Atherosclerotic Plaque Progression Research Articles

Gelatin-decorated Graphene oxide: A nanocarrier for delivering pH-responsive drug for improving therapeutic efficacy against atherosclerotic plaque

The progressive inflammatory disease atherosclerosis promotes myocardial infarction, stroke, and heart attack. Anti-inflammatory drugs treat severe atherosclerosis. They are inadequate bioavailability and cause adverse effects at higher doses. A new nanomaterial coupled pH-apperceptive drug delivery system for atherosclerotic plaque is outlined here. We have synthesized a Graphene Oxide-Gelatin-Atorvastatin (GO-Gel-ATR) nanodrug characterized by spectroscopic and imaging techniques. The encapsulation efficiency of GO-Gel-ATR (79.2%) in the loading process is observed to be better than GO-ATR (66.8%). The internal milieu of the plaque cells has a pH of 6.8. The GO-Gel-ATR displays sustained and cumulative release profile at pH 6.8 compared to ATR and GO-ATR. Our proposed nanocomposite demonstrated high cytocompatibility up to 100μg/mL in foam cells induced by Oxidized-Low Density Lipoprotein (Ox-LDL) and Lipopolysaccharides (LPS) compared to normal macrophages for 24 and 48 h. The uptake efficacy of the nanodrugs is shown to be enhanced in foam cells compared to normal macrophage. Oil red O staining of foam cells with and without drugs confirmed therapeutic efficacy. Foam cells treated with nanocomposite had more lipids efflux than ATR. The finding of the in-vitro study reveals that the GO-Gel-ATR nanocomposite carriers have the potential to deliver anti-atherosclerotic drugs effectively and inhibit atherosclerotic plaque progression.

Progression Of Atherosclerotic Plaque Determined By Computed Tomography Angiography: A Practical CCTA-based SCORE

Progression Of Atherosclerotic Plaque Determined By Computed Tomography Angiography: A Practical CCTA-based SCORE

Natto consumption suppresses atherosclerotic plaque progression in LDL receptor-deficient mice transplanted with iRFP-expressing hematopoietic cells

Natto, known for its high vitamin K content, has been demonstrated to suppress atherosclerosis in large-scale clinical trials through a yet-unknown mechanism. In this study, we used a previously reported mouse model, transplanting the bone marrow of mice expressing infra-red fluorescent protein (iRFP) into LDLR-deficient mice, allowing unique and non-invasive observation of foam cells expressing iRFP in atherosclerotic lesions. Using 3 natto strains, we meticulously examined the effects of varying vitamin K levels on atherosclerosis in these mice. Notably, high vitamin K natto significantly reduced aortic staining and iRFP fluorescence, indicative of decreased atherosclerosis. Furthermore, mice administered natto showed changes in gut microbiota, including an increase in natto bacteria within the cecum, and a significant reduction in serum CCL2 expression. In experiments with LPS-stimulated macrophages, adding natto decreased CCL2 expression and increased anti-inflammatory cytokine IL-10 expression. This suggests that natto inhibits atherosclerosis through suppression of intestinal inflammation and reduced CCL2 expression in macrophages.

Role of periodontal pathogens in atherosclerotic plaque development and progression: An overview.

Atherosclerosis is a progressive disease marked by the accumulation of lipids and fibrous components in the large arteries. It is one of the primary causes of heart disease and stroke. Periodontal diseases encompass conditions like gingivitis and periodontitis, which are multifactorial diseases associated with dysbiotic plaque biofilms that trigger an immune-inflammatory host response, eventually resulting in the destruction of periodontal tissues. Links between periodontal disease and atherosclerosis may be based on direct invasion of periodontal pathogens or inflammatory mechanisms triggered by bacteria related to periodontal lesions, locally or systemically, that may impact the initiation of the atherosclerotic lesion. The presence of periodontal pathogens within an atheromatous lesion implies hematogenous dissemination. The invasion of atheroma by periodontal pathogens results in changes in the proatherogenic and proinflammatory properties of endothelial cells, leading to endothelial dysfunction, which is a hallmark of atherosclerosis. Clinical and epidemiological studies have offered sufficient evidence of periodontitis having an adverse effect on systemic health, including atherosclerosis; however, a direct causal effect has not yet been proved. This review aims to analyse scientific results regarding the mechanism by which periodontal pathogens may cause atherosclerosis as well as to describe the role of Porphyromonas gingivalis in atherosclerotic plaque development and progression.

