Correspondence *Department of Medicine/Division of Endocrinology, Thomas Jefferson University, Philadelphia, PA 19107, USA

Email k_williams@mail.jci.tju.edu

Correspondence *Departments of Medicine and Cell Biology, The Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY 10016, USA

Email edward.fisher@med.nyu.edu

Introduction

The idea that human atheromata can regress at all has met considerable resistance over the decades.^{1, 2} Resistance to the idea of lesion regression is strengthened by the fact that advanced atheromata in humans and in animal models contain components that give an impression of permanence, such as necrosis, calcification and fibrosis. In addition, numerous theories have been proposed to explain atherogenesis that include processes thought to be difficult, if not impossible, to reverse including oxidation,³ injury,⁴ and cellular transformations resembling carcinogenesis.⁵

In this Review we summarize the failure of many established and experimental interventions to induce plaque regression, and examine other data indicating that sufficiently drastic changes in the plaque environment can stabilize and cause regression of even advanced lesions.

Evidence from animal studies: rabbits, nonhuman primates, and pigs

In the 1920s, Anichkov and colleagues reported that switching cholesterol-fed rabbits to low-fat chow over 2–3 years resulted in arterial lesions becoming more fibrous with a reduced lipid content.⁶ From a modern perspective, these results suggest plaque stabilization.⁷ To our knowledge, however, the first prospective, interventional study demonstrating substantial shrinkage of atherosclerotic lesions was performed in cholesterol-fed rabbits and reported in 1957.⁸ The dietary regimen raised total plasma cholesterol to around 26 mmol/l (1,000 mg/dl) and induced widespread lesions involving around 90% of the aorta. To mobilize tissue stores of cholesterol, animals received intravenous bolus injections of phosphatidylcholine (PC). After less than a week and a half of treatment, the remaining plaques were scattered and far smaller than initially, and three-quarters of arterial cholesterol stores had been removed.

Over the next 20 years, similar arterial benefits from the injection of dispersed phospholipids were reported by a number of groups using a variety of atherosclerotic animal models, including primates.⁹ Given the heavy reliance of atherosclerosis research on animal models, it is surprising that these impressive, reproducible results were largely ignored, even in numerous historical reviews of regression.^{1, 2, 6, 10, 11} Perhaps a factor contributing to the lack of recognition of atheromata regression was the publication of a study that showed worsening of arterial lesions in cholesterol-fed rabbits after return of the animals to regular chow.⁶ Since then, it has been established that rabbits maintain substantial diet-induced cholesterol reservoirs in the liver that allow hypercholesterolemia to persist long after the atherogenic diet is stopped.² Nevertheless, studies that cast doubt on the possibility of regression, particularly of advanced lesions, continued to emerge in other models.²

The concept of regression gained support with a short-term study in squirrel monkeys by Maruffo and Portman,¹² and more-extensive work by Armstrong and colleagues. The latter reported that advanced arterial lesions in cholesterol-fed rhesus monkeys underwent shrinkage and remodeling during long-term follow-up after a switch to low-fat or linoleate-rich diets.^{10, 13} The cholesterol-feeding induction period lasted 17 months, producing widespread coronary lesions, with fibrosis, cellular breakdown, intracellular and extracellular lipid accumulation, and 60% luminal narrowing. The subsequent regression period lasted 40 months, bringing total plasma cholesterol values down to approximately 3.6 mmol/l (140 mg/dl) and resulting in the loss of approximately two-thirds of coronary artery cholesterol, substantial reduction in necrosis, some improvement in extracellular lipid levels and fibrosis, and substantial lesion shrinkage so that only 20% luminal narrowing remained.^{10, 13} Further work by Wissler and Vesselinovich, and others confirmed and extended these findings.^{6, 11} Three decades ago, in an overview of this work, Armstrong concluded that "In the primate the answer is clear: all grades of induced lesions studied to date improve...the primate lesion shows amazing metabolic responsiveness: some extracellular as well as intracellular lipid is depleted, there is resolution of necrotic lesions, crystalline lipid tends to diminish slowly, and fibroplasia is eventually contained".¹⁰

Regression of advanced lesions in cholesterol-fed swine after reversion to a chow diet demonstrated an important sequence of events.¹⁴ Histologic examination of atheromata from these animals immediately after the high-cholesterol induction phase showed hallmarks of complex plaques, including necrosis and calcification. The regression regimen reduced total plasma cholesterol to approximately 1.8 mmol/l (70 mg/dl), implying an even lower LDL-cholesterol level. The early phase of regression showed loss of foam cells from the lesions, and an increase in non-foam-cell macrophages around areas of necrosis. Long term, the necrotic areas virtually disappeared, indicating removal of the material by an influx of functioning, healthy phagocytes.¹⁴

