Risultati per: Come stress e attacchi di cuore sono collegati

Circulation, Volume 150, Issue Suppl_1, Page A4143420-A4143420, November 12, 2024. Background:The presence of carotid plaque (CP) may serve as an indicator of panvascular atherosclerosis. However, the observed incongruity between carotid disease and the presence and severity of coronary artery disease (CAD) suggests differing mechanisms. We investigated the prognostic value of this incongruity, considering both known atherosclerosis and myocardial ischemia.Methods:In a retrospective analysis, we examined 111 patients (mean age: 64±12 years, 58% women) who underwent exercise stress echocardiography, with recent carotid artery and coronary evaluation. We computed a Vascular Disease (VasD) score, integrating the presence of carotid plaque (CP) on carotid ultrasound, known coronary artery disease (CAD), and myocardial ischemia (MyI). Subsequently, patients were followed for 5.5 years for mortality, coronary revascularization, and cardiac hospitalization.Results:During the follow-up period, 29 patients experienced the combined outcome (4 deaths, 10 revascularizations, and 22 hospitalizations). Among the cohort, 44 patients exhibited no vascular disease, while 67 displayed evidence of vascular disease, categorized as 42 with VasD of 1 (comprising 30 CP, 9 CAD, and 3 MyI), 14 with VasD of 2 (5 CP and CAD, 6 CP and MyI, 3 CAD and MyI), and 11 with VasD of 3. There were no significant differences between patients with and without VasD concerning sex, diabetes, renal function, atrial arrhythmia, baseline LVEF, and baseline diastolic function. However, patients with VasD were older, had higher H2FPEF scores, and lower exercise capacity, as well as elevated baseline and exercise-induced filling pressures. The incidence of the combined outcome showed a progressive increase with higher VasD scores (p

Circulation, Volume 150, Issue Suppl_1, Page A4146225-A4146225, November 12, 2024. Introduction:Patients who underwent arterial switch operation (ASO) for d-transposition of the great arteries (TGA) are at increased risk for early myocardial ischemia. Stress perfusion cardiac MR (SPCMR) is used as a non-invasive tool for risk stratification but interpretation is often challenging.Hypothesis:There is significant interobserver variability in SPCMR image interpretation in patients with repaired TGA.Aims:1. Determine incidence and severity of adverse effects of stress agents.2. Evaluate incidence of positive SPCMR.3. Assess agreement amongst reviewers in image interpretation.Methods:Patients with repaired TGA with SPCMR imaging from 2013 to 2024 were reviewed. Three patients with previous coronary intervention and one with severe chest pain after adenosine, unable to complete SPCMR, were excluded. 61 studies were performed in 56 patients. Images were independently reviewed by two investigators blinded to initial interpretation and clinical outcome. Perfusion defects were displayed on a circumferential polar plot using standard LV segmentation.Results:Median (IQR) age was 15 (11-17) years, weight 55 (36-68) kg, and BSA 1.6 (1.2-1.8) m2. Max heart rate was 110 (100-125) and systolic BP 127 (116-138). Eleven (20%) patients had cardiac symptoms, chest pain in 9 (16%), syncope in 1 (2%), pallor and distress in 1 (2%) infant. Adverse effects from SPCMR in 8/52 (15%) adenosine, 2/4 (50%) dobutamine, and 0/6 (0%) regadenoson were minor and resolved on stress completion. Six (10%) studies were initially interpreted as suspicious (n=5) or definitive (n=1) perfusion defect (Figure). No LGE was detected. Original interpretation did not match blinded reviews for 6 cases (Figure). Blinded reviewers agreed on 3 negative cases but interpretation differed in the other 3 cases (Figure).Conclusions:SPCMR is safe and feasible. Significant interobserver variability highlights the challenges in qualitative SPCMR interpretation for TGA. Quantitative perfusion may reduce interobserver variability. Larger multicenter studies would be helpful in further elucidating the risk profile of patient characteristics and coronary artery arrangements to determine whether routine use of SPCMR is warranted for TGA patients.

