Abstract 4146699: Blunted Hemodynamic Reactivity to Acute Mental Stress in the Lab is Associated with Autonomic Inflexibility at Home

Circulation, Volume 150, Issue Suppl_1, Page A4146699-A4146699, November 12, 2024. Background:Growing evidence suggests that blunted blood pressure and heart rate responses to acute psychological stress independently associate with an increased risk of adverse outcomes in individuals with CHD, but assessment of mental stress reactivity in clinical settings is resource intensive. An alternative approach is to passively measure stress physiology at home with wearables, which is easier to translate into clinical practice. We tested the hypothesis that blunted mental-stress hemodynamic reactivity in the lab is associated with digital biomarkers of autonomic inflexibility at home.Methods:We conducted a mental stress test in 239 participants (age < 60 years) with an MI within 8 months. Participants underwent a speech stressor task in front of an audience to induce mental stress, during which blood pressure and heart rate were measured repeatedly during a baseline 15-minute rest period and 5-minute stress challenge. Participants went home with a 7-day Holter monitor to measure autonomic function. We examined vagal autonomic inflexibility with deceleration capacity (DC), a digital biomarker calculated via phase rectified signal averaging of heart rate intervals. We also examined low frequency (LF) heart rate variability (HRV), an indirect measure of baroreceptor sensitivity. We measured mean values from 5-minute windows during sedentary periods only to avoid confounding due to physical activity. We used multivariable linear regression models to adjust for potential confounding due to age, beta-blockers, and sex.Results:The mean age was 52 years, 51% were black, and 36% were women. Lower DC most strongly associated with a blunted change in heart rate during acute mental stress challenge (adjusted p

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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 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 4139600: Characteristics and Pattern of Stress Cardiomyopathy in High Grade Subarachnoid Hemorrhage

Circulation, Volume 150, Issue Suppl_1, Page A4139600-A4139600, November 12, 2024. Background:Cardiac injury after subarachnoid hemorrhage (SAH) is a well-recognized phenomenon with electrocardiogram (ECG) changes, arrhythmias and myocardial dysfunction. Neurocardiac injury has been commonly reported with increased severity of SAH, however much of the evidence has focused on high grade SAH requiring hemodynamic support or mechanical ventilation. In this study we focused on neurocardiac injury with high grade World Federation of Neurological Surgeons (WFNS) grade 3-5 SAH requiring intensive care management.Methods:Patients admitted to our intensive care unit from 2009-2019 with an WFNS 3-5 aneurysmal SAH with an echocardiogram within 7 days of admission were included in our study. Electrocardiogram, cardiac biomarkers and data regarding mortality and neurological complications were collected retrospectively.Results:A total of 242 patients were included in our study analysis with 11 (5%), 89 (37%), and 142 (59%) had WFNS grade 3, 4 or 5 SAH, respectively. Of the 95 patients that underwent echocardiography in the first week, 38 (40%) had a reduced ejection fraction, which was mild (LVEF 40-52%) in 13 (14%), moderate (LVEF 30-39%) in 14 (15%), and severe (LVEF < 30%) in 11 (12%). Independent predictors of reduced ejection fraction included a lower presenting GCS score (OR 1.2 per one point reduction in (Glasgow Coma Score) GCS, 95% CI 1.0-1.5, p = 0.03), elevated troponin T concentration (OR 6.1, 95% CI 1.2-31.3, p = 0.03) and T wave inversion on ECG (OR 9.1, 95% CI 1.6-52.3, p = 0.01). In patients with reduced ejection fraction, classical apical wall motion abnormality was more prevalent in older populations (median age 64 years (apical) vs 50 years (basal wall motion abnormality) and 52 years (other) p = 0.03). In all wall motion abnormality groups, there was a female predominance. Classic Takotsubo wall motion was associated with an anterior SAH aneurysm location (p = 0.03) and highest proportion of moderate to severe LV dysfunction (p = 0.04). ICU mortality did not differ based on the pattern of wall motion abnormalities.Conclusion:Predictors of neurocardiac injury in high grade SAH include troponin elevation, T wave abnormalities and lower presenting GCS. Aneurysm location was associated with wall motion abnormalities and degree of LV dysfunction. Patients with WFNS 3-5 SAH are at increased risk of neurocardiac injury. ECG changes, cardiac biomarker elevation and aneurysm location can help identify patients who warrant echocardiography.

