Maximum Abdominal Aortic Aneurysm Research Articles

Abstract 1006: Pathological PERK/ATF4 Activation In Vascular Smooth Muscle Cells Drives Abdominal Aortic Aneurysm Development

Introduction: Abdominal aortic aneurysms (AAA) are characterized by vascular smooth muscle cell (VSMC) apoptosis leading to pathological aortic remodeling. Activation of the endoplasmic reticulum (ER) stress response has been linked to VSMC dysfunction but the driving factors behind ER stress activation and its role on AAA development remains poorly defined. The epigenetic enzyme, MLL1, plays a critical role in establishing cellular phenotype and regulating gene expression. We examine the MLL-mediated epigenetic regulation of the ER stress response in VSMCs during AAA development and establish the ER stress pathways as a novel target in the treatment AAAs. Methods: Single-cell sequencing was conducted on human AAA and control tissue samples. For our murine model, C57BL/6 mice were injected with an AAV encoding a PCSK9 gain-of-function mutation and then fed a saturated fat-enriched diet and infused with AngII (1 μg/kg/min) with or without 4-PBA (20mg/kg/day). Mice with vascular smooth muscle cell-specific knockout of PERK (PERK SMKO ) underwent tamoxifen injection. AAA maximum diameters were quantified and VSMCs were isolated. Eif2a, Atf4 , and Chop gene expression was examined. Apoptosis was quantified by Annexin V staining. Results: Using single-cell RNA sequencing of human aortic tissue, we identified EIF2A, ATF4 , and CHOP were profoundly upregulated in aneurysmal VSMCs as well as two murine AAA models. Mechanistically, TNFα signaling in VSMCs leads to activation of MLL1 which trimethylates histone 3 lysine 4 (H3K4me3) at NF-κB binding sites on the EIF2A and ATF4 gene promoters thereby upregulating the ER stress response and driving VSMC apoptosis. Both In vivo pharmacological inhibition of the PERK/eIF2A/ATF4 ER stress response via 4-PBA injection and vascular smooth muscle depletion of PERK (PERK SMKO ) inhibited AAA formation resulting with in significant reduction in VSMC apoptosis, elastin fragmentation, and inflammatory cytokine infiltration. Conclusions: Taken together, our results identify MLL1-mediated activation of the PERK/eIF2A/ATF4 ER stress response as a critical regulator of VSMC apoptosis in AAA formation and suggest inhibition of ER stress response as a mechanistic target for the management of AAAs.

Postoperative serum mir-28-5p level has predictive value for the prognosis after endovascular abdominal aortic aneurysm repair

BackgroundWe explored the clinical significance of miR-28-5p pre- and post-endovascular abdominal aortic aneurysm repair (EVAR) in abdominal aortic aneurysm (AAA) patients.MethodsSubjects included AAA patients receiving EVAR and non-AAA people without statistical differences from AAA patient in comorbidities/Framingham risk score. Fasting elbow venous blood (4 mL) was collected in the morning of the day of EVAR surgery and in the morning of 3 months post-EVAR. Pre-/post-EVAR serum miR-28-5p expression, AAA maximum diameter alterations, CD3+/CD4+/CD8+/TC/TG pre-/post-EVAR, and the correlations between miR-28-5p and AAA maximum diameter were investigated. Prediction of miR-28-5p on post-EVAR mortality, prognosis, and independent factors of post-EVAR death were analyzed using receiver operating characteristic curve (ROC)/Kaplan-Meier curve/univariable and multivariable Cox regression. According to the cut-off value of ROC curve for postoperative miR-28-5p was the cut-off value, and the patients were classified into the miR-28-5p high- and low-expression groups. The survival or death of both groups were compared after 48-month follow-up.ResultsSerum miR-28-5p levels in AAA patients dropped post-EVAR. AAA patients showed notable differences in CD3+/CD4+/CD8+/TC/TG levels pre-/post-EVAR. The miR-28-5p low-expression group exhibited higher CD3+/CD4+ and lower CD8+/TC/TG levels. We observed a positive correlation between post-EVAR miR-28-5p and AAA maximum diameter and between the pre-/post-EVAR miR-28-5p fold change and the AAA maximum diameter change. Postoperative miR-28-5p demonstrated good predictive value for postoperative death. Hypertension, Framingham risk score, TC, TG, and miR-28-5p were independent influencing factors of post-EVAR death.ConclusionEVAR decreased serum miR-28-5p expression in AAA patients. Post-operative miR-28-5p level and pre-/post-operative fold change level are positively-correlated with AAA diameter.

Midterm outcomes of physician-modified endovascular stent grafts for the treatment of complex abdominal aortic aneurysms in Korea: a retrospective study.

Physician-modified endovascular stent grafts (PMEG) are a good treatment option for complex abdominal aortic aneurysms (AAAs), especially in high-risk patients not amenable to open repair, and when commercial fenestrated devices are not available. We report our single-center experience with PMEG for the treatment of complex AAAs. We retrospectively reviewed patients who underwent PMEG repair for AAA from November 2016 to September 2020 at our institution. Demographic data, anatomic characteristics, perioperative and postoperative outcomes, major adverse events, and 30-day mortality were analyzed. We identified 12 patients who underwent PMEG for complex AAA. The mean age was 74 years and the mean maximal AAA diameter was 58.1 mm. Indications for treatment included 4 impending or contained ruptures, 2 mycotic aneurysms, and 6 symptomatic cases. The technical success rate was 91.7%. Aneurysm sac regression was observed in 7 patients (58.3%), including 2 cases of complete regression. There was 1 aneurysm-related mortality at 3 months due to mycotic aneurysm. Also, there was 1 postoperative complication case of transient renal failure requiring temporary dialysis. At 1 year, there was 1 branch occlusion from the initial failed cannulation case and 2 type 1A endoleaks, and there was 1 case of open explantation. PMEG showed a low technical failure rate and acceptable midterm stent durability and sac stability, comparable to conventional endovascular aneurysm repair. Despite the small number of cases, there was a tendency for a high sac regression rate, although longer follow-up is needed.

