Imunização de camundongos LDLr-/- com peptídeo mimético da LDL eletronegativa: uma potencial estratégia terapêutica para a aterosclerose / Immunization of LDLr - / - mice with electronegative LDL mimetic peptides: a potential therapeutic strategy for atherosclerosis

Introdução: A aterosclerose é uma doença inflamatória crônica decorrente de alterações na parede das artérias de médio e grande calibre e associadas a diversos fatores de risco, dentre os quais destaca-se as hiperlipidemias, ou seja, o aumento plasmático das lipoproteínas, mas também outras comorbidades, como a Síndrome Metabólica. Entre as lipoproteínas, a lipoproteína de baixa densidade (LDL) é de grande relevância na aterosclerose. Diferentes espécies de LDL modificada (LDLm) são originadas através de lipólise, glicação e proteólise, além da oxidação, variando em densidade e eletronegatividade, sendo melhor denominada LDL eletronegativa [LDL (-)]. Considerando as diferenças conformacionais entre a estrutura da ApoB-100 da LDL nativa e da LDL (-), em um estudo inicial, nosso grupo desenvolveu um anticorpo monoclonal (2C7) a partir da imunização de camundongos Balb/c com a LDL (-) humana. Em uma etapa seguinte foi mapeado o epítopo reconhecido pelo anticorpo monoclonal anti-LDL (-) através de phage display. O peptídeo ligante do anticorpo monoclonal anti-LDL (-) foi nomeado p2C7. Esse peptídeo não representa regiões da sequência linear da ApoB-100 humana, mas microdomínios conformacionais de epítopos da ApoB-100 da LDL (-), tornando-os candidatos para a imunomodulação da aterogênese. Portanto, investigar a imunomodulação induzida pelos peptídeo p2C7 miméticos da LDL (-), por representar um epítopo imunodominante da LDL (-), poderá abrir novas perspectivas terapêuticas futuras para a imunomodulação da aterosclerose. Objetivo: Avaliar a imunomodulação promovida pelo p2C7 in vivo, utilizando camundongos C57BL/6 LDLr -/- e amostras de plasma humano. Adicionalmente, no estágio (BEPE) realizado no Instituto Karolinska (dezembro de 2019 a março de 2021), investigou-se o imunometabolismo como mediador nas doenças cardiovasculares. Na parte II-A, estão descritos os resultados do estudo inicialmente proposto. Na parte II-B, apresenta-se os resultados que foram desenvolvidos posteriormente, com ampliação do escopo do projeto, abordando-se a inflamação vascular envolvida no aneurisma de aorta abdominal através de ferramentas de bioinformática. Na parte II-C, são apresentados os resultados do estudo do envolvimento da enzima indolamina 2,3 dioxigenase (IDO) na esteatohepatite não-alcoólica (NASH) e aterosclerose em camundongos ApoE-/- and ApoE/IDO/double-knockout. Metodologia: Foi avaliada a presença de anticorpos anti-p2C7 em amostras de plasma humano de indivíduos com ou sem síndrome metabólica. Realizamos a determinação de TNF circulante nas mesmas amostras e prosseguimos com regressões lineares associando os parâmetros inflamatórios com os níveis de anticorpos anti-p2C7. Camundongos C57BL/6 LDLr -/- foram imunizados com p2C7 e os adjuvantes Alum ou Montanide ISA 720, analisando-se os títulos de anticorpos contra p2C7 e LDL (-), a produção de citocinas (IL-10, IL-4, IL-2, IL-6, IFNγ, IL-17, TNFα) e células secretoras de anticorpos. Camundongos C57BL/6 LDLr -/- foram tolerizados contra os peptídeos mimotopos, com injeções intravenosas (veia caudal) e desafiados com a imunização contendo LDL (-) + Alum. Avaliou-se os títulos de anticorpos contra p2C7 e LDL (-) e a produção de citocinas (TNF-α, IFNγ, IL-12, IL-6, IL-10 e MCP-1). Os camundongos foram mantidos em dieta hipercolesterolêmica por 3 meses para formação da placa aterosclerótica. Após este período, os camundongos foram eutanasiados, avaliando-se a formação de placa aterosclerótica na artéria abdominal e arco aórtico, assim como a produção de citocinas (TNF-α, IFNγ, IL-12, IL-6, IL-10 e MCP-1). Camundongos C57BL/6 LDLr -/- foram imunizados com OVA-p2C7 e, após dieta hipercolesterolêmica de 3 meses para formação de placa aterosclerótica, foram avaliados os parâmetros inflamatórios e avaliada a captação de 18F-FDG no arco aórtico através de PET/CT. Resultados: A imunização com o p2C7 (livre) não foi capaz de induzir resposta humoral, não se observando títulos detectáveis de anticorpos reativos à p2C7 ou LDL (-) em nenhum camundongo imunizado, assim como não foram detectadas células secretoras de anticorpos específicos para a LDL (-). O grupo imunizado com Alum ou Montanide + p2C7 teve aumento significativo na produção de TNF- quando comparado com os demais grupos. O protocolo de tolerização foi realizado com sucesso, visto que os camundongos tolerizados apresentaram títulos de anticorpos inferiores aos controles para o epítopo utilizado. Apenas os camundongos tolerizados com o p2C7 apresentaram aumento significativo na produção de IL-6, IL-12, IL-10, TNF-α, IFNγ e MCP 1 após dieta hipercolesterolêmica. A imunização ativa com OVA-p2C7 foi capaz de reduzir a produção de TNF induzida pela dieta hipercolesterolêmica, assim como reduzir a captação de 18F-FDG. Conclusão: o epítopo p2C7 é altamente expresso na LDL (-) de pacientes com maior risco cardiovascular. Além disso, a imunização ativa com p2C7 também se mostra uma ferramenta promissora para prevenir e regular a inflamação causada pela LDL (-) no curso da aterosclerose