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Novembre 2024

Abstract 4144217: Ruling-out Left Main Stem Stenosis By Clinical And Stress-ECG Variables: The MASTER Case-Control Multicenter Study

Circulation, Volume 150, Issue Suppl_1, Page A4144217-A4144217, November 12, 2024. Background:The ISCHEMIA trial questioned revascularization in chronic coronary syndrome (CCS) patients, but excluding subjects with left main (LM) coronary artery disease (CAD). A widely available diagnostic method excluding LMCAD would expand the implementation of an initial noninvasive strategy.Objective:Assessing the ability of excluding LMCAD through clinical and ECG stress testing (EST) variables in patients undergoing coronary angiography (CAG) for CCS.Methods:In a multicenter retrospective case-control study we evaluated CCS subjects undergoing CAG after a maximal EST.Caseswere patients with angiographic ≥50% LM stenosis or ≥70% stenoses of both proximal left anterior descending and proximal circumflex arteries; we matched them with similar patients without LMCAD (Controls)in a 1:3 ratio. Models were internally validated through logistic regressions.Results:219Caseswere matched with 554Controls. The c-statistic was 0.80 (optimism-adjusted: 0.73). Assuming LMCAD prevalence of 5% and a misclassification cost ratio of 1:100 (ratio of the cost of performing CAG in a subject without LMCAD to the cost of not performing CAG in a patient with LMCAD), the negative predictive value was 98.6%, correctly classifying 84.5% ofCases. CAG could be spared in 57.0% of subjects, missing one LMCAD diagnosis every 70 CAGs spared in patients without LMCAD (Figure).Conclusions:Among patients with CCS, LMCAD can be predicted withacceptablediagnostic accuracy anda very highnegative predictive value through a model based on clinical and EST parameters, allowing an initial noninvasive management of most patients able to perform an EST, reducing the costs of routine coronary imaging. Such results should enlarge the applicability of the ISCHEMIA results when coronary computed tomography angiography, used in ISCHEMIA, is not available, limiting the referral to invasive CAG.

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Novembre 2024

Abstract 4142424: The impact of the stress hyperglycemia ratio on adverse prognosis in patients with chronic thromboembolic pulmonary hypertension

Circulation, Volume 150, Issue Suppl_1, Page A4142424-A4142424, November 12, 2024. Background:Risk assessment for chronic thromboembolic pulmonary hypertension (CTEPH) remain challenging. Stress hyperglycemia represents the regulation of glucose metabolism in response to stress. Meanwhile, stress hyperglycemia ratio (SHR) is recently found to reflect true acute hyperglycemic status. However, the relationship between SHR and adverse prognosis is uncertain. This study aimed to investigate the prognostic value of SHR in CTEPH patients.Methods:A total of 451 CTEPH patients with available baseline SHR measurement were enrolled between February 2014 to July 2023 at Fuwai hospital. The predictive values of SHR for adverse events were assessed.Results:During a median follow-up of 21 months, 89 (19.7%) CTEPH patients experienced adverse clinical outcomes. Kaplan-Meier curve analysis revealed that the cumulative adverse event rates were significant higher in the SHR≥0.747 with CTEPH patients, compared with patients in the SHR

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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 4138348: Mechanical stress-mediated nuclear envelope damage promotes Aortic Valve Calcification through the ZBP1-RIPK3-NF-κB signaling axis

