Development Of Cardiovascular Disease Research Articles

BRD4 promotes LPS-induced endothelial cells senescence via activating and cooperating STING-IRF3 pathway

Endothelial cells (ECs) senescence is closely associated with the initiation and development of multiple age-related cardiovascular diseases. It is necessary to explore the underlying molecular mechanisms of ECs senescence, which is not only the basis to decipher cellular senescence, but also a novel therapeutic target for the endothelial senescence-related diseases. BRD4, a key epigenetic regulator, is universally related to gene expression regulation and has been reported to accelerate cell senescence. Besides, emerging evidence has suggested that the stimulator of interferon genes protein (STING) can regulate inflammatory and senescence-related diseases. However, whether STING pathway activation is regulated by BRD4 in the context of ECs senescence remains largely unclear. Here, we observed that elevated BRD4 and activated STING-IRF3 signaling pathway during ECs senescence and further confirmed that BRD4 could abolish STING activation. We demonstrated that BRD4 could inhibit E3 ubiquitin ligase HRD1-mediated ubiquitination degradation of STING via inhibiting HRD1 transcription. In addition to the direct regulatory effect of BRD4 on STING activation, we have confirmed that BRD4 cooperates with IRF3 and P65 to promote SASP gene expression, thereby accelerating ECs senescence. Here, we proposed a novel mechanism underlying BRD4’ key dual role in activating the STING pathway during ECs senescence.

An agent-based model of the spread of behavioural risk-factors for cardiovascular disease in city-scale populations.

Cardiovascular disease (CVD) is the leading cause of mortality globally, and is the second main cause of mortality in the UK. Four key modifiable behaviours are known to increase CVD risk, namely: tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol. Behaviours that increase the risk of CVD can spread through social networks because individuals consciously and unconsciously mimic the behaviour of others they relate to and admire. Exploiting these social influences may lead to effective and efficient public health interventions to prevent CVD. This project aimed to construct and validate an agent-based model (ABM) of how the four major behavioural risk-factors for CVD spread through social networks in a population, and examine whether the model could be used to identify targets for public health intervention and to test intervention strategies. Previous ABMs have typically focused on a single risk factor or considered very small populations. We created a city-scale ABM to model the behavioural risk-factors of individuals, their social networks (spousal, household, friendship and workplace), the spread of behaviours through these social networks, and the subsequent impact on the development of CVD. We compared the model output (predicted CVD events over a ten year period) to observed data, demonstrating that the model output is realistic. The model output is stable up to at least a population size of 1.2M agents (the maximum tested). We found that there is scope for the modelled interventions targeting the spread of these behaviours to change the number of CVD events experienced by the agents over ten years. Specifically, we modelled the impact of workplace interventions to show that the ABM could be useful for identifying targets for public health intervention. The model itself is Open Source and is available for use or extension by other researchers.

The Curious Role of PAI-1 in Severe Obstructive Sleep Apnea

Plasminogen activator inhibitor-1 (PAI-1) has a significant role in fibrinolysis, atherogenesis, cellular senescence, and chronic inflammation. OSA (obstructive sleep apnea) leads to increased PAI-1 levels and the development of cardiovascular disease (CVD). The aim of this study was to determine the effects of CPAP therapy on coagulation parameters and PAI-1 in patients with severe OSA. This prospective, controlled study enrolled 57 patients who were newly diagnosed with severe OSA, 37 of whom had had good CPAP adherence after 6 months of therapy (usage of the device for at least 4 h per night), and their data were analyzed. The analysis showed a statistically significant increase in D-dimer values before CPAP therapy (415 (316.5–537.5)) vs. after therapy (499 (327–652)), p = 0.0282, and a decrease in fibrinogen values (3.665 ± 0.752 before CPAP therapy vs. 3.365 ± 0.771 after therapy, p = 0.0075)). PAI-1 concentration values before and after CPAP therapy did not differ significantly (17.35 ± 7.01 ng/mL before CPAP therapy vs. 17.42 ± 6.99 ng/mL after therapy, p = 0.9367). This study shows a tendency for fibrinolytic capacity to improve in patients with OSA after CPAP therapy, although PAI-1 levels did not differ significantly.

Risk of Cardiovascular Complications Among Type 2 Diabetes Mellitus Patients with GSTP1 Genetic Polymorphism: A Nested Case-Control Study and Docking Studies.

