京都大学 / 新制・課程博士 / 博士(医学) / 甲第24484号 / 医博第4926号 / 新制||医||1063(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 森信 暁雄, 教授 YOUSSEFIAN Shohab, 教授 齊藤 博英 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introdução: O aneurisma de aorta abdominal (AAA) é uma importante causa de morbimortalidade na população idosa. O tratamento endovascular está associado a menor morbimortalidade que o tratamento convencional, no entanto, necessita de um seguimento rigoroso com exames de imagem contrastados para confirmação da exclusão do saco aneurismático. Considerando que a formação de um aneurisma é um processo multifatorial complexo, envolvendo a remodelação destrutiva do tecido conjuntivo em todo o segmento afetado da parede da aorta e que este processo envolve uma inflamação crônica local, uma diminuição no número de células do músculo liso da túnica média, e fragmentação da matriz extracelular da aorta e ainda que um perfil de expressão aberrante de miRNAs tem sido associada a doenças humanas, incluindo disfunção cardiovascular propôs-se então a realização deste estudo envolvendo todo este processo. O objetivo principal foi quantificar e avaliar a resposta da expressão dos miRNAs à correção endovascular de aneurisma de aorta abdominal com base em dosagens séricas no seguimento de seis meses. População e Método: Foram recrutados 30 pacientes consecutivos com AAA sem outras doenças inflamatórias associadas, do Ambulatório de Cirurgia Vascular e Endovascular do HCFMRPUSP com indicação de tratamento endovascular. Foram escolhidos para estudo e dosagens séricas os miRNA-191 e miRNA-455-3p. A expressão diferencial dos miRNAs foi realizada pelo método de PCR em tempo real, após extração do RNA das amostras de sangue total em dois momentos, pré- operatório e após 6 meses de pós-operatório. Além disso, ferramentas de bioinformática foram utilizadas para determinar vias fisiopatológicas relacionadas ao AAA. Foram Colhidos dados de perfil demográfico, de seguimento clinico e exames de imagem com angiotomografia no pré-operatórios e após 6 meses. Resultados: Foi observado uma hiperexpressão dos miR-191 e miR-455-3p no sangue total dos pacientes com AAA. O tratamento endovascular dos pacientes com AAA resultou em diminuição significativa das expressões dos miRNAs estudados, indicando que a exclusão do saco aneurismático altera as expressões dos mesmos. Adicionalmente, as expressões dos miR-191 e miR-455-3p não apresentaram correlação com o diâmetro do aneurisma e a análise da influência dos diversos tipos de dispositivos utilizados para o tratamento endovascular dos AAA, não mostrou diferenças significativas nas expressões dos miR-191 e miR-455-3p. Conclusões: A hiperexpressão dos miR-191 e miR-455-3p com sua significativa redução apos o tratamento endovascular, pode sugerir a utilização dessas moléculas como potenciais biomarcadores no seguimento desses pacientes. Novos estudos com maior número de casos devem ser realizados com o objetivo de validar os dados obtidos incluindo pacientes com eventuais vazamentos. / Background: Abdominal aortic aneurysm (AAA) is an important cause of morbidity and mortality in the elderly population. Endovascular treatment is associated with lower morbidity and mortality than conventional treatment, however, it requires a rigorous follow-up with contrast imaging tests to confirm the aneurysmal sac exclusion. Considering that the formation of an aneurysm is a complex multifactorial process, involving the destructive remodeling of the connective tissue throughout the affected segment of the aortic wall and that this process involves a chronic local inflammation, a decrease in the number of smooth muscle cells of the media tunic, and fragmentation of the extracellular matrix of the aorta and although an aberrant expression profile of miRNAs has been associated with human diseases, including cardiovascular dysfunction, it was proposed to carry out this study involving this whole process. The main objective was to quantify and evaluate miRNA expression response to endovascular correction of abdominal aortic aneurysm based on serum dosages at the six-month follow-up. Population and Method: We recruited 30 consecutive patients with AAA without other associated inflammatory diseases from the Ambulatory of Vascular and Endovascular Surgery of the HCFMRPUSP with indication of endovascular treatment. The miRNA-191 and miRNA-455-3p were selected for study and serum dosages. The differential expression of the miRNAs was performed by the real-time PCR method, after extraction of RNA from the whole blood samples at two moments, preoperatively and after 6 months of follow-up. In addition, bioinformatics tools were used to determine pathophysiological pathways related to AAA. Demographic profile, clinical follow-up and imaging examinations with angiotomography performed in the preoperative period and after 6 months were collected. Results: Hyperexpression of miR-191 and miR-455-3p in whole blood of AAA patients was observed. The endovascular treatment of patients with AAA resulted in a significant decrease in the expression of the miRNAS studied, indicating that the exclusion of the aneurysmal sac altered their expression. In addition, the expression of miR-191 and miR-455-3p showed no correlation with the diameter of the aneurysm and analysis of the influence of the various types of devices used for the endovascular treatment of AAA did not show significant differences in the expression of miR-191 And miR-455-3p. Conclusions: The hyperexpression of miR- 191 and miR-455-3p with its significant reduction after endovascular treatment may suggest the use of these molecules as potential biomarkers in the follow-up of these patients. New studies with a greater number of cases should be performed with the objective of validating the data obtained including patients with possible endoleaks.

