PET/MRI of Hypoxic Atherosclerosis Using 64Cu-ATSM in a Rabbit Model

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 SUV_mean 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 SUV_mean ratios of 1.84 ± 0.12 at 8 wk after injury. IF-to-BM SUV_mean ratios were significantly higher (P < 0.001) than SF-to-BM SUV_mean 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.