Circulation, Volume 150, Issue Suppl_1, Page A4145104-A4145104, November 12, 2024. Background:The optimal timing for intervention for pulmonary and right ventricular outflow tract stenosis in adult congenital heart disease (ACHD) remains uncertain. While stress echocardiography is an established modality to improve risk stratification in stenotic left-sided lesions, its utility in right-sided valve disease in the ACHD population has not been studied. We assessed if stress echocardiographic assessment of right ventricular (RV) function during cardiopulmonary exercise testing (CPET) can facilitate risk stratification in the ACHD population.Objectives:The purpose of this study was to determine the relationship between RV augmentation on stress echocardiogram during CPET and morbidity in ACHD patients with sub-pulmonary right ventricles and right-sided stenotic lesions.Methods:A retrospective cohort study of ACHD patients with sub-pulmonary right ventricles who underwent CPET with stress echocardiogram was performed. The primary outcome was defined as having at least one of the following: 1) cardiac related hospitalization, 2) new documented arrhythmia, or 3) new or worsening heart failure. RV augmentation on stress echo was verified by concordance with a second observer.Results:The study included 87 patients, 41 (47%) with repaired tetralogy of Fallot, 9 (10.3%) with RV-PA conduits, and 9 (10.3%) with pulmonary stenosis. On baseline transthoracic echocardiogram, median peak pulmonary valve gradient was 38.7 mmHg (Q1 17.9 , Q3 49.0) and 30% of patients had RV dysfunction. On stress imaging, 13 (14.9%) did not demonstrate RV augmentation. Those without RV augmentation had a lower percent predicted peak Vo2 (61.4% vs 75.4%, p=0.007). Eleven (12.6%) met the primary outcome. Lack of RV augmentation was strongly associated with the primary outcome (OR 4.25, CI 1.04 –17.46, p = 0.04). This association remained true in patients with baseline peak PV gradients less than 50mmHg (OR 8.7, CI 1.68 – 46.79, p = 0.009) and was more pronounced in patients with tetralogy of Fallot (OR 33.99, CI 3.29 – 829, p = 0.007).Conclusions:Lack of RV augmentation on stress echo during CPET is associated with increased morbidity in ACHD patients with right-sided stenotic lesions. These results suggest that stress echocardiography at the time of CPET should be considered in this population.

Circulation, Volume 150, Issue Suppl_1, Page A4145229-A4145229, November 12, 2024. Background:Stress-induced cardiomyopathy (CM) is a form of acute transient left ventricular dysfunction triggered by underlying physiological stress which often leads to increased morbidity and mortality. Coronavirus disease 2019 (COVID-19) is thought to cause stress-induced CM due to overwhelming systemic inflammation. There is paucity of data regarding the impact of COVID-19 on in-hospital outcomes of patients with stress-induced CM. The purpose of this study is to investigate in-hospital outcomes, including mortality and cardiogenic shock, of patients with concomitant COVID-19 and stress-induced CM.Methods:We queried the 2020 USA National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified hospitalized adult patients ≥ 18 years old with stress-induced CM and concomitant COVID-19 using ICD-10 CM codes. We used a survey multivariable logistic and linear regression analysis to calculate adjusted odds ratios (aORs) for outcomes of interest. A p value of

Circulation, Volume 150, Issue Suppl_1, Page A4145174-A4145174, November 12, 2024. Background:Protein half-life and turnover are crucial for cellular function, especially under basal and stress conditions, often contributing to proteinopathies. While the impact of oxidative stress (OxS) on proteostasis is well-documented, the role of reductive stress, an overabundance of antioxidant status, in proteotoxic cardiac disease remains elusive.Hypothesis:Tested whether chronic reductive stress (cRS) impairs protein turnover and induce proteotoxic cardiac disease.Methods:In transgenic mice expressing constitutively active Nrf2 (caNrf2-TG) and non-transgenic controls (n=6/gp.), we examined the half-life and turnover rates of the myocardial proteome using D2O labeling and mass spectrometry.Results:We observed significant changes in the half-life of over 1,700 proteins, with approximately 1,200 proteins exhibiting increased half-life at 3 months, despite no noticeable defects in cardiac structure and function. Under OxS induced by isoproterenol (ISO), about 700 proteins showed reduced half-life, underscoring distinct regulatory mechanisms in protein turnover between cRS and OxS. Proteins with altered half-lives were involved in key cellular functions, including metabolism, signal transduction, immune response, transport, and cell cycle regulation under cRS, revealing novel targets undetected in an OxS context. Notably, distinct positive adaptive compensatory (59; p

