Published online before print March 1, 2007, doi: 10.1161/01.ATV.0000261709.34878.20
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© 2007 American Heart Association, Inc.
Brief Reviews |
Plaque Rupture in Humans and Mice
From the Department of Pathology (S.M.S., M.E.R.), University of Washington, Seattle; the Indiana University and Lilly Research Laboratories (Z.S.G.), Indianapolis; and the Department of Cardiology (E.F.), University of Aarhus, Denmark.
Correspondence to Stephen M. Schwartz, Department of Pathology, 815 Mercer Street, Room 421, University of Washington, Seattle, WA 98109-4714. E-mail steves{at}u.washington.edu
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Abstract |
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Despite the many studies of murine atherosclerosis, we do not yet know the relevance of the natural history of this model to the final events precipitated by plaque disruption of human atherosclerotic lesions. The literature has become particularly confused because of the common use of terms such as "instability", "vulnerable", "rupture", or even "thrombosis" for features of plaques in murine model systems not yet shown to rupture spontaneously and in an animal surprisingly resistant to formation of thrombi at sites of atherosclerosis. We suggest that use of conclusory terms like "vulnerable" and "stable" should be discouraged. Similarly, terms such as "buried fibrous caps" that imply preceding events that are unproven tend to create confusion. We will argue that such terminology may mislead readers by implying knowledge that does not yet exist. We suggest, instead, a focus on specific processes that various forms of data have implicated in plaque progression. For example, formation of the fibrous cap, protease activation, and cell death in the necrotic core can be well described and have all been modeled in well-defined experiments. The relevance of such well-defined, objective, descriptive observations in the mouse can be tested for relevance against data from human pathology.
Despite the many studies of murine atherosclerosis, we do not yet know the relevance of the natural history of this model to the final events precipitated by plaque disruption of human atherosclerotic lesions. The literature has become particularly confused because of the common use of terms such as "instability", "vulnerable", "rupture", or even "thrombosis" for features of plaques in murine model systems not yet shown to rupture spontaneously and in an animal surprisingly resistant to formation of thrombi at sites of atherosclerosis. We will argue that such terminology may mislead readers by implying knowledge that does not yet exist.
Key Words: plaque rupture • murine atherosclerosis • fibrous cap • vulnerable plaque • progression
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Introduction |
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The term "plaque rupture" in human pathology is not controversial. The term has been used for decades to identify a structural defect in the fibrous cap that separates a necrotic core of an atherosclerotic plaque from the lumen, resulting in exposure of the necrotic core to the blood via the gap in the cap (Figure 1, left panels).1–5 Often, ruptured human lesions evulse part of the plaque into the lumen, sometimes resulting in emboli. Exposure of prothrombotic molecules is presumed to precipitate the formation of a platelet-rich thrombus.
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See pages 697, 714, 969, and 973 and cover
With the exception of events seen in a small proportion of atherosclerotic mice,6,7 murine lesions have not as yet progressed to this stage. As a result, the common use of terms like "vulnerable" or "unstable" to describe mouse lesions implies a conclusion we cannot know is true.8–13 A further problem is the tendency to overuse the term "rupture" to describe murine lesions, including lesions we have described (Figures 1 and 2
). Less severe plaque injuries do occur and, for clarity, we suggest use of the more general term "disruption" to refer to any loss of the integrity of the plaque surface, ranging from a simple loss of endothelial cells to minor fissures that penetrate into the plaque without exposing the necrotic core, to frank breakdown of the fibrous cap over a necrotic core with hemorrhage into the plaque, as is seen in the murine part of Figure 1. To avoid confusion and enhance our understanding of the complex interaction between the distinct but related processes within the plaque (hemorrhage), at the plaque surface (disruption), and over the plaque (thrombosis), we suggest the use of the terminology described in the Table in the online supplement (available online at http://atvb.ahajournals.org). The online version is an expanded version with more thorough discussion of experimental models of possible vulnerable features and a review of reports of murine lesions that may be representative of human ruptured plaques which may be too infrequent for use in an experimental setting.
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Plaque Rupture Requires a Necrotic Core Covered by a Fibrous Cap |
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It may seem paradoxical that fatty streak lesions (supplemental Figure II), without a fibrous cap and covered only by endothelium, largely remain intact. Even though the endothelium overlying fatty streaks appears very delicate, any disruption is limited to the presence of apoptotic endothelial cells and, possibly, the focal adhesion of platelets.14–18 Any effort to create an animal model of plaque rupture must presuppose the existence of a fibrous cap overlying a necrotic core; this combination is required for plaque rupture in human.
