Status of biomarkers for the identification of stable or vulnerable plaques in atherosclerosis

2021 ◽  
Vol 135 (16) ◽  
pp. 1981-1997
Author(s):  
Valter Lubrano ◽  
Silvana Balzan
Keyword(s):  
Plaque Rupture ◽  
Inflammatory Cells ◽  
Prognostic Indicators ◽  
Circulating Biomarkers ◽  
Inflammatory Infiltration ◽  
Cellular Processes ◽  
Fibrous Cap ◽  
Vulnerable Plaques ◽  
Active Inflammation ◽  
Accumulation Of Lipids

Abstract Atherosclerosis is a systemic inflammation of the arteries characterized by atherosclerotic plaque due to the accumulation of lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins. Stable plaques present a chronic inflammatory infiltration, whereas vulnerable plaques present an ‘active’ inflammation involved in the thinning of the fibrous cap that predisposes to plaque rupture. Several complex biological cellular processes lead plaques to evolve from stable to vulnerable predisposing them to rupture and thrombosis. In this review, we analyze some emerging circulating biomarkers related to inflammation, ECM and lipid infiltration, angiogenesis, metalloproteinases and microRNA (miRNA), as possible diagnostic and prognostic indicators of plaque vulnerability.

Stress Concentrations of Vulnerable Plaques With a Composite Variable Core

2010 ◽  
Author(s):  
Eyass Massarwa ◽  
Aronis Ze’ev ◽  
Rami Eliasy ◽  
Rami Haj-Ali ◽  
Shmuel Einav
Keyword(s):  
Plaque Rupture ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Plaque Morphology ◽  
Rapid Progression ◽  
Stress Concentrations ◽  
Coronary Syndrome ◽  
Fibrous Cap ◽  
Vulnerable Plaques ◽  
Life Threatening

Vulnerable plaques are inflamed, active, and growing lesions which are prone to complications such as rupture, luminal and mural thrombosis, intraplaque hemorrhage, and rapid progression to stenosis. It remains difficult to assess what factors influence the biomechanical stability of vulnerable plaques and promote some of them to rupture while others remain intact. The rupture of thin fibrous cap overlying the necrotic core of a vulnerable plaque is the principal cause of acute coronary syndrome. The mechanism or mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to a life threatening athero-thrombotic lesion are not fully understood. It has been widely assumed that plaque morphology is the major determinant of clinical outcome [1, 2]. Thin-cap fibroatheroma with a large necrotic core and a fibrous cap of < 65μm was describes as a more specific precursor of plaque rupture due to tissue stress.

Abstract T MP29: Contrast-Enhanced Ultrasound is Useful for Detection of Vulnerable Plaques

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Rie Motoyama ◽  
Kozue Saito ◽  
Shuichi Tonomura ◽  
Hatsue I Ueda ◽  
Hiroharu Kataoka ◽  
...  
Keyword(s):  
High Intensity ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Contrast Enhanced Ultrasound ◽  
Histopathological Findings ◽  
Rapid Acquisition ◽  
Fibrous Cap ◽  
Vulnerable Plaques ◽  
Contrast Enhanced ◽  
Active Inflammation

Background and Purpose: Vulnerable plaques of carotid arteries are characterized as the presence of large necrotic core, intraplaque hemorrhage (IPH), intraplaque neovascularization (IPN), and active inflammation with thin fibrous cap. MRI is widely used for the qualitative evaluation of the plaques in vivo and the high-intensity plaques (HIP) on magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images indicate containing necrotic cores with IPH, which indicates vulnerable plaques. However, we encounter the symptomatic cases without the presence of HIP on MPRAGE in clinical practice. Recent studies showed the efficacy for the evaluation of IPN using contrast-enhanced ultrasound (CEUS). We aimed to assess the vulnerability of the plaques without high intensity on MPRAGE images using CEUS. Methods: Between July 2010 and June 2014, we enrolled 69 patients with internal carotid artery stenosis who underwent carotid endarterectomy (CEA) and preoperatively examined CEUS and MRI (MPRAGE). All plaques were evaluated with CEUS and the contrast effects were classified semi-quantitatively (grade 0: absent, 1: small, 2: large, 3: extensive). We also divided the plaques into two groups (HIP group or non-HIP group) based on the signal intensity of the plaques on MPRAGE images. The results of MRI and CEUS were compared with histopathological findings of CEA specimens. Results: Fifty-eight plaques of all 69 patients showed HIP (41 were symptomatic), and eleven plaques were non-HIP (five were symptomatic: amaurosis fugax in three, cerebral infarction in two). In non-HIP group, symptomatic plaques were more enhanced (three in grade 2, two in grade 3) than asymptomatic plaques (one in grade 0, five in grade 1) using CEUS. Histopathological findings of all five CEA specimens from symptomatic patients showed that extensive IPN, large necrotic core, and active inflammation with thin fibrous cap which indicated vulnerable plaques, but small amount of IPH. These histological findings were compatible with the results of CEUS and MRI findings. Conclusion: CEUS may be useful for diagnosis of vulnerable plaques without high intensity on MPRAGE images.

