Risultati per: Come stress e attacchi di cuore sono collegati

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 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.

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 A4137913-A4137913, November 12, 2024. Background:Cardiac sarcoidosis (CS) was characterized by formation of granulomas in the heart. Enhancement in myocardial inflammatory activity and oxidative stress is a crucial cause of major cardiovascular adverse events (MACE). Although immunosuppressive therapy is recommended for active CS, there is no established markers for treatment and prognosis.Hypothesis:We hypothesized that the inflammation and oxidative stress in heart were associated with MACE after steroid therapy.Aims:We identified prognostic markers for MACE in patients with CS after steroid therapy.Methods:This study was a prospective observational cohort study. Patients with CS diagnosed according to Japanese criteria were enrolled in this study. Patients with abnormal accumulation of18F-FDG in heart were treated with steroids with standard guideline-recommended protocol.18F-FDG PET were performed after more than 6 months of induction. Urinary 8-hydroxy-2′-deoxyguanosine (U-8-OHdG), a marker of oxidative DNA damage, and indices of cardiac and renal function were measured. The major outcome was a composite of the first sustained ventricular tachycardia (sVT) /sudden cardiac death (SCD), hospitalization for heart failure, and radiological relapse with exacerbation of clinical manifestation.Results:Fifty consecutive patients with CS underwent steroid therapy and followed up (median follow-up period of 58 months). 39 of 50 patients underwent 18F-FDG PET/CT more than 6 months after steroid therapy. During the follow-up period, 17 of 39 patients showed MACE, consisting of sVT/SCD (N= 11), hospitalization (N= 2) and radiological relapse (N= 4). A Cox proportional-hazard model showed that the U-8-OHdG and SUV max value of FDG-PET were independent predictors of MACE. ROC analysis revealed that the cut-off values of U-8-OHdG and SUV max for predicting the MACE were 11.6 ng/mg Cr (AUC 0.913, sensitivity 86.7%, specificity 90.0%) and 4.64 (AUC 0.878, sensitivity 76.5%, specificity 91.0%), respectively (Fig.1). Patients with a U-8-OHdG ≧11.6 ng/mg Cr or SUV max ≧4.64 had a significantly higher MACE risk (P values for U-8-OHdG and SUV max were both 0.001 by Log Rank analysis) (Fig.2). It is noted that U-8-OHdG

Circulation, Volume 150, Issue Suppl_1, Page A4119062-A4119062, November 12, 2024. Background:Vascular remodeling to match arterial diameter to tissue metabolic requirements commonly fails in ischemic disease. Endothelial cell (EC) sensing of elevated fluid shear stress (FSS) from blood flow induces vessel outward remodeling to restore physiological FSS, but mechanisms are poorly understood. The Smad1/5 pathway, which is maximally activated at physiological FSS and suppressed at higher flow, opposes activation of Akt, suggesting that inhibiting Smad1/5 may be required for outward remodeling.Methods:In vitro flow studies used ECs in a parallel plate flow chamber. In vivo mouse studies used a carotid-jugular fistula model to induce high flow outward remodeling in the carotid artery, and femoral artery ligation to examine recovery from ischemia and arteriogenesis in the hindlimb.Results:Suppression of Smad1/5 at high FSS is mediated KLF2-dependent induction of the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces arterial outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both STZ-induced type 1 and HFD-induced type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes.Conclusions:Suppression of Smad1/5 through a KLF2-BMPER pathway is required for high FSS-mediated outward remodeling. Mimicking this pathway with BMP9/10 antibodies improves vascular remodeling in diabetic mice, suggesting a potential new therapeutic approach for ischemic disease.

