Animal models of aortic aneurysm

Abstracts

Os modelos experimentais em animais vêm sendo utilizados em cirurgia vascular há décadas. O desenvolvimento de novas técnicas para tratamento endovascular dos aneurismas requer a criação de bons modelos experimentais para testar esses dispositivos e estudar seu impacto sobre a progressão da doença. Este artigo tem por objetivo revisar os modelos de aneurisma arterial descritos atualmente. Entre os diversos modelos descritos, nenhum reúne todas as características de um modelo ideal de aneurisma. Os modelos em animais de grande porte são adequados para treino, estudo de alterações em parâmetros fisiológicos durante e após a liberação dos dispositivos e integração do mesmo à parede do vaso. Algumas desvantagens significantes incluem dificuldade do manejo, alto custo, difícil manutenção e regulamentações legais, dificultando a disponibilidade de diversas espécies animais. Modelos em animais menores, como os coelhos e camundongos, embora sejam menos caros e de fácil obtenção, não são adequados para estudos de técnicas endovasculares pelas pequenas dimensões de seus vasos. Nenhum modelo descrito até o momento consegue reproduzir todas as características dos aneurismas observados em humanos. Modelos disponíveis são descritos nesta revisão, e suas vantagens e desvantagens são discutidas.

Aneurisma; aorta torácica; modelos animais; experimentação animal

REVIEW ARTICLE

Animal models of aortic aneurysm

Rodrigo Argenta^I; Adamastor Humberto Pereira^II

^IMD. Programa de Pós-Graduação: Ciências Cirúrgicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

^IIPhD. Professor adjunto, Faculdade de Medicina, UFRGS, Porto Alegre, RS. Chefe, Serviço de Cirurgia Vascular, Hospital de Clínicas de Porto Alegre (HCPA), UFRGS, Porto Alegre, RS, Brazil

Correspondence

ABSTRACT

Experimental animal models have been used in vascular surgery for decades. The development of new interventional techniques in the endovascular treatment of aneurysms requires the creation of good experimental models to test these devices and study their impact on disease progression. The aim of this article was to review arterial aneurysm models currently available. Several distinct models have been described but none of them satisfies all the requirements of an ideal aneurysm model. Large animal models are appropriate for training, study of alterations in physiological parameters during and after device delivery, and integration of this device in the vessel wall. Significant disadvantages include difficulty in handling, high costs, difficult maintenance, and government regulations, hindering the availability of several animal species. Small animal models, such as rabbits and mice, despite being inexpensive and easily available, are not appropriate for studies of endovascular techniques because of their small-diameter vessels. To date, none of the models described could mimic all features of human aneurysms. In this review, we describe the available models and discuss their advantages and limitations.

Keywords: Aneurysm, thoracic aorta, animal models, animal experiment.

Introduction

Several animal models have been used in the study of atherosclerosis-related diseases for decades. Initially, species included mainly rodents, but other species, such as avian species and, currently, non-primate and primate mammals have been used more frequently.^1,2

Originally, research focused on the pathophysiology of atherosclerosis, but advances in the understanding of these mechanisms of disease in humans and the rapid development of interventional techniques caused a shift toward the development of techniques using endovascular devices, as well as the prevention and treatment of complications inherent to such treatment modalities,^3,4 leading to a need to develop experimental models more appropriate for this purpose.

Since human response to disease cannot be precisely mimicked, there is no ideal experimental animal model.^5,6 However, each model developed makes a unique, even if modest, contribution to the understanding of the biological process of response to disease and its treatment.

The aim of this article is to review experimental models currently available in the endovascular treatment of aortic aneurysms, their characteristics and applicability in our setting.

Animal models

The main objective of an aneurysm experimental model is to mimic all pathophysiological features of human aneurysms, such as: atherosclerosis, presence of intramural thrombus, crack in the elastic layer, inflammatory infiltrate within the adventitial and medial layers, and increased proteolytic activity within the aneurysm wall.

