Atherosclerotic Plaque Research Articles

Abstract 4138304: Macrophage ZIP8 Enhances Efferocytosis and Mitigates Atherosclerosis by Modulating cellular Manganese (Mn) Homeostasis

Introduction: ZIP8, also known as SLC39A8, is a transmembrane transporter responsible for the movement of various divalent metal ions. Multiple genome-wide association studies (GWAS) have revealed a significant association between a mutation in ZIP8 (rs13107325; Ala391Thr) and cardiovascular diseases. While its physiologic role is incompletely understood, recent studies implicate that Zn2+ influx into monocytes regulated by ZIP8 is a novel factor determining their adhesion and recruitment to atherosclerotic lesions. The potential role of ZIP8 in modulating macrophage function and thereby influencing the development of atherosclerosis warrants further investigation. Methods and Results: Using an ApoE -/- ZIP8 A393T missense mutation mouse model, we quantified atherosclerotic plaque burden and lipid profiles following induction of atherosclerosis. The presence of the ZIP8 A393T missense mutation resulted in increased necrotic regions and plaque load in the atherosclerosis mouse model, while having no impact on total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) levels. Confocal microscopy and flow cytometry to investigate how reduced ZIP8 expression affects macrophage efferocytosis. When siRNA was used to knock down ZIP8 in vitro, macrophage efferocytosis was reduced. Subsequently, Macrophage-specific ZIP8 knockout mice (ZIP8 LysM ) demonstrated a decrease in the efferocytosis index in primary macrophage. Additionally, in vivo thymic and peritoneal efferocytosis assays showed an impaired efferocytosis phenotype in ZIP8 LysM mice. Confocal microscopy showed ZIP8 LysM mice have no effect on macrophage binding to apoptotic cells. The lack of or incompleteness of the F-ACTIN ring formed by macrophages surrounding apoptosis in the ZIP8 LysM mice, and the prolonged duration of phagocytosis ring formation suggests that the internalization process is compromised. The role of ZIP8 ion transport in the efferocytosis impairment mechanism was also investigated.The regulation of macrophage efferocytosis via the metabolism of D-galactose, glutamine, glutamate, and Zn 2+ is unaffected by ZIP8. Mn 2+ was identified as a vital regulatory factor in the efferocytosis function of ZIP8 in macrophages. Conclusions: ZIP8 influences the efferocytotic capacity of macrophages and regulates the clearance of apoptotic cells through Mn 2+ , suggesting that ZIP8 and Mn 2+ hold promise as a key therapeutic targets for the treatment of atherosclerotic cardiovascular diseases.

THE IMPACT OF EXOGENOUS AND ENDOGENOUS FACTORS ON VASCULAR WALL ELASTICITY AND POTENTIAL CLINICAL EFFECTS (Review Article)

Vascular aging is associated with profound changes in the structural properties of the arterial wall. Arterial hypertension, diabetes mellitus, and chronic kidney disease are the primary determinants of the loss of elasticity and reduced compliance of the vascular wall. Arterial stiffness is a key parameter for assessing the elasticity of the arterial wall and can be easily evaluated using non-invasive methods such as pulse wave velocity. Early assessment of arterial stiffness is critical, as its changes may precede the clinical manifestations of cardiovascular disease. With age, arterial walls become stiffer, leading to an increase in systolic blood pressure and an increased risk of cardiovascular events such as stroke, myocardial infarction, or heart failure. The gradual decrease in vascular elasticity is accompanied by remodeling of their structure, an increase in collagen fibers, and a decrease in elastin, which exacerbates the problem. In addition, the mechanical stress on the vascular wall, which increases with age, worsens its condition, provoking the formation of atherosclerotic plaques. Arterial stiffness, as an important biomarker of vascular aging, is also an indicator of increased cardiovascular risk, independent of other factors such as blood pressure or the presence of comorbidities. Therefore, timely diagnosis of arterial stiffness can help prevent serious complications and adjust treatment for patients at risk. Important are also preventive measures, including a healthy lifestyle, physical activity, and control of the underlying diseases that contribute to the acceleration of vascular aging processes. Moreover, the influence of endogenous and exogenous factors, such as diet, the presence of chronic diseases, and bad habits (in particular, smoking), contribute to the acceleration of these processes. Innovative diagnostic methods, such as magnetic resonance imaging (MRI) or ultrasound, allow detecting these changes at early stages and, accordingly, adapting treatment.

