© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
How to evaluate plaque vulnerability in animal models of atherosclerosis?
Department of Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
* Tel.: +1-734-662-2970; fax: +1-734-662-1480 mark.rekhter{at}pfizer.com
Received 2 July 2001; accepted 2 November 2001
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Abstract |
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 Top Abstract 1 Why animal models...2 Traditional models of...3 Animal models of...4 Reality check5 Summary and future...References |
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Prevention of heart attack and stroke depends on detection of vulnerable plaques and development of plaque-stabilizing therapies. In turn, progress in diagnostics and treatment is contingent on our understanding of molecular mechanisms of plaque vulnerability. Animal models are essential for testing mechanistic hypotheses in a controlled manner. Currently, there is no single, golden standard animal model of a vulnerable plaque. However, the whole range of experimental approaches is readily available. It includes traditional models of atherosclerosis combined with new ‘vulnerability endpoints’, as well as several models featuring spontaneous or induced plaque rupture/thrombosis. This review summarizes current literature on the animal models of vulnerable atherosclerotic plaques.
KEYWORDS Atherosclerosis; Thrombosis/embolism
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1 Why animal models and how to approach them |
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TopAbstract1 Why animal models...2 Traditional models of...3 Animal models of...4 Reality check5 Summary and future...References |
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Prevention of heart attack and stroke depends on detection of vulnerable plaques and development of plaque-stabilizing therapies [1]. In turn, progress in diagnostics and treatment is contingent on our understanding of molecular mechanisms of plaque vulnerability.
Animal models are essential for testing mechanistic hypotheses in a controlled manner. Human observations provide rich soil for making hypotheses, but for obvious ethical reasons our ability to test these hypotheses in men is very limited. Cell culture is a convenient way to ask mechanistic questions, but it lacks complexity of a real disease thus limiting the scope of testable hypotheses. Ideal animal model is situated in the middle of this range. It should be representative of a human disease and at the same time be easy to manipulate.
Vulnerable plaque is one of the toughest cases in animal model design. Plaque rupture is a complication of an already complex atherosclerotic process, and precise mechanisms of this complication remain hypothetical. A plethora of experimental approaches are available for growing atherosclerotic lesions in various animal species. When appropriate lesions are generated, at least two fundamental questions may be posed (Fig. 1): (1) Can we use ‘traditional’, uncomplicated lesions to study plaque stability?; and (2) Can we take it a step further and observe spontaneous plaque rupture and thrombosis or actively induce them?
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2 Traditional models of atherosclerosis and new endpoints of plaque vulnerability |
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TopAbstract1 Why animal models...2 Traditional models of...3 Animal models of...4 Reality check5 Summary and future...References |
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Usually, the set of endpoints accurately reflects current experimental paradigm. For years atherosclerosis has been viewed as a disease of uncontrolled plaque growth [2], hence the growth-related endpoints: atherosclerotic burden, lesion size, cell number, smooth muscle cell (SMC) proliferation, lipid accumulation, extracellular matrix accumulation, growth factor gene expression, etc.
Recently, we observed and participated in a drastic paradigm shift. The new paradigm states that occlusion of arterial lumen is not a result of uncontrolled plaque growth but an acute event driven by plaque rupture and thrombosis [3]. Thus, a culprit plaque is not necessarily large, but vulnerable (i.e. prone to rupture) and thrombogenic. Therefore, it is reasonable to suggest that the same old plaques can be characterized from the new perspective of vulnerability. This requires an establishment of new experimental endpoints reflecting vulnerability. This is not a trivial exercise since vulnerability is a prospective term. It is supposed to predict future event based upon current features of the object. Any definition of vulnerability is relative, includes unknown probability of an outcome (rupture and thrombosis) and depends on our current assumptions.
Current assumptions and some respective endpoints are described below. They mostly stem from human pathology and clinical data. Typical atherosclerotic plaque consists of highly thrombogenic lipid/necrotic core and a fibrous cap that separates thrombogenic substances of the core (mainly tissue factor) from the blood coagulation system. Disruption or erosion of the fibrous cap leads to thrombus formation [4,5]. Plaque rupture occurs as a result of interactions between external mechanical triggers and vulnerable, i.e. mechanically weak, regions of the plaque, when forces acting on the plaque exceed its tensile strength. If vulnerability is defined as propensity to rupture, plaque mechanical strength itself and underlying biological features may serve as ‘vulnerability endpoints’ [6].