Necrotic Core
Contrary to general expectations, it is not clear that increasing the rate of cell death in the necrotic core increases the probability of disruption. Recent efforts to increase the extent of the necrotic core have been based on the reasonable assumption that the necrotic core results from macrophage death and that death of the macrophage is driven by some form of apoptosis. Increases in the extent of atherosclerosis have been reported in response to knockout of the proapoptotic protein p53 in apoE*3-Leiden transgenic mice or apolipoprotein E deficient (apoE–/–) mice.19–21 The lesions in these mice showed an increase in the extent of the necrotic core. Similarly, transplantation of bone marrow from apoE–/– x ACAT-1–/– mice into apoE–/– mice increased cell death within the lesions, but led to an increase in lesion area.22 Thus, ongoing apoptosis may limit macrophage accumulation in the lesion, but not affect the rate of necrotic core formation. Conversely, a reduction in cell death attributable to transplant of BAX–/– cells also led to an increase in lesion area in fat-fed LDLR–/– mice.23 None of these experiments has, as of yet, resulted in plaques that become disrupted spontaneously.
Studies attempting to model the endogenous mechanism of formation of the necrotic core have also failed to induce rupture. Fowler proposed that macrophage death might be the result of irreversible damage to lysosomes by lipid accumulation.24 Two decades later, Fazio, Tabas, et al separately showed that inhibition of cholesterol esterification or blocking of cholesterol transport from the endoplasmic reticulum leads to lipid accumulation in plaque macrophages and an increase in formation of a necrotic core. Consistent with the paradoxical response to p53 or BAX knockout, these manipulations produced unexpected increases or failure to decrease plaque mass but not plaque rupture.25 We need to consider that two or more mechanisms of cell death in the lesion may produce distinctive results in terms of the size of the necrotic core. One pathway, primarily apoptotic and dependent on p53 or BCL2-like proteins, may determine rates of foam cell accumulation without accumulation of necrotic cell debris. A different pathway, perhaps oxLDL-induced death, the formation of cytotoxic lipids, or simply bulk accumulation may be required to disrupt the overlying fibrous cap.
Fibrous Cap
Application of terms like "vulnerable" to the murine fibrous cap is especially confusing (supplemental materials; Figure III). The human cap may be hundreds of microns in thickness and highly cellular or, in other places, may resemble a tendon with few, RNA-poor fibrocyte-like cells imbedded in a dense connective tissue matrix.26,27 Murine fibrous caps are less impressive, perhaps reflecting limitations of lesions growing in vessels that are so much smaller than their human equivalents. In any case, the murine "fibrous cap" does not appear to progress to form dense connective tissue and, instead, is usually comprised of minimal numbers of thin lamellae of loosely organized, elastin-rich connective tissue.
Surprisingly, almost nothing is known about the mechanisms controlling formation of the fibrous cap. Although there have been arguments for a circulating cell origin of the plaque smooth muscle, a recent article28 provides support for the traditional view that the fibrous tissue of intima originates from medial smooth muscle cells responding to cytokines generated by the xanthomatous macrophages.29–32 Support for a role for one cytokine in formation of the murine cap grows from two studies where ablation of PDGF decreased the number of intimal cells covering the fatty lesion.33,34 Interestingly, under these conditions there appears to be a decrease in necrotic core formation, suggesting some unknown link between the cap and cell death in the underlying macrophages.
Experimental manipulations may permit a test of the importance of fibrous cap thickness. For example, even though von der Thüsen et al were able to produce a decrease in cap thickness when they used a p53 adenovirus in apoE–/– mice,35 only 3 of 16 mice showed morphological evidence of cap breaks and only 1 of these showed thrombosis and hemorrhage. The incidence of disruption, however, was increased by infusion of phenylephrine, a vasoconstrictor, for 15 minutes. At 24 hours, plaque hemorrhage was seen in 7 of 20 animals, 1 of which showed thrombosis. The adenovirus approach targets different cell types. In contrast, a novel induction of apoptosis by targeting smooth muscle cells with a diphtheria toxin receptor expressed by the SM22-
promoter, induced marked thinning of the fibrous cap of atherosclerotic apoE–/– mice, loss of collagen and matrix, accumulation of cell debris, and intense intimal inflammation, but did not induce rupture.18 It would be fascinating to know whether the latter lesions might have ruptured if exposed to phenylephrine, or if rupture might require death in cells other than smooth muscle cells.
