Abstract 4141357: Diagnostic and prognostic value of quantitative stress perfusion CMR in the non-invasive assessment of cardiac allograft vasculopathy

Circulation, Volume 150, Issue Suppl_1, Page A4141357-A4141357, November 12, 2024. Background:Cardiac allograft vasculopathy (CAV) is a rapidly progressive form of coronary atherosclerosis limiting long-term survival after heart transplantation.Objectives:We evaluated the diagnostic and prognostic yield of quantitative stress cardiovascular magnetic resonance (CMR) perfusion for CAV detection in heart transplant recipients.Methods:Patients who received orthotopic heart transplants and underwent stress CMR for CAV assessment were included in the study and followed up for almost 2 years (median 1.8; IQR 0.9,2.7). The diagnostic accuracy of qualitative and quantitative stress CMR was assessed by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), using invasive or CT coronary angiography as the reference for CAV detection. The area under the curve (AUC) was compared for qualitative and quantitative stress CMR. Adjusted hazard ratios for major adverse cardiac events (MACE), including death and unplanned cardiac hospitalizations were derived in all patients. The global myocardial perfusion reserve index (MPRi) was obtained by normalization to the rate-pressure product.Results:In a cohort of 60 patients, n=18 (30%) had significant CAV (grade 2 or 3), and n=11 (18.3%) experienced MACE. At the Youden index threshold of 2.1, the myocardial perfusion reserve index (MPRi) demonstrated a sensitivity of 85.7%, a specificity of 70.3%, a PPV of 52.2%, and an NPV of 92.9%. The MPRi was significantly more accurate than visual assessment (p < 0.001) in identifying underlying CAV (Figure 1) and it was an independent predictor of MACE (HR:0.26;95%CI:0.07,0.93; log-rank p=0.022; Figure 2), while the visual presence of inducible myocardial perfusion defect did not (HR:2.23;95%CI:0.57,8.66; p=0.2).Conclusions:In patients with previous heart transplantation, quantitative stress CMR perfusion has incremental diagnostic and prognostic value over qualitative stress CMR for the non-invasive detection of CAV.

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Novembre 2024

Abstract 4147568: Sociodemographic Disparities Associated with Stress, Cardiovascular Disease, and Cancer Outcomes in the All of Us Research Program

Circulation, Volume 150, Issue Suppl_1, Page A4147568-A4147568, November 12, 2024. Introduction:Cardiovascular disease (CVD) and cancer are among the leading causes of morbidity and mortality worldwide. Increasing evidence suggests that sociodemographic factors such as race, ethnicity, income, education, and stress levels significantly influence the prevalence and outcomes of these diseases. TheAll of UsResearch Program provides a unique opportunity to explore these disparities across a diverse U.S. population. This study aims to examine how sociodemographic disparities are associated with stress, CVD, and cancer outcomes. We hypothesize that higher perceived stress levels, lower income, lower education levels, and minority race/ethnicity groups are associated with higher incidences of CVD and cancer.Methods:Data from 55,505All of UsResearch program participants were analyzed. Key variables included age, race, ethnicity, education, household income, perceived stress level, and history of CVD and cancer. Descriptive statistics were used to summarize participant demographics. Multivariate logistic regression models were employed to examine the associations between sociodemographic factors and the outcomes of interest (CVD and cancer).Results:Older participants had a higher prevalence of both CVD (mean age: 60.8 vs. 50.5, p < 0.001) and cancer (mean age: 63.6 vs. 51.7, p < 0.001). Black/African Americans had a higher incidence of CVD (21.3% vs. 78.7%, p < 0.001), while Whites had a higher prevalence of cancer (5.3% vs. 94.7%, p < 0.001). Lower income and higher stress levels were also associated with higher CVD incidence (

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Novembre 2024

Abstract 4138606: Toll-like Receptor 4 Signaling Establishes Trained Innate Immunity Through Interferon-Mediated Epigenetic Modifications Leading to Cardioprotection in a Stress-induced Cardiomyopathy Model