Unveiling the role of ABI3 and hub senescence-related genes in macrophage senescence for atherosclerotic plaque progression

BackgroundAtherosclerosis, characterized by abnormal arterial lipid deposition, is an age-dependent inflammatory disease and contributes to elevated morbidity and mortality. Senescent foamy macrophages are considered to be deleterious at all stages of atherosclerosis, while the underlying mechanisms remain largely unknown. In this study, we aimed to explore the senescence-related genes in macrophages diagnosis for atherosclerotic plaque progression.MethodsThe atherosclerosis-related datasets were retrieved from the Gene Expression Omnibus (GEO) database, and cellular senescence-associated genes were acquired from the CellAge database. R package Limma was used to screen out the differentially expressed senescence-related genes (DE-SRGs), and then three machine learning algorithms were applied to determine the hub DE-SRGs. Next, we established a nomogram model to further confirm the clinical significance of hub DE-SRGs. Finally, we validated the expression of hub SRG ABI3 by Sc-RNA seq analysis and explored the underlying mechanism of ABI3 in THP-1-derived macrophages and mouse atherosclerotic lesions.ResultsA total of 15 DE-SRGs were identified in macrophage-rich plaques, with five hub DE-SRGs (ABI3, CAV1, NINJ1, Nox4 and YAP1) were further screened using three machine learning algorithms. Subsequently, a nomogram predictive model confirmed the high validity of the five hub DE-SRGs for evaluating atherosclerotic plaque progression. Further, the ABI3 expression was upregulated in macrophages of advanced plaques and senescent THP-1-derived macrophages, which was consistent with the bioinformatics analysis. ABI3 knockdown abolished macrophage senescence, and the NF-κB signaling pathway contributed to ABI3-mediated macrophage senescence.ConclusionWe identified five cellular senescence-associated genes for atherogenesis progression and unveiled that ABI3 might promote macrophage senescence via activation of the NF-κB pathway in atherogenesis progression, which proposes new preventive and therapeutic strategies of senolytic agents for atherosclerosis.

High-resolution magnetic resonance imaging investigation of the connection between the triglyceride-glucose index and intracranial arterial remodeling: a retrospective cross-sectional study.

Insulin resistance (IR) is associated with atherosclerotic plaque progression and the occurrence of stroke, with the triglyceride-glucose (TyG) index serving as a surrogate indicator. The present study aimed to investigate the association between TyG index levels and intracranial arterial remodeling in patients with acute ischemic stroke (AIS). Patients with AIS who visited the Neurology Department of the Second Hospital of Hebei Medical University and underwent high-resolution magnetic resonance imaging (HR-MRI) between September 2018 and October 2021 were enrolled. A total of 123 patients were finally included in the study, with 81 excluded. The TyG index levels were measured, and the characteristics of intracranial atherosclerotic stenosis (ICAS) plaques were evaluated using HR-MRI. A logistic regression model was employed to analyze the relationship between TyG index levels and remodeling mode. Patients were divided into two groups, positive remodeling (PR) and non-positive remodeling (non-PR), based on the remodeling index (RI). Patients in the PR group had a higher TyG index than those in the non-PR group {median [interquartile range (IQR)]: 9.11 (8.82-9.51) vs. 8.72 (8.30-9.23), P<0.001}. After adjusting factors such as age and gender, the TyG index was found to be significantly correlated with intracranial arterial PR [odds ratio (OR): 3.169, 95% confidence interval (CI): 1.327-7.569, P=0.009]. In non-diabetes mellitus (DM) patients, the TyG index level in the PR group was significantly higher than that in the non-PR group (8.95±0.42 vs. 8.50±0.45, P<0.001), whereas there was no such difference in patients with DM. TyG index was correlated with intracranial vessel PR, indicating that the TyG index level may be a useful marker for predicting intracranial vessel PR.

The improvement of endothelial function by inhibition of platelet activity using acetylsalicylic acid in patients with arterial hypertension

