Hindawi Publishing Corporation

Journal of Biomedicine and Biotechnology

Volume 2011, Article ID 497841, 13 pages
doi:10.1155/2011/497841

Review Article
Animal Models of Cardiovascular Diseases

Carlos Zaragoza,1 Carmen Gomez-Guerrero,2 Jose Luis Martin-Ventura,2

Luis Blanco-Colio,2 Begon˜a Lavin,1 Ben˜at Mallavia,2 Carlos Tarin,2 Sebastian Mas,2
Alberto Ortiz,2 and Jesus Egido2
1
Department of Epidemiology, Atherothrombosis and Cardiovascular Imaging, Fundacion Centro Nacional Investigaciones
Cardiovasculares Carlos III (CNIC), Sinesio Delgado 3, 28029 Madrid, Spain
2
Renal and Vascular Research Laboratory, IIS-Fundacion Jimenez Diaz, Universidad Autonoma, Avda Reyes Catolicos 2,
28040 Madrid, Spain

Correspondence should be addressed to Jesus Egido, [email protected]

Received 11 October 2010; Revised 4 January 2011; Accepted 17 January 2011

Academic Editor: Oreste Gualillo

Copyright © 2011 Carlos Zaragoza et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models
have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment
of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and
cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal
models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology,
making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly
recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the
requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available,
models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic
diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models
available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against
human cardiovascular diseases.

1. Introduction aspect related to these human pathologies. In particular,

we will describe models of atherothrombotic diseases,
Cardiovascular diseases are the first leading cause of death
including expanding abdominal aortic aneurysms (AAA),
and morbidity in developed countries. Cardiac and vascular
thoracic aneurysms, and occlusive atherosclerotic diseases, as
complications are complex multifactorial pathologies, in
well as models of heart failure. These situations constitute
which both genetic and environmental factors are impli- today a significant challenge since predictors to evaluate
cated, thus making them very difficult to prevent. The early detection and forecast progression are crucial in
development of animal models of cardiovascular disease these pathologies, yet they are poorly explored.
(CVD), including cardiac and atherothrombotic diseases,
has provided us today with important insights into the
pathophysiology, and they were found to be essential tools to 2. Animal Models of Atherothrombotic Disease
evaluate new therapeutic strategies to predict and to prevent
2.1. Mouse Models. Atherosclerosis is a complex multifac-
these complications. torial disease with different etiologies that synergistically
Here, we will summarize the most common models promote lesion development. Mouse models have proved
of cardiovascular diseases, including those implemented in to be useful to study development and progression of
both large and small animals, designed for helping to cover atherosclerotic lesion, and several reviews have extensively
with more precision and to better understand every single discussed the different available models [1–3]. In
particular,
2 Journal of Biomedicine and Biotechnology