Circulation, Volume 150, Issue Suppl_1, Page A4138606-A4138606, November 12, 2024. Introduction:The mechanisms responsible for establishing preconditioning-induced cardioprotection remain unknown. We have shown that a high dose of isoproterenol (ISO) induces cardioprotection against a second ISO dose in mice. The durability of protection and the lack of an innate immune response suggests trained immunity as a novel cardioprotective mechanism.Hypothesis:We hypothesize that cardioprotection is conferred through trained immunity, by interferon signaling downstream of necrotic cardiac material-mediated Toll-like receptor 4 (TLR4) activation.Methods:Wild-type C57BL/6J mice were intraperitoneally injected with TLR agonists or diluent, and challenged with 300 mg/kg ISO 7 days later. Mice were assessed by 2-D echocardiography, serum cardiac troponin levels, flow cytometry immune cell counts, and Multiome (single nuclei RNA+ATAC) sequencing.Results:The TLR4 agonist lipopolysaccharide (LPS) induced cardioprotection against ISO injury, with mice having enhanced survival (P=0.049) and no changes in cardiac troponin levels (P >0.99), cardiac neutrophil influx (P >0.99) or left ventricular motion (P=0.057) relative to baseline values before injury. Treating LPS-injected mice with β-glucan reversed the effects of LPS on immune cells and abolished cardioprotection. Multiome analysis of genes linked to chromatin peaks with increased accessibility in LPS+vehicle (protected) compared to LPS+β-glucan and diluent control (non-protected) hearts revealed the interferon pathway to be up-regulated across all major cell types. Modulation of interferon signaling with monoclonal antibodies against type 1+2 interferon receptors abolished cardioprotection in LPS-treated mice, whereas pre-treatment with recombinant type 1+2 interferons induced cardioprotection. Importantly, interferon-treated hearts shared similar chromatin accessibility features and enriched transcription factor motifs, including interferon-specific motifs, with LPS-protected hearts across cell types, particularly among non-cardiomyocytes.Conclusions:TLR4-induced interferon signaling is sufficient and in part necessary for cardioprotection against ISO injury. Moreover, our findings show that epigenetic modifications downstream of interferon signaling lead to cardioprotection consistent with trained innate immunity.

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Novembre 2024

Abstract 4141350: Endothelial-Mesenchymal Transition Mediated by Mechanical Stress Prompts Atrial Fibrogenesis

Circulation, Volume 150, Issue Suppl_1, Page A4141350-A4141350, November 12, 2024. Background:Atrial fibrosis is crucial in developing atrial fibrillation (AF). Elevated atrial pressure may significantly mediate atrial fibrosis, yet its underlying mechanisms remain unclear.Methods:Patients with AF who underwent radiofrequency ablation were recruited. Clinical data, including high-density mapping and imaging information, was analyzed. Multivariate regression analysis was performed to identify risk factors for low-voltage areas in the atrium. The CS-CREM mouse model, an autonomic AF model, was previously developed by our research group. Millar pressure catheters were used to measure left ventricular, right ventricular, and right atrial pressures in CS-CREM mice. Single-nucleus sequencing was employed to map the single-cell transcriptomes of atrial samples in CS-CREM and wild-type mice at different disease stages. Human primary atrial endocardial endothelial cells (ACCE) and HUVEC cell lines were subjected to mechanical stretch using the Flexcell tension system, followed by in vitro validation experiments. Mg101, a calpain inhibitor, was administered to CS-CREM mice for in vivo validation experiments.Results:Elevated atrial pressure in AF patients was identified as a significant risk factor for atrial fibrosis. Atrial pressure-related indices were linearly correlated with atrial fibrosis. Compared to wild-type mice, CS-CREM heterozygous mice exhibited significantly higher atrial pressure and aggravated atrial fibrosis. Single-nucleus sequencing revealed that atrial endocardial endothelial cells in CS-CREM mice underwent endothelial-mesenchymal transition (EnMT) into fibroblasts, with mechanical stress protein Flna being a critical regulatory protein. In vitro experiments demonstrated mechanical stretch-induced EnMT in ACCE and HUVEC cell lines. Mechanical stretch-activated mechanosensitive receptors on ACCE cell membranes led to increased intracellular calcium levels and calpain activation, which cleaved Flna into Flna 90. Flna 90 facilitated the nuclear translocation of transcription factor Smad3/7 and TGF-β, promoting the expressions of EnMT genes. This EnMT process was reversible with Mg101. In vivo experiments showed that Mg101 reduced the incidence of AF and mitigated atrial fibrosis in CS-CREM mice.Conclusion:Mechanical stress induces cleaved Flna 90 from Flna in atrial endocardial endothelial cells, thus assisting transcription factors Smad3/7 and TGF-β in nuclear translocation, regulating EnMT and mediating atrial fibrosis.