Circulation, Volume 150, Issue Suppl_1, Page A4146699-A4146699, November 12, 2024. Background:Growing evidence suggests that blunted blood pressure and heart rate responses to acute psychological stress independently associate with an increased risk of adverse outcomes in individuals with CHD, but assessment of mental stress reactivity in clinical settings is resource intensive. An alternative approach is to passively measure stress physiology at home with wearables, which is easier to translate into clinical practice. We tested the hypothesis that blunted mental-stress hemodynamic reactivity in the lab is associated with digital biomarkers of autonomic inflexibility at home.Methods:We conducted a mental stress test in 239 participants (age < 60 years) with an MI within 8 months. Participants underwent a speech stressor task in front of an audience to induce mental stress, during which blood pressure and heart rate were measured repeatedly during a baseline 15-minute rest period and 5-minute stress challenge. Participants went home with a 7-day Holter monitor to measure autonomic function. We examined vagal autonomic inflexibility with deceleration capacity (DC), a digital biomarker calculated via phase rectified signal averaging of heart rate intervals. We also examined low frequency (LF) heart rate variability (HRV), an indirect measure of baroreceptor sensitivity. We measured mean values from 5-minute windows during sedentary periods only to avoid confounding due to physical activity. We used multivariable linear regression models to adjust for potential confounding due to age, beta-blockers, and sex.Results:The mean age was 52 years, 51% were black, and 36% were women. Lower DC most strongly associated with a blunted change in heart rate during acute mental stress challenge (adjusted p

Circulation, Volume 150, Issue Suppl_1, Page A4144014-A4144014, November 12, 2024. Introduction:Lower socioeconomic status (SES) associates with greater MACE risk in part via stress-related mechanisms. Further, a higher polygenic risk score for neuroticism (nPRS), a marker linked to stress sensitivity and chronic stress conditions, is associated with greater MACE risk. Moreover, individuals with higher nPRS are more susceptible to the cardiovascular impacts of lower SES. Yet, it remains unknown whether individuals with higher nPRS experience greater adverse changes in autonomic and inflammatory intermediaries of stress in the setting of lower SES and whether these changes contribute to MACE risk. Accordingly, we tested the hypotheses that: 1) lower SES links to MACE risk via lower heart rate variability (HRV) and higher C-reactive protein (CRP), and 2) lower SES has a greater impact on HRV and CRP among those with higher nPRS.Methods:Individuals (N=18093; median age 64 years; 54% female) with nPRS and SES data were identified in the Mass General Brigham Biobank. SES was assessed as the median income of an individual’s residential zip code with lower income defined as the lowest tertile. Higher nPRS was defined as values ≥ population median. MACE data was collected for 10 years following enrollment using ICD-10 codes. CRP (N=4117) and HRV (N=4412) data were collected from available clinical lab values and electrocardiograms, respectively, with HRV assessed as the standard deviation of all normal RR intervals.Results:In the full cohort, both HRV and CRP mediated the relationship between lower SES and MACE risk (p

Circulation, Volume 150, Issue Suppl_1, Page A4139600-A4139600, November 12, 2024. Background:Cardiac injury after subarachnoid hemorrhage (SAH) is a well-recognized phenomenon with electrocardiogram (ECG) changes, arrhythmias and myocardial dysfunction. Neurocardiac injury has been commonly reported with increased severity of SAH, however much of the evidence has focused on high grade SAH requiring hemodynamic support or mechanical ventilation. In this study we focused on neurocardiac injury with high grade World Federation of Neurological Surgeons (WFNS) grade 3-5 SAH requiring intensive care management.Methods:Patients admitted to our intensive care unit from 2009-2019 with an WFNS 3-5 aneurysmal SAH with an echocardiogram within 7 days of admission were included in our study. Electrocardiogram, cardiac biomarkers and data regarding mortality and neurological complications were collected retrospectively.Results:A total of 242 patients were included in our study analysis with 11 (5%), 89 (37%), and 142 (59%) had WFNS grade 3, 4 or 5 SAH, respectively. Of the 95 patients that underwent echocardiography in the first week, 38 (40%) had a reduced ejection fraction, which was mild (LVEF 40-52%) in 13 (14%), moderate (LVEF 30-39%) in 14 (15%), and severe (LVEF < 30%) in 11 (12%). Independent predictors of reduced ejection fraction included a lower presenting GCS score (OR 1.2 per one point reduction in (Glasgow Coma Score) GCS, 95% CI 1.0-1.5, p = 0.03), elevated troponin T concentration (OR 6.1, 95% CI 1.2-31.3, p = 0.03) and T wave inversion on ECG (OR 9.1, 95% CI 1.6-52.3, p = 0.01). In patients with reduced ejection fraction, classical apical wall motion abnormality was more prevalent in older populations (median age 64 years (apical) vs 50 years (basal wall motion abnormality) and 52 years (other) p = 0.03). In all wall motion abnormality groups, there was a female predominance. Classic Takotsubo wall motion was associated with an anterior SAH aneurysm location (p = 0.03) and highest proportion of moderate to severe LV dysfunction (p = 0.04). ICU mortality did not differ based on the pattern of wall motion abnormalities.Conclusion:Predictors of neurocardiac injury in high grade SAH include troponin elevation, T wave abnormalities and lower presenting GCS. Aneurysm location was associated with wall motion abnormalities and degree of LV dysfunction. Patients with WFNS 3-5 SAH are at increased risk of neurocardiac injury. ECG changes, cardiac biomarker elevation and aneurysm location can help identify patients who warrant echocardiography.

