Search Results for: Nelle donne lo stress danneggia la salute dell’intestino

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 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 A4141154-A4141154, November 12, 2024. Background:Acute ischemic stroke (AIS) is one of the leading causes of death and disability in adults worldwide, and effective treatments are still lacking. Cold-inducible RNA-binding protein (CIRP) is up-regulated in response to various stress conditions. Previous studies have indicated that CIBP could potentially influence the development of various diseases.Research questions:Nevertheless, the specific role and molecular mechanism of CIBP after AIS remain unclear.Methods:The levels of serum CIRP and other brain injury markers such as NSE, S100β, GSDMD, and NLRP3 were measured by ELISA to explore the relationship between CIRP and AIS. Additionally, middle cerebral artery occlusion models (MCAO) in rats were established to investigate its localization in brain tissue using immunofluorescence staining. Additionally, the CIRP knockout MCAO rat model was established, and evaluate the effect of CIRP deficiency on the neurological function of rats. while the role of CIRP was investigated through RNA sequencing and Western Blot analysis. Additionally, the potential protective effect of the CIRP inhibitor C23 on neural injury following AIS was examined.Results:(1) Compared to the healthy control group, the serum levels of CIRP and other brain injury markers (NSE, S100β) in AIS patients and MCAO rats were significantly elevated, and the elevated levels were positively correlated. (2) In the MCAO rat model, the CIRP was mainly located in neurons and microglia. (3) Compared with wild-type MCAO rats, CIRP knockout MCAO rats improved neurological function scores. (4) RNA-seq analysis revealed that genes differentially expressed between wild-type MCAO rats and CIRP knockout MCAO rats were enriched in inflammation-related pathways. (5) The expression of pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, and ASC) and inflammatory factors (IL-1β, TNF-α, etc.) decreased in CIRP knockout MCAO rats. (6) The CIRP inhibitor C23 significantly alleviated brain injury and improved neurological function. C23 treatment significantly decreased the expression levels of pyroptosis-related proteins and inflammatory factors.Conclusions:This study shows that CIRP plays an important role in AIS development. The levels of CIRP in AIS patients and MCAO rats are significantly increased and are positively correlated with nerve damage markers. Thus, supporting CIRP as a potential target for the treatment of AIS. This discovery provides new strategies for the treatment of AIS.

Circulation, Volume 150, Issue Suppl_1, Page A4139708-A4139708, November 12, 2024. Background:Racial and ethnic disparities exist in cardiovascular health (CVH) in pregnancy. While social determinants of health (SDOH) affect CVH, the extent to which SDOH assessed in early pregnancy explain racial and ethnic differences in CVH postpartum remains to be defined.Objective:This study examines the relative contribution of SDOH in early pregnancy to racial and ethnic differences in maternal CVH 2-7 years after delivery.Methods:This is a secondary analysis of the prospective nulliparous pregnancy outcomes study: Monitoring Mothers-to-be Heart Health Study (nuMoM2b-HHS) cohort. The outcome was maternal CVH defined using the American Heart Association’s Life’s Essential 8 (LE8) framework, which included body mass index, blood pressure, lipids, fasting glucose, diet, physical activity, sleep health, and smoking status, and calculated as a score of 0-100. We used the Blinder-Oaxaca decomposition to quantify the statistical contributions of differences in demographic (age and nativity), socioeconomic status ([SES], education, income, insurance, and health literacy), and psychosocial (resilience, social support, anxiety, depression, and stress) factors in early pregnancy to differences in mean postpartum CVH between the two largest self-identified minoritized racial and ethnic groups (non-Hispanic [NH] Black and Hispanic) and NH White individuals.Results:Of 4,161 assessed pregnant individuals, 17.7% identified as Hispanic, 15% as Black, and 67.3% as White. After adjusting for demographic, SES, and psychosocial factors, the average CVH score in White individuals was 12.2 (SE 1.2) points higher (better) than in Black individuals and 3.3 (SE 0.8) points higher than in Hispanic individuals (Figure, all p

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.