Macrophage infiltrates in coronary plaque erosion portend a worse cardiovascular outcome in patients with acute coronary syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R.A Montone ◽  
V Vetrugno ◽  
M Camilli ◽  
M Russo ◽  
M.G Del Buono ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Vulnerable Plaque ◽  
Cardiac Death ◽  
Cox Regression ◽  
Plaque Rupture ◽  
Culprit Lesion ◽  
Coronary Syndrome ◽  
Fibrous Cap ◽  
Plaque Erosion

Abstract Background Plaque erosion (PE) is responsible for at least one-third of acute coronary syndrome (ACS). Inflammatory activation is considered a key mechanism of plaque instability in patients with plaque rupture through the release of metalloproteinases and the inhibition of collagen synthesis that in turns lead to fibrous cap degradation. However, the clinical relevance of macrophage infiltration has never been investigated in patients with PE. Purpose In our study, we aimed at assessing the presence of optical coherence tomography (OCT)-defined macrophage infiltrates (MØI) at the culprit site in ACS patients with PE, evaluating their clinical and OCT correlates, along with their prognostic value. Methods ACS patients undergoing OCT imaging and presenting PE as culprit lesion were retrospectively selected. Presence of MØI at culprit site and in non-culprit segments along the culprit vessel was assessed. The incidence of major adverse cardiac events (MACEs), defined as the composite of cardiac death, recurrent myocardial infarction and target vessel revascularization (TVR), was assessed [follow-up median (interquartile range, IQR) time 2.5 (2.03–2.58) years]. Results We included 153 patients [median age (IQR) 64 (53–75) years, 99 (64.7%) males]. Fifty-one (33.3%) patients presented PE with MØI and 102 (66.7%) PE without MØI. Patients having PE with MØI compared with PE patients without MØI had more vulnerable plaque features both at culprit site and at non-culprit segments. In particular, culprit lesion analysis demonstrated that patients with PE with MØI had a significantly thinner fibrous cap [median (IQR) 100 (60–120) μm vs. 160 (95–190) μm, p&lt;0.001], higher prevalence of thrombus [41 (80.4%) vs. 64 (62.7%), p=0.028], lipid plaque [39 (76.5%) vs. 50 (49.0%), p&lt;0.001], TCFA [20 (39.2%) vs. 14 (13.7%), p=0.001], and a higher maximum lipid arc [median [IQR] 250.0° (177.5°-290.0°) vs. 190.0° (150.0°-260.0°), p=0.018) at the culprit lesion compared with PE without MØI. MACEs were significantly more frequent in PE with MØI patients compared with PE without MØI [11 (21.6%) vs. 6 (5.9%), p=0.008], mainly driven by a higher risk of cardiac death and TVR. At multivariable Cox regression model, PE with MØI [HR=2.95, 95% CI (1.09–8.02), p=0.034] was an independent predictor of MACEs. Conclusion Our study demonstrates that among ACS patients with PE the presence of MØI at culprit lesion is associated with a more aggressive phenotype of coronary atherosclerosis with more vulnerable plaque features, along with a worse prognosis at a long-term follow-up. These findings are of the utmost importance in the era of precision medicine because clearly show that macrophage infiltrates may identify patients with a higher cardiovascular risk requiring more aggressive secondary prevention therapies and a closer clinical follow-up. Prognosis Funding Acknowledgement Type of funding source: None

scholarly journals Potential relationship between high wall shear stress and plaque rupture that cause acute coronary syndrome: insights from optical coherence tomography based computational fluid dynamic simulation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Fukuyama ◽  
H Otake ◽  
F Seike ◽  
H Kawamori ◽  
T Toba ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Shear Stress ◽  
Acute Coronary Syndrome ◽  
Wall Shear Stress ◽  
Plaque Rupture ◽  
Optical Coherence ◽  
Lumen Area ◽  
Segmental Analysis ◽  
Coronary Syndrome ◽  
Fibrous Cap