Introduction: Atherosclerosis is a chronic inflammatory disease resulting from changes in the wall of medium and large-caliber arteries and associated with several risk factors, among which hyperlipidemias stand out, ie, the increase in plasma lipoproteins, but also other comorbidities, such as Metabolic Syndrome. Among the lipoproteins, low-density lipoprotein (LDL) is of great relevance in atherosclerosis. Different isoforms of modified LDL (LDLm) are originated through lipolysis, glycation and proteolysis, in addition to oxidation, varying in density and electronegativity, being better called electronegative LDL [LDL (-)]. Considering the conformational differences between the ApoB-100 structure of native LDL and LDL (-), in an initial study, our group developed a monoclonal antibody (2C7) from the immunization of Balb/c mice with human LDL (-). In a next step, the epitope recognized by the anti-LDL monoclonal antibody (-) was mapped using phage display. The binding peptide of anti-LDL monoclonal antibodies (-) was named p2C7. This peptide does not represent linear sequence regions of human ApoB-100, but conformational microdomains of LDL (-) ApoB-100 epitopes, making them candidates for the immunomodulation of atherogenesis. Therefore, investigating the immunomodulation induced by p2C7 peptide mimetics of LDL (-) as it represents an immunodominant epitope of LDL (-) could open new future therapeutic perspectives for the immunomodulation of atherosclerosis. Objective: To evaluate the immunomodulation promoted by p2C7 in vivo, using C57BL/6 LDLr -/- mice, and human plasma samples. In addition, in the internship (BEPE), held at the Karolinska Institute (December 2019 to March 2021), immunometabolism as a mediator of Cardiovascular Diseases was studied. In part II-A, the results of the initially proposed study are described. In part II-B, the results that were developed later are presented, expanding the scope of the project, approaching the vascular inflammation involved in the abdominal aortic aneurysm through bioinformatics tools. In part II-C, the results of the study of the involvement of the enzyme indoleamine 2,3 dioxygenase (IDO) in non-alcoholic steatohepatitis (NASH) and atherosclerosis in ApoE-/- and ApoE/IDO/double mice are presented -knockout. Methodology: The presence of anti-p2C7 antibodies in human plasma samples with or without Metabolic Syndrome was evaluated. We measured circulating TNF in the same samples and proceeded with linear regressions associating inflammatory parameters with levels of anti-p2C7 antibodies. C57BL/6 LDLr -/- mice were immunized with p2C7 and the adjuvants Alum or Montanide ISA 720, analyzing the antibody titers against p2C7 and LDL (-), the production of cytokines (IL-10, IL-4, IL -2, IL-6, IFNγ, IL-17, TNFα) and antibody-secreting cells. C57BL/6 LDLr -/- mice were tolerized against mimotope peptides with intravenous injections (caudal vein) and challenged with immunization containing LDL (-) + Alum. Antibody titers against p2C7 and LDL (-) and cytokine production (TNF-α, IFNγ, IL-12, IL-6, IL-10 and MCP-1) were evaluated. The mice were kept on a hypercholesterolemic diet for 3 months for atherosclerotic plaque formation. After this period, the mice were euthanized, evaluating the formation of atherosclerotic plaque in the abdominal artery and aortic arch, as well as the production of cytokines (TNF-α, IFNγ, IL-12, IL-6, IL-10 and MCP -1). C57BL/6 LDLr -/- mice were immunized with OVA-p2C7 and, after a 3-month hypercholesterolemic diet for atherosclerotic plaque formation, inflammatory parameters were evaluated and 18F-FDG uptake was evaluated by PET/CT. Results: Immunization with p2C7 (free) was not able to induce a humoral response, with no detectable titers of antibodies reactive to p2C7 or LDL (-) being observed in any immunized mouse, as well as no detectable antibody-secreting cells for the LDL (-). The group immunized with Alum or Montanide + p2C7 had a significant increase in TNF-α production when compared to the other groups. The tolerance protocol was successfully performed, as the tolerized mice had lower antibody titers than controls for the epitope used. Only mice tolerated with p2C7 showed a significant increase in the production of IL-6, IL-12, IL-10, TNF-α, IFNγ and MCP 1 after a hypercholesterolemic diet. Active immunization with OVA-p2C7 was able to reduce TNF production induced by the hypercholesterolemic diet, as well as to reduce 18F-FDG uptake. Conclusion: the p2C7 epitope is highly expressed in LDL (-) of patients with higher cardiovascular risk. Furthermore, active immunization with p2C7 is also a promising tool to prevent and regulate inflammation caused by LDL (-) in the course of atherosclerosis

High aneurysm wall enhancement values are associated with late sac shrinkage after endovascular repair of abdominal aortic aneurysms.

