Atherosclerotic Wall Research Articles

Olfr2-positive macrophages originate from monocytes proliferate in situ and present a pro-inflammatory foamy-like phenotype.

Olfactory receptor 2 (Olfr2) has been identified in a minimum of 30% of vascular macrophages, and its depletion was shown to reduce atherosclerosis progression. Mononuclear phagocytes, including monocytes and macrophages within the vessel wall, are major players in atherosclerosis. Single-cell RNA sequencing studies revealed that atherosclerotic artery walls encompass several monocytes and vascular macrophages, defining at least nine distinct subsets potentially serving diverse functions in disease progression. This study investigates the functional phenotype and ontogeny of Olfr2-expressing vascular macrophages in atherosclerosis. Olfr2+ macrophages rapidly increase in Apoe-/- mice's aorta when fed a Western diet (WD). Mass cytometry showed that Olfr2+ cells are clustered within the CD64 high population and enriched for CD11c and Ccr2 markers. Olfr2+ macrophages express many pro-inflammatory cytokines, including Il1b, Il6, Il12, and Il23, and chemokines, including Ccl5, Cx3cl1, Cxcl9, and Ccl22. By extracting differentially expressed genes from bulk RNA sequencing (RNA-seq) of Olfr2+ vs. Olfr2- macrophages, we defined a signature that significantly mapped to single-cell data of plaque myeloid cells, including monocytes, subendothelial MacAir, and Trem2Gpnmb foamy macrophages. By adoptive transfer experiments, we identified that Olfr2 competent monocytes from CD45.1Apoe-/-Olfr2+/+ mice transferred into CD45.2Apoe-/-Olfr2-/- recipient mice fed WD for 12 weeks, accumulate in the atherosclerotic aorta wall already at 72 h, and differentiate in macrophages. Olfr2+ macrophages showed significantly increased BrdU incorporation compared to Olfr2- macrophages. Flow cytometry confirmed that at least 50% of aortic Olfr2+ macrophages are positive for BODIPY staining and have increased expression of both tumour necrosis factor and interleukin 6 compared to Olfr2- macrophages. Gene set enrichment analysis of the Olfr2+ macrophage signature revealed a similar enrichment pattern in human atherosclerotic plaques, particularly within foamy/TREM2hi-Mφ and monocytes. In summary, we conclude that Olfr2+ macrophages in the aorta originate from monocytes and can accumulate at the early stages of disease progression. These cells can undergo differentiation into MacAir and Trem2Gpnmb foamy macrophages, exhibiting proliferative and pro-inflammatory potentials. This dynamic behaviour positions them as key influencers in shaping the myeloid landscape within the atherosclerotic plaque.

Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability

BackgroundMetabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking.MethodsIn this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque.ResultsOur study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH−) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment.ConclusionsThis study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures.

Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis.

While our understanding of the single-cell gene expression patterns underlying the transformation of vascular cell types during the progression of atherosclerosis is rapidly improving, the clinical and pathophysiological relevance of these changes remains poorly understood. Single-cell RNA sequencing data generated with SmartSeq2 (≈8000 genes/cell) in 16 588 single cells isolated during atherosclerosis progression in Ldlr-/-Apob100/100 mice with human-like plasma lipoproteins and from humans with asymptomatic and symptomatic carotid plaques was clustered into multiple subtypes. For clinical and pathophysiological context, the advanced-stage and symptomatic subtype clusters were integrated with 135 tissue-specific (atherosclerotic aortic wall, mammary artery, liver, skeletal muscle, and visceral and subcutaneous, fat) gene-regulatory networks (GRNs) inferred from 600 coronary artery disease patients in the STARNET (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task) study. Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes. Integrative analysis of these 6 clusters with STARNET revealed significant enrichments of 3 arterial wall GRNs: GRN33 (macrophage), GRN39 (SMC), and GRN122 (macrophage) with major contributions to coronary artery disease heritability and strong associations with clinical scores of coronary atherosclerosis severity. The presence and pathophysiological relevance of GRN39 were verified in 5 independent RNAseq data sets obtained from the human coronary and aortic artery, and primary SMCs and by targeting its top-key drivers, FRZB and ALCAM in cultured human coronary artery SMCs. By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis.

Identification of PPARG as key gene to link coronary atherosclerosis disease and rheumatoid arthritis via microarray data analysis.