Introdução: O aneurisma de aorta abdominal (AAA) é uma importante causa de morbimortalidade na população idosa. O tratamento endovascular está associado a menor morbimortalidade que o tratamento convencional, no entanto, necessita de um seguimento rigoroso com exames de imagem contrastados para confirmação da exclusão do saco aneurismático. Considerando que a formação de um aneurisma é um processo multifatorial complexo, envolvendo a remodelação destrutiva do tecido conjuntivo em todo o segmento afetado da parede da aorta e que este processo envolve uma inflamação crônica local, uma diminuição no número de células do músculo liso da túnica média, e fragmentação da matriz extracelular da aorta e ainda que um perfil de expressão aberrante de miRNAs tem sido associada a doenças humanas, incluindo disfunção cardiovascular propôs-se então a realização deste estudo envolvendo todo este processo. O objetivo principal foi quantificar e avaliar a resposta da expressão dos miRNAs à correção endovascular de aneurisma de aorta abdominal com base em dosagens séricas no seguimento de seis meses. População e Método: Foram recrutados 30 pacientes consecutivos com AAA sem outras doenças inflamatórias associadas, do Ambulatório de Cirurgia Vascular e Endovascular do HCFMRPUSP com indicação de tratamento endovascular. Foram escolhidos para estudo e dosagens séricas os miRNA-191 e miRNA-455-3p. A expressão diferencial dos miRNAs foi realizada pelo método de PCR em tempo real, após extração do RNA das amostras de sangue total em dois momentos, pré- operatório e após 6 meses de pós-operatório. Além disso, ferramentas de bioinformática foram utilizadas para determinar vias fisiopatológicas relacionadas ao AAA. Foram Colhidos dados de perfil demográfico, de seguimento clinico e exames de imagem com angiotomografia no pré-operatórios e após 6 meses. Resultados: Foi observado uma hiperexpressão dos miR-191 e miR-455-3p no sangue total dos pacientes com AAA. O tratamento endovascular dos pacientes com AAA resultou em diminuição significativa das expressões dos miRNAs estudados, indicando que a exclusão do saco aneurismático altera as expressões dos mesmos. Adicionalmente, as expressões dos miR-191 e miR-455-3p não apresentaram correlação com o diâmetro do aneurisma e a análise da influência dos diversos tipos de dispositivos utilizados para o tratamento endovascular dos AAA, não mostrou diferenças significativas nas expressões dos miR-191 e miR-455-3p. Conclusões: A hiperexpressão dos miR-191 e miR-455-3p com sua significativa redução apos o tratamento endovascular, pode sugerir a utilização dessas moléculas como potenciais biomarcadores no seguimento desses pacientes. Novos estudos com maior número de casos devem ser realizados com o objetivo de validar os dados obtidos incluindo pacientes com eventuais vazamentos. / Background: Abdominal aortic aneurysm (AAA) is an important cause of morbidity and mortality in the elderly population. Endovascular treatment is associated with lower morbidity and mortality than conventional treatment, however, it requires a rigorous follow-up with contrast imaging tests to confirm the aneurysmal sac exclusion. Considering that the formation of an aneurysm is a complex multifactorial process, involving the destructive remodeling of the connective tissue throughout the affected segment of the aortic wall and that this process involves a chronic local inflammation, a decrease in the number of smooth muscle cells of the media tunic, and fragmentation of the extracellular matrix of the aorta and although an aberrant expression profile of miRNAs has been associated with human diseases, including cardiovascular dysfunction, it was proposed to carry out this study involving this whole process. The main objective was to quantify and evaluate miRNA expression response to endovascular correction of abdominal aortic aneurysm based on serum dosages at the six-month follow-up. Population and Method: We recruited 30 consecutive patients with AAA without other associated inflammatory diseases from the Ambulatory of Vascular and Endovascular Surgery of the HCFMRPUSP with indication of endovascular treatment. The miRNA-191 and miRNA-455-3p were selected for study and serum dosages. The differential expression of the miRNAs was performed by the real-time PCR