To revive the long-neglected finding of rapid atherosclerosis regression after injections of dispersed phospholipids, we first sought to determine the underlying mechanism of action.^{9, 15} Aqueous dispersions of PC spontaneously form vesicular structures called liposomes. Initially, cholesterol-free PC liposomes remain intact in the circulation¹⁶ and can mobilize cholesterol from tissues in vivo^{16, 17, 18} by acting as high-capacity sinks into which endogenous HDL cholesterol shuttles lipid.^{9, 19, 20} Bolus injections of PC liposomes rapidly restore normal macrovascular and microvascular endothelial function in hyperlipidemic animals,¹⁸ remove lipid from advanced plaques in rabbits in vivo,²¹ and rapidly mobilize tissue cholesterol in vivo in humans.²² Importantly, optimization of liposomal size (120 nm) allows these particles to gradually deliver their cholesterol to the liver without suppressing hepatic LDL-receptor expression or raising plasma concentrations of LDL cholesterol.^{17, 23}

Eventually, in 1976, success in atherosclerosis regression was again achieved in rabbits, following reversion to a normal-chow diet in combination with the administration of hypolipidemic and other agents.⁶ Decades later, a series of studies achieved shrinkage of atheromata in rabbits via injections of HDL or HDL-like apolipoprotein A-I (apoA-I) and PC disks.²⁴ At first, regression seemed limited to fatty streaks;²⁴ advanced lesions remained unaffected, reinforcing the now-obsolete view that regression was possible only in early lesions.^{2, 24} A lipid-lowering regimen in rabbits was, however, found to diminish local proteolytic and prothrombotic factors in the artery wall—a finding consistent with the remodeling of atheromata into a more stable phenotype.²⁵

Evidence from animal studies: murine models of atherosclerosis

Unlike humans, mice have a naturally high plasma HDL:LDL ratio, providing a strong intrinsic resistance to atherosclerosis. Drastic manipulations of plasma lipoproteins are, therefore, required to induce arterial lipoprotein accumulation and sequelae. A revolution in murine atherosclerosis research began in the 1980s when Breslow's laboratory began applying transgenic techniques to create mouse models of human lipoprotein metabolism.²⁶ With the emerging technique of gene inactivation through homologous recombination ('knock out'), came the ability to recreate important aspects of human lipid metabolism in mice. Most mouse models of atherosclerosis are derived from two basic models: the apolipoprotein E (apoE)-null (Apoe-/-) mouse,²⁷ and the LDL-receptor-null (Ldlr-/-) mouse.²⁸ In these models, the normally low plasma apoB-lipoprotein levels are increased to atherogenic levels through the elimination of either a ligand (Apoe-/-) or a receptor (Ldlr-/-) for lipoprotein clearance. Feeding these modified mice on a cholesterol-enriched and fat-enriched diet (dubbed the 'Western' diet; WD) increased plasma apoB-lipoprotein levels to an even greater degree, resulting in accelerated plaque formation in the major arteries. A large number of atherosclerosis studies followed; here we review the comparatively small number of these studies that focused on regression.

Transplantation model

To further explore cellular and molecular mechanisms of atherosclerosis regression in murine models, we and others have developed new approaches to rapidly induce robust improvements in the plaque environment and trigger lesion remodeling. Our study group developed the technique of transplanting a segment of plaque-containing aorta from a (WD-fed) hyperlipidemic Apoe-/- mouse (an extremely pro-atherogenic milieu consisting of high plasma apoB-lipoprotein levels and low HDL-cholesterol levels), into a wild-type recipient (i.e. rapidly improving the lipoprotein environment, which is sustainable indefinitely).^{31, 43} This approach allows analysis of plaques of any degree of complexity.

We found that transplanting early^{44, 45} or advanced, complicated^{43, 46} plaques into wild-type recipients substantially reduced lesion foam-cell content, while also increasing the number of smooth muscle cells present, particularly in the cap. These findings are consistent with plaque stabilization and regression (Figure 1).^{43, 46} The loss of foam cells from early lesions was surprisingly rapid, with large decreases evident as early as 3 days after transplantation.^{44, 45} With advanced lesions, all features regressed after 9 weeks, including necrosis, cholesterol clefts and fibrosis.^{43, 46} This evidence of regression, in even advanced lesions, indicates that the negative results of numerous previous regression attempts could reflect a failure to sufficiently improve the plaque environment.

