Search Results for: Intervalli di sorveglianza per Aneurisma Aorta Addominale (AAA)

Circulation, Volume 150, Issue Suppl_1, Page A4137693-A4137693, November 12, 2024. Intro:Abdominal aortic aneurysm (AAA) is a prevalent condition in the elderly, with a significant risk of mortality if it ruptures. Despite this, there is currently no effective medical therapy to prevent AAA growth and rupture. The monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis appears to play a role in AAA development. We demonstrated the potential of CCR2 as a theranostic marker for predicting AAA rupture, along with the effectiveness of a CCR2 inhibitor (RS-504393) in mitigating rupture. We further hypothesized that CCR2 inhibition can impact monocytes/macrophages trafficking in aortic tissue.Mehtods:Sprague-Dawley rats (N=54) underwent intraluminal aortic exposure to porcine pancreatic elastase (PPE) to induce aneurysmal degeneration. To stimulate AAA rupture, rats also recieved β-aminopropionitrile (BAPN). After 3 days of PPE exposure, a group of rats with AAA were administered a CCR2 inhibitor (CCR2i) either daily until the end of the study (CCR2i Full), or discontinued at day 5 (CCR2i Short), while the remaining rats proceeded without intervention (Fig1A). Ultrasound (12MHz) was performed at 7&14 days to assess diameter, while another cohort of animals were euthanized at 6 days, prior to rupture, for single-cell RNA sequencing analysis. The relative content of inflammatory cells within the aortic tissue was analyzed.Results:Both CCR2i Short and CCR2i Full treated, exhibited a significant reduction in AAA diameter at day 7 and 14 compared to controls (p

Circulation, Volume 150, Issue Suppl_1, Page A4146208-A4146208, November 12, 2024. Background:Cigarette smoking has been identified as an important risk factor for the development of abdominal aortic aneurysm (AAA) and is known to influence levels of blood proteins. However, protein mediators of the smoking-AAA link remain unexplored. Here, we conducted a two-stage Mendelian randomization (MR) study to comprehensively pinpoint possible protein mediators by leveraging large-scale proteomic and genomic data.Methods:We first assessed the associations between genetically predicted smoking traits (lifetime smoking index, smoking initiation and cigarettes per day) and AAA risk (βtotal). We then performed a protein-wide MR analysis to explore circulating proteins associated with smoking traits (β1). Among identified proteins, we established their levels associated with AAA risk (β2). According to directionality (βtotalvs. β1×β2), pathways were constructed, and corresponding mediation proportions were estimated by (β1× β2)/ βtotal×100%. Genetic instruments for smoking traits were selected by filtering variants atP< 5×10-8andr2

Circulation, Volume 150, Issue Suppl_1, Page A4144671-A4144671, November 12, 2024. Introduction/Background:Clamping the ascending aorta in acute type A aortic dissection (aTAAD) surgery is an important technique that facilitates proximal procedures such as reinforcement and root replacement during systemic cooling and reduces extracorporeal circulation time. However, in case of aTAAD with thrombosed false lumen, clamping the aorta may lead to serious thromboembolism such as ischemic strokeResearch Questions/Hypothesis:We sought to compare the safety and the efficacy of cross-clamp of the ascending aorta with thrombosed and patent false lumen of aTAAD.Methods/Approach:From January 2004 to December 2023, a total of 1550 patients with aTAAD underwent emergent surgery at our institution. Among them, 1404 (91%) patients underwent aortic cross-clamp during systemic cooling. The completeness of the cross-cramp was 99.9%. They were divided into 2 groups based on the false lumen status in the ascending aorta: thrombosed (group T, n=399 [28%]) and patent (group P, n=1005 [72%]). After propensity score matching, 389 patients in each group were matched.Results/Data:After matching, there were no significant differences in age and male gender ratio between the groups. (Table 1A) Preoperative shock state and malperfusion were also similar. The cannulation site did not differ between the groups (Femoral artery: 79% vs. 84% for group T vs. P,P= 0.11; Subclavian artery: 12% vs. 8.0%,P= 0.12). There were no significant differences in the incidence of ischemic stroke (5.4% vs. 6.2% for group T vs. P,P= 0.65), 30-day mortality ( 2.1 vs. 4.1% for group T vs. P,P= 0.10 ), and spinal cord injury (1.3 vs. 1.0% for group T vs, P,P= 1.00), respectively. (Table 1 B）Logistic regression model revealed that thrombosed type dissection was not an independent risk factor for ischemic stroke (odds ratio 1.13, 95% confidence interval 0.66–1.92;P= 0.66).Conclusions:Cross-clamp of the ascending aorta in aTAAD surgery was very useful in that the proximal procedures could be performed during systemic cooling. Notably, in patients with thrombosed false lumen, the procedure could be performed safely without increasing the risk of cerebral complications.