Analysis of small abdominal aortic aneurysms with the radiotracer technetium-99m- 6-hydrazinylnicotinoyl-C-C-chemokine receptor-2 ligand (99mTc-HYNIC-CCR2-L) with single-photon emission computed tomography.

Monocyte chemoattractant protein-1 (MCP-1/CCL2) plays a key role for infiltration of monocytes/macrophages and studies have demonstrated that the MCP-1/C-C chemokine receptor 2 (CCR2) axis might be involved in the pathogenesis and progression of abdominal aortic aneurysms (AAA). Molecular imaging has shown potential for human clinical research studies. We evaluated the expression of CCR2 in patients with small AAA using single-photon emission computed tomography (SPECT) with the technetium-99m-6-hydrazinylnicotinoyl-C-C-chemokine receptor-2 ligand (99mTc-HYNIC-CCR2-L). A pilot study was performed to evaluate patients with small asymptomatic AAA. The equipment used was a Symbia T2 (Siemens, Germany), with radiolabeled 99mTc-HYNIC-CCR2-L. The SPECT uptake and activity were assessed and counted based on the region of interest (ROI), with nonparametric statistics being employed to compare the aneurysms site, left ventricle (Control 1) and regions with a nondiseased aorta (Control 2). The three patients were male (100%) (mean age 81 years, and mean AAA maximum diameter of 40 mm, SD 3 mm). All patients tolerated the studies well. Images were obtained at one, two and four hours. The ROI mean value of the aneurysm site was 37,783 (SD 11,890), compared to the left ventricle (Control 1) 16,779 (SD 4397) (p-value = 0.0001); ROI for the nondiseased aortic region (Control 2) was significantly lower, 12,520 (SD 2141) (p-value = 0.0001). Significant differences of CCR2 expression SPECT were found in the AAA site compared to the left ventricle and nondiseased aortic segments. The introduction of well-designed longitudinal studies with nuclear imaging modalities may assist in the molecular characterization of aneurysmal and rupture prediction.

Abstract 12885: Pathological Perk/Atf4 Activation in Abdominal Aortic Aneurysm Formation

Introduction: Abdominal aortic aneurysms (AAA) are characterized by vascular smooth muscle cell (VSMC) apoptosis leading to pathological aortic remodeling. Activation of the endoplasmic reticulum (ER) stress response has been linked to VSMC dysfunction but the driving factors behind ER stress activation and its role on AAA development remains poorly defined. The epigenetic enzyme, MLL1, plays a critical role in establishing cellular phenotype and regulating gene expression. We examine the MLL-mediated epigenetic regulation of the ER stress response in VSMCs during AAA development and establish the ER stress pathways as a novel target in the treatment AAAs. Methods: Single-cell sequencing was conducted on human AAA and control tissue samples. For our murine model, C57BL/6 mice were injected with an AAV encoding a PCSK9 gain-of-function mutation and then fed a saturated fat-enriched diet and infused with AngII (1 μg/kg/min) with or without 4-PBA (20mg/kg/day). The elastase induced AAA model was used as a secondary murine model. AAA maximum diameters were quantified and VSCMs were isolated. Eif2a, Atf4 , and Chop gene expression was examined. Apoptosis was quantified by Annexin V staining. Results: Using single-cell RNA sequencing of human aortic tissue, we identified EIF2A, ATF4 , and CHOP were profoundly upregulated in aneurysmal VSMCs as well as two murine AAA models. Mechanistically, TNFα signaling in VSMCs leads to activation of MLL1 which trimethylates histone 3 lysine 4 (H3K4me3) at NF-κB binding sites on the EIF2A and ATF4 gene promoters thereby upregulating the ER stress response and driving VSMC apoptosis. In vivo pharmacological inhibition of the eIF2A/ATF4 ER stress response via 4-PBA injection inhibited AAA formation in both the AngII-induced and elastase-induced AAA model resulting with in significant reduction in VSMC apoptosis, elastin fragmentation, and inflammatory cytokine infiltration. Conclusions: Taken together, our results identify MLL1-mediated activation of the eIF2A/ATF4 ER stress response as a critical regulator of VSMC apoptosis in AAA formation and suggest inhibition of ER stress response as a mechanistic target for the management of AAAs.