The genetic alteration in the antioxidant gene Glutathione-S-Transferases Pi 1 (GSTP1) namely GSTP1*IIe105Val (rs1695) and GSTP1*Ala114Val (rs1138272) changes the individual susceptibility to cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) by altering the substrate binding and catalytic activity. This study aims to investigate the association of GSTP1 rs1695 and rs1138272 polymorphism with CVD development in T2DM patients. Genotyping was performed with 400 study participants-group I: control; group II: T2DM; group III: CVD; and group IV: T2DM/CVD [n = 100 each] by PCR-RFLP. The rs1695 and rs1138272 polymorphism were docked against NPACT and NUBBE database and virtually screened using glide. The study reported that rs1695 polymorphism was associated with T2DM risk under dominant and allelic genetic models [OR = 1.97(1.08-3.59) p = 0.02 and OR = 1.79(1.20-2.66) p = 0.003, respectively]. The val/val genotype, dominant, recessive model, and T allelic genetic model were associated with increased CVD risk [OR = 4.15(1.97-8.73) p = < 0.01; OR = 3.16(1.65-6.04) p = < 0.01; OR = 3.47(1.91-6.31) p = < 0.01; and OR = 2.94(1.95-4.43) p = < 0.01, respectively]. In contrast, rs1695 polymorphism was not associated with CVD development among patients with T2DM. In rs1138272, the wild genotype was only detected and neither heterozygous nor val/val genotype was observed. The docking analysis revealed that the Ile105Val mutation plays a significant role in altering the GSTP1 capacity compared to the Ala115Val mutation. This suggests that the Ile105Val mutation has a greater impact on the protein's structure, function, or susceptibility to diseases compared to the Ala115Val mutation. In summary, genetic alteration in GSTP1 rs1695 potentially contributes to an increased risk of T2DM and CVD.

The Effects of Antioxidant Supplementation on the Pathologic Mechanisms of Metabolic Syndrome and Cardiovascular Disease Development

The Effects of Antioxidant Supplementation on the Pathologic Mechanisms of Metabolic Syndrome and Cardiovascular Disease Development

Sex-specific impact of psychosocial stress on hematopoiesis and blood leukocytes.

Stress exposure has been shown to modulate innate and adaptive immune responses. Indeed, stress favors myelopoiesis and monocyte generation and contributes to cardiovascular disease development. As sex hormones regulate innate and adaptive immune responses, we decided to investigate whether stress exposure leads to a different immune response in female and male mice. Our data demonstrated that psychosocial stressinduced neutrophilia in male, but not female mice. Importantly, we identified that B-cell numbers were reduced in female, but not male mice upon exposure to stress. Thus, our study revealed that the stress-induced immune alterations are sex-dependent, and this is an important feature to consider for future investigations.

The Role of Sleep in Cardiovascular Disease.

Sleep is an important component of cardiovascular (CV) health. This review summarizes the complex relationship between sleep and CV disease (CVD). Additionally, we describe the data supporting the treatment of sleep disturbances in preventing and treating CVD. Recent guidelines recommend screening for obstructive sleep apnea in patients with atrial fibrillation. New data continues to demonstrate the importance of sleep quality and duration for CV health. There is a complex bidirectional relationship between sleep health and CVD. Sleep disturbances have systemic effects that contribute to the development of CVD, including hypertension, coronary artery disease, heart failure, and arrhythmias. Additionally, CVD contributes to the development of sleep disturbances. However, more data are needed to support the role of screening for and treatment of sleep disorders for the prevention of CVD.

Salvianolic acid A alleviates H2O2-induced endothelial oxidative injury via miR-204-5p

Oxidative stress induced endothelial dysfunction plays a particularly important role in promoting the development of cardiovascular diseases (CVDs). Salvianolic acid A (SalA) is a water-soluble component of traditional Chinese medicine Salvia miltiorrhiza Bunge with anti-oxidant potency. This study aims to explore the regulatory effect of SalA on oxidative injury using an in vitro model of H2O2-induced injury in human umbilical vein endothelial cells (HUVECs). In the study, we determined cell viability, the activities of Lactate dehydrogenase (LDH) and Superoxide dismutase (SOD), cell proliferation rate and intracellular reactive oxygen species (ROS). Flow cytometry was used to detect cell apoptosis. Western-blotting was used to evaluate the expression of cell senescence, apoptosis, autophagy and pyroptosis protein factors. The expression level of miRNA was determined by qRT-PCR. Compared with H2O2-induced HUVECs, SalA promoted cell viability and cell proliferation rate; decreased LDH and ROS levels; and increased SOD activity. SalA also significantly attenuated endothelial senescence, inhibited cell apoptosis, reversed the increase of LC3 II/I ratio and NLRP3 accumulation. Furthermore, miR-204-5p was regulated by SalA. Importantly, miR-204-5p inhibitor had similar effect to that of SalA on H2O2-induced HUVECs. Our results indicated that SalA could alleviate H2O2-induced oxidative injury by downregulating miR-204-5p in HUVECs.

