Pathophysiology Of Atherosclerosis Research Articles

Proteomics analysis of coronary atherosclerotic heart disease with different Traditional Chinese Medicine syndrome types before and after percutaneous coronary intervention.

To investigate the underlying protein molecular mechanisms of "Qi stagnation and blood stasis syndrome" (QS) and "Qi deficiency and blood stasis syndrome" (QD), as two subtypes of coronary artery disease (CAD) in Traditional Chinese Medicine (TCM), following percutaneous coronary intervention (PCI). In this study, a total of 227 CAD patients with QS and 211 CAD patients with QD were enrolled; all participants underwent PCI. Label-free quantification proteomics were employed to analyze the changes in serum in two subtypes of CAD patients before and 6 months after PCI, aiming to elucidate the intervention mechanism of PCI in treating CAD characterized by two different TCM syndromes. Biochemical analysis revealed significant changes in tumor necrosis factor-α, high density lipoprotein cholesterol, blood stasis clinical symptoms observation, and Gensini levels in both patient groups post-PCI; Proteomic analysis identified 79 and 95 differentially expressed proteins in the QS and QD patient groups, respectively, compared to their control groups. complement C8 alpha chain, complement factor H, apolipoprotein H, apolipoprotein B, plasminogen, carbonic anhydrase 2, and complement factor I were altered in both comparison groups. Furthermore, enrichment analysis demonstrated that cell adhesion and connectivity-related processes underwent changes in QS patients post-PCI, whereas lipid metabolism-related pathways, including the peroxisome proliferator-activated receptor signaling pathway and extracellular matrix receptor interaction, underwent changes in the QD group. The protein-protein interaction network analysis further enriched 52 node proteins, including apolipoprotein B, lipoprotein (a), complement C5, apolipoprotein A4, complement C8 alpha chain, complement C8 beta chain, complement C8 gamma chain, apolipoprotein H, apolipoprotein A-Ⅱ, albumin, complement C4-B, apolipoprotein C3, among others. The functional network of these proteins is posited to contribute to the pathophysiology of CAD characterized by TCM syndromes. The current quantitative proteomic study has preliminarily identified biomarkers of CAD in different TCM subtypes treated with PCI, potentially laying the groundwork for understanding the protein profiles associated with the treatment of various TCM subtypes of CAD.

Evaluation of systemic immune-inflammation index for predicting severity of lower extremity arterial disease.

Predictive value of systemic immune-inflammation index (SII) has been shown in clinical outcomes and complexity of coronary artery disease, acute coronary syndrome, and heart failure. We sight to evaluate value of SII in patients with lower extremity arterial disease (LEAD). A total of 271 patients diagnosed with LEAD were included to our study. Blood samples of the patients were collected and analyzed for biochemical variables and complete blood count parameters. SII value of each patient was calculated. The complexity of atherosclerotic disease was classified according to Trans-Atlantic Inter-Society Consensus (TASC II) classification. Patients with TASC C-D were older than patients in TASC A-B group (63.06 ± 9.24years and 60.85 ± 8.75years, respectively). Other co-morbidities were comparable in both groups. Hemoglobin level and lymphocyte count were significantly lower, neutrophil, platelet counts, and SII values were significantly higher in patients with TASC C-D disease compared to that of patients with TASC A-B disease. SII showed significant correlation with the severity of LEAD (r = 0.363, p < .001). SII value of 664.24 predicted TASC C-D disease with a sensitivity and specificity of 60.8% and 73.3%, respectively. Results of multivariate logistic regression analysis showed that SII had higher odds ratio compared to platelet, neutrophil, and lymphocyte counts. Higher SII may indicate probability of more complex LEAD. This relationship seems plausible in terms of similar pathophysiology of coronary artery disease and peripheral artery disease.

