Search Results for: Come stress e attacchi di cuore sono collegati

Circulation, Volume 150, Issue Suppl_1, Page A4142846-A4142846, November 12, 2024. Background:Endothelial cells (ECs) utilize molecular mechanosensors that are critical for sensing disturbed flow (DF) to promote atherosclerosis. Copper (Cu), an essential micronutrient, is increased in human atherosclerotic plaques, while Cu chelation inhibits atherosclerosis in mice. “Cuproptosis” is a recently recognized form of programmed cell death which is driven by Cu-dependent mitochondrial protein aggregation and mitochondrial dysfunction; however, its role in atherosclerosis remains unknown.Results:Here we show that the Cu uptake transporter CTR1, which mainly localizes in the plasma membrane and caveolae/lipid rafts (C/LR), functions as a novel mechanosensor for DF to promote cuproptosis and atherosclerosis. Using X-ray fluorescence and ICP-MS analysis, we found that Cu, but not Fe and Zn levels, were increased in DF-exposed EC layers in the aortic arch of high fat diet-induced atherosclerotic (ApoE-KO) mice (2.3-fold) and cultured human aortic ECs (1.73-fold). Notably, DF vs. laminar flow (LF) increased mitochondrial Cu (1.6-fold) in ECs and induced mitochondrial dysfunction and cell death. These responses were rescued by mitochondrial-targeted Cu-depleting nanoparticle (mitoCDN) or CTR1siRNA. Functionally, the partial carotid ligation model revealed that EC-Ctr1 KO mice (by 70%) or mitoCDN (i.v.)(by 58%) reduced DF-induced atherosclerotic lesions in ApoE-KO mice, suggesting that DF-induced mitochondrial Cu promotes atherosclerosis through CTR1. Importantly, DF induced cuproptosis-related responses (increased DLAT aggregation, reduced DLAT lipoylation (47%) and Fe-S cluster proteins vs. LF), thereby increasing proteotoxic stress and decreasing mitochondrial respiration. All of these DF-induced responses were blocked by mitoCDN or CTR1siRNA. To address how DF increased mitochondrial Cu via CTR1, we performed subcellular fractionation and colocalization analysis and found that DF promoted mitochondrial Cu transporter SLC25A3 translocation to the plasma membrane (C/LR)(10.2-fold) and its association with CTR1 (2.8-fold), which were blocked by the disruption of C/LR using methyl-beta cyclodextrin. Furthermore, CTR1siRNA prevented DF-induced SLC25A3 translocation to plasma membrane.Conclusion:Endothelial CTR1 functions as a novel DF “mechanosensor” to increase mitochondrial Cu levels via recruiting mitochondrial SLC25A3 to plasma membrane C/LR where it binds to CTR1, leading to cuproptosis, which contributes to atherosclerosis.

Circulation, Volume 150, Issue Suppl_1, Page A4146568-A4146568, November 12, 2024. Background:Type B aortic dissections (TBAD) develop from a tear in the intimal layer of the aorta, distal to the left subclavian artery. This tear separates the aorta into true (TL) and false lumens (FL), increasing the risk of dilation and rupture. In cases of surgical intervention, treatment for type B aortic dissections (TBAD) after the acute phase ( > 14 days) is associated with worse outcomes. Identification of those patients who will experience aortic growth could identify patients who would benefit from early intervention. This study aims to characterize blood flow for risk stratification using 4D flow MRI. We identified possible markers of interest: entry tear velocity, pulse wave velocity (PWV), and wall shear stress (WSS).Methods:TBAD patients (n = 7; 3 F) from Emory University Hospital were enrolled. We acquired 4D flow MRI during the acute phase (3T Prisma Fit; Siemens Healthcare). We created image-derived 3D models of lumens and measured velocity at entry tears. We estimated PWV using cross correlation of waveforms at perpendicular, evenly-spaced planes throughout the true lumens. We estimated WSS throughout the false lumen using a previously developed method (Matlab, Ansys EnSight). Growth rates were measured from at follow up computed tomography exams.Results:Three of the patients (P2, P3, P7) did not grow, while P1, P4-P6 grew 2.1, 1.2, 5.3, and 2 mm/month, respectively. Peak entry tear velocities were higher in growth (143 cm/s) than non-growth (90 cm/s) cases, with P5 having the highest (180 cm/s). Forward flow was greatest in the distal end of FL near visceral branches (growth = 17.1, non-growth = 11.0 ml/cycle). Pulse wave velocity measurements between growth and non-growth were similar (4.5 and 3.5 m/s). Both averages were lower than PWV for non-dissected aortas. Regions of high vorticity and WSS can be observed in the true and FL near tears, but no trends were found between growth and non-growth cases.Conclusion:We anticipate stronger trends as enrollment continues, but our preliminary findings demonstrate the first MRI study to enroll acute TBAD subjects and identify markers of interest.Sources of Funding:This study is supported by NIH R01HL155537 and the National Center for Advancing Translational Sciences under Award Numbers UL1TR002378 and TL1R002382.

