Search Results for: Incontinenza urinaria da stress o mista

Circulation, Volume 150, Issue Suppl_1, Page A4141442-A4141442, November 12, 2024. Introduction/Background:Remote cardiac rehabilitation is becoming more popular, but most are exercise-based cardiac rehabilitation programs, and online intensive cardiac rehabilitation (ICR) programs that include not only exercise training but also dietary guidance, stress management, and group support have not been widespread.Research Questions/Hypothesis:Whether high adherence and improvement of CAD risk factors demonstrated for the online ICR program.Goals/Aims:We assessed the program adherence by participation rate as the primary endpoint and physical findings, typical CAD risks and nutritional indices as the secondary endpoint.Methods/Approach:The J-ICR program provides online instruction using Zoom (San Jose, CA: Zoom Video Communications Inc.). The program consisted of four parts: aerobic exercise training, dietary education for the Japan diet, stress management training through mindfulness, and group support (10 participants per group) for 3 hours per session, once a week for 12 weeks (36 hours total). Twenty-two patients were enrolled and adherence to the program was examined. Changes in CAD risk factors were also analyzed.Results/Data:After excluding 3 patients who withdrew consent before the program, the current study population consisted of 19 male participants. The mean age was 66 years old, 95% had hypertension, 37% had diabetes mellites and all had hyperlipidemia. Eight patients had myocardial infarction and 15 cases of angina pectoris. The average participation rate of the program was 90.2% and there was no drop out during the program. As the secondary endpoint, body weight （69.2kg vs. 68.2kg; p=0.02), systolic and diastolic blood pressure (126.8mmHg vs. 121.4mmHg; p

Circulation, Volume 150, Issue Suppl_1, Page A4145829-A4145829, November 12, 2024. Introduction/Background:Gestational diabetes mellitus (GDM) is the most common complication during pregnancy. GDM is leading to an elevated risk for the development of cardiovascular diseases both in the mother and the child in later life. Previous studies have identified fatty acid-binding protein 4 (FABP4) as a prime candidate involved in the pathophysiology of GDM. Indeed, women with GDM exhibit elevated blood levels of FABP4, suggesting its potential role as a biomarker for endothelial dysfunction and cardiovascular risk assessment in GDM.Research Question/Hypothesis:Does FABP4 affect the function of human endothelial cells from patients with GDM?Goals/Aim:Our aim is a better understanding of the role of FABP4 in fetal endothelial dysfunction of patients with GDM and the development of potential therapeutic strategies.Methods/Approach:Primary human umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords obtained from normoglycemic and GDM pregnancies. Total mRNA from HUVECs was used for bulk RNA sequencing to compare gene expression pattern. HUVECs were subjected to functional analyses assessing proliferation, migration, NO and insulin signaling. Finally, human endothelial cells were exposed to high laminar flow (30 dyn/cm2) or simvastatin (10 nM) treatment to investigate their impact on FABP4 expression and endothelial function.Results/Data:Bulk RNA sequencing data analysis revealed FABP4 as a gene overexpressed in GDM HUVECs compared to normoglycemic controls. Gene set enrichment analysis showed in addition an enrichment of genes involved in angiogenesis and Notch signaling pathways in human endothelial cells from GDM patients. GDM HUVECs had a significantly higher wound healing capacity compared to normoglycemic controls. The PI3K/AKT/mTOR pathway was enriched in GDM HUVECs. GDM HUVECs displayed impaired activation of AKT and eNOS (expression and phosphorylation) after stimulation with insulin, suggesting a possible insulin resistance. Finally, subjecting HUVECs to high laminar shear stress or simvastatin treatment caused a reduction of FABP4 mRNA expression and an increase of eNOS expression, indicating potential therapeutic strategies to improve endothelial function.Conclusions:We provided evidence that FABP4 could be involved in fetal GDM-induced endothelial dysfunction. High laminar shear stress and medications activating eNOS signaling could protect the endothelium against the negative impact of FABP4 in GDM.

