Abstract 418: ¹⁸ FDG-PET Monitors Atherosclerosis Disease Activity In Minipigs.

Abstract

Background and objectives: 18 FDG-PET imaging is used as clinical endpoint to monitor efficacy of drugs in atherosclerosis, but the link between disease activity and FDG uptake is not well understood. Previous studies in PCSK9 D374Y minipigs showed that FDG is taken up quantitatively in multiple plaque cell types. Here, we developed methods to alter disease activity of established atherosclerosis in PCSK9 D374Y minipigs and analyzed the ability of FDG-PET to monitor the changes and the underlying mechanisms. Methods: Atherosclerosis was induced in PCSK9 D374Y minipigs by high-fat feeding for 12 months. Pigs were then either euthanized for analysis of baseline atherosclerosis (Baseline pigs, n=7) or subjected to a 3-months LDL- lowering intervention with low-fat diet (LF pigs, n=8) or low-fat diet supplemented with microsomal transfer protein inhibitor (BMS-212122, 0.5mg/kg/day, MTPi pigs, n=8). Wild-type pigs on low-fat diet provided non-atherosclerotic controls (n=5). 18 FDG-PET imaging was performed in all animals at the endpoint, and serial sections of the abdominal aorta, iliac and LAD arteries were analyzed for plaque morphology, lipid accumulation (Oil Red O), and macrophage content (CD68 and muramidase). In a separate experiment, abdominal plaques from Baseline (n= 5) and MTPi pigs (n=3) were analyzed by single-cell RNA sequencing. Results: MTPi pigs reached low LDL cholesterol levels (<1.8 mM) and had significant reductions in plaque lipid content (56%, p=0.002) and necrotic area (50%, p=0.002) compared with Baseline pigs. Macrophage content was numerically, but not significantly, altered. 18 FDG signal was substantially reduced in MTPi compared with Baseline pigs (SUVmean 1.04 vs 1.54, p=0.019) reaching levels similar to non-atherosclerotic wild-type pigs (SUVmean 1.11). Analysis of scRNA-seq data indicated that reduced FDG uptake was explained by lowered glycolytic activity across multiple cell types, including macrophages, lymphocytes, and smooth muscle cells. Conclusion: 18 FDG-PET imaging can monitor disease activity in atherosclerosis because disease activity is associated with increased glycolysis across all of the major cell types of plaques.