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Novembre 2024

Abstract 4140462: Effects of Right Ventricular vs. Conduction System Pacing on Left Ventricular Systolic and Diastolic Function Reserve and Pulmonary Gas Exchange During Exercise Stress in Pacemaker Dependent Patients with Normal Left Ventricular Ejection Fraction

Circulation, Volume 150, Issue Suppl_1, Page A4140462-A4140462, November 12, 2024. Background:Right ventricular pacing (RVP) can have adverse cardiac effects and cause pacing induced cardiomyopathy (PiCM). His bundle pacing (HBP)&Left Bundle Branch area pacing (LBBAP) mimic physiologic conduction (PhysioP) and maintain biventricular synchrony.Hypothesis and Aims:Reduced left ventricular (LV) systolic function reserve in the presence of normal baseline LV ejection fraction (EF) could precede development of RV PiCM. Our aim was to compare the effects of RVP vs. PhysioP on bicycle exercise cardiopulmonary performance in patients with normal LVEF who required pacing for bradyarrhythmias.Methods:Patients with sinus rhythm and RVP or PhysioP&ventricular pacing burden of >70% who completed cardiopulmonary exercise test and simultaneous stress echocardiography (SE) were included. Pulmonary gas exchange was calculated using Ventilation/CO2 production at rest and during exercise. Changes in LV size, EF, longitudinal strain and diastolic function and gas exchange parameters were compared post and pre exercise in the 2 groups.Results:25 of 29 patients completed the study [68 ± 23 yrs, 48% M; LVEF 56±5%, 11 RVP, 14 PhysioP]. There was no difference in baseline demographic&clinical variables, exercise duration, rest and peak heart rate and blood pressure between 2 groups. Pacing duration was 2.61±1.48 yrs in RVP vs. 0.84±0.67 yrs (p=0.003) in the Physio group. Resting echocardiographic parameters (Table 1A)were comparable. Compared to RVP, reduction in LV end-diastolic volume (EDV) 3.4±14.1 ml vs. -23.1±18.1ml, p=0.006)&LV end-systolic volume (ESV -5.7±11.6 ml vs. -18.0±9.5ml, p=0.01) was more pronounced in the PhysioP group. Changes in LVEF, LV strain&diastolic function were not different between the 2 groups (Table 1B). There were no significant differences in changes in pulmonary gas exchange parameters in the 2 groups.Conclusions:In patients with normal LVEF and pacemaker dependent, RVP is associated with impaired but PhysioP with preserved LV systolic function reserve, which can be detected by exercise SE. SE may help identify patients at risk for RV PiCM. Benefit of PhysioP needs to be determined by larger studies with longer follow-up.

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Novembre 2024

Abstract 4141840: SOX17 Deficiency is Additive to High Shear Stress in Reducing Endothelial Genes Linked to BMPR2 and NOTCH and Promoting Inflammation in Pulmonary Arterial Hypertension