Associations between specific volatile organic chemical exposures and cardiovascular disease risks: insights from NHANES

IntroductionAn increasing body of research has demonstrated a correlation between pollutants from the environment and the development of cardiovascular diseases (CVD). However, the impact of volatile organic chemicals (VOC) on CVD remains unknown and needs further investigation.ObjectivesThis study assessed whether exposure to VOC was associated with CVD in the general population.MethodsA cross-sectional analysis was conducted utilizing data from five survey cycles (2005–2006, 2011–2012, 2013–2014, 2015–2016, and 2017–2018) of the National Health and Nutrition Examination Survey (NHANES) program. We analyzed the association between urinary VOC metabolites (VOCs) and participants by multiple logistic regression models, further Bayesian Kernel Machine Regression (BKMR) models and Weighted Quantile Sum (WQS) regression were performed for mixture exposure analysis.ResultsTotal VOCs were found to be positively linked with CVD in multivariable-adjusted models (p for trend = 0.025), independent of established CVD risk variables, such as hypertension, diabetes, drinking and smoking, and total cholesterol levels. Compared with the reference quartile of total VOCs levels, the multivariable-adjusted odds ratios in increasing quartiles were 1.01 [95% confidence interval (CI): 0.78–1.31], 1.26 (95% CI: 1.05–1.21) and 1.75 (95% CI: 1.36–1.64) for total CVD. Similar positive associations were found when considering individual VOCs, including AAMA, CEMA, CYMA, 2HPMA, 3HPMA, IPM3 and MHBMA3 (acrolein, acrylamide, acrylonitrile, propylene oxide, isoprene, and 1,3-butadiene). In BKMR analysis, the overall effect of a mixture is significantly related to VOCs when all chemicals reach or exceed the 75th percentile. Moreover, in the WQS models, the most influential VOCs were found to be CEMA (40.30%), DHBMA (21.00%), and AMCC (19.70%).ConclusionThe results of our study indicated that VOC was all found to have a significant association with CVD when comparing results from different models. These findings hold significant potential for public health implications and offer valuable insights for future research directions.

#805 Successful application of DALI for extracorporeal hemocorrection in a patient with LDL cholesterol serum levels (case study)

Abstract Background and Aims Plasma lipoidosis type 4 (PLD4) is a rare hereditary disease characterized by disorders of fat metabolism in the body. PLD4 occurs rare in the general population. The exact frequency of occurrence is unknown, as it depends on hereditary factors in a particular population. The relevance of the disease lies in its rarity and potential association with various complications. Patients with PLD4 have decreased levels of low-density cholesterol (LDL) and increased levels of triglycerides in the blood, which can lead to the development of atherosclerosis and other cardiovascular diseases. Plasma lipoidosis type 4 requires further researches for better understanding of its epidemiology, mechanisms of development and possible treatment strategies. In this case, we describe the case of a patient with type 4 plasmatic lipoidosis who was treated with the DALI (Direct Adsorption of Lipoproteins) technique. Anticoagulation is initiated with heparin and maintained by ACT. This technique is accompanied by decreasing the level of LDL and Lp (a) without decreasing the level of HDL and fibrinogen. The pore sizes of the polyacrylamide bed are small enough to avoid the removal of red blood cells and platelets. Activation of leukocytes and complement is minimal and clinically insignificant. Depending on the initial level of lipidemia during this procedure, it is possible to select the appropriate adsorber (DALI-500, -750, -1000). Methods of extracorporeal correction of lipid metabolism disorders should be widely introduced into healthcare practice. It should be noted that during DALI apheresis, the fibrinogen level does not decrease so sharply and is not accompanied by changes in erythrocyte aggregation. (Richter W. O., 2003). Aim of study The purpose of our study was to evaluate the effectiveness of using DALI (Direct Adsorption of Lipoproteins) in a patient with type 4 plasmatic lipoidosis. Method Patient N., 67 years old, diagnosed with IHD. Angina pectoris FC 2. Plasma lipoidosis type 4, hyperbetalipoproteinemia by autosomal dominant type of inheritance. Cysts of both kidneys. In 1997, diagnosed with: plasma lipoidosis type 4, hyperbetalipoproteinemia by an autosomal dominant type of inheritance. The plasmapheresis sessions were recommended against the increased lipid metabolism indexes. The patient regularly receives antilipidemic therapy and plasmapheresis sessions up to 2 times a year. The patient is admitted with complaints of fatigue and general weakness. According to the patient's ambulatory card, discharge summaries: CREA - 147 µmol/l, UREA – 6.3 mmol/l. GFR – 34 ml/min/1.73 m2. Total bilirubin - 9 µmol/l, direct bilirubin - 3 µmol/l. Considering the severity of the condition and the activity of the main diagnosis, a procedure with the DALI technique was started. During the hospitalization period, 3 procedures were performed, the whole of them were tolerated satisfactorily. The general condition is of moderate severity. Consciousness is clear. Hemodynamics is stable. Urination is free and painless. Diuresis is adequate. Results Hemodynamics: when connected - blood pressure – 120/82 mm Hg, heart rate – 61 beats/min. When disconnected, the patient's condition is the same, hemodynamics - blood pressure – 119/59 mm Hg, heart rate – 65 beats / min. Conclusion The usage of the apheresis method with the DALI system can effectively reduce the level of low-density lipoprotein (LDL) and Lp (a), while maintaining the content of high-density lipoprotein (HDL) and fibrinogen at a constant level. This reduction in LDL concentrations has the potential to reduce patients' risk of developing cardiovascular disease and the mortality from it.