Circulation, Volume 150, Issue Suppl_1, Page A4140978-A4140978, November 12, 2024. Introduction:The transformation of vascular smooth muscle cells (VSMCs) from contractile to synthetic is an important step in diabetic vascular remodeling. DOT1L, the only lysine methyltransferase at the H3K79me locus, has not been fully elucidated in diabetic vascular remodeling, and DOT1L-based methods may be critical in discovering phenotypic transformation of VSMCs to improve clinical outcomes in patients with diabetic cardiovascular disease.Hypothesis:Whether DOT1L promotes the phenotypic transformation of VSMCs and further affects diabetic vascular remodeling.Methods:Primary VSMCs were extracted from the thoracic aorta of healthy, SPF-free male rats. DOT1L was up-regulated or down-regulated in vitro by lentivirus infection with VSMCs, followed by an insulin stimulation. VSMCs phenotype was assessed by EdU, flow cytometry, scratch assay, Transwell chamber assay, western blot; In addition, the mechanism of DOT1L on insulin-induced phenotypic transformation of VSMCs was explored. SD rats were fed with high glucose and high fat for 4 weeks, and were given a single intraperitoneal injection of low-dose (30 mg) STZ to establish a diabetes model. After 2 weeks of continuous high-glucose and high-fat feeding, a carotid balloon injury model was established, and then lentivirus was injected into the injured artery segment to overexpress or knock down DOT1L in vivo, and the role and mechanism of diabetic VSMCs phenotype were evaluated by immunohistochemistry and western blot.Results:After 24 hours of stimulation with 100 nmol/L insulin, the expressions of VSMCs synthesized phenotype OPN, proliferative phenotype PCNA, migration phenotype MMP2 and MMP9 increased, the expression of α-SMA decreased, and proliferation and migration occurred. Down-regulation of DOT1L can inhibit the conversion of insulin-induced VSMCs from contractile to synthetic and improve diabetic vascular remodeling. Mechanistically, overexpression of DOT1L promotes the activation of JAG1/NOTCH1 signaling pathway, promotes the expression of synthetic phenotypic proteins, and inhibits the expression of contractile phenotypic proteins, which ultimately promotes the transformation of VSMCs from contractile to synthetic in diabetic environment.Conclusions:Down-regulation of DOT1L can inhibit the activation of JAG1/NOTCH1 signaling pathway, thereby inhibiting the phenotypic transformation of VSMCs and improving diabetic vascular remodeling.

Circulation, Volume 150, Issue Suppl_1, Page A4139212-A4139212, November 12, 2024. Introduction:Hypoplastic left heart syndrome (HLHS) with mitral stenosis/aortic atresia (MS/AA) is associated with worse outcomes compared to other anatomic variants. It is unclear whether this is related to left ventricle-coronary artery (LV-CA) fistula.Research Question:We sought to compare outcomes for patients with HLHS (MS/AA) with and without LV-CA fistula.Methods:Retrospective cohort study of patients with HLHS (MS/AA) who underwent stage 1 palliation at Boston Children’s Hospital 2008-2023. Presence of LV-CA fistula was defined by angiography.Results:Among 91 patients, 58 (64%) had LV-CA fistula and 33 (36%) did not. LV-CA fistula was diagnosed prior to initial palliation in 31 (53%) patients. Birth weight (BW) and gestational age (GA) were similar between groups. Mean postnatal echocardiogram ascending aorta diameter z-score was -4.29 ± 0.74 and was similar between groups. In total, 67 (75%) of patients underwent surgical stage 1 palliation and 22 (25%) underwent hybrid palliation; hybrid palliation was more common in the fistula group (36% vs 6%, p=0.007). Transplant-free survival at 1 year was 63% (95% confidence interval [CI]: 49%, 74%) and 79% (95% CI: 61%, 89%) in those with and without fistula, respectively. There was a trend towards shorter time to death or transplant in patients with LV-CA fistula than for those without (Figure 1, p=0.083). In univariate analysis, lower GA (↓1 week; HR 1.34, 95% CI 1.18, 1.51), lower BW (↓0.5 kg; HR 1.69, 95% CI 1.28, 2.23), and initial hybrid palliation (HR 3.55, 95% CI 1.82, 6.94) were associated with an increased hazard of death/transplant (all p