Circulation, Volume 150, Issue Suppl_1, Page A4147904-A4147904, November 12, 2024. Background:Cardiac amyloidosis is a rapidly progressing and severe condition leading to heart failure and reduced quality of life. Amyloid deposits impair both chronotropic and pumping functions of the heart. The Cardiopulmonary Exercise Test (CPET) is a vital tool in assessing the severity and progression of this disease.Aims:This study aims to investigate the differences in chronotropic function associated with the stages of heart failure in patients with cardiac amyloidosis and outcomes.Methods:A retrospective cohort study was conducted involving 194 patients diagnosed with cardiac amyloidosis who underwent at least one CPET from February 2010 to February 2024. Medical records were reviewed for data on the type of amyloidosis, comorbidities, and CPET results. The cohort was divided into two groups according to the Weber Classification: Weber Class A/B and Weber Class C/D. Patients who had CPET studies post-heart transplant were excluded. Statistical analyses, including Fisher’s exact test and chi-square test, were used. Cox regression model analysis, proportional hazards model for time to event. Adjustment for beta-blocker use was made to assess chronotropic incompetence. A p-value

Circulation, Volume 150, Issue Suppl_1, Page A4118086-A4118086, November 12, 2024. Background:Doxorubicin (DR), the most commonly used chemotherapy, results in dose-dependent cardiotoxicity in part by causing oxidative stress, cardiomyocyte death, and cardiac fibrosis. Whether these elicit a cardiac immune response that contributes to DR cardiomyopathy and could be targeted for cardio-protection is unknown. Wehypothesizedthat an aberrant T-cell immune response secondary to cardiac damage contributes to DR cardiomyopathy.Methods:We treated wild type (WT) mice and CD8+T-cell antigen restricted OTI mice with 5.0 mg/kg of DR or PBS weekly for 4 or 8 weeks and performed targeted antibody depletion of CD8+and CD4+T-cells. Primary mouse T-cells and cardiac fibroblasts (CFB) were used for mechanistic studies. Whole blood was analyzed by flow cytometry and proteomics in human and canine lymphoma patients before and after DR initiation.Results:DR treated mice exhibited cardiac CD8+T-cell infiltration alongside hallmarks of DR cardiomyopathy, including declined ejection fraction (EF) measured by echocardiography, cardiac cell death, and fibrosis determined by TUNEL and picrosirius red stain. Cardiac CD8+T-cells co-localized with αSMA+CFB and had enhanced expression of the degranulation marker CD107a and IFNγ in DR compared to PBS treated mice. DR hearts also showed increased gene and protein expression of the IFNγ inducible chemokinesCxcl9andCxcl10. DR resulted in increased circulating CD8+T-cells and the frequency of activated CD8+cells in the cardiac draining lymph nodes. Targeted antibody depletion of CD8+but not CD4+T-cells in the onset of DR treatment improved EF and decreased cardiac fibrosis. OTI mice were protected from DR induced EF decline, cardiac T-cell infiltration, and cardiac fibrosis, indicating an antigen-specific CD8+T-cell response.Mechanistically, DR induced ICAM-1 expression on CFB and ICAM-1 dependent adhesion of activated CD8+T-cells, which in turn increased CFB αSMA expression. Contact between CD8+T-cells and DR-treated CFB caused CD8+T-cell degranulation and Granzyme B release that contributed to CFB activation. Human and canine cancer patients followed longitudinally had increased circulating CD8+T-cells after anthracycline treatment, and human plasma levels of CXCL9/CXCL10 correlated with decreased EF post DR.Conclusion:Our data demonstrate a novel role for cytotoxic T-cells in DR cardiomyopathy across 3 species, through CXCL9/10-dependent cardiotropism and CD8+T-cell dependent fibrosis.