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

Circulation, Volume 150, Issue Suppl_1, Page A4142869-A4142869, November 12, 2024. Introduction:Adverse childhood experiences, also known as early life stress (ELS), are associated with increased risk of cardiovascular disease in later life, yet the underlying mechanisms remain elusive. Recent evidence indicates that parental life experiences can be transmitted to the offspring.Aim:To investigate the effects of ELS on cardiac structure and function in exposed parents and in their offspring, across 3 generations.Methods:We used ELS mouse model based on unpredictable separation of mouse pups (F1) from their mother (F0) each day for 3 hours from postnatal day 1 (PND1) to PND14 combined with dams exposure to an additional unpredictable stressor (forced swim in 18°C water for 5 minutes or 20-minute physical restraint in a tube) during separation. Control litters were raised normally. Echocardiography was performed at 6, 12 and 18 months in exposed animals (F0), their unexposed offspring (F1) and grand-offspring (F2). Both male and female mice were studied. Heart weight/tibia length was used to assess cardiac mass while Masson’s Trichrome was employed to detect fibrosis. Lung congestion was assessed as lung wet/dry weight ratio. Single-cell RNA sequencing (scRNAseq) was performed in MSUS and control hearts. A 6-week environmental enrichment (EE) program (cages containing running wheels, maze) was employed to test the possible rescue of ELS effects in adult males and their offspring.Results:F1 MSUS mice displayed increased LV mass, impaired diastolic function (assessed by conventional and tissue Doppler analysis) myocardial fibrosis and lung congestion. Time-dependent worsening of cardiac performance was observed from 6 to 18 months, both in males and females. ScRNAseq unveiled dysregulation of transcriptional programs underlying inflammation and lipotoxicity in the cardiomyocyte and endothelial cell clusters. MSUS offsprings did not show changes of cardiac function at 6 months, however diastolic dysfunction and lung congestion were observed at 12 and 18 months. A similar impairment of cardiac function was observed in the MSUS grandoffspring (F3). Of interest, 6-week exposure to an environmental enrichment protocol was able to improve LV mass, diastolic function and lung congestion in 12 months-old MSUS mice.Conclusions:ELS induces a transgenerational transmission of cardiac phenotypic alterations which can be rescued by EE. Our results shed light on the potential role of ELS on heart failure development and potential mitigation strategies.

Circulation, Volume 150, Issue Suppl_1, Page A4145256-A4145256, November 12, 2024. Introduction:Healthy urban environments are essential for improving cardiovascular health. Although exposure to wild green surroundings has been shown to have positive effects on mental and physical health, the effect of urban greenspaces on cardiovascular function and stress remain unclear.Research Question:Does being in an urban park decrease stress and autonomic tone as reflected by heart rate variability (HRV).Methods:We invited healthy adults (n=41; age 25-70 years) to participate in a cross-over panel study. They were randomly assigned to start in either a typical urban park or an adjacent urban space, spending 20min sitting and 20min walking. Self-reported distress and State-Trait Anxiety Index (STAI) scales were assessed before and after exposure. Pairedt-test was used to compare stress levels by site, and the effect size was calculated using regression analysis after adjusting for the level of starting distress. ECG recordings were acquired for the duration of the visit. HRV epochs of 5 min at the end of sitting or walking period and 40 min for the entire study were analyzed and compared using pairedt-test.Results:Pre-exposure distress and STAI summed scores were similar for the park and built spaces, but the level of distress was lower after visiting the park compared with built space (19.6±15.0 vs. 24.1±12.1; p=0.05). STAI scores were decreased after visiting the park, but not the built space (-5.4±8.2 vs. 0.8±6.8; p=0.003). When adjusted for the starting levels of distress, the summed STAI score after visiting the park was reduced by 6 (-10.34, -2.11), but no change for the built site. The standard deviation of NN intervals (SDNN) was higher in the park than the urban site (41.7 vs. 37.3; p=0.03) and the HR was lower (78 vs. 81; p=0.01) across the entire study epoch (40min). There was no significant change during the seated portion of visits, but across the walking portion, the values of SDNN were higher in greenspace (32.2 vs. 27.0; p= 0.01) and HR was lower (87 vs 84; p=0.02). Other HRV indices were not significantly affected.Conclusion:Visiting an urban park, but not a built environment, led to a decrease in self-reported distress, and a relative shift in the autonomic nervous system towards parasympathetic dominance. Although the relationship between changes in stress and HRV remain unclear, access to greenspaces may be an important factor in maintaining and enhancing cardiovascular health in urban environments.