Circulation, Volume 150, Issue Suppl_1, Page A4147235-A4147235, November 12, 2024. Background:Sex differences in angina frequency and health status have been previously described in patients with chronic coronary disease (CCD), with women more severely affected despite lesser coronary artery disease (CAD) severity. Psychosocial factors, such as perceived stress and depression, are associated with increased angina and are more common in women and in those with ischemia and no obstructive coronary artery disease (INOCA). We examined whether perceived stress and depressive symptoms mediate sex differences in angina severity among patients with CCD, and whether this relationship differs between those with CAD vs. INOCA.Methods:The association between sex, stress (Perceived Stress Scale-4) and depressive symptoms (Patient Health Questionnaire-8) and angina-specific health status (Seattle Angina Questionnaire, SAQ) at enrollment and changes over 1 year in North American ISCHEMIA participants and in the CIAO-ISCHEMIA study (INOCA) were compared using linear regression.Results:Among 1,626 participants (N=1,439 CAD and N=187 INOCA) with available SAQ, PSS-4 and PHQ-8 data, women had worse SAQ-7 summary scores than men in both CAD and INOCA cohorts (Table). Higher stress and depressive symptoms were associated with worse angina in both CAD and INOCA cohorts. Given consistency of results, cohorts were pooled for multivariable analysis. Female sex, PSS-4 score and PHQ-8 score were each independently associated with lower SAQ scores, (female vs. male difference -5.12 points, 95% CI -7.21, -3.02, p=0.001; PSS-4 -0.78 per point, 95% CI -1.06, -0.50, p=0.001; PHQ-8 -1.38 per point, 95% CI -1.58, -1.18, p=0.001) but CAD vs. INOCA was not and the effects were similar by sex.Conclusions:Women, with both CAD and INOCA, had worse angina and angina-related health status than men. High stress and depressive symptoms were each independently associated without a significant interaction by sex, and regardless of presence of obstructive CAD. Therefore, stress and depression levels are not a central explanation for worse health status in women than men with CAD or INOCA.

Circulation, Volume 150, Issue Suppl_1, Page A4146828-A4146828, November 12, 2024. Heart transplantation remains a vital treatment for end-stage heart failure, yet the scarcity of suitable donor hearts makes the treatment unavailable to many patients in critical need. Aged donor hearts, despite their availability, exhibit increased primary graft dysfunction and decreased survival rates post-transplantation. Addressing this critical barrier could potentially improve post-transplant outcomes and make older donor hearts a viable option. In this study, using a mouse heterotopic heart transplant model, we first confirmed that hypothermic cardioprotection was significantly impaired in aged donor hearts but preserved in young donor hearts. RNA-Seq analyses revealed down-regulation of RNA editing activity along with exacerbated Endoplasmic reticulum stress (ER stress) and increased unfolded protein response (UPR) activity in aged donor hearts post-transplantation. Supplementing cardioplegic solution with rapamycin, an inhibitor of both ER stress and UPR, relieved graft heart dysfunction in aged mice, indicating that ER stress and UPR are responsible for this dysfunction.Furthermore, we found that Adenosine Deaminase Acting on RNA-1 (ADAR1) was downregulated in aged donor hearts post-transplantation in both our mouse model and in human patients. Importantly, ADAR1 deficiency in young donor hearts abolished hypothermic cardioprotection, leading to increased UPR activity, ER stress, and cellular senescence. Conversely, overexpression of ADAR1 in aged donor hearts by a novel PEG-based nanoparticle delivery in cardioplegic solution enhanced hypothermic cardioprotection by decreasing UPR activity, ER stress, and cellular senescence.Mechanistically, ADAR1 controls the expression of p16. In aged donor hearts, ADAR1 downregulation caused an increased expression of p16, which competed for its binding with CDK4/6, leading to a decreased phosphorylation of Rb and subsequent cellular senescence.These findings suggest that ADAR1-associated RNA editing activities play a crucial role in the hypothermic cardioprotection of donor hearts. Supplementing cardioplegic solutions with nanoparticles that enhance ADAR1 activity or modulate ER stress responses may provide a promising therapeutic strategy to improve the viability and/or function of aged donor hearts in transplantation.

