Management Of Abdominal Aortic Aneurysms Research Articles

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.

Systematic Review and Meta-Analysis of the Incidence of Rupture, Repair, and Death of Small and Large Abdominal Aortic Aneurysms under Surveillance.

The ultimate goal of treating patients with abdominal aortic aneurysms (AAAs) is to repair them when the risk of rupture exceeds the risk of repair. Small AAAs demonstrate a low rupture risk, and recently, large AAAs just above the threshold (5.5-6.0 cm) seem to be at low risk of rupture as well. The present review aims to investigate the outcomes of AAAs under surveillance through a comprehensive systematic review and meta-analysis. PubMed, Embase, and the Cochrane Central Register were searched (22 March 2022; PROSPERO; #CRD42022316094). The Cochrane and PRISMA statements were respected. Blinded systematic screening of the literature, data extraction, and quality assessment were performed by two authors. Conflicts were resolved by a third author. The meta-analysis of prevalence provided estimated proportions, 95% confidence intervals, and measures of heterogeneity (I2). Based on I2, the heterogeneity might be negligible (0-40%), moderate (30-60%), substantial (50-90%), and considerable (75-100%). The primary outcome was the incidence of AAA rupture. Secondary outcomes included the rate of small AAAs reaching the threshold for repair, aortic-related mortality, and all-cause mortality. Fourteen publications (25,040 patients) were included in the analysis. The outcome rates of the small AAA group (<55 mm) were 0.3% (95% CI 0.0-1.0; I2 = 76.4%) of rupture, 0.6% (95% CI 0.0-1.9; I2 = 87.2%) of aortic-related mortality, and 9.6% (95% CI 2.2-21.1; I2 = 99.0%) of all-cause mortality. During surveillance, 21.4% (95% CI 9.0-37.2; I2 = 99.0%) of the initially small AAAs reached the threshold for repair. The outcome rates of the large AAA group (>55 mm) were 25.7% (95% CI 18.0-34.3; I2 = 72.0%) of rupture, 22.1% (95% CI 16.5-28.3; I2 = 25.0%) of aortic-related mortality, and 61.8% (95% CI 47.0-75.6; I2 = 89.1%) of all-cause mortality. The sensitivity analysis demonstrated a higher rupture rate in studies including <662 subjects, patients with a mean age > 72 years, >17% of female patients, and >44% of current smokers. The rarity of rupture and aortic-related mortality in small AAAs supports the current conservative management of small AAAs. Surveillance seems indicated, as one-fifth reached the threshold for repair. Large aneurysms had a high incidence of rupture and aortic-related mortality. However, these data seem biased by the sparse and heterogeneous literature overrepresented by patients unfit for surgery. Specific rupture risk stratified by age, gender, and fit-for-surgery patients with large AAAs needs to be further investigated.

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2-LIN28B-ELK3 Signaling.

The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single-cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)-induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier-related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early-stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post-Ang II). Mechanically, ELK3acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2-specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

Prevalence of risk factors associated with rupture of abdominal aortic aneurysm (AAA): a single center retrospective study.

Abdominal aortic aneurysm (AAA) is a severe cardiovascular disease. The mortality rate for an AAA rupture is very high. Understanding the risk factors for AAA rupture would help AAA management, but little is known about these risk factors in the Chinese population. This retrospective study included patients that were diagnosed with AAA during the last 5 years in a large national hospital in southern China. AAA patients were divided into a rupture and non-rupture group. Clinical data were extracted from the hospital medical record system. Clinical features were compared between the rupture and non-rupture groups. The associations between potential risk factors and rupture risk were evaluated using a multivariate logistic regression analysis. A total of 337 AAA patients were included for analysis in the present study. AAA diameter was significantly larger, and high-sensitivity C-reactive protein (hs-CRP) and serum creatinine levels were both significantly higher in AAA rupture patients. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were significantly lower in AAA rupture patients. After adjustment, the multivariate logistic analysis found that AAA diameter and hs-CRP were independently positively associated with AAA rupture, and HDL-C level was adversely associated with AAA rupture. Our data suggests that larger AAA diameter and higher hs-CRP level are associated with a higher risk of AAA rupture, and higher HDL-C level is associated with a lower risk of AAA rupture. The results of this study may be helpful for the management of AAA patients in southern China.

