Abstract 299: Low Levels of Extra Domain A Containing Fibronectin in Human Atherosclerotic Plaques are Associated with a Vulnerable Plaque Phenotype
Background Extra Domain A (EDA), a splice variant of fibronectin, is a ligand for Toll-like receptor4 (TLR4). Recently, EDA has been demonstrated to enhance atherosclerotic lesion formation in mice but data on EDA and human atherosclerotic disease are lacking. We hypothesized that in human atherosclerotic plaques EDA is associated with an inflammatory plaque phenotype and that plasma EDA levels are increased in atherosclerotic patients.
Methods EDA levels were measured using ELISA, in plaque and plasma samples obtained from patients undergoing carotid endarterectomy (n=206). EDA levels were associated with plaque phenotype and clinical presentation. All plaques were stained for the presence of macrophages (CD 68), smooth muscle cells (alpha-actin), collagen (picro Sirius) and elastin (EvG). The overall plaque phenotype was based on haematoxylin staining and categorized as fibrous (<10% fat), fibroatheromatous (10 – 40% fat) or atheromatous (>40% fat). Systemic EDA levels were determined in plasma from a second cohort of patients and compared between patients suffering from clinically evident atherosclerotic disease (n=73) versus risk-factor matched control patients (n=68).
Results Lower EDA plaque levels were associated with more atheromatous lesions (P=0.015), low numbers of smooth muscle cells (P=0.003) and less extensive collagen staining (P=0.071). Concomitantly, symptomatic (TIA or stroke) patients showed lower EDA plaque values compared to asymptomatic patients (17.1 ± 1.6 and 27.0 ± 3.8, P=0.004). EDA plasma levels of endarterectomy patients did not correlate with plaque phenotype (P=0.350) or symptoms (P=0.728). EDA levels did not differ between atherosclerotic versus control patients (6.4 ± 0.5 and 7.6 ± 0.6, P=0.192).
Conclusion Endogenous TLR4 ligand EDA is not a plasma marker for atherosclerotic disease. However, EDA plaque levels are associated with a stable plaque phenotype. Although EDA enhances early atherogenesis in mice, these results suggest a stabilizing role for EDA in advanced human atherosclerotic lesions.