Characterization of Atherosclerotic Plaques: A Morphological, Metabolic and Clinical Study
Date Issued
2009
Date
2009
Author(s)
Wu, Yen-Wen
Abstract
Background: Rupture of atherosclerotic plaques and subsequent formation of thrombi are currently recognized as the major cause of morbidity and mortality in ischemic stroke and cardiovascular diseases, including acute coronary syndrome. Several imaging modalities have shown promises as potential surrogate markers for atherosclerosis. They may help clinicians and investigators to directly visualize atherosclerotic plaque burden, refine cardiovascular risk assessments, and allow serial monitoring of disease activity once interventions have been initiated. he proposed major criteria for defining vulnerable plaques, based on the autopsy studies, include active inflammation (monocyte/macrophage and sometimes T-cell infiltration), thin cap with large lipid core, endothelial denudation with superficial platelet aggregation, fissured plaque and severe luminal stenosis. Conventional imaging of atherosclerosis is based on the degree of luminal stenosis and morphologic characteristics of atheromas, including X-ray contrast angiography, computed tomography (CT) and magnetic resonance (MR) imaging. Nuclear imaging also has the ability to non-invasively image pathophysiological process of atherosclerosis. Recent studies have shown that 18F-fluorodeoxyglucose (18F-FDG) accumulates in macrophage-rich plaques and the inflammatory activity of individual plaques could be detected and measured by using positron emission tomography (PET). In addition, hybrid PET/CT scanners could detect calcification and provide better localization of systemic atherosclerotic plaques, thus may allow to screen, diagnose or monitor treatment response in patients with atherosclerosis. Atherosclerosis is a complex and multifactorial disorder, and a specific profile of biomarkers may help identify subjects at risk for progressive atherosclerosis or plaque rupture. Inflammation plays a significant role in the pathogenesis and progression of atherosclerosis. Numerous systemic serological markers have been reported to provide additional information about the risk of developing cardiovascular disease and reflect the overall burden of atherosclerosis. However, many of these are not specific to systemic atherosclerosis or plaque vulnerability, and the clinical significance remains to be elucidated. Levels of cellular adhesion molecules (such as E-selectin, ICAM-1, VCAM-1) may reflect extent of expression and/or shedding of molecules on endothelial surface that are influenced by pro-inflammatory cytokines. Recent data have suggested that macrophages and vascular smooth muscle cells are important component of vulnerable plaques, and are the sources of matrix metalloproteinases (MMPs) production. Several immunochemical findings have showed that MMP-1 is abundant in the macrophage-rich shoulder regions of atherosclerotic plaques and is robustly induced by cytokines and growth factor. However, scant studies have reported that MMP-1 is associated with acute coronary syndrome and the presence of complex coronary lesions. The significance of circulating levels of MMP-1 remains to be evaluated in larger-scale clinical studies. Macrophages are important for intracellular lipid accumulation and foam cell formation in the process of atherosclerosis. MMPs secretion by macrophages is believed to play a key role in the matrix degradation that underlies atherosclerotic plaque instability. Diabetes is a major risk factor for atherosclerosis, thus we investigate the regulatory mechanism of MMP-1 in THP-1 differentiated macrophages under high glucose media.urposes: The aims of this study are to evaluate the feasibility of 18F-FDG PET/CT as a non-invasive imaging modality in the detection of systemic atherosclerosis, and correlation between characteristics of atherosclerotic plaques by using 18F-FDG PET/CT and circulating biomarkers among subjects with or without carotid stenosis. We further evaluate the role of cellular adhesion molecules in patients with transplant vasculopathy and MMP-1 in patients with significant atherosclerosis. We establish an in-vitro system of THP-1 monoblastic leukemic cell-line to explore MMP-1 and hypoxia-inducible factor-1α (HIF-1α) expression and regulation signal pathways including nuclear factor-kB (NF-kB) or c-Jun N-terminal kinase (JNK) pathways, especially in high glucose conditions. We also evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) and MMP-1.esearch Designs and Results:. We analyzed ICAM-1, VCAM-1 and E-selectin levels from the coronary sinus of 25 cardiac allograft recipients, correlated with the degree of acute rejection detected in endomyocardial biopsy specimens and the presence of transplant vasculopathy assessed with coronary angiography. We found that VCAM-1 significantly increased in patients with transplant vasculopathy compared with those without transplant vasculopathy, whereas E-selectin and ICAM-1 did not..We examined 25 patients with significant carotid stenosis (≥ 50%) and 22 controls using 18F-FDG PET/CT. 18F-FDG arterial uptake, as well as calcifications, was significantly higher in extensive distributions in patients with established carotid stenosis; but their distribution was not consistently overlapping. The values of circulating MMP-1 and leukocyte counts were significantly higher in patients with carotid stenosis (all P < 0.05). In addition, subjects with higher 18F-FDG uptake (SUVmax > 2.0) on target lesions had higher baseline and post-stenting MMP-1 levels (all P < 0.05). We further measured hs-CRP and MMP-1 in 37 patients with significant carotid stenosis and 84 controls. We also confirmed that patients with carotid stenosis exhibited significant higher MMP-1 as compared with controls, but no difference in hs-CRP. Moreover, MMP-1 elevated immediately after stenting (n = 30). In multivariate analyses, MMP-1 was negatively correlated with statin and angiotensin converting enzyme inhibitor/angiotensin-II receptor blocker use in controls.. MMP-1, hs-CRP and adiponectin were measured in 217 subjects with angiographically documented multivessel coronary artery disease (CAD, two or three-vessel disease by luminal stenosis ≥ 50%) and 81 controls. MMP-1 and hs-CRP were notably higher in patients with CAD; while adiponectin was not significantly different between two groups. Levels of hs-CRP positively correlated with body mass index and left ventricular dysfunction (R2 = 0.16, P < 0.0001); while adiponectin was significantly associated with age, gender, and levels of cholesterol and triglyceride (R2 = 0.09, P < 0.0001). On the contrary, MMP-1 was not associated with any clinical cardiovascular risk factors, and still an independent predictor (OR = 1.49, P < 0.0001) of multivessel CAD after the adjustment of clinical risk factors and hs-CRP.. We have established an in-vitro THP-1 macrophage cell model. THP-1 treated with PMA may mimic inflammatory stimulation. High glucose concentration could augment PMA-stimulated MMP-1 expression in THP-1. MMP-1 mRNA expression is through cytokines/inflammatory process, via NF-κB and JNK pathways, especially NF-κB. Of glimepiride, metformin and BRL-49653 (rosiglitazone, PPAR γ agonist), BRL-49653 notably attenuates PMA-stimulated MMP-1 expression in THP-1 in high glucose concentration. We have demonstrated that PMA could upregulate HIF-1α which is suppressed by NF-κB inhibitor. HIF-1α inducers could upregulate MMP-1 while HIF-1α inhibitor could attenuate MMP-1, suggesting MMP-1 could be regulated by HIF-1α.onclusions:his study has demonstrated that an increased coronary sinus level of sVCAM-1 is a reliable marker in assessing cardiac transplant vasculopathy. Our study has also shown that 18F-FDG PET/CT imaging could be used as an adjunct to the clinical management of high-risk atherosclerosis and an in vivo tool to study plaque biology. Elevated MMP-1 could predict the presence of advanced atherosclerosis. Higher levels and rapid surge after stenting in patients with carotid stenosis support MMP-1 is an important composition of plaques. Our investigation provides a linketween 18F FDG uptake and MMP-1. In THP-1 cell model, increased transcription of macrophage MMP-1 under high glucose conditions provides a mechanism for accelerated atherosclerosis in diabetes. MMP-1 expression is regulated via NF-κB and JNK pathways, as well as HIF-1α., thus providing a molecular basis for regulation of MMP-1 in differentiated THP-1 cells.
Subjects
Atherosclerosis
Vulnerable Plaque
18F-fluorodeoxyglucose (18F-FDG)
Positron Emission Tomography (PET)
Macrophage
Matrix Metalloproteinase-1 (MMP-1)
SDGs
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