knockout and transgenic mouse models for atherosclerosis described to develop lesions similar to those of human [17,
have been instrumental in understanding the molecular 18].
and cellular mechanisms involved in atherogenesis, and in Under normal dietary conditions, apoE/ mice have
eval- uating the effectiveness of new and existing dramatically elevated plasma levels of cholesterol, and they
atherosclerotic drugs [4]. develop extensive atherosclerotic lesions widely distributed
As wild-type mice are resistant to lesion develop- throughout the aorta [18–20]. This process can be exacer-
ment, the current mouse models for atherosclerosis are bated on a high-fat diet, with female mice more
based on genetic modifications of lipoprotein metabolism susceptible than male mice [19]. A chronological analysis
with additional dietary changes. Among them, low-density of atheroscle- rotic lesions in apoE / mice revealed
lipoprotein receptor-deficient mice (LDLR/ mice) and 
that the sequential events involved in lesion formation in
apolipoprotein E-deficient mice (apoE/ mice) are the this model are strik- ingly similar to those in larger animal
most widely used. Atherosclerotic lesions seen in these models and in humans. Predilection sites for atherosclerotic
models can be exacerbated by the addition of risk factors 
lesions in apoE / mice are the aortic root, followed by
such as hypertension or diabetes. Mice have become the aortic arch, the brachiocephalic trunk, the left carotid,
widely used as models of human atherosclerosis as they and subclavian and coronary arteries [6, 21]. Aortic lesions
offer advantage compared with other species (Table 1).
rapidly develop from initial fatty streaks comprised
primarily of foam cells with migrating smooth muscle cells
2.2. LDLR/ Mice. The LDLR/ mouse represents a to more complex lesions in middle-aged mice. These
model of familial hypercholesterolemia due to one of the advanced lesions are heterogeneous but typically composed
mutations affecting the LDLR, and the plasma lipoprotein of a necrotic core surrounded by proliferating smooth
profile resembles that of humans. Mice, which are genet- muscle cells and extracellular matrix proteins [20, 22].
ically deficient in LDLR manifested delayed clearance of The apoE/ mice are currently the most widely utilized
VLDL and LDL from plasma. As a result, LDLR / mice animal model for the study of atherosclerosis. In fact, the
exhibit a moderate increase of plasma cholesterol level effect of many genes on the development of atherosclerosis
and develop atherosclerosis slowly on normal chow diet has been examined by crossing the apoE/ mice with other
[5, 6]. Interestingly, the severity of the genetically manipulated animals. Furthermore, the apoE /
hypercholesterolemia and atherosclerotic lesions in LDLR/ mouse serves as a useful tool to: (i) identify
mice can be accelerated by feeding a high-fat, high- atherosclerosis- susceptibility-modifying genes, by the
cholesterol diet [5–7], by mutat- ing the apoB gene into candidate-gene and gene-mapping methods, (ii) decipher
an uneditable version [8, 9], and by crossing either with molecular mechanism and cell types involved in
leptin-deficient mice [10] or with apoB100 transgenic mice atherogenesis, (iii) search into the drug effects on
[11]. Under these conditions, the lesions in the aorta can atherosclerosis, and (iv) assess novel therapies that
progress beyond the foam-cell fatty- streak stage to the prevent lesion progression. In this sense, the apoE/
fibroproliferative intermediate stage. mouse model was used to test additional therapeutic
In addition to LDLR/ mice, the LDLR and apoE effects of statins beyond those attributable solely to
double-deficient mouse (LDLR / apoE /  ) which devel- cholesterollowering. One of the first observations was the
ops severe hyperlipidemia and atherosclerosis even on paradoxical effect of simvastatin on atherogenesis in both
a regular chow diet, has been proposed as a suitable apoE/ and LDLR/ mice [23]. In contrast to the
model to study the antiatherosclerotic effect of compounds atheroprotective effect of simvastatin in LDLR / mice,
without having to feed the animals an atherogenic diet age-matched apoE/ showed elevated serum total
[12, 13]. However, the response of both LDLR/ and cholesterol and increased aortic plaque area, thus suggesting
LDLR/apoE/ mice to the treatment with hypolipi- that the therapeutic effect of simvastatin may depend on
demic drugs varies from lowering of plasma cholesterol the presence of a functional apoE [23]. In spite of this,
without atherosclerosis decrease to a weak lesion reduction the antiatherosclerotic effects of other statins have been
with or without lower plasma cholesterol [4, 14]. By contrast, effectively proven in apoE/ mice [24, 25]. Several other
those mice effectively respond to agonists of peroxisome compounds, such as angiotensin II receptor antagonists or
proliferator-activated receptor (PPAR) or liver X receptor PPAR agonists [26] also reduced the extent and severity of
[15, 16]. This great variability indicates that LDLR/ is atherosclerotic lesions without lowering plasma cholesterol
probably not well-suited for analyzing the cholesterol- in apoE/ mice. However, the recent finding of increased
lowering and antiatherogenic effects of drugs. atherogenesis in apoE / mice treated with PPAR alpha and
PPAR gamma agonists is consistent with clinical findings of
the adverse cardiovascular events of dual therapy [27].
2.3. ApoE/ Mice. In 1992 two different groups simultane- Nevertheless, a major limitation of the apoE/ mouse
ously generated the apoE/ mice by homologous recom- model is the infrequency of plaque rupture and thrombo-
bination in embryonic stem cells [17, 18]. Homozygous sis, two common complications of human atherosclerosis.
deficiency in apoE gene results in a marked increase in the Ischemic cardiomyopathy has been occasionally found in
plasma levels of LDL and VLDL due to a failure in their aged mice [20], but interestingly, rapid coronary artery
clearance through the LDLR and LDLR-related proteins. The
occlusion, myocardial infarction, and even premature
apoE/ mouse contains the entire spectrum of lesions
death occur when apoE/ mice were crossed with mice
observed during atherogenesis and was the first mouse
model deficient in scavenger receptor class B type I or its
adaptor protein
Journal of Biomedicine and Biotechnology 3

TABlE 1: Animal models of atherosclerosis: advantages and limitations.

