scholarly journals An investigation into the critical role of fibre orientation in the ultimate tensile strength and stiffness of human carotid plaque caps

2020 ◽  
Author(s):  
R.D. Johnston ◽  
R.T. Gaul ◽  
C. Lally
Keyword(s):  
Atherosclerotic Plaque ◽  
Critical Role ◽  
Experimental Studies ◽  
Atherosclerotic Lesion ◽  
Collagen Fibre ◽  
Atherosclerotic Plaques ◽  
Fibrous Plaque ◽  
Carotid Plaques ◽  
Risk Of Rupture ◽  
Human Carotid

AbstractThe development and subsequent rupture of atherosclerotic plaques in human carotid arteries is a major cause of ischemic stroke. Mechanical characterization of atherosclerotic plaques can aid our understanding of this rupture risk. Despite this however, experimental studies on human atherosclerotic carotid plaques, and fibrous plaque caps in particular, are very limited. This study aims to provide further insights into atherosclerotic plaque rupture by mechanically testing human fibrous plaque caps, the region of the atherosclerotic lesion most often attributed the highest risk of rupture. The results obtained highlight the variability in the ultimate tensile stress, strain and stiffness experienced in atherosclerotic plaque caps. By pre-screening all samples using small angle light scattering (SALS) to determine the dominant fibre direction in the tissue, along with supporting histological analysis, this work suggests that the collagen fibre alignment in the circumferential direction plays the most dominant role for determining plaque structural stability. The work presented in this study could provide the basis for new diagnostic approaches to be developed, which non-invasively identify carotid plaques at greatest risk of rupture.Graphical Abstract

Deficiency of endothelial CD40 induces a stable plaque phenotype and limits inflammatory cell recruitment to atherosclerotic lesions in mice

2021 ◽  
Author(s):  
Mark Colin Gissler ◽  
Philipp Scherrer ◽  
Nathaly Anto Michel ◽  
Jan Pennig ◽  
Natalie Hoppe ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Cell ◽  
Leukocyte Adhesion ◽  
Critical Role ◽  
Atherosclerotic Lesion ◽  
Intercellular Adhesion Molecule ◽  
Atherosclerotic Plaques ◽  
Chow Diet ◽  
Stable Plaque ◽  
Plaque Phenotype

Objectives: The co-stimulatory CD40L-CD40 dyad exerts a critical role in atherosclerosis by modulating leukocyte accumulation into developing atherosclerotic plaques. The requirement for cell-type specific expression of both molecules, however, remains elusive. Here, we evaluate the contribution of CD40 expressed on endothelial cells (ECs) in a mouse model of atherosclerosis. Approach & Results: Atherosclerotic plaques of Apolipoprotein E deficient (Apoe-/-) mice and humans displayed increased expression of CD40 on ECs compared to controls. To interrogate the role of CD40 on ECs in atherosclerosis, we induced EC-specific (BmxCreERT2-driven) deficiency of CD40 in Apoe-/- mice. After feeding a chow diet for 25 weeks, EC-specific deletion of CD40 (iEC-CD40) ameliorated plaque lipid deposition and lesional macrophage accumulation but increased intimal smooth muscle cell and collagen content, while atherosclerotic lesion size did not change. Leukocyte adhesion to the vessel wall was impaired in iEC-CD40-deficient mice as demonstrated by intravital microscopy. In accord, expression of vascular adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in the vascular endothelium declined after deletion of CD40. In vitro, antibody-mediated inhibition of human endothelial CD40 significantly abated monocyte adhesion on ECs. Conclusions: Endothelial deficiency of CD40 in mice promotes structural features associated with a stable plaque phenotype in humans and decreases leukocyte adhesion. These results suggest that endothelial-expressed CD40 contributes to inflammatory cell migration and consecutive plaque formation in atherogenesis.