Novel insights of disulfidptosis-mediated immune microenvironment regulation in atherosclerosis based on bioinformatics analyses

Atherosclerosis (AS) is the leading cause of coronary heart disease, which is the primary cause of death worldwide. Recent studies have identified disulfidptosis as a new type of cell death that may be involved in onset and development of many diseases. However, the role of disulfidptosis in AS is not clear. In this study, bioinformatics analysis and experiments in vivo and in vitro were performed to evaluate the potential relationship between disulfidptosis and AS. AS-related sequencing data were obtained from the Gene Expression Omnibus (GEO). Bioinformatics techniques were used to evaluate differentially expressed genes (DEGs) associated with disulfidptosis-related AS. Hub genes were screened using least absolute shrinkage and selection operator (LASSO) and random forests (RF) methods. In addition, we established a foam cell model in vitro and an AS mouse model in vivo to verify the expressions of hub genes. In addition, we constructed a diagnostic nomogram with hub genes to predict progression of AS. Finally, the consensus clustering method was used to establish two different subtypes, and associations between subtypes and immunity were explored. As the results, 9 disulfidptosis-related AS DEGs were identified from GSE28829 and GSE43292 datasets. Evaluation of DEGs using LASSO and RF methods resulted in identification of 4 hub genes (CAPZB, DSTN, MYL6, PDLIM1), which were analyzed for diagnostic value using ROC curve analysis and verified in vitro and in vivo. Furthermore, a nomogram including hub genes was established that accurately predicted the occurrence of AS. The consensus clustering algorithm was used to separate patients with early atherosclerotic plaques and patients with advanced atherosclerotic plaques into two disulfidptosis subtypes. Cluster B displayed higher levels of infiltrating immune cells, which indicated that patients in cluster B may have a positive immune response for progression of AS. In summary, disulfidptosis-related genes including CAPZB, DSTN, MYL6, and PDLIM1 may be diagnostic markers and therapeutic targets for AS. In addition, these genes are closely related to immune cells, which may inform immunotherapy for AS.

Macrophage exosomal miR-30c-2-3p in atherosclerotic plaques aggravates microglial neuroinflammation during large-artery atherosclerotic stroke via TGF-β/SMAD2 pathway

Circulating miR-30c-2-3p has been closely related to vascular diseases, however, its role and underlying mechanisms in ischemic stroke remained unclear. Our study addressed this gap by observing elevated levels of exosomal miR-30c-2-3p in patients with acute ischemic stroke due to large artery atherosclerosis. Further investigation revealed that these exosomal miR-30c-2-3p primarily originated from macrophages within atherosclerotic plaques, exacerbating ischemic stroke by targeting microglia. Exosomes enriched with miR-30c-2-3p increased microglial inflammatory properties in vivo and aggravated neuroinflammation by inhibiting SMAD2. In summary, our findings revealed a novel mechanism whereby macrophage-derived foam cells within atherosclerotic plaques secrete exosomes with high levels of miR-30c-2-3p, thus aggravate brain damage during ischemic stroke, which serves as crucial link between the periphery and brain.

Vascular Extracellular Matrix in Atherosclerosis

The extracellular matrix (ECM) plays a central role in the structural integrity and functionality of the cardiovascular system. Moreover, the ECM is involved in atherosclerotic plaque formation and stability. In fact, ECM remodeling affects plaque stability, cellular migration, and inflammatory responses. Collagens, fibronectin, laminin, elastin, and proteoglycans are crucial proteins during atherosclerosis development. This dynamic remodeling is driven by proteolytic enzymes such as matrix metalloproteinases (MMPs), cathepsins, and serine proteases. Exploring and investigating ECM dynamics is an important step to designing innovative therapeutic strategies targeting ECM remodeling mechanisms, thus offering significant advantages in the management of cardiovascular diseases. This review illustrates the structure and role of vascular ECM, presenting a new perspective on ECM remodeling and its potential as a therapeutic target in atherosclerosis treatments.

