doi: 10.1161/01.ATV.0000038754.39483.CD
© 2002 American Heart Association, Inc.
Editorials |
Unraveling Pleiotropic Effects of Statins on Plaque Rupture
From the Department of Medicine, University of California, San Diego, La Jolla.
Correspondence to Wulf Palinski, MD, Claudio Napoli MD, Department of Medicine, 0682, University of California San Diego, 9500 Gilman Dr, MTF 110, La Jolla, CA 92093-0682. E-mail wpalinski{at}ucsd.edu cnapoli@ucsd.edu
Several large-scale clinical trials have conclusively shown that statins markedly reduce clinical endpoints of atherosclerosis.1 A plethora of studies has also reported effects of statins other than cholesterol-lowering.2 These include effects on endothelial function, such as NO generation and NO-mediated vascular relaxation, the recruitment of monocytes and T cells into the arterial intima, their subsequent activation and expression of proinflammatory factors, the proliferation of vascular smooth muscle cells (VSMCs), and other events that result in arterial remodeling (Table). However, to date only a minority of these "pleiotropic" effects of statins have been demonstrated to be truly cholesterol-independent, ie, reversible by geranylgeranyl-pyrophosphate (GGPP), but not by cholesterol. (GGPP and cholesterol represent separate branches of the mevanolate pathway downstream of the step blocked by HMG-CoA reductase inhibitors.) For example, the elegant work of Liao and colleagues3 established that the modulation of NO is due to the inhibition of GGPP that in turn affects the bioavailability of regulatory proteins, such as Ras and Rho. It has also been established that statins may inhibit atherogenesis by reducing the formation of superoxide and other oxygen radicals that modulate many intracellular signaling pathways.4 Finally, statins may affect the consequences of plaque rupture by modulating thrombosis and fibrinolysis. In fact, statins decrease the expression of tissue factor in lesions, reduce platelet activation, and improve fibrinolytic activity through preservation of endothelial function, but it is unclear whether these effects are common to the entire class of statins, because some compounds seem to exert opposite effects.5 Despite the increasing evidence obtained in vitro and in experimental models, the clinical relevance of pleiotropic effects of statins is still debated.6
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The question whether specific pleiotropic effects contribute to the overall clinical benefits of statins is not an academic one. Although neither the indication of statins for atherosclerosis-related diseases nor their dosage recommendations will be affected by the answer, both an expansion of their indication and the development of statin-analogues optimized for specific pleiotropic effects can be envisaged, if it can be shown that cholesterol-independent effects occur in vivo and reduce disease severity or manifestation. For example, the observation of anti-inflammatory effects and T cell–inhibition in vitro and the reduction of graft atherosclerosis and mortality after heart transplantation have raised the hope that statins could be indicated for a number of immune diseases associated with chronic inflammation even under normocholesterolemic conditions.7 Compounds optimized for the competitive inhibition of the leukocyte function antigen 1 (LF-1) have also been developed.8 In addition to prompting the development of statin analogues, evidence for a biological role of specific mechanisms may also provide an antiatherogenic indication for other, unrelated drugs targeting the same mechanism, eg, NO donors.9
Unfortunately, neither in vitro experiments nor clinical trials are likely to establish the impact of selective pleiotropic effects of statins on atherogenesis or its clinical sequelae. Cell culture experiments do not reflect the complex interactions between the arterial wall and circulating leukocytes, platelets, and elements of the plasmatic coagulation system, nor can they mimic the influence of multiple organ systems that govern lipid metabolism, immune responses, or regulation of blood pressure. The main difficulty in the interpretation of clinical trials is the powerful cholesterol-lowering effect of statins, because genuine pleiotropic effects and cholesterol-dependent ones frequently affect the same pathogenic mechanisms.7 Experimental models in which genetic, dietary, and other variables can be tightly controlled provide the only ethically acceptable way to determine the impact of selective pleiotropic effects, even though few of these models are truly representative of human pathology. The limitations imposed by imperfect animal models are even greater when it comes to assessing pleiotropic effects of statins on plaque vulnerability, plaque rupture, and atherothrombotic events.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bea and colleagues10 report that simvastatin promotes plaque stability in apolipoprotein E–deficient (apoE-/-) mice, independently of cholesterol lowering. In this model, cholesterol-lowering effects can be presumed minimal, because hypercholesterolemia is primarily due to increases in chylomicron remnants and VLDL, which cannot be cleared by hepatic LDL receptors or LRP via high-affinity binding to apoE. The absence of significant cholesterol-lowering by statins in this model has been experimentally validated before and used to demonstrate cholesterol-independent anti-inflammatory effects of simvastatin.11 Surprisingly, in the present longitudinal experiment spanning a much longer period (24 weeks), a significant temporary increase in plasma cholesterol was observed, the reason for which remains unknown. Although the extent of atherosclerosis increased over time in both groups and the higher plasma cholesterol level in the treatment group was associated with a consistent trend toward larger lesions, the frequency of bleeding into plaques of the brachiocephalic (innominate) artery was markedly reduced by statin treatment after 6 weeks and showed a 49% reduction when all time points were analyzed together. This was accompanied by an even greater reduction of intraplaque calcification.