(i) Rapid development of atherosclerotic plaques (i) Only partial resemblance to humans

(ii) Short reproductive cycle (ii) More atherosclerotic than atherothrombosis model

Large litters
(iii) (iii) Very high levels of blood lipids

Mouse (iv) Well-known genome

(v) Relative ease of genome manipulation

(vi) Relatively cheap

(vii) Useful for noninvasive imaging

(MRI, PET, CT, ultrasound)

(viii) Large experience

(i) Easy, available, and cheap
Rat (i) Do not develop atheroma
(ii) Useful for restenosis analysis
(i) Medium size (i) Need for high blood cholesterol levels

(ii) Fibroatheroma lesions (ii) No plaque rupture model

Rabbit
(iii) Useful for restenosis models (iii) A model of neointima formation rather than
atherosclerosis
(iv) Affordable
(i) Lesions more similar to human disease (i) High cost

Porcine (ii) Difficult handling

(ii) Valid for restenosis studies

(iii) Few genomic tools

[28, 29], thus mimicking many cardinal features of human primarily as ischemic heart disease caused by accelerated
coronary heart disease. atherosclerosis, and also as cardiomyopathy. Several
models are available to study atherosclerosis and
2.4. Transgenic Mice. Transgenic technologies have provided cardiomyopathy associated with diabetes, including apoE /
a series of very useful mouse models to study hyperlipi- and LDLR / mice in which type 1 diabetes is induced by
demia and atherosclerosis. Among them, mice expressing streptozotocin or viral injection [33, 34]. In both mice,
mutant forms of apoE, such as apoE3Leiden (E3L) and diabetes induc- tion did not markedly change plasma lipid
apoE (Arg 112 → Cys → 142) transgenic mice, are the more levels, thereby mimicking the accelerated atherosclerosis
widely studied. These mice display a lipoprotein profile seen in patients with type 1 diabetes. Importantly,
comparable to that of patients with dysbetalipoproteinemia, streptozotocin-injected atherosclerotic mice exhibited
in which plasma total cholesterol and triglycerides are mainly
increased atherosclerosis in the aortic sinus, carotid artery,
confined to (V) LDL [30]. The E3L transgenic mice develop
and abdominal aorta, as well as calcifications in the
atherosclerotic lesions with all the characteristics of human
vasculopathy, varying from fatty streak to mild, moderate, proximal aorta [34, 35].
and severe plaques [30, 31]. Furthermore, E3L transgenic In brief, mouse models have been very useful to unveil
mice and the more recently developed E3L/Cholesteryl ester the importance of inflammatory and immunological
transfer protein (CETP) transgenic mice have been shown mecha- nisms in the formation and progression of
to be more sensitive to a variety of hypolipidemic drugs atheroma plaque. Recently, an enormous interest for the
and PPAR agonists than apoE/ and LDLR/ mice [4, 32]. use of noninvasive magnetic resonance imaging (MRI) in
mouse models of atherosclerosis has arisen [36], since MRI
accurately char- acterizes the location, the size and the
2.5. Mouse Models of Diabetes-Accelerated Atherosclerosis.
shape of lesions. In addition, MRI allows the
Diabetes is a high risk factor of cardiovascular disease.
differentiation between fibrous and lipid components of
The cardiovascular complications of diabetes are manifested
regress in plaques in mice. In combination with noninvasive
imaging technologies, mouse models of atherosclerosis
today also serve to test novel
4 Journal of Biomedicine and Biotechnology