In accordance with modern ideas about the pathogenesis of thrombotic complications of cardiovascular diseases (myocardial infarction, stroke), it should be noted that platelets and platelet humoral factors play a key role in the development of thrombosis. Activated platelets are able to activate both endotheliocytes and pro-inflammatory cells - monocytes/macrophages, which take a direct part in the formation and progression of atherosclerotic plaque. The purpose of the study is to investigate the potential improvement of endothelial function through the inhibition of platelet activity using acetylsalicylic acid in patients with arterial hypertension and established atherosclerotic cardiovascular diseases. Materials and methods. We enrolled 41 patients with arterial hypertension and established atherosclerotic cardiovascular diseases in our study. The participants were divided into two groups. Group 1 comprised 20 patients who were already taking acetylsalicylic acid (ASA) before the study, while Group 2 consisted of 21 patients who had not received ASA before participating. During the 6-month study period, patients from both groups received ASA (75 mg once a day) as part of their basic therapy, which included antihypertensive and statin therapy. Platelet activity was assessed in all patients before the study and at the final stage by determining the expression of glycoproteins GPIIb-IIIa and P-selectin on their surface. Additionally, the content of endothelial progenitor cells (phenotype CD45-CD31+CD133+) and desquamated endothelial cells (phenotype CD45-CD31+CD133-) in the blood was analyzed using flow cytometry. ELISA was employed to measure the content of C-reactive protein, cytokines TNF-α and IL-10, as well as asymmetric dimethylarginine (ADMA) in the blood. Finally, all patients underwent a test with flow-dependent vasodilation of the brachial artery. Results. In patients who did not receive ASA before the study, there was a higher level of platelet activity in peripheral blood flow, along with signs of more pronounced endothelial dysfunction compared to those who received it. After 6 months of taking ASA alongside standard antihypertensive therapy, the activation level of circulating blood platelets decreased in both groups. Specifically, in patients of group 1, the expression level of CD41 (GPIIb) decreased by 31.8 % (p &lt; 0.01), and CD61 (GPIIIa) decreased by 15.2 % (p &lt; 0.01). In group 2 patients, the suppression of platelet activity was even more pronounced, with the expression level of CD41 (GPIIb) decreasing by 55.2 % (p &lt; 0.001), and CD61 (GPIIIa) decreasing by 27.5 % (p &lt; 0.05). Furthermore, in patients of group 1, the percentage of platelets carrying P-selectin on the surface decreased by 78.1 % (p &lt; 0.01). In group 2, the number of such platelets also significantly decreased by 42.5 % (p &lt; 0.05). The number of progenitor cells of endothelial cells in the circulating blood increased significantly in both groups, showing a 3-fold increase in patients of group 1 (p &lt; 0.001) and a 2.3-fold increase in patients of group 2 ( p&lt; 0.001). In patients of both groups, a significant 2-fold increase in the endothelium-dependent vasodilatation index was observed (p &lt; 0.01). At the end of the study, there was a decrease in the blood level of CRP by 12.2 % and 18.8 %, and pro-inflammatory cytokine TNF-α decreased by 50% and 57 %, respectively, in patients of groups 1 and 2 (p &lt; 0.001). Conclusion. The reduction in blood platelet activity triggered by ASA in patients with arterial hypertension and atherosclerotic cardiovascular diseases was associated with notable alterations in the intensity of systemic inflammation and the restoration of endothelial functions. These findings suggest a potential therapeutic role for ASA in modulating both platelet function and endothelial health in individuals with these conditions.

Preventive Therapies in Peripheral Arterial Disease.

Atherosclerosis, while initially deemed a bland proliferative process, is now recognized as a multifactorial-lipoprotein-mediated inflammation-driven pathway. With the rising incidence of atherosclerotic disease of the lower extremity arteries, the healthcare burden and clinical morbidity and mortality due to peripheral artery disease (PAD) are currently escalating. With a healthcare cost burden of over 21 billion USD and 200 million patients afflicted worldwide, accurate knowledge regarding the pathophysiology, presentation, and diagnosis of the disease is crucial. The role of lipoproteins and their remnants in atherosclerotic vessel occlusion and plaque formation and progression has been long established. This review paper discusses the epidemiology, pathophysiology, and presentation of PAD. PAD has been repeatedly noted to portend to poor cardiovascular and limb outcomes. We discuss major therapeutic avenues for the prevention of major cardiovascular adverse events and major limb adverse events in patients with PAD.

Relationship of Soluble Lectin-Like Low-Density Lipoprotein Receptor-1 (sLOX-1) With Inflammation and Coronary Plaque Progression in Psoriasis.

