J Clin Neurol.  2013 Jul;9(3):165-175. 10.3988/jcn.2013.9.3.165.

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

• Musialek P
• Tracz W
• Tekieli L
• Pieniazek
• Kablak-Ziembicka A
• Przewlocki T
• Stepien E
• Kapusta P
• Motyl R
• Stepniewski J
• Undas A
• Podolec P

• KMID: 2287555
• DOI: http://doi.org/10.3988/jcn.2013.9.3.165

Abstract

BACKGROUND AND PURPOSE
Several 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).
METHODS
Prospective sampling of circulating cytokines and blood lipids was performed in 300 unselected, consecutive patients with > or =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.
RESULTS
CS 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-1beta, 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-PLA2) were elevated in those with recent vs. remote symptoms (p=0.01 and p=0.02, respectively).
CONCLUSIONS
In an all-comer CS population on contemporary pharmacotherapy, low HDL-cholesterol (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.

Keyword

carotid artery stenosis; biomarkers; circulating cytokines; risk factors; stroke risk; HDL-cholesterol

MeSH Terms

1-Alkyl-2-acetylglycerophosphocholine Esterase
Adiponectin
Biomarkers
C-Reactive Protein
Carotid Arteries
Carotid Stenosis
Chemokine CCL2
Cholesterol
Constriction, Pathologic
Cytokines
Discrimination (Psychology)
Fibrinogen
Humans
Interleukin-18
Interleukin-6
Interleukin-8
Leptin
Lipoprotein(a)
Lipoproteins
Logistic Models
Nicotinamide Phosphoribosyltransferase
Odds Ratio
Osteoprotegerin
Peroxidase
Plaque, Atherosclerotic
Prospective Studies
Risk Factors
ROC Curve
Rupture
Triglycerides
Vascular Cell Adhesion Molecule-1
1-Alkyl-2-acetylglycerophosphocholine Esterase
Adiponectin
C-Reactive Protein
Chemokine CCL2
Cholesterol
Cytokines
Fibrinogen
Interleukin-18
Interleukin-6
Interleukin-8
Leptin
Lipoprotein(a)
Lipoproteins
Nicotinamide Phosphoribosyltransferase
Osteoprotegerin
Peroxidase
Triglycerides
Vascular Cell Adhesion Molecule-1

Figure

• 

  Fig. 1 Distributions of HDL-cholesterol and hsCRP* in patients with carotid stenosis according to the presence or absence of a history of carotid stenosis-associated symptoms. A: Displays HDL-cholesterol level distribution (asymptomatic carotid stenosis top, A1; symptomatic carotid stenosis bottom, A2). B: hsCRP level distribution (asymptomatic carotid stenosis top, B1; symptomatic carotid stenosis bottom, B2). HDL: high-density lipoprotein, hsCRP: high sensitivity C-reactive protein.

• 

  Fig. 2 ROC curves for determining the symptomatic status of CS. Biomarker(s) sensitivity is demonstrated as a function of 1-specificity based on a logistic model incorporating three uncorrelated biomarkers (HDL-cholesterol, TIMP, and IL-6) whose levels differed significantly between symptomatic and asymptomatic subjects. A: Contribution of each biomarker taken alone; the AUC was highest for HDL-cholesterol. B: Contributions of paired biomarkers, indicating that neither of the pairs has a higher diagnostic power than HDL-cholesterol alone (cf. A). C: ROC curve for combined HDL-cholesterol+IL-6+TIMP, indicating that this was not higher than for HDL-cholesterol alone (cf. A). AUC: area under the curve, CS: carotid stenosis, HDL: high-density lipoprotein, IL-6: interleukin-6, ROC: receiver operating characteristics, TIMP: tissue inhibitor of matrix metalloproteinases-1.

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