Abdominal Aortic Aneurysm Expansion Research Articles

Aortic Uptake of 18F-NaF and 18F-FDG and Calcification Predict the Development of Abdominal Aortic Aneurysms and Is Attenuated by Drug Therapy.

Abdominal aortic aneurysms expand over time and increase the risk of fatal ruptures. To predict expansion, the isolated assessment of 18F-fluorodeoxyglucose (FDG) and sodium fluoride (NaF) uptake or calcification volume in aneurysms has been investigated with variability in results. We systematically evaluated whether 18F-FDG and 18F-NaF uptake was predictive of abdominal aortic aneurysm expansion. Seventy-four male Sprague-Dawley rat abdominal aortic aneurysm models were imaged using positron emission tomography-computed tomography with 18F-FDG and 18F-NaF at 1, 2, 4, 6, and 8 weeks after CaCl2 or saline stimulation. In the 1-week cohort (n=25), the correlation between 18F-FDG or 18F-NaF uptake and pathological markers was investigated. In the time course cohort (n=49), animals received either atorvastatin, losartan, aldactone, or risedronate to assess the effect of these drugs, and the relationship between aortic size and sequential 18F-FDG and 18F-NaF uptake or calcification volume was examined. In the 1-week cohort, the maximum standard unit value of 18F-FDG and 18F-NaF uptake correlated with CD68- (r=0.82; P=0.001) and von Kossa staining-positive areas (r=0.89; P<0.001), respectively. In the time course cohort, 18F-FDG and 18F-NaF uptake changed in a time-dependent manner and drugs attenuated this uptake. Specifically, 18F-FDG showed high uptake at weeks 1 and 2, whereas a high 18F-NaF uptake was noted throughout the study period. Atorvastatin and risedronate showed a decreased and increased aortic size, respectively. The final aortic area correlated well with 18F-FDG and 18F-NaF uptake and calcification volume, especially at 1 and 2 weeks (18F-NaF [1 week]: r=0.61, 18F-FDG [2 weeks]: r=0.51, calcification volume [1 week]: r=0.59; P<0.001). Multiple linear regression analysis showed that the combination of these factors predicted the final aortic size, with 18F-NaF uptake at 1 week being the strongest predictor. The uptake of 18F-NaF and 18F-FDG and the calcification volume at appropriate times correlated with the development of abdominal aortic aneurysms, with 18F-NaF uptake being the strongest predictor.

Gasdermin D Inhibitor Necrosulfonamide Alleviates Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4+ T cells, CD8+ T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.

Design and Characterisation of a Read-Out System for Wireless Monitoring of a Novel Implantable Sensor for Abdominal Aortic Aneurysm Monitoring.

Abdominal aortic aneurysm (AAA) is a dilation of the aorta artery larger than its normal diameter (>3 cm). Endovascular aneurysm repair (EVAR) is a minimally invasive treatment option that involves the placement of a graft in the aneurysmal portion of the aorta artery. This treatment requires multiple follow-ups with medical imaging, which is expensive, time-consuming, and resource-demanding for healthcare systems. An alternative solution is the use of wireless implantable sensors (WIMSs) to monitor the growth of the aneurysm. A WIMS capable of monitoring aneurysm size longitudinally could serve as an alternative monitoring approach for post-EVAR patients. This study has developed and characterised a three-coil inductive read-out system to detect variations in the resonance frequency of the novel Z-shaped WIMS implanted within the AAA sac. Specifically, the spacing between the transmitter and the repeater inductors was optimised to maximise the detection of the sensor by the transmitter inductor. Moreover, an experimental evaluation was also performed for different orientations of the transmitter coil with reference to the WIMS. Finally, the FDA-approved material nitinol was used to develop the WIMS, the transmitter, and repeater inductors as a proof of concept for further studies. The findings of the characterisation from the air medium suggest that the read-out system can detect the WIMS up to 5 cm, regardless of the orientation of the Z-shape WIMS, with the detection range increasing as the orientation approaches 0°. This study provides sufficient evidence that the proposed WIMS and the read-out system can be used for AAA expansion over time.