Circulation, Volume 150, Issue Suppl_1, Page A4138946-A4138946, November 12, 2024. Background:Psychological stress affects cardiovascular (CV) health via multiple physiological and behavioral pathways. Few studies have assessed whether psychological stress impacts heart failure (HF) incidence. A prior large cohort study identified unique associations between perceived stress and HF subtype, but these associations were confounded by other health risk factors (e.g., prevalent baseline CV disease). No prospective study has evaluated these associations in women free of baseline CV disease.Goal:To evaluate the prospective association of psychological stress with incident HF and HF subtype risk in post-menopausal women.Hypothesis:Psychological stress is prospectively associated with an increased HF hospitalization risk, which may vary by HF type (HFpEF vs. HFrEF).Method:Of 29,703 post-menopausal women enrolled in the Women’s Health Initiative (WHI) free of baseline CV disease and pre-existing HF at first adjudication, psychological stress was assessed via an 11-item scale of stressful life events (SLE) over the past year (WHI screening, 1993-1998) and the 4-item Perceived Stress Scale (PSS; WHI Extension 2, 2010-2015). Incident HF was confirmed via adjudication of self-reported first hospitalization. Cox proportional hazards models adjusting for demographic, medical, and lifestyle factors were used to calculate hazard ratios associating stress quartiles with incident HF, HFpEF, and HFrEF hospitalization.Results:At screening, women were 62±7 years, 49% from underrepresented racial and ethnic populations, and 59% were at least high school graduates. At baseline women reported a mean of 2±.01 SLEs over the past year. Mean PSS scores were 4.16±3.09. Over a median of 15 years, there were 1,624 incident HF events (HFpEF, n=998; HFrEF, n=626). In fully adjusted models neither the number of SLEs or PSS scores were associated with HF risk(Table 1).Conclusions:In this WHI cohort, the number of SLEs and perceived stress were not prospectively associated with risk of HF, HFpEF, or HFrEF hospitalization. Future research is needed to understand whether specific types of stressors, stress measured more proximally to HF onset, or lab-based stress assessments may capture an association of stress with HF risk.

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

Circulation, Volume 150, Issue Suppl_1, Page A4145955-A4145955, November 12, 2024. Introduction:Cardiovascular problems are the primary cause of morbidity and death in people with diabetes mellitus.The whole nature of diabetic cardiomyopathy(DCM) is yet unknown.In order to investigate the pathogenesis of DCM and find possible treatment targets,animal models have proven invaluable.It has been common practice to create experimental models of type 2 diabetes(T2DM) using streptozotocin (STZ).Finerenone(F) is a selective mineralocorticoid receptor antagonist and reduces cardiovascular and adverse renal outcomes in diabetes.Exenatide(E) has been approved by the FDA to improve glycemic control in T2DM.Aim:The aim of this study is to investigate the possible cardiorenal protective effects of potential heart failure and chronic kidney injury associated with T2DM and to assess the potential therapeutic roles of Finerenone and Exenatide.To understand the interactions on cardiorenal outcomes of heart failure and diabetes and to effectively manage these two conditions.Methodology:Wistarmale rats with streptozotocin-induced T2DM were used.Five different groups were established as 1)Control,2)STZ,3)STZ+F,4)STZ+E,5)STZ+F+E groups.During the 21-day experiment, blood glucose concentrations were measured in all animal experimental groups.The kidney, heart tissues, and blood serum were collected. Serum urea and creatinine were exanimated.Total antioxidant status(TAS) and total oxidant status(TOS) were examined from blood serum,kidney,heart tissues by spectrophotometric assays. Kidney, heart tissues and blood IL-6, IL-1β, TNF-α gene expressions were examined by qPCR. Cardiac troponin T(cTnT) and troponin I(cTnI) gene expressions were examined by qPCR.p-STAT3 and p-NRF2 protein expressions in heart tissue were assessed by western blotting.Results:Serum urea and creatinine were significantly lower in STZ+E+F group than control group. TAS were significantly higher in STZ+E+F group than control group in serum,heart and kidney tissues.TOS, IL-1β, IL-6, and TNF-α gene expressions were lower in STZ+E+F groups than control group significantly in serum, heart and kidney tissues.cTnT and cTnI gene expressions and p-STAT3 and p-NRF2 protein expressions were lower in STZ+E+F groups than control group significantly in heart tissues.Conclusion:This study demonstrates the potential beneficial effects of Finerenone and Exenatide on cardiorenal complications in T2DM. Evaluation of these drugs in treatment strategies and further clinical trials are recommended.

