Risultati per: Come stress e attacchi di cuore sono collegati

Objectives
The objectives are to explore the relationship between study stress and anxiety in high school students and the mediating role of physical activity and mobile phone addiction.

Design
A cross-sectional study.

Setting
129 high schools were randomly selected in 13 cities of Jiangsu province, China.

Participants
High school students aged 16–19 years, age and gender balance. A total of 40 000 questionnaires were distributed, with 32 974 effectively recovered.

Primary and secondary outcome measures
Questionnaires were administered offline, covering four parts: General Demographics, Learning Stress Scale, International Physical Activity Questionnaire, Mobile Phone Addiction Scale and Generalized Anxiety Scale-7. Data analysis included path analysis and correlation analysis, along with descriptive statistics, independent sample t-test, correlation analysis and structural equation model.

Results
In this study, the proportions of anxiety, high academic pressure, low physical activity level and high mobile phone addiction were 58.18%, 46.48%, 36.40% and 39.26%, respectively. Study stress was positively correlated with anxiety (r=0.130, p physical activity level – > mobile phone addiction – > anxiety’ was 0.072, and the 95% CI of Bootstrap (0.226, 0.400), and the mediating effect was significant.

Conclusions
High school students’ learning stress can significantly positively predict anxiety levels. High school students learning stress indirectly predicts anxiety through the independent mediating effect of physical activity and mobile phone addiction, as well as the chain mediating effect of physical activity and mobile phone addiction.

Objectives
This goal of this research is to present a comprehensive method for evaluating stress and the factors that contribute to it in mothers of premature babies.

Design
Analytical cross-sectional study.

Setting
Data were collected from inpatient service for preterm infants including neonatal intensive care unit, and neonatal step-down units of the Aga Khan University Hospital—a private tertiary care hospital in Karachi, Pakistan.

Participants
Mothers aged 18 years and above who delivered preterm infants (gestational age of preterm below 37 weeks) in a private tertiary care hospital in Karachi, Pakistan.

Primary outcome
Stress in mothers of preterm infants.

Results
200 participants with a mean age of 30.12 years (SD ±5.21) were assessed. The level of stress identified using the perceived stress scale (PSS) among mothers who had delivered preterm infants was significantly higher as compared with other countries around the world. Based on the criteria of PSS scoring, the majority of the participants (92%, n=184) were categorised as having high perceived stress and 8% (n=16) of the mothers fell into the category of moderate stress.

Conclusions
The study findings suggest high levels of perceived stress among mothers of preterm infants. The factors associated with the stress among mothers of preterm infants included immunisation of newborn, education and occupation status of mothers, substance abuse by mother, gender preference from family, planning for further children, consumption of balance diet, education status of husband, mode of socialisation, years of marriage and hours of sleep.

Objectives
We conducted an implementation science mental health treatment study in western Kenya, testing strategies for scale up of evidence-based mental health services for common adult disorders using a non-specialist workforce, integrated with existing primary care (Sequential Multiple, Assignment Randomized Trial of non-specialist-delivered psychotherapy (Interpersonal Psychotherapy) and/or medication (fluoxetine) for major depression and post-traumatic stress disorder (PTSD) (SMART DAPPER)). Because study launch coincided with the COVID-19 pandemic, participants were allowed to attend treatment visits via mHealth (audio-only mobile phone) or in-person. We conducted a secondary data analysis of the parent study to evaluate preference for mHealth or in-person treatment among our study participants, including rationale for choosing in-person or mHealth treatment modality, and comparison of baseline demographic and clinical characteristics.

Design, setting, participants and interventions
Participants were public sector primary care patients at Kisumu County Hospital in western Kenya with major depression and/or PTSD and were individually randomised to non-specialist delivery of evidence-based psychotherapy or medication (n=2162).

Outcomes
Treatment modality preference and rationale were ascertained before randomised assignment to treatment arm (psychotherapy or medication). The parent SMART DAPPER study baseline assessment included core demographic (age, gender, relationship status, income, clinic transport time and cost) and clinical data (eg, depression and PTSD symptoms, trauma exposures, medical comorbidities and history of mental healthcare). Given that this evaluation of mHealth treatment preference sought to identify the demographic and clinical characteristics of participants who chose in-person or mHealth treatment modality, we included most SMART DAPPER core measurement domains (not all subcategories).

