Abstract 127: Induction of miR-21 Increases Fibrous Cap Stability in Vulnerable Atherosclerotic Lesions

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Hong Jin ◽  
Yuhuang Li ◽  
Alexandra Bäcklund ◽  
Albert Busch ◽  
Suzanne M Eken ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Cellular Proliferation ◽  
Plaque Rupture ◽  
Oxidized Ldl ◽  
Survival Rates ◽  
Experimental Models ◽  
Vascular Remodelling ◽  
Plaque Vulnerability ◽  
Plaque Instability ◽  
Asymptomatic Patients

The aim of the present study was to explore the role of miRNAs as potential regulators in patients with carotid artery stenosis and concordant vulnerable atherosclerotic plaques. A pre-determined miRNA-array of laser captured micro-dissected (LCM) tissue specimen from fibrous caps of 10 symptomatic patients (stroke or TIA within > 14 days and histo-morphologically identified ruptured lesion) compared to fibrous caps from 10 asymptomatic patients (stable lesions; high grade stenosis) discovered miR-21 as one of the two miRNAs (miRs-21 and -210) being substantially down-regulated in symptomatic patients. To functionally evaluate the contribution of miR-21 to plaque vulnerability, we created miR21 -/- / ApoE -/- mice on a C57BL/6 background. We explored the phenotype of these newly developed miR21 -/- /ApoE -/- mice in experimental models of vascular remodelling and plaque vulnerability. First, miR21 -/- mice revealed a complete lack of SMC proliferation in response to carotid ligation injury. In the second inducible plaque rupture model, using incomplete ligation of the common carotid artery with consecutive cuff placement proximal to the ligated region indicated that all miR21 -/- /ApoE -/- mice ( n =10) presented atherothombotic events and signs of severe plaque instability. The rupture rate in control miR21 +/+ /ApoE -/- mice was significantly lower at 56% ( n =9). In addition, miR21 -/- /ApoE -/- showed an increase in lesion area in the aortic root and substantially higher levels of macrophage infiltration in injured carotid arteries. Dynamic live cell imaging, using isolated aortic SMCs and peritoneal macrophages from miR21 -/- /ApoE -/- vs. miR2 +/+ /ApoE -/- mice displayed substantial lower cellular proliferation and survival rates (for SMCs), and distinct advanced inflammatory activity upon oxidized LDL (oxLDL) stimulation of macrophages. In the present study we identified miR-21 as a key modulator of pathologic processes in atherosclerosis-related vascular remodelling. Targeted, lesion-site specific overexpression of miR-21 could be a novel and powerful future strategy to stabilize vulnerable plaques by inducing pro-proliferative mechanisms in SMC-enriched fibrous caps.

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.

Abstract WP162: Impact of Carotid Artery Remodeling by T1 weighted MR Imaging for the Assessment of Plaque Vulnerability in High-grade Carotid Stenosis

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Kenji Fukuda ◽  
Koji Iihara ◽  
Naoaki Yamada ◽  
Hatsue Ueda
Keyword(s):  
Carotid Artery ◽  
Carotid Stenosis ◽  
Average Rate ◽  
Intraplaque Hemorrhage ◽  
High Grade ◽  
Plaque Vulnerability ◽  
Rapid Acquisition ◽  
Asymptomatic Patients ◽  
Artery Remodeling ◽  
The Relationship

Background- The relationship between coronary artery remodeling and plaque vulnerability has been described on the basis of symptomatology and histology. However, the association with carotid artery remodeling has not been explored in detail. The aim of this study was to validate the relationship between carotid artery remodeling and plaque vulnerability by comparing the degree of outward remodeling calculated using 3D inversion-recovery-based T1-weighted imaging (magnetization-prepared rapid acquisition gradient-echo [MPRAGE]) with the symptomatology and histology of plaques extracted during carotid endarterectomy (CEA). Methods and Results- Sixty-one patients with high-grade carotid stenosis who underwent CEA and whose plaque could be examined were included. The average rate of stenosis as per the NASCET criteria was 79.8%. The carotid remodeling index (CRI) was determined by measuring the external cross-sectional vessel area (CSVA) of the maximum stenosis of the internal carotid artery (ICA) and dividing it by the external CSVA of the distal ICA unaffected by atherosclerosis using MPRAGE imaging. The relationship between the CRI and plaque vulnerability was evaluated on the basis of symptomatology and histology. The CRI was significantly higher in symptomatic patients than in asymptomatic patients (1.98 ± 0.26 vs. 1.68 ± 0.24, p < 0.0001). A higher CRI was positively correlated with the necrotic core area (r = 0.568, p < 0.0001) as well as significantly associated with severe intraplaque hemorrhage (p < 0.0001) and the prevalence of cap inflammation with macrophage (p = 0.03) and lymphocyte (p = 0.01) infiltration. Conclusion- These results validate the relationship between carotid artery remodeling and plaque vulnerability in high-grade carotid stenosis. MPRAGE imaging is effective to assess plaque vulnerability in terms of the CRI in addition to the signal intensity of carotid plaques.

