Abstract
Looking back at animal and clinical studies published since the 1920s, the notion of rapid regression and stabilization of atherosclerosis in humans has evolved from a fanciful goal to one that might be achievable pharmacologically, even for advanced plaques. Our review of this literature indicates that successful regression of atherosclerosis generally requires robust measures to improve plasma lipoprotein profiles. Examples of such measures include extensive lowering of plasma concentrations of atherogenic apolipoprotein B (apoB)-lipoproteins and enhancement of 'reverse' lipid transport from atheromata into the liver, either alone or in combination. Possible mechanisms responsible for lesion shrinkage include decreased retention of apoB-lipoproteins within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris and other components of the plaque. Unfortunately, the clinical agents currently available cause less dramatic changes in plasma lipoprotein levels, and, thereby, fail to stop most cardiovascular events. Hence, there is a clear need for testing of new agents expected to facilitate atherosclerosis regression. Additional mechanistic insights will allow further progress.
Key Points
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Regression (i.e. shrinkage and healing) of advanced, complex atherosclerotic plaques has been clearly documented in animals, and plausible evidence supports its occurrence in humans as well
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The crucial event in atherosclerosis initiation is the retention, or trapping, of apolipoprotein-B (apoB)-containing lipoproteins within the arterial wall; this process leads to local responses to this retained material, including a maladaptive infiltrate of macrophages that consume the retained lipoproteins but then fail to emigrate
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Plaque regression requires robust improvements in the plaque environment, specifically large reductions in plasma concentrations of apoB-lipoproteins and large increases in the 'reverse' transport of lipids out of the plaque for disposal
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Regression is not merely a rewinding of progression, but instead involves emigration of the maladaptive macrophage infiltrate, followed by the initiation of a stream of healthy, normally functioning phagocytes that mobilize necrotic debris and all other components of advanced plaques
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The challenge we face is making robust improvements in the plaque environment a widely achievable clinical goal. Additional strategies to provoke stabilization and regression of human atheromata, such as direct induction of CCR7 in plaque macrophages, might eventually become clinically feasible as well
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Acknowledgements
The original studies in the authors' laboratories were supported by NIH grants HL78667, HL61814, HL84312 (EAF), HL38956, HL56984, and HL73898 (KJW). Support is also acknowledged from the American Heart Association (KJW). JEF is a recipient of an NIH National Research Service Award F30 AG029748. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.
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KJ Williams is the inventor of a number of US patents on the use of phospholipids to promote reverse lipid transport in mice (e.g. Williams KJ (1998) Method of forcing the reverse transport of cholesterol from a body part to the liver while avoiding harmful disruptions of hepatic cholesterol homeostasis. US Patent 5,746,223)
JE Feig and EA Fisher declared they have no competing interests.
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Williams, K., Feig, J. & Fisher, E. Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nat Rev Cardiol 5, 91–102 (2008). https://doi.org/10.1038/ncpcardio1086
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DOI: https://doi.org/10.1038/ncpcardio1086
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