Circulation, Volume 150, Issue Suppl_1, Page A4141840-A4141840, November 12, 2024. BACKGROUND:Pulmonary arterial hypertension (PAH) is characterized by obliteration of distal pulmonary arteries (PA) in association with endothelial cell (EC) dysfunction, leading to smooth muscle proliferation. SOX17 is a transcription factor (TF) expressed in arterial EC that is critical in vascular development. Deleterious variants causing reduced expression ofSOX17are linked to PAH, particularly in congenital heart defects (CHD) that cause increased PA flow and high shear stress (HSS).HYPOTHESIS:SOX17 deficiency is additive to HSS in compromising PAEC homeostasis and in promoting severe PAH.METHODS:SOX17was reduced ( >70%) by siRNA in primary human PAEC cultured in chamber slides in the IBIDI perfusion system. Computational modeling of distal PA indicated pathological HSS of 100 dyn/cm2in CHD with PAH whereas physiological laminar shear stress (LSS) is 15 dyn/cm2. EC were preconditioned under LSS for 24h, followed by HSS or LSS for 24h.RESULTS:SOX17 expression was increased under LSS versus static condition, as were known SOX17 target genes (e.g.,GJA5,GJA4,CGNL1,JAG1, andCTNNB1). SOX17siRNA and HSS similarly reduced SOX17 target genes and when combiningSOX17siRNA with HSS they were further decreased owing to an interaction between SOX17 and ERG, a TF reduced by HSS. Indeed, SOX17 and ERG motifs marked most enhancer and promoter H3K27acetyl marks that were reduced under HSS. We then carried out RNAseq of PAEC to find genes co-regulated by SOX17 and ERG (reduced by siRNA for either TF under LSS), decreased under HSS and more-so with HSS +SOX17siRNA. Those downregulated included SOX17 targets (e.g.,CGNL1andGJA5) and others not previously described, with links to BMPR2 signaling,YAP1(inducer of BMP ligands and suppressor of NF-kB),SETBP1(inducer of BMPR2 co-receptorBMPR1b),andTMEM100andSULT1B1important in NOTCH signaling and EC specification. We also found novel extracellular matrix target genes, e.g., elastin (ELN,top DEG),HMCN1,TMTC1and chromatin remodeler (TOX). Among genes upregulated, wereNAMPT, FAS, LYN, HPSErelated to NF-kB activation and/or inflammation.CONCLUSION:HSS plus SOX17 deficiency profoundly compromises EC homeostatic genes, among which are those affecting BMPR2 and NOTCH pathways, ELN fiber assembly, and those promoting inflammation. This can explain whySOX17mutations are associated with severe PAH in HSS-related congenital heart defects.

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Novembre 2024

Abstract 4142206: Shear Stress-based Purification Method for Human Pluripotent Stem Cell-derived Endothelial Cells

Circulation, Volume 150, Issue Suppl_1, Page A4142206-A4142206, November 12, 2024. Background:To apply human pluripotent stem cell-derived endothelial cells (hPSC-ECs) in regenerative medicine, exploring methods for highly purified ECs is desirable. Cell sorting is a versatile technique for isolating and purifying specific cell types, yet mechanical cell loss persists. Previously, we established a differentiation method for human induced pluripotent stem cell-derived ECs (hiPSC-ECs) based on lineage control using vascular endothelial growth factor (VEGF) and 8-Bromo cyclic adenosine monophosphate (cAMP). However, achieving high hiPSC-ECs purity without cell sorting has not yet been possible.Hypothesis:We speculated that applying digital rocker-generated shear stress during a specific period of hiPSC-EC induction would yield highly purified hiPSC-ECs without cell sorting.Methods:We applied cyclic share stress to the cultured cells using a digital rocker. To optimize the frequency and duration of digital rocker application, ECs purity on day 13 of differentiation (d13) was analyzed by flow cytometry for vascular endothelial cadherin (VE-Cadherin). Shear stress was measured using a simulation model. The functionality of ECs was evaluated through reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) for endothelial nitric oxide synthase (eNOS) and angiogenesis assay.Results:The optimized protocol consisted of a rocking period from day 5 (representing the EC progenitor stage) to d13, at 30 cycles/min with 13° tilt (equivalent to 1.09 dyn/cm2), which significantly increased the purity of ECs (Control vs Rocking: VE-Cadherin; 69.25±17.43 vs 86.68±6.023 %, P = 0.0090). Examining the number of cells on d13 revealed rocking stimulation reduced both ECs and non-ECs. Non-ECs were nearly absent, suggesting EC purification occurs by removing non-ECs, indicating ECs are more resistant to being eliminated by the rocking stimulation. The rocking culture also led to increased eNOS mRNA expression on d13 (Control vs Rocking: 0.5574±0.4985 vs 1.056±0.1652, P = 0.0393). The angiogenesis assay showed a longer vascular structure length trend in the rocking group, indicating enhanced angiogenic capacity. (Control vs Rocking: 15407±2929 vs 18335±3568 Pixel, P= 0.4309).Conclusion:In this study, we developed a method where digital rocker-generated shear stress during a specific period of hiPSC-EC induction not only selectively purifies ECs without cell sorting, but also enhances endothelial function, demonstrating their therapeutic potential.