Aneurysms are rare in animal species. Spontaneous aortic dissection occurs in some turkey lineages, with arterial hypertension and early atheromatous plaque formation.⁷

The genetic induction of aneurysms in rodents (blotchy mouse), based on cross-linking abnormalities in elastin and collagen, produces an aneurysm histopathologically similar to that observed in humans, with elastic fiber fragmentation and inflammatory infiltrate within the medial and adventitial layers.⁸ Aneurysms can also be produced through homozygous gene depletion into apolipoprotein E in rodents (knockout mice), resulting in atherosclerotic plaque formation and elastic fiber fragmentation.⁹

These models, despite being histopathologically similar to aneurysms observed in humans, are not appropriate for studies of endovascular treatment because they are small-sized animals with very distinct cardiovascular physiology, which makes endovascular device delivery practically impossible, as well as extrapolation of results.

The choice of experimental animal plays a crucial role in this process. In addition to characteristics inherent to the species, concerning management, weight gain, size and costs, attention should be drawn to characteristics regarding vascular response to lesion, fibrinolytic system and coagulation. Comparing one of these variables that may have a behavior very distinct from that observed in humans could create an important bias in the study. Comparative studies have demonstrated that the fibrinolytic and coagulation systems of nonhuman primates are more similar to the human system than those of dogs and swine.¹⁰ Animals commonly used in arterial aneurysm models include swine, dogs and, rarely, sheep.

Dogs have been used as experimental models in a large number of studies, probably because these animals proved to be easy models to perform noninvasive tests, such as ultrasound control and blood pressure measurement, showing limited growth and peripheral arteries with adequate diameter. Additionally, the Ad Hoc Committee of the Joint Councils of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery (North American Chapter) recommended the use of canine models in preclinical trials of vascular prostheses. According to the committee, dogs have two important characteristics: poor endothelialization of prosthetic surfaces and unpredictable trend toward hypercoagulability. These characteristics are important during thrombogenicity testing of new devices.¹¹ However, certain opposition arises within the society regarding the use of domesticated animals as experimental models, and animal costs have increased considerably. Moreover, the fibrinolytic system of dogs is very efficient, which may interfere with experimental results.¹⁰

Although swine and sheep are not appropriate for repeated measurements, they have a more competitive price than that of dogs. Sheep models are less used despite having relatively large-diameter arteries and a coagulation system similar to that of humans.

Swine arterial morphology is very similar to that of humans. These animals show a trend toward hypercoagulability and their fibrinolytic system is not as efficient as that of dogs. As dogs, swine have peripheral arteries with adequate diameter for introduction of endovascular devices. In Landrace swine, aged between 10 and 12 weeks, common femoral artery ranges from 3 to 5 mm in diameter, abdominal aorta from approximately 6 to 12 mm, and thoracic aorta has around 14 mm. Swine arterial walls are delicate and deeper in the inguinal region, thus manipulation should be careful. Abdominal aorta should be exposed retroperitoneally since the large intestine will hinder transperitoneal exposure, as well as abdominal closure. Canine aorta can be easily approached transperitoneally.¹

Neointimal structure is very similar in humans, dogs and swine. Both the number of cells and proteoglycan composition and matrix are essentially the same. However, response to vascular injury is dramatically different.^12,13 As previously mentioned, endothelial response of dog models is milder, whereas in swine models the trend toward hypercoagulability and excessive hyperplasia could lead to less encouraging results.¹⁰ The choice of the most suitable animal should, therefore, take into account not only the animal's characteristics but also the objectives of the study and the conditions of the experimental setting.

Aneurysm models

Models used to assess technical aspects, efficacy and biocompatibility of both thoracic and abdominal endoprostheses have already been described. The aneurysm patch is the most common model. Initially, focusing on the feasibility of aneurysm exclusion by endovascular stents, some relatively simple models were created. The development of endovascular treatment has encouraged the creation of models focusing on the study of specific features concerning endovascular treatment, such as migration, leakage, endotension, and study of the aneurysm neck. Some very useful models have already been developed, most of them in the abdominal aorta. The animals most commonly used are dogs and pigs. Major surgical risks include prolonged clamping that leads to paraparesis or paraplegia, hemorrhage and rupture.¹

Arterial wall patch

Due to a set of characteristics, including simple, rapid and safe manufacture, this is the model most frequently used. Models are manufactured in different animals, such as dogs, sheep and pigs. Materials vary greatly, including polyester, muscle fascia, peritoneum, jejunum, veins or polytetrafluorethylene (PTFE). The advantage of using an autologous material, such as fascia and jejunum, lies in the possibility of a progressive aneurysm increase and rupture, as observed in human aneurysms.

