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

Circulation, Volume 150, Issue Suppl_1, Page A4146263-A4146263, November 12, 2024. The cardiac adverse effects of radiation therapy include both radiation-induced valvular disease and radiation-induced coronary artery disease (RICAD). However, the management of each when present concurrently is minimally described by current research and guidelines.A 60 year-old infectious disease physician with history of Stage IIA Hodgkin Disease s/p radiation therapy in 1976 (age 13) presented to cardiology for new dyspnea on exertion. She had known valvular heart disease followed with serial echocardiograms. Repeat TTE completed showing now moderate to severe aortic stenosis, moderate aortic regurgitation, moderate tricuspid regurgitation, and mild to moderate mitral regurgitation. After exercise stress testing aborted due to decrease in systolic blood pressure with exertion, patient underwent cardiac catheterization and found to have moderate-severe aortic stenosis as well as hemodynamically significant ostial disease of the right coronary artery and distal left main coronary artery; classic bi-ostial coronary stenosis characteristic of RICAD. After multidisciplinary discussion with interventional cardiology, cardiothoracic surgery, and second opinion with tertiary valve center, she was referred for surgical revascularization and aortic valve replacement (AVR). Patient underwent AVR with a 23mm bioprosthetic aortic tissue valve replacement, aortic root enlargement, tricuspid valve repair with 28mm ring, and three vessel coronary artery bypass grafting.Notably, several retrospective studies have found increased mortality with surgical aortic valve replacement in patients with prior history of radiation with many centers preferring transcatheter aortic valve replacement as a safe and effective alternative in this demographic. Despite acknowledging this predilection, SAVR chosen in this patient specifically given her concurrent RICAD requiring revascularization. This case intimately highlights the need for further studies regarding management of radiation-induced valvular disease when complicated by RICAD.

Circulation, Volume 150, Issue Suppl_1, Page A4117345-A4117345, November 12, 2024. Introduction:Acute type A aortic dissection (ATAAD) is typically treated by replacement of the ascending aorta (+/- root) and proximal arch. However, 70-85% of patients have residual distal dissection post-repair, and 20-40% require late reoperation for aneurysmal degeneration of the distal aorta (ADDA). Since an individual patient’s risk of ADDA cannot be accurately predicted, current guidelines recommend lifelong aortic surveillance imaging for all patients.Hypothesis:Computational fluid dynamics (CFD) simulations of aortic hemodynamics post-repair can accurately identify patients at late risk of ADDA.Methods:We performed CFD simulations of 50 patients following hemi-arch replacement for ATAAD. Patient-specific 3D models were generated from the aortic root to iliac bifurcation (including arch branches) from postoperative 0.6mm contrast-enhanced CT angiograms taken

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 A4136532-A4136532, November 12, 2024. Introduction:An impaired cardiac macrophage migration inhibitory factor (MIF) signaling in aging during ischemia and reperfusion (I/R) can be rescued by a MIF agonist, MIF20. Alterations in cardiac metabolic homeostasis cause inflammation under I/R. Thus, MIF agonism with MIF20 could modulate cardiac inflammatory response during I/R.Hypothesis:MIF20 modulates the polarization of neutrophil subset and rescues the impaired immune response under I/R in aging.Methods:Young (3-months)/aged (24 months) C57BL/6 wild type (WT) mice and MIFflox/flox(3 months)/cMIF-/-(cardiomyocyte MIF deletion, 3 months) were subjected to LAD ligation of for 45 min of ischemia, followed by 24 hr of reperfusion. MIF20 (0.15 µg/kg, i.v.) was injected at 5 minutes before reperfusion. The immune cells were determined with flow cytometry. mRNA and protein were measured by real-time qPCR, immunoblotting/cytokine array.Results:Administration of MIF20 reduced myocardial infarct by I/R in young/aged WT and MIFflox/floxbut not in cMIF-/-mice. The flow cytometry showed that I/R stress dramatically triggered neutrophils infiltration, which occurred in both left ventricle and right ventricle. Intriguingly, MIF20 treatment reduced the I/R-induced neutrophil recruitment in hearts. Aged versus young WT myocardium recruited more N1 neutrophils (CD206-), while MIF20 treatment rescued the impaired N1 neutrophils response in aging. Moreover, MIF20 can increase infiltration of N2 neutrophils (CD206+) in both young and aged WT hearts. The recombinant MIF can directly trigger N2 neutrophil polarization and N1 neutrophil reduction in cMIF-/-hearts, indicating the critical role of MIF/CD74 axis in neutrophil polarization by I/R challenge. The cytokine array showed that MIF20 treatment can trigger cardiac TGF-β levels and upregulate IL-10 levels in serum under I/R, since TGF-β and IL-10 are critical factors involved in the N2 neutrophils’ polarization. Interestingly, MIF20 increased SiglecF marker on neutrophils in the aged versus young hearts, suggesting that MIF20 rescue the long-lived neutrophil population (SiglecFhigh) which could enhance phagocytosis to repair damaged myocardium during I/R conditions.Conclusions:An impairment of metabolic homeostasis and inflammatory response occurred in cardiac aging. MIF agonism with small molecule MIF20 can rescue the capacity of MIF/CD74 signaling to maintain metabolic homeostasis and inflammatory response in aging under I/R pathological conditions.