contrast agents, and to design and target specific 2.7. Porcine Models. They prevention of heart attack and
molecules involved in high-risk plaque. stroke depends on the detection of vulnerable plaques
and development of plaque-stabilizing therapies. Animal
2.6. Rabbit Models. The high-cholesterol diet rabbit model models are essential for testing mechanistic hypotheses in
has been widely used for experimental atherosclerosis. Back a controlled manner, they should be representative of a
in 1913, cholesterol was found to cause atherosclerotic human disease, and at the same time be easy to manip-
changes in the rabbit arterial intima, which is very similar ulate. However, vulnerable plaque recreation is one of the
to human atherosclerosis. Atherosclerotic lesions also toughest tasks in animal model design. Plaque rupture is
develop in normolipemic rabbits as a result of repeated, or an additional complication of an already complex process,
con- tinuous intimal injury by an indwelling aortic and the precise mechanisms involved remain hypothetical.
polyethylene catheter, balloon angioplasty or nitrogen A plethora of experimental approaches are available for
exposure. There- fore, many studies have used the rabbit growing atherosclerotic lesions in various animal species as
model with high- cholesterol diet, arterial wall injury, or, mentioned above (Table 2).
most commonly, a combination of these two methods. In Currently, there is no single and golden standard
all these models, the observed lesions resemble, at least in animal model of vulnerable plaque, but pig models are
part, those seen in human plaques, mainly regarding the probably the best way to recreate human plaque instability.
The combina- tion of diabetes and hypercholesterolemia
inflammatory compo- nent, though the vascular smooth
constitutes a good model of accelerated atherosclerosis [42],
muscle cell proliferation determines for a great deal the
and it was relevant study the role of certain biomarkers,
lesion. such as the Lp-PLA2 since these animals share a similar
The rabbit model has largely been used to study the plasma lipoprotein profile humans. In this regard, the
influence of lipid lowering (by diet or statins) on the selective inhibition of Lp-PLA2 by darapladib decreased
plaque formation and “stabilization.” Those studies have progression to advanced coronary atherosclerotic lesions
contributed to unveil the mechanisms by which lipid and confirmed a crucial role of vascu- lar inflammation not
lower- ing reduces macrophage accumulation and other associated to hypercholesterolemia, in the development of
aspects of atheroma inflammation [37, 38]. lesions implicated in the pathogenesis of myocardial
Recently, we have set up a novel rabbit model to examine infarction and stroke [43].
the influence of inflammation on atherosclerotic plaque. The Several porcine models of advanced human-like coro-
aim was to study some mechanisms by which atherosclerosis nary atherosclerosis have been employed to analyze the
is particularly severe in patients with rheumatoid arthritis. development and validation of coronary imaging technolo-
Briefly, the model consists in a combination of femoral injury gies. In the evolving era of technological development, the
in hyperlipidemic rabbits and induced acute knee arthritis. availability and use of such animal models will become
Those animals had more intensive vascular lesions than critical for the development of emerging technologies in
animals without inflammation. This model could represent interventional cardiology [44], and for the study of drug-
a novel approach to the study, inflammation-associated eluting stents [45]. In addition, the porcine models of
atherosclerosis [39]. coronary atherosclerosis allow examining the impact of
A model for plaque rupture has been also developed adventitial neovascularisation, on atherosclerotic plaque
in rabbits. Shimizu and coworkers [40] have developed a composition and vascular remodelling [46].
simple rabbit model of vulnerable atherosclerotic plaque,
with the combination of aggressive vascular injury associated 3. Animal Models of Abdominal Aortic
to a hyperlipidemic diet. The histological findings showed Aneurysms (AAAs)
that an aortic plaque had the three features of “vulnerable
plaque”: lipid-rich core, accumulation of macrophages, and Animal models of atherothrombotic AAA are essential
a thin fibrous cap. In addition, a low-density lipoprotein tools for the preclinical evaluation of new therapeutic
(LDL) receptor-deficient animal model (the WHHL rabbit) strategies for the suppression of aneurysmal degeneration
has been developed. This model resembles to human familial (Table 3). Recent insights into the mechanisms of human
hypercholesterolemia and shows evidence of progressive AAA have come from the studies in mouse models, and
disease of the aorta with accumulation of birefringent elastase- induced AAA in particular appears to recapitulate
lipids in intimal lesions and plaques, as well as in the media many features of human AAA. Here we briefly outline the
from birth to 1 year of age. most frequently used models of AAAs, and refer the reader
Although rabbit aortic arteries are smaller in vessel to recent comprehensive reviews regarding additional
diameter than human carotid artery, they allows the animal models [47–52].
studies with endovascular therapeutic devices. In addition,
the rabbit model has also been used for the
quantification of atherosclerotic aortic component by MRI. 3.1. Rat Models
This tech- nique accurately quantifies fibrotic and lipid 3.1.1. Localized Aortic Perfusion with Elastase. This model
components of atherosclerosis in the model and may consists of exposing a segment of the abdominal aorta and
permit the serial analysis of therapeutic strategies on infusing it with elastase [53]. The degradation of elastic
atherosclerotic plaque stabilization [41]. fibers triggers an inflammatory response that develops into
Journal of Biomedicine and Biotechnology 5