#3063 MRI assessment of skin and muscle sodium (23Na) and fluid volume in haemodialysis patients

Abstract Background and Aims Haemodialysis (HD) is life sustaining for patients with end-stage kidney disease (ESKD). In healthy people, sodium balance is regulated by the kidneys; in ESKD this is achieved by sodium removal during HD. Recent evidence suggests non-osmotically stored sodium in the muscle and/or skin may be a critical factor impacting the development of hypertension and cardiovascular disease (CVD). Sodium (23Na) MRI allows skin and muscle sodium storage assessment and may provide a valuable tool in evaluating sodium storage in dialysis patients. Here, 23Na MRI is used to measure muscle and skin tissue sodium concentration (TSC) in HD participants. HD participants are scanned before and after a single haemodialysis session using 23Na MRI as well as 1H T2 relaxometry to study changes in fluid status. Method Data were collected on HD patients who underwent a pre-HD 23Na MRI calf scan, then had their usual dialysis session with a dialysate sodium of 137 mmol/L, followed by a repeat post-HD 23Na MRI scan. Patient dialysis vintage, residual renal function, and ultrafiltration volume, and blood measures pre- and post-HD were collected. 1H scans were acquired for localisation and muscle segmentation (mDIXON) along with T1 and T2 mapping. 23Na images were acquired for (TSC) quantification. Reference bottles (10, 20, 30 and 40 mmol/L NaCl) were placed above the leg to calibrate TSC muscle and skin maps. Regions-of-interest (ROIs) of each muscle group and the skin were manually segmented on mDIXON scans. In each muscle group the voxel-wise mode (to avoid influence of signals from vessels) of TSC and T2 was estimated. A paired-sample t-test was performed between metrics pre-HD and post-HD. Absolute measures of ΔTSC and ΔT2 were correlated with clinical measures. Results Ten people receiving HD were recruited (age 55-73 yrs, 5 M:5F). Figure 1 shows TSC maps of the HD patients pre-HD and post-HD, with a significant reduction (p &amp;lt; 0.05) in TSC in the extensor, peroneus and gastrocnemius muscles post-HD but skin sodium showed no detectable change. Post-HD TSC significantly positively correlated with post-HD Systolic Blood Pressure (SBP) (P &amp;lt; 0.004) but not with plasma sodium. 1H T2-maps (Fig. 2A) show a significant reduction (p &amp;lt; 0.01) in muscle T2 post-HD compared to pre-HD all muscle groups (Fig. 2B). There were no significant correlations between T2 and 23Na measures, or T2 and clinical measures. There was no significant detectable change in 1H T1. Conclusion Post-HD TSC values are consistent with published data from patients dialysed against a dialysate sodium of 137 mmol/L, and shows a significant correlation of post-HD TSC with post-HD SBP. 1H muscle T2 reduced post-HD, consistent with published data, as patients change from a pre-HD hypervolemia state closer to a post-HD to euvolemia state after fluid removal. There was no correlation of absolute or ΔTSC and 1H T2 and ΔT2 values, suggesting different mechanisms for equilibrium conditions of water and sodium ion concentrations. Future studies will study the effect of dialysate sodium on muscle TSC and mechanistic links to CVD, and include the use of a dedicated skin coil to study skin sodium alongside bioimpedance fluid measures.

Dose-response relationship between physical activity and the morbidity and mortality of cardiovascular disease among individuals with diabetes: A meta-analysis of prospective cohort studies.