method, after extraction of RNA from the whole blood samples at two moments, preoperatively and after 6 months of follow-up. In addition, bioinformatics tools were used to determine pathophysiological pathways related to AAA. Demographic profile, clinical follow-up and imaging examinations with angiotomography performed in the preoperative period and after 6 months were collected. Results: Hyperexpression of miR-191 and miR-455-3p in whole blood of AAA patients was observed. The endovascular treatment of patients with AAA resulted in a significant decrease in the expression of the miRNAS studied, indicating that the exclusion of the aneurysmal sac altered their expression. In addition, the expression of miR-191 and miR-455-3p showed no correlation with the diameter of the aneurysm and analysis of the influence of the various types of devices used for the endovascular treatment of AAA did not show significant differences in the expression of miR-191 And miR-455-3p. Conclusions: The hyperexpression of miR- 191 and miR-455-3p with its significant reduction after endovascular treatment may suggest the use of these molecules as potential biomarkers in the follow-up of these patients. New studies with a greater number of cases should be performed with the objective of validating the data obtained including patients with possible endoleaks.

Introdução: O aneurisma de aorta abdominal (AAA) é uma doença prevalente e silenciosa também relacionada com a atividade inflamatória. Atualmente, a abordagem endovascular tem sido utilizada como principal técnica devido à inúmeras vantagens. Porém tem uma maior taxa de reintervenções e necessita de seguimento periódico com angiotomografias, o que aumenta custos e tem implicações como alteração da função renal além do acúmulo progressivo de radiação. Tais condições justificam a busca por possíveis biomarcadores que possam contribuir para um melhor seguimento. Objetivos: Neste estudo, buscou-se correlacionar o microRNA-1281, proteína C reativa (PCR) e a avaliação da função renal de indivíduos com AAA com a evolução dos mesmos após o tratamento endovascular. Pacientes e métodos: Foram selecionados 30 pacientes consecutivos do Ambulatório de Cirurgia Vascular e Endovascular do HCFMRP-USP, no período de janeiro de 2104 a novembro de 2015, com aneurisma de aorta abdominal e com indicação para tratamento endovascular. As dosagens séricas e avaliações angiotomográficas foram feitas no pré-operatório e 6 meses após a intervenção. Resultados: Houve uma hiperexpressão do microRNA-1281 nos pacientes com aneurisma e uma significativa redução dos seus níveis séricos após a correção endovascular. A expressão do miRNA-1281 apresentou correlação positiva com o clearence de creatinina. Houve também correlação positiva da PCR com a presença do aneurisma, e com seu diâmetro e não houve alteração significativa da função renal mensurada através das dosagens séricas de uréia, creatinina e cálculo indireto de clearence. Conclusão: O estudo mostrou que o miRNA 1281 tem boa correlação com a evolução favorável pós-tratamento endovascular do AAA, não se observando o mesmo com a proteína C reativa. Novos estudos são necessários para validar e complementar tais achados. / Introduction: Abdominal aortic aneurysm (AAA) is a prevalent and silent disease. Currently, the endovascular approach has been widely used and is the main technique due to the innumerable advantages. However, it has a higher rate of reintervention and requires periodic follow-up with tomography over the years, which increases its costs and has implications such as altered renal function besides the accumulation of radiation. Such conditions justify the search for possible biomarkers that may perhaps replace CT. Objectives: In this study, we sought to correlate the microRNA-1281, Creactive protein (CRP) and the renal function evaluation of individuals with AAA with their evolution after endovascular treatment. Patients and methods: We selected 30 consecutive patients from the Ambulatory of Vascular and Endovascular Surgery of the HCFMRP-USP, in the period from January of 2104 until November of 2015, with abdominal aortic aneurysm and with indication for endovascular treatment. Serum dosages were made preoperatively and 6 months after the intervention Results: There was a hyperexpression