Expression and Cellular Localization of CXCR4 and CXCL12 in Human Carotid Atherosclerotic Plaques

2018 ◽  
Vol 118 (01) ◽  
pp. 195-206 ◽  
Author(s):  
Sophie Merckelbach ◽  
Emiel van der Vorst ◽  
Michael Kallmayer ◽  
Christoph Rischpler ◽  
Rainer Burgkart ◽  
...  
Keyword(s):  
Protein Level ◽  
Cellular Localization ◽  
Mrna Level ◽  
Plaque Morphology ◽  
Atherosclerotic Plaques ◽  
Cxcl12 Expression ◽  
Carotid Plaques ◽  
Unstable Plaques ◽  
Human Carotid

Background and Aims The CXCR4/CXCL12 complex has already been associated with progression of atherosclerosis; however, its exact role is yet unknown. The aim of this study was to analyse the expression and cellular localization of CXCL12 and its receptor CXCR4 in human carotid atherosclerotic plaques. Methods Carotid plaques (n = 58; 31 stable, 27 unstable, based on histological characterization of plaque morphology) were obtained during carotid endarterectomy, and 10 healthy vessels were used as a control. Expression of cxcr4, cxcr7, cxcl12, ccl2/ccr2 and csf1/csf1r was analysed at mRNA, and level expression of CXCR4, CXCR7 and CXCL12 was analysed at protein level. Cellular localization was determined using consecutive and double immunohistochemical (IHC) staining and microdissection. Results At mRNA level, cxcr4, cxcr7 and cxcl12 were significantly higher expressed in stable carotid plaques compared with controls (p = 0.011, p < 0.001 and p < 0.001). Cxcl12 mRNA expression was successively augmented toward unstable plaques (p < 0.001). At protein level, CXCR4, CXCR7 and CXCL12 expression was significantly increased in both stable (p = 0.001, p < 0.001 and p = 0.035, respectively) and unstable (p = 0.003, p < 0.001 and p = 0.045, respectively) plaques compared with controls. Using IHC, CXCR4 was particularly localized in macrophages and small neovessels. Microdissection confirmed strongest expression of cxcr4 in macrophages within atherosclerotic plaques. Leukocytes and smooth muscle cells showed cxcr4 expression as well. For cxcl12, only microdissected areas with macrophages were positive. Conclusion Expression of CXCR4 and CXCL12 was significantly increased in both stable and unstable carotid atherosclerotic plaques compared with healthy vessels, both at mRNA and protein level. CXCR4 and CXCL12 were localized particularly in macrophages.

Abstract 511: Mrp8 And Mrp14,Endogenous Activators of Toll-lLke Receptor4, are Associated with Rupture-Prone Human Atherosclerotic Plaques

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mihaela G Ionita ◽  
Gerard Pasterkamp ◽  
Dominique deKleijn
Keyword(s):  
Atherosclerotic Plaque ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Lesions ◽  
Inflammatory Status ◽  
Potential Marker ◽  
Plaque Phenotype ◽  
Histological Characteristics ◽  
Unstable Plaques ◽  
Human Carotid

