Combining sirolimus-eluting stents and external irradiation in cholesterol-fed rabbits increased incomplete stent apposition and decreased re-endothelialization.

Restenosis after the implantation of a drug-eluting stent or after vascular irradiation therapy shares similar physiopathological mechanisms. No experimental data are currently available on vascular wall behavior after external irradiation on arteries stented with sirolimus-eluting stents (SES). Ten New Zealand white rabbits received a 0.5% cholesterol-enriched chow for 1 month. Bilateral iliac artery stent implantation was then performed with an SES (Cypher; Cordis Corp). The animals were randomized into either an irradiated group (I, 2 Gy external x-ray irradiation, n = 5) or a control group (C, n = 5). The cholesterol-enriched chow was continued for 1 additional month after stent implantation. The stented arteries were harvested for histological analyses. The number and the percentage of incompletely apposed stents struts (IASS) were significantly higher in irradiated versus control group (3.05 +/- 0.46 vs. 1.57 +/- 0.27 IASS, P < 0.01, and 28.44% +/- 3.97% vs. 15.2% +/- 2.46% of IASS, P < 0.01, respectively). The mean neointimal thickness behind the IASS was also higher in the irradiated group (I: 28.3 +/- 2.5 microm vs. C: 18.2 +/- 2.3 microm, P < 0.01). Re-endothelialization was lower in irradiated group (I: 44.6% +/- 17.5% vs. C: 75.2% +/- 5.7%, P < 0.01). The present study revealed that low-dose external irradiation increased incomplete stent apposition and reduced re-endothelialization of SES. These results underscore the potential deleterious cumulative side effects of these 2 procedures to prevent restenosis.

Late neointimal tissue growth behind the stent after intravascular gamma-radiation.

PURPOSE: To determine the nature of the changes of the vascular wall after intravascular brachytherapy in stented arteries leading to incomplete stent apposition. METHODS AND MATERIALS: Stents were implanted in the infrarenal aortas of rabbits, and gamma-intravascular brachytherapy (18 Gy) or a sham radiation procedure was immediately implemented. The arteries were harvested at 6 months for histologic analyses. RESULTS: The external elastic lamina area, as well as the vascular wall area behind the stent, were significantly greater in irradiated vs. control arteries (8.94 +/- 0.68 mm2 vs. 6.87 +/- 0.40 mm2 [p <0.001] and 1.56 +/- 0.13 mm2 vs. 0.72 +/- 0.07 mm2 [p <0.001], respectively). The ratio of the intimal area behind the stent related to the total intimal area was greater in the irradiated segments (control vs. irradiated: 9.0% +/- 5.9% vs. 55.3% +/- 15.5%, p <0.05). Neointimal growth of the irradiated vessels outside the stent was characterized by marked fibrin depositions and an inflammatory response around the stent struts. CONCLUSION: Our study revealed the presence of a neointimal layer specifically located behind the stent, which represented the result of an unhealed fibrin-rich tissue growth process 6 months after intravascular brachytherapy.

Intrarenal detection of nitric oxide using electron spin resonance spectroscopy in hypertensive lipopolysaccharide-treated rats.

The inhibition of nitric oxide (NO) synthesis by chronic administration of NG-nitro-l-arginine methyl ester (l-NAME) in rats is responsible for systemic hypertension. However, the mechanisms involved in this hypertension remain unclear. The effects of chronic l-NAME on kidney and blood NO production were studied in rats in a state of endotoxic shock due to lipopolysaccharide (LPS). A nitric oxide spin trapping technique using electron spin resonance (ESR) spectroscopy has been used to identify and measure the production of NO in the kidney. This method is based on the trapping of nitric oxide by a metal-chelator complex consisting of N-methyl-d-glucamine dithiocarbamate (MGD) and reduced iron (Fe2+) forming a water-soluble NO-FeMGD complex detected by ESR. After LPS injection (14 mg/kg, IV, 6 h before the sacrifice) to rats pretreated with l-NAME (10 mg/kg/d over 14 days), the NO-FeMGD complex was evaluated in the kidney (arbitrary units [AU]/g of kidney) and the density of polynuclear neutrophils was counted by light microscopy. Chronic inhibition of NO synthase by l-NAME, a nonspecific inhibitor, was responsible for a decrease of the NO-FeMGD complex levels in the kidney (24.9 +/- 1.6 AU versus 13.8 +/- 1.3 AU). LPS administration was responsible for a large increase in both NO-FeMGD complex and neutrophil levels in the kidney of normotensive rats (332.6 +/- 12.8 AU versus 24.9 +/- 1.6 AU for NO-FeMGD complex and 1.36 +/- 0.41 versus 0.11 +/- 0.03 for neutrophils). Conversely, LPS administration in hypertensive, l-NAME-pretreated rats was linked to a smaller increase in the NO-FeMGD complex (85.1 +/- 7.9 AU versus 332.6 +/- 12.8 AU) and a larger increase in glomerular neutrophils (2.48 +/- 0.36 versus 1.36 +/- 0.41) compared with normotensive rats. These results are in agreement with a direct implication of NO during LPS-and l-NAME-induced kidney injuries.