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 A4147117-A4147117, November 12, 2024. Background:Cardiovascular disease (CVD) is the primary cause of mortality worldwide, and heavy metal exposure, including lead (Pb), cadmium (Cd), and mercury (Hg), significantly impacts this global burden of disease. Heavy metal-related cardiovascular toxicity results from their ability to induce oxidative stress, inflammation, endothelial dysfunction, and dysregulation of lipid metabolism. We aim to investigate the cardiovascular disease mortality associated with high blood levels of Pb, Cd, and Hg.Method:Using the 1999–2018 National Health and Nutrition Examination Survey (NHANES) data, we examined the association of blood Pb, Cd, and Hg levels with CVD mortality. Pb, Cd, and Hg levels were transformed into quartiles. Mortality hazard ratios were calculated using Cox proportional multivariate regression models adjusting for confounders identified by way of univariate analysis and from literature. Survival across quartiles of Pb, Cd, and Hg levels are depicted using K-M curves. Survival probabilities were compared using KM curves. All analyses were conducted using STATA version 17.0Results:The study population comprised 55,081 participants spanning over 20-years period, among whom 2401 (4.36%) experienced CVD related to Pd, Cd, and Hg exposure. Of the participants, 48% were male, with the majority being White participants, followed by Hispanic and Black participants. Most participants (82.4%) had a college education or higher, 53.2% were from high-income families, and 91.3% did not report a history of CVD. Mean levels of Pb, Cd, and Hg were 0.51 µg/L, 1.62 µg/L, and 1.56 µg/L, respectively. Significant differences in CVD mortality were observed between the toxic metal exposure group and those without exposure. The mortality group was associated with a higher prevalence of diabetes, higher BMI, CVD history, and higher levels of Cd and Pb but lower Hg levels.Conclusions:In conclusion, our study revealed a higher prevalence of cardiovascular mortality in individuals with elevated blood Pb and Cd levels. In contrast, those with higher blood Hg levels exhibited reduced cardiovascular mortality

Circulation, Volume 150, Issue Suppl_1, Page A4146624-A4146624, November 12, 2024. Introduction:Ventricular assist devices (VADs) present great promise as both bridge-to-transplant and destination therapies for patients with end-stage heart failure. However, complications – such as hemolysis, thrombosis, degradation of the von Willebrand factor, and gastrointestinal bleeding – stand in the way of their widespread application. High levels of wall shear stress resulting from poor hemodynamics within the bladed flow domain are primarily responsible. Computational fluid dynamics (CFD) software was used to model the hemodynamic performance of a novel VAD with a looped, toroidal blade design intended to reduce secondary flow effects at the blade tip – and provide detailed insight into the internal flow structures, leading to the shear stress levels within.Research Questions:Does the elimination of the open blade tip suppress tip recirculation and improve hemodynamics? What are the implications for wall shear stress in such a device, and how can we optimize the geometry as to improve pump performance, while minimizing shear stress?Methods:The toroidal impeller geometry file was imported into a computer aided design (CAD) software, and the generic scanned design file (STL) was converted to a 3D CAD surface model, from which the flow domain was subsequently extracted. The model was exported to a CFD software, and simulations were subsequently run to assess pump performance and impeller hemodynamics with respect to the wall shear stress parameter.Results:The VAD achieved an integrated pressure output equivalent to 108.84mmHg at the preliminary target flow rate of 0.5kg/s. The pressure is in the ideal range for supporting left ventricular pumping function. The efficiency of the VAD was calculated to be about 27%, which is reasonable for a VAD micromachine. There were regions of shear stress shown to be above the hemolytic threshold of 400 Pa, however.Conclusions:This toroidal impeller shows promise, which can be harnessed by applying heuristic, aerodynamic design methods to improve its hemodynamics. That is, further analysis, tuning, and optimization of the blade are necessary to enhance the operating efficiency of the VAD and minimize shear stress levels – specifically, optimization of the blade geometry for more balanced work distribution and reducing profile losses, as well as optimizing the size envelope of the device, currently 25mm in diameter.

Circulation, Volume 150, Issue Suppl_1, Page A4146183-A4146183, November 12, 2024. Background:Patients with rheumatoid arthritis (RA) display around 20% increased risk of heart failure, even after adjusting for traditional atherosclerotic risk factors. The reasons behind this are not fully understood. Analogous states of chronic inflammation such as type two diabetes have been shown to be associated with deleterious effects on myocardial metabolism and energetic depletion which predispose to systolic dysfunction. The impact of RA on myocardial energetics and cardiac phenotype in individuals at risk of RA has yet to be established.Aims:Using31Phosphorous magnetic resonance spectroscopy (31P MRS) and cardiovascular magnetic resonance (CMR), we aimed to establish if myocardial energetics, measured as phosphocreatine (PCr) /ATP ratio and quantitative myocardial perfusion were reduced in individuals at risk with isolated anti-CCP positivity (CCP+ve) and those with refractory RA (RRA) compared to healthy volunteers (HV).Methods:A total of 30 age and sex matched participants were recruited (11 CCP+ve, 9 RRA and 10 HV). All subjects underwent31P MRS and comprehensive CMR protocol including volumetric analysis, quantitative myocardial perfusion and T1 mapping.Results:Table-1 shows clinical and CMR /31P MRS data.Groups were matched for age, sex, body mass index (BMI) and systolic blood pressure.Left ventricular volumes, bi-ventricular systolic function, maximal LV wall thickness and left atrial function were similar between groups. Native T1 values and LV mass were increased in both CCP+ve and RRA versus controls.PCr/ATP was significantly reduced in both CCP+ve and RRA groups compared to healthy controls.No significant difference was observed in either stress myocardial blood flow (MBF) or myocardial perfusion reserve (MPR).Conclusions:This is the first-time energetic impairment has been reported in both patients with anti-CCP positivity and refractory RA. Our findings also demonstrate increased LV mass and diffuse fibrosis in these groups compared to age, sex and BMI matched controls. These findings may provide a mechanistic insight to the increased incidence of heart failure in individuals with rheumatoid arthritis.