Divergent Effects of IL-18- and IL-18R-deficiency on Angiotensin II-induced Abdominal Aortic Aneurysm Formation

Currently, there are no pharmacological treatments for abdominal aortic aneurysms (AAA), and AAA rupture is fatal in ~90% of patients. Aortic inflammation is strongly correlated with the expansion of AAA and recently the NLRP3 inflammasome has been implicated in thedevelopment of AAA. Interleukin (IL)-18, an inflammasome-derived cytokine, exerts pro-inflammatory responses when bound to its cognate IL-18 receptor (IL-18Rα). The current project aimed to determine the effect of IL-18- and IL-18Rα-deficiency on the incidence of angiotensin (Ang) II-induced AAA. Ten-week-old male C57BL/6 (WT), IL-18-deficient ( Il18−/−) and IL-18Rα-deficient ( Il18r1−/−) mice were infused with Ang II (1.44 mg/kg/day, s.c.) for 28 days via osmotic minipump. Ang II-induced AAA incidence differed in all strains. While 52% of WT mice developed AAA (including premature deaths due to rupture), no AAAs were detected in Il18−/− mice (p&lt;0.05, n=20-23). Strikingly, Il18r1−/− mice exhibited a higher incidence of AAA and associated mortality compared to WT mice(88%; p&lt;0.05, n=23-25). Consistent with this finding, in vivo ultrasound imaging confirmed advanced dilation of the abdominal aorta at d7 after Ang II-treatment in Il18r1−/− mice cf. WT mice (1.49 ± 0.13 vs 1.15 ± 0.05 mm; p&lt;0.05; n=23-25). Single cell RNA-sequencing of Ang II-infused mouse aorta revealed Il18r1 gene expression was limited to gamma-delta T cells, suggesting these cells may be driving IL-18 mediated AAA formation. In summary, IL-18-deficiency affords protection from AAA formation, while AAA incidence and severity were augmented in Il18r1−/− mice. Neutralisation of IL-18, but not IL-18Rα inhibition, may represent a novel therapeutic strategy to treat AAA. NHMRC (GNT1143674). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 2017: Interleukin-10 Hydrogel-Based Therapy For Abdominal Aortic Aneurysm In Rodent Model

Abdominal aortic aneurysms (AAA) are diagnosed in over 200,000 patients per year in the United States. Endovascular AAA repair offers a strategy for those unable to undergo open operation; however there still exists a treatment gap for those whose anatomy is not suitable for current stent graft options. In response to this need for novel therapeutics to prevent aneurysm proliferation, the objective of this work was to expand AAA treatment options via anti-inflammatory hydrogel application with a handheld bioprinting device. Induction of AAA in 8-week-old, male, Sprague-Dawley rats was achieved via intraluminal infusion of porcine elastase and topical application of calcium chloride to the infrarenal aorta. Following a 4-week incubation period, rats were treated with IL-10 loaded hydrogel or blank control hydrogel. The IL-10 loaded hydrogel was placed concentrically around the aorta from the lowest renal artery to the aortic bifurcation. Rats were sacrificed 4 weeks post-treatment. Histologic analysis included hematoxylin and eosin, picrosirius red, and Verhoeff-Van Gieson for inflammatory cell infiltration, collagen and elastin content, respectively. Three-dimensional aneurysm reconstruction and analysis was performed using SkyScan1076 micro-CT at baseline, post-induction/pre-treatment and sacrifice. Immunohistochemistry (IHC) was used to examine the presence of macrophage infiltration (ED1/CD68) as a marker of inflammation. Three-dimensional reconstruction demonstrated appropriate aneurysm formation in both groups and successful aneurysm mitigation in the treatment group only. Post-mortem histologic analysis showed irregularity of the aortic intima, fibrosis, abnormal collagen organization and dramatically decreased elastin concentration in control rodents while treated rats demonstrated preservation of aortic architecture. IHC demonstrated a significant increase in macrophage infiltration in the control group when compared to treated. Taken together, the results demonstrate that peri-aortic application of an IL-10 loaded hydrogel mitigates AAA expansion in a rat model. This novel approach may be a potential strategy for treating patients with AAA whose anatomy is unsuitable for endovascular intervention.

Identification and Evaluation of Blood-Based Biomarkers for Abdominal Aortic Aneurysm.

