Abstract 15069: Non-invasive Detection of Hypoxia in Advanced Atherosclerotic Lesions by 18F-fluoromisonidazole-PET Imaging (FMISO-PET)

Abstract

Background: Atherosclerotic lesions are known to contain local areas of hypoxia, and lesion progression is associated with increased inflammation and angiogenesis. Macrophage infiltration/metabolic adaptation and angiogenesis are induced by hypoxia. Our objective was to assess the possibility of hypoxia detection within atherosclerotic lesions by non-invasive PET imaging using 18F-fluoromisonidazole (FMISO).

Methods: Advanced aortic atherosclerotic plaques were induced in 18 New Zealand white rabbits by a combination of atherogenic diet and two balloon endothelial denudations. Four rabbits fed standard chow served as controls. Animals underwent sequential 18F-FMISO-PET/CT and 18F-FDG-PET/CT imaging at 8 and 12 months after diet initiation. Radiotracer uptake of the abdominal aorta was determined by measurement of maximal standardized uptake values (SUVmax). After imaging, plaque hypoxia (pimonidazole), macrophages (RAM11) and neovessels (CD31) were assessed by immunohistochemistry.

Results: In vivo FMISO-PET scans of the abdominal aorta showed a direct association between time on diet and uptake of the hypoxia tracer (average SUVmax±SEM of 0.24±0.03 at 8 months, 0.35±0.06 at 12 months, vs. 0.14±0.01 for control animals). Ex vivo PET imaging confirmed the uptake of FMISO by the aorta of atherosclerotic rabbits (average SUVmax of 4.91±0.38 x10^-2 at 12 months vs. 0.15±0.01 x10^-2 in control animals). Concomitantly, FDG uptake increased in the aorta of atherosclerotic rabbits (average SUVmax±SEM of 0.53±0.03 at 8 months, 0.60±0.05 at 12 months, vs. 0.44±0.06 in control animals), suggesting a direct association between hypoxia and inflammation of the arterial wall. By immunohistochemistry, hypoxia was predominantly located in the macrophage-rich areas within the necrotic core. Interestingly, the macrophages close to the lumen were negative. Neovessels were mainly detected in the media and in the macrophage-rich hypoxic regions at the base of the plaque, suggesting a vasa vasorum origin.

Conclusion: Our findings support a role for hypoxia in the progression of atherosclerotic lesions. In vivo detection of hypoxia in advanced atherosclerotic lesions with FMISO-PET imaging emerges as a new tool for the analysis of vulnerable lesions.