Circulation, Volume 150, Issue Suppl_1, Page A4138348-A4138348, November 12, 2024. Methods and Results:We describe a comprehensive characterization of the AVICs nucleus landscape as determined by transmission electron microscopy (TEM) of samples obtained from CAVD patients. Turbulence led to nuclear envelope integrity lose in AVICs cultured in shear stress experiments, with three different fluid conditions [static (ST), laminar stress (LS), and oscillatory stress (OS)], indicated by Western blot and immunofluorescence (IF). Silencing lamin A/C (LMNA) through small interfering RNA (siRNA), accelerated nuclear envelope damage , as indicated by Western blot, qPCR, and immunofluorescence (IF). The formation of Z-DNA and its co-localization with Z-DNA binding protein (ZBP1) was observed due to the nuclear envelope damage by IF. Western blot, qPCR, IHC and IF confirmed Z-DNA-induced inflammation in AVICs through the ZBP1-RIPK3-NF-κB signaling pathway. ZBP1 and RIPK3 knockdown with siRNA markedly reduced the protein level of osteogenic markers alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), and bone morphogenetic protein 2 (BMP2) in VICs. In vivo, aortic valve disease was constructed by direct wire injury (DWI), and we showed that overexpression of LMNA by adeno-associated virus significantly decelerated the progression of aortic valve lesion induced by DWI in mice.Conclusion:Excessive mechanical stress can induce damage to the nuclear envelope of AVICs by causing cytoskeletal remodeling, initiating the formation of Z-DNA, and hastening the calcification process in AVICs and CAVD.

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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 4146930: Reported Stress Level is Associated with Cardiovascular Health in Young Adults – An Electronic Health Record Study of Nearly 1.4 Million Individuals

Circulation, Volume 150, Issue Suppl_1, Page A4146930-A4146930, November 12, 2024. Background:Young adulthood (19–39 years) is the life stage of greatest declines in cardiovascular health (CVH). It is hypothesized that this decline may be related to competing demands (e.g., stressors) of this period of the lifecourse such as work and child-rearing. The AHA’s Life’s Essential 8 CVH framework identifies the scored domains (behavioral and clinical factors), as needing to be contextualized by the important construct of psychological health (including stress). However, scarce data are available to assess the relationship between CVH and reported stress – especially among YA.Purpose:The current study aims to be the first to use Cosmos electronic health record (EHR) data to assess the relationship between YA CVH and reported stress in a nationally representative, very large sample of YAs.Methods:Cosmos is a platform hosting de-identified Epic EHR data on >250 million patients. We assessed Cosmos data from May 2022 through April 2024 to identify all YAs with reported stress data (5-point scale from “not at all” to “very much”). We then compared trends of each CVH metric across stress categories.Results:1,397,375 individuals 19 – 39 years of age had reported stress data available. The sample was 62% White, 17% Black, 4% Asian, 12% Hispanic, and 63% female. Generally, stress levels were stable across YA age groups (Figure 1). For lifestyle behavior related domains (physical activity (PA), smoking, and BMI), the prevalence of “poor” CVH scores (worst categorization) increased in YA as reported stress amount increased (Figure 2). Prevalence of “poor” scores in clinical metrics (BP, HbA1c, nonHDL-C) were not associated with stress.Conclusion:In a very large sample of YA, greater reported stress was associated worse CVH for the behavioral domains of PA, smoking and BMI. Interventions aimed at reducing stress in YA may have the added benefit of improving CVH.

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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 4140558: Circulating plasma proteins in the Fontan circulation predict mitochondrial oxidative stress

Circulation, Volume 150, Issue Suppl_1, Page A4140558-A4140558, November 12, 2024. Background:Single ventricle congenital heart disease such as hypoplastic left heart syndrome (HLHS) with a Fontan circulation constitute the largest group of children hospitalized with circulation failure, experiencing an in-hospital mortality rate of 20-50%. We investigated the mechanisms leading to circulation failure so as to identify novel therapeutic targets.Methods:Blood was collected from patients with HLHS s/p Fontan and controls with normal cardiac anatomy and function (N=6/group). Plasma microvesicles (MV) were isolated, and proteomics assessed using data independent acquisition mass spectroscopy. Dysregulated proteins with a fold change >1.5 or < -1.5, p

