High Levels of Plasma and Plaque IsoDGR-Modified Fibronectin are Associated with Rupture Prone Plaque Characteristics in Carotid Endarterectomy Patients.

Abstract

Macrophage influx is an important feature of human plaque destabilisation. Studies in mice suggest a role of the isoD(Asp)G(Gly)R(Arg) three amino acid motif in fibronectin (isoDGR-modified fibronectin) in macrophage influx. The association between isoDGR fibronectin in human plasma and plaque with plaque macrophage influx and vulnerable plaque characteristics has not been investigated in large human cohorts. Levels of isoDGR fibronectin were measured in individual plasma and plaques from carotid endarterectomy (CEA) patients from the Athero-Express biobank and associated with macrophage content and other vulnerable plaque characteristics in the carotid plaque of the same patient. Levels of isoDGR fibronectin were measured using an enzyme linked immunosorbent assay. Carotid plaque characteristics were visualised with immunohistochemistry staining and scored semi-quantitatively. Baseline characteristics were analysed with Pearson's chi squared test and Mann-Whitney U test when applicable. Uni- and multivariable logistic regression analyses were used to identify associations with adverse plaque characteristics. Plasma isoDGR fibronectin was measured in 730 CEA patients (12.3% asymptomatic). Patients with moderate or heavy plaque macrophage staining had higher levels of isoDGR fibronectin than patients with no or minor macrophage staining (multivariable odds ratio [OR] 1.40, 95% confidence interval [CI] 1.04 - 1.90; p = .028). Of the 730 CEA patients, 348 had plaque samples available for isoDGR fibronectin measurements. In the multivariable analysis, higher plaque levels of isoDGR fibronectin were associated with moderate or high plaque macrophage staining (OR 1.22, 95% CI 1.00 - 1.56; p = .049), > 40% plaque area of fat (OR 1.44, 95% CI 1.14 - 1.86; p = .004), and intraplaque haemorrhage (OR 1.38, 95% 1.12 - 1.72; p = .003). In this large human cohort study, high plasma and plaque levels of isoDGR fibronectin were associated with more plaque macrophages and other adverse plaque characteristics. This suggests the involvement of isoDGR fibronectin in human plaque destabilisation and blocking isoDGR modifications as a potential treatment modality.