Circulation, Volume 150, Issue Suppl_1, Page A4146032-A4146032, November 12, 2024. Background:Stress testing is a well-established non-invasive method commonly used in clinical practice for patients with angina. However, its benefit in diabetic patients after coronary intervention remains unclear. This systematic review aims to address this knowledge gap by evaluating the impact of routine stress testing in this specific patient population.Research Question:Does routine stress testing improve outcomes in diabetic patients with prior revascularization?Goals:We aimed to perform a systematic review and meta-analysis of studies that evaluated death, MACE and repeated revascularization episodes in diabetic patients who have prior coronary intervention.Methods:We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCT) and cohort studies evaluating diabetic patients who underwent cardiac revascularization and reporting the following outcomes: (1) Myocardial Infarction (MI) and Cardiovascular Death; (2) Ischemia; and (3) Repeat Revascularization. Statistical analysis was performed using Open Meta and heterogeneity was assessed with I2statistical.Results:We included 16924 patients from 16 studies, of which 15 were observational cohort studies and 1 was a RCT. All patients were diabetics and had a history of revascularization. Follow-up ranged from 1 to 5.2 years. The mean patient age was 60.8±9.5 years and 75% were male. MI and cardiovascular death was found in 9.8% (95% CI; range 6.8-12.8%; p

Circulation, Volume 150, Issue Suppl_1, Page A4140555-A4140555, November 12, 2024. Background:Psychological stress and poor sleep quality are interrelated and disproportionately affect adults who have multiple risk factors of cardiovascular disease (CVD). Sleep hygiene practices, such as maintaining an optimal household environment and engaging in healthy bedtime behaviors, are essential to sleep health. These practices may also impact psychological stress; however, their relationships remain under-studied. This study aimed to examine the associations among sleep hygiene practices, sleep quality, and psychological stress in adults with multiple CVD risk factors.Methods:Adults diagnosed with hypertension and type 2 diabetes completed an online survey (N = 300). Psychological stress and sleep quality were assessed using the Perceived Stress Scale 4 and the Pittsburgh Sleep Quality Index, respectively. A sleep hygiene instrument was used to examine 8 individual factors focusing on negative household environment (safety, physical comfort, temperature, and light) and poor in-bed behaviors (watching TV, playing video games, using screens, and eating). Multiple regression was employed to examine the association of each sleep hygiene factor with sleep quality and psychological stress. Subsequently, mediation analyses were conducted to examine the mediating role of sleep in the association between the composite sleep hygiene score and psychological stress.Results:Of the sample, 78% reported poor sleep quality and 44% reported high psychological stress. Individual sleep hygiene factors (e.g., unsafe household and eating at bedtime), as well as the composite sleep hygiene score, were significantly associated with poorer sleep quality and higher psychological stress. Sleep quality partially mediated the association between the composite sleep hygiene score and psychological stress (Indirect effect: 0.183; 95% bootstrap confidence interval: 0.057-0.339).Conclusions:The findings showed strong links between sleep hygiene practices, sleep quality, and psychological stress. Although causality cannot be inferred, current evidence suggests that promoting sleep hygiene education and implementing strategies to enhance sleep quality may alleviate psychological burdens in adults with multiple CVD risk factors.