Objectives : Atherosclerosis is a chronic, complex inflammatory process and is the underlying cause of stroke and myocardial infarction due to rupture of the atherosclerotic plaque leading to acute occlusion of the artery in the brain or heart. Macrophages, infiltrating atherosclerotic lesions, abundantly express Mrp8 and Mrp14. Recently Mrp8, Mrp14 and the complex Mrp8/14 have been identified as endogenous ligands of Tlr-4.The role of Tlr-4 in the development and progression of the atherosclerotic plaque is well recognized and it is associated with a rupture-prone plaque phenotype. Expression of Mrps in human plaques and its relation to plaque phenotype is unknown. For this, we investigated the levels of Mrp8, Mrp14 and Mrp8/14 complex in a large number of human atherosclerotic plaques. Methods and results : Mrp8, Mrp14 and Mrp8/14 were quantified by ELISAs in human carotid endarterectomy specimens (186 patients) and plaque phenotype was determined by immunohistochemistry. Mrp levels were higher in the unstable (58 fibro-atheromatous, 64 atheromatous) compared to the stable (64 fibrous) plaques: Mrp8 p = 0.001 ; Mrp14 p = 0.001 ; Mrp8/14 p = 0.01 . Concomitantly, Mrp8, Mrp14 and Mrp8/14 were associated with characteristics of unstable plaques: more macrophages ( p = 0.024; p = 0.002; p = 0.076 ), less smooth muscle cells ( p = 0.041; p = 0.001; p = 0.074 ), larger lipid core ( p = 0.001; p = 0.001; p=0.004 ), less collagen ( p = 0.440; p = 0.011; p = 0.372 ). Furthermore, Mrp plaque levels were positively correlated with the pro-inflammatory cytokines (IL-6 and IL-8) and matrix metalloproteinsases (MMP2, MMP8 and MMP9) plaque levels. EDA, marker of stable plaques, was negatively associated with Mrps plaque levels. Histological analysis revealed that Mrps are expressed by a subgroup of plaque macrophages localized in the plaque cap and shoulder, the most rupture-prone sites of an atherosclerotic plaque. Conclusions: We show that Mrp8, Mrp14 and Mrp8/14 are strongly associated with the histological characteristics and inflammatory status of human rupture-prone plaques and identify Mrps as a potential marker for rupture-prone plaques.

scholarly journals The cellular biology of atherosclerosis with atherosclerotic lesion classification and biomarkers

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Leta Melaku ◽  
Addisu Dabi
Keyword(s):  
Atherosclerotic Plaque ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Plaque Formation ◽  
Necrotic Core ◽  
Atherosclerotic Plaques ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Lesion Classification

Abstract Background Atherosclerosis is a chronic lipid-driven inflammatory disease with infiltration of low-density lipoprotein and is considered as the pivotal step in plaque formation. The aim of the review is to get into the fine details of pathophysiologic mechanisms responsible for atherosclerosis with atherosclerotic lesion classification. It also provides a summary of current biomarkers other than the traditional risk factors so that new treatment modalities can emerge and reduce the morbidity and mortality associated with atherosclerosis. Main body In the classification of atherosclerosis made by American Heart Association (AHA), AHA Type I lesion is the earliest vascular change described microscopically. AHA Type II lesion is primarily composed of abundant macrophages. AHA Type III lesion is the earliest of progressive lesions, while AHA Type IV lesion consists of an acellular necrotic core. Various biomarkers are implicated in different stages of the pathophysiological mechanism of plaque formation and evolution. C Reactive Protein plays a direct role in promoting the inflammatory component of atherosclerosis. Fibrinogen was demonstrated to be elevated among patients with acute thrombosis. Higher leukocyte count is associated with a greater cardiovascular risk. Cytokines have been implicated in atheroma formation and complications. High rates of protease activated receptor expression are also induced by interleukin-6 secretion in atherosclerotic lesions and areas of vascular tissue injury. Cluster of differentiation 40 receptor and its ligand have been also detected in atherosclerotic plaques. Osteopontin, acidic phosphoprotein, and osteoprotegerin have emerged as novel markers of atherosclerotic plaque composition. There are also overproductions of matrix metalloproteinases in the rupture-prone regions and promote lipid-necrotic core formation in the atherosclerotic plaque. Myeloperoxidase has been proposed as a marker of plaque instability. Oxidized low-density lipoprotein receptor 1 provides a route of entry for oxidized low-density lipoprotein into the endothelium. A human atherosclerotic lesion also expresses lipoprotein-associated phospholipase A2. Short conclusion Atherosclerotic plaques are the battlefield between an unbalanced immune response and lipid accumulation in the intima of arteries. Most of the biomarkers associated with atherosclerosis are indicators of inflammatory response and will also be used for medical purposes.