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Novembre 2024

Abstract 4125025: Association between Marital Status and Major Adverse Cardiovascular Events: Role of Stress-Related Neural-Immune Mechanisms

Circulation, Volume 150, Issue Suppl_1, Page A4125025-A4125025, November 12, 2024. Background:Chronic stress is associated with cardiovascular disease (CVD) in part through neural mechanisms that potentiate inflammation. Disrupted social connections are associated with higher chronic stress. As such, we hypothesized that: 1) previously married (divorced, separated) individuals have higher major adverse cardiovascular event (MACE) risk compared to married individuals and 2) that greater activation of stress-related neural-immune mechanisms contributes to this relationship.Methods:Participants (N=75,638) enrolled in the Mass General Brigham Biobank were studied. Marital status and MACE were identified using survey data and ICD-10 codes, respectively. A subset (N=1,121) underwent clinical18F-FDG-PET imaging, enabling assessment of stress-related neural activity as the ratio of the amygdala to prefrontal cortex activity (AmygAc). Clinical high-sensitivity C-reactive protein (hs-CRP) levels were assessed in another subset of the cohort (N=10,358). Linear and Cox regression and mediation analyses were used.Results:Among participants (median age 62 years; 53% female), 2,978 subjects developed MACE after Biobank enrollment. Previously married (vs. currently married) individuals had greater MACE risk (HR 1.33 [95% CI: 1.20,1.57], 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 4119062: A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling

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.

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Novembre 2024

Abstract 4142510: Impact of Stress Hyperglycemia Ratio on Heart Failure and Atherosclerotic Cardiovascular Events After Acute Myocardial Infarction

Circulation, Volume 150, Issue Suppl_1, Page A4142510-A4142510, November 12, 2024. Background:An acute hyperglycemic status is reportedly associated with poor prognosis in patients with acute cardiovascular diseases. Although the stress hyperglycemia ratio (SHR) is a novel index to accurately represent the hyperglycemic condition on admission, relations between SHR and clinical outcomes are not fully evaluated in a setting of acute myocardial infarction (MI).Methods:This retrospective, multicenter registry study included 2,386 patients with acute MI undergoing percutaneous coronary intervention. SHR was calculated as a blood glucose level on admission divided by the estimated average glucose derived from a glycated hemoglobin level. The co-primary endpoints of this study included heart failure (HF)-related events (a composite of all-cause death and worsening and hospitalized HF) and major atherosclerotic cardiovascular events (MACE) (a composite of all-cause death, recurrent MI, and ischemic stroke), during the index hospitalization and after discharge.Results:Of the 2,386 patients, 890 (37.3%) had diabetes, and the median SHR was 1.17 [0.99, 1.45]. HF events and MACE occurred in 680 (28.5%) and 233 (9.8%) during hospitalization. SHR was identified as a factor significantly associated with both in-hospital HF events (adjusted odds ratio 1.65, 95% confidence interval 1.18-2.29, p=0.003) and MACE (adjusted odds ratio 1.50, 95% confidence interval 1.10-2.03, p=0.009). Among 2,017 patients who survived to discharge and had follow-up information, 195 (9.7%) and 214 (10.6%) experienced HF events and MACE during the median of 536 days after discharge. Patients with the high SHR ( >1.45, 4th quartile) had an increased risk of HF events than those with SHR ≤1.45, while the incidence of MACE after discharge did not differ significantly between the two groups (Figure). The multivariable analysis confirmed the association of SHR with long-term HF events.Conclusions:In patients with acute MI, SHR was predictive of in-hospital outcomes including HF events and MACE, while after discharge, the higher SHR was associated with a higher HF risk but not with MACE. Further studies are needed to elucidate the underlying mechanisms and potential incremental benefit of SHR in stratifying patient risks after MI.

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Novembre 2024