A pilot study to evaluate a novel localized treatment to stabilize small- to medium-sized infrarenal abdominal aortic aneurysms

ObjectiveThere is no proven therapy to reduce growth rates of small- to medium-sized abdominal aortic aneurysms (AAAs). Ex vivo and animal studies have demonstrated that a novel stabilizing agent, 1,2,3,4,6-pentagalloyl glucose (PGG), delivered locally to the aneurysm sac, can bind to elastin and collagen to re-establish strength and resist enzymatic degradation. We aimed to demonstrate that a one-time administration of PGG solution to the aneurysm wall is safe and potentially effective to slow the growth of small- to medium-sized AAAs. MethodsPatients with small- to medium-sized infrarenal AAAs (maximum diameter <5.5 cm) were recruited. Via transfemoral access, a 14F or 16F dual-balloon delivery catheter was introduced into the aneurysm sac. A single, 3-minute, localized endoluminal infusion of PGG was delivered via a ‘weeping’ balloon to the aneurysm wall. Independent core laboratory measurements of maximum aneurysm sac diameter and sac volume measurements based on computed tomography angiography (CTA) were used for assessments at 1, 6, 12, 24, and 36 months. The primary endpoints were technical success and safety (major adverse events at 30 days). The secondary endpoint was growth stabilization, defined as freedom from aneurysm sac enlargement (diameter increase >5 mm per year or volume increase of >10% per year). ResultsTwenty patients (19 male) were enrolled at five centers from May 2019 to June 2022 (mean age, 67.8 years; range, 50-87 years). All procedures were technically successful. The safety profile was consistent with standard interventional procedures. Four patients demonstrated transient elevations of liver enzymes levels that returned to normal by 30 days with no clinical symptoms. Through November 2022, follow-up CTA data is available on the first 11 patients. The average changes in maximum aneurysm diameter from baseline to 6, 12, 24, and 36 months were 0.2 mm, 1.1 mm, 1.2 mm, and 0.8 mm, respectively, and the average changes in volume were 2.0%, 9.6%, 18.1%, and 11.6%, respectively. At 12 months, none of the aneurysms showed growth >5.0 mm, and three had volume growth >10%. ConclusionsThe early results of this first-in-human, small cohort study demonstrated that a single, localized PGG administration to patients with small- to medium-sized infrarenal AAAs is safe. Longer term follow-up on all 20 treated patients is needed to better assess the potential impact on aneurysm growth.

Intermediate Pressure-Normalized Strain Values Are Associated With Increased Abdominal Aortic Aneurysmal Growth Rates

Current abdominal aortic aneurysm (AAA) assessment methods rely on simple morphometric analysis of the AAA diameter and growth rate. However, evidence has shown that AAA pathology varies among patients, and morphometric analysis alone is insufficient to predict individual risk of growth. Biomechanical parameters, such as pressure-normalized aortic wall strain (εp+/PP), can provide a surrogate to vessel wall stiffness. We aimed to use our novel ultrasound elastography (USE) technique to measure ερ+/PP and correlate ερ+/PP with maximal AAA diameter and growth rate in the largest clinical trial to date. Our USE algorithm uses a finite element mesh overlayed on a 2D axial view of the user-defined AAA wall at the point of maximum diameter to track frame-to-frame displacements over a full cardiac cycle to measure ερ+/PP. ερ+/PP and growth rate were assessed between small and large AAAs based on a diameter of ≥5 cm. Patients with AAA were then separated into terciles based on ερ+/PP values of 0.0251 and 0.038 to assess differences in the AAA diameter and growth rate. Mann-Whitney U and Kruskal-Wallis tests were used to assess differences as appropriate. USE analysis was conducted on 127 patients, 16 normal aortas and 111 AAAs. A total of 79 patients had at least one follow-up clinical scan used to calculate growth rate. Of the 111 aortas, 85 were classified as small and 26 as large. AAAs showed lower ερ+/PP (stiffer) compared with nonaneurysmal aortas (0.034 ± 0.017 vs 0.044 ± 0.015 %/kPa; P = .006). There was no difference in ερ+/PP or growth rate between small and large AAAs. When divided into terciles based on ερ+/PP, there was no difference in the AAA diameter. There was a statistically significant difference in growth rate between the intermediate tercile and the outer terciles (1.46 ± 2.48 vs 3.59 ± 3.83 vs 1.78 ± 1.64 mm/y; P = .014) (Fig). Our validated USE algorithm shows that AAAs are stiffer than nonaneurysmal aortas, similar to previous reports. There was no correlation between AAA diameter and ερ+/PP, indicating that AAA stiffness is independent of diameter, and diameter thresholds alone may not accurately assess future risk of growth. AAAs in the intermediate tercile of ερ+/PP values were found to have greater growth rates than the outer tercile, indicating that an intermediate range of ερ+/PP values, regardless of diameter, place patients at increased risk for AAA growth. These findings also suggest that AAA growth may be related to a failure of collagen remodeling and may be the underlying event that leads to AAA rupture.

Contrast-enhanced CT radiomics improves the prediction of abdominal aortic aneurysm progression.

To determine if three-dimensional (3D) radiomic features of contrast-enhanced CT (CECT) images improve prediction of rapid abdominal aortic aneurysm (AAA) growth. This longitudinal cohort study retrospectively analyzed 195 consecutive patients (mean age, 72.4years ± 9.1) with a baseline CECT and a subsequent CT or MR at least 6months later. 3D radiomic features were measured for 3 regions of the AAA, viz. the vessel lumen only; the intraluminal thrombus (ILT) and aortic wall only; and the entire AAA sac (lumen, ILT, and wall). Multiple machine learning (ML) models to predict rapid growth, defined as the upper tercile of observed growth (> 0.25cm/year), were developed using data from 60% of the patients. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) in the remaining 40% of patients. The median AAA maximum diameter was 3.9cm (interquartile range [IQR], 3.3-4.4cm) at baseline and 4.4cm (IQR, 3.7-5.4cm) at the mean follow-up time of 3.2 ± 2.4years (range, 0.5-9years). A logistic regression model using 7 radiomic features of the ILT and wall had the highest AUC (0.83; 95% confidence interval [CI], 0.73-0.88) in the development cohort. In the independent test cohort, this model had a statistically significantly higher AUC than a model including maximum diameter, AAA volume, and relevant clinical factors (AUC = 0.78, 95% CI, 0.67-0.87 vs AUC = 0.69, 95% CI, 0.57-0.79; p = 0.04). A radiomics-based method focused on the ILT and wall improved prediction of rapid AAA growth from CECT imaging. • Radiomic analysis of 195 abdominal CECT revealed that an ML-based model that included textural features of intraluminal thrombus (if present) and aortic wall improved prediction of rapid AAA progression compared to maximum diameter. • Predictive accuracy was higher when radiomic features were obtained from the thrombus and wall as opposed to the entire AAA sac (including lumen), or the lumen alone. • Logistic regression of selected radiomic features yielded similar accuracy to predict rapid AAA progression as random forests or support vector machines.