of the micro-RNA -1281 in patients with aneurysm and a significant reduction of their serum levels after endovascular correction. Expression of miRNA-1281 showed a positive correlation with creatinine clearence. There was also a positive correlation of CRP with the presence of the aneurysm, and with its diameter, and there was no significant alteration of renal function measured through serum urea, creatinine and indirect clearance calculations. Conclusion: The study showed that 1281 miRNAs may prove to be a potential biomarker for eventual follow-up of patients undergoing AAA endovascular repair. New studies are needed to validate and complement these findings.

Introdução: O aneurisma de aorta abdominal (AAA) é uma doença prevalente e silenciosa também relacionada com a atividade inflamatória. Atualmente, a abordagem endovascular tem sido utilizada como principal técnica devido à inúmeras vantagens. Porém tem uma maior taxa de reintervenções e necessita de seguimento periódico com angiotomografias, o que aumenta custos e tem implicações como alteração da função renal além do acúmulo progressivo de radiação. Tais condições justificam a busca por possíveis biomarcadores que possam contribuir para um melhor seguimento. Objetivos: Neste estudo, buscou-se correlacionar o microRNA-1281, proteína C reativa (PCR) e a avaliação da função renal de indivíduos com AAA com a evolução dos mesmos após o tratamento endovascular. Pacientes e métodos: Foram selecionados 30 pacientes consecutivos do Ambulatório de Cirurgia Vascular e Endovascular do HCFMRP-USP, no período de janeiro de 2104 a novembro de 2015, com aneurisma de aorta abdominal e com indicação para tratamento endovascular. As dosagens séricas e avaliações angiotomográficas foram feitas no pré-operatório e 6 meses após a intervenção. Resultados: Houve uma hiperexpressão do microRNA-1281 nos pacientes com aneurisma e uma significativa redução dos seus níveis séricos após a correção endovascular. A expressão do miRNA-1281 apresentou correlação positiva com o clearence de creatinina. Houve também correlação positiva da PCR com a presença do aneurisma, e com seu diâmetro e não houve alteração significativa da função renal mensurada através das dosagens séricas de uréia, creatinina e cálculo indireto de clearence. Conclusão: O estudo mostrou que o miRNA 1281 tem boa correlação com a evolução favorável pós-tratamento endovascular do AAA, não se observando o mesmo com a proteína C reativa. Novos estudos são necessários para validar e complementar tais achados. / Introduction: Abdominal aortic aneurysm (AAA) is a prevalent and silent disease. Currently, the endovascular approach has been widely used and is the main technique due to the innumerable advantages. However, it has a higher rate of reintervention and requires periodic follow-up with tomography over the years, which increases its costs and has implications such as altered renal function besides the accumulation of radiation. Such conditions justify the search for possible biomarkers that may perhaps replace CT. Objectives: In this study, we sought to correlate the microRNA-1281, Creactive protein (CRP) and the renal function evaluation of individuals with AAA with their evolution after endovascular treatment. Patients and methods: We selected 30 consecutive patients from the Ambulatory of Vascular and Endovascular Surgery of the HCFMRP-USP, in the period from January of 2104 until November of 2015, with abdominal aortic aneurysm and with indication for endovascular treatment. Serum dosages were made preoperatively and 6 months after the intervention Results: There was a hyperexpression of the micro-RNA -1281 in patients with aneurysm and a significant reduction of their serum levels after endovascular correction. Expression of miRNA-1281 showed a positive correlation with creatinine clearence. There was also a positive correlation of CRP with the presence of the aneurysm, and with its diameter, and there was no significant alteration of renal function measured through serum urea, creatinine and indirect clearance calculations. Conclusion: The study showed that 1281 miRNAs may prove to be a potential biomarker for eventual follow-up of patients undergoing AAA endovascular repair. New studies are needed to validate and complement these findings.

