Prevention of intimal hyperplasia after balloon angioplasty and / or stent insertion. or How to mend a broken heart - Just say NO.

Background: Restenosis is the most frequently occurring adverse event after percutaneous intravascular treatment of atherosclerotic lesions, which limits long-term patency of the intervention. Objective: The aim of the study was to evaluate if minimizing vascular injury during treatment by insertion of self-expanding stents or modifying the reparative mechanisms by local drug delivery can reduce restenosis. Methods: Healthy pigs were used in all experiments. Iliac arteries in twenty-seven pigs were treated by percutaneous transluminal angioplasty (PTA) or insertion of balloon expandable or self-expanding stents with or without previous PTA. Endothelial damage was evaluated by scanning electron microscopy, proliferation of smooth muscle cells by histochemistry, and development of intimal hyperplasia by angiography, intravascular ultrasound and histomorphology. Percutaneous transluminal coronary angioplasty (PTCA) was performed in forty-nine pigs. They were divided into five groups according to treatment as follows: only PTCA, PTCA with local delivery of NaCl, PTCA with local delivery of the Nitric Oxide donor 3- morpholino-sydnonimine (SIN-1), and local delivery of a selective guanylate cyclase inhibitor, 1H-(1,2,4)oxadiazole(4,3- alpha)quinoxaline-1-one (ODQ) followed by SIN-1. Untreated segments distally to the treated segments served as base-line controls. The specimens were evaluated by histochemistry, biochemical analysis, angiography and histomorphology. Results: The number of proliferating smooth muscle cells (SMCs) in iliac arteries increased 3-fold after PTA compared to insertion of self-expanding stents. Endothelium was better preserved after deployment of self-expanding stents, especially those with circumscribed wall coverage (50%), compared to stents with extensive wall coverage (3-24%), or to balloonexpanded stents (6%), or to balloon dilation only (6%). At 8 weeks following treatment, arteries treated with self-expanding stents without previous PTA had less intimal hyperplasia and larger luminal diameter compared to PTA combined with stent insertion or PTA alone. After PTCA and local deposition of SIN-1, a 54% reduction of restenosis compared to PTCA and 59% reduction compared to PTCA + NaCl was apparent. The expression of nitric oxide synthase (NOS) and the ratio of intermediate filaments (IF) to actin was reduced more than 40% upon treatment with SIN-1. After c-GMP inhibition by ODQ, restenosis increased 2-fold compared to PTCA+NaCl treated arteries while the expression of NOS and the IF/actin ratio did not change compared to PTCA and to PTCA + NaCl treated segments. Conclusions: Direct stenting with self-expanding stents results in reduced SMC proliferation, better preserved endothelium, and lower restenosis rate compared to balloon angioplasty before stenting or balloon angioplasty alone. In coronary arteries the development of intimal hyperplasia can be significantly reduced with site-specific delivery of nitric oxide donor. The pathway for this effect is cGMP dependent. Early changes in NOS expression in the endothelium and the structural protein content of the vascular media are correlated to the development of intimal hyperplasia and restenosis