The GDF15 3′ UTR Polymorphism rs1054564 Is Associated with Diabetes and Subclinical Atherosclerosis

Growth differentiation factor 15 (GDF15) is a stress-response cytokine related to a wide variety of metabolic diseases. However, the impact of GDF15-specific genetic variants on the abovementioned conditions is poorly known. The aim of this study was to assess the impact of selected GDF15 single-nucleotide polymorphisms (SNPs) on metabolic disturbances and subclinical atherosclerosis. A cross-sectional study involving 153 participants of a metabolic patient-based cohort was performed. Three selected SNPs (rs888663, rs1054564 and rs1059369) in a locus on chromosome 19 including the GDF15 gene were genotyped by Polymerase Chain Reaction (PCR), and its relationship with the serum GDF15 levels, health status and clinical variables were analyzed. Of the three SNPs analyzed, only rs1054564 showed different distributions between the healthy volunteers and patients suffering lipid alterations and associated disorders. Accordingly, just the rs1054564 variant carriers showed a significant increase in GDF15 serum levels compared to the wild-type carriers. The group of variant carriers showed a higher frequency of individuals with diabetes, compared to the wild-type carrier group, without showing differences in other metabolic conditions. Additionally, the frequency of individuals with atherosclerotic carotid plaque was higher in the rs1054564 variant carriers than in the wild-type carriers. Logistic regression models identified that the presence of the rs1054564 variant carriers increase the likelihood for both diabetes and carotid plaque independently of confounding factors. Overall, the findings of this study identify the rs1054564 variant as a potential indicator for the likelihood of diabetes and subclinical atherosclerosis.

Mechanisms and treatment of atherosclerosis: focus on macrophages

Macrophages are the basic mediators and coordinators of various types of chronic inflammation and play a crucial role in the formation and development of atherosclerosis (AS). In the complex microenvironment of atherosclerotic plaques, macrophages of different sources are exposed to different signal stimuli and thus polarized into various subpopulations. Various types of macrophages with predominantly M1 and M2 phenotypes also play different regulatory roles in the initiation and progression of AS. Lipid-lowering drugs, mainly statins, are widely used in clinical practice, but the adverse reactions are obvious and there is a lack of personalized treatment. Emerging targeted macrophage and Traditional Chinese medicine (TCM)-related therapies can regulate the cellular microenvironment, inhibit the polarization of M1 macrophages, and promote the activation of M2 macrophages, providing new ideas for the prevention and treatment of AS.

Photothermal optical coherence microscopy for studying lipid architecture in human carotid arteries

Photothermal optical coherence microscopy (PT-OCM) combines the high-resolution, label-free morphological imaging of OCM with the ability to discriminate tissue composition through phase-sensitive photothermal imaging. In this study, we perform 2D imaging of human carotid endarterectomies to spectrally determine lipid distribution, with verification via histologically stained samples. The structural information from OCM is combined with the spectral information gained from measuring the resulting sample surface displacement from thermoelastic expansion, following light irradiation. PT-OCM is thus demonstrated as a potential tool in the investigation of atherosclerotic plaque lipids, contributing towards the understanding of plaque instability.

Teriparatide administration is osteoanabolic but does not impact atherosclerotic plaque calcification and progression in a mouse model of menopause

Menopause exacerbates osteoporosis and increases the risk of atherosclerotic plaque rupture, leading to cardiovascular mortality. Osteoporotic women are increasingly treated with teriparatide (TPTD, 1–34 parathyroid hormone), one of the few treatments that stimulate bone formation. Despite the fact that atherosclerotic plaque calcification is a hallmark of plaque development, the impact of TPTD administration on plaque calcification remain unclear. In this context, we sought to determine the effects of TPTD administration on atherosclerosis in ovariectomized (OVX) apolipoprotein E deficient mice (ApoE−/−), as a model of postmenopausal osteoporosis. OVX ApoE−/− mice, fed a high fat, high cholesterol diet to induce atherosclerosis, received either vehicle or TPTD daily injections (40 μg/kg/d) for 4 or 10 weeks, at which points plaques are respectively weakly and heavily calcified. After sacrifice, bone remodeling was evaluated by serum markers and bone histomorphometry. Bone architectural parameters were measured by μCT. Aortic plaques were analyzed histologically, and their calcification with von Kossa staining and the calcium tracer Osteosense. Plaque inflammation and calcification markers were measured by RT-qPCR. Intermittent TPTD increased bone volume in OVX mice, due to a higher stimulation of bone formation relatively to bone resorption. These effects were not accompanied by changes in serum levels of cholesterol, triglycerides, glucose or insulin. TPTD neither significantly affected aortic plaque size, inflammation, and calcification, even if it slightly increased vascular smooth muscle cell transdifferentiation into calcifying cells. In conclusion, TPTD exhibits osteoanabolic effects in OVX ApoE−/− mice, without significantly influencing atherosclerotic plaque progression or calcification in the short term.

