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

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

Circulation, Volume 150, Issue Suppl_1, Page A4146686-A4146686, November 12, 2024. Carvedilol (CAR) is an FDA-approved adrenergic blocker commonly given to cardiovascular disease patients. Interestingly, CAR also shows anti-cancer potential in reducing cancer-specific mortality in breast cancer patients. To advance CAR usage in cardio-oncology, we hypothesize that elucidating the molecular mechanism of the energy sensing and homeostasis pathways underlying CAR’s cardioprotective capabilities can enhance its clinical translation.Canine cardiac slices were generated from 3 euthanized pet dogs free of cardiovascular disease. CAR pretreatment (1μM, 4 hrs) with or without a 24-hr exposure to 5μM of cardiotoxic doxorubicin (DOX) was performed. Murine slices from 5 C57Bl6 mice with the same treatments as above was also performed. Direct tissue imaging on IVIS Spectrum was carried out to assess apoptosis by Annexin V staining, autophagy with autophagy detecting nanoparticle (ADN) developed in-house, and DOX retention in tissue by the inherent DOX fluorescence. Tissue was analyzed by histological staining of apoptosis and Western blot of autophagy and energy sensing pathways. Energetics quantified by Seahorse assay was performed in isolated mitochondria from cardiac slices in rat cardiomyoblasts (H9C2 cells) and human iPSC-induced cardiomyocytes (iCells).In both canine and murine cardiac slices, autophagy was significantly reduced (p

Circulation, Volume 150, Issue Suppl_1, Page A4146878-A4146878, November 12, 2024. Background:Increasing evidence support a vasoprotective role of the major endothelial NADPH oxidase isoform 4 (NOX4). NOX4 is notably induced by hypoxia.Research Question:What is the functional role of NOX4 under hypoxic conditions in the vessel wall?Aim:We aimed to elucidate NOX4’s significance in endothelial and vascular function under hypoxia.Methods:Primary cultures of human endothelial cells were exposed to hypoxia of 1% O2. Internal mammary arteries were obtained from patients undergoing coronary artery bypass grafting surgery. Surgical specimens of the artery wall proximal to occlusion were obtained from patients with peripheral arterial disease. Human NOX4 was downregulated by lentiviral shNOX4. Primary microvascular lung endothelial cells were isolated from wild-type and Nox4-/-mice. Vascular function was assessed under hypoxia in murine mesenteric arteries and aortas in a Mulvany myograph. Laminar flow was applied by cone-and-plate viscometer or ibidi pump system. NO was measured by Griess reaction, H2O2by Amplex Red Assay and gene expression by real-time PCR and Western blot.Results:Hypoxia significantly elevated NOX4 expression and activity in endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increasedNOX4expression even under normoxic conditions. In human hypoxia-prone vessels,NOX4expression strongly correlated with genes relevant for vascular function, such as prostaglandin I2 synthase (PTGIS). Endothelial function assessments under hypoxia revealed elevated contraction and endothelial dysfunction in both wild-type and Nox4-/-mice with Nox4-/-mice exhibiting the most severe alterations in endothelium-dependent vasodilation. Laminar shear stress attenuated the hypoxic response in endothelial cells, reducing HIF1a andNOX4expression while enhancing eNOS expression. NO synthase inhibition under combined hypoxia and laminar flow conditions upregulatedNOX4. Furthermore,NOX4deletion affected PECAM1 expression and endothelial cell adhesion. Inhibition of NOX4 under combined hypoxia and laminar flow increased the number of endothelial cells not aligned in the direction of flow.Conclusions:Hypoxia-induced NOX4 ensures vasodilation in both conductive and resistant arteries. Laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4. NOX4 deletion affects PECAM1 expression, reduces endothelial cell adhesion and alignment.