Abstract 3: Targeting Macrophage Necroptosis for Therapeutic and Diagnostic Interventions to Treat Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Denuja Karunakaran ◽  
Michele Geoffrion ◽  
Lihui Wei ◽  
Wei Gan ◽  
Ljubica Perisic ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Oxidized Ldl ◽  
Combined Treatment ◽  
Necrotic Core ◽  
Core Formation ◽  
Macrophage Cell ◽  
Plaque Instability

Background: Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. As such, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that in contrast to apoptosis, induces a pro-inflammatory state. We hypothesize that atherogenic ligands within the plaque promote macrophage necroptosis and this process underlies necrotic core formation and drives atherosclerotic plaque instability. Results: In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying plaque necroptosis showed that macrophages treated with oxidized LDL have increased expression of necroptotic genes RIP3 and MLKL through ROS-dependent activation of the promoter region and increased RIP3 and MLKL phosphorylation. Combined treatment with oxLDL and DAMPs (damage associated molecular patterns) amplified macrophage necroptotic cell death, indicating that additional inflammatory stimuli present in the lesion could act synergistically to promote necroptosis. Using a radiotracer developed with the necroptosis inhibitor Nec-1, we show that 123 I-Nec1 localizes specifically to atherosclerotic plaques in Apoe-/- mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe-/- mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Conclusions: Our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis.

scholarly journals Carotid artery plaque assessment using quantitative expansive remodeling evaluation and MRI plaque signal intensity

2016 ◽  
Vol 124 (3) ◽  
pp. 736-742 ◽  
Author(s):  
Yoshitaka Kurosaki ◽  
Kazumichi Yoshida ◽  
Ryu Fukumitsu ◽  
Nobutake Sadamasa ◽  
Akira Handa ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Risk Stratification ◽  
Signal Intensity ◽  
Plaque Vulnerability ◽  
Carotid Artery Plaque ◽  
Asymptomatic Patients ◽  
Group A ◽  
Group B ◽  
Group D ◽  
Ischemic Events

OBJECT Plaque characteristics and morphology are important indicators of plaque vulnerability. MRI-detected intraplaque hemorrhage has a great effect on plaque vulnerability. Expansive remodeling, which has been considered compensatory enlargement of the arterial wall in the progression of atherosclerosis, is one of the criteria of vulnerable plaque in the coronary circulation. The purpose of this study was risk stratification of carotid artery plaque through the evaluation of quantitative expansive remodeling and MRI plaque signal intensity. METHODS Both preoperative carotid artery T1-weighted axial and long-axis MR images of 70 patients who underwent carotid endarterectomy (CEA) or carotid artery stenting (CAS) were studied. The expansive remodeling ratio (ERR) was calculated from the ratio of the linear diameter of the artery at the thickest segment of the plaque to the diameter of the artery on the long-axis image. Relative plaque signal intensity (rSI) was also calculated from the axial image, and the patients were grouped as follows: Group A = rSI ≥ 1.40 and ERR ≥ 1.66; Group B = rSI< 1.40 and ERR ≥ 1.66; Group C = rSI ≥ 1.40 and ERR < 1.66; and Group D = rSI < 1.40 and ERR < 1.66. Ischemic events within 6 months were retrospectively evaluated in each group. RESULTS Of the 70 patients, 17 (74%) in Group A, 6 (43%) in Group B, 7 (44%) in Group C, and 6 (35%) in Group D had ischemic events. Ischemic events were significantly more common in Group A than in Group D (p = 0.01). CONCLUSIONS In the present series of patients with carotid artery stenosis scheduled for CEA or CAS, patients with plaque with a high degree of expansion of the vessel and T1 high signal intensity were at higher risk of ischemic events. The combined assessment of plaque characterization with MRI and morphological evaluation using ERR might be useful in risk stratification for carotid lesions, which should be validated by a prospective, randomized study of asymptomatic patients.