ABSTRACT: To analyze the correlation between aneurysm wall enhancement (AWE) values and early and late sac shrinkage after endovascular aneurysm repair (EVAR).We retrospectively analyzed 28 patients who underwent EVAR for abdominal aortic aneurysms (AAA) using a bifurcated main body stent graft. The value of AWE in the slice of the maximum AAA diameter was measured using a volumetric analysis of computed tomography images. Sac measurements before EVAR and more than 10 months after EVAR were compared, and the maximum sac shrinkage rate was calculated.The AWE value immediately after (4 to 7 days) EVAR correlated positively with the sac shrinkage rate (R2 = 0.0139). The AWE value at 6 months after EVAR was also strongly correlated with the sac shrinkage rate (R2 = 0.4982).Higher AWE values at 6 months after EVAR were strongly associated with the sac volume shrinkage rate. High AWE values may be a predictive factor for sac shrinkage and may aid in the selection of the appropriate clinical strategy after EVAR.

Treatment Strategy of Endovascular versus Open Repair for Ruptured Abdominal Aortic Aneurysm Based on the Fitzgerald Classification.

BACKGROUND: The Fitzgerald classification expresses the extension of hematoma from the ruptured abdominal aortic aneurysm (rAAA) and is related to a patient's preoperative status. The objective of this study was to propose a new decision-making method for emergency surgeries, endovascular aortic repair (EVAR), or open repair (OR) for rAAA based on the Fitzgerald classification using preoperative computed tomography images. MATERIALS AND METHODS: A multicenter observational study was performed with a questionnaire survey of rAAA from August 2010 to July 2015 in Hokkaido, Japan, and sent to 20 institutions participating in the Hokkaido Society of Aortic Stent Graft. We included 205 patients who could be stratified by the Fitzgerald classification as the subjects of this study. We categorized these patients into Fitzgerald classes I and II (first category, n = 72) and classes III and IV (second category, n = 133). The short-term results of both EVAR and OR cases were examined in the 2 categories. RESULTS: In the first category, patients in the EVAR group were older than those in the OR group. Nonetheless, the in-hospital mortality rate was lower in the EVAR group than in the OR group (0% vs. 18%; P = 0.019). In the second category, there was no difference in preoperative factors between the groups. The EVAR group showed a higher incidence rate of postoperative abdominal compartment syndrome than the OR group (12% vs. 2%; P = 0.042). The in-hospital mortality rate was comparable between the groups (24% vs. 25%; P = 0.80). Although there were no deaths in the EVAR group without preoperative shock, in-hospital mortality in the EVAR group of the second category with shock was 41% (vs. 28% in the OR group; P = 0.27). Furthermore, mortality in the EVAR group with Fitzgerald class IV was 100% (vs. 29% in the OR group; P = 0.049). CONCLUSIONS: EVAR is recommended in Fitzgerald class I or II and also in Fitzgerald class III or IV without shock because the results of EVAR were better than those of OR. Because all patients who underwent EVAR died in Fitzgerald class IV, OR would be beneficial in this patient population.

A Comparative Classification Analysis of Abdominal Aortic Aneurysms by Machine Learning Algorithms.

The objective of this work was to perform image-based classification of abdominal aortic aneurysms (AAA) based on their demographic, geometric, and biomechanical attributes. We retrospectively reviewed existing demographics and abdominal computed tomography angiography images of 100 asymptomatic and 50 symptomatic AAA patients who received an elective or emergent repair, respectively, within 1-6 months of their last follow up. An in-house script developed within the MATLAB computational platform was used to segment the clinical images, calculate 53 descriptors of AAA geometry, and generate volume meshes suitable for finite element analysis (FEA). Using a third party FEA solver, four biomechanical markers were calculated from the wall stress distributions. Eight machine learning algorithms (MLA) were used to develop classification models based on the discriminatory potential of the demographic, geometric, and biomechanical variables. The overall classification performance of the algorithms was assessed by the accuracy, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and precision of their predictions. The generalized additive model (GAM) was found to have the highest accuracy (87%), AUC (89%), and sensitivity (78%), and the third highest specificity (92%), in classifying the individual AAA as either asymptomatic or symptomatic. The k-nearest neighbor classifier yielded the highest specificity (96%). GAM used seven markers (six geometric and one biomechanical) to develop the classifier. The maximum transverse dimension, the average wall thickness at the maximum diameter, and the spatially averaged wall stress were found to be the most influential markers in the classification analysis. A second classification analysis revealed that using maximum diameter alone results in a lower accuracy (79%) than using GAM with seven geometric and biomechanical markers. We infer from these results that biomechanical and geometric measures by themselves are not sufficient to discriminate adequately between population samples of asymptomatic and symptomatic AAA, whereas MLA offer a statistical approach to stratification of rupture risk by combining demographic, geometric, and biomechanical attributes of patient-specific AAA.