Diabetes, a chronic condition affecting various organs, is frequently associated with abnormal lipid metabolism, notably increased cholesterol and triglyceride levels. These lipid abnormalities are closely linked to the development and advancement of cardiovascular disease (CVD). Although regular physical activity (PA) has consistently shown benefits in reducing CVD risk in the general population, its precise influence on CVD risk among diabetic patients remains uncertain, particularly regarding dose-response relationships. This study aimed to summarize the evidence from prospective studies on the association between PA and CVD morbidity and mortality in individuals with diabetes, and to explore the optimal levels for public health recommendation. We systematically reviewed prospective cohort studies in PubMed, EMBASE, and Web of Science up to December 2022, with inclusion criteria specifying the studies published in English and included adult participants diagnosed with diabetes. A random-effects model was used to pool the relative risk (RR) with the corresponding 95% confidence interval (CI) comparing the highest with the lowest PA categories in each study for qualitative evaluation. In addition, linear and spline regression analyses were used to estimate dose-response associations. The meta-analysis included 12 prospective cohort studies, involving a total of 109,820 participants with diabetes. The combined results revealed that higher levels of PA were associated with a reduced risk of CVD. The RR of CVD for the highest compared with the lowest PA category was 0.62 (95% CI, 0.51-0.73). In addition, there were four studies describing leisure-time physical activity (LTPA) and the pooled RR was 0.68 (95% CI, 0.52-0.83) for the highest versus the lowest activity. The linear regression model revealed that each 10 MET-h/week of incrementally higher PA was associated with a 19.0% (95% CI, 11.6%-25.7%) and a 6.9% (95% CI, 4.5%-9.3%) reduction in CVD morbidity and mortality. Additionally, spline regression curves showed nonlinear relationships between PA levels and the risk of CVD and CVD mortality (both P-nonlinearity <0.001), with a limited reduction in CVD risk and some further reduction in CVD mortality above 20 MET-h per week of PA levels. For patients with diabetes, especially type 2 diabetes, there was a dose-response relationship between increased PA and reduced risk of CVD morbidity and mortality. The observed PA threshold is consistent with the recommended level for the general population. Gradually moving from inactivity to a guideline-recommended PA level could therefore significantly reduce the burden of CVD in patients with diabetes.

#1910 Echocardiographic findings in patients with advanced diabetic kidney disease and obstructive sleep apnea

Abstract Background and Aims Obstructive sleep apnea (OSA) is associated with accelerated development of cardiovascular disease. The prevalence of OSA is increased in both type 2 diabetes (DM2) and in chronic kidney disease, and is very high in patients with diabetic kidney disease. However, the contribution of OSA to alterations in cardiac structure and function in diabetic kidney disease remains unknown. We therefore compared cardiac structure and function in diabetic kidney disease patients with or without OSA. Method In a cross-sectional study, 120 patients with DM2, a urine albumin-creatinine ratio (UACR) &amp;gt; 30 mg/g and an estimated glomerular filtration rate (eGFR) &amp;lt; 60 ml/min/1.73 m2 were tested for OSA. OSA severity was quantified by the apnea-hypopnea-index (AHI). Patients without OSA (AHI &amp;lt; 5 events/hour) were compared to patients with moderate (AHI 15-29 events/hour) or severe OSA (AHI ≥30 events/hour). Transthoracic echocardiography was conducted in all patients to evaluate cardiac structure and function. Linear regression analyses were used to assess the associations between OSA and echocardiographic parameters. Results AHI-data were available for 114 patients; 43 had no OSA, 33 had mild OSA and 38 had moderate-severe OSA. A total of 74 patients (73% men), 39 with no OSA and 35 with moderate-severe OSA, had complete data for both echocardiography and OSA. Their mean age was 71.5 ± 9.4 years, mean eGFR was 32.2 ± 12.3 mL/min/1.73 m2 and the median UACR of 533 (192–1707) mg/g. Age, smoking status, diabetes duration, eGFR, blood pressure, antihypertensive medicine, chronic obstructive pulmonary disease and atrial fibrillation were not significantly different between patients with and without OSA. Patients with moderate-severe OSA had significantly larger left atrial volume index (LAVI) (39.0 ± 19.6 vs. 28.1 ± 10.5 mL/m2, P = 0.0035), left ventricular mass index (LVMI) (49.2 ± 12.0 vs. 41.8 ± 9.7, g/m2, P = 0.0043), and right ventricular diameter (34.3 ± 5.8 vs. 28.4 ± 4.4 mm, P &amp;lt; 0.0001) compared to those without OSA (Fig. 1). Global longitudinal strain (GLS) was significantly reduced in OSA patients (−14.9 ± 3.1 vs. −16.6 ± 2.8, P = 0.0196), while no difference was observed in LV ejection fraction (54.4 ± 8.1 vs. 56.5 ± 6.2, p = 0.21). The association between OSA and LAVI, LVMI, right ventricular diameter and GLS remained significant after adjustment for age, sex, eGFR and mean arterial pressure. Conclusion Moderate-severe OSA is independently associated with alterations in cardiac structure and function in patients with diabetic kidney disease and reduced renal function. OSA could be an independent contributor to the development of heart failure in patients with diabetic kidney disease.