Circulation, Volume 150, Issue Suppl_1, Page A4141293-A4141293, November 12, 2024. Background:Although exercise stress testing (EST) has shown to unmask latent electrical substrates inPKP2-mediated arrhythmogenic cardiomyopathy (ACM), the prognostic role of EST-induced ventricular arrhythmia (VA) patterns in PKP2-ACM patients is unclear.Objective:To examine the exercise-induced VA patterns observed during EST in PKP2-ACM patients and explore their correlation with major VA outcomes.Methods:We retrospectively analyzed 621 patients with either genotype-positive ACM or genotype-positive dilated cardiomyopathy evaluated between 01/2015 and 04/2024 to identify those with a disease-causative variant inPKP2(N = 108). After exclusion of 38 PKP2-ACM patients without EST data, demographic and electrocardiographic data was extracted from the electronic medical record. The arrhythmic burden [premature ventricular contractions (PVCs), PVCs in bigeminy, PVC couplets, non-sustained VT (NSVT), sustained VT, ventricular fibrillation (VF), and PVCs/minute] during each EST phase (baseline, peak, active and passive recovery) were reviewed and correlated with major VA outcomes [sudden cardiac arrest (SCA), sustained VT, and appropriate implantable cardioverter-defibrillator (ICD) shocks].Results:A total of 186 exercise tests from 70/108 (65%) PKP2-ACM patients (mean age 36 ± 20 years, 40 % male) were analyzed. The presence and burden of PVCs occurring singly, bigeminy, couplets. and NSVT were more prevalent during the recovery phase, specifically the passive recovery phase (Table). PKP2-ACM patients with structural disease (64%) were more likely to have an increased VA burden during recovery than those without structural disease [28/45 (62%) vs 4/25 (16%); p early) is associated with an increased risk of major VAs in PKP2-ACM. Further studies are needed to understand if this observation extends to other ACM genotypes and whether EST-induced VA patterns can be used to assess therapeutic efficacy in PKP2-ACM.

Circulation, Volume 150, Issue Suppl_1, Page A4144270-A4144270, November 12, 2024. Background:Air pollution is a leading cause of cardiovascular diseases including ischemic heart disease and stroke contributing to millions of deaths, with elevated blood pressure, endothelial dysfunction, and systemic inflammation being some of the most important underlying mechanisms. Various studies showed a promising beneficial effect of indoor air purification on various health outcomes, including blood pressure. We aimed to assess the effect of indoor air purification on systolic blood pressure (SBP) and Diastolic blood pressure (DBP) and provide a rationale for home use of these filters.Methods:We searched PubMed, Web of Science, Cochrane and Scopus for published literature up to May 2024. We included studies that assessed air purification, including HEPA filters or electrostatic air filters, as an intervention compared to no intervention. The primary outcome of interest was mean changes in blood pressure both systolic and diastolic. Secondary outcomes were biomarkers of inflammation and oxidative stress. Mean difference (MD) and 95% CI was used in a fixed-effect model to analyze the data.Results:A total of 21 studies were included in our meta-analysis with a total of 1955 participants. Air purification was associated with a significant reduction in systolic blood pressure (SBP) (MD: -2.42, 95% CI: -3.42, -1.41), and diastolic blood pressure (DBP) (MD: -1.11, 95% CI: -1.76, -0.46). However, there was no significant changes in levels of inflammatory biomarkers or oxidative stress.Conclusion: Indoor air purification was associated with significant reductions in systolic and diastolic blood pressure levels, but questions arise whether these reductions are clinically relevant or not. Further studies should assess these findings.Conclusion:Indoor air purification was associated with significant reductions in systolic and diastolic blood pressure levels, but questions arise whether these reductions are clinically relevant or not. Further studies should assess these findings.

