Relation between serum levels of chemotaxis-related factors and the presence of coronary artery calcification as expression of subclinical atherosclerosis

Abstract

Background: Atherosclerotic plaque formation is characterized by recruitment of monocytes/macrophages, which contributes to its calcification by releasing pro-osteogenic cytokines. Chemotaxis-related proteins, including netrin-1, gremlin-1 and macrophage inflammatory protein-1β (MIP-1β), regulate immune cell migration. However, their relation with the presence of subclinical atherosclerosis, assessed by measures of coronary artery calcifications (CAC) in patients without known coronary artery disease (CAD), remains unclear.

Aims: To examine whether these chemoattractant-related proteins are associated with the presence of CAC in patients without known CAD.

Methods: A retrospective case-control observational study was conducted in 120 outpatients without CAD, undergoing a CAC evaluation by computed tomography with the Agatston Calcium score, categorized as CAC^- (none) and CAC⁺ (≥1). Serum biomarkers were quantified by ELISA.

Results: Lpa, dyslipidaemia and smoking were significantly higher (p=0.006, p≤0.0001 and p=0.001, respectively) in CAC⁺ patients. Serum netrin-1 levels were lower in CAC⁺ than in CAC^- patients (196.8±127.8pg/ml versus 748.3±103.2pg/ml, p≤0.0001), and a similar pattern was found for gremlin-1 (1.14±0.39ng/ml versus 4.33±1.20ng/ml, p≤0.0001). However, TNFα and MIP-1β were strongly upregulated in CAC⁺ patients (447.56±74pg/ml versus 1104±144pg/ml and 402.00±94pg/ml versus 905.0±101.6pg/ml, respectively, p≤0.001). Multivariate analyses revealed that low netrin-1 and gremlin-1 levels and high TNFα and MIP-1β amounts were associated with CAC presence, after adjustment for clinical and biochemical variables.

Conclusions: We found a netrin-1 and gremlin-1 deficiency and a TNFα and MIP-1β overproduction in CAC⁺ patients' serum. These proteins may be used to identify individuals with subclinical atherosclerosis. Further research is warranted in a larger cohort of patients to establish these chemotactic-related proteins as biomarkers that improve CAD risk stratification.

Keywords: Atherosclerosis; Biomarkers; Coronary artery calcification; Gremlin-1; Macrophage inflammatory protein-1β; Netrin-1.