Results
649 (30.3%) SMART DAPPER participants preferred treatment via mHealth, rather than in person. The most cited rationales for choosing mHealth were affordability (18.5%) (eg, no transportation cost) and convenience (12.9%). On multivariate analysis, compared with those who preferred in-person treatment, participants who chose mHealth were younger and had higher constraints on receiving in-person treatment, including transport time 1.004 (1.00, 1.007) and finances 0.757 (0.612, 0.936). Higher PTSD symptoms 0.527 (0.395, 0.702) and higher disability 0.741 (0.559, 0.982) were associated with preference for in-person treatment.

Conclusions
To our knowledge, this is the first study of public sector mental healthcare delivered by non-specialists via mHealth for major depression and/or PTSD in Sub-Saharan Africa. Our finding that mHealth treatment is preferred by approximately one-third of participants, particularly younger individuals with barriers to in-person care, may inform future mHealth research to (1) address knowledge gaps in mental health service implementation and (2) improve mental healthcare access to evidence-based treatment.

Trial registration number
NCT03466346.

Circulation, Volume 150, Issue Suppl_1, Page A4114705-A4114705, November 12, 2024. Introduction:Stress Induced Cardiomyopathy is increasingly becoming more prevalent with increasing awareness about disease condition with annual incidence of 30 cases/100000 per year and an incidence of 1-2% in the patients presenting with acute coronary syndrome.[1] Physical and emotional triggers have been linked with occurrence of Stress induced Cardiomyopathy.Methods:We have obtained the National Readmission database for the year of 2020. We have used the ICD 10 code I51.81 for stress induced cardiomyopathy and found 10450 patients in the data base. Total 494 patients had cardiac arrest and 191 patients out of this 494 had died. We have used Binary logistic regression methods to find the odd ratio for physical and emotional risk factors for stress induced cardiomyopathy.Results:Grief disorder with an odd ratio of 7.2, followed by female gender with an odd ratio of 4.1, septic shock with an odd ratio of 3.3, Hemorrhagic stroke with an odd ratio of 1.73, ischemic stroke with an odd ratio of 1.72, depression with an odd ratio of 1.5, followed by asthma exacerbation with an odd ratio of 1.35 and seizure disorder with an odd ratio of 1.34 were among the few predictors for stress induced cardiomyopathy. Incidence of Cardiac Arrest was 4.7% and mortality rate of 1.8% was observed in the patients with stress induced Cardiomyopathy.Discussion:Extreme emotional and physical triggers like stroke, septic shock are among few significant risk factors for the stress induced cardiomyopathy.

Circulation, Volume 150, Issue Suppl_1, Page A4146301-A4146301, November 12, 2024. Background:Exercise stress testing uses metabolic equivalents of tasks (METs) to measure the energy cost of activities, aiding in the assessment of exercise capacity and cardiovascular health. Despite its significance, the correlation between calf muscle pump function (CPF) and exercise stress testing remains unexplored. We aimed to evaluate the relationship between CPF and peak METs as determined by cardiopulmonary treadmill exercise stress testing.Methods:The study included adults who underwent exercise cardiopulmonary stress testing and venous plethysmography at Mayo Clinic between April 2017 and March 2020. The protocols other than Bruce, Mayo, Modified Naughton, and Naughton protocols were excluded. The CPF ejection fraction (EF) was calculated per leg based on refill volumes post-exercise as a percentage of passive drain refill. The classification of CEAP (Clinical-Etiology-Anatomy-Pathophysiology) was utilized to better understand chronic venous insufficiency (CVI).Results:A total of 155 patients who underwent both exercise stress testing and venous plethysmography were included, with a mean age of 61.31 ± 14.03 years, and 84 (54.2%) were male. The peak measured METs for normal, unilaterally reduced, and bilaterally reduced CPF were 8.5 (2.5), 7.3 (2.1), and 7.1 (2.4), respectively (p=0.004, Figure 1). Multiple linear regression models were developed with METs as the outcome to determine if CPF was an independent predictor of METs on cardiopulmonary exercise stress testing. IIn model 1, the following independent variables were included: resting heart rate, peak heart rate, peak systolic blood pressure, recovery heart rate at minute 1, and worst EF (Table 1). In model 1, with only exercise parameters, lower EF was associated with lower METs (p=0.03). In a second analysis, variables identified as statistically significant with METs in the initial model were included, along with CEAP class (model 2) and CCI (model 3) (Table 2). In model 2, CEAP class 3 or higher was associated with decreased METs on the exercise stress test. This correlation implies that individuals with moderate to severe CVI may influence exercise capacity, demonstrating the interconnectedness of the cardiovascular system. Moreover, in model 3, the CCI, a predictor for mortality, was not significantly associated with METs.Conclusion:Our findings revealed that more severe CVI (CEAP class and reduced CPF) was associated with reduced exercise capacity after accounting for other factors.

