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PET/MRI of Hypoxic Atherosclerosis Using 64Cu-ATSM in a Rabbit Model
Xingyu Nie1,2, Richard Laforest1, Andrew Elvington3
1Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri.
Abstract:
The macrophage-rich core of advanced human atheroma has been demonstrated to be hypoxic, which may have implications in plaque stability. The goal of this study was to determine the feasibility of the hypoxia PET imaging agent 64Cu-ATSM to detect hypoxia in a rabbit model of atherosclerosis imaged on a simultaneous PET/MR scanner, using MR for both attenuation correction and depiction of lesion location.
Methods:
New Zealand White rabbits fed a Western diet for 4-6 wk underwent endothelial denudation of the right femoral artery by air desiccation to induce an atherosclerotic-like lesion and underwent a sham operation on the left femoral artery. Four and 8 wk after injury, a 0- to 60-min dynamic whole-body PET/MR examination was performed after injection of approximately 111 MBq of 64Cu-ATSM. After 24 h, a 0- to 75-min dynamic PET/MR examination after injection of approximately 111 MBq of 18F-FDG was performed. The rabbits were euthanized, and the injured femoral artery (IF) and sham-operated femoral artery (SF) were collected for immunohistochemistry assessment of hypoxic macrophages (hypoxia marker pimonidazole, macrophage marker RAM-11, and hypoxia-inducible factor-1 α subunit [HIF-1α]). Regions of interest of IF, SF, and background muscle (BM) were drawn on fused PET/MR images, and IF-to-BM and SF-to-BM SUV ratios were compared using the Student t test.
Results:
Elevated uptake of 64Cu-ATSM was found in the rabbits' IF compared with the SF. 64Cu-ATSM imaging demonstrated IF-to-SF SUVmean ratios (±SD) of 1.75 ± 0.21 and 2.30 ± 0.26 at 4 and 8 wk after injury, respectively. 18F-FDG imaging demonstrated IF-to-SF SUVmean ratios of 1.84 ± 0.12 at 8 wk after injury. IF-to-BM SUVmean ratios were significantly higher (P < 0.001) than SF-to-BM SUVmean ratios both 4 and 8 wk after injury for 64Cu-ATSM and 8 wk after injury for 18F-FDG (P < 0.05). Pimonidazole immunohistochemistry at 8 wk colocalized to RAM-11 and HIF-1α.
Conclusion:
The results show that hypoxia is present in this rabbit model of atherosclerosis and suggest that 64Cu-ATSM PET/MR is a potentially promising method for the detection of hypoxic and potentially vulnerable atherosclerotic plaque in human subjects.
Insights
This study shows that 64Cu-ATSM PET/MR can detect hypoxia in atherosclerotic plaques in rabbits. This imaging method may help identify vulnerable plaques in humans.
Area of Science:
- Cardiovascular Imaging
- Molecular Imaging
- Atherosclerosis Research
Background:
- The core of human atherosclerotic plaques is often hypoxic, impacting plaque stability.
- Hypoxia in atherosclerosis is a potential target for imaging and therapeutic interventions.
Purpose of the Study:
- To assess the feasibility of using 64Cu-ATSM PET/MR to detect hypoxia in a rabbit atherosclerosis model.
- To correlate PET/MR findings with immunohistochemical markers of hypoxia and macrophages.
Main Methods:
- Atherosclerosis was induced in rabbit femoral arteries using diet and endothelial denudation.
- Dynamic PET/MR scans were performed using 64Cu-ATSM and 18F-FDG at 4 and 8 weeks post-injury.
- Immunohistochemistry was used to assess macrophage infiltration and hypoxia markers.
Main Results:
- 64Cu-ATSM showed significantly higher uptake in injured arteries compared to sham arteries at 4 and 8 weeks.
- 18F-FDG also showed increased uptake in injured arteries at 8 weeks.
- Immunohistochemistry confirmed colocalization of hypoxia markers with macrophages in injured arteries.
Conclusions:
- Hypoxia is present in this rabbit model of atherosclerosis.
- 64Cu-ATSM PET/MR is a promising tool for detecting hypoxic and potentially vulnerable atherosclerotic plaques.
- This technique could be valuable for evaluating plaque vulnerability in human subjects.