TABlE 2: Animal models of plaque rupture and plaque associated

thrombosis.
Spontaneous Induced
39–54-month-old pigs with inherited hyper=LDL
ApoE/ mice after squeezing the aorta supplemented between forceps.
cholesterolemia.
42–54-week old ApoE/ mice. Hypercholesterolemic rabbits subjected to balloon injury.
Dahl salt-sensitive hypertensive transgenic rats for human
Atherosclerotic ApoE/ mice subjected to photochemical injury.
cholesteryl ester transfer protein.
Intraperitoneal injection of Russell’s viper venom in New Zealand
— White rabbits intermittently fed with high cholesterol diet.
Intraperitoneal injection of Russel’s viper venom in Watanabe heritable
hyperlipidemic rabbits, in combination with the administration of
serotonin or angiotensin II.

an aneurysm [54, 55]. The severity of the induced AAA can throughout the adventitial and medial layers, with
be increased by adding plasmin to the infusion. This model relatively few polymorphonuclear cells localized to the
has been adapted for use in several other species, adventitia [57]. Elastase-induced injury increases the
including rabbit, mouse, and large animals. expression of MMPs, cathepsins, and other proteases [70],
with MMP-9 being localized to aneurysm-infiltrating
3.1.2. Decellularized Xenografts. This model was based on macrophages [71]. Elastase-induced AAAs thus appear to
the observation that chronic rejection of arterial allografts recapitulate many features of human AAAs, and this model
and xenografts, results in arterial wall dilatation and rupture. has become a valuable and convenient tool for systematically
Michel and coworkers decellularized a section of evaluating the roles of individual gene products in aneurysmal
abdominal aorta from one species (e.g., guinea pig), and degeneration [71–80].
the resulting tube of intact extracellular matrix was grafted When compared to calcium-chloride-induced AAA, the
into another morphologically compatible species, usually main limitation of this method is in the mechanical stress
rat [58]. The xenogenic extracellular matrix triggers the required to recreate medial elastic degradation. However,
destruction of host matrix, leading to aneurysm formation. the protocol resembles the time course of events leading
The model has been successfully used to evaluate to human AAA, including initial recruitment of leukocytes
therapeutic targets [64– 69], although the heterogeneity of and mast cells, the development of a transmural aortic
the aneurysms formed and the lack of vessel rupture are wall inflammatory response, and finally the upregulation of
significant limitations. extracellular matrix metalloproteinases and other proteases,
which induce a progressive degradation of the medial elastin
3.2. Mouse Models. The mouse has become the preferred and collagen, leading to the final aortic dilatation.
model for cardiovascular research for several reasons, includ-
ing the ease of handling, low procedure costs, and the
ability to manipulate the mouse genome. Consequently, of all 3.2.3. Angiotensin II-Induced AAA. This procedure was ini-
animal models of AAA, mouse models have provided most tially developed to define whether increased plasma concen-
of the insights into the mechanisms of human AAA. The trations of Angiotensin II (Ang II), have a direct effect on
following models are the most widely-used to date. the atherogenic process in hyperlipidemic old apoE
  / mice.
Unexpectedly, Ang II also produced large suprarenal abdom-
3.2.1. Calcium-Chloride-Induced AAA. In this method, ini- inal aortic aneurysms in these animals [81]. In this model,
tially developed in rabbits [62], calcium chloride is applied inflammation of the vessel wall is associated with signaling
periaortically in the region between the renal arteries and through AT1a receptors [82], nuclear factor- (NF-) kappaB-
the iliac bifurcation. Significant dilatation of the aorta is mediated induction of proinflammatory genes, including
MCP-1, M-CSF, iNOS, COX-2, inhibition of PPARs [83],
observed within 14 days, and the severity is significantly
activation of the NADPH oxidase p47phox [84], c-JUN N-
increased if calcium chloride is applied together with thio-
terminal [85], Rho kinases [86], and enhanced recruitment
glycolate and if animals are fed a high-cholesterol diet
of macrophages [87, 88] and extracellular matrix compo-
[56]. Unlike other models, calcium chloride application
nents and degrading enzymes [89–91], leading to vessel
induces AAA without the need for mechanical
dissection, and rupture. The severity of AAA is higher in
intervention.
hyperlipidemic apoE/ or LDLR/ male mice (∼60% of
mice), when compared to normolipidemic C57Bl/6 mice,
3.2.2. Elastase-Induced AAA. The elastase-induced model although in these models neither hyperlipidemia per se
was adapted for mice by Pyo et al. [57]. Elastase perfusion in nor atherosclerosis is considered major determinants [92–
mouse aorta causes a mild-to-moderate dilatation initially, 94].
which subsequently develops to a >100% increase in aortic The model contributed to evidence the implication of
diameter within 14 days. In this model, the degradation the rennin-angiotensin (RAS) system in aneurysmal
of medial elastin is delayed, and the subsequent aortic disease. However, two main limitations should be
wall inflammation consists of mononuclear phagocytes considered: the
6 Journal of Biomedicine and Biotechnology

TABlE 3: Current procedures for inducing AAA in animals.