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

Circulation, Volume 150, Issue Suppl_1, Page 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 A4138517-A4138517, November 12, 2024. Background:Exercise stress echocardiography is routinely used for risk stratification and diagnosis of myocardial ischemia in low-to-intermediate risk patients with suspected coronary artery disease (CAD). Discrepancies between exercise electrocardiography (EKG) and echocardiography (ECHO) are common in clinical practice. Prior literature suggests that patients with discordant stress test results generally have worse outcomes, though the extent of epicardial atherosclerotic disease remains unclear. Coronary computed tomographic angiography (CTA) has gained a class I recommendation for the assessment of atherosclerotic burden per ACC/AHA chest pain guidelines. Using non-invasive fractional flow reserve (CT-FFR), the functional significance of lesions can also be assessed. This study investigates the incidence and burden of CAD in patients with discordant exercise echocardiography findings.Methods:Patients aged 18 or older who had exercise echocardiography followed by CTA from January 1, 2013, to January 31, 2023, were retrospectively enrolled in this study and categorized into two discordant result groups: EKG+/ECHO- or EKG-/ECHO+. Those who failed to achieve the target heart rate or had a paced rhythm/left bundle branch block on baseline EKG were excluded. CTA findings were classified as no CAD, non-obstructive CAD (

Circulation, Volume 150, Issue Suppl_1, Page A4137935-A4137935, November 12, 2024. Background:We have recently reported that repetitive cardiac decompensation with multimorbidity often experienced by patients with heart failure (HF) is attributed to epigenetic modifications of hematopoietic stem cells (HSCs) in the bone marrow (BM). HF reprogrammed HSCs differentiation and altered tissue macrophage homeostasis. These findings demonstrate that the BM can carry an innate immune memory of cardiac stress that may exacerbate HF and predispose other organs to pathology.Aims:Because the stemness of HSCs is mainly regulated by mesenchymal stromal cells (MSCs) in the BM niche, we investigated phenotypic alterations of MSCs under cardiac stress.Methods&Results:Transcriptome analysis of MSCs showed preferential differentiation toward adipocytes in murine pressure overload models.In vitroassays and histological BM sections also support this finding. Furthermore, single-cell RNA sequencing of MSCs demonstrated that the percentage of adipocyte-primed MSCs increased in proportion to the severity of cardiac dysfunction, and also correlated with the frequency of myeloid-lineage progenitor cells. To investigate the influence of adipo-lineage MSCs on HSCs, we conducted BM transplantation supplemented with MSCs from control or HF mice. Recipient mice transplanted with HF-MSCs showed significant increases in myeloid-biased multipotent progenitors in BM and myeloid cells in peripheral blood. Additionally, the number of proinflammatory cardiac macrophages was significantly increased in the HF-MSCs group, promoting cardiac fibrosis and dysfunction.Conclusions:Our results demonstrated that the BM niche could perceive cardiac stress in the form of adipocytic skewing of MSCs in the setting of HF, which changed the differentiation behavior in HSCs and ultimately led to further deterioration of cardiac function through the impaired differentiation of circulating monocytes into cardiac macrophages. Therefore, suppressing the adipocytic differentiation of MSCs could have a novel therapeutic potential to avoid repeated HF events.

Circulation, Volume 150, Issue Suppl_1, Page A4125025-A4125025, November 12, 2024. Background:Chronic stress is associated with cardiovascular disease (CVD) in part through neural mechanisms that potentiate inflammation. Disrupted social connections are associated with higher chronic stress. As such, we hypothesized that: 1) previously married (divorced, separated) individuals have higher major adverse cardiovascular event (MACE) risk compared to married individuals and 2) that greater activation of stress-related neural-immune mechanisms contributes to this relationship.Methods:Participants (N=75,638) enrolled in the Mass General Brigham Biobank were studied. Marital status and MACE were identified using survey data and ICD-10 codes, respectively. A subset (N=1,121) underwent clinical18F-FDG-PET imaging, enabling assessment of stress-related neural activity as the ratio of the amygdala to prefrontal cortex activity (AmygAc). Clinical high-sensitivity C-reactive protein (hs-CRP) levels were assessed in another subset of the cohort (N=10,358). Linear and Cox regression and mediation analyses were used.Results:Among participants (median age 62 years; 53% female), 2,978 subjects developed MACE after Biobank enrollment. Previously married (vs. currently married) individuals had greater MACE risk (HR 1.33 [95% CI: 1.20,1.57], p=