Sexual dimorphism in atherosclerotic plaques of aged Ldlr−/− mice

BackgroundAtherosclerosis, the main underlying pathology of cardiovascular disease, is a chronic inflammatory disease characterized by lipid accumulation and immune cell responses in the vascular wall, resulting in plaque formation. It is well-known that atherosclerosis prevalence and manifestation vary by sex. However, sexual dimorphism in the immune landscape of atherosclerotic plaques has up to date not been studied at high-resolution. In this study, we investigated sex-specific differences in atherosclerosis development and the immunological landscape of aortas at single-cell level in aged Ldlr−/− mice.MethodsWe compared plaque morphology between aged male and female chow diet-fed Ldlr−/− mice (22 months old) with histological analysis. Using single-cell RNA-sequencing and flow cytometry on CD45+ immune cells from aortas of aged Ldlr−/− mice, we explored the immune landscape in the atherosclerotic environment in males and females.ResultsWe show that plaque volume is comparable in aged male and female mice, and that plaques in aged female mice contain more collagen and cholesterol crystals, but less necrotic core and macrophage content compared to males. We reveal increased immune cell infiltration in female aortas and found that expression of pro-atherogenic markers and inflammatory signaling pathways was enriched in plaque immune cells of female mice. Particularly, female aortas show enhanced activation of B cells (Egr1, Cd83, Cd180), including age-associated B cells, in addition to an increased M1/M2 macrophage ratio, where Il1b+ M1-like macrophages display a more pro-inflammatory phenotype (Nlrp3, Cxcl2, Mmp9) compared to males. In contrast, increased numbers of age-associated Gzmk+CD8+ T cells, dendritic cells, and Trem2+ macrophages were observed in male aortas.ConclusionsAltogether, our findings highlight that sex is a variable that contributes to immunological differences in the atherosclerotic plaque environment in mice and provide valuable insights for further preclinical studies into the impact of sex on the pathophysiology of atherosclerosis.

Coronary Volume-to-Myocardial Mass Ratio Giving Additional Insights in Coronary Artery Disease Pathophysiology.

Coronary Volume-to-Myocardial Mass Ratio Giving Additional Insights in Coronary Artery Disease Pathophysiology.

ApoB100 and Atherosclerosis: What's New in the 21st Century?

ApoB is the main protein of triglyceride-rich lipoproteins and is further divided into ApoB48 in the intestine and ApoB100 in the liver. Very low-density lipoprotein (VLDL) is produced by the liver, contains ApoB100, and is metabolized into its remnants, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL). ApoB100 has been suggested to play a crucial role in the formation of the atherogenic plaque. Apart from being a biomarker of atherosclerosis, ApoB100 seems to be implicated in the inflammatory process of atherosclerosis per se. In this review, we will focus on the structure, the metabolism, and the function of ApoB100, as well as its role as a predictor biomarker of cardiovascular risk. Moreover, we will elaborate upon the molecular mechanisms regarding the pathophysiology of atherosclerosis, and we will discuss the disorders associated with the APOB gene mutations, and the potential role of various drugs as therapeutic targets.

Analysis of the correlation between pericoronary adipose tissue mean attenuation and plaque characteristics and stenosis in coronary CT angiography.

Coronary artery disease (CAD) is a predominant cardiovascular disorder, particularly in the aging population. The pathophysiology of atherosclerosis involves lipid deposition and inflammation of the arterial walls. With coronary computed tomography angiography offering insights into coronary anatomy and pathology, parameters such as pericoronary adipose tissue mean attenuation (PCATMA) have gained significance in the understanding of cardiac diseases. A retrospective study encompassing 130 patients with CAD was conducted to analyze 269 observation points. Coronary CT Angiography was employed, with specific attention paid to the measurement of PCATMA and a qualitative and quantitative assessment of plaques. Statistical analyses were performed using Statistical Package for the Social Sciences software (version 27.0), independent samples t test, one-way ANOVA, and multivariate logistic regression analysis. There was a notable correlation between PCATMA expression and severity of coronary artery calcification and stenosis. Patients with higher coronary artery calcification scores and more pronounced stenosis had elevated PCATMA values. Variances in PCATMA based on plaque type and degree of stenosis were significant (P < .05). Multivariate logistic regression revealed that plaque presence, type, and degree of stenosis were independent determinants of PCATMA expression. PCATMA expression is closely associated with CAD progression. As plaque calcification and arterial stenosis increase, there is a concomitant increase in PCATMA expression, potentially serving as a pivotal prognostic indicator.

Fatal attractions that trigger inflammation and drive atherosclerotic disease.

