Abstract
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.
What Is New?
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.
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.
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?
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?
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?
Competing Interest Statement
The authors have declared no competing interest.
Nonstandard Abbreviations and Acronyms
- CAD
- coronary artery disease
- DES
- drug-eluting stent
- BMS
- bare metal stent
- PCI
- percutaneous coronary intervention
- SMC
- smooth muscle cell
- HCD
- high cholesterol diet
- HDL-C
- high-density lipoprotein-cholesterol
- LDL-C
- low-density lipoprotein-cholesterol
- OCT
- optical coherence tomography
- NIRF
- near infrared fluorescence
- ICG
- indocyanine green
- PFA
- phosphate-buffered paraformaldehyde
- DCs
- dendritic cells