Inflammation is the common pathogenesis of coronary atherosclerosis disease (CAD) and rheumatoid arthritis (RA). Although it is established that RA increases the risk of CAD, the underlining mechanism remained indefinite. This study seeks to explore the molecular mechanisms of RA linked CAD and identify potential target gene for early prediction of CAD in RA patients. The study utilized five raw datasets: GSE55235, GSE55457, GSE12021 for RA patients, and GSE42148 and GSE20680 for CAD patients. Gene Set Enrichment Analysis (GSEA) was used to investigate common signaling pathways associated with RA and CAD. Then, weighted gene co-expression network analysis (WGCNA) was performed on RA and CAD training datasets to identify gene modules related to single-sample GSEA (ssGSEA) scores. Overlapping module genes and differentially expressed genes (DEGs) were considered as co-susceptible genes for both diseases. Three hub genes were screened using a protein-protein interaction (PPI) network analysis via Cytoscape plug-ins. The signaling pathways, immune infiltration, and transcription factors associated with these hub genes were analyzed to explore the underlying mechanism connecting both diseases. Immunohistochemistry and qRT-PCR were conducted to validate the expression of the key candidate gene, PPARG, in macrophages of synovial tissue and arterial walls from RA and CAD patients. The study found that Fc-gamma receptor-mediated endocytosis is a common signaling pathway for both RA and CAD. A total of 25 genes were screened by WGCNA and DEGs, which are involved in inflammation-related ligand-receptor interactions, cytoskeleton, and endocytosis signaling pathways. The principal component analysis(PCA) and support vector machine (SVM) and receiver-operator characteristic (ROC) analysis demonstrate that 25 DEGs can effectively distinguish RA and CAD groups from normal groups. Three hub genes TUBB2A, FKBP5, and PPARG were further identified by the Cytoscape software. Both FKBP5 and PPARG were downregulated in synovial tissue of RA and upregulated in the peripheral blood of CAD patients and differential mRNAexpreesion between normal and disease groups in both diseases were validated by qRT-PCR.Association of PPARG with monocyte was demonstrated across both training and validation datasets in CAD. PPARG expression is observed in control synovial epithelial cells and foamy macrophages of arterial walls, but was decreased in synovial epithelium of RA patients. Its expression in foamy macrophages of atherosclerotic vascular walls exhibits a positive correlation (r = 0.6276, p = 0.0002) with CD68. Our findings suggest that PPARG may serve as a potentially predictive marker for CAD in RA patients, which provides new insights into the molecular mechanism underling RA linked CAD.

Unsteady solute transport in Casson fluid flow and its retention in an atherosclerotic wall

In the current study, a mathematical model of convective solute transport and its retention in an atherosclerotic wall is examined. The artery wall is supposed to be permeable and has cosine-shaped stenosis caused by various sorts of abnormal growth or plaque formation. The flowing blood is modeled as the suspension of all red blood cells in plasma, thought to be Casson fluid. The Immersed Boundary Method (IBM) and the Marker and Cell (MAC) method are used to numerically solve the unsteady governing equations of motion along with the appropriate initial and boundary conditions. The final results of the quantitative studies contain the corresponding flow-field and solute distribution profiles for the full arterial length. The essential components are evaluated, including the wall shear stress, wall concentration, and concentration contours. According to simulation data, the permeability of the wall directly affects the solute transport within the therapeutic region. The yield stress does, however, increase flow resistance and decrease solute uptake within the tissue. The projected outcomes are remarkably in line with previously published findings, which supports the applicability of the model under investigation.

On the Impact of Residual Strains in the Stress Analysis of Patient-Specific Atherosclerotic Carotid Vessels: Predictions Based on the Homogenous Stress Hypothesis

The identification of carotid atherosclerotic lesion at risk for plaque rupture, eventually resulting in cerebral embolism and stroke, is of paramount clinical importance. High stress in the fibrous plaque cap has been proposed as risk factor. However, among others, residual strains influence said stress predictions, but quantitative and qualitative implications of residual strains in this context are not well explored. We therefore propose a multiplicative kinematics-based Growth and Remodeling (G&R) framework to predict residual strains from homogenizing tissue stress and then investigate its implication on plaque stress. Carotid vessel morphology of four patients was reconstructed from clinical Computed Tomography-Angiography (CT-A) images and equipped with heterogeneous tissue constitutive properties assigned through a histology-based artificial intelligence image segmentation tool. As compared to a purely elastic analysis and depending on patient-specific morphology and tissue distributions, the incorporation of residual strains reduced the maximum wall stress by up to 30%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$30\\%$$\\end{document} and resulted in a fundamentally different distribution of stress across the atherosclerotic wall. Regardless residual strains homogenized tissue stresses, the fibrous plaque cap may persistently be exposed to spots of high stress. In conclusion, the incorporation of residual strains in biomechanical studies of atherosclerotic carotids may be important for a reliable assessment of fibrous plaque cap stress.