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 A4144880-A4144880, November 12, 2024. Introduction:Atherosclerosis is the leading cause of death globally. Growing evidence suggests that mitochondrial dysfunction plays a significant role in atherosclerosis. However, the progression of mitochondrial energy generation disorders during atherosclerosis development remains unclear. In 2021, our lab indicated that activation of G-Protein Coupled Receptor 55 (GPR55) in human aortic endothelial cells (HAECs) could lead to EC activation, potentially increasing inflammation by altering mitochondrial transcription. EC activation is the central pathological event in atherosclerosis. However, whether and how mitochondrial dysfunction leads to EC activationin vivoand promotes atherosclerosis through the GPR55 pathway is still unknown.Methods:Lysophosphatidylinositol (lysoPI), an endogenous ligand for GPR55 activation, was used as a stimulus (20uM for 24hrs) to treat HAECs for Seahorse mitochondrial stressin vitroanalysis. Wild-type mice, apolipoprotein E (ApoE-/-) deficiency mice, and GPR55/ApoE double knockout (DKO) mice were used for bulk RNA sequencing andEn faceanalysis.Results:DKO mice showed a significant decrease in atherogenic lesions compared to ApoE-/- mice.In vitroMito-stress indicated that GPR55 activation significantly increased basal respiration, spare capacity, maximal respiration, proton leak, and ATP production in HAECs, while inhibition of GPR55 reduced these parameters to basal levels. This suggests that GPR55 activation enhances mitochondrial function without affecting non-mitochondrial oxygen consumption, coupling efficiency, or mitochondrial membrane potential. We also generated a list of 289 genes associated with mitochondrial energy generation genetic disorders. Transcriptomic profiling of these genes in atherogenic mice fed with an HF diet for 3, 6, 12, 32, and 72 weeks showed a downward trend in significantly downregulated OXPHOS genes. This significant downregulation suggests increased OXPHOS biogenesis reprogramming as the disease progresses. Additionally, by comparing upregulated genes in ApoE-/- mice with those downregulated in DKO mice, we identified seven potential genes downstream of GPR55 signaling, including M2, MP, A1, F4, P8, H10, and S2, which are involved in the TCA cycle and metabolism, protein import, and lipid modification.Conclusion:Our study provides the first comprehensive examination of how impairments in mitochondrial OXPHOS biogenesis influence atherosclerosis progression via GPR55 signaling.

Circulation, Volume 150, Issue Suppl_1, Page A4145622-A4145622, November 12, 2024. Introduction:Endothelial cells (ECs) can improve blood perfusion in diseased blood vessels associated with peripheral artery disease, but direct injection of therapeutic cells significantly decreases their survival and functionality for angiogenesis. To address these limitations, we employed a class of mechanically tunable protein hydrogels to enhance the survival and angiogenic behavior of human induced pluripotent stem cell-derived ECs (iPSC-ECs).Hypothesis:We hypothesize that the optimal stress relaxing mechanical property of hydrogels will modulate iPSC-EC survival and function in a mouse model of hindlimb ischemia.Materials&Methods:Engineered hydrogels, termed elastin-like protein (ELP)-polyethylene glycol (PEG), consists of two components of a hydrazine-modified elastin-like protein (ELP-HYD) and an aldehyde- or benzaldehyde-modified, polyethylene glycol (PEG-ALD or PEG-BZA), which interact with each other through hydrazone dynamic covalent chemistry bonds to form ELP-PEG hydrogels. By varying the use of PEG-ALD or PEG-BZA, we created hydrogels with the same stiffness but at either fast or slow stress relaxation rates. The hydrogels were assessed by dynamic oscillatory rheology. Afterwards, 106human iPSC-ECs were encapsulated within gels and injected into a mouse limb ischemia model to assess transplant cell viability and the ability to restore vascular perfusion to the ischemic limb.Results and Discussion:Although both hydrogels had a Young’s Modulus of 500 Pa, the stress relaxation rate of the PEG-BZA was 2.5h (slow), whereas that of PEG-ALD was within minutes (fast). When the iPSC-ECs were injected into the ischemic limb within either fast or slow-relaxing hydrogels or in saline, bioluminescence imaging of the luciferase-tagged iPSC-ECs showed higher cell survival within the fast-relaxing hydrogel over the course of the first 7 days. Blood perfusion recovery by laser Doppler similarly showed higher mean perfusion ratio when cells were delivered in the fast-relaxing hydrogel.Conclusions:ELP/PEG-ALD promotes iPSC-EC cell survival and perfusion recovery in the ischemic limb.