Circulation, Volume 150, Issue Suppl_1, Page A4134792-A4134792, November 12, 2024. Background:The cardiac Na+channel NaV1.5 (encoded bySCN5A) governs cardiac inward Na+current (INa) and the fast upstroke and plateau phases of the cardiac action potential. Mutations in NaV1.5 can cause acquired or inherited arrhythmias and conduction diseases, including ~20% of cases of Brugada Syndrome (BrS). Changes in INacan impact Ca2+handling and cardiac excitation-contraction coupling. We have previously shown that SIRT1-mediated deacetylation of NaV1.5 increased INa. Recently, potential mutations (including P114T) in SIRT5, another NAD+-dependent deACYLase in the Sirtuin family localized to mitochondria, were identified in small families with BrS.Hypothesis:Sirt5 dysfunction evokes arrhythmias via Na+and Ca2+mishandling in an oxidative stress-dependent manner in mouse hearts.Aims:To explore the potential role of SIRT5 in BrS using heterologous expression systems and homozygous P114T-Sirt5 knock-in (P114T-KI) mice.Methods:Protein expression and physical interactions were detected by immunoprecipitation and immunoblot. The effects of SIRT5 on Na+current was measured using patch clamp in HEK cells and mouse cardiac myocytes. Confocal microscopy was used to measure reactive oxygen species (ROS) and for Ca2+imaging.Results:Both WT and P114T-SIRT5 co-immunoprecipitate with NaV1.5, but WT increased peak INain HEK cells while P114T did not (Fig A,B). Live-cell staining using DCFDA or mitoSOX showed that P114T-KI hearts had increased basal ROS and were more sensitive to oxidative stress induced by H2O2than WT littermates. P114T-KI hearts had increased Na+/Ca2+exchange protein 1 (NCX1) expression, and Langendorff-perfused hearts displayed abnormal Ca2+handling and arrhythmias (Fig C). Notably, treatment with the mitochondrial ROS scavenger mitotempo mitigated the aberrant Ca2+handling and arrhythmias.Conclusion:These findings suggest that the P114T-SIRT5 causes abnormal Na+and Ca2+handling and arrhythmias in a ROS-dependent manner, highlighting potential mechanisms underlying BrS. This finding may pave the way for the use of SIRT5 or its activators as novel anti-arrhythmic therapies in the future.