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Novembre 2024

Abstract 4138303: Stress Hyperglycemia Ratio Predicts MACE and All-cause Mortality in Acute Coronary Syndrome Patients: A Meta-Analysis Comparing Patient with Diabetes Mellitus and Non-Diabetes Mellitus

Circulation, Volume 150, Issue Suppl_1, Page A4138303-A4138303, November 12, 2024. Background:A higher stress hyperglycemic ratio (SHR) has been reported to be associated with adverse cardiac outcomes. However, the role of SHR in predicting clinical outcomes by comparing patients with and without diabetes mellitus is yet to be explored.Objective:To evaluate the prognostic value of the SHR for predicting major adverse cardiovascular (MACE) and all-cause mortality in ACS patients with and without diabetes mellitus.Methods:Per PRISMA guidelines, we comprehensively reviewed PubMed, Google Scholar, and SCOPUS for eligible studies reporting on SHR and its association with MACE (8 studies) and all-cause mortality (7 studies) in ACS patients. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a binary random-effects model, with results displayed as forest plots. Heterogeneity was assessed using I2 statistics, and a leave-one-out sensitivity analysis was performed. P

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Novembre 2024

Abstract 4137735: Chronic Oxidative Stress Induces Hypertension and Abdominal Aortic Aneurysm in Chemogenetic Mice Model

Circulation, Volume 150, Issue Suppl_1, Page A4137735-A4137735, November 12, 2024. Background:Aortic aneurysms account for ~10,000 deaths annually in the USA. Oxidative stress is implicated in both abdominal (AAA) and thoracic (TAA) aneurysm formation, but the mechanisms are incompletely understood. We used a chemogenetic approach to modulate oxidative stress in the vascular wall by creating a transgenic mouse (DAAO-TGTie2) that expresses yeast D-amino acid oxidase (DAAO) driven by the endothelial Tie2 promoter. DAAO generates the reactive oxygen species hydrogen peroxide from D-amino acids. Vascular tissues contain L-amino acids, so yeast DAAO is quiescent until DAAO-TGTie2mice are provided with D-amino acids. Here we characterize the cellular and molecular consequences of vascular oxidative stress in DAAO-TGTie2mice.Hypothesis:Chronic oxidative stress in the vascular wall causes arterial dysfunction.Aim:To characterize the phenotype of DAAO-TGTie2mice after oxidative stress induction in vascular endothelium.To identify the mechanisms whereby vascular oxidative stress causes arterial dysfunction and hypertension.Methods:Systolic blood pressure and aortic sonography were measured weekly in D-alanine-fed DAAO-TGTie2. Proteomic analyses were used to identify mechanistic targets, which were validated using biochemical and immunohistochemical methods.Results:D-alanine-fed DAAO-TGTie2mice develop systolic hypertension and abdominal but not thoracic aortic aneurysms; treated mice die in >3 months with burst abdominal aortic aneurysms. Transgene expression is similar in abdominal and thoracic endothelium. Levels of oxidative stress markers (oxidized proteins, lipid, and DNA) were similar in thoracic and abdominal aorta. Proteomic analyses established phenotypic switching in abdominal but not thoracic aorta, and also revealed activation of the oxidant-activated kinase ASK1 and of the MAP kinase cascade in abdominal but not thoracic aorta. Immunoblot analyses showed a marked decrease in JNK1 phosphorylation by phosphatase DUSP3 and an increase in vascular KLF4, leading to phenotypic switching of contractile to synthetic VSMCs.Conclusion:Chronic chemogenetic oxidative stress induces hypertension and abdominal aortic aneurysm formation caused by KLF4-dependent VSMC phenotypic switching.