Circulation, Volume 150, Issue Suppl_1, Page A4147602-A4147602, November 12, 2024. Coronary microvascular dysfunction (CMD), which is associated with diabetic cardiomyopathy, Takotsubo cardiomyopathy, andheart failure with preserved ejection fraction (HFpEF), is understudied. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated.Nuclear Sirtuin 6 (SIRT6) plays essential roles in gene transcriptional, stress tolerance, DNA repair, inflammation, and aging. SIRT6 is strongly associated with cardiovascular pathologies, but how SIRT6 regulates endothelial metabolisms and homeostasis under metabolic stress and the underlying mechanism remains poorly understood. It might be because global Sirt6 knockout mice are perinatally lethal caused by hypoglycemia, suggesting the essential role of SIRT6 in glucose metabolism.In our preliminary studies, we generated inducible global Sirt6 knockout mice by crossing with Sirt6 f/f mice with CAG-cre (Sirt6f/f, CAG), and mice were viable with normal glucose levels. However, they showed impaired endothelial-dependent dilation (EDD) and impaired coronary flow reserve (CFR), an index clinically used to diagnose CMD. It suggests that deletion of Sirt6 might cause EC dysfunction because Sirt6 is reported to protect EC from premature senescence and oxidative stress by sustaining high eNOS levels. Surprisingly, when we studied non-inducible Sirt6 endothelial-specific knockout (Sirt6f/f, tie-2 cre) and inducible Sirt6 endothelial-specific knockout (Sirt6 f/f,Cdh5-cre/ERT2) and wild-type (WT) mice, Sirt6f/f, Tie-2and Sirt6f/f, Cadh5mice do not phenocopy the inducible global SIRT6 knockout mice, they had normal EDD and CFR. When the mice were fed a high fat and high sugar (HFHS) diet, the Sirt6f/f, Tie-2and Sirt6f/f, Cadh5had impaired EDD, suggesting Sirt 6 functioned differently in the mice fed with chow diet or HFHS diet.We hypothesize Sirt 6 deficiency causes coronary endothelial dysfunction and contributes to CMD; activating Sirt6 will ameliorate CMD. EDD was assessed using myography (DMT). Myocardial blood flow (MBF) was measured by Doppler. Our preliminary data show that the mediator of coronary vasodilation switched from NO to H2O2in the Sirt6 knockout mice with impaired EDD. Interestingly, when the mice fed on HFHS were treated with Sirt 6 activator MDL-800, the coronary microvascular function was improved, and the blood glucose level was decreased. The underlying mechanism and the pathways involved will be elucidated.

Circulation, Volume 150, Issue Suppl_1, Page A4139170-A4139170, November 12, 2024. Background:Hypertrophic cardiomyopathy (HCM) is a global heart disease with great variability in disease severity, which can lead to significant impairment of exercise capacity. In healthy populations, oxygen consumption is related to cardiac output and arteriovenous oxygen difference. We sought to determine the relationship between hemodynamics (cardiac output and stroke volume) and oxygen consumption in HCM compared to healthy controls during maximal stress testing.Aims:To evaluate associations between the trajectories of hemodynamic function and oxygen consumption in HCM compared to healthy controls.Methods:Twenty individuals with HCM (51±15 years old, body mass index (BMI): 28±3 kg/m2, females, n=4) and 16 healthy controls (66±7 years old, 27±6 kg/m2, females, n=6) were included in the present study. Participants completed a maximal-graded stress test coupled with non-invasive hemodynamic bioreactance (cardiac output, stroke volume) and gas exchange (oxygen consumption, VO2) measurements. Data were analyzed in quartiles (exercise only) and phases (rest, pre-pedalling, exercise and recovery) of the maximal-graded stress test.Results:In HCM, cardiac output declined in the fourth quartile of the exercise phase of the stress test (-0.39 L/min,p

