Abstract 4145174: Impact of chronic reductive stress on myocardial proteome turnover: Insights into proteotoxicity and predictive cardiac remodeling

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

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Novembre 2024

Abstract 4145229: Outcomes among hospitalized patients with stress-induced cardiomyopathy and concomitant Coronavirus Disease 2019 (COVID-19) infection: Insight from the US National Inpatient Sample

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

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Novembre 2024

Abstract 4141357: Diagnostic and prognostic value of quantitative stress perfusion CMR in the non-invasive assessment of cardiac allograft vasculopathy

Circulation, Volume 150, Issue Suppl_1, Page A4141357-A4141357, November 12, 2024. Background:Cardiac allograft vasculopathy (CAV) is a rapidly progressive form of coronary atherosclerosis limiting long-term survival after heart transplantation.Objectives:We evaluated the diagnostic and prognostic yield of quantitative stress cardiovascular magnetic resonance (CMR) perfusion for CAV detection in heart transplant recipients.Methods:Patients who received orthotopic heart transplants and underwent stress CMR for CAV assessment were included in the study and followed up for almost 2 years (median 1.8; IQR 0.9,2.7). The diagnostic accuracy of qualitative and quantitative stress CMR was assessed by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), using invasive or CT coronary angiography as the reference for CAV detection. The area under the curve (AUC) was compared for qualitative and quantitative stress CMR. Adjusted hazard ratios for major adverse cardiac events (MACE), including death and unplanned cardiac hospitalizations were derived in all patients. The global myocardial perfusion reserve index (MPRi) was obtained by normalization to the rate-pressure product.Results:In a cohort of 60 patients, n=18 (30%) had significant CAV (grade 2 or 3), and n=11 (18.3%) experienced MACE. At the Youden index threshold of 2.1, the myocardial perfusion reserve index (MPRi) demonstrated a sensitivity of 85.7%, a specificity of 70.3%, a PPV of 52.2%, and an NPV of 92.9%. The MPRi was significantly more accurate than visual assessment (p < 0.001) in identifying underlying CAV (Figure 1) and it was an independent predictor of MACE (HR:0.26;95%CI:0.07,0.93; log-rank p=0.022; Figure 2), while the visual presence of inducible myocardial perfusion defect did not (HR:2.23;95%CI:0.57,8.66; p=0.2).Conclusions:In patients with previous heart transplantation, quantitative stress CMR perfusion has incremental diagnostic and prognostic value over qualitative stress CMR for the non-invasive detection of CAV.

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Novembre 2024

Abstract 4141350: Endothelial-Mesenchymal Transition Mediated by Mechanical Stress Prompts Atrial Fibrogenesis

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.

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Novembre 2024

Abstract 4145104: Can Stress Echocardiography during Cardiopulmonary Exercise Testing Help Predict Clinical Outcomes in Right-Sided Congenital Heart Disease?

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.

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Novembre 2024

Abstract 4147667: Elevated Hsp70 Does Not Rescue BAG3 Levels After Hypoxia-Reperfusion Stress or Ischemia-Reperfusion Injury