Persistent High Long-term Excess Mortality After Elective AAA Repair Especially in Women: A Large Population-based Study.

The aim of this time-trend analysis is to estimate long-term excess mortality and associated cardiovascular risk for abdominal aortic aneurysm (AAA) patients after elective repair while addressing the changes in AAA management and patient selection over time. Despite the intensification of endovascular aneurysm repair and cardiovascular risk management, Swedish population data suggest that AAA patients retain a persistently high long-term mortality after elective repair. The question is whether this reflects suboptimal treatment, a changing patient population over time, or a national phenomenon. Nationwide time-trend analysis including 40,730 patients (87% men) following elective AAA repair between 1995 and 2017. Three timeframes were compared, each reflecting changes in the use of endovascular aneurysm repair and intensification of cardiovascular risk management. Relative survival analyses were used to estimate disease-specific excess mortality. Competing risk of death analysis evaluated the risk of cardiovascular versus noncardiovascular death. Sensitivity analysis evaluated the impact of changes in patient selection over time. Short-term excess mortality significantly improved over time. Long-term excess mortality remained high with a doubled mortality risk for women (relative excess risk=1.87, 95% CI: 1.73-2.02). Excess mortality did not differ between age categories. The risk of cardiovascular versus noncardiovascular death remained similar over time, with a higher risk of cardiovascular death for women. Changes in patient population (ie, older and more comorbid patients in the latter period) marginally impacted excess mortality (2%). Despite changes in AAA care, patients retain a high long-term excess mortality after elective repair with a persistent high cardiovascular mortality risk. In this, a clear sex - but no age - disparity stands out.

Pathogenesis and management of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) causes ∼170 000 deaths annually worldwide. Most guidelines recommend asymptomatic small AAAs (30 to <50 mm in women; 30 to <55 mm in men) are monitored by imaging and large asymptomatic, symptomatic, and ruptured AAAs are considered for surgical repair. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. This review outlines research on AAA pathogenesis and therapies to limit AAA growth. Genome-wide association studies have identified novel drug targets, e.g. interleukin-6 blockade. Mendelian randomization analyses suggest that treatments to reduce low-density lipoprotein cholesterol such as proprotein convertase subtilisin/kexin type 9 inhibitors and smoking reduction or cessation are also treatment targets. Thirteen placebo-controlled randomized trials have tested whether a range of antibiotics, blood pressure-lowering drugs, a mast cell stabilizer, an anti-platelet drug, or fenofibrate slow AAA growth. None of these trials have shown convincing evidence of drug efficacy and have been limited by small sample sizes, limited drug adherence, poor participant retention, and over-optimistic AAA growth reduction targets. Data from some large observational cohorts suggest that blood pressure reduction, particularly by angiotensin-converting enzyme inhibitors, could limit aneurysm rupture, but this has not been evaluated in randomized trials. Some observational studies suggest metformin may limit AAA growth, and this is currently being tested in randomized trials. In conclusion, no drug therapy has been shown to convincingly limit AAA growth in randomized controlled trials. Further large prospective studies on other targets are needed.

An Epidemiologic Study of the Incidence and Mortality of Abdominal Aortic Aneurysms in Koreans Aged ≥50 Years from 2009 to 2018 Based on a National Database.

