Development of a novel murine model of in-stent neoatherosclerosis
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Objective
In-stent neoatherosclerosis is a phenomenon of percutaneous coronary intervention with stenting. Whilst similar to de novo atherosclerosis, it develops rapidly over 1-5 years rather than over a lifetime. No preclinical small animal models exist that allow full elucidation of neoatherosclerosis biology and future treatments. The aim of this study was to establish and validate a novel murine model of in-stent neoatherosclerosis.
Approach and Results
Murine stainless-steel stents (2.5 × 0.7 mm) were deployed into donor descending aortas of atherosclerosis-prone apolipoprotein (Apo)e -/- mice, then carotid-interposition grafted into Apoe -/- recipients. Mice (n=6-8/group) received chow or a high cholesterol diet (HCD) for 7- or 28-days post-surgery. Multimodal intravascular imaging, simultaneously combining optical coherence tomography (OCT, plaque burden) and fluorescence for indocyanine green (ICG, plaque instability), visualized in-stent neoatherosclerosis across the entire length of the stented site. Histological analyses revealed that stented vessels from mice fed HCD had neointimas with prominent lipid cores and an elevated CD68 + macrophage content, similar to human neoatherosclerosis. Mice fed chow post-stenting had distinctly different neointimas that were smooth muscle cell rich, resembling neointimal hyperplasia. Consistent with this, flow cytometry revealed a higher content of monocytes/macrophages and dendritic cells in stented aortas from mice fed HCD than in non-stented aortas.
Conclusion
We have developed and validated the first murine model that replicates the unique characteristics of human in-stent neoatherosclerosis. This project has implications for exploring the mechanisms that promote neoatherosclerosis and testing targeted new therapies.
RESEARCH PERSPECTIVE
What Is New?
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We have developed and validated a novel murine model of in-stent neoatherosclerosis, presenting a new platform that will facilitate the discovery of novel mechanistic targets of in-stent neoatherosclerosis and preventative therapies.
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This model develops lesions with a similar morphology to human in-stent neoatherosclerosis and distinct to in-stent neointimal hyperplasia, with higher extracellular lipid and macrophage content and proportionately less smooth muscle cells.
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We show a first-time visualization of murine in-stent neoatherosclerosis using bimodal intravascular imaging with simultaneous capture of structural information (optical coherence tomography, plaque burden) and the distribution of areas of plaque instability (high-sensitivity fluorescence, indocyanine green) within the plaque.
What new question does this study raise?
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How can the utility of this novel model be maximized as a platform for discovering novel agents that prevent in-stent neoatherosclerosis?
What question should be addressed next?
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Are there unique mechanisms of in-stent neoatherosclerosis, distinct to de novo atherosclerosis, that can be specifically targeted to prevent disease and ultimately increase stent performance?