Circulation, Volume 150, Issue Suppl_1, Page A4147290-A4147290, November 12, 2024. Introduction:Alcohol consumption is associated with an increase in pro-inflammatory cytokines. Acute non-infectious pericarditis may be a consequence of the alcohol-related inflammatory process. This study investigates the association between excessive alcohol consumption and the risk of acute pericarditis and myocarditis.Hypothesis:Alcohol use may be associated with myocarditis and pericarditis through oxidative stress, immunological dysfunction, and direct toxicity to the heart muscle.Methods:This is a cross-sectional study of participants in the All of Us study at the time of enrollment. Alcohol use, our primary exposure was measured using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) score. Participants were stratified based on their AUDIT scores into Low risk-(males with Audit less than 4, females with Audit less than 3),moderate risk (AUDIT 4-5 in males, 3-5 in females), high risk (AUDIT 6-7 in both males and females) severe risk (AUDIT 8-12 in both males and females). The diagnosis of pericarditis and myocarditis was identified using electronic health records at the time of enrollment. The study adjusted baseline age, sex, race, educational status, income, health insurance, and smoking status. Logistic regression models were used to evaluate the association between alcohol intake and myocarditis/pericarditis. Models were adjusted for age, sex, race, educational status, income, health insurance, and smoking status.Results:Out of 135,010 eligible participants at baseline, 220 cases of myocarditis and pericarditis were detected. People with severe alcohol intake were (n=4825) more likely to be male (n, 3125, 64.8%%), less likely to be insured (n, %=4320, 89.5%) and less likely current cigarette smokers (n, %= 1007, 9.3%). The odds of developing myocarditis or pericarditis were not statistically significantly different with increasing AUDIT-C categories as compared to never- after adjusting for confounders. (table 1)Conclusion:There was no significant association found between higher AUDIT scores and an elevated risk of myocarditis and pericarditis.

Circulation, Volume 150, Issue Suppl_1, Page A4146856-A4146856, November 12, 2024. Introduction:Turner syndrome (TS) is caused by the partial or complete absence of one sex chromosome and affects 1 in 2500 liveborn infants. Hypertension, bicuspid aortic valve, and thoracic aortic aneurysms are more prevalent in TS compared to the general population. We hypothesize that persistent abnormalities of endothelial-mesenchymal transition (endMT) in the embryo and adult mediated in part by abnormal responses to shear stress predispose to cardiovascular disease in TS. The objective of this study was to define functional and transcriptomic differences between euploid 46,XX and aneuploid 45,X induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) from adult donors with mosaic TS.Methods:iPSCs were reprogrammed from peripheral blood mononuclear cells. Individual colonies were genotyped to identify isogenic euploid and aneuploid iPSC subclones, which were differentiated into ECs using standard methods. After selection for CD31 expression, baseline EC properties and response of EC monolayers to shear stress using a cone and plate viscometer system were characterized using fluorescence microscopy, qPCR, RNA sequencing, and functional assays.Results:We generated 45,X, 46,X,iso(X)(q10) [iso], and 46,XX iPSCs from one mosaic donor. After confirming genomic integrity and pluripotency, we successfully differentiated multiple iPSC subclones of each karyotype into ECs. EC morphology, tube formation, and uptake of DiI-conjugated acetylated low-density lipoproteins were not significantly different between subclones, although 45,X ECs proliferated more slowly than 46,XX or iso ECs. Collagen gel contraction and migration by 45,X ECs was significantly higher than 46,XX or iso ECs at baseline and in response to exogenous TGF-β peptide. Comparative RNAseq and qRT-PCR analysis of 45,X and 46,XX ECs showed thatVCAM1,SNAI1,ACTA2, TWIST1, and other endMT-associated genes were significantly upregulated at baseline in 45,X ECs and were only partially suppressed by shear stress, while expression ofCDH2was decreased in 45,X ECs. We also observed that 45,X ECs but not 46,XX or iso ECs underwent spontaneous endMT in static culture conditions.Conclusion:Despite similar baseline EC phenotypes, the threshold for endMT activation appears to be lower in 45,X ECs compared to 46,XX or iso ECs. Dysregulation of endMT, possibly due to chronic derepression ofSNAI1expression, may contribute to congenital cardiovascular disease in TS.