scholarly journals Association between Circulatory and Plaque Resistin Levels with Carotid Plaque Instability and Ischemic Stroke Events

2018 ◽  
Vol 21 (6) ◽  
pp. E448-E463
Author(s):  
Ivana Jurin ◽  
Frane Paić ◽  
Stela Bulimbašić ◽  
Igor Rudež ◽  
Lovorka Đerek ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Regression Analysis ◽  
Ischemic Stroke ◽  
Carotid Artery ◽  
Carotid Artery Stenosis ◽  
Carotid Plaque ◽  
High Grade ◽  
Plaque Vulnerability ◽  
Histological Features ◽  
Plaque Instability

ses of ischemic stroke. The risk of ischemic stroke increases with the degree of carotid stenosis and plaque vulnerability. The aim of this study was to investigate the association of circulating and plaque resistin levels with plaque vulnerability and ischemic stroke events in patients with moderate- to high-grade carotid artery stenosis. Methods: 40 patients with ischemic stroke events and 38 neurologically asymptomatic patients scheduled for carotid endarterectomy were recruited for this study. Fasting blood samples for laboratory analysis were collected preoperatively and serum resistin levels were measured by enzyme-linked immunosorbent assays. Carotid endarterectomy specimens were analyzed according to the gold-standard procedure of histological classification. Plaque resistin expression was determined by standard immunohistochemical procedure. Results: Serum resistin levels and resistin plaque expression were found to be significantly higher in subjects with unstable carotid plaque (P < .001) while significantly higher serum resistin levels were also present in patients with ischemic stroke events (P < .001). In univariate stepwise logistic regression analysis, higher serum resistin levels were significantly associated with plaque instability (OR 2.223, 95% CI 1.488-3.320, P < .0001) and ischemic stroke events (OR 1.237, 95% CI 1.079-1.420, P = .002). There was also a significant association between higher serum and plaque resistin expression (OR 1.663, 95% CI1.332-2.077, P < .0001). These associations remained significant in all models of multivariate logistic regression analysis. High serum and plaque resistin levels were also significantly associated with specific histological features of plaque instability. Conclusion: The results suggests that serum resistin levels may be used as a potential biomarker of plaque vulnerability and ischemic stroke events in patients with moderate- to high-grade carotid artery stenosis and highlight the possible relationship that plaque resistin expression has with histological features of plaque vulnerability.

Abstract 324: Pathological Quantitative Assessment of Plaque Instability in Patients Undergoing Carotid Endarterectomy

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Takao Konishi
Keyword(s):  
Logistic Regression ◽  
Carotid Endarterectomy ◽  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Multivariable Logistic Regression Analysis ◽  
Diagnostic Efficiency ◽  
Plaque Instability ◽  
Fibrous Cap ◽  
Multivariable Logistic Regression ◽  
Asymptomatic Patients

Introduction: Instability of carotid atherosclerotic plaques leads to cerebral thromboemboli and ischemic symptoms. However, there has been no specific pathological quantification for the instability of carotid atherosclerotic plaque. The purpose of this study was to quantify atherosclerotic plaque instability in patients undergoing carotid endarterectomy (CEA). Methods: Carotid plaques were collected after CEA from 67 symptomatic and 15 asymptomatic patients between May 2015 and August 2016. Samples were stained with hematoxylin/eosin and Elastica-Masson (E-Masson). Immunohistochemistry was performed by using an endothelial specific antibody to CD31, CD 34 and PDGFRβ. Plaques were assessed for histopathological characteristics. Results: Multivariable logistic regression analysis demonstrated that plaque instability was independently associated with the presence of plaque rupture (odds ratio [OR], 9.75, 95% confidence interval [CI]: 1.62 to 58.6, p = 0.013), the minimal fibrous cap thickness (FCT) (OR per 10 μm 0.70, 95% CI: 0.51 to 0.96, p = 0.025), the presence of microcalcification in the fibrous cap (OR 7.82, 95% CI: 1.35 to 45.4, p = 0.022) and the intraplaque microvessels (OR 1.91, 95% CI: 1.02 to 3.57, p = 0.043). If these four independent parameters were combined to a score using the equation derived from the multivariable logistic regression model (Logit(Score) = 0.179 + 2.277 * (insert 1 if plaque rupture present; else 0) - 0.355 * (insert minimal FCT in multiples of 10 μm) + 2.057 * (insert 1 if microcalcification in the fibrous cap present; else 0) + 0.646 * (insert intraplaque microvessels /mm 2 ), the diagnostic efficiency could be improved to an AUC 0.92 (95% CI: 0.85-0.99, optimal cut-off value 0.814, sensitivity 89.6%, specificity 86.7%, PPV 96.8%, NPV 65.0%, diagnostic accuracy 89.0%). Conclusions: This study suggested the diagnostic scoring was useful for the quantification of carotid plaque instability in patients undergoing CEA.

