A study on progression of hypoxic atherosclerotic plaque in a mouse model using [64Cu]ATSM

Objectives The macrophage-rich core of advanced human atheroma has been demonstrated to be hypoxic, which may have implications in plaque stability. Previously, we have demonstrated the feasibility of using [64Cu]ATSM as a hypoxia PET imaging agent in an ApoE-/- mouse model of atherosclerosis. The goal of this study was to evaluate the relative effects of diet and genetics on hypoxia progression in atherosclerotic plaque using [64Cu]ATSM in a genetically-altered mouse model.

Methods ApoE-/- mice fed standard (SD) (n=6) or high-fat diet (HFD) (n= 6) underwent PET/CT imaging at 2-month intervals over 10 months to assess uptake of [64Cu]ATSM over time. Age-matched C57bl/6 wild type mice on SD were imaged at the same time points as a negative control (CM). Dynamic PET imaging was performed 30 minutes post injection. Using CT, regions of interest were drawn around the aortic arch with normal muscle as a reference. Aortic arch to thigh muscle (A/M) SUV ratios were calculated from the average radioactivity 10-30 minutes post injection of radiotracer.

Results ApoE-/- mice in both SD and HFD groups developed hypoxic atherosclerosis at an early age, demonstrating a significant increase in SUV ratios between PET imaging performed at 17 and 23 weeks: HFD 2.85 ± 0.46 (17 weeks) VS 4.43 ± 1.28 (23 weeks) (P < 0.05), standard diet 2.99 ± 0.92 (17 weeks) VS 5.13 ± 1.56 (23 weeks) (P < 0.05). SUV ratios in HFD and SD mice at 23 weeks were elevated in comparison to CM baseline 3.24 ± 0.33 (P<0.05), and remained significantly elevated in both SD and HFD groups at all imaging time-points over the 10-month period. There was no statistically significant difference between HFD and SD ApoE-/- mice at any time point.

Conclusions Results suggest that hypoxia occurs early in atherosclerosis development in this mouse model, that gene expression may be more important than diet in development of plaque hypoxia, and that [64Cu]ATSM may be a promising radiotracer for following development of plaque hypoxia.

Research Support This work is supported by a grant from the Diabetic Cardiovascular Disease Center, Washington University.