Update on diagnostic approach of carotid disease: From stenosis to atherosclerotic plaque morphology

Smooth muscle cells (SMC) are known to migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. It has been shown that CD98hc, a transmembrane protein with a known role in amino acid transport and integrin signaling, is involved in proliferation and survival of various cell types including SMC. Based on these data, we hypothesized that CD98hc deficiency selectively in SMC would have pathogenic effects on atherosclerosis development and plaque composition. To test this, we utilized mice with SMC-specific deletion of the CD98hc ( CD98hc fl/fl SM22Cre + ) to determine the effects of CD98hc deficiency on SMC function in the context of atherosclerosis. We performed in vitro proliferation and survival/apoptosis assays to investigate the role of CD98hc in the proliferation and survival of primary mouse aortic vascular smooth muscle cells. We found that VSMC isolated from whole aortas of CD98hc -/- animals displayed approximately 60% reduced cell counts compared to control (41 ± 8.2% of control) after 5 days in culture. EdU assays in vivo showed a defect in the ability of CD98hc -/- SMC to proliferate, with 25% reduction in EdU-positive VSMC compared to controls (2.3 ± 0.2% vs 3 ± 0.2%). In addition, caspase-3 staining of SMC in vitro displayed a 41% increase in propensity of CD98hc -/- SMC to undergo apoptosis compared to controls (7.9 ± 0.6% vs 5.6 ± 0.5%). Furthermore, the absence of CD98hc in SMC caused a sharp increase in phosphorylated p-38, which was partially abrogated towards control levels when the cells were treated with PDGF-BB to induce proliferation. Long-term atherosclerosis study using SMC-CD98hc -/- /LDLR -/- mice showed that atherosclerotic plaque morphology was altered with increased necrotic core area (25.8 ± 1.9% vs 10.9 ± 1.6% necrotic core area per plaque area) due to a reduction in infiltration of SMC within the plaque (2.1 ± 0.4% vs 4.3 ± 0.4% SM22α positive area per plaque area) compared to control LDLR -/- mice. These data support an important role for CD98hc and its regulation of p-38 MAP kinase signaling in aortic vascular smooth muscle cell proliferation and survival. We conclude that CD98hc is critical for the formation of fibrous cap that is important in maintaining the stability of atherosclerotic plaque.

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Computational Analysis of Atherosclerotic Plaque Vulnerability Due to Hemodynamic Effects

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176045 ◽

2007 ◽

Author(s):

Ramses Galaz ◽

Rosaire Mongrain ◽

Valerie Pazos ◽

Richard Leask ◽

Jean Claude Tardif

Keyword(s):

Atherosclerotic Plaque ◽

Plaque Rupture ◽

Developed Countries ◽

Mechanical Failure ◽

Myocardial Infarctions ◽

Plaque Morphology ◽

Myocardial Tissue ◽

Physical Interaction ◽

Tissue Properties ◽

Atherosclerotic Plaque Rupture

Atherosclerotic plaque rupture has been extensively associated with acute myocardial infarctions, the leading cause of death in developed countries. When a plaque ruptures in the coronary arteries, it often leads to a clot formation that restricts the flow of blood downstream of the coronaries causing damage to the myocardial tissue. Hemodynamic factors combined with certain plaque morphologies and material properties play an important role in the mechanical failure of the plaque [1]. It is essential for clinicians to understand the vulnerability of plaques and the particular physiological conditions that lead to their mechanical failure. Our study focused on understanding the physical interaction between blood flow, plaque morphology and tissue properties to assess the plaque’s degree of vulnerability.

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Association between fibrinogen and fibrinogen γ’ and atherosclerotic plaque morphology and composition in symptomatic carotid artery stenosis: Plaque-At-RISK study

Thrombosis Research ◽

10.1016/j.thromres.2019.02.030 ◽

2019 ◽

Vol 177 ◽

pp. 130-135 ◽

Cited By ~ 3

Author(s):

A.C. van Dijk ◽

S.J. Donkel ◽

T. Zadi ◽

M.A.H. Sonneveld ◽

F.H.B.M. Schreuder ◽

...