Automatic Segmentation, Detection, and Diagnosis of Abdominal Aortic Aneurysm (AAA) Using Convolutional Neural Networks and Hough Circles Algorithm.

PURPOSE: An abdominal aortic aneurysm (AAA) is known as a cardiovascular disease involving localized deformation (swelling or enlargement) of aorta occurring between the renal and iliac arteries. AAA would jeopardize patients' lives due to its rupturing risk, so prompt recognition and diagnosis of this disorder is vital. Although computed tomography angiography (CTA) is the preferred imaging modality used by radiologist for diagnosing AAA, computed tomography (CT) images can be used too. In the recent decade, there has been several methods suggested by experts in order to find a precise automated way to diagnose AAA without human intervention base on CT and CTA images. Despite great approaches in some methods, most of them need human intervention and they are not fully automated. Also, the error rate needs to decrease in other methods. Therefore, finding a novel fully automated with lower error rate algorithm using CTA and CT images for Abdominal region segmentation, AAA detection, and disease severity classification is the main goal of this paper. METHODS: The proposed method in this article will be performed in three steps: (1) designing a classifier based on Convolutional Neural Network (CNN) for classifying different parts of abdominal into four different classes such as: abdominal inside region, aorta, body border, and bone. (2) After correct aorta detection, defining its edge and measuring its diameter with the use of Hough Circle Algorithm (which is an algorithm for finding an arbitrary shape in images and measuring its diameter in pixel) is the second step. (3) Ultimately, the detected aorta, depending on its diameter, will be categorized in one of these groups: (a) there is no risk of AAA, (b) there is a medium risk of AAA, and (c) there is a high risk of AAA. RESULTS: The designed CNN classifier classifies different parts of abdominal into four different classes such as: abdominal inside region, aorta, body border, and bone with the accuracy, precision, and sensitivity of 97.93, 97.94, and 97.93% respectively. The accuracy of the proposed classifier for aorta region detection is 98.62% and Hough Circles algorithm can classify 120 aorta patches according to their diameter with accuracy of 98.33%. CONCLUSIONS: As a whole, a classifier using Convolutional Neural Network is designed and applied in order to detect AAA region among other abdominal regions. Then Hough Circles algorithm is applied to aorta patches for finding aorta border and measuring its diameter. Ultimately, the detected aortas will be categorized according to their diameters. All steps meet the expected results.

Financial implications of coding inaccuracies in patients undergoing elective endovascular abdominal aortic aneurysm repair.

OBJECTIVE: Previous cost analyses have found small to negative margins between hospitalization cost and reimbursement for endovascular aneurysm repair (EVAR). Hospitals obtain reimbursement on the basis of Medicare Severity Diagnosis Related Group (MS-DRG) coding to distinguish patient encounters with or without major comorbidity or complication (MCC). This study's objective was to evaluate coding accuracy and its effect on hospital cost for patients undergoing EVAR. METHODS: A retrospective, single university hospital review of all elective, infrarenal EVARs performed from 2010 to 2015 was completed. Index procedure hospitalizations were reviewed for MS-DRG classification, comorbidities, complications, length of stay (LOS), and hospitalization cost. Patients' comorbidities and postoperative complications were tabulated to verify accuracy of MS-DRG classification. Misclassified patients were audited and reclassified as "standard" or "complex" on the basis of a corrected MS-DRG: standard for 238 (major cardiovascular procedure without MCC) and complex for 237 (major cardiovascular procedure with MCC). RESULTS: There were 104 EVARs identified, including 91 standard (original MS-DRG 238, n = 85; MS-DRG 254, n = 6) and 13 complex hospitalizations (original MS-DRG 237, n = 9; MS-DRG 238, n = 3; MS-DRG 253, n = 1). On review, 3% (n = 3) of the originally assigned MS-DRG 238 patients were undercoded while actually meeting MCC criteria for a 237 designation. Hospitalizations coded with MS-DRG 253 and 254 were considered billing errors because MS-DRG 237 and 238 are more appropriate and specific classifications as major cardiovascular procedures. Overall, there was a 9.6% miscoding rate (n = 10), representing a total lost billing opportunity of $587,799. Mean LOS for standard and complex hospitalizations was 3.0 ± 1.5 days vs 7.8 ± 6.0 days (P < .001), with respective intensive care unit LOS of 0.4 ± 0.7 day vs 2.6 ± 3.1 days (P < .001). Postoperative complications occurred in 23% of patients; however, not all met the Centers for Medicare and Medicaid Services criteria as MCC. Miscoded complexity was found to be due to postoperative events in all patients rather than to missed comorbidities. Mean hospitalization cost for standard and complex patients was $28,833 ± $5597 vs $41,543 ± $12,943 (P < .001). Based on institutional reimbursement data, this translates to a mean loss of $5407 per correctly coded patient. Miscoded patients represent an additional overall reimbursement loss of $140,102. CONCLUSIONS: Our study reveals a large lost billing opportunity with miscoding of elective EVARs from 2010 to 2015, with errors in categorization of the procedure as well as miscoding of complexity. The revenue impact is potentially significant in this population, and additional reviews of coding practices should be considered.