Plaque mechanical properties are mostly determined by extracellular matrix, specifically fibrillar collagen [7], and extracellular lipids [8]. Plaques with thin fibrous cap and large lipid/necrotic core are considered vulnerable. Hence the cap/core ratio is the most basic ‘vulnerability endpoint’. The consistency of the lipid core depends on lipid composition and temperature [9]. A soft core may be more vulnerable since it may not be able to bear the imposed circumferential stress, which is then redistributed to the fibrous cap where it may be critically concentrated [8].
Likewise, collagen content, distribution and cross-linking further characterize strength-related cap properties [1,10,11]. Unraveling an underlying biology of collagen turnover leads to the numerous downstream endpoints. Collagen content is a result of dynamic balance between its synthesis and degradation. Consequently, detection of collagen degradation products suggests plaque vulnerability [12]. Collagen degradation is driven by proteinases, mostly matrix metalloproteinases and cathepsins [13,14]. Therefore presence of these enzymes is another popular ‘vulnerability endpoint’. These proteinases can be synthesized and secreted by both macrophages and SMC, while their synthesis is stimulated by macrophage-derived cytokines. In general, macrophages are viewed as predominantly ‘matrix-degrading’ cells [15,16]. Macrophages are also known to be a major source of tissue factor in the plaque [17–19]. Therefore, macrophage accumulation is another accepted predictor of both plaque vulnerability and thrombogenicity.
Formation of a new matrix is dependent on SMC, the main source of collagen synthesis [1]. Since collagen is responsible for plaque mechanical strength, SMC accumulation is associated with plaque stability. Ironically, from this perspective, as opposed to the ‘growth’ paradigm, SMC migration and proliferation are ‘good’, while SMC death is ‘bad’. Accordingly, SMC number and death (mostly apoptosis-driven) rate serve for characterization of plaque vulnerability [20]. It is also suggested that T-cells exacerbate plaque vulnerability via inhibition of collagen production by SMC [21].
Accumulation of macrophages and T-cells, i.e. local inflammation, is associated with classical gross features of inflammation like increased temperature. These features are being explored as functional ‘vulnerability endpoints’ [22]. Recently, Shiomi et al. even introduced morphometric ‘vulnerability index’, the ratio of plaque area occupied by lipid components (macrophages+extracellular lipids) and by fibrimascular components (smooth muscle cells+collagen fibers) [23]. Microscopic features of bone fide stable and vulnerable plaque are shown in Fig. 2.
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Clearly, this list can be extended almost indefinitely to cater for specific molecular mechanisms involved in plaque destabilization. The majority of described endpoints can be measured both in human and experimental atherosclerotic lesions. Genetic manipulations, as well as drug and antibody treatment can change plaque phenotype in animal models thereby providing important clues to the mechanisms of plaque vulnerability. Thus, traditional animal models of atherosclerosis combined with a new set of relevant endpoints are very useful in the study of plaque vulnerability. The challenge is to validate new endpoints and find new ways of measurement. From the technical perspective, increasing use of genetically modified mice demands further miniaturization of the assays, especially in vivo functional and imaging tools.
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3 Animal models of plaque rupture and plaque-associated thrombosis |
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TopAbstract1 Why animal models...2 Traditional models of...3 Animal models of...4 Reality check5 Summary and future...References |
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Although the majority of questions related to plaque vulnerability as a propensity to rupture can be addressed using traditional animal models of atherosclerosis, specific questions that relate to the mechanisms of rupture per se and rupture-driven thrombosis require the models featuring plaque rupture and thrombosis.
There are two principal approaches to designing animal models of plaque rupture: look for spontaneous rupture/thrombosis and actively trigger them (Fig. 1).
3.1 Spontaneous plaque rupture/thrombosis
Until recently, spontaneous rupture was considered an extremely rare or non-existent event in animal models of atherosclerosis. To detect elusive rupture, investigators either used more exotic animal models and/or waited longer then usual and looked in unexpected places.