Large-scale population studies of the incidence of and mortality from abdominal aortic aneurysm (AAA) are needed to develop healthcare policies and priorities. The aim of this study was to estimate the incidence of AAA and the all-cause mortality from it among Koreans aged ≥50 years from 2009 to 2018 using data from the Korean National Health Insurance System Database. The crude and standardized incidence and all-cause mortality of the disease among patients with unruptured AAA were calculated. A total of 73,933 AAA patients were identified. The overall incidence of AAA in adults ≥50 years during the study period was 37.5 per 100,000 population (49.7 per 100,000 in men and 26.8 per 100,000 in women), with an increase from 32.33 per 100,000 persons in 2009 to 46.85 per 100,000 in 2018. The crude all-cause mortality rate of patients with untreated AAA was 21.26/100 person-years in 2009 and 8.87/100 person-years in 2018, with decreasing trends observed both in men and women. This nationwide study showed that the incidence of AAA in Koreans aged ≥50 years in 2018 was 63.40 per 100,000 in men and 32.07 per 100,000 in women. The overall rates were 0.06% and 0.03%, respectively, with an increasing trend. Mortality has decreased in both treated and untreated patients. The observed increase in incidence suggests a rising burden of AAA in the Korean population, particularly among men. The decreasing mortality rates may indicate improvements in the management and treatment of AAA over the study period.

Endovascular Solutions for Abdominal Aortic Aneurysms: Fenestrated, Branched and Custom-Made Devices.

Abdominal aortic aneurysm (AAA) has a prevalence of 4.8%. AAA rupture is associated with significant mortality, thus surgical intervention is generally required once the aneurysm diameter exceeds 5.5cm. Endovascular aneurysm repair (EVAR) is the predominant repair modality for AAA. However, in patients with complex aortic anatomy, fenestrated or branched EVAR is a superior repair option vs standard EVAR. Fenestrated and branched endoprostheses can be off-the-shelf or custom-made, which offers a more individualised approach. To summarise and evaluate the clinical outcomes achieved by fenestrated EVAR (FEVAR) and branched EVAR (BEVAR), and to explore the role of custom-made endoprostheses in contemporary AAA management. A literature search using Ovid Medline and Google Scholar was conducted to identify literature pertaining to the use and outcomes of fenestrated, branched, fenestrated-branched and custom-made endoprostheses for AAA repair. FEVAR is an effective repair modality for patients with AAA that offers similar early survival, improved early morbidity but higher rates of reintervention in comparison to open surgical repair (OSR). Compared with standard EVAR, FEVAR is associated with similar in-hospital mortality yet higher rates of morbidity, especially regarding renal outcomes. BEVAR outcomes are rarely reported exclusively in the context of AAA repair. When reported, BEVAR is an acceptable alternative to EVAR in the treatment of complex aortic aneurysms and has similar reported complication issues to FEVAR. Custom-made grafts are a good alternative treatment option for complex aneurysms where hostile aneurysm anatomy precludes the use of conventional EVAR and sufficient time is available for the manufacturing of such devices. FEVAR offers a very effective treatment for patients with complex aortic anatomy and has been well-characterised over the past decade. RCTs and longer-term studies are desirable for unbiased comparison of non-standard EVAR modalities.

The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development.

To determine macrophage-specific alterations in epigenetic enzyme function contributing to the development of abdominal aortic aneurysms (AAAs). AAA is a life-threatening disease, characterized by pathologic vascular remodeling driven by an imbalance of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Identifying mechanisms regulating macrophage-mediated extracellular matrix degradation is of critical importance to developing novel therapies. The role of SET Domain Bifurcated Histone Lysine Methyltransferase 2 (SETDB2) in AAA formation was examined in human aortic tissue samples by single-cell RNA sequencing and in a myeloid-specific SETDB2 deficient murine model induced by challenging mice with a combination of a high-fat diet and angiotensin II. Single-cell RNA sequencing of human AAA tissues identified SETDB2 was upregulated in aortic monocyte/macrophages and murine AAA models compared with controls. Mechanistically, interferon-β regulates SETDB2 expression through Janus kinase/signal transducer and activator of transcription signaling, which trimethylates histone 3 lysine 9 on the TIMP1-3 gene promoters thereby suppressing TIMP1-3 transcription and leading to unregulated matrix metalloproteinase activity. Macrophage-specific knockout of SETDB2 ( Setdb2f/fLyz2Cre+ ) protected mice from AAA formation with suppression of vascular inflammation, macrophage infiltration, and elastin fragmentation. Genetic depletion of SETDB2 prevented AAA development due to the removal of the repressive histone 3 lysine 9 trimethylation mark on the TIMP1-3 gene promoter resulting in increased TIMP expression, decreased protease activity, and preserved aortic architecture. Lastly, inhibition of the Janus kinase/signal transducer and activator of the transcription pathway with an FDA-approved inhibitor, Tofacitinib, limited SETDB2 expression in aortic macrophages. These findings identify SETDB2 as a critical regulator of macrophage-mediated protease activity in AAAs and identify SETDB2 as a mechanistic target for the management of AAAs.

