Regression of atherosclerosis: insights from animal and clinical studies

Abstract

Background: Based on studies that date back to the 1920s, regression and stabilization of atherosclerosis in humans has gone from just a dream to one that is achievable. Review of the literature indicates that the successful attempts at regression generally applied robust measures to improve plasma lipoprotein profiles. Examples include extensive lowering of plasma concentrations of atherogenic apolipoprotein B and enhancement of reverse cholesterol transport from atheromata to the liver.

Findings: Possible mechanisms responsible for lesion shrinkage include decreased retention of atherogenic apolipoprotein B within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of lesional foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris as well as other components of the plaque. This review will highlight the role key players such as LXR, HDL and CCR7 have in mediating regression.

Conclusion: Although much progress has been made, there are many unanswered questions. There is, therefore, a clear need for preclinical and clinical testing of new agents expected to facilitate atherosclerosis regression with the hope that additional mechanistic insights will allow further progress.

Keywords: CCR7; HDL; atherosclerosis; macrophages; regression.

Figure 1. Regression of plaques in the mouse transplantation model

ApoE−/− mice were fed a Western diet for 16 weeks to develop advanced atherosclerosis. Aortic arches from these mice were either harvested and analyzed by histochemical methods, or they were transplanted into apoE−/− (‘progression’) or wild-type (‘regression’) recipient mice. Three or seven days later, the same analyses were performed. Shown are the histochemical results for the foam-cell marker CD68 (red). The pictures show the immunostaining of representative aortic lesions in cross section. The virtual absence of foam cells can be seen in the ‘regression’ group. In contrast with the ‘regression’ results, the ‘progression’ group showed persistence of foam cells.

Figure 2. Retention, responses and regression

Arrows are color-coded to indicate crucial mechanisms in the retention of atherogenic apolipoprotein B within the arterial wall, the key initiating step in atherogenesis (yellow); local responses to the retained and modified lipoproteins that lead to plaque growth and evolution (red); and then regression of all plaque components after robust improvements in the plasma lipoprotein profile, such as increased concentrations of natural and artificial mediators of reverse lipid transport (green). LDL, low-density lipoprotein; IDL, intermediate density lipoprotein; sVLDL, small VLDL; PGs, proteoglycans; SMase, sphingomyelinase; SMC, smooth muscle cell; LpL, lipoprotein lipase; TF, tissue factor; MMPs, matrix metalloproteinases; UC, unesterified cholesterol; AqD, aqueous diffusion; ABC, ATP binding cassette transporters; SR-BI, scavenger receptor B–I; HDL, high-density lipoprotein; PC, phosphatidylcholine.