Development of a Novel Murine Model of In-Stent Neoatherosclerosis

BACKGROUND: In-stent neoatherosclerosis is a complication of percutaneous coronary intervention with stenting. Although similar to de novo atherosclerosis, it develops rapidly within 1 to 5 years rather than over a lifetime. No preclinical small animal model exists to fully elucidate neoatherosclerosis biology or evaluate targeted therapies. This study aimed to establish and validate a novel murine model of in-stent neoatherosclerosis.

METHODS: Murine stainless-steel stents (2.5×0.7 mm) were deployed into donor descending aortas of atherosclerosis-prone (Apo)e−/− (apolipoprotein E) mice, then carotid-interposition grafted into Apoe−/− recipients. Mice (n=6–8/group) received chow or a high-cholesterol diet for 7 or 28 days post surgery. A novel miniaturized probe was used to image the stented vessel of a mouse fed high-cholesterol diet for 28 days. Neointimas in stented vessels were histologically and flow cytometrically assessed.

RESULTS: Bimodal intravascular imaging combined optical coherence tomography (plaque burden) with fluorescence detection of indocyanine green (plaque instability) to visualize in-stent neoatherosclerosis along the entire stented segment. Histological analyses revealed that stented vessels from mice fed high-cholesterol diet had neointimas with prominent lipid cores and abundant CD68+ macrophages, reminiscent of human neoatherosclerosis. Mice fed chow post stenting had distinctly different neointimas that were smooth muscle cell rich, resembling neointimal hyperplasia. Flow cytometry revealed a higher content of monocytes/macrophages in stented aortas from mice fed high-cholesterol diet than in nonstented aortas.

CONCLUSIONS: We have developed and validated the first murine model that replicates the unique characteristics of human in-stent neoatherosclerosis. This has implications for exploring the mechanisms that promote neoatherosclerosis and testing targeted new therapies.