Circulation, Volume 150, Issue Suppl_1, Page A4140118-A4140118, November 12, 2024. Introduction:Accurately identifying and characterizing patients with hypertrophic cardiomyopathy (HCM) is critical for population management and care optimization.Research Question:To develop natural language processing (NLP) algorithms to identify and characterize obstructive (oHCM) and non-obstructive (nHCM) HCM patients directly from echocardiograms, and to compare with the presence or absence of HCM-related diagnosis codes.Methods:We developed and validated NLP algorithms to identify HCM from all adult (age≥18yrs) echocardiograms performed from 2010-2019 in Kaiser Permanente Northern CA (KPNC), capturing measures of any HCM, HCM subtype, hypertrophy subtype, septal and posterior LV wall thickness, resting and stress/Valsalva LVOT gradients, and systolic anterior motion. We developed a rules-based algorithm (following AHA/ACC criteria) to classify patients as having HCM, including oHCM or nHCM subtypes, and possible HCM (defined as wall thickness ≥2cm without other criteria meeting an HCM definition). We evaluated the presence of HCM-related ICD-9/10 diagnosis codes among patients classified as HCM/non-HCM from echocardiograms using NLP, and linked baseline demographics and clinical parameters from our integrated electronic medical record.Results:Among 472,405 adults with echocardiograms, we identified 2,892 patients with HCM based upon NLP-derived measures (all NLP measures achieved >95% positive predictive value and >95% negative predictive value), including 1,585 (55%) with oHCM, 1,145 (40%) with nHCM, and 162 (6%) which could not be classified (Figure). Among those 2,892 patients, 1,283 did not have any associated HCM ICD-9/10 diagnosis codes (Table). Among 469,513 patients with no identified HCM from NLP-based algorithms, HCM ICD-9/10 diagnosis codes existed in 1,567 patients (Table). We also identified 4,593 patients with possible HCM by NLP, only 4.5% of whom had an associated HCM code. Among confirmed HCM patients by NLP, oHCM patients were slightly older (66 vs 61 yrs), more likely female (53% vs 43%), had similar mean septal wall thickness (1.7cm vs 1.7cm), but were more likely to have a septal hypertrophy subtype (46% vs 28%) compared to nHCM patients.Conclusions:Echocardiogram-based NLP methods can improve the identification of and care for HCM patients. Many patients with possible HCM may be underdiagnosed, representing an opportunity for quality improvement.

Circulation, Volume 150, Issue Suppl_1, Page A4145153-A4145153, November 12, 2024. Introduction:Cardiac cephalgia is an under-recognized type of headache.Description of Case:A 68-year-old female with past medical history of chronic headaches presents with one week of non-radiating central chest pain, exertional dyspnea, palpitations, lightheadedness, and worsening headaches. The headaches were described as a “stabbing and throbbing” pain starting at the vertex and radiating anteriorly. Triggers included stress, and associated symptoms included photophobia and nausea. An electrocardiogram was notable for new T-wave inversions in the inferior leads. An echocardiogram demonstrated an ejection fraction of 44% with regional akinesis of the inferior and inferolateral walls. Patient proceeded for left heart catheterization, which depicted total occlusion of the middle segment of the right coronary artery; a stent was successfully placed and dual antiplatelet therapy was initiated. Following stent placement, she endorsed resolution of her chronic headaches and has not had recurrence.Discussion:This case presents a patient with chronic headaches, initially diagnosed as migraines and occipital neuralgia. She had previously been treated with triptans and botulinum toxin without effect. Resolution of her headaches following revascularization suggest that cardiac cephalgia may be the underlying etiology. Cardiac cephalgia is a secondary headache disorder that is related to cardiac ischemia. It has classically been described as a headache that is triggered by exertion or stress and alleviated by rest or nitrates. Pathophysiology is incompletely understood but current theories include referred pain, simultaneous constriction of cerebral and coronary vessels, reduced cardiac output resulting in increased cardiac pressures and therefore decreased venous return from the brain, and cardiac ischemia-induced neurotransmitter release leading to cerebral vasodilation. The diagnosis of this condition is supported by a temporal relationship between coronary ischemia and headache onset. Interestingly, this patient had a headache onset several months before exhibiting signs of coronary ischemia but had an acute worsening at the time of presentation. It is important to keep cardiac cephalgia on the differential for patients with headaches in order to prevent treatment with agents, such as triptans and ergot derivatives, that are contraindicated in coronary artery disease.