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Murine Plaque Disruption |
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We (M.E.R., S.M.S.) were the first to report a murine model with a reproducible frequency of disruption with plaque hemorrhage.36 Between 30 and 40 weeks of age, about 80% of lesions in the brachiocephalic arteries of C57BL/6 apoE–/– mice showed plaque hemorrhage. Serial sections (Figure 2; supplemental Figure VI) show that the hemorrhage arises at the shoulder region where the fibrous cap was either absent or minimal. Similar lesions were later reported by Renard et al in the LDLR–/– mouse with atherosclerosis accelerated by diabetes37 and at a lower frequency in apoE–/– mice used as a control.38
The use of serial sections is important, because (intra)plaque hemorrhage might also occur via breakdown of small intraplaque vessels as have been described in murine lesions of the aortic arch,39 and a recent study by micro CT40 found a strong correlation between plaque hemorrhage and the extent of plaque vasa vasorum in atherosclerotic mice. The CT data did not show neovessels seen in the intima and provided no data on the brachiocephalic arteries. Intraplaque vessels have been described in mouse atherosclerotic plaques of the aorta, but not in brachiocephalic lesions.39–41 We have not seen intraplaque vessels in the brachiocephalic lesions, even when we attempted to highlight the vessels by staining with VE-cadherin antibodies or by perfusion with the vascular tracer, horseradish peroxidase (S.M.S. and M.E.R., unpublished results, 2006). It is therefore unlikely that breakdown of intraplaque vessels accounts for plaque hemorrhage in lesions of the brachiocephalic artery.
About the same time as our report of plaque hemorrhage, Jackson and colleagues reported "acute plaque rupture" with luminal thrombosis in the brachiocephalic artery of apoE–/– mice without convincing evidence of hemorrhage into the plaque.42,43 They refer to this change as "acute plaque rupture", although as illustrated in our drawing based on their work (Figure 3, right side), the extent of disruption may be very small.44 Interpretation of their initial reports was complicated because an unexplained high number of mice died suddenly and were found decomposed. Reasons for the frequency of deaths in this model, approximately 25% in 2 months of the diet, have remained unexplained. The absence of similar data in other studies may relate to strain background, a mixed C57BL/6-129 versus the usual C57BL/6 used as a background in most studies of apoE–/–, or toxicity of severe hypercholesterolemia induced by their diet.
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In any case, the model described by the Jackson group is unique in resulting in thrombotic occlusion and possibly death. That said, the definition of rupture used by this group bears little resemblance to plaque rupture, as defined in humans. A more appropriate term for such minimal disruption with thrombosis, if real and not postmortem clots, might be "erosion". Farb et al, as well as others, have used "erosion" to describe thrombotic occlusion of human coronary arteries at autopsy in the absence of breakdown of a fibrous cap and exposure of a necrotic core.1,45 This lesion characteristically includes endothelial denudation, though we do not know whether the endothelial loss is the cause or a result of the thrombus. Like the lesions reported by Jackson et al, erosion does not expose a necrotic core, or even require the presence of a necrotic core, because many of these fatal human lesions are fibrous lesions without necrotic cores.45
In contrast to our work and the work from Jackson, lesions approaching the extent of disruption seen in human lesions (Figure 1) have been seen, as reported by Calara et al6 and others7 in a few older atherosclerotic mice. Unfortunately, the incidence, perhaps reflecting real stochastic variables, is too low to be useful in experimental studies.
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Fissures in the Lateral Xanthoma of Mice Versus Ruptures in Human Plaques |
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We propose to use "fissuring" to describe less extensive breaks in plaques that, if a necrotic core is present, may extend down to the core, but with no or only minimal loss of plaque material (supplemental Table). The murine hemorrhagic lesions described above by our group (S.M.S., M.E.R.) meet this definition better than they meet the criteria for rupture. Serial sections show that these fissures appear in xanthomatous areas near the lesion shoulders, rather than through the fibrous cap itself (Figure 1; supplemental Figure VI). This sort of disruption through a macrophage-rich cell mass, to our knowledge, has not been described in human lesions. Importantly, unlike human plaque rupture, as discussed below, the murine hemorrhagic lesions do not precipitate thrombosis, in contrast to what Jackson et al described for the much smaller defects in the same artery.43 Thus, we use the term "fissure" to describe the degree of surface disruption required for plaque hemorrhage in mice, but retain a distinction from human plaque rupture.
