Multiple Biological Predictors for Vulnerable Carotid Lesions

Abstract

Background: In this study a multiscore analysis of various biomarkers including matrix metalloproteinases (MMPs), inflammatory factors and other clinical parameters was performed to establish a set of reliable biomarkers for improved detection of plaque instability in patients with advanced carotid stenosis. Methods: Study patients (n = 101) were classified as histologically stable (n = 37) or unstable (n = 64). Serum levels of MMP-1, -2, -3, -7, -8, -9, MMP inhibitors TIMP-1, -2, and inflammatory factors such as tumor necrosis factor (TNF-α), interleukin (IL)-1β, -6, -8, -10, and -12 were measured by ELISA assays. Multiscore analysis was performed using multiple receiver operating characteristics analysis and determination of appropriate cutoff values. Results: Circulating levels of MMP-1, -7, TIMP-1, TNF-α, and IL-8 were significantly enhanced in patients with unstable plaques compared to individuals with stable lesions, mean differences being 1.2 (p = 0.032), 2.5 (p = 0.004), 30.0 (p = 0.014), 1.3 (p = 0.047), and 2.2 (p = 0.033), respectively. The combination of MMP-1, -7, TIMP-1 and IL-8 demonstrated the highest positive predictive value of 89.4% and negative predictive value of 60.1% for patients correctly classified as individuals with unstable and stable carotid lesions by means of blood sample analysis. Conclusions: Multiple relevant biomarkers that play a decisive role in plaque instability can improve the correct determination of vulnerable carotid plaques in patients with advanced carotid artery stenosis.

Toll-Like Receptor 4 Immunohistochemical Expression Is Enhanced in Macrophages of Symptomatic Carotid Atherosclerotic Plaques

“…Moreover, recent data suggest that TLR4 signaling is involved in the compensatory process of outward arterial remodeling and activation of matrix metalloproteinases, which in turn are linked to plaque destabilization [30], implying thus a potential involvement of TLR4 in the ‘vulnerable’ atherosclerotic plaque. In other words, activated macrophages within plaques are capable of degrading the extracellular matrix by secretion of matrix metalloproteinases, which can be stimulated by TLR4 activation and which induces plaque degradation and rupture [31].…”

Impact of chronic kidney disease on carotid plaque vulnerability

“…Correction for multiple testing was determined by using the Benjamini and Hochberg approach that considers the fraction of the false positives over the amount of tests declared significant and does not reduce the overall statistical power. 19 Values of P Ͻ .05 were considered statistically significant.…”

“…[14][15][16] Furthermore, several studies and our own data have already demonstrated increased levels of MMPs in the blood of patients with advanced carotid atherosclerosis. [17][18][19][20] CKD is also associated with elevation of some MMPs. 21 At present, the effect of CKD on carotid plaque morphology and plaque vulnerability is unknown.…”

New prognostic biomarkers in patients with ischemic stroke

“…Also, higher circulating levels of MMP-10 in ischemic stroke patients than in controls there have been found [13] . Besides, there have been found higher TIMP-1 concentrations in brain tissue of patients with cerebral infarction in comparison with brain tissue of healthy cerebral areas [14] , higher expression of TIMP-1 in monocytes of ischemic stroke patients with than in healthy controls [15] , higher blood TIMP-1 concentrations in patients with ischemic stroke than in healthy subjects [16][17][18][19] , and an there is association between neurological clinical outcome and plasma TIMP-1 levels at 7 days of clinical ischemic [20] .…”

“…Also, higher circulating levels of MMP-10 in ischemic stroke patients than in controls there have been found [13] . Besides, there have been found higher TIMP-1 concentrations in brain tissue of patients with cerebral infarction in comparison with brain tissue of healthy cerebral areas [14] , higher expression of TIMP-1 in monocytes of ischemic stroke patients with than in healthy controls [15] , higher blood TIMP-1 concentrations in patients with ischemic stroke than in healthy subjects [16][17][18][19] , and an there is association between neurological clinical outcome and plasma TIMP-1 levels at 7 days of clinical ischemic [20] .In a study by our team was found that patients suffering a malignant middle cerebral artery infarction (MMCAI) showed higher serum MMP-9, MMP-10 and TIMP-1 levels than healthy subjects [21] . Another new finding of our study was that non-surviving MMCAI patients showed higher circulating TIMP-1 and MMP-10 concentrations than survivors, and that there is an association between circulating TIMP-1 levels and mortality.…”