Circulation, Volume 150, Issue Suppl_1, Page A4147667-A4147667, November 12, 2024. The co-chaperone BAG3 is critical for protein quality control at the cardiac sarcomere. BAG3 binds to Hsp70 and coordinates the assembly of the CASA (chaperone-assisted selective autophagy) complex, thus supporting proteostasis and cardiomyocyte contractility. BAG3 mutations and/or decreased BAG3 levels are associated with cardiomyopathies, whereas BAG3 overexpression rescues ventricular function after myocardial infarction in mice. Despite BAG3’s promise as a therapeutic target, the mechanisms underlying BAG3 regulation are largely unresolved. Here, we investigate the mechanisms of BAG3 downregulation after stress. We found that BAG3 protein is reduced in human dilated cardiomyopathy hearts compared to non-failing hearts, yet there is an increase inbag3mRNA transcript, suggesting BAG3’s downregulation in heart disease may be controlled post-transcriptionally. To identify these post-transcriptional pathways, we subjected neonatal rat ventricular myocytes (NRVMs) to prolonged hypoxia-reoxygenation (H/R) stress, which recapitulated the decrease in BAG3 levels observed in human heart disease. Notably, disrupting Hsp70 binding to BAG3 in NRVMs via the drug JG-98 decreases BAG3’s half-life by ~90%, suggesting that Hsp70 protects BAG3 from degradation. Loss of Hsp70-mediated protection could contribute to declining BAG3 levels, so we quantified Hsp70 abundance after H/R stress in NRVMs, finding no significant change. We also found that overexpressing inducible Hsp70 did not rescue BAG3 levels. To examine BAG3 regulationin vivo,we subjected wildtype mice to ischemia-reperfusion injury. After 24 hours, male mice had no change in Hsp70 abundance in the left ventricle, whereas Hsp70 was significantly upregulated in female mice. Despite this difference in Hsp70, BAG3 levels were decreased by ~20% in both sexes. Thus, ourin vivoandin vitrodata both suggest that BAG3 downregulation is not caused by loss of Hsp70 binding/protection. Interestingly, the decline in full-length BAG3 (85 kDa) was accompanied by an increase in a BAG3 cleavage product at 74 kDa. We analyzed this product via mass spectrometry, discovering that it lacks a third of the WW domain, which is involved in autophagy. In future experiments, BAG3 cleavage will be explored as a potential mechanism of BAG3 loss. Such mechanisms will provide insight into how to maintain BAG3 levels, and thus cardiac function, during stress.

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Novembre 2024

Abstract 4141710: Artificial Intelligence Guided Stress Perfusion Cardiac Magnetic Resonance Versus Standard-Of-Care in Stable Chest Pain Syndromes

Circulation, Volume 150, Issue Suppl_1, Page A4141710-A4141710, November 12, 2024. Background:Stress perfusion CMR has excellent diagnostic and prognostic values in assessing chest pain syndromes. AI-guided methods may overcome complex scanning and increase clinical adaptation of stress CMR.Aim:To assess the benefits of AI-guided stress perfusion CMR.Methods:Consecutive patients with stable chest pain underwent stress CMR using either a standard scanning method (SOC) or an AI-assist (AIA) machine learning protocol to automate scan planning, plane prescription, sequence tuning, and image reconstruction. Scan duration, the ratio of scan preparation time over the entire scan duration, and scan quality using a 5-point scale were compared between AIA and SOC. Cox regression models were constructed to associate evidence of ischemia on stress CMR, by either scanning method, with composite endpoints including cardiovascular death, non-fatal MI, unstable angina hospitalization, and late CABG. A second composite endpoint included the performance of additional cardiac imaging tests (stress imaging and CCTA) and invasive coronary procedures after CMR.Results:Among 594 patients (62.8 ± 14 years), 29% underwent stress CMR with AIA. 26% had stress-perfusion ischemia, and 39% had LGE present. AIA stress CMR had lower scan duration (median 44.0 [IQR 40-47] vs. 52.5 min [IQR 46-60]; p

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Novembre 2024

Abstract 4143635: Stress-related Sleep Disturbance Inflames Myocardial cGAS-STING Pathway through activating bone marrow macrophage

Circulation, Volume 150, Issue Suppl_1, Page A4143635-A4143635, November 12, 2024. Background/Introduction:Delayed bedtime following stress disorder is prevalent in waves of pandemics and modern life. Considered to be a specific and important contributor to cardiovascular health, stress-related sleep disturbance has an unmet need in steady preclinical models. We previously found exciting corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) area of mice could induce 3-hour-long wakefulness.Methods:The chemogenetic method of designer receptors exclusively activated by designer drugs (DREADD) system was adopted to mimic stress-related sleep disturbance. We transfected PVH CRH neurons with rAAV-hSyn-DIO-hM3Dq-mCherry and rAAV-Crh-CRE. Prolonged CRH neuron activation was induced by daily intraperitoneal injection of clozapine N-oxide (CNO, 3mg/kg) at 9 am. Bulk RNA-sequencing and bioinformatics analysis were conducted for mechanistic exploration.Results:2-week repeated chemogenetic activation of PVH CRH neurons induced a 5-fold corticosterone release, consistent with increased daily 3-hour wakefulness and corresponding decreases in both rapid eye movement (REM) as well as non-REM sleep. Over 30% of chronic CRH activation mice displayed difficulties in maintaining balance and experienced premature mortality. Mice subjected to prolonged CRH activation showed impaired left ventricular ejection fraction (67.9% versus 48.2%, p=0.0011), and immune cell infiltration demonstrated by histological staining. Intriguingly, the number of circulating monocytes increased. Then, we performed bulk RNA-sequencing of heart and bone marrow from CRH-activated and control mice. Differential gene expression and gene set enrichment analysis (GSEA) indicated marked activation of interferon-beta-related pathways in both tissues. Cytosolic DNA-sensing pathway and related key effector genes (cGAS, Cxcl10, Ccl5) were found up-regulated in the heart, while the mitochondrial oxidative phosphorylation pathway was suppressed. We further adopted the CIBERSORT tool to estimate immune infiltration in heart tissues and characterized M1 macrophage as the main pro-inflammatory cell. In our stress-related sleep disturbance mouse model, macrophages in the heart and bone marrow shared similar properties inducing interferon-stimulated genes.Conclusion(s):Taken together, we report a failing heart in a mouse model of stress-related sleep disturbance. The neuro-immune axis involvement and molecular mechanisms merit in-depth explorations.