3D patient-specific modeling and structural finite element analysis of atherosclerotic carotid artery based on computed tomography angiography

The assessment of carotid plaque vulnerability is a relevant clinical information that can help prevent adverse cerebrovascular events. To this aim, in this study, we propose a patient-specific computational workflow to quantify the stress distribution in an atherosclerotic carotid artery, by means of geometric modeling and structural simulation of the plaque and vessel wall. Ten patients were involved in our study. Starting with segmentation of the lumen, calcific and lipid plaque components from computed tomography angiography images, the fibrous component and the vessel wall were semi-automatically reconstructed with an ad-hoc procedure. Finite element analyses were performed using local pressure values derived from ultrasound imaging. Simulation outputs were analyzed to assess how mechanical factors influence the stresses within the atherosclerotic wall. The developed reconstruction method was first evaluated by comparing the results obtained using the automatically generated fibrous component model and the one derived from image segmentation. The high-stress regions in the carotid artery wall around plaques suggest areas of possible rupture. In mostly lipidic and heterogeneous plaques, the highest stresses are localized at the interface between the lipidic components and the lumen, in the fibrous cap.

Mechanical properties of atherosclerotic plaques, caps and walls of arterial vessels: a mobile test bench experiments

Within the framework of this study, a methodology and a prototype of a test bench for conducting experiments on compression of biological tissue samples have been developed. The test bench for the implementation of the technique consists of high–precision scales (measuring accuracy up to 0.01 g, maximum weight - 5 kg), an electronic caliper (measuring accuracy up to 0.01 mm) with 3D-printer pads that are attached to grips, as well as video cameras. Thanks to such a mobile stand, it was possible to conduct a series of experiments (a total of 99 tests) to determine the Young's modulus of atherosclerotic plaques and areas of vascular walls removed from the body no later than a few hours. This made it possible to collect a database of the mechanical characteristics of the plaques as close as possible to the real properties. In addition, regression dependences were constructed between the Hounsfield numbers corresponding to dense atherosclerotic deposits discernible on a CT scan and the Young modules obtained during experiments. Such dependencies will further allow determining the mechanical properties of plaques in vivo based on computed tomography data. The technique was verified by mechanical experiments on the universal testing machine Instron 3342 and on a mobile test bench on samples of hard (with pronounced calcification) and soft plaques. 7 experiments were conducted for each type of samples. The results differed by no more than 4.3 % for soft plaques and no more than 9.5 % for hard plaques. To test the inter-expert reliability of the methodology, a number of experiments were conducted with the involvement of two independent participants. Each of the three mobile stand operators performed 5 tests on soft rubber samples. The study of inter-expert reliability allowed us to show the independence of the methodology from the skills and qualifications of the operator.

Malondialdehyde as an Important Key Factor of Molecular Mechanisms of Vascular Wall Damage under Heart Diseases Development.

This mini review is devoted to a specific issue: the role of malondialdehyde (MDA)-a secondary product of free radical lipid peroxidation-in the molecular mechanisms of the formation of primary atherosclerotic vascular wall lesions. The principal difference between this review and the available literature is that it discusses in detail the important role in atherogenesis not of "oxidized" LDL (i.e., LDL particles containing lipohydroperoxides), but of LDL particles chemically modified by the natural low-molecular weight dicarbonyl MDA. To confirm this, we consider the data obtained by us earlier, indicating that "atherogenic" are not LDL oxidized as a result of free radical lipoperoxidation and containing lipohydroperoxy derivatives of phospholipids in the outer layer of particles, but LDL whose apoprotein B-100 has been modified due to the chemical reaction of terminal lysine residue amino groups of the apoB-100 with the aldehyde groups of the MDA (Maillard reaction). In addition, we present our original data proving that MDA injures endothelial glycocalyx that suppress the ability of the endothelium to control arterial tone according to changes in wall shear stress. In summary, this mini review for the first time exhaustively discloses the key role of MDA in atherogenesis.