Blood-based biomarkers for abdominal aortic aneurysm (AAA) have been studied individually; however, we considered a panel of proteins to investigate AAA prognosis and its potential to improve predictive accuracy. Using a prospectively recruited cohort of patients with/without AAA (n = 452), we conducted a prognostic study to develop a model that accurately predicts AAA outcomes using clinical features and circulating biomarker levels. Serum concentrations of 9 biomarkers were measured at baseline, and the cohort was followed for 2 years. The primary outcome was major adverse aortic event (MAAE; composite of rapid AAA expansion [>0.5 cm/6 months or >1 cm/12 months], AAA intervention, or AAA rupture). Using 10-fold cross-validation, we trained a random forest model to predict 2 year MAAE using (1) clinical characteristics, (2) biomarkers, and (3) clinical characteristics and biomarkers. Two-year MAAE occurred in 114 (25%) patients. Two proteins were significantly elevated in patients with AAA compared with those without AAA (angiopoietin-2 and aggrecan), composing the protein panel. For predicting 2 year MAAE, our random forest model achieved area under the receiver operating characteristic curve (AUROC) 0.74 using clinical features alone, and the addition of the 2-protein panel improved performance to AUROC 0.86. Using a combination of clinical/biomarker data, we developed a model that accurately predicts 2 year MAAE.

The role of diabetes on the development of abdominal aortic aneurysms (AAA)

An abdominal aortic aneurysm (AAA) is a pathological local dilatation of the abdominal aorta that may develop from a variety of causes. With a 80% mortality rate, it is mainly linked to male gender, age above 65 years, smoking, and a family history of AAA. Ultrasonography is an effective method for screening males who are 65 or older for AAA. Endovascular aneurysm repair (EVAR) procedure reduces 30-day operative mortality and hospital stay, becoming a global standard. Both open and endovascular surgery aim to cut off the aneurysm's circulation, preventing it from rupturing. Diabetes mellitus (DM) may provide protection against regrowth and the need for additional intervention after endovascular AAA repair, thereby limiting the enlargement and rupture of AAAs. Hyperglycemia thickens the aortic walls and reduces wall stress in diabetic patients' abdominal aortas. It stabilizes collagen structure and promotes the synthesis of collagen type IV. Anti-diabetic drugs like metformin, thiazolidinedione, and dipeptidyl peptidase 4 inhibitors (DPP-4i) have been shown in both animal and human studies to protect against aortic aneurysms. In a dose-response pattern, these antidiabetic drugs may lower the prevalence, incidence, and enlargement rate of AAA.

Ketosis prevents abdominal aortic aneurysm rupture through C–C chemokine receptor type 2 downregulation and enhanced extracellular matrix balance

Abdominal aortic aneurysms (AAAs) are prevalent with aging, and AAA rupture is associated with increased mortality. There is currently no effective medical therapy to prevent AAA rupture. The monocyte chemoattractant protein (MCP-1)/C–C chemokine receptor type 2 (CCR2) axis critically regulates AAA inflammation, matrix-metalloproteinase (MMP) production, and extracellular matrix (ECM) stability. We therefore hypothesized that a diet intervention that can modulate CCR2 axis may therapeutically impact AAA risk of rupture. Since ketone bodies (KBs) can trigger repair mechanisms in response to inflammation, we evaluated whether systemic ketosis in vivo could reduce CCR2 and AAA progression. Male Sprague–Dawley rats underwent surgical AAA formation using porcine pancreatic elastase and received daily β-aminopropionitrile to promote AAA rupture. Rats with AAAs received either a standard diet, ketogenic diet (KD), or exogenous KBs (EKB). Rats receiving KD and EKB reached a state of ketosis and had significant reduction in AAA expansion and incidence of rupture. Ketosis also led to significantly reduced aortic CCR2 content, improved MMP balance, and reduced ECM degradation. Consistent with these findings, we also observed that Ccr2−/− mice have significantly reduced AAA expansion and rupture. In summary, this study demonstrates that CCR2 is essential for AAA expansion, and that its modulation with ketosis can reduce AAA pathology. This provides an impetus for future clinical studies that will evaluate the impact of ketosis on human AAA disease.