Keyword(s):

At Risk ◽

Carotid Artery ◽

Atherosclerotic Plaque ◽

Carotid Artery Stenosis ◽

Artery Stenosis ◽

Plaque Morphology ◽

Symptomatic Carotid

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AS-13: Atherosclerotic Plaque Morphology and Serous Hypersensitive C-Reactive Protein in Patients with Premature Coronary Heart Disease

The American Journal of Cardiology ◽

10.1016/j.amjcard.2010.01.043 ◽

2010 ◽

Vol 105 (9) ◽

pp. 6A

Author(s):

Lijian Gao ◽

Rongai Xie ◽

Jun Chen ◽

Jilin Chen ◽

Yuejin Yang ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Atherosclerotic Plaque ◽

Plaque Morphology ◽

C Reactive Protein ◽

Premature Coronary Heart Disease ◽

Reactive Protein

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Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice

Atherosclerosis ◽

10.1016/j.atherosclerosis.2013.02.023 ◽

2013 ◽

Vol 228 (1) ◽

pp. 69-79 ◽

Cited By ~ 25

Author(s):

Ling Yan ◽

Per Bjork ◽

Radu Butuc ◽

Joseph Gawdzik ◽

Judy Earley ◽

...

Keyword(s):

Atherosclerotic Plaque ◽

Plaque Morphology ◽

Beneficial Effects

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Virtual Transcriptomics

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.315969 ◽

2021 ◽

Author(s):

Andrew J. Buckler ◽

Eva Karlöf ◽

Mariette Lengquist ◽

T. Christian Gasser ◽

Lars Maegdefessel ◽

...

Keyword(s):

Gene Expression ◽

Myocardial Infarction ◽

Computed Tomography ◽

Ischemic Stroke ◽

Atherosclerotic Plaque ◽

Computed Tomography Angiography ◽

Machine Intelligence ◽

Diagnostic Methods ◽

Plaque Morphology ◽

Atherosclerotic Cardiovascular Disease

Objective: Therapeutic advancements in atherosclerotic cardiovascular disease have improved prevention of ischemic stroke and myocardial infarction, but diagnostic methods for atherosclerotic plaque phenotyping to aid individualized therapy are lacking. In this feasibility study, we aimed to elucidate plaque biology by decoding the molecular phenotype of plaques through analysis of computed-tomography angiography images, making a predictive model for plaque biology referred to as virtual transcriptomics. Approach and Results: We employed machine intelligence using paired computed-tomography angiography and transcriptomics from carotid endarterectomies of 40 patients undergoing stroke-preventive surgery for carotid stenosis. Computed tomography angiographies were analyzed with novel software for accurate characterization of plaque morphology and plaque transcriptomes obtained from microarrays, followed by mathematical modeling for prediction of molecular signatures. Four hundred fourteen coding and noncoding RNAs were robustly predicted using supervised models to estimate gene expression based on plaque morphology. Examples of predicted transcripts included ion transporters, cytokine receptors, and a number of microRNAs whereas pathway analyses demonstrated enrichment of several biological processes relevant for the pathophysiology of atherosclerosis and plaque instability. Finally, the ability of the models to predict plaque gene expression was demonstrated using computed tomography angiographies from 4 sequestered patients and comparisons with transcriptomes of corresponding lesions. Conclusions: The results of this pilot study show that atherosclerotic plaque phenotyping by image analysis of conventional computed-tomography angiography can elucidate the molecular signature of atherosclerotic lesions in a multiscale setting. The study holds promise for optimized personalized therapy in the prevention of myocardial infarction and ischemic stroke, which warrants further investigations in larger cohorts.

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The Effect of Plaque Morphology on Cap Stresses in Coronary Arteries

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80647 ◽

2012 ◽

Author(s):

A. C. Akyildiz ◽

L. Speelman ◽

H. Nieuwstadt ◽

R. Virmani ◽

J. Wentzel ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Disease ◽

Sudden Death ◽

Coronary Arteries ◽

Atherosclerotic Plaque ◽

Vessel Wall ◽

Thrombus Formation ◽

Plaque Formation ◽

Plaque Morphology

Atherosclerosis is a cardiovascular disease characterized by plaque formation in the vessel wall. The region of an atherosclerotic plaque separating its pathological content from the lumen is called cap. Cap rupture initiates thrombus formation and may lead to myocardial infarction and sudden death [1].

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