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Novembre 2024

Abstract 4145256: Urban Greenspace Exposure, Stress, and Cardiovascular Function.

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.

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Novembre 2024

Abstract 4134792: SIRTUIN5 Modulates Na+/Ca2+ Handling Via Oxidative Stress Dependent Manner In Mouse Heart

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.

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Novembre 2024

Abstract 4146754: The Prognostic Value of Dobutamine Stress Echocardiography in Liver Pre-Transplant Evaluation

Circulation, Volume 150, Issue Suppl_1, Page A4146754-A4146754, November 12, 2024. Background:Dobutamine stress echocardiography (DSE) is a frequently used tool in cardiovascular (CV) risk assessment of liver transplantation (LT) candidates. Its prognostic value compared to traditional cardiac risk stratification remains unclear.Research Question:How does the prognostic value of pre-transplant DSE in LT candidates compare to the revised cardiac risk index (RCRI)?Aim:Compare DSE’s prognostic value to RCRI in LT patients and analyze post-transplant CV outcomes.Methods:This single-center study included adult patients undergoing pre-transplant DSE as part of LT evaluation from 2008-2021. DSE were categorized as positive, negative, or inadequate. Primary outcomes were post-operative ischemic cardiac events and mortality, with secondary outcome of transplant delays from inadequate DSE. Mann-Whitney U and Fischer’s exact tests compared variables; logistic regression assessed RCRI and DSE for 30-day mortality and cardiac events.Results:Of 981 LT candidates, 644 (66%) had pre-transplant DSE with minimum 2-year follow-up. Average age was 57 ± 7 years, with 33% women. Four and eleven patients experienced cardiac events and mortality 1 (p-value 0.50), 0.51 for DSE (p-value 0.82), and 0.52 for RCRI >1 and DSE combined (p-value 0.80) in predicting 30-day mortality and cardiac events.Conclusion:Our study demonstrates limited prognostic value of DSE above RCRI score alone for predicting post-transplant mortality. Inadequate DSE was frequent and extended LT wait times. Further research is necessary to define clinically relevant subgroups and refine CV risk assessment in LT candidates.

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Novembre 2024

Abstract 4143303: Association of Preeclampsia with Long-Term Coronary Microvascular Dysfunction Utilizing Cardiac Stress Magnetic Resonance Imaging