Circulation, Volume 150, Issue Suppl_1, Page A4140185-A4140185, November 12, 2024. Introduction:Several studies have linked mental health disorders and substance abuse as risk factors for stress cardiomyopathy (SC). However, the true burden of these disorders amongst patients with stress cardiomyopathy remains unknown.Methods:We used the 2016-2020 National Inpatient Sample database to identify hospitalizations for SC who underwent diagnostic catheterization. We assessed the proportion of patients diagnosed with a substance abuse or mental health disorder. Subsequently, the association of these disorders in SC compared to patients admitted for myocardial infarction (MI) was assessed using the chi-square test.Results:From 2016 to 2020, there were 33,075 hospitalizations for stress cardiomyopathy who were diagnosed by cardiac catheterization. Of these patients, 5,920 (17.9 %) had depression, 8,500 (25.7 %) had anxiety, 1058 (3.2 %) had severe stress reactions, and 16,372 (49.5 %) were diagnosed with a mental health disorder. 9,955 (30.1 %) were smokers, 5,358 (16.2%) abused hallucinogens, 5,457 (16.5 %) abused cocaine, 5,457 (16.5%) abused sedatives, 6,019 (18.2 %) abused cannabis, 5,920 (17.9%) abused opioids, 6,416 (19.4 %) abused alcohol. Subsequently, the association of stress cardiomyopathy with mental and substance abuse disorder was compared with patients admitted with myocardial infarction See Table 1.Conclusion:Mental health and substance abuse disorders are common in patients diagnosed with SC. These disorders are more commonly present in SC compared to MI. Further research is needed to assess the significance of these findings.

Circulation, Volume 150, Issue Suppl_1, Page A4140181-A4140181, November 12, 2024. Systemic hyperglycemia causes tissue damage and triggers cardiovascular disease (CVD). Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are a novel class of glucose-lowering agents that have shown unexpected benefits in clinical trials for the treatment of CVDs. We aim to investigate the underlying mechanisms of how SGLT-2 inhibitors alleviate CVDs associated with elevated glucose stress. iPSC-derived cardiomyocytes (iPSC-CM) were incubated with high glucose concentrations for 72 hours. Mitochondrial function in these cardiomyocytes was assessed by flow cytometry with JC-1 staining and ATP luminescence assay. Intracellular reactive oxygen species (ROS) and intramitochondrial calcium stress were measured using CellROX, MitoSOX, and Rhod-2 AM staining. Patch clamp was employed to determine ion current changes in the cardiomyocytes. Mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were determined using the Seahorse XFe96 analyzer. In addition, qPCR, Western blot, and DM mouse heart histological analysis were performed to assess the regulation of associated molecules. The results indicated that exposure to a high glucose environment caused cardiomyocyte injury and impaired mitochondrial biosynthesis. Empagliflozin exhibited a beneficial effect on mitochondrial function by reducing ROS production and calcium deposition. It also mitigated the reduction in respiratory OCR of cardiomyocytes induced by high glucose incubation. Furthermore, molecular analysis revealed that Empagliflozin attenuated the dysregulation of mitochondrial calcium channels and biosynthesis by reducing associated gene expression, includingBcl2,Mfn1,Mx2,Oas1,Ant3,Mcu,Micu1,Vdac1,Ryr2, andCypd-ppid. Histological analysis of DM mouse hearts demonstrated that reduced MFN2 and ZBP1 were target molecules for hyperglycemia-induced reduction of calcium channel currents in cardiomyocytes and could be restored by Empagliflozin treatment. This study concludes that high glucose stress diminishes mitochondrial calcium channel regulators MFN2 and ZBP1 in cardiomyocyte, which reduces calcium channel currents and leads to sensitization of cardiomyocyte to arrhythmogenesis, resulting in VT/VF. It provides experimental evidence for the clinical efficacy of Empagliflozin in ameliorating CVDs and managing diabetes-related CVDs.