Abdominal Aortic Aneurysm Response to Interleukin-10 Hydrogel-Based “Bio-Ink” Therapy in Rodent Models

Abdominal Aortic Aneurysms (AAA) are the pathological expansion of the aorta, which can rupture and cause significant mortality. Approximately 200,000 AAA cases occur annually in the US, with more than 15,000 cases resulting in death. Risk factors for AAA are similar to those of cardiovascular disease states, particularly cigarette smoking, and AAA patients are generally elderly, Caucasian males. Currently, no medical therapy exists for AAA outside of surgical intervention. We previously hypothesized that the early initiation and propagation of stages in AAA development are inflammatory driven. This process results in a weaker aortic wall, whichwe have evidenced through increased elastin breakdown products and inflammatory markers in AAA patients in comparison to matched controls. This project investigated the use of a novel anti-inflammatory hydrogel to ameliorate AAA progression.&#x0D; Our study uses a gelatin-based biodegradable bio-ink containing the anti-inflammatory cytokine interleukin-10 (IL-10), which was applied to the aorta with a novel hydrogel extruding “BIOPENCIL” device. We used a previously described rodent model consisting of intra-luminal injection of elastase in the infrarenal aorta combined with topical application of calcium chloride; alternatively, topical calcium chloride was used alone for AAA development. The BIOPENCIL was used to deliver the hydrogel containing IL-10 or control at the time of AAA creation. The animals were euthanized 14 or 21 days post-procedure and evaluated for AAA volume, surface area, and diameter alongside molecular analyses to evaluate for immunological changes between control and treatment groups. We predict that the rodent groups treated with IL-10 will not have AAA expansion, while the control group will see AAA expansion. This is based onlongitudinal data from weekly ultrasounds and will be confirmed with microCT.

Suppression of Inflammation-induced Abdominal Aortic Aneurysm Formation by Induction of Elastin Tolerance

Abdominal aortic aneurysm (AAA) is a vascular disease process whereby the aorta expands to apoint where rupture may occur. This serious condition is diagnosed in approximately 200,000 people in the United States per year and accounts for over 15,000 deaths annually. The only medical intervention proven to reduce the risk of AAA rupture is surgical repair; however, such repair is associated with high risk of death, reduced quality of life, and high expense. AAA is caused by the weakening of the artery wall due to inflammation-induced destruction of its structural components. Our clinical data shows increased levels of circulating elastin degradation products in patients with AAA, especially smokers, compared to risk factor matched controls. This observation led us to hypothesize that an immune reaction to elastin fragments initiates the inflammatory cascade in the aorta that leads to AAA formation. To test this hypothesis, C57BL/6 mice were injected with poly(lactide-co-glycolide) nanoparticle-encapsulated IL-10 to induce immune tolerance or nanoparticle-encapsulated control ovalbumin. Injection of elastin fragments was performed 7 days later to induce an immune response. AAA of the infrarenal aorta was induced by topical application of elastase during laparotomy procedure 14 days after nanoparticle injection. Aorta diameter was measured 16 days post-operatively with Microfil. Immunologic changes were evaluated by cytokine analysis, Tr1/Th17 cell ratio inperipheral blood, and splenic Th17 and Tr1 response to elastin. Based on prior work, we expect that induction of elastin tolerance using poly(lactide-co-glycolide) nanoparticle-encapsulated IL-10 will suppress abdominal aortic aneurysm expansion and promote an anti-inflammatoryenvironment characterized by increased Tr1/Th17 cell ratio, increased levels of anti-inflammatory cytokines, and decreased pro-inflammatory cytokine expression.

Evaluation of Roxithromycin as a Treatment Option for Small Abdominal Aortic Aneurysms: An Integrated Study of Meta-analysis and Network Pharmacology.