Circulation, Volume 150, Issue Suppl_1, Page A4147041-A4147041, November 12, 2024. Background:Endotrophin, a peptide derived from the COL6A3 chain that is released during COL6 formation, has been associated with cardiorenal outcomes in human observational studies and has demonstrated a strong association with adverse outcomes in heart failure with preserved ejection fraction. Endotrophin may modulate various biologic processes, but its potential causal cardiovascular effects are at present poorly understood.Research Questions/Aims:We aimed to investigate the potential causal effects of COL6A3-derived endotrophin on cardiorenal outcomes in humans, and its mediating mechanisms.Methods:Using genetic summary data from the UK Biobank (Olink, N=51,637) and deCODE (SOMAScan, N=35,365) studies, we first validated genetic instruments for COL6A3-derived endotrophin. We then leveraged those genetic instruments to investigate the effects of endotrophin inhibition on primary cardiorenal outcomes, including coronary artery disease, abdominal aortic aneurysm (AAA), chronic kidney disease, and heart failure (HF). Results informed our secondary analyses, where we investigated the effects of endotrophin on pulse pressure and aortic diameter. Next, using independent genetic association summary statistics (N=200,000-1,000,000), we explored the human proteome to gain insights into mechanisms of action, and the human phenome to assess the widespread health implications of COL6A3-derived endotrophin. We adjusted for multiple comparisons using the false discovery rate method.Results:MR findings revealed a significant association between COL6A3-derived endotrophin inhibition and reduced risk of HF (OR=0.60; 95%CI=0.51, 0.77) and AAA (OR=0.49; 95%CI=0.31, 0.77). Proteome-wide MR suggested that genetically proxied COL6A3-derived endotrophin inhibition was significantly associated with reduced COL28A1 (β=-0.71; 95%CI= -0.88, -0.53) and MAM domain containing-2 (MAMDC2; β=-0.71; 95%CI=-0.84, -0.57) levels. Phenome-wide association MR analyses suggested that genetically proxied COL6A3-derived endotrophin inhibition was associated with reduced risk of thoracic aortic aneurysm (OR=0.35, 95%CI=0.21, 0.59) and bronchiectasis (OR=0.26, 95%CI=0.14, 0.48).Conclusions:This is the first study to validate genetic instruments for COL6A3-derived endotrophin, and to provide genetic evidence supporting a causal role for endotrophin on HF and AAA risk. Clinical trials are required to further explore the effect of pharmacologically perturbing COL6A3-derived endotrophin levels.

Circulation, Volume 150, Issue Suppl_1, Page A4141690-A4141690, November 12, 2024. Background:Arterial calcification often occurs with bone mineral loss in osteoporosis, for which bisphosphonates are a standard therapy. Mice lacking the matrix GLA protein (Mgp) exhibit lethal arterial calcification and cranial bone formation deficits causing dental malocclusion. Mgp not only binds to hydroxyapatite but also inhibits the bone morphogenic protein activation of Runx2 transcription factor, which drives the osteogenic conversion of arterial smooth muscle cells (SMCs). Prior studies showed bisphosphate therapy ameliorates warfarin-induced arterial calcification in rats. This study investigated whether bisphosphonate (Alendronate,ALN) treatment could address bone deficits and arterial calcification in Mgp-null mice.Methods:Mgp-null mice were subjected to various doses of Alendronate therapy starting at weaning or postnatal day 3. Dental malocclusion severity was assessed by incisor trimming frequency. Arterial calcification was quantified by Alizarin red staining and µ-CT.Results:In Mgp-null mice, susceptibility to aortic artery calcification was not uniform but varied by location, with calcification highest at the proximal aorta. Of note, recurring nodes of calcification were found to correspond to branch points of vertebral arteries, with internodal regions showing less calcification. Alendronate therapy started at 3 weeks of age ameliorated dental malocclusion in Mgp-null mice of both sexes and improved but did not normalize body weight gain in males and females. However, no improvement in arterial calcification was observed at 7 weeks. Similarly, Alendronate therapy at lower doses from postnatal day 3 for 5 weeks ameliorated dental malocclusion and improved but did not normalize body weight gain in both sexes, while at higher doses, Alendronate prevented incisor development and caused growth retardation in both wild type and Mgp-null mice. However, Alendronate accelerated the appearance of Runx2 in SMCs of the aorta and worsened internodal arterial calcification in Mgp-null mice in a dose-dependent fashion, but not in Mgp-hemizygous or wild type mice.Conclusion:Our study reveals an important dichotomy in Mgp’s function in bone and arteries. The bone deficits in Mgp-null mice, highlighted by incisor malocclusion, could be rescued by bisphosphonate treatment, whereas the arterial calcification could not. Thus, Mgp performs an essential function to prevent arterial calcification that cannot be restored by bisphosphonate therapy.