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Potential Artifacts |
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Interpretation of small breaks in the endothelium like the "acute plaque rupture" described by Johnson et al, eg, their Figure 1 and 2
44 are sufficiently small that it may be difficult to rule out artifacts. Although endothelial death and increased turnover does happen over atherosclerotic lesions, especially in shoulder regions of the plaque, regeneration is rapid enough that denuded areas are rarely seen in well-fixed tissue.14–18,46 Because atherosclerotic lesions in mice, even after fixation, are fragile and breaks can occur during handling, it is very valuable, as is the case for the plaque hemorrhage shown in Figure 1 (see also supplemental Figure VI), to have certain evidence of some event that could only occur if the disruption had been in the living animal. Jackson et al suggest that luminal thrombus may be such a change. In a recent study where their animals were intentionally euthanized and perfusion fixed to avoid concerns with postmortem artifacts, thrombotic material was only seen in association with discontinuities of the plaque surface, implying that the thrombi were the result of disruption of the luminal surface in vivo.43 Unfortunately, the article does not provide much detail on the composition of the thrombus and only a few displaced erythrocytes beneath an interrupted endothelium (called intraplaque hemorrhage) were considered enough to prove that the plaque surface was disrupted before death.44 Moreover, although the mice were reported to have thrombotic material in the lumen,43 no reports have been given on the pathology of the brains. It would obviously be very important to find out if this is a model for a thromboembolic stroke originating in an atherosclerotic artery supplying the brain. Identification of extravasation of erythrocytes is obviously critical to this discussion. In most cases, the distinctive morphology of the red cells, as seen in conventional stains or in a Movat stain, is sufficient to identify plaque hemorrhage in a perfusion-fixed animal. However, caution should be used when identifying the products of hemolyzed red cells as hemorrhage. Tinctorial properties alone can be misleading, so it is useful to identify red cells by electron microscopy or use specific antibodies to identify red cell proteins.47 The presence of fibrin in lesions would provide independent evidence for injury, but not proof of disruption, because intramural coagulation might occur, even without disruption.48 Unfortunately, currently available antibodies are not useful because of problems with distinguishing fibrinogen from fibrin. Although there have been claims to stain for fibrin in murine lesions using antibodies,38,44,49 the antibodies used are either known to be unable to distinguish murine fibrinogen from fibrin,48 or lack published data demonstrating the needed specificity.44 The best evidence that fibrin has formed is electron microscopy showing the characteristic electron-dense fibrillar structure with 215 angstrom cross striations. To date, fibrin has not been seen in spontaneous plaque hemorrhage by electron microcopy (S.M.S., unpublished data, 2003). However, a recent study by Gough et al of lesions disrupted by activated matrix metalloproteinase (MMP)-9 did demonstrate that large amounts of fibrinogen (or perhaps fibrin) were present at sites of plaque disruption, and others have claimed to see luminal fibrin, based on staining with other antibodies not yet shown to be specific for fibrin.13,38,50
Another way of supporting a claim that an injury occurs in vivo is to show that the injury is effected by in vivo actions of a drug. Jackson’s group has reported that their disruptions were decreased by treatment with pravastatin.44 This confirms that, as observed by one of the current authors (M.E.R.),51 statin treatment may change the composition of atherosclerotic plaques. However, such changes might also change fragility, so the experiment does not prove that the observed disruptions occurred in vivo.44 An in vivo test of endothelial integrity, such as evidence of hemorrhage through a defect or use of horseradish peroxidase would be helpful to detect even minor disruptions, such as occur when endothelial cells die, or round up during mitosis.52,53
Finally, caution needs to be expressed about identification of both acute and organized thrombi in arteries. It would be desirable in reports of thrombi to have more detail about the thrombus itself. Arterial thrombi formed under rapid flow conditions are characterized by aggregated platelets and sheets of fibrin, which are not seen when stagnant blood clots postmortem, or when blood clots or is crosslinked during an imperfect perfusion fixation. In older thrombi, cells from the vessel wall migrate into the thrombus which, of course, is not seen with postmortem clots, and the thrombus becomes organized with time. Finally, as discussed above, it is difficult to distinguish fibrin from fibrinogen, and care needs to be exercised using special stains or poorly defined antibodies.