Atherosclerosis is the salient, underlying cause of cardiovascular diseases, such as arrhythmia, coronary artery disease, cardiomyopathy, pulmonary embolism and myocardial infarction. In recent years, atherosclerosis pathophysiology has evolved from a lipid-based to an inflammation-centric ideology. This narrative review is comprised of review and original articles that were found through the PubMed search engine. The following search terms or amalgamation of terms were used: "cardiovascular disease," "atherosclerosis," "inflammation," "GRP78," "Hsp60," "oxidative low-density lipoproteins," "aldehyde dehydrogenase," "β2-glycoprotein," "lipoprotein lipase A," "human cytomegalovirus." "SARS-CoV-2," "chlamydia pneumonia," "autophagy," "thrombosis" and "therapeutics." Emerging evidence supports the concept that atherosclerosis is associated with the interaction between cell surface expression of stress response chaperones, including GRP78 and Hsp60, and their respective autoantibodies. Moreover, various other autoantigens and their autoantibodies have displayed a compelling connection with the development of atherosclerosis, including oxidative low-density lipoproteins, aldehyde dehydrogenase, β2-glycoprotein and lipoprotein lipase A. Atherosclerosis progression is also concurrent with viral and bacterial activators of various diseases. This narrative review will focus on the contributions of human cytomegalovirus as well as SARS-CoV-2 and chlamydia pneumonia in atherosclerosis development. Notably, the interaction of an autoantigen with their respective autoantibodies or the presence of a foreign antigen can enhance inflammation development, which leads to atherosclerotic lesion progression. We will highlight and discuss the complex role of the interaction between autoantigens and autoantibodies, and the presence of foreign antigens in the development of atherosclerotic lesions in relationship to pro-inflammatory responses.

Wnt Signaling in Atherosclerosis: Mechanisms to Therapeutic Implications.

Atherosclerosis is a vascular disease in which inflammation plays a pivotal role. Receptor-mediated signaling pathways regulate vascular inflammation and the pathophysiology of atherosclerosis. Emerging evidence has revealed the role of the Wnt pathway in atherosclerosis progression. The Wnt pathway influences almost all stages of atherosclerosis progression, including endothelial dysfunction, monocyte infiltration, smooth muscle cell proliferation and migration, and plaque formation. Targeting the Wnt pathway to treat atherosclerosis represents a promising therapeutic approach that remains understudied. Blocking Wnt signaling utilizing small molecule inhibitors, recombinant proteins, and/or neutralizing antibodies ameliorates atherosclerosis in preclinical models. The Wnt pathway can be potentially manipulated through targeting Wnt ligands, receptors, co-receptors, and downstream signaling molecules. However, there are challenges associated with developing a real world therapeutic compound that targets the Wnt pathway. This review focuses on the role of Wnt signaling in atherosclerosis development, and the rationale for targeting this pathway for the treatment of atherosclerosis.

Diet-Induced Severe Hyperhomocysteinemia Promotes Atherosclerosis Progression and Dysregulates the Plasma Metabolome in Apolipoprotein-E-Deficient Mice.

Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several factors regulate homocysteine levels, including the activity of several enzymes and adequate levels of their coenzymes, including pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin (vitamin B12). To better understand the biological influence of HHcy on the development and progression of atherosclerosis, apolipoprotein-E-deficient (apoE-/- mice), a model for human atherosclerosis, were fed a hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a control diet (CD). After eight weeks, the plasma, aorta, and liver were collected to quantify methylation metabolites, while plasma was also used for a broad targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe accumulation of plasma and hepatic homocysteine and an increased BCA plaque burden were observed, thus confirming the atherogenic effect of the HHD. Moreover, a decreased methylation capacity in the plasma and aorta, indirectly assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) was detected in HHD mice together with a 172-fold increase in aortic cystathionine levels, indicating increased flux through the transsulfuration pathway. Betaine and its metabolic precursor, choline, were significantly decreased in the livers of HHD mice versus CD mice. Widespread changes in the plasma metabolome of HHD mice versus CD animals were detected, including alterations in acylcarnitines, amino acids, bile acids, ceramides, sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional lipid metabolism. This study confirms the relevance of severe HHcy in the progression of vascular plaque and suggests novel metabolic pathways implicated in the pathophysiology of atherosclerosis.