Psoriasis is a chronic inflammatory condition associated with coronary artery disease risk. Uptake of oxidized low-density lipoprotein by the lectin-like low-density lipoprotein receptor-1 triggers release of the soluble extracellular domain of the receptor (sLOX-1). We sought to characterize the relationship between sLOX-1, inflammation, and coronary plaque progression in psoriasis. A total of 327 patients with psoriasis had serum sLOX-1 levels measured at baseline by an ELISA-based assay. Stratification by high-sensitivity C-reactive protein ≥4.0 mg/L (quartile 4), identified 81 participants who had coronary plaque phenotyping at baseline and were followed longitudinally by coronary computed tomography angiography. Subjects within high-sensitivity C-reactive protein quartile 4 were middle-aged (51.47±12.62 years), predominantly men (54.3%) with moderate psoriasis disease severity (6.60 [interquartile range, 3.30-13.40]). In the study cohort, participants with sLOX-1 above the median displayed increased vulnerable coronary plaque features. At baseline, sLOX-1 was associated with total burden (rho=0.296; P=0.01), noncalcified burden (rho=0.286; P=0.02), fibro-fatty burden (rho=0.346; P=0.004), and necrotic burden (rho=0.394; P=0.002). A strong relationship between sLOX-1, noncalcified burden (β=0.19; P=0.03), and fibro-fatty burden (β=0.29; P=0.003) was found in fully adjusted models at baseline and 1- and 4-year follow-up. Finally, coronary plaque features progressed over 1 year regardless of biologic or systemic treatment in subjects with high sLOX-1. Patients with psoriasis with both high sLOX-1 and high-sensitivity C-reactive protein levels have increased coronary plaque burden associated with atherosclerotic plaque progression independent of biologic and systemic treatment. Thus, sLOX-1 might be considered as a promising marker in coronary artery disease risk estimation beyond traditional risk factors. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01778569.

The role of EZH2 and H3K27me3 epigenetic signature in modulating T-cell polarization in atherosclerosis

Abstract Background Atherosclerosis is a chronic inflammatory disease, characterized by the formation of luminal plaques in arteries. Atheroprogression is accompanied by strong immune activation, during which T cells play a pivotal role. Genes driving T-cell activation are regulated by the polycomb repressive complex 2(PRC2), whose major component is the Enhancer of Zeste Homolog 2(EZH2), responsible for the methylation of Histone 3 Lysine 27(H3K27me3) epigenetic mark. Purpose We hypothesize that EZH2 mediates T-cell activation and modulates T-helper (Th) cell polarization, thus atherogenesis. Methods To study the effect of EZH2 in atherosclerosis, we backcrossed mice with Ezh2 flanked by loxP-sites sensitive to Cre-mediated inactivation in T cells to apolipoprotein E (Apoe-/-)mice and fed a high cholesterol diet to have hyperlipidemic Ezh2fl/flCd4CreApoe-/-mice and controls. Atherosclerotic plaque progression and immune cell phenotyping were assessed by histology, flow cytometry (FC), gene and protein expression analysis and single cell (sc)RNA-sequencing (Seq) as well as by functional in vitro assays. Results T cell-specific EZH2 deficiency resulted in a significant reduction in H3K27me3 in T-cells. Female Ezh2fl/flCd4Cre mice developed 34% less atherosclerotic plaques in the aortic root compared to wildtype (WT) littermates. FC analysis of spleen and lymph nodes of Ezh2fl/flCd4Cre mice revealed a shift from naive to effector CD4+ T cells, and the majority were Th2 cells (p&amp;lt;0.0001). Accordingly, plasma levels of lL4 and aortic IL4 transcripts were increased in Ezh2fl/flCd4Cre mice(p=0.05 and p=0.0079, respectively). Functional analysis revealed that splenic CD4+ T cells from Ezh2fl/flCd4Cre mice showed decreased migratory capacity towards the chemokines CXCL10, CCL17, CCL22, CCL19. To unravel mechanisms driving the type 2 immune response, bulk RNA-Seq of CD4+ T cells and scRNA-Seq of splenic CD3+ T cells from Ezh2fl/flCd4Cre and WT mice revealed that CD4+ T cell EZH2 deficiency caused upregulation of promyelocytic leukemia zinc finger (Plzf), a transcription factor of NKT cells of the NKT2 subtype, characterized by high IL4 production. Via FC we confirmed the increase in splenic NKT cells in Ezh2fl/flCd4Cre mice. Likewise, Plzf aortic mRNA levels were also significantly increased(p=0.002). To exploit the translational potential of T cell-specific EZH2 targeting, we treated Jurkat T cells with EZH2 inhibitors, the FDA-approved drug Tazemetostat and GSK126. Corroborating our in vivo data, EZH2 inhibitor-treated cells showed decreased H3K27me3 and 70% reduced migration towards the chemokine CXCL12. Conclusions Our study demonstrates that CD4+ T-cell specific EZH2 deficiency impairs T cell-migration and skews the immune response towards a type 2 response, resulting in protection against atherosclerosis. We aim at investigating whether the epigenetic mark H3K27me3 in T cells may be a promising therapeutic target for future cardiovascular immunotherapies.