Aortobifemoral reconstruction in open abdominal aortic aneurysm repair is associated with increased morbidity and mortality

ObjectiveMuch attention has been given to the influence of anatomic and technical factors, such as maximum abdominal aortic aneurysm diameter and proximal clamp position, in open abdominal aortic aneurysm repair (OSR). However, no studies have rigorously examined the correlation between site of distal anastomosis and OSR outcomes despite conventional wisdom that more proximal sites of anastomosis are preferrable when technically feasible. This study aimed to test the association between sites of distal anastomosis and clinical outcomes for patients undergoing primary elective OSR. MethodsOur study included 5683 patients undergoing primary elective OSR at 233 centers from 2014 to 2020. Using a variety of statistical methods to account for potential confounders, including multivariable logistic regression and Cox proportional hazards modeling, as well as subgroup analysis, we examined the association between site of distal anastomosis and clinical outcomes in elective OSR. Primary outcomes were major in-hospital complication rate, 30-day mortality, and long-term survival. ResultsPatients undergoing elective aortobifemoral reconstruction (n = 672) exhibited significantly increased rates of smoking, chronic obstructive pulmonary disease, and peripheral artery disease in comparison to patients undergoing elective OSR with distal anastomosis to the aorta (n = 2298), common iliac artery (n = 2163), or external iliac artery (n = 550). Patients undergoing aorto-aortic tube grafting were significantly less likely to exhibit iliac aneurysmal disease and significantly more likely to be undergoing elective OSR with a suprarenal or supraceliac proximal clamp position. Using multivariable logistic regression and Cox proportional hazards analysis to control for important confounders, such as age, smoking status, and medical history, we found that distal anastomosis to the common femoral artery was associated with increased odds of major in-hospital complications (adjusted odds ratio, 1.79; 95% confidence interval, 1.46-2.18; P < .001) and reduced long-term survival (adjusted hazard ratio, 1.44; 95% confidence interval, 1.09-1.89; P = .010). We observed no significant differences in 30-day mortality across sites of distal anastomosis in our study population. ConclusionsIt is generally accepted that more proximal sites of distal anastomosis should be selected in OSR when technically feasible. Our findings support this hypothesis by demonstrating that distal anastomosis to the common femoral artery is associated with increased perioperative morbidity and reduced long-term survival. Careful diligence regarding optimization of preoperative health status, perioperative care, and long-term follow-up should be applied to mitigate major complications in this patient population.

A Novel Preoperative Risk Assessment Tool to Identify Patients at Risk of Contrast-Associated Acute Kidney Injury After Endovascular Abdominal Aortic Aneurysm Repair

Contrast-associated acute kidney injury (CA-AKI) after endovascular abdominal aortic aneurysm repair (EVAR) is associated with mortality and morbidity. Risk stratification remains a vital component of preoperative evaluation. We sought to generate and validate a preprocedure CA-AKI risk stratification tool for elective EVAR patients. We queried the Blue Cross Blue Shield of Michigan Cardiovascular Consortium database for elective EVAR patients and excluded those on dialysis, with a history of renal transplant, death during procedure, and without creatinine measures. Association with CA-AKI (rise in creatinine > 0.5 mg/dL) was tested using mixed-effects logistic regression. Variables associated with CA-AKI were used to generate a predictive model via a single classification tree. The variables selected by the classification tree were then validated by fitting a mixed-effects logistic regression model into the Vascular Quality Initiative dataset. Our derivation cohort included 7,043 patients, 3.5% of whom developed CA-AKI. After multivariate analysis, age (odds ratio [OR] 1.021, 95% confidence interval [CI] 1.004-1.040), female sex (OR 1.393, CI 1.012-1.916), glomerular filtration rate (GFR) < 30 mL/min (OR 5.068, CI 3.255-7.891), current smoking (OR 1.942, CI 1.067-3.535), chronic obstructive pulmonary disease (OR 1.402, CI 1.066-1.843), maximum abdominal aortic aneurysm (AAA) diameter (OR 1.018, CI 1.006-1.029), and presence of iliac artery aneurysm (OR 1.352, CI 1.007-1.816) were associated with increased odds of CA-AKI. Our risk prediction calculator demonstrated that patients with a GFR < 30 mL/min, females, and patients with a maximum AAA diameter of > 6.9 cm are at a higher risk of CA-AKI after EVAR. Using the Vascular Quality Initiative dataset (N=62,986), we found that GFR < 30 mL/min (OR 4.668, CI 4.007-5.85), female sex (OR 1.352, CI 1.213-1.507), and maximum AAA diameter > 6.9 cm (OR 1.824, CI 1.212-1.506) were associated with an increased risk of CA-AKI after EVAR. Herein, we present a simple and novel risk assessment tool that can be usedpreoperatively to identify patients at risk of CA-AKI after EVAR. Patients with a GFR <30 mL/min, maximum AAA diameter > 6.9 cm, and females who are undergoing EVAR may be at risk for CA-AKI after EVAR. Prospective studies are needed to determine the efficacy of our model.