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 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.

Circulation, Volume 150, Issue Suppl_1, Page A4141905-A4141905, November 12, 2024. Introduction:Epidemiological evidence suggests a link between acute air pollution exposure and ventricular arrhythmias, with increased reactive oxygen species (ROS) production as a key mechanism. However, a cause-effect relationship remains unclear, studies on chronic effects are lacking, and the impact of strategies limiting ROS production has not been studied in detail.Aims:To analyze the effects of chronic intratracheal instillation of diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, investigate the underlying mechanisms, and assess the impact of cerium oxide nanoparticles (CeO2NP) as a ROS-detoxifying strategy.Methods:Male and female Sprague-Dawley rats were intratracheally instilled with saline without or with DEPs (7.5 g/Kg, 0.375 mL/Kg, 3 times/week, for 1-3 weeks). Rats were then sacrificed and hearts perfused through the aorta in a Langendorff system. Incidence of premature ventricular beats (PVBs) and non-sustained and sustained ( >30s) ventricular tachyarrhythmias (VT) were assessed by programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed by conventional histology, Western Blot, RT-PCR, and the oxidized/reduced glutathione (GSH/GSSG) ratio. The potential protective effect of ROS-detoxifying CeO2NP (0.5 mg/Kg/week, i.p.) was also analyzed.Results:DEP exposure increased the incidence and duration of inducible sustained VTs. This pro-arrhythmic effect associated with a moderate rise in interstitial collagen deposition (from 3.11±0.12 in controls to 4.80±0.21 % in DEP-exposed rats, Student’s t test, p

Circulation, Volume 150, Issue Suppl_1, Page A4140505-A4140505, November 12, 2024. Introduction:Syncope is a common condition often leading to testing and hospital admissions. Research assessing sex-based differences in the workup as well as disposition following emergency department (ED) syncope visits is scarce. In this study, we sought to address this gap using a national database.Methods:From 2010 to 2019, we identified syncope patients using ICD-9 and ICD-10 codes. Using data from the IBM MarketScan Research Database, which captures de-identified individual-level health data from approximately 100 commercial payers and self-insured corporations in the United States, we assessed the incidence of testing using CPT codes in the 3 months following syncope diagnosis. Furthermore, we evaluated the percentage of syncope patients discharged from the ED. Sex-based comparisons were performed using the Chi-square test.Results:A total of 557,416 patients (54.0% women) were included in the cohort to assess for testing disparities (these are the patients who had at least 3 months of continuous enrollment following syncope diagnosis). Compared to men, women had significantly lower testing in most domains: long-term monitoring (6.8% vs. 7.4%), echocardiogram (13.3% vs. 17.2%), cardiac stress test (4.0% vs. 7.4%), chest X-ray (17.7% vs. 25.5%), imaging for pulmonary embolism (1.5% vs. 2.0%) and carotid Doppler ultrasound (5.4% vs. 7.3%); p< 0.001 for all above comparisons, figure 1A. Tilt table testing was similar between both sexes (1.4% vs. 1.3%).A total of 1,325,023 patients (58.1% women) were included in the ED disposition cohort. Women presenting to the ED with syncope were more likely to be discharged compared to men (78.7% vs 72.1%; p< 0.001), and this trend remained consistent throughout the study period, figure 1B.Conclusion:Women presenting with syncope are less likely to receive testing compared to men, and more likely to be discharged from the ED. There is a need to evaluate the reasons behind these disparities and assess their impact on patients’ outcomes.