The following steps are performed: aorta is clamped and lumbar or intercostal thoracic arteries are controlled with double repairs. Longitudinal aortotomy is followed by patch suture on the arterial wall and consequent clamping release. Both transperitoneal and retroperitoneal approach can be performed. Before (endovascular or conventional) intervention, an intervening period of 3 to 12 weeks is needed for animal recovery and tissue healing.^6,14-19

This model offers additional advantages such as the possibility to manufacture large-sized aneurysms, allowing the study of the resistance to kink of the endovascular device inside the aneurysm sac. Preservation of lumbar or intercostal thoracic arteries allows the study of the perfusion of the aneurysm sac by retrograde flow (endoleak) and a potential shrinking aneurysm. Materials already used in this technique include polyester,^14,20 abdominal fascia^14,15 with or without peritoneum,¹⁶ jejunum,^17,18 iliac vein,²¹, or bovine pericardium.¹⁹ Spontaneous thrombosis or profuse mural thrombus formation of nontreated aneurysms was not observed in this experimental model when polyester^14,20 and jejunum^17,18 were used.

Synthetic material (polyester) was used in most cases, with low operative mortality rate, around 7%. However, periprosthesis reaction seems to occur more often in dogs, resulting in hydronephrosis and renal insufficiency due to ureteral involvement, in addition to intestinal obstruction.¹⁴ Shrinking aneurysm was not observed after its exclusion in the cases in which synthetic material was used.

A more complex model was described by Uflacker,²² in which, after creating the aneurysm by suturing the polyester pocket on the anterior wall of the abdominal aorta in Yucatan pigs, a stent-graft was used to exclude the aneurysm, and the aneurysm sac was filled with a polymer (DEAC-glucosamine). The objective was to demonstrate endoleak prevention by filling of the aneurysm sac with polymer. Two animals developed paralysis of the hind limbs, and aneurysm sac shrinkage was observed only after 6 weeks.²²

Aneurysms created from fascia patches of the abdominal rectum show higher morbidity and mortality rates, ranging from 11 to 33%.^14-16,23 Main causes were paraplegia, fatal hemorrhage after defects during anastomosis or aneurysm rupture, in addition to hematoma in the site of patch removal. Aneurysm rupture occurred in approximately one third of all animals within 3 weeks.^14,15,23 These aneurysms tend to grow during follow-up. There was no thrombus formation in such aneurysms, but shrinkage was observed after stent-graft placement excluded the aneurysm.^15,16,23 This unfavorable outcome probably results from the fact that the fascia has dominant-oriented fibers, hindering patch suture and, consequently, leading to a longer arterial clamp time. Such difficulties are not reported when a vein is used as a patch.^21,24 The latter showed diameter growth in approximately 19% of the cases during follow-up. After endovascular lesion exclusion, a 10% diameter reduction was observed and, as expected, a total thrombosis within the vascular lumen.²¹

Models using jejunum patch have greater tendency toward rupture.^17,18 Most aneurysms (88%) ruptured between 18 hours and 11 days after creation. Even after exclusion, they showed high risk for rupture in the presence of leak. Due to the great surgical trauma, morbidity rate reached 45%. Aneurysms successfully excluded exhibited intense shrinkage, including total disappearance of the aneurysm sac.¹⁷

Bovine pericardium has already been used in the creation of a common iliac artery aneurysm saccular model.¹⁹ The inexistence of arterial branches facilitated aneurysm manufacture, but also represented a limitation since only type II endoleaks could be studied. Easy handling, low costs, and material stability were points underscored by the authors. Ruptures were not reported, and the aneurysms created showed endothelialization, although mural thrombi were not observed.