#1841 Trimethylamine N-oxide (TMAO) induces the formation of endothelial extracellular vesicles

Abstract Background and Aims Endothelial dysfunction caused by the accumulation of uremic toxins is an important contributor to the development of cardiovascular disease in patients with chronic kidney disease (CKD). The uremic toxin trimethylamine n-oxide (TMAO) is associated with oxidative stress, vascular calcification, and inflammation, triggering the release of several proinflammatory molecules and Extracellular Vesicles (EVs). Clinical studies have shown that patients with CKD have high levels of circulating EVs, however, their role is still poorly understood. In this dysfunctional scenario, EVs can be used as damage biomarkers for CKD, as they carry information from their cells of origin. Here, we aim to elucidate the formation of EVs in endothelial cells exposed to TMAO. Method Human endothelial cells (EA.hy926, ATCC CRL-2922) were exposed for 24 h with TMAO at uremic concentrations (7.49 mg/L). EVs were isolated by differential ultracentrifugation. Protein concentration was analyzed by Pierce™ BCA Protein Assay Kit, and particle size and particle concentration were analyzed by NanoParticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), and Scanning Electron Microscopy (SEM). EVs were stained with calcein and their internalization in endothelial cells was analyzed with Fluorescence Confocal Microscopy. Results TMAO treatment at uremic concentration induced the formation of EVs with a size of 202.8 ± 3.1 nm (image 1B) and 1.09 × 109 ± 2.68 × 107 particles/mL and a total protein concentration of 88.57 µg/mL. The morphological features of EVs are shown in images 1C-1F. TMAO-induced EVs were incorporated by endothelial cells, being dispersed in the cytoplasm or perinuclear regions (images 1G and end 1H). Conclusion TMAO was able to induce the formation of EVs in endothelial cells, with characteristics morphological features. When compared to control EVs (image 1A), TMAO-EVs have a more heterogeneous size, which indicate a change in the size pattern, and thus the nature of the EVs induced by TMAO. TMAO-EVs were able to be internalized by human endothelial cells. This uptake can be closely related to the effects of EVs in endothelial cells, but more experiments need to be performed. Taken together, these data could contribute to understanding how the formation and uptake of TMAO-EVs by the endothelium occurs, relating their effects to the cardiovascular complications of CKD.

Effectiveness of structured exercise program on insulin resistance and quality of life in type 2 diabetes mellitus-A randomized controlled trial.

Impaired glucose control & Insulin resistance are reported to be risk factors for the development of cardiovascular diseases. To find the effects of a structured exercise program on insulin resistance, glycaemic control, functional capacity, and quality of life in patients with Type 2 diabetes mellitus. Randomized, controlled trial. Diabetic Foot Clinic, Department of Physiotherapy & Department of General Medicine, Kasturba Hospital in Manipal, Karnataka, India. 160 participants aged between 30-65 years with Type 2 diabetes mellitus. A set of structured exercise programs (aerobic, resistance, and combined) along with the standard hospital care was performed 3-5 times weekly for 12 weeks. Fasting Insulin Level, Homa-IR, Six-minute walk test (6MWT), and WHOQOL-BREF questionnaire at baseline and 12th week. Body composition analysis, Fasting Blood Sugar, Postprandial Blood Sugar, Glycated Haemoglobin (HbA1c), and GPAQ questionnaire at baseline and 12th week. Significant differences have been observed in Homeostasis model assessment for insulin resistance (Homa-IR) (F (1, 144) = 89.29, p < 0.001); Fasting insulin (FI) (F (1, 144) = 129.10, p < 0.001); Fasting blood sugar (FBS) (F (1, 144) = 12.193, p< 0.001); Post prandial blood sugar (PPBS) (F (1, 144) = 53.015, p< 0.001); glycated haemoglobin (HbA1c) (F (1, 144) = 80.050, p < 0.001); WHOQOL-Physical health (F (1, 144) = 20.008, p< 0.001), Psychological (F (1, 144) = 77.984, p< 0.001), Social relationship (F (1, 144) = 44.866, p< 0.001); Environmental (F (1, 144) = 69.974, p< 0.001); Six minute walk test (6MWT) (F (1, 144) = 84.135, p< 0.001) in the study group when compared with the control group from baseline to 12th week. The study reveals that a 12-week structured exercise training program effectively reduces insulin resistance, improves quality of life, enhances functional capacity, and improves glycaemic control in type 2 diabetes mellitus.

