Abstract 4144671: Safety and Efficacy of Aortic Cross-Clamp for Thrombosed Acute Type A Aortic Dissection

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.

Read More

Abstract 4146208: Blood protein mediators of association between smoking and abdominal aortic aneurysm: exploration integrating human proteomic and genomic data

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

Read More

Abstract 4142845: Efficacy of full petticoat TEVAR in Stanford type B aortic dissection with patent false lumen and computational fluid dynamics analysis of the remodeling mechanism

Circulation, Volume 150, Issue Suppl_1, Page A4142845-A4142845, November 12, 2024. Introduction:Uncomplicated Stanford type B acute aortic dissection is traditionally managed with strict blood pressure control. However, many patients who survive the acute phase develop dissecting aortic aneurysms owing to false lumen expansion in the chronic phase.Objectives:This study investigated treatment strategies for Stanford type B aortic dissection, specifically comparing the outcomes of full provisional extension to induce complete attachment (PETTICOAT) thoracic endovascular aortic repair (TEVAR) with those of simple entry closure using TEVAR. This study aimed to elucidate the long-term results of full PETTICOAT TEVAR and the mechanisms underlying false lumen expansion or suppression through computational fluid dynamics analysis.Methods:This retrospective study included 22 patients diagnosed with Stanford type B aortic dissection: 12 in the full PETTICOAT group and 10 in the entry closure group. Computed tomography images were analyzed at various time points till four years postoperatively by measuring the aortic, true lumen, and false lumen diameters at four levels. Statistical analyses were performed using Welch’s t-test, and statistical significance was defined as p < 0.05. Additionally, blood flow analysis was performed for one case from each group. We aimed to approximate solutions from the fluid equations, visualize blood flow, and compare hemodynamic parameters, namely wall shear stress and oscillatory shear index.Results:In the fourth postoperative year, there was a significant difference in aortic diameter (p = 0.012) and false lumen diameter (p = 0.001) at level 3 (diaphragm level of the descending aorta), and the full PETTICOAT group showed smaller values indicative of favorable remodeling. Blood flow analysis revealed elevated oscillatory shear index values in the false lumens of the entry closure group, suggesting a correlation with false lumen expansion.Conclusions:Full PETTICOAT TEVAR demonstrated positive long-term outcomes by reducing the false lumen and preventing aortic enlargement. This study provides insights into the underlying hemodynamic mechanisms, emphasizing the potential of computational fluid dynamics analysis in understanding aortic dissection treatment strategies.

Read More

Abstract 4139212: Long Term Outcomes of Patients with Hypoplastic Left Heart Syndrome and Left Ventricle-Coronary Artery Fistula

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

Read More

Abstract 4140048: The Critical Role of Visceral Adipose Tissue in the Temporal Progression of Cardiac Remodeling Due to Pressure Overload

Circulation, Volume 150, Issue Suppl_1, Page A4140048-A4140048, November 12, 2024. Background:Myocardial fibrosis is a key indicator of cardiac remodeling caused by pressure overload, involving a complex interplay of mechanical, inflammatory, and neurohormonal factors. Our recent studies reveal a harmful interaction between visceral adipose tissue (VAT) and the heart during aging, where profibrotic proteins from VAT and plasma contribute to heart fibrosis. We hypothesize that transverse aortic constriction (TAC)-induced pressure overload induces VAT remodeling and VAT profibrotic secretome that aggravates cardiac fibrosis and compromises heart function.Purpose:- To determine the interaction between VAT and heart-To assess the time course of TAC-induced transcriptomic changes in presence or absence of VATMethods:We divided wild-type male mice (5-month-old, n=10/group) into four groups: a visceral Lipectomy group and a Sham group two weeks before either a moderate TAC (26G; i.e. gradient between left ventricle and aorta of 30mmHg) or a sham surgery. We sacrificed the mice at 1- and 8-week after TAC. We performedin vivometabolic tests, echocardiography, and invasive hemodynamics, followed byex vivotissue analysis. We subsequently examined cardiac transcriptomic changes in TAC versus control groups, as well as the effect of visceral lipectomy through RNA-seq followed by Partial Least Squares Regression and Over-Representation Pathway Analysis.Results:TAC-induced cardiac pressure overload initiates a pathological heart-VAT crosstalk stimulating a senescence-like profibrotic (TGFb, Spp1) and proinflammatory secretory phenotype (TNFa, IL6, PAI1) in VAT as early as 1 week after TAC. Importantly, we demonstrate that VAT lipectomy reverses TAC-induced cardiac remodeling and restores normal heart function. Transcriptomic analyses show the powerful effect of TAC on gene expression, notably profibrotic (MMP9, TGFb1, Col1a1) and prohypertrophic genes (Nppa, Nppb) increase. After 1 week, TAC had a stronger effect than lipectomy, while 8 weeks post-TAC, lipectomy could reverse all the transcriptomic changes induced by TAC with a transcriptomic profile of TAC+lipectomy similar to sham group.Conclusion:This study highlighted the exacerbation by VAT of the detrimental impact of TAC on the heart. Our findings show a dynamic crosstalk between the heart and VAT orchestrated by the secretome of the adipose tissue resulting in transcriptomic and physiological heart changes.