Abstract Background The direct relationship between plaque rupture (PR) that cause acute coronary syndrome (ACS) and wall shear stress (WSS) remains uncertain. Methods From the Kobe University ACS-OCT registry, one hundred ACS patients whose culprit lesions had PR documented by optical coherence tomography (OCT) were enrolled. Lesion-specific 3D coronary artery models were created using OCT data. Specifically, at the ruptured portion, the tracing of the luminal edge of the residual fibrous cap was smoothly extrapolated to reconstruct the luminal contour before PR. Then, WSS was computed from computational fluid dynamics (CFD) analysis by a single core laboratory. Relationships between WSS and the location of PR were assessed with 1) longitudinal 3-mm segmental analysis and 2) circumferential analysis. In the longitudinal segmental analysis, each culprit lesion was subdivided into five 3-mm segments with respect to the minimum lumen area (MLA) location at the centered segment (Figure. 1). In the circumferential analysis, we measured WSS values at five points from PR site and non-PR site on the cross-sections with PR. Also, each ruptured plaque was categorized into the lateral type PR (L-PR), central type PR (C-PR), and others according to the relation between the site of tearing and the cavity (Figure. 2). Results In the longitudinal 3-mm segmental analysis, the incidences of PR at upstream (UP1 and 2), MLA, and downstream (DN1 and 2) were 45%, 40%, and 15%, respectively. The highest average WSS was located in UP1 in the upstream PR (UP1: 15.5 (10.4–26.3) vs. others: 6.8 (3.3–14.7) Pa, p&lt;0.001) and MLA segment in the MLA PR (MLA: 18.8 (6.0–34.3) vs. others: 6.5 (3.1–11.8) Pa, p&lt;0.001), and the second highest WSS was located at DN1 in the downstream PR (DN1: 5.8 (3.7–11.5) vs. others: 5.5 (3.7–16.5) Pa, p=0.035). In the circumferential analysis, the average WSS at PR site was significantly higher than that of non-PR site (18.7 (7.2–35.1) vs. 13.9 (5.2–30.3) Pa, p&lt;0.001). The incidence of L-PR, C-PR, and others were 51%, 42%, and 7%, respectively. In the L-PR, the peak WSS was most frequently observed in the lateral site (66.7%), whereas that in the C-PR was most frequently observed in the center site (70%) (Figure. 3). In the L-PR, the peak WSS value was significantly lower (44.6 (19.6–65.2) vs. 84.7 (36.6–177.5) Pa, p&lt;0.001), and the thickness of broken fibrous cap was significantly thinner (40 (30–50) vs. 80 (67.5–100) μm, p&lt;0.001), and the lumen area at peak WSS site was significantly larger than those of C-PR (1.5 (1.3–2.0) vs. 1.4 (1.1–1.6) mm2, p=0.008). Multivariate analysis demonstrated that the presence of peak WSS at lateral site, thinner broken fibrous cap thickness, and larger lumen area at peak WSS site were independently associated with the development of the L-PR. Conclusions A combined approach with CFD simulation and morphological plaque evaluation by using OCT might be helpful to predict future ACS events induced by PR. Funding Acknowledgement Type of funding source: None

Activated inflammatory cells are associated with plaque rupture in carotid artery stenosis

Surgery ◽  
1997 ◽  
Vol 122 (4) ◽  
pp. 757-764 ◽  
Author(s):  
Sandra C Carr ◽  
Andrew Farb ◽  
William H Pearce ◽  
Renu Virmani ◽  
James S.T Yao
Keyword(s):  
Carotid Artery ◽  
Carotid Artery Stenosis ◽  
Plaque Rupture ◽  
Inflammatory Cells ◽  
Artery Stenosis