Performance of current claims-based approaches to identify aortic dissection hospitalizations.

OBJECTIVE: To describe index visits for acute aortic dissection (AD) to an academic center and validate the prevailing claims-based methodology to identify and stratify them. METHODS: Inpatient hospitalizations at a single center assigned an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for AD from January 2005 to September 2015 were identified. Diagnoses were verified by review of medical records and imaging studies. All visits were secondarily stratified with the algorithm based on ICD-9 codes. Sensitivity and specificity analyses were conducted to evaluate the ability of the algorithm to correctly identify acute AD by Stanford class and treatment modality (type A open repair [TAOR], type B open repair [TBOR], thoracic endovascular repair [TEVAR], medical management [MM]). RESULTS: In the study interval, there were 1245 visits coded for AD attributed to 968 unique patients. Chart review verification demonstrated that the majority of visits were for AD (79%; n = 981), of which 32% (n = 310) were for an index acute AD event. The true distribution of acute AD visit classifications was TAOR (46.1%; n = 143), TBOR (5.2%; n = 16), TEVAR (7.7%; n = 24), and MM (39.4%; n = 122). The algorithm, which used ICD-9 codes, identified 631 acute visits and stratified them as TAOR (27.1%; n = 171), TBOR (4.1%; n = 26), TEVAR (4.9%; n = 31), and MM (63.9%; n = 403). Analyses demonstrated high specificities, but generally low sensitivities of the algorithm (TAOR: sensitivity, 58%, specificity, 92%; TBOR: sensitivity, 13%, specificity, 98%; TEVAR: sensitivity, 17%, specificity, 98%; MM: sensitivity, 73%, specificity, 72%). CONCLUSIONS: The prevalent claims-based strategy to identify hospitalizations with acute AD is specific, but lacks sensitivity. Caution should be exercised when studying AD with ICD-9 codes and improvements to existing claims-based methodologies are necessary to support future study of acute AD.

Early Outcomes After Branched and Fenestrated Endovascular Aortic Repair in Octogenarians.

AIM: To compare early outcome after complex endovascular aortic repair in octogenarians (age ≥ 80 years) versus non-octogenarians (age < 80 years) treated with fenestrated or branched stent grafts. METHODS: Single centre retrospective analysis from a prospectively collected database of all patients undergoing repair with fenestrated or branched stent grafts for para/suprarenal aortic aneurysm, type Ia endoleak after previous endovascular aortic repair, and thoraco-abdominal aortic aneurysm between January 2015 and December 2017. Early all cause mortality, major adverse events, and need for re-intervention were analysed for non-octogenarians (age < 80 years) and octogenarians (age ≥ 80 years) at the time of repair. RESULTS: 207 patients (58 [28%] females) with a median age of 73 years (IQR 68-78) underwent repair with fenestrated or branched stent grafts. There were 169 (81%) non-octogenarians with a median age of 72 years (IQR 65-76) and 38 (19%) octogenarians with a median age of 82 years (IQR 81-84). The number of patients with chronic kidney disease was significantly higher in the octogenarians (63 [37%] vs. 22 [58%], p = .03]. Nineteen patients (9%) died. The early mortality rate was higher in the octogenarians (12 [7%] vs. 7 [18%], p = .06]. Mortality rate was 4% (6/148) for elective and 22% (13/59) for urgently treated patients. Similar rates of post-operative sepsis, stroke, respiratory problems, need for dialysis, and spinal cord injury were found in both groups. Two patients in each group had early stent graft related re-interventions. The octogenarian group had increased post-operative creatinine values (1.0 [0.8-1.4] vs. 1.4 [1.0-1.9], p = .01). After multiple logistic regression, ASA class ≥4 and rupture were independent factors of early all cause mortality. CONCLUSIONS: Complex endovascular repair in octogenarians has higher early all cause mortality compared with non-octogenarians. Rupture and higher ASA class of ≥4 are independent predictors for early mortality. Age ≥80 years was found to be an independent predictor for higher early all cause mortality.

Decision Tree Based Classification of Abdominal Aortic Aneurysms Using Geometry Quantification Measures.

Abdominal aortic aneurysm (AAA) is an asymptomatic aortic disease with a survival rate of 20% after rupture. It is a vascular degenerative condition different from occlusive arterial diseases. The size of the aneurysm is the most important determining factor in its clinical management. However, other measures of the AAA geometry that are currently not used clinically may also influence its rupture risk. With this in mind, the objectives of this work are to develop an algorithm to calculate the AAA wall thickness and abdominal aortic diameter at planes orthogonal to the vessel centerline, and to quantify the effect of geometric indices derived from this algorithm on the overall classification accuracy of AAA based on whether they were electively or emergently repaired. Such quantification was performed based on a retrospective review of existing medical records of 150 AAA patients (75 electively repaired and 75 emergently repaired). Using an algorithm implemented within the MATLAB computing environment, 10 diameter- and wall thickness-related indices had a significant difference in their means when calculated relative to the AAA centerline compared to calculating them relative to the medial axis. Of these 10 indices, nine were wall thickness-related while the remaining one was the maximum diameter (Dmax). Dmax calculated with respect to the medial axis is over-estimated for both electively and emergently repaired AAA compared to its counterpart with respect to the centerline. C5.0 decision trees, a machine learning classification algorithm implemented in the R environment, were used to construct a statistical classifier. The decision trees were built by splitting the data into 70% for training and 30% for testing, and the properties of the classifier were estimated based on 1000 random combinations of the 70/30 data split. The ensuing model had average and maximum classification accuracies of 81.0 and 95.6%, respectively, and revealed that the three most significant indices in classifying AAA are, in order of importance: AAA centerline length, L2-norm of the Gaussian curvature, and AAA wall surface area. Therefore, we infer that the aforementioned three geometric indices could be used in a clinical setting to assess the risk of AAA rupture by means of a decision tree classifier. This work provides support for calculating cross-sectional diameters and wall thicknesses relative to the AAA centerline and using size and surface curvature based indices in classification studies of AAA.