Circulation, Volume 150, Issue Suppl_1, Page A4141927-A4141927, November 12, 2024. Background:Prior data suggest the MI risk may be higher with paroxysmal AF (PAF) vs. non-paroxysmal AF (non-PAF). Proposed mechanisms include tachycardia-induced oxidative stress (via LOX-1) with microvascular flow abnormalities, ischemia downstream of a fixed coronary obstruction, and plaque rupture.Methods:We compared MI rates in pts with PAF vs. non-PAF in COMBINE AF, a patient-level metanalysis of 4 RCTS of DOACs vs warfarin (ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY,ROCKET AF). Secondary endpoints were ischemic stroke and CV death. Cox proportional-hazards models stratified by trial and adjusted for elements of the CHADS-VASc score were constructed. Sensitivity analyses were performed across subgroups, omitting pts on lower-dose DOAC regimens, and accounting for competing risk of death.Results:Of 71,466 pts, 16,609 (23%) had PAF at enrollment. Pts with PAF vs non-PAF were similar age (median 72 vs 72. P=0.15), but more likely women (43 vs 36%), with prior CAD (35 vs 31%), and on aspirin (41 vs 32%); but less likely Asian race (12 vs 15%) or with CHADS-VASc score >4 (59 vs 60%), p160,000 pt-yrs of follow-up, 1033 MIs occurred: 277 (1.67%) in pts with PAF vs 766 (1.40%) in pts with non-PAF, corresponding to rates of 0.81% and 0.70% per pt-year. The HRadjfor MI with PAF vs non–paroxysmal AF was 1.17 [1.02-1.35], p=0.028 (Fig). Ischemic stroke occurred in 364 (2.19%) vs 1425 (2.60%) pts with PAF vs non–paroxysmal AF (HRadj0.81 [0.72-0.91], p

Circulation, Volume 150, Issue Suppl_1, Page A4119062-A4119062, November 12, 2024. Background:Vascular remodeling to match arterial diameter to tissue metabolic requirements commonly fails in ischemic disease. Endothelial cell (EC) sensing of elevated fluid shear stress (FSS) from blood flow induces vessel outward remodeling to restore physiological FSS, but mechanisms are poorly understood. The Smad1/5 pathway, which is maximally activated at physiological FSS and suppressed at higher flow, opposes activation of Akt, suggesting that inhibiting Smad1/5 may be required for outward remodeling.Methods:In vitro flow studies used ECs in a parallel plate flow chamber. In vivo mouse studies used a carotid-jugular fistula model to induce high flow outward remodeling in the carotid artery, and femoral artery ligation to examine recovery from ischemia and arteriogenesis in the hindlimb.Results:Suppression of Smad1/5 at high FSS is mediated KLF2-dependent induction of the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces arterial outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both STZ-induced type 1 and HFD-induced type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes.Conclusions:Suppression of Smad1/5 through a KLF2-BMPER pathway is required for high FSS-mediated outward remodeling. Mimicking this pathway with BMP9/10 antibodies improves vascular remodeling in diabetic mice, suggesting a potential new therapeutic approach for ischemic disease.

Circulation, Volume 150, Issue Suppl_1, Page A4140702-A4140702, November 12, 2024. Background:Single ventricle (SV) and hypoplastic left heart syndrome (HLHS) present significant sex differences in terms of surgical outcomes and long-term prognosis between male and female patients. Peripheral blood mononuclear cells (PBMCs) drive tissue damage and cardiac dysfunction, contributing to the sex-specific clinical outcomes.Aims:We used single-cell RNA sequencing (scRNA-seq) to assess gene expression profiles in PBMCs, aiming to gain insights into sex effects and identify new biomarkers for assessing disease prognosis.Methods:We studied PBMCs from 32 cases with SV/HLHS. The experiments were conducted in 3 independent batches (9 females/11 males; 2 females/6 males; 2 females/2 males), using 10X Chromium Single Cell Gene Expression assay (10x Genomics, Single Cell 3′ v3). Sequencing was performed using the Illumina NovaSeq6000. The data analysis was conducted using the Seurat R package, employing SCTransform for data normalizing and scaling (Satija, Farrell et al. 2015, Butler, Hoffman et al. 2018). To mitigate batch effects, the 3 batches were analyzed separately.Results:42 genes were consistently identified of differential expression (DE) (|log2FC|≥0.25,Padj