An abdominal aortic aneurysm rupture risk score: a pilot study for combining precise aortic measurements and clinical factors

ObjectiveCurrent screening and management for abdominal aortic aneurysms (AAAs) are based on maximal aortic diameter criteria. This study sought to compare anatomic and clinical factors between ruptured and intact AAAs to identify predictors of rupture. MethodsPatients treated for AAAs at Thomas Jefferson University Hospital from 2010 to 2021 were reviewed from intact AAAs (iAAAs), ruptured AAAs (rAAAs), and no aortic pathology (NP) groups. Preoperative computed tomography angiography (CTA) studies were retrospectively measured with Aquarius iNtuition (TeraRecon Inc). Maximal diameter, length, mural thrombus volume (MTV), and calcification volume were measured from the lowest renal artery to the femoral artery. A rupture risk score was calculated using AAA diameter (1 point), percent ≥MTV 50% (1 point), number of antihypertensive agents <2 (1 point), not on cholesterol-lowering medication (1 point), and active smoking (1 point) for a 5-point total score. ResultsCTAs from 48 patients (age, 69.5 ± 8.1 years; 87.5% male) were measured (23 iAAAs, 15 rAAAs, and 10 controls). When compared with iAAAs, the maximal AAA diameter (rAAA, 7.71 cm; iAAA, 6.02 cm; P = .005) and %MTV (rAAA, 66.1%; iAAA, 45.3%; P = .0001) were greater in patients with rAAAs. Mean AAA rupture risk score was greater in patients with rAAAs than those with iAAAs (rAAA, 3.40 ± 1.12; iAAA, 1.78 ± 1.44; P < .001) with 100% of rAAAs and 47.8% of iAAAs having a score 2 or greater. ConclusionsThis study demonstrates that AAA diameter, percent MTV, blood pressure control, and active smoking are significant risk factors for AAA rupture. Patients with multiple risk factors (risk score ≥2) were more likely to rupture and should be considered high risk.

Biomechanics and early sac regression after endovascular aneurysm repair of abdominal aortic aneurysm

BackgroundSac regression after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAA) is regarded as a marker of successful response to treatment. Several factors influence sac behavior after EVAR, yet little is known about the value of preoperative biomechanics. The aim of this study was to investigate the difference in aortic biomechanics between patients with and without sac regression. MethodsPatients treated with standard EVAR for infrarenal AAA at the Karolinska University Hospital between 2009 and 2012 with one preoperative and a minimum of two postoperative computed tomography angiography (CTA) scans were considered for inclusion in this single-center retrospective cohort study. Biomechanical indices such as AAA wall stress and wall stress-strength ratio as well as intraluminal thrombus (ILT) thickness and stress were measured preoperatively in A4ClinicRE (VASCOPS GmbH). AAA diameter and volume were analyzed on preoperative, 30-day, and 1-year CTAs. Patients were dichotomized based on sac regression, defined as a ≥5 mm decrease in maximal AAA diameter between the first two postoperative CTA scans. Multivariable logistic regression was used for analysis of factors associated with early sac regression. ResultsOf the 101 patients treated during the inclusion period, 64 were included. Thirty-nine (61%) demonstrated sac regression and 25 (39%) had a stable sac or sac increase. The mean patients age (73 years vs 76 years), male sex (85% vs 96%), and median AAA diameter (58 mm vs 58.5 mm) did not differ between patients with and without sac regression. Although no difference in preoperative biomechanics was seen between the groups, multivariable logistic regression revealed that a larger AAA diameter (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.06-1.51; P = .009) and smoking (OR, 22.1; 95% CI, 2.78-174; P = .003) were positively associated with sac regression. In contrast, the lumen diameter (OR, 0.87; 95% CI, 0.77-0.98; P = .023), ILT thickness (OR, 0.85; 95% CI, 0.75-0.97; P = .013), aspirin or direct-acting oral anticoagulant use (OR, 0.11; 95% CI, 0.02-0.61; P = .012), and mean ILT stress (OR, 0.35; 95% CI, 0.14-0.87; P = .024) showed a negative association. Patients with sac regression had fewer reinterventions (log-rank P = .010) and lower mortality (log-rank P = .012) at the 5-year follow-up. ConclusionsThis study, characterizing preoperative biomechanics in patients with and without sac regression, demonstrated a negative association between mean ILT stress and ILT thickness with a change in sac diameter after EVAR. Given that the ILT is a highly dynamic entity, further studies focusing on the role of the thrombus are needed. Furthermore, patients presenting with early sac regression had improved outcomes after EVAR.