Abdominal aortic aneurysm (AAA) is a segmental, progressive, and fatal vascular disorder, and the current strategy for small AAAs is close observation alone.The purpose of this study is to summarize the available evidence to assess the effects of antibiotics on small abdominal aortic aneurysms (AAA). We searched PubMed, EMBASE, Web of Science, and Scopus from inception to September 29, 2023, and included randomized controlled trials (RCTs) that evaluated the effects of antibiotics on small AAAs in humans. We first performed a meta-analysis to assess the effects of antibiotics on small AAAs. Afterward, network pharmacology analysis was applied to investigate the optimal drug generated from the meta-analysis results. We searched Pharmmapper and GeneCards to obtain the common potential targets of the selected drug and AAA-related targets. The protein-protein interaction network and functional enrichment analysis were performed by the STRING database, Cytoscape 3.7.2 software, and R, respectively. Docking studies were carried out for validation. We incorporated data from six RCTs involving a total of 997 patients. The results of this meta-analysis revealed that roxithromycin exhibited a modest yet statistically significant protective effect in terms of slowing down the AAA expansion rate. Furthermore, our subsequent bioinformatics analysis pinpointed MMP-2, MMP-9, ALB, MMP-3, and CCL-5 as potential therapeutic targets that could be explored for the treatment of AAA using roxithromycin. In conclusion, the study indicates roxithromycin is a promising drug for treating small AAAs and supports its underlying clinical use in small AAAs.

Antiplatelet or Anticoagulant Therapy for Abdominal Aortic Aneurysms: Growth and Clinical Outcomes.

Intraluminal thrombi in the abdominal aortic aneurysms (AAA) were demonstrated to increase aneurysm growth. The effect of treatments on thrombus reduction upon AAA enlargement and clinical endpoints is uncertain Therefore, this study aimed to investigate the effect of antiplatelet and anticoagulant therapy on AAA growth and clinical outcomes. A total of 357 patients with AAAs were enrolled in this study. They were divided into 2 groups based on their medical therapies. Patients on antiplatelet and anticoagulant therapy were assigned to group 1 (n = 234) and group 2 (n = 92), respectively. The greatest reduction in thrombus diameter change was observed in patients with anticoagulant therapy (group 1, -2.26 mm; group 2, -8.16 mm; P =.001). The greatest aneurysmal enlargement was found in patients with antiplatelet therapy. There was less AAA progression with anticoagulant therapy than with the other therapy (group 1, 2.08 mm; group 2, 1.31 mm P =.027. The more operational need was observed in patients with antiplatelet therapy than in patients with anticoagulant therapy ( group 1 67, group 2 16, P =.036) Conclusion: In our study, it was revealed that anticoagulant therapy has been associated with decreased thrombus diameter and less aneurysmal enlargement compared with antiplatelet therapy. Furthermore, this beneficial effect on the thrombus size and aneurysmal diameter decreased the operational need in patients with anticoagulant therapy.

Effect of Antiplatelet Agents on Abdominal Aortic Aneurysm Process: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aims to investigate whether antiplatelet agents are associated with the reduction, expansion, and rupture of abdominal aortic aneurysm (AAA). A thorough exploration was conducted on four prominent databases, namely EMBASE, Ovid, PubMed, and Scopus, to identify studies that reported the influence of antiplatelet agents on the sac development of AAA. The assessment was carried out until March 2023. R software v.4.1 was used for statistical analysis. After reviewing 13 publications which included a total of 5392 patients (1446 in the antiplatelet group and 2540 in the control group), a meta-analysis was conducted. The results of the analysis revealed that there was no significant difference in the annual growth rate of AAA diameter between those who received antiplatelet agents and those who did not (mean difference (MD) = -0.04, 95% CI = [-0.37, 0.30]; heterogeneity: p 0.01, = 91%, 2 = 0.1278). Additionally, there was no difference in the number of patients who experienced aneurysm diameter expansion between the two groups, significantly (odds ratio (OR) = 0.96, 95% CI = [0.41, 2.25]; heterogeneity: p 0.01, = 78%, 2 = 0.5849). Antiplatelet agents do not affect AAA's reduction, expansion, or rupture. There is no benefit to AAA patients taking antiplatelet agents for the purpose of slowing down growth rates of sac diameter.

