Risultati per: Lo stress può essere causa di infarto ed ictus

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 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.

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.

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.

Circulation, Volume 150, Issue Suppl_1, Page A4146135-A4146135, November 12, 2024. Background:Epicardial adipose tissue (EAT) is increasingly recognized as a key factor in the development of atrial fibrillation (AF). In addition to direct myocardial infiltration by adipocytes affecting conduction properties, EAT may also promote an arrhythmogenic substrate through paracrine and endocrine effects. EAT was shown to preferentially generate oxidase-dependent reactive oxygen species (ROS) when compared to subcutaneous fat. While a role for myocardial ROS in the development of AF is well established, a separate role for EAT oxidative stress remains unexplored.Hypothesis:Oxidative stress in the EAT contributes to atrial electrical remodeling and development of AF.Aims:Determine the effect of EAT-restricted gene therapy with NOX2 shRNA on atrial electrical remodeling in the short-term canine atrial tachypacing (ATP) model of AF.Methods:A single-chamber pacemaker was inserted for the ATP model. Animals developed persistent AF after 4-6 weeks, after which the atria were harvested. Unpaced animals were used as controls. Expression of NOX2 in the EAT was assessed by qPCR. EAT oxidative stress was determined by IHC for 8-OHdG, a marker of DNA oxidative damage. A subset of animals underwent an open-chest gene injection procedure restricted to the EAT (with a plasmid expressing NOX2 shRNA or a scrambled sequence) prior to initiation of ATP for 9 days. A terminal EP study determined regional atrial ERP and AF inducibility.Results:NOX2 expression was significantly increased in the EAT of animals with ATP-induced AF when compared to unpaced controls (Panel A, p

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

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=

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

Circulation, Volume 150, Issue Suppl_1, Page A4143092-A4143092, November 12, 2024. Background:Very high level, lifelong aerobic exercise results in lower ventricular stiffness and left ventricular wall stress (LVWS) LVWS is an important predictor of future heart failure risk. To what degree LVWS changes with various doses of lifelong aerobic exercise is unknown.Objective:The purpose of this study was to determine the impact of lifelong exercise on LVWS.Methods:Seniors (n = 58) who consistently participated in lifelong patterns of exercise training were recruited and categorized into 3 groups: “sedentary” (

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

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 (

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.

Circulation, Volume 150, Issue Suppl_1, Page A4141274-A4141274, November 12, 2024. Background:Atherosclerosis is the most common cause of cardiovascular death. Oxidative stress is related to the initiation and progression of atherosclerosis. However, how oxidative stress affects the progression of atherosclerosis in vivo has not yet been fully investigated. Non-obstructive general angioscopy (NOGA) can meticulously visualize directly aortic atherosclerosis in vivo. The purpose of this study was to evaluate the relationships between oxidative stress and NOGA-derived aortic plaques.Methods:We investigated 120 consecutive cases with coronary artery disease evaluated for the aorta by NOGA between July 2021 and February 2024. Atherosclerotic lesions of the aorta were screened using NOGA immediately after coronary arteriography. NOGA examination evaluated the counts of ruptured plaques, chandelier signs, intense yellow plaques, and red thrombi in the aorta. Regarding the number of each plaque, we assessed the proportion of aortic findings detected by NOGA at each vertebral level. Derivatives of reactive oxygen metabolites (d-ROMs) levels as indices of reactive oxygen species production were evaluated.Results:The mean age was 66 years, and the median d-ROM value was 289 U.CARR [interquartile range: 251-339]. The d-ROM value was significantly correlated with the proportion of ruptured plaques (r=0.28, p=0.015), but not correlated with the other plaque characteristics. In a multiple linear regression analysis for the proportion of ruptured plaques in the aorta, d-ROMs were one of the independent factors adjusted for age, sex, hypertension, dyslipidemia, and diabetes mellitus (β=0.14, p=0.004).Conclusion:The value of d-ROMs was related to the proportion of ruptured plaques in the aorta, but not to the proportion of the other plaque characteristics. Oxidative stress may help to elucidate the mechanism for the progression of aortic atherosclerosis.

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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