Women with large intact abdominal aortic aneurysms remain untreated

ObjectiveA lower elective repair rate among women with abdominal aortic aneurysms (AAAs) has been a consistent finding. Reasons behind this gender gap have not been thoroughly outlined. MethodsThis was a retrospective multicenter cohort study (ClinicalTrials.gov: NCT05346289) at three European vascular centers in Sweden, Austria and Norway. Patients in surveillance with AAAs were consecutively identified starting from January 1, 2014, until reaching a total sample size of 200 women and 200 men. All individuals were followed for 7 years through medical records. Final treatment distributions and the proportion of “truly untreated” (surgically untreated despite reaching guideline-directed thresholds: 50 mm for women and 55 mm for men) were determined. In a complementary analysis, a universal 55-mm threshold was used. Gender-specific primary reasons behind untreated statuses were clarified. Eligibility for endovascular repair among the truly untreated was assessed in a structured computed tomography analysis. ResultsWomen and men had similar median diameters at inclusion (46 mm; P = .54) and at treatment decisions (55 mm; P = .36). After 7 years, the repair rate was lower among women (47% vs 57%). More women were truly untreated (26% vs 8%; P < .001) despite similar mean ages as for male counterparts (79.3 years; P = .16). With the 55-mm threshold, 16% women still classified as truly untreated. Similar reasons for nonintervention were captured for women and men (50% due to comorbidities alone, 36% morphology and comorbidity). The endovascular repair imaging analysis revealed no gender differences. Among truly untreated women, ruptures were common (18%), and mortality was high (86%). ConclusionsSurgical AAA management differed between women and men. Women could be underserved in terms of elective repairs: one in every four women was untreated with over-the-threshold AAAs. The lack of obvious gender differences in eligibility analyses could imply unmeasured discrepancies (eg, in disease extent or patient frailty).

Quality Improvement Report: Adherence to Follow-up Recommendations for Incidental Abdominal Aneurysms.

The use of national guidelines for the management of incidental radiologic findings remains low. Therefore, improving adherence to and consistency with follow-up recommendations for incidental findings was undertaken in a large academic practice. A gap analysis was performed, and incidental findings of abdominal aneurysms for which reporting management recommendations could be improved were identified. The Kotter change management framework was used, and institution-specific dictation macros were developed and implemented in February 2021 for the management of abdominal aortic aneurysms (AAAs), renal artery aneurysms (RAAs), and splenic artery aneurysms (SAAs). A retrospective medical record review was conducted for February through April in 2019, 2020, and 2021 to assess reporting adherence and imaging and clinical follow-up. Personal feedback was provided to radiologists in July 2021 with repeat data collection in September 2021. A significant increase in the number of correct follow-up recommendations was reported for incidental AAAs and SAAs after implementation of the macro (P < .001). However, there was no significant change for RAAs. Providing personal feedback to radiologists further improved adherence with standard recommendation macros for common findings and dramatically increased adherence for rare findings such as RAAs. New macros resulted in an increase in AAA and SAA imaging follow-up (P < .001). Institution-specific dictation macros were found to improve adherence to reporting recommendations for incidental abdominal aneurysms, with further improvement seen after feedback, which can have a significant effect on clinical follow-up. © RSNA, 2023.