METABOLOMIC STUDY FOR THE IDENTIFICATION OF SYMPTOMATIC CAROTID PLAQUE BIOMARKERS

Carotid artery stenosis is mainly produced due to the progressive accumulation of atherosclerotic plaque in the vascular wall. The atherosclerotic plaque is characterized by the accumulation of lipids, low density proteins, expression of chemokines and adhesion molecules, and migration of monocytes and lymphocytes into the plaque. Its rupture can produce stroke, but embolic propensity depends principally on the composition and vulnerability of plaque rather than the severity of stenosis. It is important, then, to ascertain which patients with carotid arterial stenosis have a greater risk of developing neurological symptomatology. Here, we present a metabolomic study by using nuclear magnetic resonance (NMR) spectroscopy in atheroma plaque and serum samples from patients with recently symptomatic and asymptomatic carotid stenosis to search for metabolites that could be used as biomarkers associated with plaque vulnerability and subsequent risk of rupture. Thirty-eight atheromatous plaque samples (24 asymptomatic patients and 14 symptomatic) and 70 serum samples (43 asymptomatic and 27 symptomatic) were studied by NMR spectroscopy. The data were analysed using multivariate statistics (PLS-DA) to determine a model to discriminate between symptomatic and asymptomatic samples (atheroma plaques and sera). The calculated PLS-DA models showed a 100% sensitivity and a 96.6% specificity for the cross validation to discriminate between symptomatic and asymptomatic plaques, and 88,37% sensitivity and 77,78% specificity when serum samples were analysed. According to the results of our multivariate and univariate analysis, the most discriminative metabolites for plaque vulnerability were threonine in serum samples, and glutamate in plaque samples. Also, an analysis of the main metabolic pathways involved in plaque vulnerability revealed that D-glutamine and D-glutamate metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis were the most affected pathways in plaque and serum, respectively.

Localization of Hemostasis Elements in Aspirated Coronary Thrombi at Different Stages of Evolution.

The structure of aspirated coronary thrombus in ST-segment elevation myocardial infarction (STEMI) is still being studied. Our aims were to characterize coronary thrombi of different ages, focusing on the appearance of activated protein C (APC/PC) and its relation to the elements of neutrophil extracellular traps (NETs), and the factors closely related to fibrin as factor XIII (FXIII) and α2 plasmin inhibitor (α2-PI). The thrombi of n = 24 male patients with atherosclerotic coronary plaque rupture related to native coronary artery occlusion were selected for histopathology analysis. Thrombus age was distinguished as fresh, lytic, and organized, and then analyzed by immunofluorescent staining and confocal microscopy. FXIII was present at a high level and showed a high degree of co-localization with fibrin in all stages of thrombus evolution. The amount of α2-PI was low in the fresh thrombi, which increased significantly to the lytic phase. It was evenly distributed and consistently associated with fibrin. APC/PC appeared in the fresh thrombus and remained constant during its evolution. The presence of NET marker and CD66b was most dominant in the lytic phase. APC/PC co-localization with the elements of NET formation shows its role in NET degradation. These observations suggest the importance of searching for further targeted therapeutic strategies in STEMI patients.

PTP1B Modulates Carotid Plaque Vulnerability in Atherosclerosis Through Rab5-PDGFRβ-Mediated Endocytosis Disruption and Apoptosis.

