Effect of evolocumab on the progression and stability of atherosclerotic plaques as evaluated by grayscale and iMAP-IVUS

Abstract

Background: Evolocumab inhibits the proprotein convertase subtilisin/kexin type 9 protein and is a potent cholesterol-lowering drug. However, the relationship between evolocumab and inflammation, and the effects of evolocumab on the stability of atherosclerotic plaques remain unknown. Methods: Twenty-seven purebred New Zealand rabbits were fed with an atherogenic diet for 2 weeks. The abdominal aortic endothelium was balloon-injured. The rabbits were divided into the atorvastatin (2 mg/kg/day; Ato), evolocumab (7 mg/kg/2 weeks, Evo) and control groups. Intravascular ultrasound (IVUS) images of the abdominal artery were analyzed at 10 and 18 weeks. Additionally, the serum levels of the biomarkers were measured at baseline, and at 10 and 18 weeks. Results: The serum levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and monocyte chemoattractant protein-1 (MCP-1) increased after 10 weeks of administration of the proatherosclerotic diet, while the levels of high-density lipoprotein cholesterol (HDL-C) and transforming growth factor-β (TGF-β) decreased. The reduction in the serum levels of triglycerides, total cholesterol, LDL-C, MCP-1, TGF-β, and toll-like receptor 4 (TLR4) following treatment with evolocumab was higher than that of atorvastatin. Both evolocumab and atorvastatin reduced the percent atheroma volume. Evolocumab increased the fibrotic% and decreased the necrotic%. Correlation analysis revealed that the levels of triglycerides, total cholesterol, LDL-C, MCP-1, TGF-β, and TLR4 were negatively correlated with the fibrotic%, but were positively correlated with the necrotic%. Multivariate linear regression analysis revealed that treatment with atorvastatin, and especially evolocumab, was a consistent predictor of the percent atheroma volume, and fibrotic and necrotic composition. Conclusions: Proprotein convertase subtilisin/kexin type 9 regulates the serum levels of lipid and cholesterol may via inflammatory pathways. The results also indicate that evolocumab is more potent than atorvastatin in suppressing the progression and stability of atherosclerotic plaque in rabbits.