Low HDL cholesterol and hyperglicemia are metabolic syndrome components associated with plaque progression in patients with chronic coronary syndrome: a PARADIGM study

Abstract Background The metabolic syndrome (MetS), a cluster of dyslipidemia, hyperglicemia and hypertension predicts future cardiovascular disease and death in general populations. Purpose We aimed to assess whether MetS and its components may impact on coronary plaque progression (PP), at serial coronary computed tomography angiography (CCTA), and major adverse cardiovascular events (MACE) in patients with chronic coronary syndrome (CCS). Methods A total of 1200 CCS patients (aged 60.9±9.3 years, 55.4% male) who underwent serial CCTA (≥2 years apart) and had available data on glucose/lipid metabolism and outcome, were analysed from the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. MetS and its components were categorized according to NCEPT ATPIII definition. Plaque volumes were measured in coronary segments (≥ 2 mm in diameter) and summed to provide total plaque volume (PV, mm3) and percent atheroma volume (PV/vessel volume*100) (PAV, %) per patient at baseline and follow-up. Rapid PP was defined as annualized PAV increase (∆PAV) ≥1.0%/year. MACE included non-fatal myocardial infarction, any cause death and unplanned coronary revascularization (&amp;gt;30 days after first CCTA). Results MetS was present in 366 patients (31%). The median interscan period was 3.2 years (IQR 1.9) and rapid PP occurred in 341 patients (28%). MetS was associated with a higher total PV (133±183 vs 97±163, P&amp;lt;0.001) and PAV (7.1±9.3 vs 5.4±8.0, P&amp;lt;0.001) at baseline and a higher annual change in both PV (18.5±23.4 vs 13.9±22.5, P&amp;lt; 0.001) and PAV (0.9±1.1 vs 0.7±1.0, P&amp;lt;0.001) (Figure 1A). At a multivariable logistic regression analysis, MetS independently predicted rapid PP (OR 1.50, 95%CI 1.11-2.02, p&amp;lt;0.01) after adjustment for other risk factors not included among its components (age, gender, smoking habits, family history, hypercholesterolemia, previous CAD), statin treatment and baseline PAV. Among MetS components, diabetes under treatment or fasting plasma glucose &amp;gt;100 mg/dL (OR 1.37, 95%CI 1.02-1.84, p&amp;lt;0.05) and low HDL cholesterol (&amp;lt;40 mg/dL in males and &amp;lt; 50 mg/dL in females) (OR 1.76, 95%CI 1.29-2.39, p&amp;lt;0.001) were independently associated with rapid PP. They had an additive effect on baseline PAV and annualized PAV increase (Figure 1B). The median follow-up duration was 8.23 years (IQR 3.61). MACE occurred in 201 patients (16.8%) (17 death, 11 non-fatal MI, 173 unplanned revascularizations). At multivariable Cox regression analysis, rapid PP was a strong and independent predictor of events (HR 1.72, 95% CI 1.29-2.28, P&amp;lt;0.001) after correction for all risk factors including MeS or its components and baseline PAV. Conclusions Independently of other risk factors and treatment MetS is associated with a higher coronary atherosclerotic burden and rapid PP which are in turn strong predictors of MACE in patients with CCS. Among MetS components hyperglycemia and low HDL-C are major determinants of rapid PP.Figure 1

MPI/FLI/CTA multi-modality imaging of atherosclerotic plaque with plexind1-targeted nanoparticles

Abstract M1 macrophage is one of important components which contribute to the progression of atherosclerotic plaques.[1]Previous research of our team showed that plexind1 was expressed more in atherosclerotic plaques at vascular bifurcation than those at straight site and co-localized with M1 macrophages. This study aims to develop a novel multimodal imaging platform by designing a nanoprobe targeting plexind1 to detect and monitor bifurcation lesion and provide detecting method for animal research. Methods A novel multimodal imaging agent,A12-Fe3O4-Cy7, was constructed by coupling superparamagnetic iron oxide nanoparticle (SPIONs) with cyanine 7 N-hydroxysuccin imide ester（Cy7）and nanobody A12 which could target plexind1 specifically. The physical and biological properties were evaluated. To assess the A12-Fe3O4-Cy7 recognition and monitoring for plaque,high-fat-fed 10-week and 20-week Apoe-/- atherosclerosis mouse models were imaged using MPI and FLI,and both 3D images were fused with CTA. HE,Prussian blue and plexind1 immunohistochemical staining were performed on mouse carotid tissue sections. Results The A12-Fe3O4-Cy7 was of favorable stability, biocompatibility（concentration&amp;lt; 200ug/ml) and targeting effect.It could detect, locate, and monitor atherosclerotic plaques at bifurcation of carotid artery in ApoE-/- mice accurately and sensitively, showing significantly higher MPI and FLI signals both in vivo and ex vivo compared with both themselves before nanoprobe injection and two control groups(n=3,p&amp;lt;0.05). FLI is more sensitive than MPI to detect high-fat-fed 10-week mouse plaques.The results were confirmed histologically. Conclusion A12-Fe3O4-Cy7 might serve as a method to detect plaques at the bifurcation by targeting plexind1 in vivo. Limitations MPI is tested only in mouse models presently and it requires combination with CT to provide anatomical information. Besides，there was no intervention on plexind1,so the mechanism of plexind1 in bifurcation plaque occurrence and progression is not illustrated clearly,which is worth exploring in the future.In vitro and vivo assessmentIn vivo and ex vivo imaging