Read More

Abstract 4132409: Caspase-4/11 promotes a high-fat diet and chronic kidney disease-accelerated vascular inflammation via caspase-4/11-IL-1b two-tier trained immunity

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

Read More

Abstract 4138717: Infective Root Aortitis: Medical Therapy Alone or Medical Therapy and Surgery?

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.

Read More

Abstract 4146394: Plasma proteomics reveals the potential causal impact of ECM proteins on abdominal aortic aneurysm

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

Read More

Abstract 4117345: Predicting Downstream Aneurysmal Degeneration Following Type A Dissection Repair With Computational Fluid Dynamics

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

Read More

Abstract 4138097: Single-Cell Analysis Reveals Critical Role of Macrophage Epsin in Regulating Origin of Foam Cell in Atherosclerosis

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.

Read More

Abstract 4141400: Inhibition of Chylomicron Uptake Stimulates Treg Accumulation

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.

Read More

Abstract 4144964: Low-Dose IL-2 Lowers Arterial Inflammation and Trends Towards Lower MACE in patients with ACS: The results of the IVORY trial and IVORY FINALE study

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

Read More

Abstract 4141399: Chronic Moderate Alcohol Consumption In ApoE-/- Mice Impaires Vascular Endothelial Function Through Redox Dysregulation of Rac1

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.

Read More

Abstract 4138754: Analysis of Polarization Changes in Ascending Aortic Endothelial Cells Induced by Aortic Valve Regurgitation

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.

Read More

Abstract 4141690: Bisphosphonate therapy improves bone deficits but worsens arterial calcification in Mgp-null mice

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.

Read More

Abstract 4141352: Can quantifiable aortic or coronary artery calcifications in the standard of care baseline CT or PET-CT scan of patients with Hodgkin or non-Hodgkin lymphoma serve as a predictor of Major Adverse Cardiovascular Events?

Circulation, Volume 150, Issue Suppl_1, Page A4141352-A4141352, November 12, 2024. Background:Major adverse cardiovascular events (MACE), including myocardial infarction, acute coronary syndrome, ischemic heart disease requiring revascularization, stroke, and heart failure, have been documented as significant contributors to mortality in cancer survivors. Coronary artery calcium (CAC) can predict MACE in non-cancer populations, while calcium in the aorta (CA) has not been evaluated as a prognostic marker. Every patient diagnosed with cancer undergoes a standard-of-care Positron Emission Tomography-Computed Tomography (PET-CT) or a chest CT before the initiation of chemotherapy.Hypothesis:To determine whether the CAC or CA of patients with Hodgkin’s or non-Hodgkin’s lymphoma, derived from standard-of-care PET-CT/chest CT, can predict the incidence of MACE.Methods:Patients treated with anthracycline-based chemotherapy, diagnosed and followed from January 1, 2013, through June 30, 2023, were included. Patients who did not undergo a PET-CT or CT, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CAC, CA, or CAC-CA was associated with the development of MACE. Calcium was retrospectively quantified using TeraRecon software (Durham NC) and categorized as: 0, 1-99, and >100. Outcome analyses was estimated using the Kaplan-Meier method.Results:326 patients were included, mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was found in 89 patients and CA in 140. In the univariate regression model, a statistically significant association was found with values >100 for CA, CAC and CAC-CA with the risk of MACE. (Fig 1a/b/c). CAC equal to 0 demonstrated a significant protective effect against MACE. (Fig 1a). In the multivariable analysis, these associations persisted even after adjusting for comorbidities. (Table 1).Conclusion:CAC, CA and CAC/CA >100 in the standard-of-care CT/PET CT are predictors of MACE in lymphoma patients undergoing anthracycline treatment, a CAC equal to 0 has protective effect, these relationships remained statistically significant after adjusting for comorbidities.

Read More