Aim of the study was to analyze the influence of comorbidities, demographic and surgical risk factors on early and late results of non-ruptured and ruptured abdominal aortic aneurysm. In the introduction the aim of the study and objectives are listed. In the review of the literature main problems of pending topic are analyzed. The methodology is described in a special chapter. The results of 373 patients’ surgical treatment of abdominal aortic aneurysm were analyzed. Eighty-four of them were operated due to the abdominal aortic aneurysm rupture. Follow-up results of 153 patients were analyzed in a special chapter. The influence of comorbidities, demographic and surgical risk factors on mortality and complication rate after operations for ruptured abdominal aortic aneurysm were assessed. Analysis of follow-up results clarified risk factors influencing survival after operation of abdominal aortic aneurysm. Assessment of the results showed that mean age of patients is lower and comorbidities is more severe as compared with the data presented for Western countries. The patients’ age, condition of cardiac and pulmonary systems, volume of operation were the most influencing risk factors on the outcome of surgical treatment of the abdominal aortic aneurysm. / Tyrimo tikslas – išanalizuoti gretutinių ligų ir demografinių bei chirurginių rizikos veiksnių įtaką neplyšusios bei plyšusios pilvinės aortos aneurizmos artimiems bei atokiesiems chirurginio gydymo rezultatams. Įvade išdėstomi tyrimo tikslai bei uždaviniai, pateikiama literatūros apžvalga, kurioje apibendrinamos pagrindinės su nagrinėjama tema susijusios problemos. Atskirame skyriuje aprašyta tyrimo metodika. Disertacijoje išnagrinėti 373 pacientų, operuotų dėl pilvinės aortos aneurizmos, gydymo rezultatai. Aštuoniasdešimt keturi jų gydyti dėl plyšusios pilvinės aortos aneurizmos. Atskirai išnagrinėta 153 pacientų vėlyvieji gydymo rezultatai. Nustatyta mirtingumo ir komplikacijų po plyšusių pilvinės aortos aneurizmų operacijų priklausomybė nuo įvairių rizikos veiksnių artimuoju pooperaciniu laikotarpiu. Skyriuje, kur analizuojami vėlyvieji operacijų rezultatai, nustatyti svarbiausieji veiksniai, nulemiantys išgyvenamumą. Išsamūs šių tyrimų rezultatai pateikti dviejuose disertacijos skyriuose. Nustatyta, kad tiriamųjų pacientų amžiaus vidurkis buvo mažesnis, o gretutinės patologijos buvo daugiau palyginus su duomenimis, pateiktais Vakarų šalių literatūroje. Taip pat nustatyta, kad didžiausią įtaką gydymo rezultatams darė paciento amžius, širdies bei plaučių patologija, operacijos apimtis.