Circulation, Volume 150, Issue Suppl_1, Page A4141975-A4141975, November 12, 2024. Background:Refugee populations often experience high rates of cardiovascular disease (CVD). Factors such as significant physiological stress, trauma, limited access to healthcare, substance abuse, and poor lifestyle choices contribute to disease progression and an increased incidence of cardiovascular events. We sought to evaluate the feasibility of using wearables to obtain high-fidelity ECG signals for CVD screening in refugees in Jordan.Methods:This observational cross-sectional study involved outpatients at one of four regional United Nations’ primary care clinics for Palestinian refugee in Jordan. Research assistants collected health histories from consented patients and recorded a 30-second, 6-lead ECG using a handheld, Bluetooth-enabled, wearable device (KardiaMobile 6L, AliveCor Inc., Mountain View, CA, USA). The digital ECG signals were stored on the Bluetooth-synced mobile device and then exported to a cloud server for offline analysis. The raw ECG recordings were preprocessed, and a single median beat was calculated per lead. Waveforms were segmented, and duration and amplitude measures were determined using a previously validated custom algorithm (University of Pittsburgh, PA, USA). All ECG recordings were reviewed by an independent physician.Result:The sample included 31 patients (age 52±13, 64% Females). Risk factors were prevalent in this group, including hypertension (74%), high cholesterol (65%), diabetes (64%), in-camp living (33%), and smoking (30%). Figure 1 shows the population-averaged median beat with 99% CI distribution of this sample. Mean QRS duration was 95±23 ms (range 53−150) and QTc interval was 403±53 (range 267−513). Most patients were in normal sinus rhythm (84%), and remaining patients were in atrial fibrillation or flutter (16%). Other clinically significant abnormalities included non-specific ST-T changes (9.7%), left bundle branch block (1.6%), and LVH with left ventricular strain (1.6%).Conclusion:This pilot study demonstrated that it is feasible to obtain high fidelity ECG signals using wearables to screen for CVD in refugees. Such affordable, noninvasive, point-of-care screening tools could enable early diagnosis and treatment in these patients.

Circulation, Volume 150, Issue Suppl_1, Page A4144097-A4144097, November 12, 2024. Introduction:Coronary-bronchial artery fistula (CBF) is a rare finding with an incidence of 0.08 to 0.61%. Patients may present with chest pain, dyspnea, or hemoptysis. Transcatheter interventions provide definitive treatment for symptomatic patients. Herein, we present a case of recurrent chest pain due to CBF involving the sinoatrial nodal (SAN) artery.Case:A 75-year-old lady presented with recurrent midsternal chest pain for several years. Her medical history was notable for pulmonary emboli (PE), and antiphospholipid syndrome. Initial investigation showed mildly elevated high sensitivity troponin to 28.9 ng/L. ECG showed normal sinus rhythm without ischemic abnormalities. Prior ischemic work-up including dobutamine stress echocardiogram and invasive coronary angiography was unremarkable. Ventilation perfusion (V/Q) scan showed multiple areas of VQ mismatch. Computed tomography coronary angiography (CTCA) showed a dominant RCA with a 2.5 mm communication between the SAN artery and left bronchial artery. After a heart team discussion, the patient was offered definitive treatment. A 6 Fr FR4 Mach 1 Guide catheter was used for selective right coronary angiography. A steerable microcatheter floppy 0.014”x 300 cm wire was used to engage the fistula originating from SAN artery (Figure 1). A micro vascular plug was successfully deployed over the wire without endangering sinus nodal supply. Post-intervention there was decrease in flow from the SAN to the bronchial artery (Figure 2). At one month follow up the patient was chest pain free.Discussion:Patients with pulmonary vascular disease might be predisposed to CBF, as chronic pulmonary ischemia might augment collateral blood flow. As a result, coronary steal phenomenon may lead to atypical angina. CTCA is a helpful screening tool, while transcatheter intervention may benefit symptomatic individuals.Conclusion:CBF should be considered in patients with history of PE and recurrent chest pain of unclear etiology.