Circulation, Volume 150, Issue Suppl_1, Page A4141778-A4141778, November 12, 2024. Background:Coronary microvascular dysfunction (CMD) is a cause of ischemia with non-obstructive coronary arteries (INOCA), but mechanisms underlying CMD are not well understood. We previously reported a proinflammatory whole blood transcriptional signature among INOCA patients with versus without CMD. Here we sought to broadly identify pathways beyond inflammation with potential relevance to CMD mechanisms.Methods:We prospectively enrolled females with ischemic symptoms or myocardial ischemia on stress testing who underwent invasive coronary angiography with

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

Circulation, Volume 150, Issue Suppl_1, Page A4132657-A4132657, November 12, 2024. Background:Cardiac rehabilitation (CR) patients demonstrate a high burden of chronic conditions (CC). Both multimorbidity (MM; ≥2 coexisting CC) and aging negatively impact functional capacity, whereas CR improves performance. Age-related difference in cardiorespiratory fitness (CRF, peak oxygen uptake (VO2)) in CR patients with MM has not been studied.Hypothesis:We hypothesized improvement in CRF will be attenuated by MM with increasing age in CR patients.Aims:We aimed to identify age-related differences in CRF improvement in CR patients with MM.Methods:Patients ≥18 yrs old who attended ≥1 CR sessions from 1999-2017 and completed cardiopulmonary exercise stress test before and after CR were included. The prevalence of CC was assessed using Rochester Epidemiology Project records-linkage system. Age categories included: Younger (18-49 yrs), Midlife (50-64 yrs) and Older (≥65 yrs). CRF categories included: 8%. Analysis included Kruskal-Wallis and Chi-squared.Results:Of 622 patients, 75.4% were male. Mean age: 62.9±11.2 yrs; Younger (n=70) age: 42.7±6.8 yrs, 67.1% male; Midlife (n=283) age: 58.3±4.3 yrs, 78.8% male; Older (n=269) age: 73.0±5.2 yrs, 74.0% male. BMI was 29.9±5.4 kg/m2(Younger: 30.0±6.7, Midlife: 30.4±5.6, Older: 29.3±4.7; p

Circulation, Volume 150, Issue Suppl_1, Page A4118444-A4118444, November 12, 2024. Background:Childhood cancer survivors are at risk of right ventricular (RV) dysfunction in relation to cardiac toxicity due to chemotherapy and radiation therapy. This study tested the hypothesis that RV contractile reserve and RV-pulmonary arterial (PA) coupling are altered in long-term survivors of childhood cancers.Methods:Thirty survivors (60% men) aged 24.3 ± 5.2 years at 15.3 ± 6.3 years after completion of chemotherapy and thirty healthy control subjects (47% men) were studied. Resting and submaximal supine bicycle stress echocardiography was performed for assessment of RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), left ventricular (LV) and RV longitudinal strain, mitral and tricuspid annular velocities and myocardial acceleration during isovolumic contraction (IVA). The slope of the RV force-frequency relationship was derived from the change in IVA with the change in heart rate during exercise (△IVA/△heart rate), while RV-PA coupling was determined by the ratio between TAPSE and pulmonary arterial acceleration time indexed to RV ejection time (PAATi).Results:At rest, tricuspid annular systolic velocity and RV systolic strain were significantly lower in survivors (P< 0.05 for both), while RV FAC, TAPSE and IVA were similar between the two groups (P > 0.05 for all). During submaximal exercise testing, all RV systolic functional indices were significantly lower in survivors than controls (P< 0.05 for all). The slope of the RV force-frequency relationship was significantly flatter in survivors compared to controls (0.038 ± 0.002 vs 0.059 ± 0.003 m/sec2beats/min,P< 0.001). For RV-PA coupling, TAPSE/PAATi was similar between survivors and controls at baseline but became significantly lower in survivors during submaximal exercise (P= 0.002).Conclusions:The RV contractile reserve and RV-PA coupling are impaired during exercise in long-term survivors of childhood cancers. Future studies aimed at determining the clinical and prognostic significance of these impairments are warranted.