Pericarditis and Takotsubo Syndrome-Diagnosis of Cardiac Complications of Post-Acute COVID-19 Syndrome in a 77-Year-Old Woman.

The SARS-CoV-2 virus infection most often takes the form of acute COVID-19 respiratory disease, but in some patients, it turns into acute COVID-19 syndrome after a few weeks. Cardiac complications occur in the form of acute and post-acute diseases and the most common are myocarditis, pericarditis, arrhythmias, and acute coronary syndromes or Takotsubo syndrome. Cardiovascular complications are often the cause of hospitalization and death in COVID-19 patients. We present the case of a 77-year-old woman who was admitted to the clinic with suspected myocardial infarction. Coronary arteriography revealed atherosclerotic wall lesions, and echocardiography showed a good contractility of the left ventricle and fluid in the pericardial sac. Pericarditis was diagnosed. In the following days, acute kidney damage was observed, and one hemodialysis session was performed. On the sixth day of hospitalization, a sudden cardiac arrest occurred, and the patient was resuscitated. The echocardiogaphy showed abnormal contractility of the left ventricular with the ejection fraction of 15%—Takotsubo image. After a few hours, a cardiac arrest occurred again, and the patient died.

Dicarbonyl-Dependent Modification of LDL as a Key Factor of Endothelial Dysfunction and Atherosclerotic Vascular Wall Damage.

The review presents evidence that the main damage to the vascular wall occurs not from the action of “oxidized” LDL, which contain hydroperoxy acyls in the phospholipids located in their outer layer, but from the action of LDL particles whose apoprotein B-100 is chemically modified with low molecular weight dicarbonyls, such as malondialdehyde, glyoxal, and methylglyoxal. It has been argued that dicarbonyl-modified LDL, which have the highest cholesterol content, are particularly “atherogenic”. High levels of dicarbonyl-modified LDL have been found to be characteristic of some mutations of apoprotein B-100. Based on the reviewed data, we hypothesized a common molecular mechanism underlying vascular wall damage in atherosclerosis and diabetes mellitus. The important role of oxidatively modified LDL in endothelial dysfunction is discussed in detail. In particular, the role of the interaction of the endothelial receptor LOX-1 with oxidatively modified LDL, which leads to the expression of NADPH oxidase, which in turn generates superoxide anion radical, is discussed. Such hyperproduction of ROS can cause destruction of the glycocalyx, a protective layer of endotheliocytes, and stimulation of apoptosis in these cells. On the whole, the accumulated evidence suggests that carbonyl modification of apoprotein B-100 of LDL is a key factor responsible for vascular wall damage leading to atherogenesis and endothelial dysfunction. Possible ways of pharmacological correction of free radical processes in atherogenesis and diabetogenesis are also discussed.

Silencing of IGF2BP1 restrains ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and promoting autophagy in macrophages.

Atherosclerosis (AS) is a chronic inflammatory disease with the formation and accumulation of macrophage-derived foam cells in the subendothelial space of blood vessels as one major characteristic. Insulin-like growth factor 2 messenger RNA (mRNA) binding protein 1 (IGF2BP1) is an RNA-binding factor and its elevation has been reported to be associated with macrophage infiltration into the atherosclerotic vascular wall. This study aims to investigate the roles of IGF2BP1 in AS-associated foam cell formation. Herein, ApoE-/- mice fed with high-fat diet developed atherosclerotic lesions in the aorta, where IGF2BP1 expression was upregulated and autophagy was impaired. IGF2BP1 expressed in F4/80+ macrophages and coexisted with p62. In vitro, IGF2BP1 expression was upregulated in RAW264.7 macrophages exposed to oxidized low-density lipoprotein (ox-LDL) (100 μg/ml). Interestingly, silencing of IGF2BP1 ameliorated ox-LDL-induced lipid accumulation and inflammation, and enhanced autophagic flux in macrophages. Furthermore, the expression of RUNX family transcription factor 1 (RUNX1), a gene that is able to inhibit autophagy in multiple cell types, was elevated in atherosclerotic aortas and in ox-LDL-treated macrophages. In addition, RNA immunoprecipitation results revealed that IGF2BP1 is bound to RUNX1 mRNA. Alterations induced by IGF2BP1 knockdown in ox-LDL-treated macrophages were abolished by RUNX1 overexpression. Furthermore, afterautophagy inhibitor 3-methyladenine administration, silencing of IGF2BP1-reduced lipid accumulation and inflammation were recovered in RAW264.7 cells. In summary, our study demonstrated that silencing of IGF2BP1 restrained ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and facilitating autophagy in macrophages. IGF2BP1/RUNX1 axis may be considered as a potential therapeutic target in AS.