Circulation, Volume 150, Issue Suppl_1, Page A4147100-A4147100, November 12, 2024. Introduction:Perceived stress is known as the feeling of uncontrollability in one’s life and the inability to cope with the amount of stress one is experiencing due to one’s circumstances. There is evidence indicating that perceived stress may be a risk factor for cardiovascular disease (CVD). However, it is unclear whether perceived stress is associated with higher left ventricular mass index (LVMI), a measure of target organ damage and strong predictor of CVD.Aim:We examined the association between perceived stress and LVMI.Methods:The Masked Hypertension Study is a multi-site study that assessed the prevalence and predictors of masked hypertension in working adults from the New York Metropolitan area. A total of 1011 participants were recruited for the study; 826 participants completed the Perceived Stress Scale questionnaire and an echocardiogram. The perceived stress scale is a 14-item likert scale that assesses different situations that affects our perceived stress or our feelings in certain situations. It has a scale of 1 to 5 with 1 being never to 5 being very often. LVMI was determined according to the 2D method based on the American Society of Echocardiography (ASE) recommendations.Linear regression models were specified predicting LVMI from perceived stress. Covariates were sex, race/ethnicity, age, BMI, systolic bp, diastolic bp, and caregiving status.Results:Of the 826 participants, 40.7% were male, 6.9% were Black, 11.9% were Hispanic/Latinx , and 48.79% were caregivers. Mean (SD) age was 45.3 (10.3) years, mean body mass index was 27.6 (5.3) kg/m2, and mean SBP and DBP were 114.7 (12.0) and 74.8 (8.5). Mean perceived stress score was 21.8 (7.6) and mean LVMI was 63.3 (15.7) gm/m2.Contrary to our hypothesis, perceived stress was not significantly associated with LVMI, B = -0.00, 95% CI: -0.13, 0.13, p= 0.98.Conclusion:There was not an association between perceived stress and LVMI. Future research should examine whether other types of stresses/stressors are related to LVMI and the implications of this for patients and their health.

Circulation, Volume 150, Issue Suppl_1, Page A4138546-A4138546, November 12, 2024. Introduction:Takotsubo cardiomyopathy (TCM) is a reversible cardiac condition often precipitated by emotional or physical stress. Certain medications have also been implicated. While prognosis is generally favorable, associated QTc prolongation and ventricular arrhythmias can be life threatening, necessitating identification of potential triggers. This report highlights TCM in a patient using high-dose berberine, a plant alkaloid known for its hypoglycemic properties.Case description:A 69-year-old female with a history of type 2 diabetes mellitus, and hyperlipidemia presented after a syncopal event. It was preceded by sudden onset of dizziness, nausea, and vomiting. She had been using berberine for a year to lower her blood sugar and had recently switched to a higher dose of a more potent formulation. Vitals were unremarkable. Initial evaluation revealed a prolonged QTc interval of 659 ms (Figure 1A) and elevated troponin-I levels. She was treated with intravenous magnesium, which improved her QTc to 540 ms and revealed new T-wave inversions in the precordial leads. Echocardiogram showed an ejection fraction (EF) of 35%, with LV apical akinesia and hypercontractile basal segments. Cardiac catheterization ruled out significant coronary artery disease, leading to a diagnosis of TCM. Berberine was discontinued, and guideline-directed medical therapy was initiated. Given the presentation with syncope and high suspicion of aborted sudden cardiac death (SCD), she was discharged with a wearable cardioverter-defibrillator (WCD) as a precaution due to the risk of ventricular arrhythmias during recovery. At her 8-week follow-up, QTc and EF had normalized (Figure 1B), prompting WCD removal.Conclusion:The pathophysiology of berberine-induced cardiomyopathy remains uncertain and requires further research. This case underscores the importance of recognizing the potential cardiotoxic effects of berberine, particularly when used in high doses. A thorough medication and supplement history is crucial in patients presenting with unexplained cardiac symptoms. The reversible nature of TCM, when promptly recognized and treated, highlights the need for comprehensive follow-up to ensure recovery of cardiac function.