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Novembre 2024

Abstract 4143599: Subpopulation Benefits and Adverse Events of Prophylactic Methylprednisolone for Infant Heart Surgery: An Analysis of the STRESS Trial

Circulation, Volume 150, Issue Suppl_1, Page A4143599-A4143599, November 12, 2024. Background:The Steroids to Reduce Systemic Inflammation after Infant Heart Surgery (STRESS) trial randomized 1200 infants undergoing cardiac surgery with cardiopulmonary bypass to prophylactic intraoperative methylprednisolone (MP) versus placebo.Aims:Evaluate benefits and harms associated with MP in subset populations.Methods:STRESS participants were categorized based on STAT Mortality Category (1-3 and 4-5), age (neonate ≤ 30 days< non-neonate), prematurity (< 37 weeks gestation) and any chromosomal or syndromic diagnoses (CSD). Key postoperative outcomes included any steroid administration (< 72 hours after surgery), peak blood glucose (7 days), thrombosis, and infections.Results:The cohort consisted of 30% (364/1200) neonates, 16% (193/1197) premature, and 81% (969/1197) STAT 1-3 operations. Stratified analyses demonstrated notable beneficial effects with MP including reduced use of postoperative hydrocortisone in neonates (OR 0.39 [0.25-0.60]), those following STAT 1-3 (OR 0.65 [0.47-0.91]) and STAT 4-5 operations (OR 0.57 [0.34-0.97]), term infants (OR 0.62 [0.47-0.83]), and those without CSD (OR 0.63 [0.46-0.86]). MP associated with lower thrombosis occurrence among neonates (OR 0.37 [0.16-0.87]) and term infants (OR 0.38 [0.19-0.75]). Notable adverse associations with MP included increased postoperative peak blood glucose levels and insulin use (all subgroups, P

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Novembre 2024

Abstract 4140852: Total Burden of Posttraumatic Stress Disorder on Incident Cardiovascular Disease Among Women Veterans

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?

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Novembre 2024

Abstract 4143744: Cross-talk between oxidized LDL, oxidative stress and renin-angiotensin-aldosterone system: Impact on endothelial function and atherosclerosis

Circulation, Volume 150, Issue Suppl_1, Page A4143744-A4143744, November 12, 2024. Introduction/Background:Hypertension and hypercholesterolemia are important risk factors of endothelial dysfunction and atherosclerosis. Previous studies suggested a crosstalk between an activated renin-angiotensin-aldosterone system (RAAS), reactive oxygen species (ROS) and oxidized low-density lipoproteins (oxLDL) in atherosclerosis, but the underlying molecular mechanisms are not well understood.Research Question/Hypothesis:Can we identify novel signaling pathways controlling the molecular crosstalk of the RAAS with ROS and oxLDL in endothelial dysfunction and atherosclerosis?Methods/Approach:The impact of AT1R blockade on oxLDL-induced superoxide anion formation and endothelial dysfunction was studied in human umbilical artery endothelial cells and aortic rings of wild-type mice by chemiluminescence and Mulvany myograph. We cloned 5’-terminal deletions of the AT1R promoter and assessed the luciferase activity in human endothelial cells. Oct-1 binding to the human AT1R promoter region was studied by EMSA. Further assays included real-time PCR, confocal microscopy, Western blotting, G protein reporter assays, phospho-ERK1/2 antibodies and specific siRNAs. The data were validated in heart of obese C57BL/6 mice and cardiac and aortic tissue of AT1a/AT1bdouble knockout micein vivo.Results/Data:AT1R promoter activation studies upon Ang II- and oxLDL-stimulation in endothelial cells revealed that Ang II and oxLDL activate AT1R signaling through G protein Gα12/13, followed by activation of ERK1/2 MAP kinases, and transcription and translation of Oct-1, resulting in up-regulation of AT1R, LOX-1 and NOX2 expression, which could be antagonized by specific inhibitors at each step of the identified signaling cascade. AT1R blockade improved oxLDL-induced endothelial dysfunction in aortic rings of wild-type mice. Male C57BL/6 mice fed a high-fat diet exhibited upregulation of Oct-1 levels in cardiac tissues, compared to normal controls, while AT1a/AT1bdouble knockout mice demonstrated downregulation of Oct-1, AT1R, LOX-1, and NOX2 on mRNA and protein level in cardiac and aorta tissue, thus confirming the identified signaling cascadein vivo.Conclusions:Oct-1 is an essential transcription factor for Ang II- and oxLDL-induced upregulation of AT1R and LOX-1 expression in endothelium, thus identifying a novel molecular cross-talk of oxLDL with ROS signaling and the RAAS contributing to development of endothelial dysfunction and atherosclerosis.

