Correlations Between Intracranial Aneurysms And Thoracic Aortic Aneurysms

This project investigates the clinical occurrence of concurrent thoracic aortic aneurysms (TAA) and intracranial aneurysms (ICA). We hypothesized that patients with a TAA have an increased risk of harboring a concurrent ICA, and likewise that patients with an ICA have an increased risk of harboring a concurrent TAA relative to the general population. In a separate arm of this project, we hypothesized that a pre-defined gene expression profile, based on the expression levels of 41 specific genes measured in peripheral blood cells, will exhibit a characteristic expression pattern in ICA patients and thereby have utility in detecting the presence of ICA. To accomplish the first objective of this project, we reviewed the charts of patients with TAA who also had recent intracranial imaging to document the prevalence of concurrent ICA and compared this rate to the ICA prevalence in the general population. Likewise, we reviewed the charts of patients with ICA who also had recent thoracic imaging to document the prevalence of concurrent TAA. To investigate the gene expression profile for detecting ICA, we collected peripheral blood samples from ICA patients and non- aneurysmal controls and measured the expression levels of 39 pre-defined genes in a signature aneurysm profile using real-time PCR. The observed pattern of expression of these genes was compared to a pre-defined signature aneurysm pattern to predict the aneurysm status of each sample. We found that 9.0% of 212 TAA patients we studied harbor a concurrent ICA. Patients with descending TAA and hypertension had significantly higher rates of concurrent ICA. We also found that 4.5% of 359 ICA patients we studied harbor a concurrent TAA. ICA patients over 70 years of age had an increased rate of concurrent TAA. We also analyzed gene expression in the blood samples of 17 ICA patients and 15 controls. By comparing the observed pattern of gene expression to a predefined signature aneurysm pattern, we were able to detect ICA from a peripheral blood test with an 88% sensitivity and overall accuracy of 63%. In conclusion, this project finds that patients with TAA are at an increased risk relative to the general population of harboring a concurrent ICA. Likewise, patients with ICA are at an increased risk relative to the general population of harboring a concurrent TAA. Our early results show that a peripheral blood test based on the gene expression pattern of 39 genes holds promise as a sensitive screening test for ICA

In vitro image characteristics of an abdominal aortic stent graft: CTA versus 3D MRA

Percutaneous stent-grafting is increasingly employed as a less invasive alternative to surgery for the treatment of infrarenal abdominal aortic aneurysms. It requires long-term imaging follow-up, to document the structural integrity of the device, to exculude perigraft channels and endograft leakages, as well as the shrinkage of the aneurysmal sac. The expectation of severe stent induced artifacts and safety concerns have prevented 3D MRA from being used. The purpose of this in vitro study was to investigate the imaging characteristics of a bifurcated stent graft with 3D MRA (3D Frourier transform fast spoiled GRE) at 1.5 T in comparison to those of CTA. Measurement of the stent wall thickness and luminal diameter were made on a agar gel embedded stent graft at five locations on both CTA and MRA images. The stent graft was depicted as a dark ring on MR images. Wall thickness measurments at the five locations of the stent graft overestimated the true stent thickness, while luminal diameters were slightly underestimated. Measurement differences between MR and CT were not statistically significant (P=0.67;P=0.85). Artifacts emanating from the platinum markers were considerably less severe on the MR-images. A wider area of signal loss was seen only at the insertion of the iliac stent leg into the aortic stent portion due to the overlap of two radio-opaque platinum markers. 3D MRA images should permit a comprehensive assessment of the arterial lumen, and of perivascular tissue

Theoretical impact of insecticide-impregnated school uniforms on dengue incidence in Thai children.

BACKGROUND: Children carry the main burden of morbidity and mortality caused by dengue. Children spend a considerable amount of their day at school; hence strategies that reduce human-mosquito contact to protect against the day-biting habits of Aedes mosquitoes at schools, such as insecticide-impregnated uniforms, could be an effective prevention strategy. METHODOLOGY: We used mathematical models to calculate the risk of dengue infection based on force of infection taking into account the estimated proportion of mosquito bites that occur in school and the proportion of school time that children wear the impregnated uniforms. PRINCIPAL FINDINGS: The use of insecticide-impregnated uniforms has efficacy varying from around 6% in the most pessimistic estimations, to 55% in the most optimistic scenarios simulated. CONCLUSIONS: Reducing contact between mosquito bites and human hosts via insecticide-treated uniforms during school time is theoretically effective in reducing dengue incidence and may be a valuable additional tool for dengue control in school-aged children. The efficacy of this strategy, however, is dependent on the compliance of the target population in terms of proper and consistent wearing of uniforms and, perhaps more importantly, the proportion of bites inflicted by the Aedes population during school time

Biomechanical and morphological aspects of abdominal aortic aneurysm growth and rupture