Figure 1 Regression of advanced atherosclerotic plaques in the mouse transplantation model.

Apolipoprotein E (apoE)-null mice (Apoe-/-) were fed on a Western diet for 40 weeks to develop advanced atherosclerosis. Aortic arches from these mice were either (A) harvested and analyzed by histochemical methods, or they were transplanted into (B) Apoe-/- ('progression') or (C) wild-type ('regression') recipient mice. Nine weeks later, the same analyses were performed. Shown are the histochemical results for the foam-cell marker CD68 (brown), and the vascular smooth-muscle-cell marker, -actin (purple). The pictures show the immunostaining of representative aortic lesions in cross section. The virtual absence of foam cells and the presence of a fibrous cap can be seen in the 'regression' group. In contrast with the 'regression' results, the 'progression' group showed persistence of foam cells and no development of a fibrous cap. Permission obtained from Lippincott Williams & Wilkins © Trogan E et al. (2004) Serial studies of mouse atherosclerosis by in vivo magnetic resonance imaging to detect lesion regression after correction of dyslipidemia. Arterioscler Thromb Vasc Biol 24: 1714–1719.

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Cellular and molecular biology of regression

By using our transplantation model, we characterized cellular and molecular features of the regressing plaque. An early question we sought to answer concerned the fate of the disappearing foam cells—was their disappearance due to apoptosis and phagocytosis by newly recruited macrophages, or by emigration? In collaboration with Gwendalyn Randolph, we used fluorescence-activated cell-sorting based on a nonimmunogenic polymorphism of leukocyte common antigen (CD45) to distinguish between macrophages from the donor and those from the recipient. We showed that the rapid loss of foam cells was largely accounted for by their emigration into regional and systemic lymph nodes,^{44, 45} and interestingly, that many retained their foamy appearance (EA Fisher, unpublished data).

With impaired emigration identified as a key, but reversible, derangement of macrophage function within atheromata, the direction of our research changed. Again in collaboration with Randolph, we implicated candidate lipoprotein-derived lipids that impaired macrophage emigration in vitro.^{44, 47} We found that the wild-type milieu provoked foam cells to display markers characteristic of both macrophages and, surprisingly, dendritic cells, which enabled emigration.^{44, 45} The dendritic cell phenotype is associated with a severe inflammatory response,⁴⁸ which initially seems inconsistent with a favorable outcome;⁴⁹ however, consistent with our findings, dendritic cells are known to sample native antigens in tissues and emigrate to lymph nodes as part of their role in the innate immune system.⁵⁰

Using laser microdissection to remove foam cells from regressing and nonregressing plaques,⁵¹ analyses revealed the presence of mRNA for CCR7⁴⁴ (chemokine [C-C motif] receptor 7), which is required for dendritic cell emigration.⁵² Interestingly, injection of wild-type recipient animals with antibodies against the two CCR7 ligands, CCL19 and CCL21, inhibited the majority of foam cells from emigrating from the aortic transplant lesions—establishing a functional role for CCR7 in regression.⁴⁵ We are currently focusing on mechanisms of Ccr7 induction in foam cells from regressing plaques, as well as identifying other factors that block or facilitate foam-cell emigration.

As expected, mRNA concentrations of several well-known proteins implicated in atherothrombosis, such as vascular cell adhesion protein 1, monocyte chemotactic protein 1 and tissue factor, are decreased in foam cells during regression.⁴⁵ Contrary to expectation, however, the level of mRNA for the nuclear oxysterol liver X receptor (LXR)—known to be induced in vitro by oxidized sterols⁵³—significantly increased in vivo, as did its antiatherogenic target, the ATP-binding cassette transporter A1 (Abca1).⁴⁵ Systemic administration of an LXR agonist caused lesion regression in Ldlr-/- mice,⁵⁴ although the concomitant development of fatty liver has dampened enthusiasm for this approach in humans.⁵⁵ Of note, activation of LXR stimulates Ccr7 expression in vitro⁵⁶ and we hypothesize that increased LXR activity promotes regression partly by stimulating CCR7-dependent foam-cell emigration. Overall, these findings indicate that regression does not simply comprise the events leading to lesion progression in reverse order; instead it involves specific cellular and molecular pathways that eventually mobilize all pathologic components of the plaque.

