Effect Of Icospaent Ethyl On In Vivo Atheroma Progression And Inflammatory Protease Activity

Background: Icosapent ethyl (IPE), a high purity ethyl ester of eicosapentaenoic acid (EPA), is FDA-approved to reduce cardiovascular events among patients with or at risk for cardiovascular disease with elevated triglyceride levels. However, in vivo mechanisms underlying these findings remain unclear. Here we investigated whether IPE reduces plaque progression and inflammation using intravascular molecular-structural imaging. Methods: Cholesterol-fed balloon-injured rabbits (N=16) bearing aortic atherosclerosis underwent intravascular ultrasound (IVUS) analysis of plaque burden and near-infrared fluorescence-optical coherence tomography (NIRF-OCT) molecular imaging of plaque inflammatory cathepsin protease activity (ProSense VM110 NIRF agent, 4 mg/kg/iv) at 6 weeks. Next, rabbits were randomized to control (N=8) or IPE (Vascepa, Amarin, NJ) treated group (N=8, 1 g/kg/day) milled in the diet. Four weeks later, imaging was repeated, animals were sacrificed, and histopathology analysis of dissected plaque was employed. Results: Quantitative IVUS analyses (40mm segment, 3200 slices/16 rabbits) revealed that IPE significantly suppressed atheroma progression (ΔPAV, 5.2% [2.36-12.98] vs. 9.1% [4.26-12.25] control, p=0.03). Inflammatory plaque cathepsin activity detected by NIRF-OCT was similar (ΔNIRF average plaque 17.6 [6.2- 51.5] vs. 30.5 [4.9- 55.5] nM control, p=0.19)). On fluorescence microscopy, however, plaques from IPE-treated animals exhibited reduced NIRF signal (1.16% [0.03-3.94] vs. 3.13% [0.04-12.92], p=0.005)) and fewer RAM11+ macrophages (23.5±15.6 vs. control 32.9±12.6 macrophages/section, 25 sections/group, p=0.04). In IPE-treated animals, plasma EPA levels were elevated (p<0.05), and EPA metabolite levels, particularly 5,6-diHETE, were also elevated in resected plaques (p<0.05). Conclusion: IPE reduces in vivo plaque progression and plaque cathepsin protease activity and plaque macrophages, providing novel experimental evidence supporting the anti-atherosclerosis effects of IPE.