Abstract 13582: Interferon Regulatory Factor 8 Promotes Abdominal Aortic Aneurysm via Inducing Type I Conventional Dendritic Cell Differentiation

Introduction: Abdominal aortic aneurysm (AAA) remains to be the most common true aneurysm worldwide. Previous studies identified the participation of dendritic cells (DC) in the pathogenesis of AAA. However, the detailed subtypes involved and mechanisms remain unknown. Our previous RNA-Seq data determined dramatically increased Irf8 in AAA samples, which drives DC differentiating to Type I conventional dendritic cells (cDC1). Aim: The aim of the work is to determine the role of interferon regulatory factor 8 (IRF8) in the development of AAA. Methods and Results: Murine AAA were induced via elastase infusion. The single-cell transcriptomic sequencing of CD45+ cells in murine AAA samples identified the dramatically increased cDC1. By flow cytometry, we found that the ratio of CD103 + cDC1s reached maximum at day 7. Compared with the control group, Irf8 CAG-LSL Itgax Cre mice ( Irf8 overexpression in DC) suffered significantly more severe aneurysm expansion, elastin degradation and apoptosis of smooth muscle cells, while the AAA development in Irf8 flox/flox Itgax Cre mice ( Irf8 deletion in DC) was less sharp. Batf3 -/- mice which were cDC1 depleted, showed similar characteristic in AAA expansion with Irf8 flox/flox Itgax Cre mice. The effective CD8 + T cells increased significantly in Irf8 CAG-LSL Itgax Cre mice than the control group, while decreased in Irf8 flox/flox Itgax Cre ones. Deletion of Clec9a which blocks cross-present dead-cell-associated antigens to the CD8 + T cells, also attenuated AAA development, in accordance with Irf8 flox/flox Itgax Cre mice in gross anatomy and pathology changes. Conclusion: Our findings suggest that the activation of IRF8 promotes cDC1 differentiation, which subsequently activate CD8 + T cells and contribute to destruction of the aortic-wall and AAA formation.

Preemptive Embolization of the Lumbar Arteries and Inferior Mesenteric Artery to Prevent Abdominal Aortic Aneurysm Enlargement Associated with Type 2 Endoleak Following Endovascular Aneurysm Repair.

This study aims to evaluate the efficacy of preemptive embolization (PE) of the lumbar arteries (LAs) and inferior mesenteric artery (IMA) (PELI) for preventing abdominal aortic aneurysm (AAA) enlargement associated with type 2 endoleak (T2EL). Patients who underwent endovascular aneurysm repair (EVAR) between January 2015 and December 2020 were classified into the control (without PE), IMA (PE of a patent IMA with a diameter ≥2.5 mm), and PELI (PE of patent LAs with a diameter ≥2 mm and IMA) groups. The rate of freedom from AAA enlargement following EVAR (enlargement ≥5 mm from pre-EVAR) was compared using the log-rank test. The prevalence of T2EL at 6 months and 1 year after EVAR was compared using Fisher's exact test. The cumulative rates of freedom from AAA enlargement at 54 months after EVAR (maximum observational period in the PELI group) were as follows: control group, 77.5%; IMA group, 62.5%; and PELI group, 100%. The mean CT follow-up periods of the control, IMA, and PELI groups were 46.4 ± 22.3, 31.1 ± 20.6, and 22.9 ± 15.5 months, respectively. None of the 31 patients in the PELI group experienced AAA enlargement after EVAR, whereas 2 out of the 16 patients in the IMA group and 20 out of the 98 patients in the control group had AAA enlargement. No significant differences were observed in the rate of freedom from AAA enlargement (PELI group vs. IMA group, P = 0.11; PELI group vs. control group, P = 0.11). The prevalence of T2EL was significantly lower in the PELI group than in the control group at 6 months (13.6% in PELI group vs. 42.1% in control group, P = 0.02) and 1 year (14.3% in PELI group vs. 40.0% in control group, P = 0.04). PELI was significantly associated with a low prevalence of T2EL and may prevent T2EL-associated AAA enlargement.

Intermediate pressure-normalized principal wall strain values are associated with increased abdominal aortic aneurysmal growth rates.