Protein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase and modulates platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) signaling in vascular smooth muscle cells (VSMCs) via endocytosis. However, the related molecular pathways that participated in the interaction of endo-lysosome and the trafficking of PDGFR are largely unknown. This study aims to determine the subcellular regulating mechanism of PTP1B to the endo-lysosome degradation of PDGFR in atherosclerotic carotid plaques, thereby offering a potential therapeutic target for the stabilization of carotid plaques. The immunohistochemical staining technique was employed to assess the expression levels of both PDGFR-β and Caspase 3 in stable and vulnerable carotid plaques. Tunnel staining was utilized to quantify the apoptosis of carotid plaques. Live-cell imaging was employed to observe endocytic motility, while cell apoptosis was evaluated through Propidium Iodide staining. In an invivo experiment, ApoE-/- mice were administered a PTP1B inhibitor to investigate the impact of PTP1B on atherosclerosis. The heightened expression of PDGFR-β correlates with apoptosis in patients with vulnerable carotid plaques. At the subcellular level of VSMCs, PDGFR-β plays a pivotal role in sustaining a balanced endocytosis system motility, regulated by the expression of Rab5, a key regulator of endocytic motility. And PTP1B modulates PDGFR-β signaling via Rab5-mediated endocytosis. Additionally, disrupted endocytic motility influences the interplay between endosomes and lysosomes, which is crucial for controlling PDGFR-β trafficking. Elevated PTP1B expression induces cellular apoptosis and impedes migration and proliferation of carotid VSMCs. Ultimately, mice with PTP1B deficiency exhibit a reduction in atherosclerosis. Our results illustrate that PTP1B induces disruption in endocytosis and apoptosis of VSMCs through the Rab5-PDGFRβ pathway, suggesting a potential association with the heightened vulnerability of carotid plaques.

Hypertension and Cardiovascular Outcomes in Inflammatory and Autoimmune Diseases: A Systematic Review and Meta-analysis.

This review aimed to investigate the prevalence of hypertension and cardiovascular (CV) complications in various inflammatory and autoimmune diseases (IAD). Despite recent improvements in the management of IAD, patients with IAD still have an increased CV mortality and CV complications, mostly related to CV risk factors such as hypertension and inflammation. We systematically searched MEDLINE and EMBASE libraries for controlled studies involving hypertension and CV complications in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), psoriasis including psoriatic arthritis (PsA), Sjogren's syndrome (SS), or antineutrophil cytoplasmic antibody-associated vasculitis (AAV) between January 2000 and March 2022. We extracted data on the prevalence of hypertension and CV complications. Then, random-effects meta-analyses and exploratory multivariate meta-regression were performed to explore factors related to the prevalence of hypertension.Of 2726 studies screened, 122 were selected for the meta-analysis. The prevalence of hypertension was higher among patients with IAD than controls, with an overall unadjusted odds ratio (OR) [95% confidence interval] of 1.67 [1.58-1.76] and an adjusted OR of 1.36 [1.24-1.50]. All diseases were found to be associated with increased risk of hypertension: SLE, adjusted OR 3.40 [1.93-6.00]; psoriasis, OR 1.32 [1.16-1.51]; PsA, OR 1.49 [1.15-1.94]; RA, OR 1.28 [1.04-1.58]; SS, OR 2.02 [1.19-3.44]. Age and female sex were significantly associated with hypertension in patients with IAD. The risk of CV complications was increased: ischemic heart disease, adjusted OR 1.38 [1.21-1.57]; cerebrovascular disease, OR 1.37 [1.03-1.81]; heart failure, OR 1.28 [1.05-1.55]; atherosclerotic plaques presence, OR 2.46 [1.84-3.29].The prevalence of hypertension and CV complications is higher among patients with IAD. Screening and management of hypertension appears to be of paramount importance in these patients.

The alpha 7 nicotinic acetylcholine receptor agonist PHA 568487 dampens inflammation in PBMCs from patients with newly discovered coronary artery disease.

The alpha 7 nicotinic acetylcholine receptor (α7nAChR) regulates inflammation in experimental models and is expressed in human peripheral blood mononuclear cells (PBMCs) and in human atherosclerotic plaques. However, its role in regulating inflammation in patients with cardiovascular disease is unknown. This study aims to investigate whether α7nAChR stimulation can reduce the inflammatory response in PBMCs from patients with newly diagnosed coronary artery disease (CAD). Human PBMCs, extracted from patients with verified CAD (n = 38) and control participants with healthy vessels (n = 38), were challenged in vitro with lipopolysaccharide (LPS) in combination with the α7nAChR agonist PHA 568487. Cytokine levels of the supernatants were analyzed using a multiplex immunoassay. Patients in the CAD group were reexamined after 6 mo. The immune response to LPS did not differ between PBMCs from control and CAD groups. α7nAChR stimulation decreased TNFα in both control and CAD groups. The most pronounced effect of α7nAChR stimulation was observed in patients with CAD at their first visit, where 15 of 17 cytokines were decreased [IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p70), IL-17A, G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1β, and TNFα]. In conclusion, stimulation with α7nAChR agonist PHA 568487 dampens the inflammatory response in human PBMCs. This finding suggests that the anti-inflammatory properties of the α7nAChR may have a role in treating CAD.NEW & NOTEWORTHY The α7nAChR is an important regulator of inflammation; however, its anti-inflammatory function in patients with newly diagnosed coronary artery disease (CAD) remains unclear. We demonstrate that stimulation of α7nAChR with PHA 568487 attenuates the inflammatory response in immune cells extracted from healthy controls and patients with newly diagnosed CAD, with a more pronounced effect observed in patients with CAD. This suggests that the anti-inflammatory properties of α7nAChR may have a role in treating chronic inflammatory diseases.