Animal models of plaque rupture have been severely criticized in the past, and none more than murine models.12 It is now well established that several transgenic and knockout models develop advanced atherosclerotic lesions not only in the aortic origin, where particular anatomic and hemodynamic conditions may influence its pathogenesis, but throughout the entire aorta, major aortic branch sites, and coronary arteries.13–18 The occurrence of plaque rupture in mice has long been denied, but again "the mouse may get the last laugh."19 Superficial and deep plaque erosion, intraplaque bleeding, occasional thrombi originating from the necrotic core of advanced atheroma, and blood-filled channels consistent with revascularization of a ruptured plaque have all been described in mice.16,20–22 However, substantial anatomical, physiological, and hemodynamic differences between human and murine plaques impose a very cautious extrapolation of the results obtained in murine models to humans. For example, the murine media consists of just a few cell layers and their lesions have a far greater propensity to invade the media, often resulting in the formation of aneurysms. Murine lesions fitting the definition of early fatty streaks, ie, consisting mainly of foam cells, frequently cause significant stenosis that may lead to altered flow and shear stress, whereas equivalent lesions in humans have negligible hemodynamic consequences. Pronounced sex differences in immune-related functions are also increasingly noted in mice, and differences between human and murine coagulation system may exist.17 Nevertheless, human and murine vulnerable plaques have many common features and manifestations of plaque instability may be less different than presently assumed (Figure). Murine models would be particularly attractive because of the relative ease with which genes implicated in atherogenesis, arterial remodeling, and plaque rupture can be manipulated in mice, and because microarrays are available that permit the simultaneous assessment of the differential expression of many murine genes in vivo.23
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Bea et al focused on events in the brachiocephalic artery. This site is particularly prone to atherogenesis and bleeding20–22 and shows a high frequency of plaques with multiple cap-like structures. Although alternative explanations exist,19 such lesions may indicate repeated episodes of rupture and rapid lesion growth.22 In the mouse, these lesions are more frequent than classical atheromas with a single fibrous cap, but they are also seen in humans. Given the surprisingly high frequency of erosion and rupture, it is puzzling that Bea and colleagues did not observe intraluminal thrombi that were noted at this site by other investigators.21,22 The low incidence of plaque rupture and spontaneous thrombosis in other murine arteries16 and the lack of fibrin accumulations is one of the main arguments held against murine models. This clearly constitutes a major practical obstacle for studies of spontaneous plaque rupture, but one that may not persist for long. Already, several reports have appeared in the literature that artificially enhanced plaque vulnerability and/or increased the frequency of their rupture by exogenous interventions.24,25 Induced myocardial infarction, albeit without signs of plaque rupture, have also been described.26 One may challenge such manipulations as not being representative of pathogenic mechanisms leading to the vulnerable plaque in humans or its rupture.27 Most importantly, the crucial clinical consequences–occlusive thrombi resulting in infarction and death–have not been seen in these mice. However, better mouse models that may overcome these important objections are on the horizon. Crosses between apoE-/- mice and mice deficient for the scavenger receptor BI (SR-BI-/-) developed by Krieger’s group are characterized by very early and extensive atherogenesis, even when fed normal chow.28 Their coronary atherosclerosis is comparable to that in 2-year-old apoE mice16 and shows extensive fibrin deposits indicative of plaque hemorrhage and coagulation. Most importantly, this is associated with multiple spontaneous infarctions with characteristic ECG abnormalities, enlarged hearts, defects of myocardial function (reduced ejection fraction and contractility), tissue necrosis, and death.28 This should finally put to rest the notion that mice cannot be models of plaque rupture, just as the development of the apoE mouse put to rest the dogma that mice cannot develop "real" atherosclerotic lesions. It also proves in principle that conditions in mice can be modulated to the point where their pathogenic events mimic those in humans. This should stimulate the development of other models (see legend to the Figure). Nevertheless, models closer to the human may still be needed to corroborate results obtained in mice.
It will probably be only a matter of time until the apoE-/- x SR-BI-/- model will be used to investigate the mechanisms predisposing to plaque rupture and to assess the protective effect of statins. In the meantime, the results of Bea et al10 provide the first in vivo evidence that statins reduce plaque vulnerability independently of cholesterol lowering. However, several caveats have to be kept in mind. The first is the relatively high dose of statins in this and other studies. Although a faster drug metabolism in rodents may attenuate the physiological significance of this discrepancy, the implications in terms of the accumulation of statins or active metabolites in cellular membranes and lipid-rich tissues in general remain a concern. Another caveat regards the temporary rise in cholesterol. The presumption is that statins inhibit HMG-CoA reductase and consequently the synthesis of both cholesterol and isoprenoids in mice, as they do in humans, and that the lack of reduction of murine plasma cholesterol levels is solely attributable to the prevalence of lipoprotein particles lacking the ligand for hepatic LDL receptors. If, however, the rise in cholesterol was not coincidental and the effect of statins on the mevanolate pathway were different from that in humans, the relevance of the model and the present findings would be questionable.
As indicated in the Table, in vivo evidence for genuine pleiotropic effects of statins is sparse. The present article adds reduced calcification, but offers no additional insights into the mechanisms actually responsible for plaque instability. Cholesterol-independent effects of statins on lesion composition that could contribute to weakening of the cap have previously been established in monkeys.29 Macrophage-secreted metalloproteinases are thought to be an important cause of fibrous cap weakening,30 although the impact of individual enzymes has not been established.31–33 This assumption is strengthened by the observation that pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinase expression, and cell death in human carotid plaques.34 However, other protective effects of statins on macrophages, T cells, and inflammatory conditions prevailing in plaques and potentially contributing to plaque rupture35 cannot be ruled out. Clearly, much more work will be necessary to establish that specific pleiotropic effects of statins contribute to reduced plaque vulnerability and rupture in humans.36–81
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