Sudden death resulting from rupture of an aneurysm is strongly related to AAA [11]. Although the introduction of EVAR has significantly reduced the risk of periprocedural morbidity and mortality, the identification and validation of effective medical therapies to suppress progression of early AAA remains a significant unmet medical need [12]. For patients where repair is not indicated, the current recommendation is clinical follow-up with observations performed regularly to limit the progression of AAA [7, 8]. Unfortunately, even though most AAAs are identified at an early stage of the disease, no medical intervention, including aggressive attempts to modify conventional cardiovascular risk factors, has proven effective in limiting progressive diameter enlargement or eventual rupture [12, 13]. Considering that patients with small AAA are often treated surgically due to aneurysm enlargement or signs of rupture during follow-up [7], there is an urgent need to understand the development of AAA and to identify drugs targeting the progressive expansion of the disease [7].
Animal models are useful strategic tools to investigate the mechanisms underlying the formation and development of AAAs [2, 11]. To date, several animal models including the elastase (PPE) model, the calcium chloride model, the angiotensin II model, the xenograft model, and the transgenic model of AAA have been introduced in rodents [2, 7, 11]. Among these models, the PPE model has been used most extensively due to high reproducibility in smaller animals and the occurrence of dilatation at 1 week following induction, though this model requires technically difficult major surgery [7, 9–11]. In the current study, we induced the PPE model of AAA in rats [7, 9, 10]. A comparison of control (group I) and PPE injected (group II) groups indicated that AD3 was significantly larger in group II compared with group I, and AD3/AD1 was significantly higher in group II compared to group I. These results suggest that the PPE model of AAA was effectively induced. TG was significantly higher in group I compared to group (II to IV). The difference between group I and group II to IV was whether PPE was applied or not. And, a report suggested that there could be possibility of correlation between lipid and cation contents and susceptibility to elastolysis [14]. So, we suggest that we need to evaluate an effect of PPE on TG through further study.
With recent deepening of research in vascular pathophysiology and molecular biology, pathological changes of AAA wall including vascular SMC apoptosis, oxidative stress, chronic inflammation, as well as over-degradation and remodeling of ECM have been described [2, 7, 15]. Medial degeneration with simultaneous destruction of SMC and elastic lamellae is a pathognomonic sign of human aneurysmatic aorta and is evident in all AAA induction studies using animal models [2, 7, 10]. Evidence suggests that the inflammatory process is essential for AAA formation in humans and that certain inflammatory mediators including matrix metalloproteinase (MMP)-2 and MMP-9, plays a key role [2]. The inflammatory reaction is important for the development and progression of AAA and stimulates effects including chronic inflammation, ECM deterioration, and vascular structure remodeling [10, 16]. This inflammatory process is evident in aorta harvested from animals subjected to chemical induction [2]. Pathophysiological research has focused on the impact of changes in the expression of elastin-degrading enzymes on human and experimental AAA, especially MMPs, thiol proteases, and their respective inhibitors [10]. Atherosclerosis is a common underlying pathophysiologic phenomenon in coronary, peripheral and aneurysmal disease, and plays a role in AAA development in humans. Similarly, certain induction methods in animals seem to activate the formation of atherosclerosis as well [2, 17]. Furthermore, atherosclerosis is related to increased intra-aortic thrombus formation, another process related to the development of AAA in humans, and macrophages have been found to participate in aortic diseases including atherosclerosis and AAA. Several histopathological features of AAA resemble those of atherosclerosis, including macrophage infiltration, cholesterol-loaded macrophage-derived foam cells, apoptotic macrophages, and SMC senescence [10]. In the current study, among PPE injected groups (group II to IV), AD3 was significantly larger in group III (hypercholesterol group) compared to group II (normocholesterol group), and AD3/AD1 was significantly higher in group III compared to group II. Similarly, inflammatory cellularity was significantly greater in group III compared to group II. Taken together, these results suggest that cholesterol was proportionally associated with inflammation of aortic wall and expansion of AAA.
Unfortunately, there are no current pharmacotherapies proven to attenuate the rate of progression and minimize the rupture risk of AAA [17]. Several studies have demonstrated that statins (lipid-lowering agents) reduce vascular inflammation and can stimulate atherosclerotic plaque regression [17, 19, 20]. The reduction of vascular inflammation has been shown to address a key pathophysiologic collagenolytic pathway involved in AAA progression [16, 17]. Furthermore, statins have been shown in both animal and human studies to reduce collagen breakdown by stabilizing imbalances in MMPs and tissue inhibitors of MMPs [17, 21]. Salata et al [22], suggested that statin application would not only reduce the growth rate of AAA but could also reduce the risk of mortality in patients undergoing open repair perioperatively. Although the underlying mechanism has not been well understood thus far, statin application has exerted protective effects on the endothelial function, inflammatory reaction, oxidative stress, thrombosis and plaque stability, affecting the occurrence of cardiovascular complications and the progression of AAA [23, 24]. Luan et al [25], demonstrated that statin application would alter the inflammatory environment of aneurysm inflammation, rather than directly lowering the blood lipid levels. Evidence both in vitro and in vivo found that statin therapy downregulates the expression of metalloproteinase [23, 25]. The current study found that between hypercholesterol groups (group III and IV), AD3 was significantly larger in group III (statin(-)) compared with group IV (statin(+)) and AD3/AD1 was higher in group III compared to group II although this difference did not reach statistical significance. Therefore, we suggest that a lipid-lowering agent (statin) plays a role in reducing the expansion of AAA.
There are several limitations. This study presents small sized samples, and provides preliminary data that must be confirmed through larger sampled follow-up experiments to identify the detailed mechanisms [10]. Any similarity between animal models and human aneurysms is based on tissue samples from end-stage disease [2]. Aneurysm formation in humans is a long process, and the underlying pathophysiological process behind it is mostly unknown [2]. This is presented by the fact that results from animal AAA-model studies have consistently been very difficult to be reproduced in humans [2]. The variable animal models used to induce AAAs indicates that no model completely mirrors the human AAA [11]. This is a central limitation with animal models and should be taken into consideration when evaluating the results from AAA animal models [2].