Abstract
Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.
Highlights
Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures
We have reported that the cholesteryl ester transfer protein (CETP) inhibitor des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, increases high density lipoprotein cholesterol (HDL-C) levels[13], enhances endothelial repair, improves endothelial function, inhibits vascular smooth muscle cell proliferation and reduces intimal hyperplasia in New Zealand White (NZW) rabbits following endothelial denudation of the abdominal aorta[13] and in NZW rabbits with balloon injury and stent deployment in the iliac artery[14]
The present study, which indicates that increasing HDL-C levels by inhibiting CETP activity is associated with reduced intimal hyperplasia in grafted veins, may be a further strategy for improving vein graft patency
Summary
Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. Increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation. HDLs attenuate vascular inflammation[8], suppress vascular smooth muscle cell (VSMC) proliferation[9], promote endothelial repair[10], and enhance endothelial function[11] These cardioprotective functions of HDLs suggest that increasing endogenous HDL-C levels may reduce vein graft occlusion. We have reported that the CETP inhibitor des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, increases HDL-C levels[13], enhances endothelial repair, improves endothelial function, inhibits vascular smooth muscle cell proliferation and reduces intimal hyperplasia in New Zealand White (NZW) rabbits following endothelial denudation of the abdominal aorta[13] and in NZW rabbits with balloon injury and stent deployment in the iliac artery[14]
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