Total Iodine Contrast-free Strategy for the Endovascular Management of Abdominal Aortic Aneurysms in Chronic Kidney Disease Patients: A Pilot Study

To retrospectively evaluate the feasibility and effectiveness of the endovascular treatment of patients with abdominal aortic aneurysm and chronic kidney disease (CKD) without the need for using iodinated contrast media throughout the diagnostic, therapeutic, and follow-up pathway. A retrospective review of prospectively collected data concerning 251 consecutive patients presenting an abdominal aortic or aorto-iliac aneurysm who underwent endovascular aneurysm repair (EVAR) from January 2019 to November 2022 at our academic institution was performed in order to identify patients with feasible anatomy with respect to manufacturer's instructions for use and with CKD. Patients whose preoperative workout included duplex ultrasound and plain computed tomography for preprocedural planning were extracted from a dedicated EVAR database. EVAR was performed with the use of carbon dioxide (CO2) as the contrast media of choice, whereas follow-up examinations consisted of either duplex ultrasound, plain computed tomography, or contrast-enhanced ultrasound. Primary endpoints were technical success, perioperative mortality, and early renal function variations. Secondary endpoints were all-type endoleaks and reinterventions, midterm aneurysm-related and kidney-related mortality. Forty-five patients had CKD and were treated electively (45/251, 17.9%). Of them, 17 patients were managed with a total iodinated contrast media-free strategy and constituted the object of the present study (17/45, 37.8%; 17/251, 6.8%). In 7 cases, an adjunctive planned procedure was performed (7/17, 41.2%). No intraoperative bail-out procedures were needed. This extracted cohort of patients presented similar mean preoperative and postoperative (at discharge) glomerular filtration rate values, 28.14 (SD 13.09; median 28.06, interquartile range (IQR) 20.25) ml/min/1.73m2 and 29.33 (SD 14.61; median 27.35, IQR 22) ml/min/1.73m2, respectively (P=0.210). Mean follow-up was 16.4months (SD 11.89; median 18, IQR 23). During follow-up, no graft-related complications occurred in terms of either thrombosis, type I or III endoleaks, aneurysm rupture, or conversion. The mean glomerular filtration rate at follow-up was 30.39ml/min/1.73m2 (SD 14.45; median 30.75, IQR 21.93), with no significant worsening in comparison with preoperative and postoperative values (P=0.327 and P=0.856 respectively). No aneurysm- or kidney-related deaths occurred during follow-up. Our initial experience shows that total iodine contrast-free abdominal aortic aneurysm endovascular management in patients with CKD may be feasible and safe. Such an approach seems to guarantee the preservation of residual kidney function without increasing the risks of aneurysm-related complications in the early and midterm postoperative periods, and it could be considered even in the case of complex endovascular procedures.

Circular RNA suppression of vascular smooth muscle apoptosis through the miR-545-3p/CKAP4 axis during abdominal aortic aneurysm formation.

Abdominal aortic aneurysms (AAA) are an important cause of cardiovascular deaths. The loss of vascular smooth muscle cells (VSMCs) has been reported to be related to the pathology of AAA. This study focused on investigating the function of circ_0002168 in VSMC apoptosis. Levels of genes and proteins were measured by quantitative real-time-polymerase chain reaction (qRT-PCR) and Western blot. The growth of VSMCs was determined by using cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry and the evaluation of caspase-3 activity analysis, reactive oxygen species (ROS) production as well as lactate dehydrogenase (LDH) activity. The binding between miR-545-3p and circ_0002168 or Cytoskeleton-associated protein 4 (CKAP4) was confirmed by bioinformatics analysis, dual-luciferase reporter, RNA immunoprecipitation, and pull-down assays. Circ_0002168 decreased in the aortic tissues of patients with AAA. Functionally, ectopic overexpression of circ_0002168 dramatically induced proliferation and suppressed apoptosis in VSMCs. Mechanistically, circ_0002168 sequestered miR-545-3p to release CKAP4 expression via the ceRNA mechanism, indicating the circ_0002168/miR-545-3p/CKAP4 feedback loop in VSMCs. Increased miR-545-3p and a decreased CKAP4 expression were observed in patients with AAA. Rescue experiments showed that miR-545-3p reversed the protective effects of circ_0002168 on VSMC proliferation. Moreover, inhibition of miR-545-3p could restrain the apoptosis of VSMCs, which was abolished by CKAP4 silencing. Circ_0002168 has a protective effect on VSMC proliferation by regulating the miR-545-3p/CKAP4 axis, adding further understanding of the pathogenesis of AAA and a potential therapeutic approach in AAA management.