Circulation, Volume 150, Issue Suppl_1, Page A4147177-A4147177, November 12, 2024. Heart failure is a leading cause of death in the United States, and is associated with significant myocardial deterioration. cAMP and cGMP play critical roles in cardiovascular biology and disease. cAMP and cGMP form multiple spatially discrete and functionally distinct cyclic nucleotide ‘pools,’ each associated with unique multi-protein complexes comprising cyclases, PDEs, and other signaling molecules, contributing to distinct biological functions. Phosphodiesterase 10A (PDE10A) is able to hydrolyze both cAMP and cGMP. Our previous published study provides strong evidence supporting a critical role of PDE10A induction in pathological cardiac remodeling and suggest the therapeutic potential of PDE10A inhibition. However, the cellular and molecular mechanisms and the sources of cyclic nucleotides that are regulated by PDE10A remain unknown. Our encouraging results revealed that the anti-hypertrophic effect of PDE10A inhibition/deficiency is dependent on cAMP/PKA signaling in cultured adult mouse cardiomyocytes (CM). We identified the existence of adenosine-dopamine receptor (A2AR-D2R) heterodimer and the connection of PDE10A with A2AR-D2R signaling, by which PDE10A inhibition uniquely promotes heterodimerization of A2AR-D2R, and biased activation of D2R/β-arrestin2 (βarr2) through A2AR/cAMP/PKA-mediated phosphorylation of D2R in CMs. Consistent with what we found in CM, disruption of A2AR-D2R heterodimer or D2R/ βarr2-biased activation significantly abolish the protective effects of PDE10A inhibition on cardiomyopathy and dysfunctionin vivo. Additionally, we found that activation of D2R/βarr2 signaling attenuates stress-induced cardiac remodeling and dysfunctionin vivo. Together, these results strongly suggest that PDE10A plays a critical role in pathological cardiac remodeling by promoting CM hypertrophy through regulation of A2AR-D2R/βarr2 biased signaling. Targeting PDE10A and GPCR heterodimerization in CMs may represent a novel therapeutic strategy for treating cardiac diseases.

Circulation, Volume 150, Issue Suppl_1, Page A4141135-A4141135, November 12, 2024. BACKGROUND:Right atrial (RA) dysfunction related to right ventricular (RV) function has been reported in patients with repaired TOF. Increased liver stiffness in these patients has also been reported. Whether RA function worsens under exercise stress, and its relationship with worsened liver stiffness is unknown.HYPOTHESIS:In patients after TOF repair, RA functional reserve during exercise stress is reduced and correlated with raised liver stiffness and RV dysfunction.METHODS:19 patients (8 male) aged 17.92 ± 3.81 at 16.06 ± 3.98 years after repair and 25 controls (16 male, aged 19.99 ± 1.67 years) were studied. RA mechanics was assessed by speckle-tracking echocardiography (STE) at rest and during bicycle exercise, with quantification of positive, negative, and total strain, and strain rates at ventricular systole (aSRs), early diastole (aSRed), and atrial contraction (aSRac). RAFR is calculated as (Change in RA total strain x [1-1/ baseline RA total strain]). Biventricular (RV, LV) function were quantified using Doppler interrogation and STE. Hepatic shear wave velocity (c) and tissue elasticity (E) were measured using shear wave elastography.RESULTS:At rest, patients had lower RA positive, negative and total strain, aSRs and aSRed than control subjects (all p

Circulation, Volume 150, Issue Suppl_1, Page A4147941-A4147941, November 12, 2024. Introduction:Fractional flow reserve (FFR) is an invasive, lesion-specific surrogate for myocardial ischemia. However, the impact of an FFR-guided invasive strategy on outcomes in chronic coronary disease (CCD) when compared to a conservative strategy is unclear.Purpose:To compare the outcomes of patients with CCD enrolled in the ISCHEMIA trial randomized to the invasive (INV) arm who underwent FFR during initial angiography with those randomized to a conservative (CON) strategy with optimal medical therapy alone.Methods:The ISCHEMIA data set was obtained from the NHLBI. Patients randomized to the INV arm who underwent FFR at initial angiography were compared to those who were treated with a CON strategy using optimal medical therapy. Unadjusted cumulative event probabilities were estimated using the Kaplan-Meier method. The co-primary endpoints of interest were cardiovascular death (CV) death and myocardial infarction (MI). Secondary outcomes included all-cause mortality and health status as determined by the Seattle Angina Questionnaire (SAQ) angina frequency (AF), quality of life (QoL) and summary scores (SS).Results:Of the 5,179 patients with CCD and at least moderate ischemia on stress testing, 2,322 were randomized to the CON strategy and 2,475 were randomized to the INV strategy. Of these, 428 underwent angiography with FFR (INV-FFR). CON patients were younger than INV-FFR patients (64.3 [9.6] years vs. 65.5 [8.7] years, P=0.013). The incidence of hypertension, diabetes, smoking, BMI, or prior MI did not differ between groups. SAQ AF, QoL, and SS scores did not differ between groups at baseline. CON patients had more vessels with greater than 70% stenosis (1.49 [0.9] vs. 1.24 [1.0], P