Circulation, Volume 150, Issue Suppl_1, Page A4141446-A4141446, November 12, 2024. Emerging evidence suggests that vascular stress from cardiovascular-related co-morbidities promotes microvascular dysfunction, a key component in the development of heart failure with preserved ejection fraction. The sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has been shown to reduce both morbidity and mortality associated with heart failure with preserved ejection fraction, however the full scope of influence of this therapy on human microvascular function remains unknown. We hypothesized that pre-treatment of isolated human microvessels with empagliflozin will prevent stress-induced endothelial dysfunction as evidenced by preserving both the magnitude of flow-induced dilation (FID) as well as the ability to dilate to nitric oxide. Human resistance arterioles (80-250µm) from healthy adults (defined as patients with ≤1 risk factor for cardiovascular disease) were dissected from discarded surgical adipose tissue and treated with empagliflozin (1µM), or vehicle control (ethanol) for 16-20 hours prior to the flow experiment. Vessels were cannulated for videomicroscopy and subjected to high intraluminal pressure (150mmHg, 30 min), an acute stress known to induce endothelial dysfunction. Vessels were pre-constricted with endothelin-1 prior to initiation of flow. A nonlinear logistic regression was used to determine differences between curves. Compared to vehicle control, vessels pre-treated with empagliflozin (1µM ) exhibited nitric oxide-dependent FID as dilation was impaired in the presence of the nitric oxide synthase inhibitor L-NAME (EC50 Control: 10.7 vs L-NAME 83.45, p=0.0107). This data suggests that empagliflozin, an SGLT2 inhibitor, promotes microvascular resilience to stress via preservation of nitric oxide-mediated FID. The ability to elicit stress resilience may explain in part some of the cardiovascular benefits associated with SGLT2 inhibitors and may offer unique opportunities for early intervention or prevention of microvascular dysfunction associated with comorbidities that contribute to heart failure with preserved ejection fraction.

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

Circulation, Volume 150, Issue Suppl_1, Page A4145408-A4145408, November 12, 2024. Background:Stress cardiomyopathy (SCM) is rarely triggered by ketamine and seldom leads to cardiogenic shock. Ketamine-induced catecholaminergic surge can lead to myocardial stunning with transient ischemia and subsequent reversible heart failure. Mechanical circulatory support can be successfully leveraged in SCM-associated cardiogenic shock while awaiting myocardial recovery.Case Presentation:A 28-year-old female with chronic pain was admitted for failure to thrive secondary to opioid-induced gastroparesis. The patient was weaned off opiates while on ketamine over 4 days. After halting ketamine, the patient had a cardiac arrest with eventual return of spontaneous circulation. After being extubated, she developed chest pain, hypotension, and ventricular tachycardia with anterolateral ST elevations, troponin leak, and lactic acidosis. TTE revealed an EF

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

Circulation, Volume 150, Issue Suppl_1, Page A4145148-A4145148, November 12, 2024. Introduction:Junctophilin-2 (JPH2) plays essential roles in multiple cardiac processes including calcium handling, t-tubule structure, and gene regulation. We recently showed JPH2 also has a mitochondrial role as it binds the mitochondrial protein mitofusin-2 (MFN2) and modulates mitochondrial metabolic function. However, the impacts of JPH2 disease-causing variants on MFN2 binding and subsequent cellular responses to metabolic stressors are unknown.Methods:Disease-associated variants in the MFN2 binding domain of JPH2 were engineered and recombinantly expressed in E. coli cells. Purified proteins were then subjected to pulldown experiments to assess MFN2 protein binding. Alphafold3 modeled how MFN2 and JPH2 and JPH2 E169K mutants interacted in the presence or absence of fatty acids. Wildtype JPH2 or JPH2 E169K expression was directed by a doxycycline inducible promoter after being cloned into the AAVS1 locus in JPH2 knockout iPSC-cardiomyocytes. In vitro metabolic stress was induced by incubating iPSC-CM with 150 μM oleate, 150 μM palmitate, and 500 μM carnitine overnight. Super resolution confocal microscopy visualized mitochondria integrity, nuclei shape and size, and lipid droplet accumulation and morphology.Results:In pulldown experiments, the JPH2 E169K mutation disrupted MFN2 binding. Alphafold3-based modeling showed JPH2 E169K disrupted the interaction between the two proteins when modeled with or without lipids (A-D). Control, wild type JPH2, and JPH2 E169K iPSC-CM displayed divergent responses to in vitro metabolic stress. JPH2 E169K cells exhibited pathological mitochondrial network changes characterized by a lower mitochondrial footprint and less network branches (E-G). In addition, the JPH2 E169K iPSC-CM accumulated significantly more lipid droplets in the cytoplasm and the nucleus, and the JPH2 E169K lipid droplets were significantly larger than the other cell types (H-K). Finally, the accumulation of lipid droplets impacted nuclear morphology as the JPH2 E169K cells had nuclear hypertrophy and nuclei were more ellipse-shaped (L-N).Conclusion:The JPH2 E169K variant disrupts MFN2 binding, which results in heightened metabolic stress characterized by lipid droplet accumulation and mitochondrial and nuclear morphological changes. These results implicate a new pathophysiological mechanism for how the JPH2 E169K mutation causes cardiac dysfunction.

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

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