Geometric, biomechanical and molecular analyses of abdominal aortic aneurysm

Background Abdominal aortic aneurysm (AAA) is defined as a dilatation of the abdominal aorta of 30 mm in diameter or more. Main risk factors are smoking, age and male sex. Pathophysiological features include inflammation, smooth muscle cell loss and destruction of the extracellular matrix. The AAA is typically asymptomatic but can expand and eventually rupture, with a mortality of 70-80% as a result. Risk factors for rupture include a large diameter, female sex, active smoking, high blood pressure and low body mass index (BMI). There is no medical treatment to inhibit growth or rupture of AAA. The only measure to prevent rupture in a large AAA is aortic surgery. This intervention carries its own significant risk of morbidity and mortality, necessitating a risk stratification method. The diameter is currently used to decide when to operate on an AAA and it is repeatedly monitored until the threshold for surgery is reached. However, this measurement leaves room for improvement, as the individual aneurysm growth rate is difficult to predict and some large AAAs do not rupture while in other patients, small AAAs rupture during surveillance. Finite element analysis (FEA) is a method by which biomechanical rupture risk can be estimated based on patient characteristics and a computed tomography (CT)-derived 3D model of an AAA. Microarray analysis allows high-throughput analyses of tissue gene expression. Aims The overall aim of this thesis was to explore and develop new strategies to improve, refine and individualize management of patients with AAA, by applying geometric, biomechanical and molecular analyses. Methods and Results In study I, the CTs of 146 patients with AAAs of diameters between 40 and 60 mm were analyzed with three-dimensional (3D) segmentation and FEA. Simple and multiple regression analyses were performed. Female sex, patient height, lumen volume, body surface area (BSA) and low BMI were shown to be associated with the biomechanical rupture risk of AAA. Study II included 191 patients with AAAs of diameters between 40-50 mm. The AAAs were analyzed with 3D segmentation and FEA after which prediction algorithms were developed by use of machine learning strategies. More precise diameter measurements improved prediction of growth and four-year prognosis of small AAAs. Biomechanical indices and lumen diameter were predictive of future rupture or symptomatic AAA. Growth and rupture required different prediction models. In study III, 37 patients, 42 controls and a validation cohort of 51 patients were analyzed with respect to their circulating levels of neutrophil elastase-derived fibrin degradation products (E-XDP). The results showed that E-XDP was a sensitive marker for AAA, independently of examined comorbidities, and its concentration in peripheral blood correlated with the AAA diameter and the volume and mechanical stress of the intraluminal thrombus (ILT). It was further increased by the presence of coexisting aneurysms. Study IV included 246 tissue samples, divided into tunica media and adventitia, from 76 patients with AAA and 13 organ donor controls, analyzed by microarrays. There were large differences between the transcriptomes of AAA and control media and adventitia. Processes related to inflammation were transmural, whereas the upregulation of proteolysis, angiogenesis and apoptosis along with downregulation of smooth muscle- and differentiation-related gene sets were specific for the aneurysm media. Active smoking increased oxidative stress in all tissues and increased inflammation and lipid-related processes in AAA. The growth rate of the AAA diameter correlated with adaptive immunity in media and lipid processes in adventitia. Conclusions In this thesis, we show that known clinical risk factors and certain geometric properties are associated with biomechanical deterioration of AAAs. Furthermore, geometric and biomechanical analyses can enhance prediction of outcome. Importantly, there are differences between prediction of AAA growth and rupture. Finally, a biomarker was discovered and the transcriptome of AAA including effects of the ILT, smoking and rapid diameter growth rate, was mapped and we envision that the data may be used for future biomarker and drug target discovery

GEREJA KRISTEN JAWA UNGARAN

Tugas Akhir ini dilatarbelakangi oleh kebutuhan jemaat Gereja Kristen Jawa Ungaran di dalam melaksanakan ibadah rutin dan pelayananan gereja. Permasalahan yang diangkat untuk dicari solusi desainnya adalah sebagai berikut : 1) Berapa besaran ruang yang diperlukan agar kegiatan ibadah dan pelayanan jemaat Gereja Kristen Jawa Ungaran dapat terfasilitasi, 2) Apa standar-standar yang harus dipenuhi di dalam menentukan ruang ibadah dan fasilitas pelayanan di Gereja Kristen Jawa Ungaran, 3) Bagaimana Gereja Kristen Jawa Ungaran dapat menerapkan arsitektur Jawa sebagai perwujudan komunitas jemaat Kristen Jawa di dalam gereja. Penekanan desain pada Gereja Kristen Jawa Ungaran ini adalah arsitektur yang bernafaskan kebudayaan Jawa. Gereja dengan arsitektur kebudayaan Jawa memberikan identitas khusus pada Gereja Kristen Jawa, membedakan gereja ini dengan gereja-gereja lain di kota Ungaran, serta memberikan suasana yang cocok dengan ibadah jemaat Gereja Kristen Jawa Ungaran. Kajian diawali dengan mempelajari pengertian dari agama Kristen, pengertian gereja Kristen, sejarah Gereja Kristen Jawa, pelaku dan pelayanan liturgi gereja, dan istilah-istilah yang sering digunakan di dalam gereja. Setelah itu dilakukan pendataan standar-standar di dalam membangun sebuah gereja. Dilakukan juga tinjauan mengenai lokasi di Ungaran menurut karakter geografis dan budayanya. Menggabungkan antara budaya Jawa dengan nilai kekristenan tetapi tetap mampu memberikan solusi dalam permasalahan kebutuhan jemaat yang ada merupakan tantangan tersendiri. Akhirnya, seluruh kajian dituangkan dalam bentuk program ruang dan konsep-konsep perancangan yang diaplikasikan ke dalam desain yang dipresentasikan ke dalam bentuk gambar-gambar arsitektur