Circulation, Volume 150, Issue Suppl_1, Page A4143303-A4143303, November 12, 2024. Introduction:Preeclampsia is a hypertensive disorder of pregnancy associated with cardiovascular disease. Systemic peripartum microvascular alternations have been implicated in pregnancies complicated by preeclampsia. Whether coronary microvascular dysfunction is a potential mediator of preeclampsia-associated cardiovascular risk is unknown. We aimed to determine whether individuals with a history of preeclampsia have coronary microvascular dysfunction measured by cardiac magnetic resonance imaging (CMR) at least 5 years postpartum.Methods:Women with singleton pregnancies complicated by preeclampsia and a comparator group with uncomplicated, normotensive deliveries were identified and prospectively enrolled to undergo regadenoson stress perfusion CMR (1.5T Signa Artist GE HealthCare) at least 5 years postpartum. Using the dual sequence technique, fully quantitative perfusion values were determined using Fermi deconvolution. Myocardial perfusion reserve (MPR) was calculated as the ratio of stress to rest myocardial blood flow (MBF).Results:Twenty-three subjects (41.0 ± 6 years, 12.7 ± 5 years post-partum) were included. Women with a history of preeclampsia (n=11) were compared to a control group of women with prior normotensive pregnancy (n=12) (Figure 1A). Obesity and diabetes were more common with preeclampsia, but there was no significant difference in the presence of hypertension between the groups (Table 1A). There was no difference in stress MBF. However, preeclampsia was associated with higher rest MBF (1.47 ± 0.54 mL/g/min vs. 1.19 ± 0.29 mL/g/min; p=0.07) and MPR (1.96 ± 0.46 vs 2.66 ± 1.0; p=0.02) compared to normotensive pregnancy (Figure 1). Similarly, corrected MPR remained significantly lower with prior preeclampsia versus uncomplicated pregnancy (2.36 ± 1.0 vs 3.36 ± 1.46; p=0.03).Conclusions:In this study, we observed significantly reduced coronary microvascular function following a pregnancy complicated by preeclampsia at least 5 years postpartum. Heightened cardiovascular risk factors may attenuate this association; however, these observations indicate that systemic microvascular dysfunction in preeclampsia also involves the coronary microcirculation. Further research is needed to better understand the timing and association of these microvascular changes concerning preeclampsia and later heart disease.

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Novembre 2024

Abstract 4138946: Psychological Stress and Risk of Heart Failure and Its Subtypes in the Women’s Health Initiative

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.

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Novembre 2024

Abstract 4146434: Factors Associated with Subsequent Catheterization and Identification of High-Grade Obstructive Coronary Artery Disease in Patients Without Known Coronary Disease and a Low to Moderate Short-Term Risk PET/CT Stress Test

Circulation, Volume 150, Issue Suppl_1, Page A4146434-A4146434, November 12, 2024. Background:PET/CT stress test may be performed to risk stratify patients including those without known coronary artery disease (CAD) who may be at risk for short-term adverse cardiac events. In patients with low- to moderate (LTM) risk for short-term MACE and without a known history of CAD, a small percentage of these patients will undergo a coronary angiogram within 90-days, of which some will be diagnosed with high-grade stenosis. The purpose of this study is to determine factors associated with this approach and findings.Methods:Patients without a history of known CAD (n=43,271) undergoing a PET/CT from 2018-2023 at Intermountain Health, with scan interpreted clinically as LTM short-term risk for adverse cardiac events, and ischemic burden 70% stenosis in any vessel), an a priori list of clinical data and PET/CT results were examined.Results:Within 90 days of the LTM risk PET/CT, 3,163 (8.2%) had a coronary angiogram. Of these, 806 (25.5% of angiograms and 2.1% of total LTM) had high-grade CAD. The PET/CT ancillary findings were associated with the largest odds of performing an angiogram and the presence of high-grade CAD (Tables). Factors most likely to be associated with performing an angiogram were an ischemic burden of 7.5-10% (adjusted-OR [adj. OR]=11.54), coronary artery calcification (CAC) score of >300 (adj.-OR =1.62), and myocardial blood flow (MBF) of MBF 2.3). Other clinical parameters associated, after adjustment, with an angiogram were age, male sex, hypertension, elevated troponin, and inpatient status. Many of the same factors were found to be associated with the identification of high-grade CAD. However, being an inpatient was associated with increased odds of angiogram but a decrease in odds of high-grade CAD.Conclusions:In patients without a known history of CAD who underwent PET/CT clinically adjudicated as LTM short-term risk and ischemic burden

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Novembre 2024

Abstract 4145955: In An Experimental Type 2 Diabetes Mellitus Model Induced With Streptozotocin, The Combined Use of Finerenone and Exenatide Reduced Inflammation and Oxidative Stress In The Heart and Kidney Tissues and Improved The Health of The Heart

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.

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Novembre 2024

Abstract 4138606: Toll-like Receptor 4 Signaling Establishes Trained Innate Immunity Through Interferon-Mediated Epigenetic Modifications Leading to Cardioprotection in a Stress-induced Cardiomyopathy Model

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.

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Novembre 2024