Neutrophil gelatinase-associated lipocalin (NGAL) circulating levels are related to LDL Myocardial infarction

Background: Low-density lipoprotein receptors (LDL-R) in hepatocytes are degraded by the enzyme Neiutrophophil gielatinase-associated lipocalin (NGAL) A brand-new target for lipid-lowering treatment is Neiutrophophil gielatinase-associated lipocalin (NGAL) inhibition. Three subsets of monocytes, which play a critical role in the pathophysiology of atherosclerosis, are known. Objectives: The aim of this study was to examine whether circulating levels of Neiutrophophil gielatinase-associated lipocalin (NGAL) are associated with LDL liped subsets. Materials and Methods: We included 70 patients with coronary artery disease. Neiutrophophil gielatinase-associated lipocalin (NGAL) levels were measured and LDL liped and 30 control health. Results: Eighty percent of the patients were men, with a mean age between 40 and 70. Patients increese displayed greater Neiutrophophil gielatinase-associated lipocalin (NGAL) -levels compared to the 30 male control group. Neiutrophophil gielatinase-associated lipocalin (NGAL) levels in the blood were associated with CM treatment in patients, whereas NCM had the opposite effect. Patients whose levels of Neiutrophophil gielatinase-associated lipocalin (NGAL) were greater than the median displayed a significantly higher. Conclusions: Endurance training, resistance training, and combined training improve cardiovascular risk factors associated with obesity. These types of training methods also improve cardiovascular risk factors in school obese children. Also, they can be used as effective exercise programs for these people. Therefore, EET, RET, and CET used in this study, especially EET, can be recommended as a non-medical way to improve the incidence of cardiovascular risk factors and obesity-related disorders in obese boys.

A comprehensive proteomic profiling of urinary exosomes and the identification of early non-invasive biomarker in patients with coronary artery disease

Urinary small extracellular vesicles or exosomes (uEVs) source could be an emerging trove of biomarkers in coronary artery disease (CAD). It is a chronic inflammatory disease having a long asymptomatic phase of fatty-fibrous development in arteries leading to angina, myocardial infarction, and death. Our study was aimed at identifying differential protein expression profiling of uEVs in CAD. We collected urine samples of CAD patients (n = 41) age 18–65 years and gender matched healthy controls (n = 41). We isolated uEVs using differential ultracentrifugation. Further, uEV samples were characterized by western blotting exosome markers (Flotillin, TSG, CD63, and CD9), nano tracking analysis, and transmission and scanning electron microscopy. A total of 508 proteins were identified by iTRAQ-based mass spectrometry. We observed protein expression levels of AZGP1, SEMG1/2, ORM1, IGL, SERPINA5, HSPG2, prosaposin, gelsolin, and CD59 were upregulated, and UMOD, KNG1, AMBP, prothrombin, and TF were downregulated. Protein-protein interactions, gene ontology and pathway analysis were performed to functionally annotate identified uEVs proteins. A novel uEVs differential protein signature is shown. On validating UMOD protein by ELISA in two clinically different CAD, stable-CAD patients had lower levels than healthy controls whereas recent myocardial infarction patients had lowest. Our findings suggest UMOD importance as early diagnostic biomarker. SignificanceCoronary artery disease is a chronic inflammatory disease caused by gradual deposition of cholesterol and fat along with other proteins to develop plaque inside arteries. This further leads to blockage of artery, heart attack and death. There are no identifiable early biomarkers to diagnose this. For the first time, we have identified the differentially expressed proteins isolated from non-invasive uEV of CAD patients compared to healthy controls by using MS Orbitrap and iTRAQ labelling of peptides. We have identified decreased levels of UMOD protein in CAD. These findings have been confirmed by ELISA. Furthermore, the levels of UMOD were observed as more highly decreased in recent myocardial infarction CAD patients, indicating the importance of this protein as an early diagnostic biomarker. Conclusively, our study represents a non-invasive urinary EVs trove of differentially expressed proteins in CAD. This will form a groundwork for understanding the pathophysiology of CAD and will help in future translational research utilizing uEVs.

HYPERURICEMIA AND ACUTE CORONARY SYNDROME, A LITERATURE REVIEW

Hyperuricemia is associated with numerous side effects, including cardiovascular diseases. Epidemiological studies, conducted recently, suggest that hyperuricemia has a significant association with acute coronary syndrome. Accumulated data also indicate that elevated uric acid in the serum has a role in the pathophysiology of atherosclerosis in the coronary arteries. This article summarizes the latest literature data regarding uric acid serum levels and acute coronary syndrome, and describes the mechanism of action of uric acid on the coronary arteries. Further studies are needed to show whether the decrease of uric acid serum levels leads to better outcomes in cardiovascular diseases.