Circulation, Volume 150, Issue Suppl_1, Page A4138717-A4138717, November 12, 2024. Clinical presentation:A 75-year-old male with previous 3 vessel CABG and bioprosthetic aortic valve (BAV) surgical replacement in 2013 was admitted with severe sepsis from diabetic foot ulcer complicated with Group A Streptococcus bacteremia and infective root aortitis.Imaging Findings:Initial technically limited transthoracic echocardiogram was followed by a transesophageal echocardiogram (TEE) that demonstrated a well seated BAV with mildly thickened leaflets but no vegetations, mild intra-valvular regurgitation, and 9 mm end-diastolic soft tissue echoreflectant thickening of the posterior aortic root (AoR) extending up 3 cm from the aortic annulus to the ascending aorta (Fig 1A,B). There were no signs of perivalvular abscess formation. Initial FDG PET-CT demonstrated heterogenous hypermetabolic activity at the annulus of the BAV (Fig 1C) and AoR (Fig 1D) consistent with aortitis.Decision-making:In the absence of guidelines for the management of these patients, a multidisciplinary team including cardiology, cardiothoracic surgery, and infectious disease opted for a conservative medical therapy instead of high-risk surgery. Patient then underwent left foot first digit amputation to achieve infectious source control. Upon completion of 4 out of 6 weeks of intravenous ceftriaxone 2 grams daily, repeat TEE showed improved AoR thickening to 6 mm (Fig 1E,F), no AoR abscess, and unchanged BAV structure and function. Repeat FDG PET-CT at the same time of TEE demonstrated persistent but improved hypermetabolic activity of the BAV annulus and AoR. After 10 weeks of IV antibiotics, repeat FDG PET-CT showed further decrease in metabolic activity on both areas. However, an Indium-111 labeled leukocyte scan showed no activity at the BAV annulus and root (Fig 1G) and therefore indicated healed AoR aortitis, which was further supported by significant decrease of ESR and CRP initial values of 126 mm/hr and 122.7 mg/L to 11 mm/hr and 3 mg/L, respectively. Patient is currently clinically stable 8 months later.Conclusion:This case illustrates that a conservative management of infective AoR aortitis with an extended course of intravenous antibiotics is a reasonable alternative to high-risk re-do valve and root surgery.

Circulation, Volume 150, Issue Suppl_1, Page A4146394-A4146394, November 12, 2024. Background:Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Genetic studies have identified numerous associated loci, many potentially encoding plasma proteins. However, the causal effects of plasma proteins on AAA have not been thoroughly studied. We used genetic causal inference approaches to identify plasma proteins that have a potential causal impact on AAA.Methods:Causal inference was performed using two-sample Mendelian randomization (MR). For AAA, we utilized recently published summary statistics from a multi-population genome-wide association (GWAS) meta-analysis including 39,221 individuals with, and 1,086,107 individuals without, AAA from 14 cohorts. We used protein quantitative trait loci (pQTLs) identified in two large-scale plasma-proteomics studies (deCODE and UKB-PPP) to generate genetic instruments. We tested 2409 plasma proteins for possible causal effects on AAA using two-sample MR with inverse variance weighting and common sensitivity analyses to evaluate the MR assumptions. Bayesian colocalization and gene ontology (GO) enrichment analyses provided additional insights.Results:MR identified 77 plasma proteins whose levels were associated with AAA at FDR0.7), indicating that the plasma levels and AAA likely shared causal variants. Among those supported by both MR and colocalization were previously experimentally validated proteins such as PCSK9 (OR 1.3; 95%CI 1.2-1.4; P