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Novembre 2024

Abstract 4146032: Routine stress testing in diabetic patients after coronary intervention: a systematic review and single arm meta-analysis

Circulation, Volume 150, Issue Suppl_1, Page A4146032-A4146032, November 12, 2024. Background:Stress testing is a well-established non-invasive method commonly used in clinical practice for patients with angina. However, its benefit in diabetic patients after coronary intervention remains unclear. This systematic review aims to address this knowledge gap by evaluating the impact of routine stress testing in this specific patient population.Research Question:Does routine stress testing improve outcomes in diabetic patients with prior revascularization?Goals:We aimed to perform a systematic review and meta-analysis of studies that evaluated death, MACE and repeated revascularization episodes in diabetic patients who have prior coronary intervention.Methods:We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCT) and cohort studies evaluating diabetic patients who underwent cardiac revascularization and reporting the following outcomes: (1) Myocardial Infarction (MI) and Cardiovascular Death; (2) Ischemia; and (3) Repeat Revascularization. Statistical analysis was performed using Open Meta and heterogeneity was assessed with I2statistical.Results:We included 16924 patients from 16 studies, of which 15 were observational cohort studies and 1 was a RCT. All patients were diabetics and had a history of revascularization. Follow-up ranged from 1 to 5.2 years. The mean patient age was 60.8±9.5 years and 75% were male. MI and cardiovascular death was found in 9.8% (95% CI; range 6.8-12.8%; p

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Novembre 2024

Abstract 4141934: Psychosocial Stress Subgroups and Cardiovascular Disease (CVD) Events in the Multi-Ethnic Study of Atherosclerosis (MESA)

Circulation, Volume 150, Issue Suppl_1, Page A4141934-A4141934, November 12, 2024. Introduction:Heightened psychosocial stress is a CVD risk factor. While stressors are common and often co-occur, identifying sources and patterns of psychosocial stress exposure may provide insight into individual susceptibility to CVD. Therefore, we sought to identify and examine the longitudinal associations of baseline psychosocial stress subgroups with CVD events in MESA.Methods:Data from 6,349 adults (aged: 62.2±10.2 years; 52.9% women) from the MESA cohort with no prior CVD event at baseline (years 2000-2002) were used in this analysis. Latent class analysis (LCA) was used to specify distinct stress subgroups based on 6 variables: chronic burden, neighborhood safety, adequate food shopping, neighborhood noise, lifetime- and past-year discrimination. Five classes were determined after examining traditional fit indices. Adjudicated fatal and nonfatal CVD events were ascertained in annual follow-up visits through the year 2019. Cox proportional hazards models with sequential adjustment of baseline variables were used to examine the associations between subgroup membership and CVD events.Results:Five distinct stress subgroups were identified via LCA and were labeled “moderate neighborhood noise” (12.1%), “excessive noise/crime” (6.4%), “elevated on all” (6.3%), “high discrimination/safe neighborhood” (21.4%), “optimal” (53.8%) (see figure). By the year 2019, 1,121 participants had experienced a CVD event. Membership in the “elevated on all” and “high discrimination/safe neighborhood” subgroups (see table) were associated with higher risk of a CVD event when adjusted for sociodemographic characteristics and cardiovascular health metrics. However, when adjusted for measures of anxiety and depression, possible mediators, only membership in the “high discrimination/safe neighborhood” subgroup was associated with increased risk of a CVD event.Conclusions:Among 5 distinct stress subgroups those experiencing high discrimination had higher risk for CVD events.