Leukemia Inhibitory Factor Receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr-/- mice

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the IL-6 cytokine family, such as Interleukin-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development.Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr-/- mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n=15) or control solvent (n=15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice.Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.

Neovascularization as a Leading Mechanism of Intraplaque Hemorrhage and Carotid Plaque Destabilization: A Narrative Review.

Intraplaque neovascularization (IPN) is considered a leading mechanism causing carotid plaque destabilization. We provide an objective and comprehensive summary of the biology, imaging techniques, and treatment options related to carotid IPN. Plaque neovascularization has been reported to originate mainly from the adventitial vasa vasorum as a response to hypoxia. The leakage and rupture of neovessels lead to the formation of extravasations and foci of inflammation that destabilize the plaque. Vascular endothelial growth factor and its receptors are key regulators of neoangiogenesis. Neovascularization can be analyzed by advanced computed tomography and magnetic resonance imaging. The basic tools for the ultrasound assessment of IPN are contrast-enhanced ultrasound, superb microvascular imaging, and ultrasound molecular imaging. A promising direction of research seems to be the identification of patients with advanced plaque neovascularization. A simple test assessing low-velocity flow in the IPN can detect patients at risk of stroke before they experience rupture of defective neovessels and intracerebral embolism. In addition to surgical treatment, the stabilization of carotid atherosclerotic plaque can be supported pharmacologically. Statins have the best-documented role in this respect. The ideal moment of intensified therapeutic intervention in patients with previously stable carotid plaque is its increased neovascularization. However, the time frame in which intracerebral embolization may occur is unknown, and therapeutic intervention may be too late. The formation of deficient neovessels can currently be non-invasively evaluated with ultrasound. Superb microvascular imaging may change the clinical approach for asymptomatic patients at risk of cerebral ischemia.

Piezo1-mediated mechanotransduction enhances macrophage oxidized low-density lipoprotein uptake and atherogenesis.

Macrophages in the vascular wall ingest and clear lipids, but abundant lipid accumulation leads to foam cell formation and atherosclerosis, a pathological condition often characterized by tissue stiffening. While the role of biochemical stimuli in the modulation of macrophage function is well studied, the role of biophysical cues and the molecules involved in mechanosensation are less well understood. Here, we use genetic and pharmacological tools to show extracellular oxidized low-density lipoproteins (oxLDLs) stimulate Ca2+ signaling through activation of the mechanically gated ion channel Piezo1. Moreover, macrophage Piezo1 expression is critical in the transduction of environmental stiffness and channel deletion suppresses, whereas a gain-of-function mutation exacerbates oxLDL uptake. Additionally, we find that depletion of myeloid Piezo1 protects from atherosclerotic plaque formation in vivo. Together, our study highlights an important role for Piezo1 and its respective mutations in macrophage mechanosensing, lipid uptake, and cardiovascular disease.

Anomalous origin of right coronary artery from left anterior descending coronary artery presenting with syncope – a case report

Introduction and importance: Non-dominant right coronary artery (RCA) is supposed to be benign as it does not result in large myocardial infarction. Still, in this case, non-dominant RCA from left anterior descending (LAD) artery not only produces ischemia but also results in incessant ventricular tachycardia, which is a life-threatening arrhythmia because of compromised blood flow. However, RCA is free of atherosclerotic plaque, which is the main cause of ischemia/infarction and subsequent arrhythmia. Case presentation: A 21-year-old male was admitted to the emergency cardiology ward of the National Institute of Cardiology following an episode of syncope. The patient reported a sudden loss of consciousness without preceding symptoms. Clinical discussion: The present case highlights the importance of a comprehensive evaluation and diagnosis in the management of syncope in young patients. The case presented here revealed a rare finding of a single coronary artery with a left main origin and an anomalous RCA emerging from the LAD artery. This is a very unusual presentation, with less than 50 occurrences recorded in the medical literature. This abnormality is classified as a single coronary artery anomaly (CAA), which means that the coronary arteries arise from a single coronary ostium within the aorta. Conclusion: In conclusion, CAA is an uncommon cause of SCA that can easily be overlooked without a systematic approach. In this report, we discuss the case of a patient who was discovered to have an anomalous RCA that branched off from the LAD artery.