Exosomal miR-17-5p from adipose-derived mesenchymal stem cells inhibits abdominal aortic aneurysm by suppressing TXNIP-NLRP3 inflammasome

BackgroundPreclinical studies have suggested that adipose-derived mesenchymal stem cells (ADSCs) transplantation can suppress abdominal aortic inflammation and aneurysm expansion through paracrine factors. Yet, the mechanism of action is not fully understood. In the present study, we further examined the function and mechanism of ADSC-derived exosomes (ADSC-exos) and their microRNA-17-5p (miR-17-5p) on the abdominal aortic aneurysm (AAA) progression.MethodsADSC-exos were isolated and identified. DiR and PKH67 staining were used to trace ADSC-exo in vivo and in vitro. Raw264.7 cells were applied to perform in vitro experiments, while a murine AAA model induced using angiotensin II (Ang II) was used for in vivo testing. The expression level of miR-17-5p in macrophages and Ang II-treated macrophages after ADSC-exos treatment was determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The target relation between miR-17-5p and thioredoxin-interacting protein (TXNIP) was identified by a dual-luciferase reporter gene assay. Artificial activation and block of experiments of miR-17-5p and TXNIP were conducted to clarify their functions in inflammation during AAA progression. The severity of AAA between groups was assessed by maximal aorta diameter, AAA incidence, survival rate, and histological stainings. Besides, inflammasome-related proteins and macrophage pyroptosis were further evaluated using western blot, RT-qPCR, and enzyme-linked immunosorbent assay (ELISA).ResultsThe ADSC-exos were isolated and identified. In vivo testing showed that ADSC-exos were mainly distributed in the liver. Meanwhile, in vitro experiments suggested that ADSC-derived exosomes were taken up by macrophages, while inside, ADSC-exos miR-17-5p decreased a TXNIP induced by Ang II by directly binding to its 3′-untranslated region (3’UTR). Furthermore, overexpression of miR-17-5p enhanced the therapeutic function of ADSC-exos on inflammation during AAA expansion in vivo, while its inhibition reversed this process. Finally, overexpressed TXNIP triggered macrophage pyroptosis and was alleviated by ADSC-derived exosomes in vitro.ConclusionADSC-exos miR-17-5p regulated AAA progression and inflammation via the TXNIP-NLRP3 signaling pathway, thus providing a novel insight in AAA treatment.

Prediction of abdominal aortic aneurysm growth by artificial intelligence taking into account clinical, biologic, morphologic, and biomechanical variables.

To develop a prediction model that could risk stratify abdominal aortic aneurysms (AAAs) into high and low growth rate groups, using machine learning algorithms based on variables from different pathophysiological fields. A cohort of 40patients with small AAAs (maximum diameter 32-53mm) who had at least an initial and a follow-up CT scan (median follow-up 12months, range 3-36months) were included. 29 input variables from clinical, biological, morphometric, and biomechanical pathophysiological aspects extracted for predictive modeling. Collected data were used to build two supervised machine learning models. A gradient boosting (XGboost) and a support vector machines (SVM) algorithm were trained with 60% and tested with 40% of the data to predict which AAA would achieve a growth rate higher than the median of our study cohort. Receiver operating characteristics (ROC) curves and areas under the curve (AUC) were used for the evaluation of the developed algorithms. XGboost achieved the highest AUC in predicting high compared to low AAA growth rate with an AUC of 81.2% (95% CI from 61.1 to 100%). SVM achieved the second highest performance with an AUC of 68.8% (95% CI from 46.5 to 91%). Based on the best performing algorithm, variable importance was estimated. Diameter-diameter ratio (maximum diameter/neck diameter), Tortuosity from Renal arteries to aortic bifurcation, and maximum thickness of the intraluminal thrombus were found to be the most important factors for model predictions. Other factors were also found to play a significant but less important role. A prediction model that can risk stratify AAAs into high and low growth rate groups could be developed by analyzing several factors implicated in the multifactorial pathophysiology of this disease, with the use of machine learning algorithms. Future studies including larger patient cohorts and implementing additional risk markers may aid in the establishment of such methodology during AAA rupture risk estimation.

Predictive Parameters for Rupture in Abdominal Aortic Aneurysms

The current screening and management guidelines for abdominal aortic aneurysms (AAAs) are based on maximal aortic diameter criteria. This study compared the aortic measurements between ruptured and intact AAAs to identify the prognostic markers for rupture. Patients treated for AAAs at Thomas Jefferson University Hospital from 2014 to 2021 were randomly selected from intact AAAs (iAAAs), ruptured AAAs (rAAAs), and no aortic pathology (NP) groups. Preoperative computed tomography angiography studies were retrospectively measured using Aquarius iNtuition (TeraRecon Inc, Durham, NC). The maximal diameter, length, mural thrombus volume (MTV), and Hounsfield calcification were measured from the lowest renal artery to the femoral artery. The aortic height index (AHI = maximal AAA diameter + length/height) was calculated to control for height. One-way analysis of variance, followed by Tukey’s multiple comparison tests and Pearson’s correlation, was performed using Prism, version 9.3.1 (GraphPad, San Diego, CA). Computed tomography angiography from 45 patients (age, 69.40 ± 8.28 years; 86.6% male) were measured for the iAAA (n = 19; 42.2%), rAAA (n = 16; 35.6%), and NP (n = 10; 22.2%) groups. Compared with those with iAAAs, the maximal AAA diameter (7.71 cm vs 6.19 cm; P = .022) and MTV (180.8 cm3 vs 91.79 cm3; P = .0323, Fig 1) was larger for the rAAA patients. The infrarenal aortic length correlated positively with the AAA diameter [r(43) = 0.66; P < .0001; Fig 2) and an increase in AAA diameter compared with NP (rAAA, 12.89 cm; iAAA, 13.03 cm; NP, 9.75 cm; P < .0001). The AHI was elevated in the rAAA compared with the iAAA patients (4.50 cm/m vs 3.43 cm/m; P = .0102; Fig 1). No other parameter differed between the rAAA and iAAA patients. Our study has demonstrated that the AAA diameter, MTV, and AHI are significant predictors of rupture of AAAs. Additionally, the infrarenal aortic length might be a viable prognostic marker for AAA vessel wall strength, warranting further investigation. These results will assist in identifying patients at high risk of rupture.Fig 2Abdominal aortic aneurysm (AAA) diameter vs length correlation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Positive association between calcium channel blocker treatment and persistent type II endoleak.