Graft interposition

In these models, an arterial segment is resected and replaced with a graft made of polyester,^25,26 polyurethane,^27-30 or even an autologous vein.²⁸

When we use a premanufactured material, such as polyester and polyurethane, aneurysm dimensions are predetermined, and its behavior is considered relatively stable. When the harvested arterial segment is long, the degree of difficulty in the technique increases, as well as morbidity of this procedure. Mortality rates range from 12 to 60%, probably due to a longer arterial clamp time, greater bleeding, and lumbar artery attachment.^25,27,31

Experimental models have gradually developed to mimic specific situations, especially leaks. In such cases, the leak is produced via a prosthesis defect, retrograde branch flow or from proximal and distal fixation points of the device, thus keeping perfusion of the aneurysm sac.^31-33

Elastase-induced models

Although this model shows characteristics similar to those found in human aneurysms, its feasibility in large-animal models, which could undergo endovascular treatment, is complex. Elastase determines the progressive development of the fusiform aneurysm as a result of immune-mediated elastin destruction. We can observe destruction of the elastic lamina and inflammatory cell infiltration in the medial layer.^34-36 A model with such characteristics has already been produced in dogs, infusing saline solution with porcine elastase into the abdominal aorta, after lumbar artery attachment and clamping, for 1 hour.³⁷

Technical challenges in the production of this model have already been addressed. Such difficulties were later confirmed, when another research team failed to reproduce the technique, observing aortic thrombosis in 67% of the animals.³⁸

Transluminal dilation

Minimal surgical trauma is an advantage of this method. The first model was created accidently through a lesion on a canine aortic wall using a catheter.³⁹

Thereafter, attempts were based on exaggerated balloon dilation of the aortic wall. Surprisingly, 90% thoracic aorta dilation and 110% abdominal aorta dilation resulted in only 15% of lumen increase in the first and 40% in the second. Dilation caused rupture of the medial and intima layers, whereas the adventitial layer, although with small hemorrhages, remained intact. Additionally, subsequent intimal hyperplasia prevented aortic growth.⁴⁰

The problem was resolved by using a stent and 200% dilation of both (aorta and stent).⁴¹ Although the angiographic outcome was interesting, similarities between the produced aneurysm and human aneurysms are limited.

Unprofitable attempts

Exaggerated-diameter balloon dilation of the aortic wall may result in rupture, with fatal consequences.⁴⁰

Direct aortic approach, causing mechanical lesions by injection of toxic agents or liquid CO₂, could not produce effective models.⁴² Although there is a report of an effective aneurysm model by resection of the adventitial layer and 70% of the medial layer,⁴² the results of this model could not be reproduced later, and an additional balloon angioplasty procedure was needed for aortic segment dilation.⁴³

In vitro

Parameters can be controlled by direct approach in this model. The model is composed of an artificial aneurysm, connected to a tube system, in which liquid is pumped, with pressure- and volume-controlled pulsatile pumps.

In these models, the aneurysm is composed of latex or polytetrafluorethylene, and the system has transducers for pressure and volume measurement. These models are useful in the investigation of pressure transmission through the aneurysm wall, with total or partial aneurysm exclusion. The contents of the aneurysm sac can be replaced with gelfoam or thrombus to investigate the effect of attenuate pressure.^44-47 Such model can be useful in understanding hydrodynamics and other physical processes to which the aneurysm is submitted during exclusion.

Conclusion

An experimental model that can mimic the main features of human aneurysms, such as atherosclerosis, thrombosis and histopathological changes, is yet to be developed. Some models, however, have demonstrated to be appropriate for the study of specific points in the pathological process involving aneurysmatic disease.

In addition to using models for the study of treatment outcomes and the disease itself, a need for skills training of inexperienced endovascular surgeons underscores the importance of using animal models.⁴⁸

Aortic aneurysm models with short, crooked or conical neck would have potentially great practical utility, since these situations are actual challenges to vascular surgeons. Such models, however, have not been described.

Additionally, a fast-paced technological development of endovascular devices and ethical implications resulting from their use should further encourage researchers to develop experimental models more closely resembling aneurysmatic disease.

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Publication Dates

• Publication in this collection
  02 Oct 2009
• Date of issue
  June 2009

History

• Received
  10 Oct 2008
• Accepted
  30 Jan 2009