Lipid Lowering Therapy and Stabilization of Atherosclerotic Plaques

1999 ◽  
Vol 82 (S 01) ◽  
pp. 60-61 ◽  
Author(s):  
Dirk Müller-Wieland ◽  
Wilhelm Krone
Keyword(s):  
Thrombus Formation ◽  
Inflammatory Cells ◽  
Cardiovascular Complications ◽  
Lipid Lowering ◽  
Atherosclerotic Plaques ◽  
Lipid Lowering Therapy ◽  
New Paradigm ◽  
Clinical Prognosis ◽  
Fibrous Cap ◽  
Lowering Therapy

SummaryLipid-lowering therapy leads to a great reduction of cardiovascular complications, but has almost no effect on the degree of stenosis of coronary arteries. These and other studies have lead to a new paradigm of coronary artery disease, i. e. clinical prognosis is not only determined by the extent of a single stenosis, but mainly by the number and structure of atherosclerotic plaques. Rupture of an instable or vulnerable plaque, characterized by a large lipid-rich central core, inflammatory cells, and a thin fibrous cap, causes sudden thrombus formation and thereby acute coronary syndromes. There is accumulating evidence that cholesterol lowering can result in plaque stabilization and improvement of endothelial dysfunction.

scholarly journals Inflammatory cells in perivascular adipose tissue and the integrity of the tunica media in atherosclerotic coronary arteries

2019 ◽  
Author(s):  
Ruda Zorc-Pleskovič ◽  
Marjeta Zorc ◽  
Dušan Šuput ◽  
Aleksandra Milutinović
Keyword(s):  
Adipose Tissue ◽  
Coronary Arteries ◽  
Obstructive Coronary Artery Disease ◽  
Inflammatory Cells ◽  
Elastic Membrane ◽  
Inflammatory Infiltration ◽  
Perivascular Adipose Tissue ◽  
Tunica Media ◽  
External Elastic Membrane ◽  
The Media

Obstructive coronary artery disease (CAD) is characterized by inflammation within the atherosclerotic coronary arteries. Infiltration of inflammatory cells into muscular media can lead to remodeling and weakening of the arterial wall. We examined the relationship between inflammatory infiltration in perivascular adipose tissue (PVAT), state of the external elastic membrane, and the intensity of inflammatory infiltration in the tunica media of coronary arteries obtained by endarterectomy from symptomatic patients with diffuse CAD. We analyzed endarterectomy sequesters from 22 coronary arteries that contained the intima, media, a part of the adventitia, and PVAT in at least one part of the sequester. The coronary arteries were divided into two groups according to the presence or absence of inflammatory infiltration in PVAT. Staining with hematoxylin-eosin and by the Movat's method showed atherosclerotic changes in the intima and media. Immunohistochemistry (anti-leukocyte common antigen [LCA] antibody) was used for the detection of leukocytes. We found a significant positive correlation between inflammatory infiltration in PVAT and preservation of the external elastic membrane of coronary arteries. Furthermore, we found a significant negative correlation between inflammatory infiltration in PVAT and the intensity of inflammatory infiltration in the media. It seems that the integrity of the external elastic membrane and the proinflammatory properties of PVAT restrain inflammatory cells within PVAT. Both effects may prevent the migration of inflammatory cells into the media and delay the development of CAD.

Abstract 13: Inhibition of Nudt6 Stabilizes Advanced Atherosclerotic Plaques

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Hong Jin ◽  
Yuhuang Li ◽  
Ekaterina Chernogubova ◽  
Alexandra Bäcklund ◽  
Stina Sellberg ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Survival Rates ◽  
Atherosclerotic Plaques ◽  
Protein Coding ◽  
Fibrous Cap ◽  
Asymptomatic Patients ◽  
Rupture Model