Circulation, Volume 150, Issue Suppl_1, Page A4147117-A4147117, November 12, 2024. Background:Cardiovascular disease (CVD) is the primary cause of mortality worldwide, and heavy metal exposure, including lead (Pb), cadmium (Cd), and mercury (Hg), significantly impacts this global burden of disease. Heavy metal-related cardiovascular toxicity results from their ability to induce oxidative stress, inflammation, endothelial dysfunction, and dysregulation of lipid metabolism. We aim to investigate the cardiovascular disease mortality associated with high blood levels of Pb, Cd, and Hg.Method:Using the 1999–2018 National Health and Nutrition Examination Survey (NHANES) data, we examined the association of blood Pb, Cd, and Hg levels with CVD mortality. Pb, Cd, and Hg levels were transformed into quartiles. Mortality hazard ratios were calculated using Cox proportional multivariate regression models adjusting for confounders identified by way of univariate analysis and from literature. Survival across quartiles of Pb, Cd, and Hg levels are depicted using K-M curves. Survival probabilities were compared using KM curves. All analyses were conducted using STATA version 17.0Results:The study population comprised 55,081 participants spanning over 20-years period, among whom 2401 (4.36%) experienced CVD related to Pd, Cd, and Hg exposure. Of the participants, 48% were male, with the majority being White participants, followed by Hispanic and Black participants. Most participants (82.4%) had a college education or higher, 53.2% were from high-income families, and 91.3% did not report a history of CVD. Mean levels of Pb, Cd, and Hg were 0.51 µg/L, 1.62 µg/L, and 1.56 µg/L, respectively. Significant differences in CVD mortality were observed between the toxic metal exposure group and those without exposure. The mortality group was associated with a higher prevalence of diabetes, higher BMI, CVD history, and higher levels of Cd and Pb but lower Hg levels.Conclusions:In conclusion, our study revealed a higher prevalence of cardiovascular mortality in individuals with elevated blood Pb and Cd levels. In contrast, those with higher blood Hg levels exhibited reduced cardiovascular mortality

Circulation, Volume 150, Issue Suppl_1, Page A4125701-A4125701, November 12, 2024. Background:Racial and ethnic disparities have been reported in catheter ablation in adults. There are limited data on the impact of race/ethnicity on the diagnosis and management of children with Wolff-Parkinson-White pattern (WPW).Hypothesis:Diagnosis of WPW by electrocardiogram (ECG) and risk stratification by exercise stress test (EST) and electrophysiology study (EPS) will differ by race/ethnicity in children.Methods:We performed a retrospective cohort study of patients 0-21 years old, excluding those with congenital heart disease, at a children’s hospital from 1991-2021. The primary exposure was race/ethnicity. Outcomes were 1) diagnosis of WPW on ECG, 2) undergoing EST, and 3) undergoing EPS. Likelihood and time to outcome were assessed with multivariable logistic regression adjusted for birth year and Cox regression, respectively.Results:The cohort consisted of 1,638,746 patients (White 53.0%, Black 21.0%, Hispanic 6.8%, Asian 4.2%, Multi-racial 2.0%, Other 11.0%, and Missing 1.7%). WPW was diagnosed in 898 patients (0.05%). After adjusting for birth year, Asian, Black, and Other race were associated with lower odds of WPW diagnosis compared to White patients (OR 0.57, 0.66, 0.70; p≤0.01). There was no association between race and age at first diagnosis (p=0.2). A total of 616 WPW patients (69%) underwent EST. Compared with White patients, Asian, Hispanic, and Other race were less likely to undergo EST (OR 0.39, 0.59, 0.62; p≤0.04), and those who did had their EST at later ages (HR 0.59, 0.65, 0.46; p≤0.04). A total of 739 WPW patients (82%) underwent EPS. Compared with White patients, Black, Hispanic, and Other race were less likely to undergo EPS (OR 0.44, 0.53, 0.59; p≤0.02), and those who did had their EPS at later ages (HR 0.60, 0.63, 0.66; p≤0.004).Conclusion:This analysis found that non-White racial and ethnic groups are less likely to be diagnosed with WPW. This may reflect differences in WPW prevalence by race/ethnicity, but differential access to ECG cannot be ruled out. Among WPW patients, however, Asian and Hispanic patients are approximately half as likely to undergo EST, while Black and Hispanic patients are approximately half as likely to undergo EPS, compared to White patients.