Spontaneous hemorrhage and rupture were found in the coronary arteries of the unique pigs with inherited hyper-low-density lipoprotein (LDL) cholesterolemia [24]. These complications were evident only in 39–54 month-old animals. Recently, Rosenfeld et al. described high frequency of intraplaque hemorrhage and a fibrotic conversion of necrotic zones accompanied by loss of the fibrous cap in the innominate artery of apoE–/– mice aged 42–54 weeks [25]. The innominate (brachiocephalic) artery, a small vessel connecting the aortic arch to the right subclavian and right carotid artery, has been previously overlooked since the vast majority of studies concentrated on the aortic root and aortic arch. These observations emphasize that the character of atherosclerotic lesions is site-dependent. Finally, Johnson and Jackson reported that 37–59 week-old apoE–/– mice fed a diet supplemented with 21% lard and 0.15% cholesterol, died spontaneously. Postmortem observations revealed luminal thrombi associated with ruptured plaques in brachiocephalic artery [26]. It is yet to be determined why spontaneous death of apoE–/– mice was not observed by the other investigators. Although both reports present time-consuming and not fully optimized models, they demonstrate the possibility of spontaneous plaque rupture in mice, pinpoint the strain and anatomical site prone to plaque rupture. This certainly represents a breakthrough in the field of plaque vulnerability.
Another groundbreaking study was recently published by Herrera et al. [27]. It has been demonstrated that Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein developed spontaneous combined hyperlipidemia, coronary heart disease and decreased survival. Specifically, the authors reported occlusive thrombosis of left ventricular intramyocardial artery. Neither plaque rupture nor erosion was found in association with these thrombi. Although precise mechanisms of plaque associated thrombosis in these animals are unclear the data shows that combination of hypertension and dyslipidemia not only exacerbate atherosclerosis, but also increases plaque vulnerability.
3.2 Induced plaque rupture/thrombosis
Any attempt to induce plaque rupture in an animal model is quite risky since actual triggers of rupture are still unknown.
One approach is to ignore the complexity of the clinically relevant triggers and use direct mechanical injury of the plaque. For example, platelet- and fibrin-rich thrombi can be induced in association with atherosclerotic plaques in ApoE–/– mice after squeezing the aorta between forceps [28]. Although simplistic, this strategy is valid for assessment of plaque thrombogenicity. In a similar fashion, accelerated atherosclerotic lesions can be developed in rabbits by combination of balloon injury and hypercholesterolemia, and then mechanically disrupted by inflation of angioplasty balloon in the arterial lumen [29]. Although experiments of this sort were primarily designed under the umbrella of restenosis, they can be viewed upon and applied as a tool to study plaque vulnerability.
We have developed a rabbit model in which an atherosclerotic plaque can be ruptured at will after an inflatable balloon becomes embedded into the plaque [30]. This model as well can be used for induction of thrombi associated with plaque rupture. Furthermore, the pressure needed to inflate the plaque-covered balloon may be an index of overall plaque mechanical strength. This technique enabled a direct demonstration of hypercholesterolemia-driven mechanical weakening of atheroma [10]. However, the model is very labor-intensive. Alternative strategies of biomechanical measurements with or without plaque disruption will be of value.
Experimental atherosclerotic lesions can be injured using multiple techniques. Response to injury can be measured and interpreted in terms of plaque vulnerability. Eitzman et al. applied a photochemical reaction to elicit thrombus formation overlying and atherosclerotic plaque in ApoE–/– mice [31]. Time necessary to develop occlusive thrombosis was used as an endpoint.
While direct disruption provides experimental convenience and ease of interpretations, a more clinically relevant model is necessary to study the mechanisms of plaque rupture. This venue was pioneered by Constantinides and Chakravarti 40 years ago [32]. Atherosclerotic plaques were produced in New Zealand White rabbits by intermittent cholesterol feeding. Triggering of thrombosis was then accomplished by intraperitoneal injection of Russel's viper venom (a procoagulant and endothelial toxin) followed by intravenous injection of histamine, a vasopressor in rabbits. This work was recently reproduced by Abela et al. [33]. The authors have modified an original procedure by introducing balloon injury of the aorta early in the preparatory phase to accelerate plaque development. The animals frequently developed acute aortic thrombi, but the thrombi were mostly associated with endothelial toxicity rather than with true plaque rupture. It was suggested that in this regard, this model could be more representative of the inflammatory erosions that accompany sudden death [6]. In a very similar fashion, Nakamura et al. challenged Watanabe heritable hyperlipidemic rabbits with Russel's viper venome combined with serotonin or angiotensin II [34]. This treatment induced an acute myocardial infarct in some animals. However, there was no correlation between coronary arteriosclerosis and myocardial infarct in this model. Apparently, combination of hypercoagulation, endothelial injury and local vasoconstriction could be sufficient for cardiac ischemia. Unfortunately, myocardial pathology was not associated with plaque rupture.