Identification of Key Genes Associated with Endothelial Cell Dysfunction in Atherosclerosis Using Multiple Bioinformatics Tools.

Atherosclerosis is the most notable cardiovascular disease, the latter being the main cause of death globally. Endothelial cell dysfunction plays a major role in the pathogenesis of atherosclerosis. However, it is currently unclear which genes are involved between endothelial cell dysfunction and atherosclerosis. This study was aimed at identifying these genes. Based on the GSE83500 dataset, the quantification of endothelial cell function was conducted using single-sample gene set enrichment analysis; the coexpression modules were conducted using weighted correlation network analysis. After building module-trait relationships, tan and yellow modules were regarded as hub modules. 10 hub genes from each hub module were identified by the protein-protein interaction network analysis. The key genes (RAB5A, CTTN, ITGB1, and MMP9) were obtained by comparing the expression differences of the hub gene between atherosclerotic and normal groups from the GSE28829 and GSE43292 datasets, respectively. ROC analysis showed the diagnostic value of key genes. Moreover, the differential expression of key genes in normal and atherosclerotic aortic walls was verified. In vitro, we establish a model of ox-LDL-injured endothelial cells and transfect RAB5A overexpression and shRNA plasmids. The results showed that overexpression of RAB5A ameliorates the proliferation and migration function of ox-LDL-injured endothelial cells, including the ability of tubule formation. It was speculated that the interferon response, Notch signaling pathways, etc. were involved in this function of RAB5A by using gene set variation analysis. With the multiple bioinformatics analysis methods, we detected that yellow and tan modules are related to the abnormal proliferation and migration of endothelial cells associated with atherosclerosis. RAB5A, CTTN, ITGB1, and MMP9 can be used as potential targets for therapy and diagnostic markers. In vitro, overexpression of RAB5A can ameliorate the proliferation and migration function of ox-LDL-injured endothelial cells, and the possible molecules involved in this process were speculated.

Unseen Artificial Intelligence-Deep Learning Paradigm for Segmentation of Low Atherosclerotic Plaque in Carotid Ultrasound: A Multicenter Cardiovascular Study.

Background: The early detection of carotid wall plaque is recommended in the prevention of cardiovascular disease (CVD) in moderate-risk patients. Previous techniques for B-mode carotid atherosclerotic wall plaque segmentation used artificial intelligence (AI) methods on monoethnic databases, where training and testing are from the “same” ethnic group (“Seen AI”). Therefore, the versatility of the system is questionable. This is the first study of its kind that uses the “Unseen AI” paradigm where training and testing are from “different” ethnic groups. We hypothesized that deep learning (DL) models should perform in 10% proximity between “Unseen AI” and “Seen AI”. Methodology: Two cohorts from multi-ethnic groups (330 Japanese and 300 Hong Kong (HK)) were used for the validation of our hypothesis. We used a four-layered UNet architecture for the segmentation of the atherosclerotic wall with low plaque. “Unseen AI” (training: Japanese, testing: HK or vice versa) and “Seen AI” experiments (single ethnicity or mixed ethnicity) were performed. Evaluation was conducted by measuring the wall plaque area. Statistical tests were conducted for its stability and reliability. Results: When using the UNet DL architecture, the “Unseen AI” pair one (Training: 330 Japanese and Testing: 300 HK), the mean accuracy, dice-similarity, and correlation-coefficient were 98.55, 78.38, and 0.80 (p < 0.0001), respectively, while for “Unseen AI” pair two (Training: 300 HK and Testing: 330 Japanese), these were 98.67, 82.49, and 0.87 (p < 0.0001), respectively. Using “Seen AI”, the same parameters were 99.01, 86.89 and 0.92 (p < 0.0001), respectively. Conclusion: We demonstrated that “Unseen AI” was in close proximity (<10%) to “Seen AI”, validating our DL model for low atherosclerotic wall plaque segmentation. The online system runs < 1 s.