Association of triglyceride glucose index and triglyceride glucose-body mass index with sudden cardiac arrest in the general population

BackgroundInsulin resistance (IR) significantly contributes to cardiovascular disease (CVD) development. Triglyceride glucose (TyG) index and triglyceride glucose-body mass index (TyG-BMI) are recognised as convenient proxies for IR. However, their relationship with sudden cardiac arrest (SCA) remains unclear.MethodsThis prospective cohort analysis included 355,242 UK Biobank participants with available TyG index and TyG-BMI data and no history of CVD. Cox proportional risk models assessed the association between the TyG index, TyG-BMI and SCA risk. Additionally, Accelerated Failure Time (AFT) models were employed to investigate the timing of SCA onset. The impact of dynamic increases in TyG index and TyG-BMI levels on SCA risk was examined using restricted cubic spline.ResultsOver a median follow-up period of 165.4 months (interquartile range 156.5–174 months), 1,622 cases of SCA were recorded. Multivariate Cox regression analysis revealed a 9% increase in SCA risk per standard deviation increase in TyG index (adjusted hazard ratio (aHR) = 1.09, 95% confidence interval (CI) 1.04–1.15) and an 14% increase per standard deviation increase in TyG-BMI (aHR 1.14, 95% CI 1.09–1.2). AFT models indicated earlier median times to SCA occurrence with increasing quintiles of TyG index and TyG-BMI compared to the lowest quintile (P for trend < 0.05). SCA risk was linearly (P = 0.54) and non-linearly (P = 0.007) correlated with gradual increases in TyG index and TyG-BMI levels, respectively. Sex-stratified analyses showed stronger associations in women.ConclusionsHigher TyG index and TyG-BMI levels are associated with an increased SCA risk and earlier onset, particularly in women.

Assessing Glycosylated Hemoglobin Thresholds for Development of Cardiovascular Disease by Racial and Ethnic Groups.

Diabetes is the strongest risk factor for cardiovascular disease, and although glycosylated hemoglobin (HbA1c) levels are known to vary by race, no racial and ethnic-specific diagnostic thresholds exist for diabetes in prediction of cardiovascular disease events. The purpose of this study is to determine whether HbA1c thresholds for predicting major adverse cardiovascular events (MACEs) differ among racial and ethnic groups. This is a retrospective cohort study of Kaiser Permanente Northern California adult members (n=309 636) with no history of cardiovascular disease who had HbA1c values and race and ethnicity data available between 2014 and 2019. Multivariable logistic regression was used to evaluate the odds of MACEs by the following racial and ethnic groups: Filipino, South Asian, East Asian, Black, White, and Hispanic. A Youden index was used to calculate HbA1c thresholds for MACE prediction by each racial and ethnic group, stratified by sex. Among studied racial and ethnic groups, South Asian race was associated with the greatest odds of MACEs (1.641 [95% CI, 1.456-1.843]; P<0.0001). HbA1c was a positive predictor for MACEs, with an odds ratio of 1.024 (95% CI, 1.022-1.025) for each 0.1% increment increase in HbA1c. HbA1c values varied between 6.0% and 7.6% in MACE prediction by race and ethnicity and sex. White individuals, South Asian individuals, East Asian women, and Black men had HbA1c thresholds for MACE prediction in the prediabetic range, between 6.0% and 6.2%. Black women, Hispanic men, and East Asian men had HbA1c thresholds of 6.2% to 6.6%, less than the typical threshold of 7.0% that is used as a treatment goal. Findings suggest that the use of race and ethnic- and sex-specific HbA1c thresholds may need to be considered in treatment goals and cardiovascular disease risk estimation.

Роль ацетилхолиновой системы и ее компонентов в формировании постковидных синдромов (обзор)