Circulation, Volume 150, Issue Suppl_1, Page A4138097-A4138097, November 12, 2024. Background:Excessive lipid aggregation in macrophages triggers foam cell formation, contributing to arterial plaque development. This underlies the chronic vascular condition of atherosclerosis like coronary heart disease and ischemic stroke. Epsins, endocytic adaptor proteins, are recognized as key accelerators of atherosclerosis progression, particularly in individuals adhering to a Western diet (WD). However, the intricate molecular mechanisms governing the role of epsins in foam cell formation, disease progression, and potential therapeutic interventions remain elusive. Here, we aim to probe the metabolic regulatory functions of epsins in atherosclerosis and design the potential treatment strategies.Methods:We established mouse models fed a WD (16 weeks), including ApoE-deficient (ApoE-/-) mice and macrophage-specific deletion of epsin in ApoE-deficient backgrounds (LysM-DKO/ApoE-/-). Foam cell formation is dramatically hindered in WD-fed LysM-DKO/ApoE-/-compared to ApoE-/-mice.Results:Single-cell transcriptomic profiling of aorta cells revealed 20 cell types, including seven VSMC subtypes, five macrophage subtypes, endothelial cells, and others. Pathway enrichment analysis showed that modulating VSMC1 is involved in inflammation and migration, while VSMC2 is associated with VSMC phenotype switching. We observed increased populations of modulating VSMC1, VSMC2, foamy-Trem2, and inflammatory macrophages in ApoE-/-mice, which decreased significantly in epsin-deficient mice. The RNA velocity analysis revealed that modulating VSMC2 transitioned towards macrophages with probabilities of 0.7 in ApoE-/-mice and 0.01 in LysM-DKO/ApoE-/-mice. Additionally, epsin deletion reversed endothelial cell dysfunction by preventing the endothelial-to-mesenchymal transition. Using MEBOCOST tool, we identified the cholesterol, glucose mediated cell-signals are downregulated in LysM-DKO/ApoE-/-. Moreover, enhanced inflammatory signals via ligands such as Il1b and C1qa in VSMCs are downregulated when epsin is depleted.Conclusion:Single-cell data analysis reveals that epsin deletion reduces foam cell formation and rewires VSMC cells function by inhibiting VSMC2 to macrophage transition. Cholesterol and glucose-mediated metabolic signals play a pivotal role in atherosclerotic lesion formation. Epsin deletion diminishes these metabolic, and inflammatory signals. Therefore, targeting epsin could offer a novel therapeutic strategy for treating atherosclerosis.

Circulation, Volume 150, Issue Suppl_1, Page A4117345-A4117345, November 12, 2024. Introduction:Acute type A aortic dissection (ATAAD) is typically treated by replacement of the ascending aorta (+/- root) and proximal arch. However, 70-85% of patients have residual distal dissection post-repair, and 20-40% require late reoperation for aneurysmal degeneration of the distal aorta (ADDA). Since an individual patient’s risk of ADDA cannot be accurately predicted, current guidelines recommend lifelong aortic surveillance imaging for all patients.Hypothesis:Computational fluid dynamics (CFD) simulations of aortic hemodynamics post-repair can accurately identify patients at late risk of ADDA.Methods:We performed CFD simulations of 50 patients following hemi-arch replacement for ATAAD. Patient-specific 3D models were generated from the aortic root to iliac bifurcation (including arch branches) from postoperative 0.6mm contrast-enhanced CT angiograms taken