scholarly journals Markers of Inflammation Associated with Plaque Progression and Instability in Patients with Carotid Atherosclerosis

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Enrico Ammirati ◽  
Francesco Moroni ◽  
Giuseppe Danilo Norata ◽  
Marco Magnoni ◽  
Paolo G. Camici
Keyword(s):  
Carotid Artery ◽  
Carotid Atherosclerosis ◽  
Plaque Rupture ◽  
Subclinical Atherosclerosis ◽  
Systemic Disease ◽  
Traditional Cardiovascular Risk Factor ◽  
Plaque Instability ◽  
Atherosclerosis Progression ◽  
Markers Of Inflammation ◽  
Cerebrovascular Events

Atherosclerosis is the focal expression of a systemic disease affecting medium- and large-sized arteries, in which traditional cardiovascular risk factor and immune factors play a key role. It is well accepted that circulating biomarkers, including C-reactive protein and interleukin-6, reliably predict major cardiovascular events, including myocardial infarction or death. However, the relevance of biomarkers of systemic inflammation to atherosclerosis progression in the carotid artery is less established. The large majority of clinical studies focused on the association between biomarkers and subclinical atherosclerosis, that is, carotid intima-media thickening (cIMT), which represents an earlier stage of the disease. The aim of this work is to review inflammatory biomarkers that were associated with a higher atherosclerotic burden, a faster disease progression, and features of plaque instability, such as inflammation or neovascularization, in patients with carotid atherosclerotic plaque, which represents an advanced stage of disease compared with cIMT. The association of biomarkers with the occurrence of cerebrovascular events, secondary to carotid plaque rupture, will also be presented. Currently, the degree of carotid artery stenosis is used to predict the risk of future cerebrovascular events in patients affected by carotid atherosclerosis. However, this strategy appears suboptimal. The identification of suitable biomarkers could provide a useful adjunctive criterion to ensure better risk stratification and optimize management.

NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis

2017 ◽  
Vol 56 (1) ◽  
Author(s):  
Wolf Eilenberg ◽  
Stefan Stojkovic ◽  
Alexandra Kaider ◽  
Nicolas Kozakowski ◽  
Christoph M. Domenig ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Carotid Artery Stenosis ◽  
Carotid Atherosclerosis ◽  
Heart Association ◽  
Statin Treatment ◽  
Artery Stenosis ◽  
Plaque Vulnerability ◽  
Symptomatic Carotid ◽  
Asymptomatic Patients

AbstractBackground:Neutrophil gelatinase associated lipocalin (NGAL) is expressed in atherosclerotic lesions and was recently implicated in the pathogenesis of cardiovascular pathologies. Statins are known to exert stabilizing effects on atherosclerotic plaque. The aims of our study were (1) to investigate the association of serum NGAL and metalloproteinase (MMP)-9/NGAL complex with the vulnerability of the atherosclerotic plaque, and (2) to reveal the effects of statin treatment on circulating NGAL and MMP-9/NGAL levels in patients with carotid artery stenosis.Methods:We examined the levels of NGAL and MMP-9/NGAL in blood samples from 136 patients with carotid artery stenosis by specific enzyme-linked immunosorbent assays.Results:Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of American Heart Association [AHA]), displayed the highest levels of NGAL (both p<0.0001) and MMP-9/NGAL complex (p=0.0004 and p=0.004, respectively). Moreover, patients with symptomatic carotid atherosclerosis had significantly higher NGAL levels compared to asymptomatic patients (p=0.0007). The statin-treated group (n=108) demonstrated lower NGAL (73.9 vs. 128.0 μg/L, p<0.0001) and MMP-9/NGAL (28.9 vs. 40.6 μg/L, p=0.046) as compared to the non-statin group (n=28). Furthermore, in multivariate regression analysis NGAL, but not MMP-9/NGAL levels, were independently associated with symptomatic carotid artery stenosis. In addition, statin treatment was independently associated with lower NGAL levels.Conclusions:Circulating NGAL and MMP-9/NGAL are associated with plaque vulnerability in patients with carotid artery stenosis. Statin treatment could contribute to plaque stabilization by reducing circulating NGAL and MMP-9/NGAL levels.