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Proteolysis and Murine Lesion Disruption |
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 TopAbstractIntroductionPlaque Rupture Requires a...Murine Plaque DisruptionFissures in the Lateral...Potential Artifacts Proteolysis and Murine Lesion... Consequences of Plaque...OpportunitiesReferences |
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Although there is widely held belief that proteases play a critical role in disruption and rupture of the human lesion, studies of protease expression in advanced lesions in experimental animals have produced confusing results.38,54,55 It is important to realize that a protease, which might disrupt a fibrous cap in a thick human lesion, may have very different effects in the thinner vessel wall and more macrophage-rich lesions seen in most experimental animals. For example, the induction of aneurysm, but not rupture, by proteases induced by angiotensin in atherosclerotic mice could be a result of the difference in vessel wall structure in the murine model.56
Falkenberg and colleagues expressed urokinase in the endothelium overlying atherosclerotic lesions in fat-fed rabbits, rather than mice, to take advantage of the greater accessibility of the endothelium for viral gene transfer. The urokinase plasminogen activator (uPA)-transduced arteries had 70% larger intimas than control-transduced arteries, smaller lumens, and evidence for degradation of elastic laminae. Along with genetic data on elastin mutations from others,57 these data suggest that elastin may serve to keep the artery open, and that loss of elastin as a result of endothelial-targeted overexpression may allow inward pathological remodeling as is found in some advanced atherosclerotic disease.
The most extensively studied molecular candidates for rupture-producing proteases are the MMPs. Until recently, most of these studies produced evidence only for changes the authors considered as important for stability of lesions without objective evidence of disruption. For example, using the apoE–/– mouse, Johnson and colleagues studied double knockouts for MMPs 3, 7, 9, and 12.13 Knockouts of 3 and 9 produced larger lesions with more "buried fibrous caps", a feature we will discuss below. In contrast, MMP-12 and MMP-7 knockouts showed increased smooth muscle cell content. The authors interpreted these data as evidence that the normal function of MMP-3 and 9 are protective; MMP-7 is neutral; whereas MMP-12 is destabilizing. Overexpression studies give a very different and more complex set of conclusions, dependent on when MMPs are expressed and activated. MMP-1 is an interstitial collagenase and would be expected to promote plaque rupture. Lemaitre et al54 expressed human MMP-1 under a macrophage-specific promoter in apoE–/– mice. To their surprise, overexpression of MMP-1 resulted in decreased experimental lesion size with no evidence of plaque rupture. MMP-9 has received the most attention. Increased MMP-9 activity and expression are detected in the shoulders of advanced human lesions58 correlated with degradation of collagen, suggesting that MMP-9 would be destabilizing.9 However, MMP-9 also promotes in interstitial collagen assembly59 by smooth muscle cells, which might lead one to expect MMP-9 to contribute to the mechanical strength of the plaque. The actual effect turns out to be even more complex, depending on how the enzyme is delivered and how it is activated. Increased transient expression of MMP-9 via intraluminal adenoviral delivery, largely confined to the vessel lining,60 did not produce any form of fibrous cap disruption. Instead, there was intralesional hemorrhage attributed to neoangiogenesis, as well as increased outward (expansive) remodeling without increasing macrophage infiltration. The latter is in good agreement with the previously reported effect of MMP-9. MMP-9 deficiency in the MMP-9–/– apoE–/– mouse impaired the compensatory enlargement of the carotid artery characteristic of lesion development seen in the apoE–/– mouse,61 as well as in human atherosclerotic lesions.62 Interestingly, outward arterial remodeling is also a characteristic associated with human plaque rupture, pointing out that we simply know too little to predict how an enzyme may act in the complex plaque milieu.63,64 Evidence for the importance of knowing where a protease is activated comes from Gough et al. Transplanted macrophages expressing an auto-activating form of MMP-9–induced plaque disruption in 9 of 10 mice when overexpressed in vivo in advanced atherosclerotic lesions of apoE–/– mice, as compared with frequencies of about 1 of 9 in the controls.38 Thus, MMP-9, expressed in the right place and time, can rupture the plaque.
In summary, lesion disruption, in 1 case approaching the severity of human plaque rupture,38 has been caused experimentally by interventions with proapoptotic stimuli and with targeted delivery of MMP-9.
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Consequences of Plaque Disruption in Mice |
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Surprisingly, hemorrhagic lesions in murine plaques do not develop luminal thrombus, even though the hemorrhage infiltrates the necrotic core. Fibrin is absent in the hemorrhage itself, even when studied by electron microscopy (S.M.S. and M.E.R., unpublished data, 2003). Although the failure to form fibrin in the lesion or to develop a thrombus is disappointing, it is not entirely surprising. Fibrin is not seen when normal rat arteries undergo injury with an inflated balloon catheter.65 This, however, reflects the lack of tissue factor in nonatherosclerotic vessels.66 The claim by Jackson et al to see spontaneous luminal thrombosis is important, but remains to be confirmed by others.