Variations in the Drainage Pattern of Testicular and Renal Veins, and Bilateral Duplication of Renal Arteries with Prehilar Divisions

The dissection of a 76-year-old male donor with a consent for research and publication, revealed variations of the renal and testicular vasculature where the right testicular vein joined a right accessory renal vein to form a common trunk that opened into the right renal vein. The left renal vein descended obliquely to the left ventral to the pair of left renal arteries, under crossed the prehilar branches of the arteries dorsally as it approaches the left kidney and entered the hilum posterior to the arterial branches. Both kidneys were supplied by two renal arteries (superior and inferior). The left superior renal artery followed the course of the left renal vein, crossed inferiorly ventral to the inferior renal artery, and then the last part of the left renal vein to enter the lower corner of the hilum of the left kidney. The bilaterally duplicated renal arteries broke up into anterior and posterior prehilar (early) divisions that entered the respective kidney. The co-occurrence of such multiple and complex a variation is of nephron-urological importance and can complicate nephro-surgeries, interventional radiologic procedures and the management of abdominal aortic aneurysm.

HMGB1/TLR4 signaling pathway enhances abdominal aortic aneurysm progression in mice by upregulating necroptosis.

The age-associated increases in aseptic inflammation and necroptosis are closely related to the emergence of various age-associated diseases. In this study, the role of HMGB1/TLR4-induced necroptosis in abdominal aortic aneurysm (AAA) formation was investigated. First, the levels of sterile inflammatory mediators (HMGB1, TLR4) and necroptosis markers were measured in the abdominal aortas of young and old C57BL/6JNifdc mice. We observed that sterile inflammatory mediators and necroptosis markers were greatly increased in the abdominal aortas of old mice. Then, angiotensin II (Ang II)-induced AAA model in APOE-/- mice was used in this study. Mice AAA models were treated with the RIP1 inhibitor necrostatin-1 (Nec-1) or the TLR4 inhibitor TAK-242, respectively. We found that HMGB1, TLR4, and necroptosis markers were elevated in old mice compared with those in young mice. Same elevation was also found in the development of AAA in APOE-/- mice. In addition, the necroptosis inhibitor Nec-1 alleviated Ang II-induced AAA development while downregulating the expression of HMGB1/TLR4. After blocking TLR4 with TAK-242, the expression of necroptosis markers decreased significantly, and the progression of AAA was also alleviated in APOE-/- mice. Our results indicated that HMGB1/TLR4-mediated necroptosis enhances AAA development in the Ang II-induced AAA model in APOE-/- mice and that TLR4 might be a potential therapeutic target for AAA management.

Netrin-1 Monoclonal Antibody-Functionalized Nanoparticle Loaded with Metformin Prevents the Progression of Abdominal Aortic Aneurysms.

Abdominal aortic aneurysms (AAAs) are a global health and economic burden. Therapeutic strategies to inhibit the progression of AAAs are currently lacking. Recently, the therapeutic effect of metformin on aneurysms has attracted considerable interest. However, the unfavorable pharmacokinetic properties of metformin limit its feasibility for AAA treatment. We constructed a metformin-loaded netrin-1-responsive AAA-targeted nanoparticle (Tgt-NP-Met) for AAA management. Evaluation of the therapeutic effect of Tgt-NP-Met was performed by in vitro and in vivo experiments. Our results showed that the binding of netrin-1 monoclonal antibodies enhanced the AAA-targeting capability of nanoparticles (NPs). Moreover, Tgt-NP-Met administration prevented AAA development and reduced the aneurysm diameter in apolipoprotein E (ApoE)-deficient (ApoE-/-) mice that received continuous infusion of angiotensin II. Furthermore, metformin prevented AAA progression by inhibiting the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, which is mediated by macrophage infiltration and activation. Our findings identify metformin as a functional suppressor for macrophage-mediated phenotypic transformation of VSMCs and Tgt-NP-Met as an efficient therapeutic strategy for AAA management.