Myocardial bridge analysis by multidetector computed tomography and its association with coronary atherosclerosis

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Mohamed Ismail Ahmed Abd El Ati Mousa ◽  
Yasser Gomaa Mohamed ◽  
Ahmed Mohamed Onsy
Keyword(s):  
Coronary Artery ◽  
Coronary Angiography ◽  
Atherosclerotic Plaque ◽  
Significant Risk ◽  
Atherosclerotic Lesion ◽  
Lesion Group ◽  
Atherosclerotic Plaques ◽  
Myocardial Bridge ◽  
Group A ◽  
Group B

Abstract Background Myocardial Bridging an inborn coronary abnormality, is defined as a segment of a major epicardial coronary artery, the tunneled artery, that goes intramurally through the myocardium beneath the muscle bridge. Objective To evaluate noninvasively the presence and distribution of atherosclerotic plaques in relation to myocardial bridge coronary segments and to determine the prevalence of myocardial bridges and their location and morphology by using MDCT. Patients and Methods The study population consisted of 55 patients presented with chest pain, referred for MDCT coronary angiography and found to have myocardial bridge at during the period from April 2018 and August 2019. 23 patients was found having Myocardial Bridge and coronary artery atherosclerotic plaques included in Group (A), 29 persons found having Myocardial Bridge without CAD included in Group (B). All patients were subjected to detailed history taking, clinical evaluation, ECG analysis and MSCT coronary angiography. Results In the present study, patients with atherosclerotic plaque (group A) (n = 29), mean age was 52.41 ± 10.55 years ranged from 35.0 to 73.0 years, 41.4% were males, while in Myocardial bridge without atherosclerotic lesion group (group B) (n = 26), mean age was 51.65 ± 7.58 ranged from 38.0 to 65.0 years., 30.8% were males. Conclusion Our study showed that diabetes mellitus and dyslipidemia are a significant risk factor for developing atherosclerotic plaque in the segment proximal to myocardial bridge. Myocardial bridge were usually located over the Mid segment of the left anterior descending coronary artery

Mechanical Characterization of Fresh Human Carotid Atherosclerotic Plaque

2009 ◽  
Author(s):  
Eoghan Maher ◽  
Arthur Creane ◽  
Sherif Sultan ◽  
Niamh Hynes ◽  
Caitríona Lally ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Mechanical Characterization ◽  
External Carotid ◽  
Atherosclerotic Plaques ◽  
Finite Element Models ◽  
Tissue Properties ◽  
Surgical Interventions ◽  
The Relationship ◽  
Human Carotid

Quantifying the properties of atherosclerotic plaques is critical to improving our understanding of the pathogenesis of the disease. Furthermore realistic tissue properties are vital in order to obtain legitimate results from finite element models of surgical interventions used to treat cardiovascular disease. The aim of this study is to determine the mechanical properties of fresh human carotid plaques immediately following removal during endarterectomy. A number of studies have reported atherosclerotic plaque properties previously [1–3], however all of these tested cadaveric tissue. This study will further investigate in-patient and inter-patient variability, the relationship between plaque properties and their clinical classification (calcified, mixed or echolucent) and the location of the sample (common, internal, external carotid).

Molecular imaging of matrix metalloproteinases in atherosclerotic plaques

2012 ◽  
Vol 107 (03) ◽  
pp. 409-416 ◽  
Author(s):  
Sébastien Lenglet ◽  
Aurélien Thomas ◽  
Pierre Chaurand ◽  
Katia Galan ◽  
François Mach ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Atherosclerotic Plaque ◽  
Proteolytic Enzymes ◽  
Imaging Techniques ◽  
Atherosclerotic Plaques ◽  
Vessel Lumen ◽  
Risk Of Rupture ◽  
Risk Assessment And Prevention ◽  
Experimental Findings ◽  
Acute Event