Tyrimo tikslas – išanalizuoti gretutinių ligų ir demografinių bei chirurginių rizikos veiksnių įtaką neplyšusios bei plyšusios pilvinės aortos aneurizmos artimiems bei atokiesiems chirurginio gydymo rezultatams. Įvade išdėstomi tyrimo tikslai bei uždaviniai, pateikiama literatūros apžvalga, kurioje apibendrinamos pagrindinės su nagrinėjama tema susijusios problemos. Atskirame skyriuje aprašyta tyrimo metodika. Disertacijoje išnagrinėti 373 pacientų, operuotų dėl pilvinės aortos aneurizmos, gydymo rezultatai. Aštuoniasdešimt keturi jų gydyti dėl plyšusios pilvinės aortos aneurizmos. Atskirai išnagrinėta 153 pacientų vėlyvieji gydymo rezultatai. Nustatyta mirtingumo ir komplikacijų po plyšusių pilvinės aortos aneurizmų operacijų priklausomybė nuo įvairių rizikos veiksnių artimuoju pooperaciniu laikotarpiu. Skyriuje, kur analizuojami vėlyvieji operacijų rezultatai, nustatyti svarbiausieji veiksniai, nulemiantys išgyvenamumą. Išsamūs šių tyrimų rezultatai pateikti dviejuose disertacijos skyriuose. Nustatyta, kad tiriamųjų pacientų amžiaus vidurkis buvo mažesnis, o gretutinės patologijos buvo daugiau palyginus su duomenimis, pateiktais Vakarų šalių literatūroje. Taip pat nustatyta, kad didžiausią įtaką gydymo rezultatams darė paciento amžius, širdies bei plaučių patologija, operacijos apimtis. / Aim of the study was to analyze the influence of comorbidities, demographic and surgical risk factors on early and late results of non-ruptured and ruptured abdominal aortic aneurysm. In the introduction the aim of the study and objectives are listed. In the review of the literature main problems of pending topic are analyzed. The methodology is described in a special chapter. The results of 373 patients’ surgical treatment of abdominal aortic aneurysm were analyzed. Eighty-four of them were operated due to the abdominal aortic aneurysm rupture. Follow-up results of 153 patients were analyzed in a special chapter. The influence of comorbidities, demographic and surgical risk factors on mortality and complication rate after operations for ruptured abdominal aortic aneurysm were assessed. Analysis of follow-up results clarified risk factors influencing survival after operation of abdominal aortic aneurysm. Assessment of the results showed that mean age of patients is lower and comorbidities is more severe as compared with the data presented for Western countries. The patients’ age, condition of cardiac and pulmonary systems, volume of operation were the most influencing risk factors on the outcome of surgical treatment of the abdominal aortic aneurysm.

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.

Abdominal aortic aneurysm (AAA) is a devastating disease that exhibits permanent lumen expansion typically in the infrarenal aorta. AAA is prevalent among aged population, especially in males. Despite the incidence in women is lower, studies indicate the tortuosity is more severe and aortic rupture risk is higher in women. In most patients, AAA remains asymptomatic until it ruptures leading to sudden and fatal hemorrhage. To date, there is no proven medical therapy that can prevent the expansion or rupture. Human observational studies implicate the presence of AAA is associated with both high plasma low-density lipoprotein-cholesterol (HDL-C) and low plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. To examine the role of specific lipoproteins in development of AAA, angiotensin (Ang) II-induced AAA was firstly determined in apolipoprotein AI deficient (apoAI -/-) mice in both C57BL/6 and LDL receptor deficient (LDL receptor -/-) backgrounds. The deletion of apoAI led to a significant decrease of HDL-C concentrations. However, we were unable to define any exacerbation of AngII-induced AAA in either normo- or hyperlipidemic mice with apoAI deficiency. Next we compared AngII-induced AAA formation using multiple mouse strains with dietary manipulation to generate different severities of hypercholesterolemia. We demonstrated the apolipoprotein B (apoB)-containing lipoproteins promoted the development of AngII-induced AAA. Moreover, ezetimibe administration significantly reduced both apoB-containing lipoproteins and AAA formation. Together, our studies demonstrate that elevated apoB-containing lipoproteins, contribute to the development of AngII-induced AAA. To investigate the role of apoB-containing lipoproteins on established AAA, male LDL receptors -/- mice fed a Western diet were infused with AngII for 4 weeks to induced AAA. Then mice with AAA were stratified into either a group maintained on western diet or switched to a normal diet. AngII infusion was continued for an additional 8 weeks. The diet switch resulted in significantly reduced plasma cholesterol concentrations, which was attributable to the decrease of apoB-containing lipoproteins. We found a profound inhibition of aneurysm progression in diet switched mice associated with attenuated macrophage accumulation and medial thickening. Collectively, our data demonstrate that apoB-containing lipoproteins promote the progression of established AAA.

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.