the raw data making comparisons difficult. Patient specific NWPRT models show monocyte infiltration is most likely at or around the iliac bifurcation.

The renin angiotensin system (RAS) exerts many diverse physiological functions throughout the body, mediated by its effector peptide, angiotensin II (AngII). AngII has been linked with a variety of different functions ranging from the initiation of severe vascular pathologies, such as atherosclerosis and abdominal aortic aneurysm (AAA), to mundane physiological processes of fluid homeostasis, vascular contraction, and regulation of blood pressure. To provide a potential link between these functions, an in-depth analysis of regional effects of AngII on aortic vasculature was performed. The studies presented in this dissertation tested the overall hypothesis of whether regional changes exist in the vasculature in response to angiotensin II (AngII). We first infused AngII into C57BL/6 animals and studied the aortic morphology in detail. On first glance, we detected a thickening throughout the aorta, with no overt changes from region to region. However, upon further analysis, it was demonstrated that there was a region-specific aortic arch hyperplasia, versus the hypertrophy in the remainder of the aorta. Through a series of experiments, this hyperplasia was linked to the redox-mediated protein Id3. Further analysis of the vasculature demonstrated AngII exerted aortic contractions which were limited to the infrarenal aorta. These contractions were mediated by the AT1b receptor subtype in the RAS. We also demonstrate that AngII leads to suprarenal specific formation of AAA, which can be attenuated by the deletion of specific innate immune mediator proteins, such as MyD88 and TLR4. Overall, these data suggest many region-specific roles for AngII in the aortic vasculature and provide many novel findings as to the cause of these effects.

Aryl Hydrocarbon Receptor (AhR) is a ligand-actviated receptor known as the dioxin receptor. Environmental pollutants called dioxin-like toxicants are found in food, cigarette smoke, automobile exhaust and air. Therefore, they could chronically amplify the pathology of numerous chronic inflammatory diseases. AhR is a well known target of these environmental chemicals that disrupt endocrine signaling. By the year 2020, the number of people older than 60 years is expected to top 1 billion. The burden of treating chronic disease is significant both in dollars spent and in lost productivity. The need to identify risk factors for chronic diseases must be evaluated along with diet and lifestyle factors that will promote healthy aging. The studies presented in this dissertation tested the hypothesis that habitual exposure to dioxin-like contaminants contributes to chronic inflammatory disease states through activation of AhR pathway. Due to their lipophilicity, dioxin like toxicants (like PCB 77) accumulated in mice' visceral adipose tissue and induced adipocytes maturation and ectopic fat deposition. Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCB 77) can cause endothelial cells activation and inflammation by inducing pro-inflammatory signaling pathways. In our studies, PCB 77 had cumulative effects in Angiotensin II - induced Abdominal Aortic Aneurysm (AAA) by exacerbating inflammation in and around the aortic wall. More, PCB 77 increased mortality in mice that developed AAA. In order to appreciate the AhR involvement in inflammation we used a mouse model of Inflammatory Bowel Disease(IBD). Mice that had a reduced Ahr Receptor expression developed a less severe colitis and had a decreased general inflammatory status. These data provide evidence that exposure to environmental toxicants could augment inflammation and contribute to the social burden of obesity and obesity related chronic inflammatory diseases.

L’athérosclérose et la pathologie anévrysmale sont principalement caractérisées par un remodelage de laparoi artérielle au cours de leur évolution. Ce travail a examiné un aspect de la destruction de la paroiartérielle à travers l’étude de la métalloprotéase MMP-14 au cours de l’athérome et un aspect dereconstruction artérielle à travers l’étude d’une thérapie cellulaire d’un modèle d’Anévrysme de l’AorteAbdominale (AAA) par Cellules Souches Mésenchymateuses (CSMs).En utilisant un modèle de greffe de Moëlle Osseuse (MO) dans des souris Ldlr-/-, nous avons montré que ladélétion d’expression de MMP-14 dans les cellules issues de la MO provoquait une accumulation decollagène interstitiel dans la plaque athéromateuse sans modification de la composition cellulaire nivariation de taille. Une mesure de l’activité collagénolytique par substrat fluorescent a confirmé que ladélétion en MMP-14 chez les macrophages provoquait une baisse de l’activité collagénolytique. Cetteactivité est indépendante de l’activité MMP-2 et MMP-8 et pourrait être médiée partiellement parl’activation de MMP-13. Nous avons mis en évidence la présence de CSMs à la surface luminale de thrombus de AAA et nous avonsmontré une diminution significative des CSMs circulantes chez des patients porteurs de AAA. Nous avonspu stabiliser la croissance de AAA expérimentaux chez le rat à partir de xénogreffe artérielle par perfusionendoluminale de CSMs. La perfusion de CSMs provoquait une diminution de l’inflammation à court termeet favorisait la reconstruction artérielle par accumulation de collagène et d’élastine à moyen terme.En conclusion, l’activité collagénolytique de MMP-14 est un des mécanismes moléculaires possibles del’évolution de la plaque athéromateuse par rupture de plaque. Elle ouvre la perspective d’une nouvelleapproche thérapeutique et pourrait être une cible comme substrat pour une imagerie fonctionnelle de laplaque athéromateuse. L’évolution de la maladie anévrysmale pourrait être secondaire à une altération dessystèmes de réparation tissulaire dont les CSMs seraient des acteurs clé. La perfusion endoluminale desCSMs dans un modèle expérimental a permis la restauration de ces systèmes de réparation tissulaire etouvre la perspective d’un nouvel outil thérapeutique contre les AAA / Pas de résumé anglais