Current abdominal aortic aneurysm (AAA) assessment relies on analysis of AAA diameter and growth rate. However, evidence demonstrates that AAA pathology varies among patients and morphometric analysis alone is insufficient to precisely predict individual rupture risk. Biomechanical parameters, such as pressure-normalized AAA principal wall strain (/PP, %/mmHg), can provide useful information for AAA assessment. Therefore, this study utilized a previously validated ultrasound elastography (USE) technique to correlate /PP with the current AAA assessment methods of maximal diameter and growth rate. Our USE algorithm utilizes a finite element mesh, overlaid a 2D cross-sectional view of the user-defined AAA wall, at the location of maximum diameter, to track two-dimensional, frame-to-frame displacements over a full cardiac cycle, using a custom image registration algorithm to produce /PP. This metric was compared between patients with healthy aortas and AAAs (≥3 cm) and compared between small and large AAAs (≥5 cm). AAAs were then separated into terciles based on /PP values to further assess differences in our metric across maximal diameter and prospective growth rate. Non-parametric tests of hypotheses were used to assess statistical significance as appropriate. USE analysis was conducted on 129 patients, 16 healthy aortas and 113 AAAs, of which 86 were classified as small AAAs and 27 as large. Non-aneurysmal aortas showed higher /PP compared to AAAs (0.044 ± 0.015 vs. 0.034 ± 0.017%/mmHg, p = 0.01) indicating AAA walls to be stiffer. Small and large AAAs showed no difference in /PP. When divided into terciles based on /PP cutoffs of 0.0251 and 0.038%/mmHg, there was no difference in AAA diameter. There was a statistically significant difference in prospective growth rate between the intermediate tercile and the outer two terciles (1.46 ± 2.48 vs. 3.59 ± 3.83 vs. 1.78 ± 1.64 mm/yr, p = 0.014). There was no correlation between AAA diameter and /PP, indicating biomechanical markers of AAA pathology are likely independent of diameter. AAAs in the intermediate tercile of /PP values were found to have nearly double the growth rates than the highest or lowest tercile, indicating an intermediate range of /PP values for which patients are at risk for increased AAA expansion, likely necessitating more frequent imaging follow-up.

Pharmacological Inhibition of Gasdermin D Suppresses Angiotensin II-Induced Experimental Abdominal Aortic Aneurysms.

Gasdermin D, a molecule downstream of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing inflammasome, forms the membrane pore for the secretion of interleukin (IL)-1β and IL-18, and also mediates pyroptosis. This study was to explore the influence of treatment with disulfiram, a small molecule inhibitor to gasdermin D, on the formation and progression of experimental abdominal aortic aneurysms (AAA). AAAs were induced in 10-week-old male apolipoprotein E deficient mice by subcutaneous infusion of angiotensin II (1000 ng/min/kg body weight) for 28 days via osmotic minipumps. Three days prior to angiotensin II infusion, disulfiram (50 mg/kg) or an equal volume of saline as the vehicle control was administered daily via oral gavage. The influence on experimental AAAs was analyzed by serial measurements of aortic diameters via ultrasonography, grading AAA severity and histopathology at sacrifice. Serum IL-1β and IL-18 levels, systolic blood pressure, total cholesterol, and triglyceride were also measured. Additional experiments assayed the influences on the cell viability and IL-1β secretion of in vitro activated macrophages. Disulfiram significantly reduced the enlargement, incidence, and severity of angiotensin II-induced experimental AAAs with attenuation of medial elastin breaks, mural macrophage accumulation, and systolic blood pressure. The AAA suppression was also associated with reduced systemic levels of IL-1β but not IL-18. However, disulfiram treatment had no impact on body weight gain and lipid levels in aneurysmal mice. Additionally, disulfiram treatment also markedly reduced the secretion of IL-1β from activated macrophages with a limited effect on cell viability in vitro. Gasdermin D inhibition by disulfiram attenuated angiotensin II-induced experimental AAAs with reduced systemic IL-1β levels and in vitro activated macrophage IL-1β secretion. Our study suggests that pharmacological gasdermin D inhibition may have translational potential for limiting clinical AAA progression.

Nicotine Administration Augments Abdominal Aortic Aneurysm Progression in Rats.