Apolipoprotein B and functional HDL in atheromata regression

In transplantation models, wild-type recipients have low levels of apoB-lipoproteins and high HDL levels relative to the Apoe-/- donors. Both lipoprotein factors could facilitate lesion regression, and we have used the transplant model to distinguish their contributions. Diseased aortic segments from Apoe-/- donors were transplanted into human apoA-I transgene expressing Apoe-/- mice³¹ that have wild-type levels of HDL cholesterol (1.7 mmol/l [65 mg/dl]) but high apoB-lipoprotein levels. Over 5 months, these transplanted plaques showed considerable foam-cell depletion,³¹ but the level of regression seen in this model during follow-up was lower than that observed in previous studies using wild-type recipients.⁴⁵ Together these studies suggest that raising plasma functional HDL levels through enhanced apoA-I production is sufficient to favorably remodel atheromata, but that a stronger effect is achieved when high levels of functional HDL are combined with large reductions in the concentration of circulating apoB-lipoproteins.

Nonsurgical models of plaque regression

Other new approaches for rapidly inducing robust improvements in the plaque environment in mice are primarily genetic, thereby enabling results to be tested in nonsurgical models of plaque regression. In collaboration with Stephen Young, we characterized the 'Reversa' mouse, in which inactivation of the gene for microsomal triglyceride transfer protein, which is required for hepatic secretion of apoB, can be induced.⁵⁷ Reversal of hyperlipidemia delays progression⁵⁷ and induces plaque regression,⁵⁸ which in our preliminary studies, was also associated with induction of Ccr7 expression in foam cells (J Feig et al., unpublished data).

Another nonsurgical model is the hypomorphic ApoE/Mx1–Cre mouse,⁵⁹ in which apoE levels are only 2–5% of normal because of a floxed neomycin resistance cassette in intron 3 that impairs transcription. These mice have normal lipid levels while maintained on a chow diet, but when placed on a high-fat or high-cholesterol diet, their levels of plasma cholesterol drastically increase (>25.9 mmol/l [1,000 mg/dl]). Either excision of the cassette with Cre recombinase to restore normal ApoE transcription, or simply switching the animals back to standard chow quickly normalizes the dyslipidemia. To study regression, ApoE/Mx1–Cre mice were fed on an atherogenic diet for 18 weeks, followed by a chow diet for 16 weeks, either with or without reinduction of ApoE transcription.⁶⁰ En face aortic analyses showed a 40% reduction in the lipid-containing surface area in the uninduced animals, and a further 30% reduction (70% total) in the induced mice compared with controls at baseline. Analysis of plaque cross-sections showed that the concentration of subendothelial foam cells was reduced in the lesions in both sets of treated mice, with a substantial reduction of neutral lipid from the necrotic cores of the lesions in the induced mice. Thus, the majority of plaque improvement arose from changes in the plasma lipoprotein profiles, with additional, unexplained effects of ApoE in the induced mice, consistent with prior work.^{39, 40}

The resolving plaque: rapid stabilization and regression

As summarized in this Review, for the better part of a century, data from both animal and human studies have indicated that atherosclerotic lesions at all stages of development can regress. Under some circumstances, regression and beneficial remodeling might even occur rapidly. Although cautious about drawing definitive conclusions from these data, we believe that through the use of agents that target specific biological processes, stabilization and regression of established lesions in humans are achievable clinical goals.

The key initiating event in atherosclerosis is the retention, or trapping, of cholesterol-rich lipoproteins within the arterial wall.^{15, 83, 84} The retained lipoproteins become modified, particularly by local enzymes, and they provoke a series of responses that can account for all known features of this disease, including endothelial dysfunction and the development of the lipid-rich, vulnerable plaque. Recruitment of macrophages into early-stage lesions could enable phagocytosis and disposal of small quantities of retained lipoproteins. Our recent work indicates that downstream products of retained and modified lipoproteins are particularly dangerous because they eventually block the normal emigration of monocyte-derived cells (i.e. macrophages, dendritic cells) from the plaque, thereby accelerating disease progression.^{44, 47} These cells then become abnormally persistent within the lesion and exhibit a series of strikingly maladaptive responses that include the secretion of lipases, which greatly accelerate further lipoprotein retention and modification,^{85, 86} proteases, which weaken the overlying fibrous cap,⁸⁷ and tissue factor, which ensures vigorous clot formation upon plaque rupture (Figure 2).⁸⁸

Figure 2 Retention, responses and regression.