Unraveling the role of galectin-3 in cardiac pathology and physiology.

Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging.

Elevated plasma pyruvate kinase M2 concentrations are associated with the clinical severity and prognosis of coronary artery disease.

Pyruvate kinase M2 (PKM2) was involved in the pathophysiology of atherosclerosis and coronary artery disease (CAD). We tested whether plasma PKM2 concentrations were correlated with clinical severity and major adverse cardiovascular events (MACEs) in CAD patients. A total of 2443 CAD patients and 238 controls were enrolled. The follow-up time was two years. Plasma PKM2 concentrations were detected by enzyme-linked immunosorbent assay (ELISA) kits (Cloud-Clone, Wuhan, China) using SpectraMax i3x Multi-Mode Microplate Reader (Molecular Devices, San Jose, USA). The predictors of acute coronary syndrome (ACS) were assessed by logistic regression analysis. The association between PKM2 concentration in different quartiles and MACEs was evaluated by Kaplan-Meier (KM) curves with log-rank test and Cox proportional hazard models. The predictive value of PKM2 and a cluster of conventional risk factors was determined by Receiver operating characteristic (ROC) curves. The net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) were utilized to evaluate the enhancement in risk prediction when PKM2 was added to a predictive model containing a cluster of conventional risk factors. In CAD patients, PKM2 concentration was the independent predictor of ACS (P < 0.001). Kaplan-Meier cumulative survival curves and Cox proportional hazards analyses revealed that patients with a higher PKM2 concentration had higher incidence of MACEs compared to those with a lower PKM2 concentration (P < 0.001). The addition of PKM2 to a cluster of conventional risk factors significantly increased its prognostic value of MACEs. Baseline plasma PKM2 concentrations predict the clinical severity and prognosis of CAD.

Cells in Atherosclerosis: Focus on Cellular Senescence from Basic Science to Clinical Practice.

Aging is a major risk factor of atherosclerosis through different complex pathways including replicative cellular senescence and age-related clonal hematopoiesis. In addition to aging, extracellular stress factors, such as mechanical and oxidative stress, can induce cellular senescence, defined as premature cellular senescence. Senescent cells can accumulate within atherosclerotic plaques over time and contribute to plaque instability. This review summarizes the role of cellular senescence in the complex pathophysiology of atherosclerosis and highlights the most important senotherapeutics tested in cardiovascular studies targeting senescence. Continued bench-to-bedside research in cellular senescence might allow the future implementation of new effective anti-atherosclerotic preventive and treatment strategies in clinical practice.

The Link between miRNAs and PCKS9 in Atherosclerosis.

Cardiovascular disease (CDV) represents the major cause of death globally. Atherosclerosis, as the primary cause of CVD, is a chronic immune-inflammatory disorder with complex multifactorial pathophysiology encompassing oxidative stress, enhanced immune-inflammatory cascade, endothelial dysfunction, and thrombosis. An initiating event in atherosclerosis is the subendothelial accumulation of low-density lipoprotein (LDL), followed by the localization of macrophages to fatty deposits on blood vessel walls, forming lipid-laden macrophages (foam cells) that secrete compounds involved in plaque formation. Given the fact that foam cells are one of the key culprits that underlie the pathophysiology of atherosclerosis, special attention has been paid to the investigation of the efficient therapeutic approach to overcome the dysregulation of metabolism of cholesterol in macrophages, decrease the foam cell formation and/or to force its degradation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine proteinase that has emerged as a significant regulator of the lipid metabolism pathway. PCSK9 activation leads to the degradation of LDL receptors (LDLRs), increasing LDL cholesterol (LDL-C) levels in the circulation. PCSK9 pathway dysregulation has been identified as one of the mechanisms involved in atherosclerosis. In addition, microRNAs (miRNAs) are investigated as important epigenetic factors in the pathophysiology of atherosclerosis and dysregulation of lipid metabolism. This review article summarizes the recent findings connecting the role of PCSK9 in atherosclerosis and the involvement of various miRNAs in regulating the expression of PCSK9-related genes. We also discuss PCSK9 pathway-targeting therapeutic interventions based on PCSK9 inhibition, miRNA levels manipulation by therapeutic agents, and the most recent advances in PSCK9 gene editing using CRISPR/Cas9 platform, meganuclease, and base editors.