Abstract 14313: A Proteomic Atlas of Human Coronary Artery Reveals the Pathological Progression of Atherosclerosis

Introduction: The key molecular mechanisms associated with human atherosclerotic plaque progression, atherosclerotic lesion initiation and plaque destabilization are not fully understood. Hypothesis: Different stages of atherosclerosis (AS) progression have distinct pathological processes. Some key proteins induce AS progression. Methods: We employed 20 coronary artery samples among 4 explanted hearts from coronary heart disease patients. Each heart contains stages of unaffected control (NC), pathological intimal thickening (PIT), fibroatheroma (FA), transition to thin-cap fibroatheroma (TCFA) and ruptured plaque (RP), which were validated by hematoxylin and eosin (H&amp;E) staining. We performed quantitative proteomics in each of the samples based on tandem-mass-tags and liquid chromatography-tandem mass spectrometry. Furthermore, we measured proteins in human coronary artery tissue via immunofluorescence. Results: Proteomics revealed that extracellular matrix (ECM) organization was the most significantly enriched pathway in PIT. FA exhibited an enrichment of immunologic processes, such as neutrophil degranulation, myeloid leukocyte activation and innate immune response. Molecular profiles of TCFA and RP are similar, with complement and coagulation cascades pathway as a hallmark of these stages. Clustering analysis of DEPs displayed 4 clusters, notably cluster 2 had a precipitous elevation from FA to TCFA. Within this cluster, we identified a high-rank molecule: macrophage-capping protein (CAPG). Immunohistochemistry and immunofluorescence revealed that CAPG is highly elevated in plaque compared to NC and is specifically expressed in the plaque. Conclusions: ECM organization was continuously dysregulated in AS progression. Immune response might initiate the atherosclerotic plaque. Complement and coagulation cascades pathway was a hallmark of TCFA and RP. CAPG might be a therapeutic target for AS progression.

Abstract 18121: Gaps in Initiation of Evidence-Based Medical Therapies in Patients With Ischemia With Nonobstructive Coronary Artery Disease

Introduction: Ischemia with nonobstructive coronary artery disease (INOCA) is associated with major adverse cardiovascular events (MACE) due to atherosclerotic plaque progression, rupture of high-risk plaque and microvascular dysfunction. While there is evidence for use of ACE inhibitors/ARBs and statins to reduce MACE in patients with coronary artery disease (CAD), gaps in implementation of maximal medical therapy in patients after diagnosis of INOCA is not well described. We hypothesize that cardioprotective medications may be underutilized in patients with INOCA. Methods: Patients (n=443) with ischemic symptoms associated with ECG changes or troponin rise, no history of CAD and with nonobstructive CAD on noninvasive or invasive coronary assessment between 2010-2021 at Indiana University Health, Indianapolis, were included in this study. Results: In 226 women and 217 men with mean age 58.5 yrs, 315 underwent invasive angiography and 128 coronary CTA. Compared to baseline, initiation rates of cardioprotective agents were low after INOCA diagnosis for statins (37.9%) and aspirin (ASA, 36.1%) (Figure 1A). Among eligible patients, statins and ASA were underutilized in 42% and 44% respectively. There were no statistically significant differences in prescribing patterns of ASA and statin based on gender or race (Figure 1B). Conclusions: There are significant gaps in the prescription of cardioprotective medications including statins, ASA, ACEI/ARB and beta blockers in patients with INOCA at a quaternary care hospital. If this pattern is similar to the rest of the country, the factors associated with underutilization of these medications needs to be explored further.