Three-dimensional growth and biomechanical risk progression of abdominal aortic aneurysms under serial computed tomography assessment

Abstract Growth of abdominal aortic aneurysms (AAAs) is often described as erratic and discontinuous. This study aimed at describing growth patterns of AAAs with respect to maximal aneurysm diameter (Dmax) and aneurysm volume, and to characterize changes in the intraluminal thrombus (ILT) and biomechanical indices as AAAs grow. 384 computed tomography angiographies (CTAs) from 100 patients (mean age 70.0, standard deviation, SD = 8.5 years, 22 women), who had undergone at least three CTAs, were included. The mean follow-up was 5.2 (SD = 2.5) years. Growth of Dmax was 2.64 mm/year (SD = 1.18), volume 13.73 cm3/year (SD = 10.24) and PWS 7.3 kPa/year (SD = 4.95). For Dmax and volume, individual patients exhibited linear growth in 87% and 77% of cases. In the tertile of patients with the slowest Dmax-growth (< 2.1 mm/year), only 67% belonged to the slowest tertile for volume-growth, and 52% and 55% to the lowest tertile of PWS- and PWRI-increase, respectively. The ILT-ratio (ILT-volume/aneurysm volume) increased with time (2.6%/year, p < 0.001), but when adjusted for volume, the ILT-ratio was inversely associated with biomechanical stress. In contrast to the notion that AAAs grow in an erratic fashion most AAAs displayed continuous and linear growth. Considering only change in Dmax, however, fails to capture the biomechanical risk progression, and parameters such as volume and the ILT-ratio need to be considered

Dipeptidyl peptidase-4 is increased in the abdominal aortic aneurysm vessel wall and is associated with aneurysm disease processes.

BACKGROUND:Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease, and until today there is no other treatment available than surgical intervention. Dipeptidyl peptidase-4 (DPP4)-inhibitors, used clinically to treat type 2 diabetes, have in murine models been shown to attenuate aneurysm formation and decrease aortic wall matrix degradation, inflammation and apoptosis. Our aim was to investigate if DPP4 is present, active and differentially expressed in human AAA. METHODS AND RESULTS:DPP4 gene expression was elevated in both media and adventitia of AAA tissue compared with control tissue, as measured by microarrays and qPCR, with consistent findings in external data. The plasma activity of DPP4 was however lower in male patients with AAA compared with age- and gender-matched controls, independently of comorbidity or medication. Immunohistochemical double staining revealed co-localization of DPP4 with cells positive for CD68, CD4 and -8, CD20, and SMA. Gene set enrichment analysis demonstrated that expression of DPP4 in AAA tissue correlated with expression of biological processes related to B- and T-cells, extracellular matrix turnover, peptidase activity, oxidative stress and angiogenesis whereas it correlated negatively with muscle-/actin-related processes. CONCLUSION:DPP4 is upregulated in both media and adventitia of human AAA and correlates with aneurysm pathophysiological processes. These results support previous murine mechanistic studies and implicate DPP4 as a target in AAA disease

A large proportion of patients with small ruptured abdominal aortic aneurysms are women and have chronic obstructive pulmonary disease.

OBJECTIVE:In a population-based cohort of ruptured abdominal aortic aneurysms (rAAAs), our aim was to investigate clinical, morphological and biomechanical features in patients with small rAAAs. METHODS:All patients admitted to an emergency department in Stockholm and Gotland, a region with a population of 2.1 million, between 2009-2013 with a CT-verified rupture (n = 192) were included, and morphological measurements were performed. Patients with small rAAAs, maximal diameter (Dmax) ≤ 60 mm were selected (n = 27), and matched 2:1 by Dmax, sex and age to intact AAA (iAAAs). For these patients, morphology including volume and finite element analysis-derived biomechanics were assessed. RESULTS:The mean Dmax for all rAAAs was 80.8 mm (SD = 18.9 mm), women had smaller Dmax at rupture (73.4 ± 18.4 mm vs 83.1 ± 18.5 mm, p = 0.003), and smaller neck and iliac diameters compared to men. Aortic size index (ASI) was similar between men and women (4.1 ± 3.1 cm/m2 vs 3.8 ± 1.0 cm/m2). Fourteen percent of all patients ruptured at Dmax ≤ 60 mm, and a higher proportion of women compared to men ruptured at Dmax ≤ 60 mm: 27% (12/45) vs. 10% (15/147), p = 0.005. Also, a higher proportion of patients with a chronic obstructive pulmonary disease ruptured at Dmax ≤ 60 mm (34.6% vs 14.6%, p = 0.026). Supra-renal aortic size index (14.0, IQR 13.3-15.3 vs 12.8, IQR = 11.4-14.0) and peak wall rupture index (PWRI, 0.35 ± 0.08 vs 0.43 ± 0.11, p = 0.016) were higher for small rAAAs compared to matched iAAAs. Aortic size index, peak wall stress and aneurysm volume did not differ. CONCLUSION:More than one tenth of ruptures occur at smaller diameters, women continuously suffer an even higher risk of presenting with smaller diameters, and this must be considered in surveillance programs. The increased supra-renal aortic size index and PWRI are potential markers for rupture risk, and patients under surveillance with these markers may benefit from increased attention, and potentially from timely repair