Circulation, Volume 150, Issue Suppl_1, Page A4143965-A4143965, November 12, 2024. Background:It is known that oxidative stress (OS) and complex fractionated atrial electrograms play an important role in AF. However, the effect of reactive oxygen species (ROS) on complex fractionated atrial electrograms (CFAEs) in persistent atrial fibrillation patients remains unsettled. While previous CFAE ablation studies have mixed results, it is currently also unclear which types of CFAEs should be targeted with ablation during the clinical electrophysiological (EP) study.ObjectiveWe hypothesized that ROS are dynamically involved in the creation of a vulnerable substrate leading to overlying CFAEs and that regions of CFAEs that may reflect high OS are uniquely sensitive to acute ROS scavenging with N-acetylcysteine (NAC) in persistent AF patients.Methods:We performed in 5 patients with persistent AF high-density mapping in the left and right atrium (LA, RA) pre/post-NAC (intravenous, dose 100mg/kg) (Figure 1A) using the HD-grid catheter (EnSite, Abbott) (Figure 1B). We analyzed cycle length (CL) and dominant frequency (DF), organization index (OI), fractionation index (FI), and regions demonstrating >10% change in these parameters and CFAEs (definition EnSite) >50% change post-NAC.Results:NAC (Figure 2) affected AF electrogram measures in atrial sub-regions, increasing CL in the left lateral free wall, right atrial free wall, affecting DF/OI preferentially in the left atrial superior wall and CFAEs (Figure 3A, B) in the left atrial inferior wall (Figure 3C). Acute administration of NAC caused significantly greater percentage changes in CFAEs in the LA (165%) pre vs post-NAC compared to percentage changes in CL (40%), DF (33%), OI (37%) and FI (16%) (P=0.002) (Figure 3D). 35% of all CFAEs in the LA and 21% in the RA were sensitive ( >50% change, P=0.02) to ROS scavenging.Conclusion:Acute administration of NAC organizes AF electrogram characteristics in subregions in the left and right atrium and has a greater effect on CFAEs in the left atrium compared to other established AF electrogram characteristics. About one third of all CFAEs are ROS dependent. These uniquely sensitive CFAE regions to ROS scavenging may constitute a new smart therapeutic target in patients with persistent AF.

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?

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

Circulation, Volume 150, Issue Suppl_1, Page A4146651-A4146651, November 12, 2024. Background:The Fontan surgery for treating hypoplastic left heart syndrome has significantly improved postoperative mortality. However, the materials commonly used for conduits, such as PTFE, can cause complications, such as graft calcification over long-term follow-up, which causes flow restriction and lower exercise tolerance as clinical complications. To address these issues, we have developed a tissue-engineered vascular graft (TEVG) composed of biodegradable polymers that are replaced by autologous tissue, called “neotissue,” which exhibits histological similarity to native vessels(Figure1) and resistance to calcification. We are investigating the functional properties of this neotissue, focusing on distensibility, an essential function accommodating blood volume, and its impact on flow dynamics.Methods:We evaluated chronic sheep models (6-8 years post-implantation) with thoracic inferior vena cava (IVC) interposition grafts of TEVG (n=5) and PTFE (n=5), as well as age-matched surgically naive sheep (n=5). Using our established in vivo distensibility testing protocol(Figure1b), we measured distensibility in the target regions and compared the groups. Additionally, we utilized the 3D geometries obtained from 3D angiography to create patient-specific computational flow dynamics simulations using a software, SimVascular, allowing us to investigate the impact of distensibility and graft 3D morphology on flow dynamics.Results:Distensibility measurements showed no significant difference between TEVG (173.67±98.74[%100mmHg]) and native vessels (268.57±199.57), while PTFE grafts (10.35±12.67) exhibited significantly lower compliance compared to the other two groups(Figure1). The 3D fluid model simulations generated by SimVascular revealed that the native IVC revealed uniform dilation and smooth blood flows by fluid stress. TEVGs showed small velocity acceleration in the middle. In contrast, since the PTFE grafts were not distensible, they caused significant flow velocity acceleration and high wall shear stress at the graft region(Figure2,3).Conclusions:The TEVG neotissue demonstrated significantly higher distensibility than PTFE grafts and was not significantly different from native vessels. The simulation demonstrated that the differences in distensibility in response to fluid volume impact flow dynamics, which relate to the clinical complications of Fontan patients. TEVG has the potential to mitigate these complications.