IYSC06 - High plasma levels of IsoDGR fibronectin levels are associated with more plaque macrophages in a large cohort of carotid endarterectomy patients

Objectives: During atherosclerotic plaque progression to a more rupture-prone plaque, plaques accumulate more macrophages and foam cells. Deamidation of the NGR (Asn-Gly-Arg) motif to the isoDGR (isoAsp-Gly-Arg) motif in fibronectin (IsoDGR fibronectin) enhances in vitro monocyte and endothelial cell activation while blockage of isoDGR reduce macrophage influx in the mouse liver. Although this strongly suggests a role of isoDGR fibronectin in macrophage influx in the atherosclerotic matrix and thereby increase the risk of atherosclerotic events, plasma isoDGR fibronectin has not been analysed in large human cohorts with atherosclerotic plaque histology available.

Methods: Using the Athero Express biobank, plasma isoDGR fibronectin was measured in carotid endarterectomy (CEA) patients using an ELISA. Carotid plaque macrophage staining was done using a CD68 staining and scored semi-quantively. Plasma IsoDGR fibronectin measurements were dichotomised over de median. Baseline characteristics were analysed with Pearson’s Chi-squared test and Mann-Whitney U-test when applicable.

Results: In total, plasma isoDGR fibronectin was measured in 731 CEA patients, of which 14% were asymptomatic. CEA patients that had a plasma isoDGR fibronectin level higher than the median showed more moderate to heavy macrophage staining in plaque histology (57% vs 47%, p=0.009) and is in agreement with the in vitro and mouse data. In contrast, however, CEA patients with higher levels of plasma isoDGR were less likely to have a history of risk factors as hypertension (83% vs 89% , p=0.021), coronary artery disease (28% vs 37%, p=0.012) and peripheral arterial occlusive disease (20% vs 27%, p=0.013). There were no significant differences in pre-operative symptoms between the two isoDGR fibronectin groups.

Conclusions: High plasma levels of isoDGR fibronectin are associated with more plaque macrophages and low occurrence of atherosclerotic risk factors before CEA. This may suggest a dual role of isoDGR fibronectin between plasma and plaque and for this we currently investigate isoDGR fibronectin content in the carotid plaque.