Noninvasive Assessment of Hypoxia in Rabbit Advanced Atherosclerosis Using 18F-fluoromisonidazole PET Imaging
Background—Hypoxia is an important microenvironmental factor influencing atherosclerosis progression by inducing foam-cell formation, metabolic adaptation of infiltrated macrophages and plaque neovascularization. Therefore, imaging plaque hypoxia could serve as a marker of lesions at risk.
Methods and Results—Advanced aortic atherosclerosis was induced in 18 rabbits by atherogenic diet and double balloon endothelial denudation. Animals underwent 18F-FMISO PET and 18F-fluorodeoxyglucose (18F-FDG) PET imaging after 6-8 months (atherosclerosis induction) and 12-16 months (progression) of diet initiation. Four rabbits fed standard chow served as controls. Radiotracer uptake of the abdominal aorta was measured using standardized uptake values (SUV). Following imaging, plaque hypoxia (pimonidazole), macrophages (RAM-11), neovessels (CD31) and hypoxia-inducible factor-1α (HIF-1α) were assessed by immunohistochemistry. 18F-FMISO uptake increased with time on diet (SUVmean, 0.10±0.01 in non-atherosclerotic animals versus 0.20±0.03 (P=0.002) at induction and 0.25±0.03 (P<0.001) at progression). Ex vivo PET imaging corroborated the 18F-FMISO uptake by the aorta of atherosclerotic rabbits. 18F-FDG uptake also augmented in atherosclerotic animals, with a SUVmean of 0.43±0.02 at induction versus 0.35±0.02 in non-atherosclerotic animals (P=0.031), and no further increase at progression. By immunohistochemistry, hypoxia was mainly located in the macrophage-rich areas within the atheromatous core, whereas the macrophages close to the lumen were hypoxia-negative. Intraplaque neovessels were found predominantly in macrophage-rich hypoxic regions (pimonidazole+/HIF-1α+/RAM-11+).
Conclusions—Plaque hypoxia increases with disease progression and is present in macrophage-rich areas associated with neovascularization. 18F-FMISO PET imaging emerges as a new tool for detection of atherosclerotic lesions.
- Received July 5, 2013.
- Accepted February 5, 2014.