Extracellular Matrix Changes in Stented Human Coronary Arteries

Abstract

Background— Restenosis after stenting occurs secondary to the accumulation of smooth muscle cells (SMCs) and extracellular matrix (ECM), with the ECM accounting for >50% of the neointimal volume. The composition of the in-stent ECM has not been well characterized in humans. Methods and Results— Postmortem human coronary arteries (n=45) containing stents underwent histological assessment of neointimal proteoglycans, hyaluronan, collagen (types I and III), SMCs, and CD44 (a cell surface receptor for hyaluronan). The mean duration of stent implantation was 18.7 months; stents in place ≥3 to <9 months (n=17) were assigned to group 1, stents ≥9 to <18 months old (n=19) to group 2, and stents ≥18 months old (n=9) to group 3. In groups 1 and 2, neointimal versican and hyaluronan staining was strongly positive, colocalized with α-actin-positive SMCs, and was greater in intensity compared with group 3. Conversely, decorin staining was greatest in group 3. The neointima of both group 1 and 2 stents was rich in type III collagen, with reduced staining in group 3. Type I collagen staining was weakest in group 1 stents, with progressively stronger staining in groups 2 and 3. SMC density and stent stenosis were significantly reduced in group 3 stents compared with groups 1 and 2. CD44 staining colocalized with macrophages and was associated with increased neointimal thickness. Conclusions— The ECM within human coronary stents resembles a wound that is not fully healed until 18 months after deployment, followed by neointimal retraction. ECM contraction may be a target for therapies aimed at stent restenosis prevention.