Arrows are color-coded to indicate crucial mechanisms in the retention of atherogenic apolipoprotein B lipoproteins within the arterial wall: the key initiating step in atherogenesis (orange); local responses to the retained and modified lipoproteins that lead to plaque growth and evolution (red); and 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). Abbreviations: ABC, ATP binding cassette transporters; apoA-I, apolipoprotein A-I; AqD, aqueous diffusion; ChEase, cholesteryl esterase; IDL, intermediate-density lipoprotein; IFN-, interferon ; IL-4, interleukin 4; LpL, lipoprotein lipase; MMPs, matrix metalloproteinases; PC, phosphatidylcholine; SMase, sphingomyelinase; SMC, smooth muscle cell; SRBI, scavenger receptor B-I; sVLDL, small very-low-density lipoprotein; TF, tissue factor; UC, unesterified cholesterol. Permission obtained from Lippincott Williams & Wilkins © Williams KJ and Tabas I (2005) Lipoprotein retention and clues for atheroma regression. Arterioscler Thromb Vasc Biol 25: 1536–1540.

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Given that retained and modified lipoproteins are atherogenic,^{83, 84} it follows that removal of the offending material should be beneficial.^{9, 15} Cholesterol of even advanced human atheromata dynamically exchanges with that in the plasma.^{89, 90} We presume that other biologically active lipids in plaques, either transported there or locally generated, can also be removed.¹⁵ Even extracellular lipid, a major component of type III and IV lesions⁶⁴ and a key feature of lipid-rich vulnerable plaques,⁹¹ might be amenable to mobilization.^{6, 10, 15} HDL cholesterol, the major endogenous mediator of reverse lipid transport, can readily enter the interstitial space,⁹² and we recently demonstrated the penetrance of HDL-like particles specifically into atherosclerotic lesions.⁹³

These data imply a simple model for plaque regression (Figure 2). Major reduction in plasma apoB-lipoprotein concentrations slows further entry and retention within the arterial wall. Major enhancement of reverse lipid transport removes cellular but also extracellular lipid deposits. An early change seen following these environmental changes is restoration of normal endothelial function.^{18, 94, 95} We hypothesize that at some point, lipoprotein-derived lipids that had been blocking monocyte-derived cell emigration become scarce enough to enable monocytes to leave the plaque, via a process resembling dendritic cell emigration. The emigrating cells take with them their intracellular lipid, and their potential for secretion of unhelpful lipases, proteases and tissue factor.^{44, 45} Removal of necrotic debris, calcifications and fibrosis also occurs,^{6, 10, 43, 66} facilitated, in theory, by new, normally functioning macrophages (i.e. they enter the regressing plaque, phagocytose and digest what they can, and donate exchangeable material to acceptor lipoproteins, but then leave).^{14, 96} Our study group^{18, 44, 45} and others³⁰ have shown that these processes can occur surprisingly rapidly.

Conclusions and future directions

For regression of atheromata to become a realistic therapeutic goal, clinical practitioners must be provided with tools that extensively change plasma lipoprotein concentrations and plaque biology while avoiding adverse effects. To date, the animal and human studies that achieved clear-cut plaque regression required large reductions in plasma levels of apoB-lipoproteins, sometimes combined with brisk enhancements in reverse lipid transport. Agents to lower plasma apoB-lipoprotein concentrations include statins and cholesterol-absorption inhibitors. Although these two classes of agents have proven safe in widespread clinical use, most patients will not achieve and sustain the dramatically low LDL-cholesterol levels seen in chow-fed nonhuman primates.⁹⁷ Efforts to explore other strategies that lower apoB-lipoprotein levels are underway,^{98, 99} but progress may be difficult because of potential adverse effects or inconvenient modes of administration. Experimental agents designed to accelerate reverse lipid transport from plaques into the liver include PC liposomes, apoA-I/PC complexes, apoA-I mimetic peptides, and two remaining CETP inhibitors.^{15, 100, 101} These experimental agents are either in clinical trials or preclinical testing.^{15, 81, 101} An extracorporeal device that delipidates HDL and returns the unloaded particles to the circulation is also undergoing testing.⁸¹ Besides the CETP inhibitors, other orally administered small molecules have been investigated preclinically for their potential to enhance HDL-cholesterol levels and reverse lipid transport, such as agonists for LXR and peroxisome proliferator-activated receptors.⁸¹

On the basis of experimental data summarized above, we expect that the best regression results will be observed when plasma LDL-cholesterol concentrations are reduced and HDL function in reverse lipid transport is enhanced. Additional strategies, such as specific induction of pro-emigrant molecules to provoke the emigration of foam cells from the arterial wall, should also attract pharmaceutical interest. Rapid stabilization and regression of established plaques occurs in experimental settings in animals and humans, and we should know shortly whether plaque regression is within our grasp in the broader clinical setting as well.

Acknowledgments

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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Subject areas under which this article appears: Vascular disease