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

Circulation, Volume 150, Issue Suppl_1, Page A4141191-A4141191, November 12, 2024. Introduction:Regular physical exercise is widely recognized for its beneficial effects on overall health. Despite emerging evidence that early-life experiences profoundly impact adult and aged health, the long-term effects of early-life exercise remain uncertain.Hypothesis:We hypothesized that early-life exercise extends healthspan and attenuates cardiovascular aging in aged mice.Methods:Male and female C57BL/6J mice were subjected to a 3-month swimming exercise regimen starting from 1 month of age (1.5 hour per day, 5 days per week), while no exercise intervention was conducted at other times. The sedentary group was raised under similar conditions. The healthspan of aged male and female mice was assessed, including overall metabolic function, cardiovascular function, frailty index and other relevant measurements. Transcriptional profiling of young and old mice was performed to gain insights into the mechanisms underlying the effects of early-life exercise on aging.Results:Early-life exercise improved metabolic health in aged mice. Assessment of body composition showed increased lean mass in the exercise group. When subjected to food deprivation stress in metabolic chambers, aged mice with early-life exercise exhibited increased energy expenditure, carbohydrate oxidation, and fat oxidation levels in both males and females. Evaluation of frailty index at 24 months of age, involving 31 frailty phenotypes, indicated lower frailty index score in the early-life exercise group, suggesting an attenuation of age-related phenotypes. While no significant differences were observed in blood pressure and cardiac systolic function, early-life exercise was associated with improved cardiac diastolic function at 19 months of age. Furthermore, early-life exercise resulted in decreased heart-carotid pulse wave velocity and improved endothelial-dependent vascular relaxation in aged mice, indicating better vascular function in elderly mice with early-life exercise.Conclusions:The findings demonstrate that early-life exercise contributes to an increased healthspan, as evidenced by enhanced metabolic health and reduced frailty. Both male and female aged mice exposed to early-life exercise exhibit improved cardiovascular function.

Circulation, Volume 150, Issue Suppl_1, Page A4140702-A4140702, November 12, 2024. Background:Single ventricle (SV) and hypoplastic left heart syndrome (HLHS) present significant sex differences in terms of surgical outcomes and long-term prognosis between male and female patients. Peripheral blood mononuclear cells (PBMCs) drive tissue damage and cardiac dysfunction, contributing to the sex-specific clinical outcomes.Aims:We used single-cell RNA sequencing (scRNA-seq) to assess gene expression profiles in PBMCs, aiming to gain insights into sex effects and identify new biomarkers for assessing disease prognosis.Methods:We studied PBMCs from 32 cases with SV/HLHS. The experiments were conducted in 3 independent batches (9 females/11 males; 2 females/6 males; 2 females/2 males), using 10X Chromium Single Cell Gene Expression assay (10x Genomics, Single Cell 3′ v3). Sequencing was performed using the Illumina NovaSeq6000. The data analysis was conducted using the Seurat R package, employing SCTransform for data normalizing and scaling (Satija, Farrell et al. 2015, Butler, Hoffman et al. 2018). To mitigate batch effects, the 3 batches were analyzed separately.Results:42 genes were consistently identified of differential expression (DE) (|log2FC|≥0.25,Padj

