The pathophysiologic basis of abdominal aortic aneurysm progression: a critical appraisal

Abstract

An aneurysm of the abdominal aorta is a common pathology and a major cause of sudden death in the elderly. Currently, abdominal aortic aneurysms (AAAs) can only be treated by surgery and an effective medical therapy is urgently missing. The pathophysiology of AAAs is complex and is believed to be best described as a comprehensive inflammatory response with an accompanying proteolytic imbalance; the latter being held responsible for the progressive weakening of the aortic wall. Remarkably, while interference in inflammatory and/or proteolytic cascades proves highly effective in preclinical studies, emerging clinical studies consistently fail to show a benefit. In fact, some anti-inflammatory interventions appear to adversely influence the disease process. Altogether, recent clinical observations not only challenge the prevailing concepts of AAA progression, but also raise doubt on the translatability of findings from rodent models for growing AAA.

Four Surgical Modifications to the Classic Elastase Perfusion Aneurysm Model Enable Haemodynamic Alterations and Extended Elastase Perfusion

“…2,3 Activation of the innate immune system and the phenotype change of vascular smooth muscle cells represent compensatory vascular wall repair mechanisms. 4,5 However, this is observation based on tissue from end stage disease, yet lacking the final clue for the initial stimulus of aneurysm formation. Thus, clinical studies targeting such mechanisms have been unable to abrogate the natural course of disease, prevent rupture, or alter aneurysm growth.…”

“…1B). 2,5,13 However, the fusiform shape, restricted to the infrarenal aorta, only partly mimics human aneurysm morphology, and studying the influence of haemodynamics, such as aortic outflow, is currently not possible. 14e16 In this study, the aim was to improve the current shortcomings of the classic PPE model by microsurgical modifications enabling aortic and iliac flow modulation and elastase perfusion of segments other than the infrarenal aorta in order to mimic different human aneurysm morphologies for translational research.…”

Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation

“…9 Yet, despite overwhelming evidence of an inflammatory process in AAA, anti-inflammatory therapies aimed at some targets identified in preclinical models have not resulted in consistent AAA stabilization in clinical studies. 10 Therefore, further research is needed to identify and validate additional pathways that participate in aneurysmal process.…”

Editor's Choice – Pharmaceutical Management of Small Abdominal Aortic Aneurysms: A Systematic Review of the Clinical Evidence

“…45 The second of the tested interventions was the antiinflammatory group, with anti-inflammatory referring to an anti-microbial action, in the case of AAA because of a suspected causative role for chlamydia infection in the disease, or alternatively anti-inflammatory in the context of chronic tissue inflammation that is thought to drive AAA progression (doxycycline, mast cell inhibition). 46 Although aspirin has anti-inflammatory properties, it is unclear whether the dose used for anti-platelet therapy is sufficient to exert an anti-inflammatory effect on the aneurysm wall. Again, there was no evidence for a beneficial effect of antiinflammatory strategies on AAA progression.…”

“…37 The above conclusions contrast sharply with the available preclinical evidence that shows that pharmaceutical interference with aspects of the RAS system, cholesterol metabolism, vascular inflammation or protease activity alleviates aneurysm formation in rodent models of the disease 4,5 ; an observation pointing to impaired translatability of the available preclinical models. 46 In conclusion, there is currently no established medical therapy for the stabilization of growing AAA. Interpretation of the available data is hampered by its moderate quality.…”