According to the latest data, COVID-19 is classified as a respiratory virus. However, it has been proven to cause a significant multi-organ dysfunction. Despite the increase in the effectiveness of treatment tactics, a post-COVID-19 symptom complex has been observed in patients after recovery, manifesting itself as cephalalgia, brain fog, high fever, muscle weakness and a decrease (or increase) in arterial pressure. To describe this condition, a clinical characteristic has been proposed: post-acute COVID-19 syndrome (PACS). Approximately 57 % of patients hospitalized with COVID-19 have symptoms of PACS even one year after initial infection with COVID-19. This pathological condition is being actively studied, but the question of the causes of PACS and its development mechanisms remains open. One of the possible reasons behind this symptomatology, in our opinion, is a disorder of the body’s acetylcholine system and its components. The acetylcholine system plays an integral role in various physiological and pathophysiological processes, such as the regulation of the muscular system, immune and inflammatory reactions, wound healing, as well as the development of cardiovascular, respiratory and other diseases. A key way of translating acetylcholine signals in the body is through the use of neurotransmission via a chemical synapse. Based on current literature data, there is reason to believe that viral invasion can significantly change the functional activity of the vagus nerve by disrupting signal transmission in a synapse. We believe that the hyperimmune response caused by COVID-19 triggers a chain of pathological mechanisms that are associated with disrupted nitric oxide production and imbalance in acetylcholine and its receptors. An understanding of these processes may open up prospects for improving the effectiveness of treatment and rehabilitation of patients with COVID-19.

ADVERSE EVENTS ASSOCIATED WITH GLP1–RECEPTOR AGONISTS TREATMENT IN DIABETIC PATIENTS WITH HIGH CARDIOVASCULAR RISK: A META–ANALYSIS

Abstract Background GLP1–receptor agonists (GLP1–RA) have been associated with a reduction of cardiovascular (CV) outcomes in diabetic patients with high cardiovascular risk. However, these drugs have some adverse effects. The aim of this study was to assess the relative risk (RR) of adverse effects in patients with a high risk of developing CV disease treated with GLP1–agonists. Methods we considered randomized controlled trials (RCTs) aimed to assess the cardiovascular effects of GLP1–RA in diabetic patients with high CV risk. The following outcomes were explored: pancreatitis, severe hypoglycemia, renal and urinary serious adverse events (SAE), gastrointestinal SAE and AE, pancreatic cancer, and neoplasms. Results 8 RCTs, enrolling 60008 patients, were included in the analysis. There was no difference between GLP1–RA and placebo in the risk of pancreatitis (RR 0.99; 95% CI 0.73–1.35; p=0.972), severe hypoglycemia (0.93; 95% CI 0.76–1.15; p=0.501), renal and urinary SAE (0.94; 95% CI 0.82–1.07; p=0.339), pancreatic cancer (RR 0.98; 95% CI 0.56–1.70; p=0.936) and neoplasms (RR 1.02; 95% CI 0.95–1.09; p=0.547) (Fig 1 A e B). Conversely, GLP1–agonist treatment was associated with an increased risk of gastrointestinal AE (RR 1.95; 95% CI 1.23–3.06; p=0.004) (Fig 2). However, when gastrointestinal SAE were considered, GLP1–agonists demonstrated similar risk compared to placebo (RR 1.09; 95% CI 0.92–1.28; p= 0.318) (Fig 2). Conclusion in diabetic patients with high cardiovascular risk, the treatment with GLP1–RA has been associated with an increased risk of gastrointestinal AE. No difference in severe gastrointestinal AE has been associated with GLP1–RA.

Synergistic integration of deep learning with protein docking in cardiovascular disease treatment strategies.

This research delves into the exploration of the potential of tocopherol-based nanoemulsion as a therapeutic agent for cardiovascular diseases (CVD) through an in-depth molecular docking analysis. The study focuses on elucidating the molecular interactions between tocopherol and seven key proteins (1O8a, 4YAY, 4DLI, 1HW9, 2YCW, 1BO9 and 1CX2) that play pivotal roles in CVD development. Through rigorous in silico docking investigations, assessment was conducted on the binding affinities, inhibitory potentials and interaction patterns of tocopherol with these target proteins. The findings revealed significant interactions, particularly with 4YAY, displaying a robust binding energy of -6.39 kcal/mol and a promising Ki value of 20.84 μM. Notable interactions were also observed with 1HW9, 4DLI, 2YCW and 1CX2, further indicating tocopherol's potential therapeutic relevance. In contrast, no interaction was observed with 1BO9. Furthermore, an examination of the common residues of 4YAY bound to tocopherol was carried out, highlighting key intermolecular hydrophobic bonds that contribute to the interaction's stability. Tocopherol complies with pharmacokinetics (Lipinski's and Veber's) rules for oral bioavailability and proves safety non-toxic and non-carcinogenic. Thus, deep learning-based protein language models ESM1-b and ProtT5 were leveraged for input encodings to predict interaction sites between the 4YAY protein and tocopherol. Hence, highly accurate predictions of these critical protein-ligand interactions were achieved. This study not only advances theunderstanding of these interactions but also highlights deep learning's immense potential in molecular biology and drug discovery. It underscores tocopherol's promise as a cardiovascular disease management candidate, shedding light on its molecular interactions and compatibility with biomolecule-like characteristics.