Multimarker Approach in Discriminating Patients with Symptomatic and Asymptomatic Atherosclerotic Carotid Artery Stenosis

Abstract

Background and PurposezzSeveral circulating biomarkers have been implicated in carotid atherosclerotic plaque rupture and thrombosis; however, their clinical utility remains unknown. The aim of this study was to determine the role of a large biomarker panel in the discrimination of symptomatic (S) vs. asymptomatic (A/S) subjects in a contemporary population with carotid artery stenosis (CS).MethodszzProspective sampling of circulating cytokines and blood lipids was performed in 300 unselected, consecutive patients with ≥50% CS, as assessed by duplex ultrasound (age 47-83 years; 110 with A/S and 190 with S) who were referred for potential CS revascularization.ResultszzCS severity and pharmacotherapy did not differ between the A/S and S patients. The median values of total cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a) did not differ, but high-density lipoprotein (HDL) cholesterol was significantly higher (p<0.001) and triglycerides were lower (p=0.03) in the A/S-CS group than in the S-CS group. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein were higher (p=0.04 and p=0.07, respectively) in the S-CS group. Circulating visfatin, soluble CD 40 receptor ligand, soluble vascular cell adhesion molecule, leptin, adiponectin, IL-1β, IL-8, IL-18, monocyte chemoattractant protein-1, myeloperoxidase, matrix metalloproteinases-8, -9, and -10, and fibrinogen were similar, but tissue inhibitor of matrix metalloproteinases-1 (TIMP) was reduced in S-CS compared to A/S-CS (p=0.02). Nevertheless, incorporation of TIMP and IL-6 did not improve the HDL-cholesterol receiver operating characteristics for S-CS status prediction. S-CS status was unrelated to angiographic stenosis severity or plaque burden, as assessed by intravascular ultrasound (p=0.16 and p=0.67, respectively). Multivariate logistic regression analysis revealed low HDL-cholesterol to be the only independent predictor of CS symptoms, with an odds ratio of 1.81 (95% confidence interval=1.15-2.84, p=0.01) for HDL <1.00 mmol/L (first quartile) vs. >1.37 (third quartile). In S-CS, osteoprotegerin and lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) were elevated in those with recent vs. remote symptoms (p=0.01 and p=0.02, respectively).ConclusionszzIn an all-comer CS population on contemporary pharmacotherapy, low HDLcholesterol (but not other previously implicated or several novel circulating biomarkers) is an independent predictor of S-CS status. In addition, an increase in circulating osteoprotegerin and Lp-PLA2 may transiently indicate S transformation of the carotid atherosclerotic plaque.

Association between the Lipoprotein-Associated Phospholipase A2 Activity and the Progression of Subclinical Atherosclerosis

“…Despite accumulating evidence showing an increased risk of clinical CVD events to be associated with the Lp-PLA2 level, the association between the Lp-PLA2 level and subclinical atherosclerosis is less established, and the findings of limited cross-sectional and casecontrol studies are inconsistent [7][8][9][10][23][24][25] . In the present analysis, the Lp-PLA2 level was found to be significantly associated with the presence of baseline carotid plaque in men, but not women.…”

Circulating Chemerin Is Associated With Carotid Plaque Instability, Whereas Resistin Is Related to Cerebrovascular Symptomatology

“…44,45 Along with others, we also detected no significant differences in adiponectin levels between symptomatic versus asymptomatic subjects with moderate-to high-grade CAS. 46,47 Interestingly, it was recently reported that perivascular adiponectin expression, rather than circulating adiponectin, is significantly associated with symptomatology in patients undergoing CEA. Perivascular adipose tissue surrounding symptomatic carotid plaques expressed 1.9-fold higher levels of adiponectin than asymptomatic plaques.…”

Commentary: Carotid Artery Revascularization for Stroke Prevention

“…4,14,21 For a significant proportion of these patients, a "not-yetsymptomatic" or "at risk of symptomatic transformation" label would be more accurate than the "asymptomatic" label, but the field suffers from lack of effective risk discrimination tools. 19 While the need for revascularization in symptomatic patients is not controversial (albeit the treatment arrives too late to prevent brain damage! ), it is surprising to the vascular community that, in the absence of any reliable evidence, vocal and powerful calls are being made to "stop revascularization in asymptomatic patients" 22 and "just stick to medical therapy."…”