Circulation, Volume 150, Issue Suppl_1, Page A4143729-A4143729, November 12, 2024. Post-traumatic stress disorder (PTSD) is associated with hypertension and increased heart rate, which are risk factors for cardiovascular disease including thoracic aortic aneurysms. A connection between stress and aortopathy has been suggested, yet mechanisms linking the two remain unknown. We hypothesize that PTSD-induced mechanical signals alter thoracic aortic wall homeostasis, which can predispose to aortopathy. C57BL/6 mice underwent traumatization consisting of inescapable foot shock, single prolonged stress, and single housing. PTSD phenotype was assessed through behavioral testing for the DSM-V PTSD criteria. Group-housed control mice did not undergo the traumatization but were subjected to behavioral testing. Z-scores for each behavioral test were generated and mice with z-scores above the 85% confidence interval on all criteria were considered to have a PTSD-like phenotype. This protocol yielded a PTSD phenotype in 30% of mice mimicking the human proportion of PTSD development following a traumatic experience. PTSD mice had significantly higher systolic blood pressures (PTSD (n=10), 149 ± 7mmHg; control (n=10), 123 ± 9mmHg, p

Circulation, Volume 150, Issue Suppl_1, Page A4146917-A4146917, November 12, 2024. Introduction:Myocardial infarction (MI) leads to cardiac myocyte death and scarring, resulting in significant biomechanical remodeling of the left ventricle (LV). Maladaptive LV remodeling post-MI is known to contribute to the development of heart failure (HF). Understanding the role of LV free wall (LVFW) biomechanical remodeling in the transition of infarcted hearts to HF will improve prognostic capabilities and intervention strategies. Our objective in this study was to assess the association between LVFW anisotropic stiffening and organ-level functional adaptations.Methods:MI was induced in WKY rats via the ligation of the LAD artery, and transthoracic echocardiography was performed to measure ejection fraction (EF). Fresh LVFW myocardial samples were harvested and subjected to biaxial tensile loading hearts were harvested at five timepoints: sham, and weekly from 1wk to 4wk post-MI (n=6 for each timepoint). The samples were stretched to 30% along the circumferential and longitudinal directions, and stiffness (slope of stress-stretch curves at 30% stretch) in each direction was measured. The ratio between longitudinal and circumferential stiffnesses was defined as the LVFW anisotropy.Results:EF reduced post-MI (Fig. 1A), and pre- and post-MI changes in EF (denoted by ΔEF) showed a significant reduction at later timepoints (Fig. 1B). Although circumferential stiffness remained unchanged with time (Fig. 1C), longitudinal stiffness tended to increase post-MI, thus altering the overall anisotropy of LVFW tissues (Fig. 1C). The correlation between the anisotropy and EF indicated that an increased longitudinal bias post-MI was strongly correlated with reduced EF and LV decompensation (Fig. 1D).Conclusions:Our results suggest that the myocardium stiffness changesanisotropicallywith a bias in the longitudinal direction post-MI. The strong correlation between myocardial anisotropy and EF suggests that studying alterations in LVFW biomechanical markers and their relationships with deteriorations in LV function could provide insights into the mechanisms of transition to HF post-MI. The quantification of these markers through cardiac imaging offers to improve early prognostication of HF post-MI.

Circulation, Volume 150, Issue Suppl_1, Page A4143788-A4143788, November 12, 2024. Background:Physical activity (PA) reduces cardiovascular (CV) disease risk, and this has recently been shown to be due, in part, to reduction of stress-related neural activity (SNA). Further, the CV benefits of PA are higher in individuals likely to have higher baseline SNA (i.e., those with depression/anxiety). Moreover, anxiety and depression associate with increased risk of deep venous thrombosis (DVT) partly through increased SNA, yet it remains unknown how PA impacts this relationship.Hypotheses:1) PA associates with lower risk of DVT, 2) this PA benefit is more pronounced in individuals with anxiety and depression.Aims:To evaluate the association between PA and DVT risk and the differential benefits among subjects with anxiety or depression.Methods:Subjects enrolled in the Mass General Brigham Biobank were studied; total PA was derived from a health survey that assessed different activities during the previous year. Highervslower PA was defined according to quintiles of PA in our population (low PA: 1° and 2° quintile; high PA: 4° and 5° quintile; subjects in the 3° quintile were excluded to avoid possible overlaps). Depression, anxiety, and DVT were defined using ICD codes. Subjects