Species AAA models

Calcium Chloride [56].
Elastase infusion [57].
Murine Angiotensin-II-infused AAA: used in hyperlipidemic (ApoE/ or LDLR/) male mice or in wild-type C57BL/6 mice in
conjunction with repeated administration of neutralizing TGF-β antibodies [50].
Decellularized xenografts: grafting of abdominal aortic extracellular matrix from one species to a compatible recipient of a
different species [58].
Spontaneous [59].
Elastase-induced AAA: similar to the murine model [60], also applicable to the carotid artery [61].
Rabbit
Calcium chloride [62].
Surgical model: dilatation of the infrarenal aorta with an angioplasty balloon followed by infusion of pancreatic porcine
Pig elastase [63].

suprarenal location of the aneurysm (in contrast to the related procedures. Despite the benefits, however, pigs have
infrarenal location in humans) and the clinical relevance significant disadvantages, including complex animal han-
of RAS inhibition, since the association of RAS in human dling, the requirement of special housing and surgical
AAA has provided controversial results, pointing towards room facilities, the elevated cost of the animals, and the
necessary large population studies. reduced sample sizes per assay.

3.2.4. Spontaneous Mouse Mutants. The blotchy mouse is 3.5. Thoracic Aortic Aneurysm (TAA). Elastic tissue degra-
a mouse strain containing a spontaneous mutation on the dation is also related to the development of thoracic aortic
X chromosome which leads to abnormal intestinal copper aneurysm (TAA), and mouse models have significantly
absorption. These animals have weak elastic tissue due to advanced the understanding of this pathology. TAA is a
failed crosslinking of elastin and collagen, and develop aortic characteristic feature of Marfan syndrome (MFS), a
aneurysms mainly in the aortic arch, thoracic aorta, and disorder caused by mutations that affect the structure or
occasionally in the abdominal aorta [59]. However, results expression of the extracellular matrix protein fibrillin-1, a
from this model are difficult to interpret, since the glycoprotein that is associated of extracellular proteins,
mutation produces many severe additional effects. including integrin receptors and insoluble elastin [97].
Fibrillin-1 mutations in MFS decrease ECM sequestration
3.3. Rabbit Models. Several of the same interventions used in of latent TGFβ, thus rendering it more prone to or
mice are also implemented in rabbits, including elastase infu- accessible for activation [98– 100]. TAA progression in MFS
sion [60] and calcium chloride application to the is driven by elastic fiber cal- cification, vascular wall
abdominal aorta [56]. Another intervention used in rabbits inflammation, intimal hyperplasia, structural collapse of
is elastase infusion in the right carotid artery [61]. The the vessel wall, impaired activation of MAP kinase
main advantage of rabbits over other animal models is that signaling, and altered synthesis of ECM proteins and
rabbit aneurysms more closely resemble human aneurysms matrix-degrading enzymes (MMPs) [101]. Systemic
hemodynamically and histologically. Rabbit models also administration with TGFβ antagonists has been successfully
combine several of the attractive features of small animals, used to mitigate vascular disease in mouse models of MFS
such as the easy housing and handling. In addition, and in children with severe and rapidly progressive MFS
similarly to large animals, rabbit aneurysms can be [97, 102]. Moreover, studies in mouse models have shown
monitored by accessing through the femoral artery, thus that fibulin-4 and LRP1 are also associated with TAA [103,
providing an excellent model for testing endovascular 104].
therapies [95, 96].
4. Animal Models of Heart Failure
3.4. Porcine Models. Porcine models of AAA have provided
significant information about the changes that occur after Models of heart disease in small animals, particularly rats,
AAA induction and about the responses to stent deployment. have been very useful for the assessment of pharmacolog-
A recently-developed porcine model combines mechanical ical therapies. In addition, several target genes have been
dilatation by balloon angioplasty with enzymatic degrada- identified in genetically modified mouse models. Many of
tion by infusion of a collagenase/elastase solution. The model these genes have proved to be crucial in the initiation and
is characterized by gradual AAA expansion associated with progression of heart disease. Below, we describe the animal
degradation of aortic wall elastic fibers, an inflammatory models currently used to study heart failure, which are
cell infiltrate, and persistent smooth muscle cell loss [63]. also summarized in Table 4.
A broad number of similarities were found between this
model and human AAA, and the procedure may also
4.1. Rat Models. Rat models have dominated research into
represent an excellent method to evaluate endovascular heart damage because, while rats share many of the benefits
of mice (low cost, ease of handling, etc.), their larger
Journal of Biomedicine and Biotechnology 7

TABlE 4: Current procedures for inducing heart damage in animals.