Estudio de selección de microRNA como posibles biomarcadores de aneurisma de aorta abdominal / Screening of microRNAs as possible biomarkers in abdominal aortic aneurysm

Introducción: Los microRNA (miR) son RNA de pequeño tamaño involucrados en la regulación de numerosos procesos biológicos. Debido a su estabilidad y a su capacidad para detectarse en fluidos, se han convertido en objeto de estudio como posibles biomarcadores de diferentes patologías. Objetivo: Seleccionar un número reducido de miR candidatos a ser biomarcadores de aneurisma de aorta abdominal (AAA). Material y métodos: Se determinó la expresión de 179 miR en el plasma de 7 pacientes y 7 voluntarios sanos, mediante paneles prediseñados, basados en la tecnología de RT-qPCR. Resultados: Hemos seleccionado 10 miR disregulados en pacientes como buenos candidatos para su estudio como biomarcadores debido a su implicación en diversos procesos biológicos relacionados con el desarrollo y evolución de AAA. Conclusiones: Aunque son necesarios estudios adicionales y de validación, algunos de estos miR podrían ser biomarcadores no invasivos de AAA (AU)

Introduction: MicroRNAs (miRs) are small RNA molecules that are involved in several biological processes. Due to their stability and their presence in biological fluids, several studies over the last few years have focused on the use of miRs as biomarkers of different pathologies. Objective: Selection of a group of miRs candidates to be validated as potential biomarkers of abdominal aortic aneurysm (AAA). Material and methods: A total of 179 miRs were quantified in 7 patients with AAA and in 7 healthy donors, using predesigned panels based on RT-qPCR technology. Results: A total of 10 miRs, dysregulated in patients, were selected as good candidates for studying them as biomarkers. It has been observed that most of these miRs participate in several biological processes related to the formation and development of AAAs. Conclusion: Additional, as well as validation, studies are needed, but some of these miRs could be non-invasive AAA biomarkers (AU)

Morphologic characteristics and endovascular treatment of primary infrarenal aortic dissections.

OBJECTIVE: We report the morphologic characteristics and endovascular treatment of primary infrarenal aortic dissections (PIRADs). METHODS: A retrospective study was conducted with 38 consecutive PIRAD patients between January 2010 and May 2016 in our vascular center. Patient demographics, morphologic characteristics, endovascular modalities, and periprocedural and follow-up outcomes were recorded. Patients with symptomatic PIRADs or asymptomatic PIRADs of a maximum diameter >30 mm were indicated for endovascular aneurysm repair (EVAR). We proposed a morphologic categorization of PIRADs into two types (I and II) according to the location of the entry tears and an endovascular strategy for treating type I PIRADs with tubular stent grafts (SGs) and type II PIRADs with bifurcated SGs. RESULTS: According to the categorization, the study recruited 13 patients with type I and 25 patients with type II PIRADs. The patients were predominantly men, with an average age of 60.8 ± 15.2 years. Type I PIRADs usually had larger true lumens (22.6 ± 6.3 vs 13.6 ± 4.0 mm; P = .002) and relatively smaller false lumens (8.4 ± 2.3 vs 19.9 ± 16.1 mm; P = .012). Type II PIRADs had more entry tears (2.2 ± 0.6 vs 1.7 ± 0.6; P = .024) and longer dissections (109.4 ± 38.8 vs 73.9 ± 39.0 mm; P = .011). All patients underwent EVAR, with 19 tubular and 22 bifurcated SGs. One patient died during the hospital stay. The technical success rate was 94.8% (36/38), and the clinical success rate was 97.4% (37/38). During follow-up of 36 patients for 28.8 ± 17.7 months, 2 patients with type II PIRADs developed left iliac extension occlusion at 3 and 6 months after EVAR, and only 1 patient underwent reintervention. All patients survived throughout the follow-up. No endoleak or aortic enlargement was observed. Computed tomography angiography demonstrated a patent infrarenal aorta with completely thrombosed false lumen in all PIRAD patients (36/36 [100.0%]). In both types of PIRAD, EVAR yielded a significant decrease in the maximum diameter of the infrarenal aorta, with a significant increase in the true lumen size and a significant decrease in the false lumen size (P < .05). CONCLUSIONS: The morphologic categorization of PIRADs based on the location of the entry tears appeared to be feasible. The endovascular strategy was safe and effective, with high rates of technical success and clinical success and favorable follow-up outcomes.