The impact of neighborhood social disadvantage on abdominal aortic aneurysm severity and management

ObjectiveRecent studies have highlighted socioeconomic disparities in the severity and management of abdominal aortic aneurysm (AAA) disease. However, these studies focus on individual measures of social disadvantage such as income and insurance status. The area deprivation index (ADI), a validated measure of neighborhood deprivation, provides a more comprehensive assessment of social disadvantage. Therefore, we examined the impact of ADI on AAA severity and its management. MethodsWe identified all patients who underwent endovascular or open repair of an AAA in the Vascular Quality Initiative registry between 2003 and 2020. An ADI score of 1 to 100 was assigned to each patient based on their residential zip code, with higher ADI scores corresponding with increasing deprivation. Patients were categorized by ADI quintiles. Outcomes of interest included rates of ruptured AAA (rAAA) repair versus an intact AAA repair and rates of endovascular repair (EVAR) versus the open approach. Logistic regression was used to evaluate for an independent association between ADI quintile and these outcomes. ResultsAmong 55,931 patients who underwent AAA repair, 6649 (12%) were in the lowest ADI quintile, 11,692 (21%) in the second, 15,958 (29%) in the third, 15,035 (27%) in the fourth, and 6597 (12%) in the highest ADI quintile. Patients in the two highest ADI quintiles had a higher proportion of rAAA repair (vs intact repair) compared with those in the lowest ADI quintile (8.8% and 9.1% vs 6.2%; P < .001). They were also less likely to undergo EVAR (vs open approach) when compared with the lowest ADI quintile (81% and 81% vs 88%; P < .001). There was an overall trend toward increasing rAAA and decreasing EVAR rates with increasing ADI quintiles (P < .001). In adjusted analyses, when compared with patients in the lowest ADI quintile, patients in the highest ADI quintile had higher odds of rAAA repair (odds ratio, 1.4; 95% confidence interval, 1.2-1.8; P < .001) and lower odds of undergoing EVAR (odds ratio, 0.54; 95% confidence interval, 0.45-0.65; P < .001). ConclusionsAmong patients who underwent AAA repair in the Vascular Quality Initiative, those with higher neighborhood deprivation had significantly higher rates of rAAA repair (vs intact repair) and lower rates of EVAR (vs open approach). Further work is needed to better understand neighborhood factors that are contributing to these disparities to identify community-level targets for improvement.

Effects of abdominal aortic aneurysm appropriateness dashboard on clinical practice