Circulation, Volume 150, Issue Suppl_1, Page A4146878-A4146878, November 12, 2024. Background:Increasing evidence support a vasoprotective role of the major endothelial NADPH oxidase isoform 4 (NOX4). NOX4 is notably induced by hypoxia.Research Question:What is the functional role of NOX4 under hypoxic conditions in the vessel wall?Aim:We aimed to elucidate NOX4’s significance in endothelial and vascular function under hypoxia.Methods:Primary cultures of human endothelial cells were exposed to hypoxia of 1% O2. Internal mammary arteries were obtained from patients undergoing coronary artery bypass grafting surgery. Surgical specimens of the artery wall proximal to occlusion were obtained from patients with peripheral arterial disease. Human NOX4 was downregulated by lentiviral shNOX4. Primary microvascular lung endothelial cells were isolated from wild-type and Nox4-/-mice. Vascular function was assessed under hypoxia in murine mesenteric arteries and aortas in a Mulvany myograph. Laminar flow was applied by cone-and-plate viscometer or ibidi pump system. NO was measured by Griess reaction, H2O2by Amplex Red Assay and gene expression by real-time PCR and Western blot.Results:Hypoxia significantly elevated NOX4 expression and activity in endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increasedNOX4expression even under normoxic conditions. In human hypoxia-prone vessels,NOX4expression strongly correlated with genes relevant for vascular function, such as prostaglandin I2 synthase (PTGIS). Endothelial function assessments under hypoxia revealed elevated contraction and endothelial dysfunction in both wild-type and Nox4-/-mice with Nox4-/-mice exhibiting the most severe alterations in endothelium-dependent vasodilation. Laminar shear stress attenuated the hypoxic response in endothelial cells, reducing HIF1a andNOX4expression while enhancing eNOS expression. NO synthase inhibition under combined hypoxia and laminar flow conditions upregulatedNOX4. Furthermore,NOX4deletion affected PECAM1 expression and endothelial cell adhesion. Inhibition of NOX4 under combined hypoxia and laminar flow increased the number of endothelial cells not aligned in the direction of flow.Conclusions:Hypoxia-induced NOX4 ensures vasodilation in both conductive and resistant arteries. Laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4. NOX4 deletion affects PECAM1 expression, reduces endothelial cell adhesion and alignment.

Circulation, Volume 150, Issue Suppl_1, Page A4117646-A4117646, November 12, 2024. Introduction:The HeartMate 3 (HM3) LVAD, was shown to have a higher survival free of hemocompatibility related adverse events (HRAE) compared to its predecessors (HM2, HVAD). Superior HM3 outcomes are attributed to wide blood flow pathways coupled with frictionless movement and intrinsic pulsatility, reducing shear stress and blood stasis. It is unknown if improved hemocompatibility can withstand pump restart after prolonged shutdown. We herein report a case of HM3 pump stoppage without subsequent HRAE.Case Presentation:A 41-year-old male underwent HVAD implant in 2019 for advanced non-ischemic cardiomyopathy. This was exchanged to HM3 for recurrent neurological events despite therapeutic anticoagulation. Ten months after exchange, he awakened one morning to find his LVAD had been off for an unknown period but had not heard any device alarms (85dB if on battery power, 165dB if on wall power). Since he felt well he changed to battery power resulting in immediate pump restart. Log file analysis showed pump stoppage 2 am – 10 am, without preceding low flow alarms or power elevations.Management and Outcomes:In the ER INR was 1.5 (2.8 one week prior) and systemic heparin was started. Evaluation included: 1) CT brain without acute infarcts 2) echocardiogram without intracardiac thrombus 3) CT Angiography with patency of the inflow cannula and outflow graft 4) stable serial LDH measurements. The controller was exchanged, and analysis noted normal function. 1-year later the patient is maintained on warfarin and aspirin 325mg without further HRAE. Given the patient’s neurologic history and pump stoppage event, we did not invoke ARIES trial guidance and thus continued aspirin.Conclusion:Pump stoppage occurs when there is complete battery depletion, disconnection of both power leads, or the percutaneous lead from system controller. Our case is unique in that the duration of pump shutdown was 8 hours and INR subtherapeutic, without HRAE in the background of neurologic events on HVAD support. It has been previously reported that complete outflow graft thrombosis can occur shortly after LVAD decommissioning. The HM3 User Manual recommends restarting the pump immediately if off for a few minutes and using clinical judgment for longer durations due to increased risk for thromboembolic events. Our case adds to the paucity of existing data on improved hemocompatibility of the HM3 during rare circumstances of the ultimate test in hemocompatibility: complete pump shut down.