Overview of aortic aneurysm management in the endovascular era.

Management of aortic aneurysm disease has changed in the endovascular era, with the majority of patients opting for stent-graft repair of abdominal and thoracic aneurysms. An understanding of this vascular condition is important for primary care, emergency medicine, medicine specialists, and vascular surgeons alike. Awareness of the patient risk factors for aneurysmal degeneration, sac rupture, and medical management allows physicians to screen appropriate patient populations, which decreases aneurysm-related mortality due to rupture. The evolving endovascular techniques available today have made more patients eligible for this less-invasive repair, which has lower mortality and morbidity compared with open surgery with aorta replacement. This review provides contemporary information on the etiology, natural history, evaluation, and management of aortic aneurysm disease. The complications of prior aortic repair, whether performed via endovascular or open surgery intervention, are equally important to understanding not only for vascular surgeons performing these procedures, but also for primary care, emergency department, and medicine specialists who are evaluating these patients in an office or hospital setting.

Surgical treatment of abdominal aortic aneurysms in infancy and early childhood.

OBJECTIVE: Pediatric abdominal aortic aneurysms (AAAs) are rare. The intent of this report was to review the presentation and surgical management of AAAs in infancy and early childhood. METHODS: The clinical courses of young children undergoing AAA surgery were subjected to a retrospective review and analysis. RESULTS: Eleven children, nine boys and two girls, ranging in age from 2 weeks to 6 years, underwent surgical treatment of AAA at the University of Michigan from 2002 to 2014. Aneurysms were supraceliac (2), suprarenal (2), pararenal (2), or infrarenal (5). Associated iliac aneurysms (3) affected two children. Concomitant stenoses affected the renal (14), superior mesenteric (4), and celiac (3) arteries. AAAs were attributed to developmental defects (7), including three arising immediately beyond aortic narrowings; infection after umbilical artery catheterization (2); tuberous sclerosis (1); and trauma (1). Primary operative interventions included aneurysmectomy with a thoracoabdominal bypass (4), open aneurysmorrhaphy (2), closed aneurysmorrhaphy (2), and aneurysmectomy with an infrarenal aortoaortic bypass (1) or an aortoiliac bypass (2). Perioperative death occurred in one child who had preoperative heart and renal failure. Aortic graft occlusion affected two children at 1 month and 3 years postoperatively. The remaining children incurred no aortic reconstruction-related morbidity. Follow-up among the 10 survivors averaged 4.9 years. CONCLUSIONS: Successful surgical treatment of AAAs in infants and young children requires careful execution of a diverse group of surgical techniques based on the etiology, the child's size and growth potential, and the aneurysm's location and coexisting branch involvement.

Automatic Classification of Ultrasound Screening Examinations of the Abdominal Aorta.

Our work facilitates the identification of veterans who may be at risk for abdominal aortic aneurysms (AAA) based on the 2007 mandate to screen all veteran patients that meet the screening criteria. The main research objective is to automatically index three clinical conditions: pertinent negative AAA, pertinent positive AAA, and visually unacceptable image exams. We developed and evaluated a ConText-based algorithm with the GATE (General Architecture for Text Engineering) development system to automatically classify 1402 ultrasound radiology reports for AAA screening. Using the results from JAPE (Java Annotation Pattern Engine) transducer rules, we developed a feature vector to classify the radiology reports with a decision table classifier. We found that ConText performed optimally on precision and recall for pertinent negative (0.99 (0.98-0.99), 0.99 (0.99-1.00)) and pertinent positive AAA detection (0.98 (0.95-1.00), 0.97 (0.92-1.00)), and respectably for determination of non-diagnostic image studies (0.85 (0.77-0.91), 0.96 (0.91-0.99)). In addition, our algorithm can determine the AAA size measurements for further characterization of abnormality. We developed and evaluated a regular expression based algorithm using GATE for determining the three contextual conditions: pertinent negative, pertinent positive, and non-diagnostic from radiology reports obtained for evaluating the presence or absence of abdominal aortic aneurysm. ConText performed very well at identifying the contextual features. Our study also discovered contextual trigger terms to detect sub-standard ultrasound image quality. Limitations of performance included unknown dictionary terms, complex sentences, and vague findings that were difficult to classify and properly code.

Computational Biomechanics in Thoracic Aortic Dissection: Today's Approaches and Tomorrow's Opportunities.

Dissection of an artery is characterised by the separation of the layers of the arterial wall causing blood to flow within the wall. The incidence rates of thoracic aortic dissection (AoD) are increasing, despite falls in virtually all other manifestations of cardiovascular disease, including abdominal aortic aneurysm (AAA). Dissections involving the ascending aorta (Type A) are a medical emergency and require urgent surgical repair. However, dissections of the descending aorta (Type B) are less lethal and require different clinical management whereby the patient may not be offered surgery unless complicating factors are present. But how do we tell if a patient will develop a complication later on? Currently, there is no consensus and the evidence base is limited. There is an opportunity for computational biomechanics to help clinicians decide as to which cases to repair and which to manage with blood pressure control. In this review article, we look at AoD from both the clinical and biomechanical perspective and discuss some of the recent computational studies of both Type A and B AoD. We then focus more on Type B where the real opportunity for patient-specific modelling exists. Finally, we look ahead at some of the promising areas of research that may help clinicians improve the decision-making process surrounding Type B AoD.