An anti-inflammatory Glyburide-loaded nanoghost for atherosclerosis therapy: A red blood cell based bio-mimetic strategy

Inflammation control is becoming a critical strategy for atherosclerosis management, because inflammation is involved in plaque progression. In this regard, a biomimetic strategy using cell membrane-coated nanoparticles has some promising advantages. In the study, a RBC membrane-based nanoghost containing Glyburide (Glibenclamide) was prepared using an extrusion method. The hydrodynamic size and zeta potential of the nanoghost were changed compared to PLGA nanoparticles. In addition, a nanoghost with a diameter and shell size of 125 nm and 8.3 nm was obtained based on the TEM measurement. The fabricated nanoghost was not only hemocompatible but also was biocompatible, showing no significant induction of apoptosis. According to RT-PCR assay, the expression levels of inflammatory genes including NLRP3, IL-1β, IL-18 caspase1, 8 and 9 were decreased. In accordance with in vitro anti-inflammation properties, total foam cells, total surface area in tunica intima and population of CD14+ cells were decreased in the rabbit model of atherosclerosis upon nanoghost treatment, compared to positive control. Furthermore, macrophages in aorta sections exhibited M1 to M2 polarization. In general, the development of Glyburide-loaded nanoghost can be considered as a potential therapeutic for controlling the progression and inflammation of atherosclerotic plaque.

Association between Intermediate-Density Lipoprotein Particles and the Progression of Carotid Atherosclerosis: A Community-Based Cohort Study.

Experimental studies report that intermediate-density lipoprotein (IDL), the precursor of low-density lipoprotein, promotes atherosclerotic plaque formation. However, whether IDL is involved in the development of atherosclerosis in humans is still unclear. The aim of this community-based study is to examine the association between IDL particle (IDL-P) concentrations and the 5-year progression of carotid atherosclerosis. Baseline IDL-P concentrations were measured using nuclear magnetic resonance spectroscopy in 927 participants aged 45-74 years with no history of cardiovascular disease (CVD) at baseline. To estimate the association between baseline IDL-P concentrations and 5-year progression of carotid atherosclerosis, indicated by atherosclerotic plaque progression and changes in total plaque area (TPA), multivariable-adjusted regression was employed. During the 5-year follow-up period, 45.8% of participants developed new plaques. Baseline IDL-P concentrations were significantly associated with the progression of carotid atherosclerosis. Participants in the highest quartile of IDL-P concentrations exhibited 1.36-fold (95% confidence interval [CI]: 1.09-1.68) increased progression of carotid plaque and 1.67-fold (95% CI: 1.04-2.69) higher TPA than those in the lowest quartile. These relationships were independent of baseline concentrations of low-density lipoprotein particles and very-low-density lipoprotein particles and their subclasses. Elevated IDL-P concentrations were independently associated with the progression of carotid atherosclerosis, suggesting that IDL-P is a novel risk factor for the development of atherosclerosis.

Transcriptomics Analysis Revealed Key Genes Associated with Macrophage Autophagolysosome in Male ApoE-/- Mice Aortic Atherosclerosis.

Atherosclerosis (AS) is the most common cause of cardiovascular and cerebrovascular diseases. However, the mechanisms underlying atherosclerotic plaque progression remain unclear. This study aimed to investigate the genes associated with the development of atherosclerosis in the aorta of ApoE-/- male mice, which could serve as novel biomarkers and therapeutic targets in interventions to halt plaque progression. Eight-week-old ApoE-/- mice were fed a normal purified laboratory diet or a Western Diet (WD) for 6 or 22 weeks. High-throughput sequencing technology was used to analyze the transcriptomes of the aortas of four groups of mice that were exposed to different dietary conditions. We retrieved and downloaded the human Arteriosclerosis Disease Chip dataset GSE100927 from the Gene Expression Omnibus (GEO) database and selected 29 cases of carotid atherosclerotic lesions and 12 cases of normal carotid tissues as the experimental and control groups, respectively, to further verify our dataset. In addition, we used quantitative reverse transcription polymerase chain reaction (QT-PCR) to verify the expression levels of the core genes in an atherosclerosis mouse model. There were 265 differentially expressed genes (DEGs) between the ApoE-/- Male mice AS22W group and Sham22W group. In addition to the well-known activation of inflammation and immune response, t the autophagy-lysosome system is also an important factor that affects the development of atherosclerosis. We identified five core genes (Atp6ap2, Atp6v0b, Atp6v0d2, Atp6v1a, and Atp6v1d) in the protein-protein interaction (PPI) network that were closely related to autophagosomes. Hub genes were highly expressed in the carotid atherosclerosis group in the GSE100927 dataset (P < 0.001). QT-PCR showed that the RNA level of Atp6v0d2 increased significantly during the development of atherosclerotic plaque in ApoE-/- male mice. Five core genes which affect the development of aortic atherosclerosis through the autophagy-lysosome system, especially Atp6v0d2, were screened and identified using bioinformatic techniques.