Circulation, Volume 150, Issue Suppl_1, Page A4146347-A4146347, November 12, 2024. Background:Acute ischemic stroke (AIS) is a leading cause of mortality and disability globally, disproportionately affecting Black and Latinx populations who experience increased morbidity and mortality compared to their white counterparts. At one month, roughly 50% of AIS survivors experience mood disturbances (e.g., anger, irritability, and aggression) and exhibit a lower health-related quality of life (HRQOL) compared to pre-AIS levels. Downstream biomarkers of mitochondrial dysfunction such as oxidative stress may be important pathophysiological mechanisms underlying mood disturbance symptoms, stroke severity, and long-term functional recovery.Purpose:To examine associations among early and late peripheral plasma lipid levels, mood disturbance symptoms (e.g., anger, irritability), and HRQOL outcome over 3 months (baseline/study day 5, and months 1, 3) in persons following AIS.Methods:The pilot study is a non-probability, convenience sample of adult subjects ( > 18 years of age) with a diagnosis of AIS. Lipidomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS) of untargeted lipids. The Agilent 6545 LC/Q-TOF platform was used to determine the absolute concentration of lipid species from peripheral plasma samples collected days 1, 3, 5 and months 1 and 3 post-AIS. General linear mixed models were used to test the predictive association of lipidomic biomarker mean value of peripheral plasma lipid levels and symptoms and outcomes over time (baseline and months 1 and 3).Results:We analyzed 82 subjects (age = 64 ± 12.1, 52% male, 78% Black, and 94% with hypertension). Elevated oxidative stress biomarkers (e.g., lipoxygenases, arachidonic acid, glycosylphosphatidylinositol) were associated with higher severity of anger and irritability symptoms, and a poorer HRQOL from baseline to 1- and 3-months post-AIS (p=0.04).Conclusion:An untargeted LC-MS lipidomics approach was used to identify lipids following AIS. Because oxidative stress plays a key regulatory role in complex downstream cellular function, these findings may be of great significance in understanding AIS pathophysiology that has the potential to inform personalized preventive strategies.

Circulation, Volume 150, Issue Suppl_1, Page A4131424-A4131424, November 12, 2024. Introduction:Anomalous aortic origin of a coronary artery (AAOCA) can result in sudden cardiac death in the young and risk stratification is challenging. Though dobutamine stress cardiac MRI (DS-CMR) is feasible in pediatric patients, exercise stress CMR (ES-CMR) has lower rates of adverse events, higher diagnostic accuracy, and the ability to better reflect the physiologic changes occurring with exercise. No studies have evaluated ES-CMR in the pediatric population. We aim to describe our institution’s experience with ES-CMR using supine bicycle ergometry in patients with AAOCA.Methods:We retrospectively reviewed the medical records of AAOCA patients who underwent ES-CMR at our institution between 2011 and 2024 for demographic, clinical presentation, cardiopulmonary exercise test (CPET) and ES-CMR data. The exercise-based portion of the CMR consisted of supine cycle ergometry utilizing a ramp protocol, immediately after which perfusion imaging was performed. We used descriptive statistics for data analysis.Results:Of 38 patients who underwent ES-CMR, the median age was 16 years (range 13-24) and 68% were male. Diagnoses included anomalous right coronary artery (N=28), anomalous left coronary artery (N=8), and single coronary artery (N=1 single right, N=1 single left). Median maximal heart rate (HR) during ES-CMR was 160 bpm (range 130-190, median 80% predicted) with a median maximal HR during patients’ most recent CPET of 187 bpm (range 160-203, median 97% predicted). No patients had perfusion defects at rest or with exercise stress, or evidence of myocardial scarring. There were no adverse events.Discussion:We demonstrate for the first time the use of ES-CMR in a cohort of pediatric and young adult patients with AAOCA. ES-CMR can provide a unique modality to assess for ischemia at rest and stress as a means of risk stratification and simulate physiologic changes occurring with exercise stress in a single study. Although maximum heart rates during supine cycle ergometry are lower than those reached during CPET, they are similar to those reached during DS-CMR. ES-CMR can be a helpful and safe diagnostic tool in patients with AAOCA.