ObjectiveThe Society for Vascular Surgery published abdominal aortic aneurysm (AAA) practice guidelines in 2003, 2009, and 2018 to improve the management and treatment of AAAs. In 2014, our vascular surgery department implemented a quarterly AAA dashboard (AAAdb) to record the perioperative outcomes and guideline compliance with a focus on intervention appropriateness and procedural follow-up, which supplemented our Vascular Quality Initiative data. From the available reported evidence and expert consensus opinions, nine additional criteria for the appropriate treatment of AAAs <5 cm in women and <5.5 cm in men were noted, when applicable. The purpose of our study was to assess the effects of AAAdb implementation on adherence to society and institutional guidelines, documentation of treatment rationale, and the quality of follow-up. MethodsWe performed a retrospective review of elective open and endovascular AAA repair at a single institution from 2010 to 2018. The AAAdb was implemented in the middle of this period in 2014. The patient demographics, aortic size, repair indication, repair type, 30-day mortality, and postoperative and 1-year follow-up imaging findings were analyzed. The primary outcome was adherence to intervention appropriateness and the follow-up guidelines. The categorical factors were summarized using frequencies and percentages and compared using the Pearson χ2 test or Fisher exact test. Continuous measures were summarized using the mean ± standard deviation and compared between study periods using two-sample t tests. ResultsFrom 2010 to 2018, 1549 patients had undergone elective AAA repair: 657 before and 892 after AAAdb implementation. No differences were found in AAA size after AAAdb (5.6 ± 1.2 cm vs 5.6 ± 1.1 cm; P = .88). However, the proportion of size-appropriate repairs increased (64.1% vs 71.3%; P = .003). The proportion of small AAA repairs with a documented rationale had increased (64.4% vs 80.5%; P < .001), with rapid disease progression cited most often. No difference was found in 30-day mortality (1.2% vs 1.5%; P = .69). Follow-up imaging after endovascular abdominal aortic aneurysm repair increased at <60 days postoperatively (76% vs 84%; P = .004) and at 1 year of follow-up (78% vs 86%; P = .0005). The proportion of patients with endoleak at <60 days postoperatively had increased in the post-AAAdb cohort (21% vs 29%; P = .012). ConclusionsThe AAAdb served as a centerpiece for improving the appropriateness of care and compliance with national and institutional guidelines, including treatment of small AAAs in special circumstances. Its implementation was associated with higher quality follow-up and surveillance in a high-volume, regional aortic center. Consideration should be given to adding additional criteria to the Society for Vascular Surgery guidelines and Vascular Quality Initiative reporting.

NADPH Oxidases in Aortic Aneurysms.

Abdominal aortic aneurysms (AAAs) are a progressive dilation of the infrarenal aorta and are characterized by inflammatory cell infiltration, smooth muscle cell migration and proliferation, and degradation of the extracellular matrix. Oxidative stress and the production of reactive oxygen species (ROS) have been shown to play roles in inflammatory cell infiltration, and smooth muscle cell migration and apoptosis in AAAs. In this review, we discuss the principles of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase/NOX) signaling and activation. We also discuss the effects of some of the major mediators of NOX signaling in AAAs. Separately, we also discuss the influence of genetic or pharmacologic inhibitors of NADPH oxidases on experimental pre-clinical AAAs. Experimental evidence suggests that NADPH oxidases may be a promising future therapeutic target for developing pharmacologic treatment strategies for halting AAA progression or rupture prevention in the management of clinical AAAs.

Effect of Telmisartan on the Peak Wall Stress and Peak Wall Rupture Index of Small Abdominal Aortic Aneurysms: An Exploratory Analysis of the TEDY Trial

This study was an unplanned exploratory analysis of a subset of participants from the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. It aimed to assess the efficacy of the angiotensin 1 receptor blocker telmisartan in reducing abdominal aortic aneurysm (AAA) peak wall stress (PWS) and peak wall rupture index (PWRI) among individuals with small AAAs. Participants with AAAs measuring 35 - 49 mm in maximum diameter were randomised to receive telmisartan 40 mg or identical placebo in the TEDY trial. Participants who had computed tomography angiography performed at entry and at least one other time point during the trial (12 or 24 months) were included in the current study. Orthogonal AAA diameter, PWS, and PWRI were measured using previously validated methods. The annual change in PWS and PWRI from baseline was compared between participants allocated telmisartan or placebo using linear mixed effects models. These models were either unadjusted or adjusted for risk factors that were different in the groups at entry (p < .100) or systolic blood pressure (SBP) at one year. Of the 207 participants recruited to TEDY, 124 were eligible for inclusion in this study. This study included 65 and 59 participants from the telmisartan and placebo groups, respectively. The PWS and PWRI were not significantly different in the two groups at baseline. Participants allocated telmisartan had a slower annual increase in PWS (-4.19; 95% CI -8.24, -0.14 kPa/year; p= .043) and PWRI (-0.014; 95% CI -0.026, -0.001; p= .032) compared with those allocated placebo after adjusting for risk factors. After adjustment for SBP at one year, telmisartan did not significantly reduce annual increases in PWS or PWRI. The findings of this study suggest that telmisartan limits the rate of increase in PWS and PWRI of small AAAs by reducing blood pressure.