Circulation, Volume 150, Issue Suppl_1, Page A4134655-A4134655, November 12, 2024. Original research:Background:The objective is to evaluate the outcomes of percutaneous coronary intervention (PCI) in patients with alcoholic cirrhosis presenting with ST-segment elevation myocardial infarction (STEMI).Methods:We analyzed data from the National Inpatient Sample (NIS) for the years 2016-2020. Our cohort included patients admitted with STEMI and a secondary diagnosis of alcoholic cirrhosis, excluding those under 18 or those not receiving PCI. Propensity score matching using a kernel method was applied to adjust for 22 variables, including patient demographics, hospital characteristics, and comorbid conditions.Results:Among 119,799 patients, 98 had alcoholic cirrhosis. These patients exhibited higher mortality (18% vs. 5%) and longer hospital stays (5.4 days vs. 3.6 days). They also had increased risks of acute blood loss anemia (13% vs. 3.5%) and gastrointestinal bleeding (18% vs. 2%). Additionally, acute kidney injury was more prevalent in the cirrhosis group (25.5% vs. 14%). Although heart failure exacerbation and cardiac arrhythmias were more common, these were not statistically significant (Table 1).Conclusion:Our study indicates a significantly higher mortality rate among patients with alcoholic cirrhosis undergoing PCI for STEMI. These patients are also at increased risk of postoperative bleeding due to compromised liver function and hemostatic abnormalities, as reflected by higher incidences of acute blood loss anemia and gastrointestinal bleeding. Additionally, there is an elevated risk of acute kidney injury post-PCI, highlighting the need for renal-protective strategies. These findings stress the necessity for specialized care, vigilant monitoring, and tailored protocols to address the unique challenges faced by this population, aiming to reduce morbidity and mortality.

Circulation, Volume 150, Issue Suppl_1, Page A4141139-A4141139, November 12, 2024. Background:The underlying mechanisms of microvascular dysfunction in Takotsubo cardiomyopathy (TCM) remain incompletely understood.Aim:As CD34+cells are central to coronary microvascular homeostasis we investigated the potential association between CD34+cell count and changes in left ventricular function in patients with TCM.Methods:In a single-center prospective pilot cohort study we included 19 consecutive patients with TCM treated at our center between January 1st, 2022, and December 31st,2023. Patients with a history of malignancy were not considered for this analysis. TCM diagnosis was established per InterTac Registry criteria. Patients were enrolled within 24h of admission and underwent comprehensive clinical examination, blood biochemical and hematological analysis, and echocardiography at baseline and 6-month follow-up. CD34+cell count was measured using Beckman-Coulter Navios EX flow cytometry with standard antibodies according to ISAGE protocol.Results:Patient average age was 66±7 years, all patients were female, and hypertension and diabetes were present in 11 (57%) and 16 (84%) patients, respectively. The initial clinical presentation of TCM was acute chest pain in 15 (79%) patients and 16 (84%) patients displayed symptoms and signs of acute heart failure. Physical or psychological stress was identified in 17 (89%) of patients. Mean baseline left ventricular ejection fraction (LVEF) was 53±11% with apical dyskinesia being present in all patients. A peak mean troponin and NT-proBNP serum levels were 2353±2917 pg/mL and 3273±3196 pg/mL, respectively. The average baseline CD34+ cell count was 1.26±1.0×106/L. We established a significant positive correlation between baseline LVEF (r=0.54; P=0.03) and LVOT VTI (r=0.61; P=0.01) and CD34+ cell count. When stratifying patients on LVEF, patients with LVEF≥50% displayed significantly higher CD34+ cell count than patients with LVEF