Species Heart failure models

Myocardial damage
Chemical: isoproterenol administration [106].
Electrical: overlapping burns [107].
Surgical: coronary artery ligation [105].
Murine Ischemia Reperfusion:
Transient occlusion of the left coronary artery [108].
Cryoinfarction: cryo-injuries to the epicardium [109].
Pressure overload: aortic constriction and banding. Aortic stenosis [110, 111].
Transgenic models of dilated cardiomyopathy: mutation of cardiac α-actin protein [112].
Spontaneous: WHHLMI rabbits [113].
Rabbit Coronary artery occlusion: similar to the murine model, also applicable to the carotid artery. This is an excellent
model for testing endovascular therapies [114].
Pressure overload: aortic banding [115], valvular stenosis [116].
Microembolization [117].
Dog Tachycardia: ventricular pacing [118].
Aortic stenosis [119].
Surgical model: balloon occlusion of coronary arteries [120].
Pig Tachycardia: pacing-induced supraventricular tachycardia [121].

size greatly facilitates surgical and postsurgical procedures. While this is also a valid method, the degree of heart damage
Myocardial damage in rat hearts is induced by three proce- produced is not consistent among laboratories, limiting the
dures: surgical, pharmacological, or electrical. reproducibility of the results obtained with this procedure.
The surgical method, first developed by Pfeffer and
coworkers, consists of ligating the left coronary artery [105].
In this procedure, left thoracotomy is performed on the 4.2. Mouse Models. Against the many general advantages of
working with mice (ease of handling, low pregnancy times,
anesthetized rat, and the heart is rapidly exteriorized by
etc.), investigators choosing them as models of heart
gentle pressure on the right side of the thorax. The left
failure must consider two important limitations: the small
coronary artery is either ligated or heat cauterized
size of the heart and the structural differences with respect
between the pulmonary artery outflow tract and the left
to the human cardiovascular system. Nonetheless, the
atrium. The heart is then returned to its normal position
availability of transgenic and knockout strains and the
and the thorax immediately closed. Several modifications
relative ease with which new genetic modifications can be
have been introduced to improve performance and to
introduced make the mouse one of the most attractive
reduce animal mortality, and left coronary artery ligation is
models for research into the molecular basis of heart failure.
the most common method used to induce acute myocardial
damage in rat and other animal models. One important One of the most widely used models of heart failure in
mice is the left coronary artery ligation procedure, adapted
modification is temporary occlusion followed by
from rat. In some protocols the artery is occluded perma-
reperfusion, allowing flow recovery through the previously
nently, but recently procedures for temporary occlusion have
occluded coronary artery bed. Left coronary artery ligation
been introduced to reproduce human ischemia/reperfusion
can thus be used to evaluate diverse parameters resulting
injury [108]. In this method the left anterior descending
from either permanent ischemia or ischemia/reperfusion.
coronary artery is occluded and then reperfused, allowing
Pharmacological induction of heart damage was first
flow recovery through the previously occluded coronary
implemented by Bagdon and coworkers in 1963 and is
artery bed. Reperfusion is monitored visually, and the infarct
achieved by treatment with the beta-one adrenergic receptor
can be analyzed by histopathological techniques, and can
(B-AR) agonist isoproterenol [106]. Isoproterenol adminis-
be documented in real time by non invasive high
tration before ischemia exerts a cardioprotective action in
frequency. The areas at risk and the infarct size are
rats, but at the right dose it induces cardiac myocyte necrosis
revealed by staining with Evans blue dye and
and extensive LV dilatation and hypertrophy.
triphenyltetrazolium chloride and are assessed by
Isoproterenol treatment and left coronary artery ligation
computerized planimetry. This model has confirmed the
in rats are efficient and reproducible methods that provide benefits of reperfusion, since infarct size was found to be
valuable information about the underlying mechanisms significantly lower than after permanent occlusion of the
implicated in human heart disease. coronary artery.
The electrical method consists of generating overlapping The method has been further modified to analyze
burns in exposed rat hearts by applying a 2-mm-tipped ischemic preconditioning of the heart. In this method, the
soldering iron to the epicardium of the left ventricle [107]. left coronary artery is repeatedly occluded to subject the
heart to several rounds of brief ischemia and reperfusion,
8 Journal of Biomedicine and Biotechnology