Myocardial infarcts were also documented in an elegant study of Caligiuri et al. [35] that was performed on hypercholesterolemic (apoE–/–, LDR–/– double knock-out) mice. Exposure of mice with coronary atherosclerosis to mental stress or hypoxia led to acute ischemia and myocardial infarction followed by inflammation and fibrosis in the heart. All these pathological changes could be prevented by a blocker of the endothelin type A receptor. Importantly, control mice did not developed myocardial infarcts. This experimental paradigm comes as close as possible to a real clinical situation. However, no signs of plaque rupture or plaque-associated thrombosis were described. It is possible that mental stress increased heart workload, hypoxic stress reduced oxygen delivery to the heart muscle, and both events were precipitated by acute coronary vasoconstriction. Therefore, in this model, myocardial pathology could be developed in plaque rupture-independent fashion. However, it is hard to exclude the possibility that plaque rupture and coronary thrombosis were overlooked.
We have recently reported some preliminary data where central stress was emulated in apoE–/– mice by intracerebroventricular injection of a corticotropine releasing factor (‘stress-hormone’) [36]. In this study, stress was associated with plaque rupture, thrombosis and paraplegia. It is yet to be determined what intermediate molecules or events were involved into this central stress-induced plaque rupture and thrombosis.
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4 Reality check |
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TopAbstract1 Why animal models...2 Traditional models of...3 Animal models of...4 Reality check5 Summary and future...References |
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Our description of ‘vulnerability endpoints’ and models featuring vulnerable plaques is mostly based upon admittedly oversimplified definition of vulnerability as propensity to rupture hence an emphasis on the plaque mechanical properties and biological mechanisms that control plaque mechanical strength. Although rational, this approach has several major limitations.
First, it is ‘plaque-centric’ and does not take into account the processes that lead to the occlusive thrombus formation after plaque rupture, including blood vessel–wall interactions, blood coagulability, sustained vasoconstriction and sympathetic discharge. To the best of our knowledge, there are no studies or animal models, where these important features are systematically analyzed. It seems that relevant approaches independently exist in the thrombosis literature (recently reviewed in [37]), but they are primarily used in animals with intact vasculature and are still to merge with models of atherosclerosis.
Second, current modeling of vulnerable plaques emphasizes acute nature of plaque rupture. However, in reality several layers of ‘spontaneous’ plaque fissures are frequently observed in the coronary arteries and aortas of patients who died of non-cardiac diseases [38]. It would be useful to reproduce this interesting clinical phenomenon in the animal model(s).
Third, although current paradigm ‘inflammation–collagen degradation–rupture–thrombosis’ seems to prevail, emerging clinical data (reviewed in Ref. [5]) suggest that coronary thrombi can arise without plaque rupture and without signs of severe local inflammation. Pathophysiological mechanisms of this phenomenon are poorly understood. We are not aware of similar phenomena in any currently available animal model. Therefore, successful modeling is contingent upon generation and testing of specific mechanistic hypotheses.
Any model is based upon a limited set of assumptions and therefore by default has it's own limitations. A model often exaggerates only one feature of a complex process to make analysis more convenient and more accurate. It stands true for traditional models of atherosclerosis, some of which are primarily driven by lipid accumulation and some by cell proliferation. Nevertheless, these models facilitated accumulation of useful knowledge relevant to the mechanisms of plaque development. We hope that new generation of animal models will help to elucidate mechanisms of plaque vulnerability. Successful design and application of these models is impossible without knowing their limitations.
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5 Summary and future directions |
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TopAbstract1 Why animal models...2 Traditional models of...3 Animal models of...4 Reality check5 Summary and future...References |
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Currently, there is no single, golden standard animal model of a vulnerable plaque. However, the whole range of experimental approaches is readily available. It includes traditional models of atherosclerosis combined with new ‘vulnerability endpoints’, as well as several models featuring spontaneous or induced plaque rupture/thrombosis.
Numerous specific questions can be posed and answered using available experimental arsenal. Genetically modified mice will facilitate unraveling the role of individual genes in plaque vulnerability. Animal models will also help to identify biomarkers of vulnerable lesions. To support these studies, further efforts are needed for validation of the endpoints and optimization of assays. Specifically, the growing popularity of mouse models demands miniaturization of various assays and especially imaging tools.
It has also become evident that animal models of plaque rupture are not a dream but an emerging reality. These models can address specific questions related to molecular mechanisms of plaque rupture and plaque-associated thrombosis. Obviously, this is just the beginning of systematic experimental efforts, and we can expect that new models will be faster, more reproducible, and more relevant to clinical situations. Better animal models will facilitate detection of vulnerable plaques and development of plaque-stabilizing therapies.
Time for primary review 21 days.
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