Type II endoleaks are the most common complication occurring after endovascular abdominal aortic aneurysm repair (EVAR). The aims of our study were to evaluate the impact of persistent type II endoleak on sac dynamics post-EVAR, and to study the association between non-anatomical factors including polymorphisms associated with abdominal aortic aneurysm (AAA) and persistent type II endoleak. The cohort comprises 210 patients undergoing EVAR between January 2010 and December 2018. A persistent type II endoleak was defined as any type II endoleak lasting longer than six months and included also a type II endoleak diagnosed after six months or more post-EVAR during the 36-month follow-up period confirmed with CT-angiography. Anteroposterior AAA maximum diameter and AAA volume were measured pre-EVAR and 36 months post-EVAR using CT-angiographic pictures. Sac progression was defined as at least 5 mm increase, sac regression as at least 5 mm decrease in the sac diameter in relation to the preprocedural diameter. Sociodemographic information, comorbidities, treatment, laboratory parameters, selected anatomical and genetic factors were all analyzed to determine their impact on persistent type II endoleak. The adjustments included age, hypertension, diabetes mellitus, dyslipidemia, sex, smoking in multivariate analyses. When postprocedural diameter and volume were evaluated, adjustments included also preprocedural diameter/volume. After exclusion, 178 patients with mean age 72.4±7.60 years remained for analysis. Persistent type II endoleak was found in 27.5% of patients (N.=49) and 2.94-times increased risk of sac progression in multivariate analysis (P=0.033). In multivariate analysis, AAA diameter in patients with persistent type II endoleak was 4.31 mm greater than in patients without (B=4.31; P=0.014); and its presence was also associated with 22.0 cm3 greater sac volume (B=22.0; P=0.034) compared to patients without persistent type II endoleak. Treatment with calcium channel blockers increased risk of persistent type II endoleak 2.11-times in multivariate analysis (OR=2.11; 95% CI: 1.05-4.25; P=0.037). No association between persistent type II endoleak and selected polymorphisms associated with AAA and other observed factors were found. Risk of persistent type II endoleak was more than doubled in patients taking calcium channel blockers. Patients with persistent type II endoleak had greater anteroposterior sac diameter and sac volume compared to patients without persistent type II endoleak.

Association of abdominal aortic aneurysm diameter indexed to patient height with symptomatic presentation and mortality

BackgroundThe current guidelines have recommended repair of abdominal aortic aneurysms (AAAs) according to the maximal AAA diameter and/or its growth rate. However, many studies have suggested that the AAA diameter alone is not sufficient to predict the risk of rupture or symptomatic presentation. Several investigators have attempted to relate the AAA diameter to the body surface area in predicting for rupture. However, these calculations have not resulted in conclusive evidence. We sought in the present analysis to introduce a novel diameter-to-height index (DHI) and test its utility in predicting for symptomatic presentations, including rupture and 30-day and 5-year mortality. MethodsThe Vascular Quality Initiative database (2003-2020) was used to identify patients who had undergone open or endovascular AAA repair. The DHI was defined as the AAA diameter in centimeters divided by the height in centimeters, yielding a score of 1 to 10. Multivariable logistic regression analysis was performed to assess the risk of symptomatic presentation, including rupture and 30-day mortality. Receiver operating characteristic curves were plotted, and survival analysis techniques were used to determine the hazard of 5-year mortality. ResultsA total of 64,595 patients were identified, of whom, 16.3% had presented with symptomatic AAAs, including rupture. Endovascular AAA repair was performed for 69.8% of the symptomatic AAAs and 84.3% of asymptomatic AAAs (P < .001). The symptomatic group were more likely to be women (24.6% vs 19.8%; P < .001) and Black (7.81% vs 4.44%; P < .001). The mean DHI was higher in the symptomatic group than in the asymptomatic group (mean DHI, 3.92 ± 1.1 vs 3.24 ± 0.7; P < .001). The adjusted odds of a symptomatic presentation increased with an increasing DHI (adjusted odds ratio [aOR], 1.70; 95% confidence interval [CI], 1.59-1.83; P < .001). Active smoking increased the risk of a symptomatic presentation (aOR, 1.38; 95% CI, 1.28-1.51; P < .001). However, the use of preoperative statins and beta-blockers significantly reduced the odds of a symptomatic presentation (aOR, 0.58; 95% CI, 0.53-0.64; P < .001; and aOR, 0.76; 95% CI, 0.69-0.84; P < .001), respectively. Compared with the AAA diameter, the receiver operating characteristic curve for the DHI to predict for symptomatic status was slightly, but significantly, higher (aOR, 0.702; 95% CI, 0.695-0.708; vs aOR, 0.695; 95% CI, 0.688-0.701; P < .001). The DHI increment was associated with a 1.08 greater odds of 30-day mortality (aOR, 1.08; 95% CI, 1.01-1.15; P < .001) for those with symptomatic AAAs. Similarly, the hazard of 5-year mortality was increased with an increasing DHI (adjusted hazard ratio, 1.20; 95% CI, 1.13-1.29; P < .001) only for those with asymptomatic AAAs. ConclusionsThe DHI is a simple tool that could be more effective than the AAA diameter in predicting for symptomatic presentations. The DHI varied by sex and race, which could collectively help to provide an individualized prognosis. The DHI can additionally predict the 5-year mortality after AAA repair for those with asymptomatic AAAs only. However, the odds of 30-day mortality remained similar in both groups.