Abdominal aortic aneurysms (AAAs) are dilatations of the abdominal aorta that pose a risk of rupture. The only effective treatment is intervention prior to rupture, but this is also associated with mortality and morbidity. It is therefore important to weigh the risks of intervention with the potential benefit. Current treatment guidelines recommend using the maximal aneurysm diameter (Dmax) as the indicator for rupture risk, and rec- ommend considering intervention in men with AAAs > 55 mm, and >50 mm in women. Patients with small AAAs are put in surveillance, and the Dmax is followed until it reaches the threshold. The current policy is relatively efficient on a population-level but lacks specificity for individuals. Some patients rupture before this threshold, and many remain stable despite passing it. Aneurysm growth is often described as erratic, but measure- ments are affected by several levels of uncertainty. Biomechanical assessment, where 3D models of AAAs from computed tomography angiographies (CTAs) are analysed by finite element analysis, may improve risk prediction. In the first study a population-based cohort of 192 patients with ruptured AAAs and CT imaging available at rupture were studied. A significant portion of patients ruptured with AAAs smaller than 60 mm, 10% of men and 27 % of women. When normalizing Dmax for body surface area (so-called aortic size index) there was, however, was not difference between the sexes. In an analysis of small, ruptured AAAs compared to Dmax, age and sex-matched asymptomatic AAAs, peak wall rupture index (PWRI), but not peak wall stress (PWS) was increased in the ruptured AAAs. In the second study, a cohort of 100 patients with at least three computed tomog- raphy examinations were analysed with 3D morphological and biomechanical analysis. The growth pattern of AAAs appeared continuous and conferred well to a linear growth model. The evolution of the different analysed indices, Dmax, aneurysm volume and bio- mechanical stress did, however, not parallel each other. Intraluminal thrombus (ILT) grew faster than the lumen, but lumen volume growth was more closely related to increase in biomechanical stress. In the third study, a cohort of 67 patients with 109 CTA examinations prior to rupture were identified. The relation between biomechanical variables and time-to-rupture was investigated. In small and medium sized AAAs (< 70 mm), PWRI, but not PWS, was associ- ated with time-to-rupture, also when adjusting for potential confounders, aneurysm size and sex. The results further show that women have an approximately two-fold increased hazard ratio for AAA rupture, compared to men, when adjusted for AAA size. In the fourth study lumen area is indicated as a potentially useful rupture risk marker. Ruptured AAAs, compared to Dmax-matched asymptomatic AAAs, have a larger luminal area, and the luminal area is related to biomechanical stress, even when adjusting for an- eurysm size, or ILT area. In conclusion, the results of this thesis indicate areas of potential improvement in the current care of patients with AAAs, explores the 3D growth of AAAs, and strengthens the potential role for biomechanical analysis. These results may in the future have rele- vance for personalizing timing of treatment for patients with AAAs, and the evaluation of pharmacological therapy for AAAs

Risk factors and mouse models of abdominal aortic aneurysm rupture

Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults. In clinical practice, the most established predictor of AAA rupture is maximum AAA diameter. Aortic diameter is commonly used to assess AAA severity in mouse models studies. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Previous research suggests that aortic wall structure and strength, biomechanical forces on the aorta and cellular and proteolytic composition of the AAA wall influence the risk of AAA rupture. Mouse models offer an opportunity to study the association of these factors with AAA rupture in a way not currently possible in patients. Such studies could provide data to support the use of novel surrogate markers of AAA rupture in patients. In this review, the currently available mouse models of AAA and their relevance to the study of AAA rupture are discussed. The review highlights the limitations of mouse models and suggests novel approaches that could be incorporated in future experimental AAA studies to generate clinically relevant results

Molecular imaging of abdominal aortic aneurysms

Abdominal aortic aneurysm (AAA) disease is characterised by an asymptomatic, permanent, focal dilatation of the abdominal aorta progressing towards rupture, which confers significant mortality. Patient management and surgical decisions currently rely on aortic diameter measurements via abdominal ultrasound screening. However, AAA rupture can occur at small diameters or may never occur at large diameters. Therefore, there is a need to develop molecular imaging-based biomarkers independent of aneurysm diameter that may help stratify patients with early-stage AAA to reduced surveillance. AAA uptake of [18F]fluorodeoxyglucose on positron emission tomography (PET) has been demonstrated previously; however, its glucose-dependent uptake may overlook other key mechanisms. The cell proliferation marker [18F]fluorothymidine ([18F]FLT) is primarily used in tumour imaging. The aim of the overall study for this thesis was to explore the feasibility of [18F]FLT PET / computed tomography (CT) to visualise and quantify AAA in the angiotensin II (AngII)-infused mouse model. The experiments presented in this thesis revealed increased uptake of [18F]FLT in the 14-day AngII AAA model than in saline controls, followed by a decrease in this uptake at 28 days. Moreover, in line with the in vivo PET/CT findings, Western blotting of aortic tissue revealed increased levels of thymidine kinase-1 (the substrate of [18F]FLT) and nucleoside transporters in the 14-day AngII AAA model than in saline controls, followed by decreased expression levels at 28 days. A pilot experiment further demonstrated that [18F]FLT PET/CT could be used to detect an early therapeutic response to oral imatinib treatment in the AngII AAA model. Therefore, [18F]FLT PET/CT may be a feasible modality to detect and quantify cell proliferation in the AngII AAA murine model. The findings of this thesis are encouraging for the application of [18F]FLT PET/CT in patients with small AAA