Circulation, Volume 150, Issue Suppl_1, Page A4147384-A4147384, November 12, 2024. Introduction:Hyperlipidemia promotes atherosclerosis, a leading cause of myocardial infarction and stroke. Atherosclerosis is commonly associated with endothelial dysfunction. Elevated levels of p66Shc and sumoylated proteins have been implicated in hyperlipidemia-induced endothelial dysfunction. Recently, we discovered that SUMO2 modifies p66Shc at lysine-81, regulating its function. However, the role of endogenous p66ShcK81 sumoylation remains unclear.Methods:We used LDLr-/- mice and p66ShcK81R knock-in mice on an LDLr-/- background (p66ShcK81R-KI x LDLr-/-). Hyperlipidemia was induced by feeding the mice a high-fat diet for 4 weeks. We monitored body weight gain and measured serum total cholesterol levels. Endothelial function, oxidative stress, and sumoylation were assessed in the aortas. Additionally, we performed global mass spectrometry to identify the molecular signaling pathways regulated by p66ShcK81-SUMO2ylation in endothelial cells.Results and Discussion:To determine the contribution of SUMO2 to this sumoylated pool of proteins, we treated human umbilical vein endothelial cells with oxidized LDL and knocked down SUMO2 with siRNA. The majority of the sumoylated proteins were found to be SUMO2-conjugated, suggesting that SUMO2 is primarily affected in hyperlipidemia. In LDLr-/- mice on a high-fat diet, we observed increased expression of SUMO2/3-conjugated proteins compared to controls. Feeding a high-fat diet induced a similar increase in serum cholesterol levels as well as weight gain in both LDLr-/- and p66ShcK81R-KI x LDLr-/- mice. Vascular reactivity revealed significant impairment of endothelium-dependent vasorelaxation of aortic rings in LDLr-/- mice. However, aortic rings from p66ShcK81R-KI x LDLr-/- mice displayed vasorelaxation similar to control p66ShcK81R-KI mice. We also noted increased oxidative stress (8-OHdG levels) in LDLr-/- mice, which was significantly reduced in p66ShcK81R-KI x LDLr-/- mice. Lastly, mass spectrometry data indicated that p66ShcK81-SUMO2ylation promotes mitochondrial dysfunction and impairs Rho-GTPase signaling in endothelial cells.Conclusion:Our findings demonstrate that p66ShcK81 mediates hyperlipidemia-induced endothelial dysfunction and oxidative stress. Investigating the role of specific molecules regulated by p66ShcK81-SUMO2ylation may lead to the discovery of novel tools to manage endothelial dysfunction caused by hyperlipidemia.

Circulation, Volume 150, Issue Suppl_1, Page A4140852-A4140852, November 12, 2024. Introduction:Posttraumatic stress disorder (PTSD) is an independent cardiovascular disease (CVD) risk factor with high prevalence in women, particularly women veterans (WV). While the impact of PTSD on ischemic heart disease (IHD) and stroke has been well established, its impact on a comprehensive set of CVD outcomes has not been studied in WV, a growing population at high risk for CVD in the U.S. The goal of this project was to investigate the impact of PTSD on a comprehensive set of CVD conditions in WV.Methods:National Veterans Health Affairs (VHA) electronic health records were used to identify all women who visited any VAs from 1/1/2000 to 12/31/2019. PTSD and CVD were identified based on International Classification of Disease versions 9 and 10 diagnoses ( 1 inpatient or 2 outpatient encounter documentations). Incident CVD outcomes included first onset of IHD, stroke, cardiomyopathy/heart failure (HF), pulmonary arterial hypertension/pulmonary hypertension (PH), atrial flutter/fibrillation (AF), peripheral arterial disease (PAD), venous thromboembolism (VTE), and aortic stenosis (AS). Propensity score matching and Cox survival analyses were performed to assess associations of PTSD with incident CVD outcomes.Results:We identified 622,312 WV, with 140,210 (22.53%) with PTSD. After 1:1 matching, 202,896 patients were included in the final analysis. WV had a mean age of 39.1 years, and the mean [MOU1] follow-up was 5.72 years. Table 1 reveals the association of PTSD with an incident CVD composite and the different component outcomes individually.Conclusion:In a large sample of WV, we demonstrate significant and clinically relevant associations of PTSD with a comprehensive set of incident CVD outcomes. The potential association with some of the specific outcomes warrant further investigation. Maybe more of a call to action for PTSD screening and treatment to potentially offset CVD risk instead?