Standardizing Methods of Reading CT Maximum Aortic Diameters Amongst Experts Reduces Variations and Discordance, Improving Accuracy

There is no consensus on the method of obtaining abdominal aortic aneurysm (AAA) maximum diameters based on computed tomographic angiography, and the reproducibility and accuracy of different methods have recently been debated due to advancements in imaging. This study compared the two most common methods based on orthogonal planes and centerline of flow to determine the discordances and accuracy amongst experiences readers. The computed tomographic angiography max diameters of 148 AAAs were measured by three experienced observers, including a vascular surgeon, a radiologist and an imaging cardiologist. Observers used two different methods with standardized protocols: multiplanar reformations based on orthogonal planes, and a software using 3D aortic reconstructions to create centerline flow lumen providing diameters based on cross sections perpendicular to this lumen. Agreements and reliability of measurement methods were assessed by intra-class correlation coefficient and Bland - Altman analysis. Discordances between measurements of the methods and the original reported measurement, as well as outside hospitals were compared. The average age of the cohort was 75 years and aortic diameters ranged from 3.8 to 9.6 cm. For orthogonal readings, there were agreements within 3 mm between 86% and 92% of the time, while centerline - reading agreement was between 88% and 94%, which was not statistically significant. The intra-class correlation coefficient was high between method type and between readers. Within methods, agreement was between 0.96 and 0.97, while within - reader agreement measures was between 0.96 and 0.98. In comparison to the original and the outside hospital reports, 10% ≥ of the original and 20% ≥ of the outside hospital reported measurements were discordant between the readers. Maximal AAA measurements can have substantial variability leading to clinical significance and change in patient management and outcomes. Based on the results, orthogonal and centerline measurement methods have equally high agreements and concordance within 3 mm and low variations at a high volume center. However, when compared to the official read reports, there is high discordance rates that can significantly alter patient outcomes. A standardized method of measurement maximum diameter can reduce variations and discordances among different methods.

Endovascular Aortic Repair in Patients of Advanced Age

Purpose: Treatment decisions for the elderly with abdominal aortic aneurysms (AAAs) are challenging. With advancing age, the risk of endovascular aneurysm repair (EVAR) increases while life expectancy decreases, which may nullify the benefit of EVAR. The purpose of this study was to quantify the impact of EVAR on 1-year mortality in patients of advanced age. Materials and Methods: The 2003–2020 Vascular Quality Initiative Database was utilized to identify patients who underwent EVAR for AAAs. Patients were included if they were 80 years of age or older. Exclusions included non-elective surgery or missing aortic diameter data. Predicted 1-year mortality of untreated AAAs was calculated based on a validated comorbidity score that predicts 1-year mortality (Gagne Index, excluding the component associated with AAAs) plus the 1-year aneurysm-related mortality without repair. The primary outcome for the study was 1-year mortality. Results: A total of 11 829 patients met study criteria. The median age was 84 years [81, 86] with 9014 (76.2%) being male. Maximal AAA diameters were apportioned as follows: 39.6% were <5.5 cm, 28.6% were 5.5–5.9 cm, 21.3% were 6.0–6.9 cm, and 10.6% were ≥7.0 cm. The predicted 1-year mortality rate without EVAR was 11.9%, which was significantly higher than the actual 1-year mortality rate with EVAR (8.2%; p<0.001). The overall rate of perioperative MACE was 4.4% (n = 516). Patients with an aneurysm diameter <5.5cm had worse actual 1-year mortality rates with EVAR compared to predicted 1-year mortality rates without EVAR. In contrast, those with larger aneurysms (≥5.5cm) had better actual 1-year mortality rates with EVAR. The benefit from EVAR for those with Gagne Indices 2–5 was largely restricted to those with AAAs ≥ 7.0cm; whereas those with Gagne Indices 0–1 experience a survival benefit for AAAs larger than 5.5 cm. Conclusion: The current data suggest that EVAR decreases 1-year mortality rates for patients of advanced age compared to non-operative management in the elderly. However, the survival benefit is largely limited to those with Gagne Indices 0–1 with AAAs ≥ 5.5 cm and Gagne Indices 2–5 with AAAs ≥ 7.0 cm. Those of advanced age may benefit from EVAR, but realizing this benefit requires careful patient selection.

Validation of an assessment tool for estimation of abdominal aortic aneurysm compression in diagnostic ultrasound

The study investigated ultrasound (US) transducer push, tantamount to applied transducer pressure, during abdominal aortic aneurysm (AAA) US scanning in a simulated non-clinical setup.During an assessment of maximal AAA diameter on a three-dimensional print-based AAA phantom, US transducer push varied as much as 2000% (range: 0.52–12.45 kPa) amongst 16 experienced sonographers. The mean transducer push was 5.54 ± 3.91 kPa (CV = 0.71).Deformation of a standardized gel-pad allowed for transducer push calculation based on US images; Young’s modulus of the gel-pad was estimated to 44,26 N/m2.The method is theoretically validated in a safe and non-clinical environment. Future investigations with the aim of clinical validation of the gel-pad principle on AAA patients are suggested, including the objectification of the magnitude of an eventual transducer push-related error during US AAA diameter measurement.