Matrix metalloproteinase inhibition reduces intimal hyperplasia in a porcine arteriovenous-graft model

Abstract

Background: The patency of arteriovenous (AV) polytetrafluoroethylene grafts for hemodialysis is impaired by intimal hyperplasia (IH) at the venous outflow tract. IH mainly consists of vascular smooth muscle cells, fibroblasts, and extracellular matrix proteins. Because matrix metalloproteinases (MMPs) are enzymes able to degrade extracellular matrix proteins such as elastin and collagen and also stimulate migration of vascular smooth muscle cells, we hypothesized that BB2983 (a broad-spectrum MMP inhibitor) could reduce IH in AV grafts. Methods: In 12 pigs, AV grafts were created bilaterally between the carotid artery and the jugular vein. Six pigs received the oral MMP inhibitor (MMPi), and six pigs served as a control. Four weeks after AV shunting, the grafts and adjacent vessels were excised and underwent histologic analysis. Quantification of elastin content was performed on Elastin von Gieson-stained sections. Results: At the venous outflow tract, IH was strongly inhibited after MMPi when compared with the control group (1.02 ± 0.26 mm2 vs 2.14 ± 0.38 mm2; P = .027). The medial area did not differ significantly. In the control group elastin density decreased compared with nonoperated veins. This decrease was not observed in the MMPi group (nonoperated, 6.3% ± 0.4%; MMPi, 7.2% ± 0.7% vs untreated, 3.6% ± 0.5%; P = .0004). Outward remodeling of the vein was not influenced by MMP inhibition. Conclusion: MMPi reduces IH formation at the venous outflow tract of AV grafts in pigs, probably by inhibiting elastin degradation. These data suggest that MMP inhibitors might be useful for minimizing IH in AV grafts, thus prolonging patency rates of AV grafts in patients on hemodialysis.