Genetic risk score and epicardial adipose tissue: the new tools with impact on cardiovascular risk assessment

Abstract Background Cardiovascular disease (CVD) remains the leading cause of death worldwide. One of its main contributors is coronary artery disease (CAD), a complex multifactorial disease influenced by hereditary and environmental factors. A better cardiovascular risk assessment is a real challenge in our daily clinical practice. Evidence points to high Epicardial Adipose Tissue (EAT) volume as an essential player in the pathophysiology of CAD. On the other hand, genetic predisposition to CAD remains crucial to improve cardiovascular risk assessment and treatment. It is unknown whether the association between these two risk markers improved the ability to predict CV events. Objective Evaluate whether a high EAT volume added to a Genetic Risk Score (GRS) improves the predictive ability to discriminate CV events in an asymptomatic population without known CVD. Methods A prospective cohort was performed with 1024 participants (mean age 51.6±8.2 years, 75.6% male) selected from controls of the GENEMACOR Study. The GRS was created from 33 genetic variants associated with CAD by GWAS, choosing those with a hazard ratio (HR) higher than 1. EAT volume was measured with a quantitative semi-automated procedure using a postprocessing workstation-TeraRecon Aquarius Workstation (version 4.4.7, TeraRecon, Inc., San Mateo, CA, USA). We evaluated the discriminative ability of the GRS model without (model 1) and with EAT volume (model 2) using the Harrel C statistics. Categorical free Net Reclassification Improvement (cfNRI) and Integrated Discrimination Index (IDI) reclassified patients. Results Cox regression analysis showed that GRS and EAT remained in the equation with an HR of 1.140 (p=0.002) and HR of 1.221 (p=0.002), respectively. C-statistic demonstrated that the predictive value for MACE was 0.588 (95%CI 0.445-0.731) for GRS and increased to 0.689 (95%CI 0.577-0.801) when EAT volume was added to GRS, showing a better discrimination capacity for MACE. The difference between the two C indexes was significant (p=0.003). CfNRI reclassified 58.9% of the population (p=0.001), and IDI improved the discrimination when EAT was included in the GRS model (IDI=0.012; p=0.015). Conclusion Our results displayed that the GRS associated with a high EAT volume increased the discriminative ability to predict MACE occurrence. Improving the identification of high-risk patients at a subclinical stage could avoid atherosclerosis progression and events occurrence through more rigorous and earlier preventive and even therapeutic measures.

Abstract 13799: A Systems Approach to Target Discovery Identifies the Novel Role of lncRNA-SPANXA2-OT1 in Macrophage Chemotaxis

Background: Coronary artery disease (CAD) remains the leading cause of mortality worldwide. Macrophages play a crucial role in recruiting immune cells and regulating the inflammatory milieu through the release of a diverse array of cytokines and chemokines in CAD. Long noncoding RNAs (lncRNAs) interact with DNA, RNA, miRNA, and proteins which makes them attractive therapeutic targets. We hypothesized that the lncRNA, SPANXA2-OT1 , regulates macrophage chemotaxis in CAD. Methods and Results: Gene-expression meta-analysis and weighted gene co-expression network analysis (WGCNA) of human CAD datasets identified 26 lncRNA-mRNA co-expression modules (Fig A). Network prioritization of top co-expression modules identified the SPANXA2-OT1 as a potential key candidate. The conservation analysis revealed that SPANXA2-OT1 is conserved only in primates. We validated the candidate coding-noncoding RNA regulatory triad in primary macrophages derived from healthy human PBMCs (n= 3-10). Loss-of-function experiments using antisense oligonucleotide (ASO) against SPANXA2-OT1 demonstrated decreased monocyte chemotaxis signature (Figure B and D), as recorded by unbiased global proteomics and RNA expression (IL8, CCL19 and CCL23) data. The expression of S PANXA2-OT1 was stimulated by IL1β (Fig C) and RNA in situ hybridization demonstrated it to be highly expressed in cytoplasm (Fig E) of macrophages. Luciferase assay established that SPANXA2-OT1 binds to miR-338 through its miRNA response elements (Fig F). Gain-of-function ( miR-338 mimic) and loss-of-function ( SPANXA2-OT1 ASO) experiments revealed that SPANXA2-OT1 : miR-338 axis regulates the expression of monocyte chemotactic genes (e.g., IL-8 ) that may contribute to the pathophysiology of CAD (Fig G and H). Conclusion: Our results indicate that the lncRNA SPANXA2-OT1 regulates chemokine signature in macrophages and may provide a molecular basis for the identification of novel therapeutic targets for CAD.