Natural antisense transcripts (NATs), a non-coding RNA subclass, being transcribed in antisense direction to protein coding genes, are an intriguing novel class of targetable modulators, exerting crucial effects on gene expression. Aim of the current study was to investigate the contribution of NATs to atherosclerotic plaque vulnerability. Using laser capture micro-dissection, we isolated fibrous caps tissue of carotid artery plaques from 20 symptomatic patients with ruptured lesions vs. 20 samples from asymptomatic patients with stable lesions. A human transcriptome array (HTA; GeneChip 2.0 ) was used to profile the expression of all currently annotated RNA transcripts. Nucleoside diphosphate-linked moiety X motif 6 (NUDT6) was identified as one of the most significantly up-regulated transcripts in fibrous caps of ruptured lesions. Interestingly, NUDT6 is an established antisense RNA targeting the fibroblast growth factor 2 (FGF2). Of importance, FGF2 was among the most significantly down-regulated transcripts in ruptured lesions, corresponding to elevated NUDT6 expression. In situ hybridization in both, human and mouse carotid atherosclerotic plaques, confirmed substantially higher expression levels of NUDT6 in ruptured lesions compared to stable. In addition, in situ hybridization revealed a distinct co-localization with smooth muscle cells (SMCs) in advanced plaques. Overexpression of NUDT6 in cultured human carotid artery SMCs effectively limited FGF2 on the mRNA as well as protein level. Furthermore, reduction of NUDT6 via siRNA stimulated proliferation and blocked apoptosis in SMCs. In an inducible atherosclerotic plaque rupture model using incomplete ligation and cuff placement on common carotid arteries of male apoE -/- mice, NUDT6 inhibition with gapmeRs was able to significantly improve SMC survival rates, leading to thicker fibrous caps, and to reduce the plaque rupture rate compared to scramble-gapmeR control-treated mice (22% vs . 63%, p = 0.03). The present study presents NUDT6 as a novel crucial antisense regulator of fibrous cap stability through steering SMC survival via targeting its sense RNA transcript FGF2.

Analysis of Radiofrequency Ultrasound Signals

2011 ◽  
pp. 55-93
Author(s):  
Attila Thury ◽  
Héctor M. Garcia-Garcia ◽  
Evelyn Regar
Keyword(s):  
Coronary Atherosclerosis ◽  
Plaque Rupture ◽  
Local Treatment ◽  
Natural History Study ◽  
Strain Measurements ◽  
Preventive Cardiology ◽  
Vulnerable Plaques ◽  
One Stop ◽  
Very High ◽  
Radiofrequency Signal

IVUS opened new perspectives in our understanding of human coronary atherosclerosis and triggers of ACS (especially plaque rupture as its most dominant cause). Throughout this chapter we list the shortcomings of conventional (greyscale) IVUS to characterize tissue components of plaques and the potentials of radiofrequency signal processing to overcome these. In recent years, the technology matured, and especially with VH and IB-IVUS, many clinical studies showed accurate plaque estimation. Results of a prospective, natural history study have just been presented and proved the ability of VH to predict ACS. Palpography derives compositional information from functional (strain) measurements. Assessing several characteristics of a given plaque could potentially enhance invasive risk stratification by identifying very high-risk plaques, thereby reducing the number of vulnerable plaques that need to be serially followed and ultimately treated. Moreover, if a safe prophylactic local treatment was available, a sophisticated IVUS procedure would be a part of a “one-stop-shop” in preventive cardiology.

scholarly journals TWEAK/Fn14 Activation Participates in Skin Inflammation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qilu Liu ◽  
Shengxiang Xiao ◽  
Yumin Xia
Keyword(s):  
Cell Fate ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Inflammatory Cells ◽  
Skin Inflammation ◽  
Tnf Receptor ◽  
Inflammatory Infiltration ◽  
Papillomavirus Infection ◽  
Chemotactic Protein

Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) participates in multiple biological activities via binding to its sole receptor—fibroblast growth factor-inducible 14 (Fn14). The TWEAK/Fn14 signaling pathway is activated in skin inflammation and modulates the inflammatory responses of keratinocytes by activating nuclear factor-κB signals and enhancing the production of several cytokines, including interleukins, monocyte chemotactic protein-1, RANTES (regulated on activation, normal T cell expressed and secreted), and interferon gamma-induced protein 10. Mild or transient TWEAK/Fn14 activation contributes to tissular repair and regeneration while excessive or persistent TWEAK/Fn14 signals may lead to severe inflammatory infiltration and tissue damage. TWEAK also regulates cell fate of keratinocytes, involving the function of Fn14-TNF receptor-associated factor-TNF receptor axis. By recruiting inflammatory cells, promoting cytokine production, and regulating cell fate, TWEAK/Fn14 activation plays a pivotal role in the pathogenesis of various skin disorders, such as psoriasis, atopic dermatitis, cutaneous vasculitis, human papillomavirus infection and related skin tumors, and cutaneous autoimmune diseases. Therefore, the TWEAK/Fn14 pathway may be a potential target for the development of novel therapeutics for skin inflammatory diseases.

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