Inflammation and elastin degradation are key hallmarks in the pathogenesis of abdominal aortic aneurysms (AAAs). It has been acknowledged that activation of alpha7 nicotinic acetylcholine receptors (α7nAChRs) attenuates inflammation, termed the cholinergic anti-inflammatory pathway (CAP). Thus, we hypothesize that low-dose nicotine impairs the progression of elastase-induced AAAs in rats by exerting anti-inflammatory and anti-oxidative stress properties. Male Sprague-Dawley rats underwent surgical AAA induction with intraluminal elastase infusion. We compared vehicle rats with rats treated with nicotine (1.25 mg/kg/day), and aneurysm progression was monitored by weekly ultrasound images for 28 days. Nicotine treatment significantly promoted AAA progression (p = 0.031). Additionally, gelatin zymography demonstrated that nicotine significantly reduced pro-matrix metalloproteinase (pro-MMP) 2 (p = 0.029) and MMP9 (p = 0.030) activity in aneurysmal tissue. No significant difference was found in the elastin content or the score of elastin degradation between the groups. Neither infiltrating neutrophils nor macrophages, nor aneurysmal messenger RNA (mRNA) levels of pro- or anti-inflammatory cytokines, differed between the vehicle and nicotine groups. Finally, no difference in mRNA levels of markers for anti-oxidative stress or the vascular smooth muscle cells' contractile phenotype was observed. However, proteomics analyses of non-aneurysmal abdominal aortas revealed that nicotine decreased myristoylated alanine-rich C-kinase substrate and proteins, in ontology terms, inflammatory response and reactive oxygen species, and in contradiction to augmented AAAs. In conclusion, nicotine at a dose of 1.25 mg/kg/day augments AAA expansion in this elastase AAA model. These results do not support the use of low-dose nicotine administration for the prevention of AAA progression.

Abstract 270: Multi-transcriptomic Profiling Reveals Novel Molecular Mediators During Abdominal Aortic Aneurysm Expansion.

Abdominal aortic aneurysm (AAA), a life-threatening condition associated with high morbidity and mortality rates, is despite decades of intense research still mostly treated by surgical repair as currently no medical therapy is available. Long non-coding RNAs (lncRNAs) are highly cell type specific and potential molecular disease modulators, posing potential drug targets. We performed single cell (sc) RNA and combined total (bulk) RNA sequencing to study the transcriptome of AAAs from patients undergoing open aortic repair. Further, we implemented hybridization-based RNA in situ sequencing (HybRISS) to localize highly intriguing genes within the tissue.In this current study, we examined three different sequencing datasets (total RNA from dilated vs. non- dilated AAA specimen from an individual patient each, AAA vs. control from individual patients and one scRNA-seq dataset). Six lncRNAs could be cross-referenced between all three datasets. All of these lncRNAs presented a cell-type specific expression pattern, with three lncRNAs being highly enriched within the SMC cluster. We found all newly identified lncRNAs conserved in our bulk and scRNA-seq datasets of experimentally-induced AAA in mice and LDLR-deficient Yucatan mini-pigs. Further, potential novel regulator genes could be visualized in human AAA tissue sections using HybRISS to resolve their distinct location and co-expression pattern within the diseased tissue. In summary, our approach utilizing dilated and non-dilated human tissue specimens, different preclinical models and resulting datasets demonstrate that combining bulk Seq, scRNA-Seq data and spatially resolved sequencing methods are powerful tools to detect and describe novel lncRNAs as disease modulators.

Outcomes of embolization procedures for type II endoleaks following endovascular abdominal aortic repair.

The objective of this study was to investigate the mid-term outcomes of embolization procedures for type II endoleak after endovascular abdominal aortic repair, and clarify the risk factors for aneurysm enlargement after embolization procedures. This was a retrospective multicenter registry study enrolling patients who underwent embolization procedures for type II endoleaks after EVAR from January 2012 to December 2018 at 19 Japanese centers. The primary end point was the rate of freedom from aneurysm enlargement, more than 5mm in the aortic maximum diameter, after an embolization procedure. Demographic, procedural, follow-up, and laboratory data were collected. Continuous variables were summarized descriptively, and Kaplan-Meier analyses and a Cox regression model were used for statistical analyses. A total of 315 patients (248 men and 67 women) were enrolled. The average duration from the initial embolization procedure to the last follow-up was 31.6± 24.6months. The rates of freedom from aneurysm enlargement at 3 and 5years were 55.4± 3.8% and 37.0± 5.2%, respectively. A multivariate analysis revealed that a larger aortic diameter at the initial embolization procedure and the presence of a Moyamoya endoleak, defined as heterogeneous contrast opacity with an indistinct faint border, were associated with aneurysm enlargement after embolization management. The embolization procedures were generally ineffective in preventing further expansion of abdominal aortic aneurysms in patients with type II endoleaks after EVAR, especially in patients with a large abdominal aortic aneurysm and/or a presence of a Moyamoya endoleak.