Circulation, Volume 150, Issue Suppl_1, Page A4143988-A4143988, November 12, 2024. While its role in aging processes in mammals is largely unknown, activation of transient receptor potential ankyrin 1 (TRPA1), a sensor for noxious cold and oxidative stress , has been shown to decelerate aging and promote longevity in invertebrate animal models. Our previous study demonstrated that knockout of the Trpa1 gene accelerated age-related cardiac fibrosis and dysfunction in mice. The present study aimed to investigate whether activation of TRPA1 with its selective agonist allyl isothiocyanate (AITC) prevents age-related cardiac remodeling and dysfunction. Male and female 78-week-old aging C57BL/6J mice were randomized to receive either control diet or diet containing AITC (15 mg/Kg) for 26 weeks, and 12-week-old C57BL/6J mice were used as young controls. Transthoracic echocardiography was performed at the end of the experiment and showed that 104-week-old male and female aged mice that received control diet for 26 weeks developed restrictive-like diastolic dysfunction with significantly increased E/A ratio (2.41±0.84 vs. 1.22±0.03,P

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

Circulation, Volume 150, Issue Suppl_1, Page A4142998-A4142998, November 12, 2024. Introduction:Subclinical leaflet thrombosis is an increasingly recognized complication in patients undergoing transcatheter aortic valve replacement (TAVR). Patients with hypoattenuated leaflet thickening (HALT) and reduced leaflet motion (RELM) have a higher incidence of strokes and transient ischemic attacks. Early clinical data suggested that HALT is more common in supra-annular than intra-annular transcatheter aortic valves (TAVs). It was postulated that intra-annular TAVs have a larger neo-sinus volume and are potentially at a higher risk of blood flow stagnation in the neo-sinus region than supra-annular devices. However, recent clinical data obtained from the Evolut Low-Risk trial and the PARTNER 3 Cardiac CT sub-study showed that the incidence of HALT was comparable between supra-annular Evolut R (30.9%) and intra-annular SAPIEN 3 (28%) devices at one year.Hypothesis:We hypothesized that TAV leaflet design plays a vital role in the initiation and growth of leaflet thrombosis.Aim:The study aimed to optimize the leaflet and frame geometry of TAVs to mitigate the risk of subclinical leaflet thrombosis using an interactive parametric design platform that streamlines the engineering design process.Methods:We developed an automated computational framework to optimize the design of TAV leaflets in ANSYS Workbench, aiming to minimize (i) blood stasis on the surface of the TAV leaflets and (ii) the peak stress experienced by the tissue. Seven design variables were defined to modify the leaflet geometry and valve position (Figure 1).Results:The design platform revealed a complex response of the design variables, underscoring the importance of numerical optimization to obtain an optimal valve geometry. A considerable reduction in the blood stasis and maximum in-plane principal stress (31%) was observed in comparison to commercially available TAVs.Conclusions:The simulation results revealed that the leaflet geometry plays a vital role in the degree of blood stasis on the surface of the TAV leaflets and the stress experienced by the tissue. The optimized TAV design could reduce the risk of subclinical leaflet thrombosis in patients undergoing TAVR.