Circulation, Volume 150, Issue Suppl_1, Page A4141400-A4141400, November 12, 2024. Introduction:Chylomicrons are major lipid fuel for cells. They contain dietary triglycerides, cholesterols, and apolipoproteins. In the intestine, apolipoprotein C-III (apoC-III) is produced during fat feeding, and secreted onto chylomicrons. ApoC-III is a key regulator of chylomicron hydrolysis and clearance through its inhibitory effects on lipoprotein lipase (LPL) and low-density lipoprotein receptor (LDLr) in multiple tissues. In humans, genetic polymorphisms in apoC-III are directly tied to plasma triglyceride levels and cardiovascular disease risk. As a result, apoC-III is a major drug target with antisense therapies already in clinical trials. Though plasma chylomicrons and the lipids they carry are well-known instigators of cardiovascular disease, they also deliver necessary lipid fuels to organs and cells that require energy. As an important regression factor in cardiovascular diseases, regulatory CD4+ Foxp3+T cells (Tregs) are a highly oxidative lymphocyte subset, and Tregs heavily rely on fatty acids to fuel their differentiation, proliferation, and anti-inflammatory functions.Hypothesis:Though Tregs rely on FA for ATP generation, few studies consider how Tregs encounter their lipid fuel and whether this process is regulated. We hypothesized that chylomicrons deliver triglyceride to Tregs, and that apoC-III would regulate this process through receptor inhibition.Methods:We used purified chylomicrons and albumin-bound fatty acid, Seahorse metabolic flux analysis of Tregs, andin vivofunctional assays of inflammatory bowel disease. Finally, we asked whether these processes may be at play during atherosclerosis, where both Tregs and chylomicron lipids are critical factors.Results:Our studies reveal: CD4+Foxp3+Tregs endocytose chylomicrons lipids (both FFA and cholesterol); oxidative phosphorylation in Tregs is stimulated by lipids in apoC-III containing chylomicrons; these events can be targeted to change Treg accumulation and suppressive function in the gut and the aorta. We find that the inhibition of chylomicron uptake by Tregs also coincides with an increase in Treg accumulation at sites of inflammation, and a decrease in their expression of apoptotic markers.Conclusions:These data suggest a link between chylomicron lipid metabolism and apoptosis in anti-inflammatory Tregs. Further research will be conducted to reveal the mechanism of Treg chylomicron uptake and how regulation of this pathway alters Treg metabolism and apoptosis.

Circulation, Volume 150, Issue Suppl_1, Page A4144964-A4144964, November 12, 2024. Major adverse cardiovascular (CV) events (MACE) occur in a substantioal percentage of individuals following acute coronary syndromes (ACS), primarily driven by residual vascular inflammation. Anti-inflammatory drugs have improved CV outcomes but their use is limited by significant side-effects. Low-dose interleukin 2 (IL2) increases regulatory T (Treg) cells, which are powerful endogenous regulators of the immune response, and could provide a new, targeted anti-inflammatory strategy in high-risk ACS patients. In IVORY, we hypothesised that treatment with low-dose IL2 would reduce arterial inflammation measured by18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), compared to placebo. In IVORY FINALE we hypothesised that low dose IL2 could reduce MACE compared to placebo at follow up (up to 5 years.)IVORY was a double-blind, placebo-controlled, Phase IIb trial randomising ACS patients with high-sensitivity CRP levels ≧ 2mg/L to receive either 1.5×106IU IL2 or placebo (1:1). Dosing consisted of a daily induction (5 days) and a weekly maintenance phase (7 weeks).18F-FDG-PET/CT imaging of the ascending aorta and carotid arteries was performed before and after treatment. The primary outcome was the difference in the mean maximum target-to-background ratio (TBRmax) in the index vessel on follow-up imaging between the groups.60 patients (IL2:placebo, n=31:29) completed the trial. Arterial inflammation in the index vessel was lower at the end of treatment in the IL2 group than in placebo (TBRmax = -0.171[-7.7%], 95% CI -0.308 to -0.034, p=0.015)[Fig1]. In more inflamed areas with a mean TBRmax ≧ 2 (active slices), the difference between the groups was greater (-0.185 [-8.3%], P=0.009, 95% CI -0.323 to -0.0478). Overall, the additive treatment effect of low-dose IL2 was greater at higher baseline inflammation [Fig 2]. Low-dose IL2 significantly increased circulating Tregs compared to placebo (p

