An age of 55 years at 4-7% –

An Abdominal aortic aneurysm (AAA) by definition is a permanent localised loss of arterial wall parallelism and is the product of a progressive disease that increases the arterial diameter which if ruptured, can cause sudden death. The incidence of the disease is associated with lifestyle related risk factors such as smoking but also increases with age to become most prevalent in men over the age of 55 years at 4-7% – making AAA the 10th leading cause of death in the U.S (Davis, Rateri and Daugherty. 2014). Despite this, the current therapeutic armamentarium remains inadequate; offering only close surveillance and open or endovascular repair – both of which are very costly. In order to develop therapies and preventatives against the disease, the pathobiology behind its formation and progression must be fully understood but there is still a paucity in this knowledge.AAA PathobiologyIn conductance arteries such as the abdominal aorta, the flow of blood exerts pressure upon the intraluminal walls, but they withstand this pressure through continuous production of an extracellular matrix (ECM) by vascular smooth muscle cells (VSMC) of the media. However, if the adventitial lining becomes disrupted through hypertension or trauma, an inflammatory cascade is instigated through the recruitment of macrophages and pro-inflammatory mediators. Macrophages together with apoptotic VSMCs produce proteolytic enzymes that degrade and disorganise the ECM of the artery wall which is the most widely accepted cause of triggering AAA development. As a result, intraluminal thrombi (ILT) can develop which release endogenous proteases to activate the fibrinolytic system and the destructive matrix metalloproteinases (MMP) (Davis, Rateri and Daugherty. 2014). Consequently, the wall is thinned, and its strength is compromised which expands the diameter of the aorta – increasing the risk of a life-threatening ruptured aneurysm.Animal models of AAATo explore the disease initiation, animal models can be used as they offer an opportunity to imitate the inflammatory cascade above and destructive determinants of an AAA which cannot be examined through end-stage human AAA tissue segments acquired through surgery. However, animal models are also limiting as they exhibit characteristics that manifest within weeks rather than the decades it takes to develop a human AAA and so their contribution to the understanding of aneurysm development is limited. Elastase Perfusion ModelFirst developed in 1990, the elastase model involves aortic dilatation through perfusion of a clamped infra-renal portion of the aorta with elastase as shown in Figure 2 (Anidjar, et al. 1990). The rationale for the elastase model comes from the artery walls dependence upon elastin to provide its structural integrity, and it is known that during AAA progression this elastin is disrupted and so elastase in this model exploits this vulnerability and penetrates the medial layer to injure elastic fibres.Studies using elastase have shown hallmark features of a human aneurysm including ILT formation, elastin degradation and infiltration of the media by macrophages and leukocytes (Poulson, Stubbe et al. 2016).The advent of endovascular treatment using stenting for AAAs and the use of imaging techniques such as ultrasound to monitor AAA expansion rendered rodent models translationally inadequate due to their physical constraints and so there was an increased need for larger animal models that anatomically imitate a human aorta for interventional testing (Matsushita, Kobayashi, et al. 1999). Correspondingly, the elastase model was utilised in the dog and rabbit to successfully develop an aneurysm, but the likelihood of successful translation to the clinic is doubtful as neutrophils dominate the AAA of these larger animals which is very dissimilar to the human AAA biology (Furubayashi, Takai, et al. 2007).Calcium Chloride ModelSimilar to the elastase model, the Calcium Chloride (CaCl2) model is proposed to also target elastin (fig.3) by applying a gauze soaked in CaCl2 to the peri-aortic infra-renal portion of the aorta, however this requires major surgery (Wang, Krishna and Golledge. 2013). Modification of this model with the addition of thioglycollate promotes calcification, but it does not exhibit many other features of the disease as shown in the table below and so its applicability is finite (Liu. 2012).Angiotensin II ModelThe Angiotensin II (AngII) model in mice is now the most common rodent model thanks to a huge global shift in recent years from the use of the elastase model (Fig 4). This model is favourable as it is technically simple and uses the well-established hyperlipidaemic apolipoprotein E deficient or LDL receptor deficient mouse strains, however it is time consuming and expensive. Angiotensin II in these mice strains stimulate a nitric-oxide dependent intracellular signalling pathway in endothelial cells; impacting the cells permeability and causing an immediate inflammatory response of macrophages within the intima (Senemaud, Caligiuri, et al. 2017). Such infiltration triggers ECM proteolysis, medial hypertrophy and thrombosis – all features of a Human AAA (Daugherty, Cassis et al. 2004). The huge advantage of this model is the ability to closely manipulate the genetic background, infusion and diet to develop atherosclerosis which is not seen in other models of AAA. This atherosclerotic milieu allows for exploration of the specific pathophysiological role of lipids and obesity in AAA development. However, the AngII model is limited by the 20% mortality rate during infusion and its topography, as these aneurysms develop supra-renally which is unlike that seen in the human and other models (Fig. 5).ConclusionDespite decades of work to elucidate the perpetrating factors behind the triggering, progression, and subsequent rupture of an AAA, there is still a shortcoming in the molecular understanding. Animal models continue to provide an intriguing insight into individual biochemical contributions to an aneurysm such macrophage infiltration, but their use is limited as none reproduce the natural history and all of the histological features necessary to perfectly mimic a human AAA. Hence, to date, animal models have failed to influence clinical practice and so their translational relevance remains questionable, but perhaps the specificity of these models and others will allow innovative therapeutics targeting distinct pathophysiological mechanisms of AAAs to be developed in the future.