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

Circulation, Volume 150, Issue Suppl_1, Page A4144814-A4144814, November 12, 2024. Animals during hibernation suffer no ischemic consequences from their very much decrease heart/respiration rates, otherwise incompatible with life, but humans lost the ability to hibernate (presumably when their ancestors gained independence from the weather) and are highly vulnerable to ischemia. In a snail hibernation model, we isolated a brain metabolite only present in the plasma and brain of hibernating snails, and we characterized it with HPLC/MS. We found it is an activator of PHLPP1, a critical phosphatase in the conserved AMPK/mTOR signaling networks implicated in hibernation and fuel sensing (O2, glucose, amino acids). We synthesized it chemically and named it Snail Neurometabolite Activator of PHLPP1 (SNAP). We hypothesized that SNAP may inducehibernation in snails as well as mouse cells and organs that normally do not exhibit hibernation.We utilized in vivo, in vitro and ex vivo models, using Alberta snails, mouse-derived fibroblasts and ischemia and reperfusion (IR) injury model with Langendorff-perfused mouse hearts, to assess the effects of SNAP on snail hibernation, as well as the fuel deprivation-induced stress resistance in mouse-derived cells and hearts.SNAP injections in snails induced reversible hibernation indistinguishable from physiologic.SNAP specifically dephosphorylates the PHLPP1 targets p-S6K and p-AKT (downstream of mTOR and AMPK respectively) in fibroblasts cultured in hypoxic and low-glucose conditions for 3 days, significantly suppressed O2consumption, apoptosis, and cell-cycle progression, but enhanced autophagy formation. Upon discontinuation of SNAP and return to normal culture conditions, the SNAP-treated cells had preserved metabolism and re-entered the cell cycle at much higher rates compared to the vehicle, suggesting protection from ischemia and reperfusion (IR) injury and entrance in a reversible hibernation-like state. Furthermore, SNAP conferred cardioprotective effects during IR injury by preserving LV pressure, max and min dp/dt and re-entering normal function much earlier at reperfusion compared to the vehicle.SNAP offers protection from IR injury, inducing a hibernation-like state in mice cells and hearts, with wide implications for heart attack/stroke, preservation of donated organs for transplantation or even ultra-long space travel.

Circulation, Volume 150, Issue Suppl_1, Page A4144104-A4144104, November 12, 2024. Introduction:Following myocardial infarction (MI), extracellular matrix (ECM) degradation significantly contributes to adverse left ventricular (LV) remodeling mediated by the activation of matrix metalloproteinases (MMPs). Intramyocardial injection of hydrogels that locally release MMP inhibitors are designed to modulate MMP activation, increase wall thickness, reducing wall stress, resulting in improved regional mechanics and function. Pressure-volume (PV) analysis is an established approach for evaluation of cardiac performance.Methods:Chronic reperfused MI was created by a 90-min LAD occlusion in swine (n=16). PV loop analysis was performed using simultaneous 3D echocardiography and invasive LV pressures at baseline and 5 weeks post-MI. Therapeutic hydrogels were delivered by direct intramyocardial injection (9×100 μl) at 7 days post-MI using hyaluronic acid hydrogels alone (HA-Only) (n=4) or hyaluronic acid that releases an MMP inhibitor doxycycline (HA-DOX) (n=5) into the MI region. Outcomes were compared to control MI pigs (n=7) at 5 weeks post-MI to assess therapeutic benefits. MMP inhibition was measured by uptake of the SPECT MMP targeted radiotracer,99mTc-RP805 in the infarct region.Results:Quantitative indices of remodeling from representative PV loops are shown in Figure 1 A-C. LV end-diastolic volume (LVEDV) corrected for body weight (BW) was significantly greater in the MI-controls at 5 weeks post-MI compared to the HA-DOX group (Fig 1D, p=0.035, t-test). There was a statistically significant difference in LV end-diastolic pressure (LVEDP) (Fig 1E) between MI-controls and HA-DOX (p=0.025, ANOVA). There was a trend for decreased LV compliance (Fig 1F) in MI-controls based on the EDPVR V30. These changes correlated with a significant decrease in99mTc-RP805 in the MI region of HA-DOX animals compared to controls (Fig 1G).Conclusion:LV PV analysis demonstrated significant adverse remodeling in control pigs that was reduced by early intramyocardial delivery of a DOX releasing hydrogel post-MI. Delivery of both hydrogels prevented some measures of adverse LV remodeling, with prevention of LV dilatation and reduction in LVEDP and correlated with a decrease in MMP activation by SPECT99mTc-RP805.