The Effects of the oxLDL/β2GPI/anti-β2GPI Complex on Macrophage Autophagy and its Mechanism.

Previous research has established that the oxidized low-density lipoprotein/β2-glycoprotein I/anti-β2-glycoprotein I antibody (oxLDL/β2GPI/anti-β2GPI) complex can stimulate macrophages to secrete molecules associated with atherosclerosis (AS), such as monocyte chemotactic protein 1 (MCP-1), tissue factor (TF), and tumor necrosis factor-α (TNF-α). This complex also enhances the uptake of oxLDL, thereby accelerating foam cell formation through the Toll-like receptor-4/nuclear factor kappa B (TLR4/NF-κB) pathway. Given the critical role of macrophage autophagy in the instability of vulnerable atherosclerotic plaques, it is imperative to investigate whether the oxLDL/β2GPI/anti-β2GPI complex influences macrophage autophagy in AS. This study aims to elucidate the effects and underlying mechanisms of the oxLDL/β2GPI/anti-β2GPI complex on macrophage autophagy in AS. Experiments were conducted using murine macrophage RAW264.7 cells and the human monocytic cell line THP-1. Western blot analysis was employed to determine the expressions of autophagy-associated markers and signaling pathway proteins. Autophagosomes were detected through mRFP-GFP-LC3 adenoviral transfection and transmission electron microscopy (TEM). Treatment of macrophages with the oxLDL/β2GPI/anti-β2GPI complex resulted in decreased expressions of Beclin1 and LC3 proteins, alongside an upregulation of SQSTM1/P62 protein expression. Additionally, there was a reduction in the number of autophagosomes and autolysosomes. An increase in the phosphorylation levels of phosphoinositide-3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) was also observed. Notably, the expressions of autophagy-associated markers were partially restored when the TLR4/NF-κB and PI3K/AKT/mTOR pathways were inhibited by their respective inhibitors. Our findings indicate that the oxLDL/β2GPI/anti-β2GPI complex inhibits macrophage autophagy in AS via the TLR4/NF-κB and PI3K/AKT/mTOR signaling pathways.

Morphological characterization of coronary plaques in young indian patients with acute coronary syndrome: A multicentric study

ObjectivesThe prevalence of atherosclerosis and acute coronary syndrome (ACS) is increasing in young Indians (18–50 years of age). However, the characteristics of atherosclerotic plaques in such individuals are poorly understood, presenting distinct challenges for the management of ACS. This study aims to analyze plaque characteristics in young Indian patients with ACS who underwent percutaneous coronary intervention (PCI) using optical coherence tomography (OCT) imaging. MethodsThis was a prospective, multicentric, non-interventional study on patients aged 18–50 years presenting with ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction, or unstable angina, and were scheduled to undergo OCT-guided PCI. Major adverse cardiac events (MACE) were assessed post-procedure and at the 6-month and 12-month follow-ups. ResultsThe study included 100 ACS patients (mean age = 43.6 ± 5.2 years), with 51% presenting with STEMI. Pre-PCI OCT assessment showed that fibrous plaques (75%) were most common followed by plaques containing macrophages (27%), microchannels (20%), and calcified nodules (14%). In addition, plaque rupture, plaque erosion, and lipid-rich plaques, along with red, white, and mixed thrombi, were observed in 31%, 25%, 24%, 21%, 14%, and 17% (total thrombus occurrence = 52%) of the patients, respectively. At 12 months, the MACE (coronary artery bypass graft) rate was 1%. ConclusionsYoung Indian patients with ACS displayed a range of plaque morphologies identified through pre-PCI OCT. Among these, fibrous plaques were the most prominent type, followed by plaques containing macrophages. Additionally, plaque rupture, plaque erosion, and lipid-rich plaques were also observed in this population.