Atheroprotective Effect of Fucoidan in THP-1 Macrophages by Potential Upregulation of ABCA1.

Targeting foam cells reduces the risk and pathophysiology of atherosclerosis, of which they are one of its early hallmarks. The precise mechanism of action of fucoidan, a potential anti-atherogenic drug, is still unknown. Our objective was to assess the ability of fucoidan to regulate expression of ATP-binding cassette transporter A1 (ABCA1) in ox-LDL-induced THP-1 macrophages. Molecular docking was used to predict how fucoidan interacts with anti-foam cell markers, and further in vitro experiments were performed to evaluate the protective effect of fucoidan on modulating uptake and efflux of lipids. THP-1 macrophages were protected by 50 µg/mL of fucoidan and were then induced to form foam cells with 25 µg/mL of ox-LDL. Expression levels were assessed using RT-qPCR, and an Oil Red O stain was used to observe lipid accumulation in THP-1 macrophages. In addition, ABCA1 protein was examined by Western blot, and cellular cholesterol efflux was determined using fluorescently labeled cholesterol. Under a light microscope, decreased lipid accumulation in ox-LDL-induced-THP-1 macrophages pre-treated with fucoidan showed a significant effect, although it did not affect the expression of scavenger receptors (SR-AI and CD36). It is interesting to note that fucoidan dramatically increased the gene and protein expression of ABCA1, perhaps via the liver X receptor-α (LXR-α). Moreover, fucoidan's ability to increase and control the efflux of cholesterol from ox-LDL-induced THP-1 macrophages revealed how it may alter ABCA1's conformation and have a major effect on how it interacts with apolipoprotein A (ApoA1). In vitro results support a rationale for predicting fucoidan and its interaction with its receptor targets' predicted data, hence validating its anti-atherogenic properties and suggesting that fucoidan could be promising as an atheroprotective.

The Influence of Sex, Age, and Race on Coronary Artery Disease: A Narrative Review.

Cardiovascular disease has remained one of the leading causes of mortality in the world. The basic pathophysiology of coronary artery disease (CAD) is a reduction of the blood flow in coronary vessels, leading to restricted blood flow to the heart muscle. Both modifiable and non-modifiable risk factors contribute to its multifactorial etiology. The clinical presentation ranges from asymptomatic to typical symptoms like chest pain, shortness of breath, and left arm or jaw pain. The purpose of this review is to investigate and analyze the variation of CAD depending on the biological sex, age, race, or ethnicity and how it might differ in the studied population while comparing the symptoms and prognosis of CAD. For this research, PubMed's database was used. A total of 926 articles were selected using pre-determined inclusion and exclusion criteria, with 74 articles eligible to be included in the narrative review. Studies were selected from the general population of patients with CAD, regardless of their severity, stage of diagnosis, and treatment plan. The scale for the assessment of non-systematic review articles (SANRA) was used to assess the quality of the study. As humans age, the incidence of CAD increases, and people over 75 are more likely to have multiple-vessel CAD. It has been observed that South Asians have the highest rate of CAD at 24%, while the White population has the lowest at 8%. The prevalence of CAD also depends on race, with the White population having the lowest rate at 3.2%, followed by Hispanics at 5%, Black women at 5.2%, and Black men at 5.7%. Younger Black women tend to have more chest pain. Men with CAD commonly experience chest pain, and women are more likely to present with atypical symptoms. Modifiable risk factors such as smoking and alcoholism are more commonly observed in young men than in young women. Coronary artery disease in the elderly, female, minority, and Black patients is associated with a higher mortality rate. Acknowledging the prevalence of certain risk factors, signs, results, and responses to treatment in certain socio-demographic groups, as well as the provision and accessibility of diagnosis and treatment, would lead to a better outcome for all individuals. The impact of this shift can range from an earlier diagnosis of CAD to a faster and more customized treatment plan tailored to each patient's individual requirements.