NIA Long Life Family Study: Objectives, Design, and Heritability of Cross-Sectional and Longitudinal Phenotypes.

The NIA Long Life Family Study (LLFS) is a longitudinal, multicenter, multinational, population-based multigenerational family study of the genetic and nongenetic determinants of exceptional longevity and healthy aging. The Visit 1 in-person evaluation (2006–2009) recruited 4 953 individuals from 539 two-generation families, selected from the upper 1% tail of the Family Longevity Selection Score (FLoSS, which quantifies the degree of familial clustering of longevity). Demographic, anthropometric, cognitive, activities of daily living, ankle-brachial index, blood pressure, physical performance, and pulmonary function, along with serum, plasma, lymphocytes, red cells, and DNA, were collected. A Genome Wide Association Scan (GWAS) (Ilumina Omni 2.5M chip) followed by imputation was conducted. Visit 2 (2014–2017) repeated all Visit 1 protocols and added carotid ultrasonography of atherosclerotic plaque and wall thickness, additional cognitive testing, and perceived fatigability. On average, LLFS families show healthier aging profiles than reference populations, such as the Framingham Heart Study, at all age/sex groups, for many critical healthy aging phenotypes. However, participants are not uniformly protected. There is considerable heterogeneity among the pedigrees, with some showing exceptional cognition, others showing exceptional grip strength, others exceptional pulmonary function, etc. with little overlap in these families. There is strong heritability for key healthy aging phenotypes, both cross-sectionally and longitudinally, suggesting that at least some of this protection may be genetic. Little of the variance in these heritable phenotypes is explained by the common genome (GWAS + Imputation), which may indicate that rare protective variants for specific phenotypes may be running in selected families.

Atherosclerotic lesion-specific copper delivery suppresses atherosclerosis in high-cholesterol-fed rabbits.

Dietary cholesterol supplements cause hypercholesterolemia and atherosclerosis along with a reduction of copper concentrations in the atherosclerotic wall in animal models. This study was to determine if target-specific copper delivery to the copper-deficient atherosclerotic wall can block the pathogenesis of atherosclerosis. Male New Zealand white rabbits, 10-weeks-old and averaged 2.0 kg, were fed a diet containing 1% (w/w) cholesterol or the same diet without cholesterol as control. Twelve weeks after the feeding, the animals were injected with copper-albumin microbubbles and subjected to ultrasound sonication specifically directed at the atherosclerotic lesions (Cu-MB-US) for target-specific copper delivery, twice a week for four weeks. This regiment was repeated 3 times with a gap of two weeks in between. Two weeks after the last treatment, the animals were harvested for analyses of serum and aortic pathological changes. Compared to controls, rabbits fed cholesterol-rich diet developed atherosclerotic lesion with a reduction in copper concentrations in the lesion tissue. Cu-MB-US treatment significantly increased copper concentrations in the lesion, and reduced the size of the lesion. Furthermore, copper repletion reduced the number of apoptotic cells as well as the content of cholesterol and phospholipids in the atherosclerotic lesion without a disturbance of the stability of the lesion. The results thus demonstrate that target-specific copper supplementation suppresses the progression of atherosclerosis at least in part through preventing endothelial cell death, thus reducing lipid infiltration in the atherosclerotic lesion.

Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress.

Atherosclerosis remains the underlying process responsible for cardiovascular diseases and the high mortality rates associated. This chronic inflammatory disease progresses with the formation of occlusive atherosclerotic plaques over the inner walls of vascular vessels, with oxidative stress being an important element of this pathology. Oxidation of low-density lipoproteins (ox-LDL) induces endothelial dysfunction, foam cell activation, and inflammatory response, resulting in the formation of fatty streaks in the atherosclerotic wall. With this in mind, different approaches aim to reduce oxidative damage as a strategy to tackle the progression of atherosclerosis. Special attention has been paid in recent years to the transcription factor Nrf2 and its downstream-regulated protein heme oxygenase-1 (HO-1), both known to provide protection against atherosclerotic injury. In the current review, we summarize the involvement of oxidative stress in atherosclerosis, focusing on the role that these antioxidant molecules exert, as well as the potential therapeutic strategies applied to enhance their antioxidant and antiatherogenic properties.

