Abstract
3342
Introduction: Atherosclerosis is the underlying cause of most cardiovascular disease. Chronic activation of the innate immune system drives inflammation and atherosclerosis. Currently, there is no effective treatment. Statins have been widely used for atherosclerosis treatment by lowering cholesterol levels in blood. However, its effect in immune cells during the treatment is unknown. It is known that inflammatory monocytes/macrophages are of paramount importance in atherogenesis (or plaque progression). C-C motif chemokine receptor 2 (CCR2) is highly expressed on the surface of proinflammatory monocyte/macrophage, making it a candidate biomarker to determine the variation of these cells following statin treatment. Herein, we used a CCR2 targeted PET tracer of 64Cu-DOTA-ECL1i to track the dynamic change of proinflammatory monocytes/macrophages following statin therapy.
Methods: We chose rosuvastatin (RSV) since it is considered the most potent statin derivative with a long half-life and a favorable safety profile. The sensitivity and specificity of 64Cu-DOTA-ECL1i imaging CCR2 was demonstrated in apolipoprotein knock-out (ApoE-/-) mice fed with high fat diet via competitive receptor blocking studies. Its uptake at atherosclerotic lesions were also correlated with plaque sizes during the progression of atherosclerosis. ApoE-/- mice on high fat diet (HFD) for 20-weeks were treated with HFD containing RSV (10 mg/kg) for 4 and 8 weeks. CCR2 PET/CT, serum cholesterol concentration, and mouse weight were measured before and after treatments in the same cohort of mice. After treatments, aortas were collected for tissue analyses including hematoxylin and eosin staining, immunofluorescent staining, and flow cytometry.
Results: The imaging sensitivity and specificity of 64Cu-DOTA-ECL1i was demonstrated in ApoE-/- mice with significantly (p<0.0001, n=5) decreased uptake at aortic arch via competitive receptor blocking study. The gradual increase of tracer uptake also correlated with the progression of plaques. In contrast to baseline histology of aortic artery at 20 weeks post HFD showing significant calcification and necrotic cores, ApoE-/- mice at 4- and 8-week post RSV showed largely reduced lipid pool without any calcification. Following RSV treatment, 64Cu-DOTA-ECL1i showed gradually decreased tracer uptake at aortic arch from baseline (SUV=0.42±0.05, n=9), to 4-week (SUV=0.42±0.09, n=4) and 8-week (SUV=0.33±0.07, n=6) post RSV treatment. Immunofluorescent staining and flow cytometry also supported the imaging results.
Conclusions: Rosuvastatin treatment showed its effect on monocytes/macrophages during the treatment in in atherosclerosis. The imaging sensitivity and specificity of CCR2 PET demonstrated its potential to monitor RSV treatment response. Future studies will extend the RSV treatment time frame for improved outcome.