Inhibition of plaque progression and promotion of plaque stability by glucagon-like peptide-1 receptor agonist: Serial in vivo findings from iMap-IVUS in Watanabe heritable hyperlipidemic rabbits

Background and aims: Glucagon-like peptide-1 (GLP-1) is thought to inhibit development of aortic atherosclerosis and plaque formation. However, whether GLP-1 stabilizes fully developed atherosclerotic plaque or alters the complicated plaque composition remains unclarified. Methods: Ten Watanabe heritable hyperlipidemic (WHHL) rabbits were divided into GLP-1 receptor agonist treatment group and control group. After confirmation of atherosclerotic plaques in brachiocephalic arteries by iMap intravascular ultrasound (iMAP-IVUS), GLP-1 receptor agonist lixisenatide was administered to WHHL rabbits at 30 nmoL/kg/day for 12 weeks by osmotic pump. An equal volume of normal saline was administered in a control group. After evaluation by iMAP-IVUS at 12 weeks, brachiocephalic arteries were harvested for pathological histological analysis. Results: iMAP-IVUS analysis revealed larger fibrotic plaque components and smaller necrotic and calcified plaque components in the GLP-1 group than in the control group; % fibrotic area: 66.30 +/- 2.06% vs. 75.14 +/- 2.62%, p < 0.01, % necrotic area: 23.25 +/- 1.87% vs. 16.17 +/- 2.27%, p +/- 0.02, % calcified area: 2.15 +/- 0.24% vs. 1.00 +/- 0.18%, p < 0.01), indicating that GLP-1 receptor agonist might modify plaque composition and increase plaque stability. Histological analysis confirmed that GLP-1 receptor agonist treatment improved smooth muscle cell (SMC)-rich plaque with increased fibrotic content. Furthermore, plaque macrophage infiltration and calcification were significantly reduced by GLP-1 receptor agonist treatment; % SMC area: 6.93 +/- 0.31% vs. 8.14 +/- 0.48%, p +/- 0.02; % macrophage area: 9.11 +/- 0.80% vs. 6.19 +/- 0.85%, p < 0.01; % fibrotic area: 54.75 +/- 1.63% vs. 69.60 +/- 2.12%, p +/- 0.02; % calcified area: 3.25 +/- 0.67% vs. 0.75 +/- 0.15%, p +/- 0.02). Conclusions: GLP-1 receptor agonist inhibited plaque progression and promoted plaque stabilization by inhibiting plaque growth and modifying plaque composition. (C) 2017 Elsevier B.V. All rights reserved.