Circulation, Volume 150, Issue Suppl_1, Page A4141614-A4141614, November 12, 2024. Background:Children with critical congenital heart disease (CHD) often require complex open-heart surgery with long aortic cross-clamp times (XC). Despite refinement in cardioplegia, ventricular dysfunction due to inadequate myocardial protection remains a major clinical challenge. Glucagon-like peptide-1 (GLP-1) has proven cardioprotective properties. This study characterizes the mechanisms of injury of long XC and investigates cardioprotective properties of GLP-1(28-36), a naturally occurring fragment of GLP-1.Method&Results:A pediatric surgical model of cardiopulmonary bypass and long XC was developed in 4-5 wk-old Yorkshire pigs. Pigs were subjected to 90-min XC (modelling common CHD repair, e.g. Tetralogy of Fallot) or 180-min XC (modelling complex CHD repair, e.g. corrected transposition). After 90-min XC [n=8], analysis of cardiac function at baseline vs. 2-h post-bypass revealed reduced ejection fraction (55±6% vs. 28±4%; P

Circulation, Volume 150, Issue Suppl_1, Page A4141399-A4141399, November 12, 2024. Background:Chronic alcohol consumption is known to impair endothelial function and contribute to cardiovascular disease. However, the effects of moderate alcohol consumption on vascular function, especially in the presence of atherogenic risk factors like hypercholesterolemia, remain inconsistent and unclear.Methods and Results:To simulate chronic moderate and heavy drinking in hypercholesterolemic conditions, ApoE deficient (ApoE−/−) mice were fed a Lieber-DeCarli liquid diet with ethanol (2g/kg/day for moderate and 5g/kg/day for heavy drinking) or isocaloric maltose (5g/kg/day as control) for 12 weeks. In vivo flow-mediated vasodilation (FMD) of the femoral artery was assessed at 6 and 10 weeks. Both moderate and heavy alcohol consumption significantly impaired endothelium-dependent FMD, while endothelium-independent FMD increased after 10 weeks, indicated by higher FMD values in the presence of L-NAME, an eNOS inhibitor. Moderate and heavy drinking also promoted aortic endothelial permeability (measured by Evan’s blue dye infiltration) and atherosclerotic lesions at the aortic root. In aorta and endothelium-rich lung tissues, protein S-glutathionylation levels were elevated in both drinking groups, coinciding with eNOS inactivation (reduced dimer to monomer ratio), impaired Rac1 RhoGTPase activity, and increased Rac1 glutathionylation. In human aortic endothelial cells, ethanol exposure dose-dependently promoted protein S-glutathionylation and lowered glutaredoxin-1 (Grx1) levels. Moderate ethanol treatment (25mM) alone had negligible impact on eNOS and Rac1 activities but caused endothelial dysfunction under metabolic stress or Grx1 knockdown, mirroring animal study findings.Conclusions:This study provides evidence that moderate alcohol consumption can cause vascular endothelial dysfunction in the presence of hypercholesterolemia. The underlying mechanism involves S-glutathionylation-centered redox dysregulation of Rac1 and eNOS.