Circulation, Volume 150, Issue Suppl_1, Page A4140558-A4140558, November 12, 2024. Background:Single ventricle congenital heart disease such as hypoplastic left heart syndrome (HLHS) with a Fontan circulation constitute the largest group of children hospitalized with circulation failure, experiencing an in-hospital mortality rate of 20-50%. We investigated the mechanisms leading to circulation failure so as to identify novel therapeutic targets.Methods:Blood was collected from patients with HLHS s/p Fontan and controls with normal cardiac anatomy and function (N=6/group). Plasma microvesicles (MV) were isolated, and proteomics assessed using data independent acquisition mass spectroscopy. Dysregulated proteins with a fold change >1.5 or < -1.5, p

Circulation, Volume 150, Issue Suppl_1, Page A4117594-A4117594, November 12, 2024. The “theory of developmental origins of health and disease” posits that stress in critical developmental periods will program life-course health and may affect cardiovascular (CV) health. Mothers at risk for premature delivery receive synthetic glucocorticoids (sGC) to enhance fetal lung maturation and manage fetal respiratory distress, but sGC exposure is linked to long-term CV dysfunction in offspring. Four groups of male baboons were studied: sGC exposedin uteroat middle age (sGC-MA, 13.8±0.2Y), older sGC exposedin utero(sGC-O, 17.1±0.4Y), middle age unexposed (CTR-MA, 13.5±0.6Y), and older, unexposed baboons (CTR-O, 17.4±0.4Y). Gated, breath-hold, cine cardiac magnetic resonance imaging was performed at 3 Tesla (Siemens TIM Trio) to assess left ventricular (LV) function and myocardial strain, analyzed using cvi42® software. Mitochondrial electron transport chain (ETC) complex activity was analyzed using LV tissue from sGC-O and CTR-O euthanized baboons. Protein quantification was used to measure mitochondrial function and RNA-seq assessed differential gene expression and gene ontology (GO) enrichment. Unpaired t-tests were used. Data are reported as mean ± SD. Stroke volume and ejection fraction were similar in the elderly groups (4 sGC-O, 8 CTR-O). However, higher end-systolic and end-diastolic sphericity indexes (SI) and shorter LV axis lengths indicated remodeling. Also, global longitudinal and radial strains were reduced (both p

Circulation, Volume 150, Issue Suppl_1, Page A4141934-A4141934, November 12, 2024. Introduction:Heightened psychosocial stress is a CVD risk factor. While stressors are common and often co-occur, identifying sources and patterns of psychosocial stress exposure may provide insight into individual susceptibility to CVD. Therefore, we sought to identify and examine the longitudinal associations of baseline psychosocial stress subgroups with CVD events in MESA.Methods:Data from 6,349 adults (aged: 62.2±10.2 years; 52.9% women) from the MESA cohort with no prior CVD event at baseline (years 2000-2002) were used in this analysis. Latent class analysis (LCA) was used to specify distinct stress subgroups based on 6 variables: chronic burden, neighborhood safety, adequate food shopping, neighborhood noise, lifetime- and past-year discrimination. Five classes were determined after examining traditional fit indices. Adjudicated fatal and nonfatal CVD events were ascertained in annual follow-up visits through the year 2019. Cox proportional hazards models with sequential adjustment of baseline variables were used to examine the associations between subgroup membership and CVD events.Results:Five distinct stress subgroups were identified via LCA and were labeled “moderate neighborhood noise” (12.1%), “excessive noise/crime” (6.4%), “elevated on all” (6.3%), “high discrimination/safe neighborhood” (21.4%), “optimal” (53.8%) (see figure). By the year 2019, 1,121 participants had experienced a CVD event. Membership in the “elevated on all” and “high discrimination/safe neighborhood” subgroups (see table) were associated with higher risk of a CVD event when adjusted for sociodemographic characteristics and cardiovascular health metrics. However, when adjusted for measures of anxiety and depression, possible mediators, only membership in the “high discrimination/safe neighborhood” subgroup was associated with increased risk of a CVD event.Conclusions:Among 5 distinct stress subgroups those experiencing high discrimination had higher risk for CVD events.