Abstract P137: Hypercholesterolemia Aggravates In-stent Restenosis In Rabbits By Escalating Vascular Inflammation

Abstract

Background: Hypercholesterolemia (HC) has previously been shown to augment restenotic response in several animal models. However, the mechanistic aspects of in-stent restenosis (ISR) on an HC background are not fully understood. Methods: HC was induced in 5 NZW rabbits by hypercholesterolemic diet (HCD) fed for 4 weeks prior to bilateral implantation of stainless steel stents in the iliac location. The diet was continued until sacrifice. In parallel, stents were deployed in the iliac arteries of 5 normocholesterolemic (NC) rabbits. All animals were euthanized 4 weeks after stenting. Harvested arteries were formalin-fixed. The stent struts were dissolved in a mixture of nitric and hydrofluoric acids. The destented arteries were paraffin-embedded, sectioned, stained according to the Verhoeff-vanGieson method, and the lumen area, neointimal thickness, neointimal area, neointima-to-media ratio, and percent of luminal stenosis were determined morphometrically. A semiquantitative scale was used to assess the intensity and spread of TNFa expression by immunohistochemistry (IHC). The prevalence of peri-strut macrophages (MΦ) was determined by IHC as a percentage of a strut circumference infiltrated with MΦ. Results: HC diet drastically increased severity of ISR (Fig). The corresponding values of the lumen area, neointimal thickness, neointimal area, neointima-to-media ratio and percent of luminal stenosis for the groups of NC and HC animals were 1.86±0.44 vs 1.48±0.54 (p<0.05), 0.06±0.02 vs 0.31±0.14 (p<0.0001), 0.66±0.16 vs 2.07±0.56 (p<0.0001), 1.99±0.11 vs 4.57±0.76 (p<0.0001), and 26.35±4.78 vs 57.89±13.71 (p<0.0001). Compared to NC animals, TNFa immunopositivity and MΦ infiltration of peri-strut areas increased in HC group animals 1.81- and 2.58-fold, respectively (p<0.001 for both). Conclusions: The inflammatory response to stent deployment is intensified in HC metabolic conditions, leading to the augmented neointimal expansion and ISR.