followed by permanent occlusion. This approach has iden- Another model of heart failure is the dilated cardiomy-
tified several ischemia-induced genes that confer tolerance to opathy. Human dilated cardiomyopathy has been modeled
a subsequent ischemic event [122]. in rabbits and pigs by inducing chronic tachycardia with a
More recently, a model of myocardial infarction was pacemaker [121, 127]. Transgenic mouse models, involving
developed, in mice and rats, in which a series of cryo- mutations that predispose to dilated cardiomyopathy, have
injuries is generated in the heart. This new model is also proved very useful. These models have identified an
yielding promising results [109]. association of cytoskeletal and contractile proteins with
this pathology, and very recently a transgenic model
4.3. Large Animal Models of Heart Failure. Small animal expressing a mutated cardiac alpha-actin gene was
models have provided significant insights into human car- provided, in which calcium sensitivity of myofilaments is
diac pathophysiology. However, rodent and human hearts decreased and the expression of calcium/calmodulin-
differ in their architecture, heart rates, oxygen consumption, dependent kinase IIdelta (CaMKIIdelta) is increased [112].
contractility, protein expression, and even stem cell Inhibition of CaMKII- delta in these animals prevented the
popula- tions, and there is therefore an obvious need for increase in p53 and apoptotic cardiomyocytes and
models of heart failure in large animals. ameliorated cardiac function.
The first large animals used to study heart failure were
dogs, in which models of myocardial infarction and serial
microembolization of the coronary artery were developed 5. Conclusion
[117]. However, the preferred large animal model of heart
damage is the pig, because the collateral coronary circulation Animal models of cardiovascular disease yield important
and arterial anatomy of pigs and humans are very similar insights into the genetic basis of human cardiovascular
and infarct size can be accurately predicted [123]. Among diseases and provide a test bed for pharmacological and
several models of MI in pigs, one of the most widely treatments. Nonetheless, investigators need to carefully
used is balloon occlusion of the left anterior descending consider their choice of model: no single method per-
coronary artery. In this model, a catheter is inserted through fectly recreates the human disease, and there are related
the femoral artery, positioning an angioplasty balloon over considerations of cost, infrastructure and the requirement
a guide wire at a position distal to the second largest for specialized personnel. Taking these considerations into
diagonal branch of the artery, and infarction is induced account, experimenters therefore need to select models that
by balloon inflation [120]. The similar size and cardiac best reproduce the aspect of disease being investigated. In
physiology of pigs and humans mean that this model offers particular, when moving from bench to bedside it is essential
major advantages over models in other species. However, the to test procedures in relevant models that yield highly
method requires specialized equipment, dedicated surgical reproducible results, but despite these limitations, given
facilities and skilled personnel, limiting the number of the range of animal models available today it will always
laboratories able to conduct these studies. be possible to devise an appropriate strategy, and animal
The rabbit, much less expensive than pig, offers a models remain the best tools for advancing the understanding
compromise solution. Rabbit models of heart failure, of the mechanism of human cardiovascular disease.
includ- ing coronary artery occlusion models [114], have
major advantages over other species. For example, the Acknowledgments
composition of sarcomeric proteins in rabbits is similar to
that in humans, and the sarcolemmic reticulum Authors’ work has been supported by Ministerio de
contributes about 70% of calcium elimination. In addition, Ciencia y Tecnolog´ıa (SAF2007/63648, SAF2008/04629,
the WHHLMI rabbit strain provides a model of SAF2009/11749, PI10/00072), CAM (S2006/GEN-0247), FIS
spontaneous myocardial infarction requiring no surgical (RECAVA RD06/0014/0035, PS09/00447), European Net-
intervention. This model was developed by selective breeding work (HEALTH F2-2008-200647), Euro Salud EUS2005-
of coronary atherosclerosis- prone WHHL rabbits [124]. The 03565 and cvREMOD 091100. C. Zaragoza and C. Gomez-
main limitation of the WHHLMI model is that it does not Guerrero contributed equally.
feature plaque rupture, whereas in humans coronary plaque
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