[A juxtarenal aneurysm: definition, classification, diagnosis and treatment].

An abdominal aortic aneurysm is one of the most severe manifestations of atherosclerosis, and their number has a steady tendency to increase. Due to the most complicated surgical technique, from infrarenal aneurysms a group of juxtarenal aneurysms was singled out. The presented herein review of the literature is a generalization of the currently existing data of foreign and Russian literature concerning the definition, classification, diagnosis and treatment of juxtarenal aneurysms of the abdominal aorta. Formulated and outlined herein are present-day approaches to treatment of juxtarenal aneurysms.

Results of complex aortic stent grafting of abdominal aortic aneurysms stratified according to the proximal landing zone using the Society for Vascular Surgery classification.

BACKGROUND: Advances in endovascular technology have led to the successful treatment of complex abdominal aortic aneurysms. However, there is currently no consensus on what constitutes a juxtarenal, pararenal, or suprarenal aneurysm. There is emerging evidence that the extent of the aneurysm repair is associated with outcome. We compare the outcomes of 150 consecutive patients treated with a fenestrated or branched stent graft and present the data stratified according to the Society for Vascular Surgery classification based on proximal anatomic landing zones. METHODS: A prospectively collected database of consecutive patients undergoing fenestrated or branched stent graft insertion in a tertiary center between 2008 and 2013 was retrospectively analyzed. Aneurysms were subdivided into zones according to where the area of proximal seal could be achieved in relation to the visceral arteries. Zone 8 covers the renal arteries, zone 7 covers the superior mesenteric artery, and zone 6 covers the celiac axis. Patient demographics, operative variables, mortality, and major morbidity were analyzed by univariate and multivariate analysis to assess for differences between zones. RESULTS: During the study period, 150 patients were treated. There were 49 in zone 8, 76 in zone 7, and 25 in zone 6. Prior aortic surgery had been performed in 19 patients, which included 11 patients with previous endovascular aneurysm repairs. There was significantly increased blood loss (P < .001), operative time (P < .0001), total hospital stay (P = .018), and intensive care unit stay (P < .0001) as the zones ascended the aorta. There were 14 inpatient deaths recorded across all zones with a 30-day mortality rate of 8%. Logistic regression analysis for 30 day mortality showed a significant increase as the zones ascended (P = .007). Kaplan-Meier analysis showed that 5-year survival significantly deteriorated as the zones ascended (P = .039), with no significant difference in the freedom from reintervention curves between zones (P = .37). CONCLUSIONS: We have shown that the extent of the aneurysm repair as determined by the proximal sealing zone is associated with outcome. Mortality, operative duration, blood loss, and hospital stay all significantly increased as the zones ascended. These data also validate the use of the proposed new classification based on aortic anatomy.

Performance of the Endurant stent graft in challenging anatomy.

OBJECTIVE: This study aimed to compare perioperative and postoperative outcomes after endovascular repair of abdominal aortic aneurysms (AAAs) in patients with various neck morphologic features. METHODS: Data from the Endurant Stent Graft Natural Selection Global Postmarket Registry (ENGAGE) were used for the analyses. Patients were categorized into three different groups according to proximal aortic neck anatomy: regular (REG), intermediate (INT), and challenging (CHA). REG was defined as AAAs with a proximal neck ≥15 mm combined with a suprarenal angulation (α) ≤45 degrees and an infrarenal neck angulation (ß) ≤60 degrees. INT was defined as AAAs with a proximal neck of 10 to 15 mm combined with α ≤45 degrees and ß ≤60 degrees or with a proximal neck of >15 mm combined with α ≤60 degrees and ß = 60 to 75 degrees or α = 45 to 60 degrees and ß ≤75 degrees. CHA was defined as infrarenal necks that exceed at least one of the three defining factors. RESULTS: Overall, 925 patients (75.9%) had REG anatomy, 189 patients (15.5%) had INT anatomy, and 104 patients (8.5%) had CHA anatomy. Patient demographics and risk factors were similar. There was a significant difference in AAA diameter between the REG and CHA groups (59.4 mm vs 65.2 mm; P < .001). Technical success was similar among groups (REG 99.1% vs INT 99.5% vs CHA 97.1%). There were no differences in mortality or the need for secondary procedures within 30 days or at 1 year. A significantly higher rate of type I endoleaks within 30 days was seen in CHA compared with REG (adjusted odds ratio, 0.15; 95% confidence interval, 0.05-0.46) and INT (adjusted odds ratio, 0.08; 95% confidence interval, 0.01-0.70), but there was no difference at 1-year follow-up. CONCLUSIONS: This real-world, global experience shows promising results and indicates that endovascular AAA repair with the Endurant stent graft (Medtronic Vascular, Santa Rosa, Calif) is safe and effective in patients with challenging aortic neck anatomy. However, long-term follow-up of patients is required to confirm results.