SummaryIschaemic stroke and myocardial infarction often result from the sudden rupture of an atherosclerotic plaque. The subsequent arterial thrombosis occluding the vessel lumen has been widely indicated as the crucial acute event causing peripheral tissue ischaemia. A complex cross-talk between systemic and intraplaque inflammatory mediators has been shown to regulate maturation, remodeling and final rupture of an atherosclerotic plaque. Matrix metalloproteinases (MMPs) are proteolytic enzymes (released by several cell subsets within atherosclerotic plaques), which favour atherogenesis and increase plaque vulnerability. Thus, the assessment of intraplaque levels and activity of MMP might be of pivotal relevance in the evaluation of the risk of rupture. New imaging approaches, focused on the visualisation of inflammation in the vessel wall and plaque, may emerge as tools for individualised risk assessment and prevention of events. In this review, we summarize experimental findings of the currently available invasive and noninvasive imaging techniques, used to detect the presence and activity of MMPs in atherosclerotic plaques.

Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation

2014 ◽  
Vol 111 (06) ◽  
pp. 1089-1101 ◽  
Author(s):  
Massimo Lenti ◽  
Emanuela Falcinelli ◽  
Marcella Pompili ◽  
Paola De Rango ◽  
Valentina Conti ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Matrix Metalloproteinase ◽  
Platelet Activation ◽  
Matrix Metalloproteinase 2 ◽  
Atherosclerotic Plaques ◽  
Active Matrix ◽  
Carotid Plaques ◽  
Cerebrovascular Events ◽  
Human Carotid

SummaryPurified active matrix metalloproteinase-2 (MMP-2) is able to promote platelet aggregation. We aimed to assess the role of MMP-2 expressed in atherosclerotic plaques in the platelet-activating potential of human carotid plaques and its correlation with ischaemic events. Carotid plaques from 81 patients undergoing endarterectomy were tested for pro-MMP-2 and TIMP-2 content by zymography and ELISA. Plaque extracts were incubated with gel-filtered platelets from healthy volunteers for 2 minutes before the addition of a subthreshold concentration of thrombin receptor activating peptide-6 (TRAP-6) and aggregation was assessed. Moreover, platelet deposition on plaque extracts immobilised on plastic coverslips under high shear-rate flow conditions was measured. Forty-three plaque extracts (53%) potentiated platelet aggregation (+233 ± 26.8%), an effect prevented by three different specific MMP-2 inhibitors (inhibitor II, TIMP-2, moAb anti-MMP-2). The pro-MMP-2/TIMP-2 ratio of plaques potentiating platelet aggregation was significantly higher than that of plaques not potentiating it (3.67 ± 1.21 vs 1.01 ± 0.43, p<0.05). Moreover, the platelet aggregation-potentiating effect, the active-MMP-2 content and the active MMP-2/pro-MMP-2 ratio of plaque extracts were significantly higher in plaques from patients who developed a subsequent major cardiovascular event. In conclusion, atherosclerotic plaques exert a prothrombotic effect by potentiating platelet activation due to their content of MMP-2; an elevated MMP-2 activity in plaques is associated with a higher rate of subsequent ischaemic cerebrovascular events.

microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans

2012 ◽  
Vol 107 (04) ◽  
pp. 619-625 ◽  
Author(s):  
Bernd Denecke ◽  
André Rostalsky ◽  
Mihail Hristov ◽  
Thomas A. Koeppel ◽  
Kiril Bidzhekov ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Mirna Expression ◽  
Expression Profiles ◽  
Atherosclerotic Lesion ◽  
Vascular Diseases ◽  
Atherosclerotic Plaques ◽  
Monocyte Subset ◽  
Monocyte Subsets ◽  
Cardiovascular Biology ◽  
Classical Monocytes