Circulation, Volume 150, Issue Suppl_1, Page A4141399-A4141399, November 12, 2024. Background:Chronic alcohol consumption is known to impair endothelial function and contribute to cardiovascular disease. However, the effects of moderate alcohol consumption on vascular function, especially in the presence of atherogenic risk factors like hypercholesterolemia, remain inconsistent and unclear.Methods and Results:To simulate chronic moderate and heavy drinking in hypercholesterolemic conditions, ApoE deficient (ApoE−/−) mice were fed a Lieber-DeCarli liquid diet with ethanol (2g/kg/day for moderate and 5g/kg/day for heavy drinking) or isocaloric maltose (5g/kg/day as control) for 12 weeks. In vivo flow-mediated vasodilation (FMD) of the femoral artery was assessed at 6 and 10 weeks. Both moderate and heavy alcohol consumption significantly impaired endothelium-dependent FMD, while endothelium-independent FMD increased after 10 weeks, indicated by higher FMD values in the presence of L-NAME, an eNOS inhibitor. Moderate and heavy drinking also promoted aortic endothelial permeability (measured by Evan’s blue dye infiltration) and atherosclerotic lesions at the aortic root. In aorta and endothelium-rich lung tissues, protein S-glutathionylation levels were elevated in both drinking groups, coinciding with eNOS inactivation (reduced dimer to monomer ratio), impaired Rac1 RhoGTPase activity, and increased Rac1 glutathionylation. In human aortic endothelial cells, ethanol exposure dose-dependently promoted protein S-glutathionylation and lowered glutaredoxin-1 (Grx1) levels. Moderate ethanol treatment (25mM) alone had negligible impact on eNOS and Rac1 activities but caused endothelial dysfunction under metabolic stress or Grx1 knockdown, mirroring animal study findings.Conclusions:This study provides evidence that moderate alcohol consumption can cause vascular endothelial dysfunction in the presence of hypercholesterolemia. The underlying mechanism involves S-glutathionylation-centered redox dysregulation of Rac1 and eNOS.

Circulation, Volume 150, Issue Suppl_1, Page A4138754-A4138754, November 12, 2024. Background:Fragility of the ascending aortic wall has been reported in patients with aortic regurgitation (AR), thought to be affected by turbulence in the ascending aorta. However, the mechanism behind this effect is unclear. We hypothesized that turbulence in the ascending aorta of AR patients causes changes in the polarization of endothelial cells. This study aimed to clarify that the polarization of endothelial cells in the ascending aortic wall is altered in AR patients.Methods:Twenty patients who underwent ascending aortic replacement at our institution from October 2022 to July 2023 were included: ten with thoracic aortic aneurysms (TAA) and ten with TAA and AR. The polarization of endothelial cells in the greater curvature of the ascending aortic wall collected during surgery was evaluated by measuring the ratio of the long axis to the short axis, the angle between the long axis and the blood flow axis, and the alignment of the Golgi apparatus and nucleus parallel to the blood flow.Results:There were no significant differences in patient background between the AR and non-AR groups. Additionally, there was no significant difference in the diameter of the ascending aorta between the two groups (AR vs. non-AR, 47.7±3.8 mm vs. 44.5±2.2 mm, p=0.479). The long axis to short axis ratio (aspect ratio) of endothelial cells in the ascending aorta was significantly smaller in the AR group than in the non-AR group. The angle (θ) between the long axis of the endothelial cells and the blood flow axis was significantly smaller in the AR group than in the non-AR group. The ratio of Golgi apparatus and nucleus alignment parallel to the blood flow was significantly lower in the AR group than in the non-AR group. Degeneration of the aortic tunica media was also observed in the AR group compared to the non-AR group.Conclusion:The results of this study suggest that the presence of AR alters the polarization of endothelial cells in the ascending aortic wall.

Circulation, Volume 150, Issue Suppl_1, Page A4132409-A4132409, November 12, 2024. Introduction:Chronic kidney disease (CKD) is a common inflammatory disease affecting >15% of the adult population and 50% of all patients with advanced/end stages (4 to 5) of CKD have cardiovascular disease.Research Questions:How multiple disease risk factors interplay to accelerate vascular inflammation in CKD.Aim:To determine whether hyperlipidemia and CKD have a synergy in accelerating vascular inflammation via trained immunity (TI).Methods:we performed aortic pathological analysis and RNA-sequencing in high-fat diet (HFD)-fed 5/6 nephrectomy CKD (HFD+CKD) mice.Results:1)HFD+CKD increases aortic cytosolic lipopolysaccharide (LPS) levels, caspase-11 (casp11) activation, and 998 gene expressions of TI pathways in the aorta (first-tier TI mechanism);2)Casp11—/—decreases aortic neointima hyperplasia, aortic recruitment of macrophages, and casp11-gasdermin D-mediated cytokine secretion;3)Casp11—/—decreases N-terminal gasdermin D (N-GSDMD) membrane expression on aortic endothelial cells and aortic IL-1b levels;4)LPS transfection into human aortic endothelial cells results in casp4 (human)/casp11 (mouse) activation and increases N-GSDMD membrane expression;5)IL-1b serves as thesecond-tier mechanism underlyingHFD+CKD-promoted TI.Conclusion:Hyperlipidemia and CKD accelerate vascular inflammation by promoting two-tier trained immunity