3D-Ultrasound Based Mechanical and Geometrical Analysis of Abdominal Aortic Aneurysms and Relationship to Growth

The heterogeneity of progression of abdominal aortic aneurysms (AAAs) is not well understood. This study investigates which geometrical and mechanical factors, determined using time-resolved 3D ultrasound (3D + t US), correlate with increased growth of the aneurysm. The AAA diameter, volume, wall curvature, distensibility, and compliance in the maximal diameter region were determined automatically from 3D + t echograms of 167 patients. Due to limitations in the field-of-view and visibility of aortic pulsation, measurements of the volume, compliance of a 60 mm long region and the distensibility were possible for 78, 67, and 122 patients, respectively. Validation of the geometrical parameters with CT showed high similarity, with a median similarity index of 0.92 and root-mean-square error (RMSE) of diameters of 3.5 mm. Investigation of Spearman correlation between parameters showed that the elasticity of the aneurysms decreases slightly with diameter (p = 0.034) and decreases significantly with mean arterial pressure (p &lt; 0.0001). The growth of a AAA is significantly related to its diameter, volume, compliance, and surface curvature (p &lt; 0.002). Investigation of a linear growth model showed that compliance is the best predictor for upcoming AAA growth (RMSE 1.70 mm/year). To conclude, mechanical and geometrical parameters of the maximally dilated region of AAAs can automatically and accurately be determined from 3D + t echograms. With this, a prediction can be made about the upcoming AAA growth. This is a step towards more patient-specific characterization of AAAs, leading to better predictability of the progression of the disease and, eventually, improved clinical decision making about the treatment of AAAs

Gene Expression Signature in Peripheral Blood Detects Thoracic Aortic Aneurysm

BACKGROUND: Thoracic aortic aneurysm (TAA) is usually asymptomatic and associated with high mortality. Adverse clinical outcome of TAA is preventable by elective surgical repair; however, identifying at-risk individuals is difficult. We hypothesized that gene expression patterns in peripheral blood cells may correlate with TAA disease status. Our goal was to identify a distinct gene expression signature in peripheral blood that may identify individuals at risk for TAA. METHODS AND FINDINGS: Whole genome gene expression profiles from 94 peripheral blood samples (collected from 58 individuals with TAA and 36 controls) were analyzed. Significance Analysis of Microarray (SAM) identified potential signature genes characterizing TAA vs. normal, ascending vs. descending TAA, and sporadic vs. familial TAA. Using a training set containing 36 TAA patients and 25 controls, a 41-gene classification model was constructed for detecting TAA status and an overall accuracy of 78+/-6% was achieved. Testing this classifier on an independent validation set containing 22 TAA samples and 11 controls yielded an overall classification accuracy of 78%. These 41 classifier genes were further validated by TaqMan real-time PCR assays. Classification based on the TaqMan data replicated the microarray results and achieved 80% classification accuracy on the testing set. CONCLUSIONS: This study identified informative gene expression signatures in peripheral blood cells that can characterize TAA status and subtypes of TAA. Moreover, a 41-gene classifier based on expression signature can identify TAA patients with high accuracy. The transcriptional programs in peripheral blood leading to the identification of these markers also provide insights into the mechanism of development of aortic aneurysms and highlight potential targets for therapeutic intervention. The classifier genes identified in this study, and validated by TaqMan real-time PCR, define a set of promising potential diagnostic markers, setting the stage for a blood-based gene expression test to facilitate early detection of TAA

Prediction of Abdominal Aortic Aneurysm Growth by Automatic Segmentation and Radiomics Feature Quantification

An accurate assessment of abdominal aortic aneurysm (AAA) progression is essential to its clinical management. Currently, the maximum diameter of AAA at diagnosis is considered as the primary indicator of rupture risk. However, it is not optimal as rupture can happen at any size. Several patient-specific factors may also influence AAA rupture risk. Given the clinical variability in aneurysm progression, additional prognostic markers are desirable to enhance patient-specific risk stratification. Radiomics is an image processing technique that extracts quantitative and high-dimensional features from medical images. While it has emerged as a novel approach for solving diagnosis in oncology, its application in cardiovascular diseases is still limited. This study set out with an aim to determine the feasibility of radiomics in identifying AAA with a fast growth rate (&gt;0.3cm/year) using CT images. An automatic AAA segmentation algorithm was developed in our pipeline. Based on the radiomics features of an 84 CT dataset, supervised classification models were implemented with two feature selection algorithms and two classifiers in a machine-learning framework. An AUC of 0.80 was achieved and the predictive power was proved through comparisons to the maximum diameter and conventional risk factors. Further multivariate analysis suggested that a radiomics-based classification model could be used as an independent, yet strong predictor for fast AAA growth rate