An unusual long standing metallic foreign body in nasopharynx in an adult

&lt;p class="abstract"&gt;This case report was to highlight the occurrence of a long standing unusual foreign body in the nasopharynx in an adult. Foreign bodies are common in ENT practice universally. At times they may present as emergency requiring urgent intervention and many a times they go unnoticed as these are not suspected. Nasopharyngeal foreign bodies are rare in any age group. A 70 year old man presented to neurology department with complaints of headache of 1 month duration. CT brain angiography showed atherosclerotic wall calcifications in bilateral cavernous segment of ICA and there was an incidental detection of a metallic foreign body in the posterior wall of oropharynx. History revealed accidental ingestion of a ring into mouth at 1 year of age. Diagnostic nasal endoscopy (DNE) was done, FB (foreign body) ring was seen at the level of left torus tubarius in nasopharynx and same removed in to intraorally. Care should be taken while removing these FBs. Digital manipulation for removal of such FBs are hazardous and should be avoided at all cost.&lt;/p&gt;

Unruptured Paraclinoid Carotid Aneurysms Occur More Frequently in Younger Ages.

PurposeWe investigated the age distribution of cerebral saccular aneurysms in various locations to clarify the differences by location and discuss the mechanism of formation.Materials and MethodsWe retrospectively assessed clinical material obtained from 1,252 unruptured aneurysms treated with endovascular embolization between 2004 and 2019. Age, sex, laterality, and size were investigated by the location of aneurysms, classified as cavernous internal carotid artery (ICA), paraclinoid ICA, supraclinoid ICA, anterior communicating artery, anterior cerebral artery, middle cerebral artery, basilar artery complex, and posterior inferior cerebellar artery. Paraclinoid aneurysms were subclassified into 3 patterns according to their projecting direction: S-type, with superior protrusion; M-type, with medial protrusion; and P-type, with posteroinferior protrusion.ResultsThere was no significant difference by location for sex, laterality, and size. The mean age of patients with paraclinoid aneurysms (56.5 years old) was significantly lower than that of other aneurysm patients (64.3 years old). Notably, 40% of the patients with M-type aneurysms were <50 years old. This percentage was significantly higher than that of aneurysms at other locations (P<0.05).ConclusionWe found a young female predominance for patients with paraclinoid carotid aneurysms. This study may suggest that congenital factors contribute to paraclinoid aneurysm formation as well acquired factors, such as hemodynamic stress, atherosclerotic wall damage, and local inflammation.

Supraclinoid internal carotid artery blister-like aneurysms: hypothesized pathogenesis and microsurgical clipping outcomes

BackgroundBlister-like aneurysms (BLAs) on the supraclinoid segment of the internal carotid artery (ICA) are an enigma of cerebrovascular disease. Neither has a definite pathogenesis been so far identified, nor have uniform treatment guidelines been established for them. Our aim was to develop a hypothesis regarding the evolution of BLAs according to their macroscopic morphologies and to evaluate the efficacy of microsurgical clipping.MethodsThe clinical data and morphological features of 15 consecutive patients with 16 BLAs on the supraclinoid ICA were retrospectively reviewed. The treatment strategies were analyzed, and functional outcomes were evaluated using the modified Rankin scale (mRS). Favorable outcomes were defined as a mRS score of 0–2.ResultsMorphologically, aneurysm growth with expansion of the aneurysm neck before the surgical procedure occurred in two ruptured and one unruptured aneurysm. Daughter bleb formation was observed in two ruptured and five unruptured aneurysms. A varied degree of parent artery sclerosis was observed in nine patients. Thirteen patients were treated with direct surgical clipping, one patient was treated with clipping and wrapping, and the remaining patient was treated with an encircling clipping graft. Favorable and unfavorable outcomes were observed in 13 and two cases, respectively. Follow-up angiograms revealed 4 cases of stenosis with respective degree of mild, 30%, 50%, and 80% without any neurological dysfunction.ConclusionsWe suggest a hypothesis that BLAs on the supraclinoid ICA may share different evolving mechanisms between ruptured and unruptured lesions. A majority of them can be reliably and safely obliterated by direct clipping technique, except for the aneurysms accompanied with severely atherosclerotic parent walls.