scholarly journals Immune Mechanisms of Plaque Instability

2022 ◽  
Vol 8 ◽  
Author(s):  
Teresa Gerhardt ◽  
Arash Haghikia ◽  
Philip Stapmanns ◽  
David Manuel Leistner
Keyword(s):  
Cardiovascular Risk ◽  
Plaque Rupture ◽  
Global Perspective ◽  
Lipid Lowering ◽  
Plaque Vulnerability ◽  
Plaque Instability ◽  
Immune Mechanisms ◽  
Plaque Disruption ◽  
Therapeutic Concepts

Inflammation crucially drives atherosclerosis from disease initiation to the emergence of clinical complications. Targeting pivotal inflammatory pathways without compromising the host defense could compliment therapy with lipid-lowering agents, anti-hypertensive treatment, and lifestyle interventions to address the substantial residual cardiovascular risk that remains beyond classical risk factor control. Detailed understanding of the intricate immune mechanisms that propel plaque instability and disruption is indispensable for the development of novel therapeutic concepts. In this review, we provide an overview on the role of key immune cells in plaque inception and progression, and discuss recently identified maladaptive immune phenomena that contribute to plaque destabilization, including epigenetically programmed trained immunity in myeloid cells, pathogenic conversion of autoreactive regulatory T-cells and expansion of altered leukocytes due to clonal hematopoiesis. From a more global perspective, the article discusses how systemic crises such as acute mental stress or infection abruptly raise plaque vulnerability and summarizes recent advances in understanding the increased cardiovascular risk associated with COVID-19 disease. Stepping outside the box, we highlight the role of gut dysbiosis in atherosclerosis progression and plaque vulnerability. The emerging differential role of the immune system in plaque rupture and plaque erosion as well as the limitations of animal models in studying plaque disruption are reviewed.

MicroRNAs as sentinels and protagonists of carotid artery thromboembolism

2020 ◽  
Vol 134 (2) ◽  
pp. 169-192
Author(s):  
Sneha Raju ◽  
Jason E. Fish ◽  
Kathryn L. Howe
Keyword(s):  
Carotid Artery ◽  
Atherosclerotic Plaque ◽  
Carotid Plaque ◽  
Molecular Mechanisms ◽  
Clinical Decision Making ◽  
Plaque Rupture ◽  
Cell Communication ◽  
Clinical Decision ◽  
Plaque Instability

Abstract Stroke is the leading cause of serious disability in the world and a large number of ischemic strokes are due to thromboembolism from unstable carotid artery atherosclerotic plaque. As it is difficult to predict plaque rupture and surgical treatment of asymptomatic disease carries a risk of stroke, carotid disease continues to present major challenges with regard to clinical decision-making and revascularization. There is therefore an imminent need to better understand the molecular mechanisms governing plaque instability and rupture, as this would allow for the development of biomarkers to identify at-risk asymptomatic carotid plaque prior to disease progression and stroke. Further, it would aid in creation of therapeutics to stabilize carotid plaque. MicroRNAs (miRNAs) have been implicated as key protagonists in various stages of atherosclerotic plaque initiation, development and rupture. Notably, they appear to play a crucial role in carotid artery thromboembolism. As the molecular pathways governing the role of miRNAs are being uncovered, we are learning that their involvement is complex, tissue- and stage-specific, and highly selective. Notably, miRNAs can be packaged and secreted in extracellular vesicles (EVs), where they participate in cell–cell communication. The measurement of EV-encapsulated miRNAs in the circulation may inform disease mechanisms occurring in the plaque itself, and therefore may serve as sentinels of unstable plaque as well as therapeutic targets.

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