Circulation, Volume 150, Issue Suppl_1, Page A4132820-A4132820, November 12, 2024. Connexin-43 (Cx43) plays a critical role in the propagation of action potentials among cardiomyocytes and proper cardiac contractility. In healthy cardiomyocytes, Cx43 is located at the intercalated disk; however, Cx43 remodeling is observed in cardiac pathologies and is linked with arrhythmogenesis and sudden cardiac death. Utilizing a mouse model of Duchenne muscular dystrophy (DMDmdx), we have previously demonstrated that cardiac Cx43 is laterally localized, forming undocked hemichannels that activate via S-nitrosylation in response to isoproterenol-evoked cardiac stress. This activation leads to the disruption of cardiac membrane permeability, triggered activity, and deadly arrhythmogenic behaviors. To establish the direct role of S-nitrosylated Cx43 in DMD cardiomyopathy, we developed a specific knock-in mouse line in which the single Cx43 site for S-nitrosylation, cysteine 271 (Cys271), was substituted with a serine (C271S+/-). Here, we developed a DMDmdx:C271S+/-line (4–6 months old), exhibiting reduced levels of S-nitrosylated Cx43 after crossing DMDmdx mice and C271S+/-mouse lines to assess the effect of β-adrenergic stimulation-induced cardiac stress and heart dysfunction. We show that cardiac Cx43 remodeling was not prevented in DMDmdx:C271S+/-, similar to what was shown in DMDmdxmice via immunofluorescence analysis. In addition, DMDmdxmice displayed an increased number of deadly arrhythmogenic events, increased Ca2+signaling, and prolonged action potentials in Langendorff-perfused whole hearts via optical mapping, compared to wild-type and DMDmdx:C271S+/-mice. Similarly, isoproterenol treatment evoked severe myocardial injury, increased levels of plasmatic cardiac troponin I (cTnI), and 40% mortality in DMDmdxmice. Notably, DMDmdx:C271S+/-mice, similar to DMDmdxmice treated with the Cx43 hemichannel blocker Gap19, exhibited cardioprotection compared to the cardiac dysfunction observed in DMDmdxmice. Therefore, these findings strongly suggest that S-nitrosylation of Cx43 proteins at site Cys271 represents a fundamental NO-mediated mechanism involved in the induction of arrhythmias and myocardial injury in DMDmdxafter β-adrenergic stress.

Circulation, Volume 150, Issue Suppl_1, Page A4148019-A4148019, November 12, 2024. Background:Heparan sulfate (HS) proteoglycans act as mechanosensors on endothelial cells (ECs), regulating EC morphology and function. HS expression is affected by culture under static or dynamic conditions. HS response to inflammatory stimulus under both conditions is not well characterized. This study investigated HS expression on human aortic ECs (HAECs) under static and arterial flow conditions.Hypothesis:Inflammation modeled by TNFa significantly decreases HS epitope on HAECs under both static and arterial flow conditions.Aims:To establish the effect of TNFa on HS expression in HAECs.Methods:Passages 4 through 8 HAECs (ATCC) were cultured to confluence in endothelial growth medium (Vasculife) in Ibitreat µ-Slide 8 well high chambered coverslip slides or Ibitreat µ-Slide VI 0.4 flow channel slides. Cells were treated with TNFa at 100 ng/mL for 3 hours under static conditions or conditioned with 10 dyn/ cm2 of shear stress for 24 hours and then treated with TNFa at the same concentration added to the circulating media for 3 hours. HAECs were fixed in 2% paraformaldehyde/ 0.1% glutaraldehyde for 30 minutes followed by blocking with 2% goat serum for 30 minutes, both at room temperature. Primary antibody to the 10E4 HS epitope was incubated at 4°C overnight (1:100; 10E4 epitope, AMS Biotechnology, USA) followed by incubation in Alexa Fluor 488 goat anti-mouse secondary antibody (1:300, Molecular Probes, USA) for 1 hour at room temperature. HAECs nuclei were stained using 4′,6-diamidino-2-phenylindole and immersed in phosphate buffered saline for confocal imaging using a laser scanning microscope (Zeiss, LSM 880, 20X).Results:TNFa significantly (p < 0.05) increased HS expression in HAEC monolayers treated under static conditions compared to untreated control and heparinase III treated HAECs (Figure 1A). HAEC monolayers conditioned under arterial shear stress expressed significantly (p < 0.05, ANOVA with Tukey’s post-hoc) higher HS levels compared to baseline static controls; however, flow conditioned HAECs did not show any difference in HS expression under untreated compared to TNFa conditions (Figure 1B).Conclusion:These data indicate that fluid shear stress may program endothelial cells to significantly alter their HS expression and response to inflammatory stimuli.