Purification, structural characteristics and anti-atherosclerosis activity of a novel green tea polysaccharide

A new homogeneous polysaccharide (TPS3A) was isolated and purified from Tianzhu Xianyue fried green tea by DEAE-52 cellulose and Sephacryl S-500 column chromatography. Structural characterization indicated that TPS3A mainly consisted of arabinose, galactose, galacturonic acid and rhamnose in a molar ratio of 5.84: 4.15: 2.06: 1, with an average molecular weight of 1.596 × 104 kDa. The structure of TPS3A was characterized as a repeating unit consisting of 1,3-Galp, 1,4-Galp, 1,3,6-Galp, 1,3-Araf, 1,5-Araf, 1,2,4-Rhap and 1-GalpA, with two branches on the C6 of 1,3,6-Galp and C2 of 1,2,4-Rhap, respectively. To investigate the preventive effects of TPS3A on atherosclerosis, TPS3A was administered orally to ApoE-deficient (ApoE−/−) mice. Results revealed that TPS3A intervention could effectively delay the atherosclerotic plaque progression, modulate dyslipidemia, and reduce the transformation of vascular smooth muscle cells (VSMCs) from contractile phenotype to synthetic phenotype by activating the expression of contractile marker alpha-smooth muscle actin (α-SMA) and inhibiting the expression of synthetic marker osteopontin (OPN) in high-fat diet-induced ApoE−/− mice. Our findings suggested that TPS3A markedly alleviated atherosclerosis by regulating dyslipidemia and phenotypic transition of VSMCs, and might be used as a novel functional ingredient to promote cardiovascular health.

Our Hidden Enemy: Ultra-Processed Foods, Inflammation, and the Battle for Heart Health.

Over the past few decades, we have witnessed unprecedented growth in new data that has fundamentally changed our traditional understanding of the progression of atherosclerotic plaques, as well as our strategies for preventing cardiovascular diseases, especially atherosclerosis. It was once believed that atherosclerosis was primarily caused by abnormal lipid buildup in the vessel intima, leading to plaque growth and luminal stenosis, with or without rupture. This perspective has now evolved to encompass more complex pathways, wherein the accumulation of abnormal products of oxidation and inflammation are the most likely factors mediating the growth of atherosclerotic plaques. The review aims to provide a comprehensive and detailed exploration of the relationship between ultra-processed foods, chronic inflammation, cardiovascular diseases, obesity, insulin resistance, and the role of the gut microbiota. It touches on several important aspects of modern diet and health.

Increasing Soluble P-Selectin Levels Predict Higher Peripheral Atherosclerotic Plaque Progression.

The adhesion molecule P-selectin is expressed by endothelial cells and platelets. It is involved in platelet activation and leukocyte adhesion, both important processes in the pathogenesis of atherosclerosis. Our study was designed to assess the predictive value of soluble P-selectin (sP-selectin) on the progression of peripheral atherosclerosis. This is an observational, single-center, cohort study that included 443 patients with established cardiovascular disease (CVD) or at least one cardiovascular risk factor. Over a period of 4 years, each patient underwent three-dimensional (3D) ultrasound to assess the plaque volume of the carotid and femoral arteries once per year. In addition, plasma sP-selectin levels were measured at each visit. The association between changes in sP-selectin and peripheral atherosclerotic plaque progression was assessed using growth curve models. 338 patients were available for statistical analysis. Each standard deviation increase in sP-selectin was significantly (p < 0.001) associated with a 46.09 mm3 higher plaque volume. In ROC-analysis, changes in sP-selectin over time showed an optimal cut-off value around Δ 0.0 µg/mL sP-selectin and significantly improved the predictive value of the ESC-SCORE (AUC for the combination of both parameters was 0.75 (95% CI 0.68-0.81, p < 0.001). Patients with increasing sP-selectin showed a significantly higher plaque progression compared to patients with decreasing or stable sP-selectin levels (202 mm3 vs. 110 mm3, p < 0.001). Increasing sP-selectin levels can predict higher atherosclerotic plaque progression as measured by 3D ultrasound. We suggest serial measurements of sP-selectin as an easily measurable biomarker for peripheral atherosclerotic plaque progression.