SummarySmall non-coding microRNAs (miRNAs) have emerged to play critical roles in cardiovascular biology. Monocytes critically drive atherosclerotic lesion formation, and can be subdivided into a classical and non-classical subset. Here we scrutinised the miRNA signature of human classical and non-classical monocytes, and compared miRNA expression profiles of atherosclerotic plaques from human carotid arteries and healthy arteries. We identified miRNAs to be differentially regulated with a two-fold or higher difference between classical and non-classical monocyte subsets. Moreover, comparing miRNA expression in atherosclerotic plaques compared to healthy arteries, we observed several miRNAs to be aberrantly expressed, with the majority of miRNAs displaying a two-fold or higher increase in plaques and only few miRNAs being decreased. To elucidate similarities in miRNA signatures between monocyte subsets and atherosclerotic plaque, expression of miRNAs highly abundant in monocytes and plaque tissues were compared. Several miRNAs were found in atherosclerotic plaques but not in healthy vessels or either monocyte subset. However, we could identify miRNAs co-expressed in plaque tissue and classical monocytes (miR-99b, miR-152), or non-classical monocytes (miR-422a), or in both monocytes subsets. We thus unravelled candidate miRNAs, which may facilitate our understanding of monocyte recruitment and fate during atherosclerosis, and may serve as therapeutic targets for treating inflammatory vascular diseases.Note: The editorial process for this article was fully handled by Prof. G. Y. H. Lip, Editor-in-Chief.

scholarly journals Anti-Apolipoprotein A-1 IgG Influences Neutrophil Extracellular Trap Content at Distinct Regions of Human Carotid Plaques

2020 ◽  
Vol 21 (20) ◽  
pp. 7721
Author(s):  
Rafaela da Silva ◽  
Daniela Baptista ◽  
Aline Roth ◽  
Kapka Miteva ◽  
Fabienne Burger ◽  
...  
Keyword(s):  
Carotid Stenosis ◽  
Experimental Atherosclerosis ◽  
Neutrophil Extracellular Trap ◽  
Atherosclerotic Plaques ◽  
Carotid Plaques ◽  
Apolipoprotein A ◽  
Artery Segment ◽  
Enhanced Expression ◽  
And Function ◽  
Human Carotid

Background: Neutrophils accumulate in atherosclerotic plaques. Neutrophil extracellular traps (NET) were recently identified in experimental atherosclerosis and in complex human lesions. However, not much is known about the NET marker citrullinated histone-3 (H3Cit) expression and functionality in human carotid plaques. Moreover, the association between the proatherosclerotic autoantibody anti-apolipoprotein A-1 (anti-ApoA-1 IgG) and NET has never been investigated. Methods: Atherosclerotic plaques have been obtained from 36 patients with severe carotid stenosis that underwent carotid endarterectomy for severe carotid stenosis. Samples were sectioned into upstream and downstream regions from the same artery segment. Plaque composition and expression of NET markers neutrophil elastase (NE) and H3Cit were quantified by immunohistochemistry. H3Cit expression and function was evaluated by immunofluorescence and confocal analysis in a subset of patients. Results: Pathological features of vulnerable phenotypes were exacerbated in plaques developed at downstream regions, including higher accumulation of neutrophils and enhanced expression of NE and H3Cit, as compared to plaques from upstream regions. The H3Cit signal was also more intense in downstream regions, with significant extracellular distribution in spaces outside of neutrophils. The percentage of H3Cit colocalization with CD66b (neutrophils) was markedly lower in downstream portions of carotid plaques, confirming the extrusion of NET in this region. In agreement, the maximum distance of the H3Cit signal from neutrophils, extrapolated from vortex distance calculation in all possible directions, was also higher in downstream plaques. The serum anti-ApoA-1index positively correlated with the expression of H3Cit in downstream segments of plaques. Expression of the H3Cit signal outside of neutrophils and H3Cit maximal distance from CD66b-positive cells increased in plaques from serum positive anti-ApoA-1 patients compared with serum negative patients. Conclusion: NET elements are differentially expressed in upstream versus downstream regions of human carotid plaques and may be influenced by circulating levels of anti-ApoA-1 IgG. These findings could warrant the investigation of NET elements as potential markers of vulnerability.

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