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Novembre 2024

Abstract 4137935: Adipogenesis in Bone Marrow Niche under Cardiac Stress Worsens Cardiac Function

Circulation, Volume 150, Issue Suppl_1, Page A4137935-A4137935, November 12, 2024. Background:We have recently reported that repetitive cardiac decompensation with multimorbidity often experienced by patients with heart failure (HF) is attributed to epigenetic modifications of hematopoietic stem cells (HSCs) in the bone marrow (BM). HF reprogrammed HSCs differentiation and altered tissue macrophage homeostasis. These findings demonstrate that the BM can carry an innate immune memory of cardiac stress that may exacerbate HF and predispose other organs to pathology.Aims:Because the stemness of HSCs is mainly regulated by mesenchymal stromal cells (MSCs) in the BM niche, we investigated phenotypic alterations of MSCs under cardiac stress.Methods&Results:Transcriptome analysis of MSCs showed preferential differentiation toward adipocytes in murine pressure overload models.In vitroassays and histological BM sections also support this finding. Furthermore, single-cell RNA sequencing of MSCs demonstrated that the percentage of adipocyte-primed MSCs increased in proportion to the severity of cardiac dysfunction, and also correlated with the frequency of myeloid-lineage progenitor cells. To investigate the influence of adipo-lineage MSCs on HSCs, we conducted BM transplantation supplemented with MSCs from control or HF mice. Recipient mice transplanted with HF-MSCs showed significant increases in myeloid-biased multipotent progenitors in BM and myeloid cells in peripheral blood. Additionally, the number of proinflammatory cardiac macrophages was significantly increased in the HF-MSCs group, promoting cardiac fibrosis and dysfunction.Conclusions:Our results demonstrated that the BM niche could perceive cardiac stress in the form of adipocytic skewing of MSCs in the setting of HF, which changed the differentiation behavior in HSCs and ultimately led to further deterioration of cardiac function through the impaired differentiation of circulating monocytes into cardiac macrophages. Therefore, suppressing the adipocytic differentiation of MSCs could have a novel therapeutic potential to avoid repeated HF events.

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Novembre 2024

Abstract 4138517: Role of Coronary Computed Tomographic Angiography in Patients with Discordant Findings on Exercise Stress Echocardiography

Circulation, Volume 150, Issue Suppl_1, Page A4138517-A4138517, November 12, 2024. Background:Exercise stress echocardiography is routinely used for risk stratification and diagnosis of myocardial ischemia in low-to-intermediate risk patients with suspected coronary artery disease (CAD). Discrepancies between exercise electrocardiography (EKG) and echocardiography (ECHO) are common in clinical practice. Prior literature suggests that patients with discordant stress test results generally have worse outcomes, though the extent of epicardial atherosclerotic disease remains unclear. Coronary computed tomographic angiography (CTA) has gained a class I recommendation for the assessment of atherosclerotic burden per ACC/AHA chest pain guidelines. Using non-invasive fractional flow reserve (CT-FFR), the functional significance of lesions can also be assessed. This study investigates the incidence and burden of CAD in patients with discordant exercise echocardiography findings.Methods:Patients aged 18 or older who had exercise echocardiography followed by CTA from January 1, 2013, to January 31, 2023, were retrospectively enrolled in this study and categorized into two discordant result groups: EKG+/ECHO- or EKG-/ECHO+. Those who failed to achieve the target heart rate or had a paced rhythm/left bundle branch block on baseline EKG were excluded. CTA findings were classified as no CAD, non-obstructive CAD (

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Novembre 2024