The other consequence of previous plaque rupture in man is the presence of layered scars containing organized thrombotic debris.1,67–69 By analogy, Jackson and his colleagues propose that previous episodes of rupture in mice may be represented by "buried fibrous caps".43 In 2005, buried fibrous caps (smooth muscle cell–rich layers, invested with elastin and usually overlain with foam cells) were described within plaques, associated with positive staining for fibrin.44 In our opinion, the published pictures (Figures 1C, 4A, and B44) appear quite dissimilar to healed plaque rupture in humans (supplemental Figure IV), where the Sirius red collagen stain and polarized light has been used to detect a discrete defect in the old and dense collagen of the cap (type I, yellow), filled in by newer and more loosely arranged collagen (type III, green) containing an increased density of smooth muscle cells.69 Moreover, mural thrombi have not as yet been described by our groups or by other investigators, even though layered lesions are often seen in more advanced murine lesions in our own studies. The more obvious hypothesis, in our opinion, is that "buried caps" represent episodic plaque growth with formation of superficial fatty streaks, ie, xanthomas, over older lesions resulting in a layered plaque phenotype, as shown in Figure 4 (and supplemental Figure V). This interpretation is consistent with the morphology showing intermediate stages of cap formation associated with superficial xanthomas and with recent cell kinetic studies showing that fresh macrophages are deposited on the surface of later lesions, rather than appearing within the lesions.38,70 The answer, ultimately, will require either better evidence for mural thrombus formation or, perhaps, an experimental test of the buried cap phenomenon, possibly using the p53 model, the diphtheria toxin model, or the MMP-9 model to study the response to intentionally induced plaque disruptions.
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Opportunities |
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If we leave behind the need to define terms carefully, there are several experimental opportunities to discuss.
It may be important to remember that almost all of the work in mice described here was done in a single genetic background, ie, the C57BL/6 strain. In 1985, Paigen and her colleagues71 screened strains of mice for their ability to form fatty streaks and identified C57BL/6 as especially susceptible independently of lipid levels. She suggested that the gene for this trait be called Ath1. The nature of Ath1 could be very important to our discussion of advanced lesions. Recently, the gene for OX40 ligand, an inflammatory mediator in the tumor necrosis factor (TNF)/Fas death receptor ligand family, has been identified as a major part of the C57BL/6 atherosclerosis-susceptible phenotype.72 Recent evidence from Pei et al shows that the susceptibility of C57BL/6 is intrinsic to the vessel wall.73 Identification of the specific atherosclerosis sensitivity genes, combined with new methods for accelerating analysis of murine genetic crosses,74 may make it possible to cross such regions into other strains and look for loci that contribute to plaque progression and rupture.
One example of such a genetic approach may come from the obvious fact that the advanced atherosclerotic plaque is a lesion of age. Oxidation is a major topic of research in atherosclerosis and in aging. Most of this is beyond the purview of this review, other than to note that most of the experimental studies have focused, once again, on the effect of antioxidants on fatty streak formation, rather than on features of the advanced plaque.29,75 Moreover, oxygen and other free radical products are not the only issues in relation to aging. For example, humans with a splicing defect in lamin A, develop fatal arteriosclerotic vascular disease in their teens, despite an absence of lipid disorders, hypertension, or diabetes.76 At least to date, mice with similar mutations have not been reported to develop accelerated atherosclerotic disease. However, a recent study suggests that the lamin mutation is associated with loss of medial smooth muscle, a late feature in most human atherosclerosis and one that appears to be exacerbated in humans with progeria.77,78
Finally, autopsy studies in humans show that many plaque ruptures occur without forming an occlusive thrombus. It is not possible to overestimate the importance of understanding why some plaque disruptions, even the mild disruption seen in erosions, lead to occlusive thrombus, whereas more extensive disruption, ie, plaque rupture, can occur with little consequence. Here, the contrast in the 2 models of disease in the murine brachiocephalic artery is quite dramatic. In the model we have studied (M.E.R., S.M.S.), spontaneous, obviously extensive plaque injury does not result in thrombosis. In the other model discussed above from Jackson and his colleagues, the same site, but with strain differences and a different diet, shows a subtle, but apparently thrombogenic plaque injury severe enough, perhaps, to lead to the animals’ deaths. Regardless of the semantics of "plaque rupture", this difference needs to be studied and clarified.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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Original received May 18, 2006; final version accepted February 2, 2007.
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References |
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