Understanding the pathogenesis of abdominal aortic aneurysms

Abstract

An aortic aneurysm is a dilatation in which the aortic diameter is ≥3.0 cm. If left untreated, the aortic wall continues to weaken and becomes unable to withstand the forces of the luminal blood pressure resulting in progressive dilatation and rupture, a catastrophic event associated with a mortality of 50-80%. Smoking and positive family history are important risk factors for the development of abdominal aortic aneurysms (AAA). Several genetic risk factors have also been identified. On the histological level, visible hallmarks of AAA pathogenesis include inflammation, smooth muscle cell apoptosis, extracellular matrix degradation and oxidative stress. We expect that large genetic, genomic, epigenetic, proteomic and metabolomic studies will be undertaken by international consortia to identify additional risk factors and biomarkers, and to enhance our understanding of the pathobiology of AAA. Collaboration between different research groups will be important in overcoming the challenges to develop pharmacological treatments for AAA.

Keywords: animal models; doxycycline; embryologic origin; epigenetics; extracellular matrix; genetic susceptibility; inflammation; matrix metalloproteinases; risk factors; smoking.

Figure 1. Regional variation in the aorta of embryologic origin, structure and disease susceptibility

Different parts of the aorta are from different embryologic origin. Disease susceptibility also varies, with the infrarenal abdominal aorta being more prone to atherosclerosis and aneurysm formation than the thoracic aorta. VSMC—vascular smooth muscle cell. Modified and reproduced with kind permission from Springer Science+Business Media:Tromp et al. [6].

Figure 2. Genetic map of non-syndromic thoracic and abdominal aortic aneurysms

Underlying genetic factors contributing to the aneurysmal diseases differ based on the site of the clinical manifestation. Vertical lines adjacent to the chromosome ideograms indicate regions identified by DNA linkage studies, and round symbols indicate locations of SNPs found in genome-wide (GWAS) or candidate gene association studies. See Supplementary Table for details on the studies. The ideograms can be obtained from “Idiogram Album: Human” (copyright^© 1994 David Adler, University of Washington, Department of Pathology) at http://www.pathology.washington.edu/research/cytopages/idiograms/human/.

Figure 3. Summary of the pathogenesis of AAA

Several biological processes and risk factors have been identified that contribute to AAA pathogenesis. Genes in the biological pathways have been used in candidate gene studies. VSMC, vascular smooth muscle cell; ECM, extracellular matrix; ROS, reactive oxygen species; MMPs, matrix metalloproteinases. Reproduced with permission from Boddy et al. Drug News Perspect 2008, 21(3): 142–148 [37]. Copyright © 2008–2015 Prous Science, S.A.U. or its licensors. All rights reserved. DOI: 10.1358/dnp.2008.21.3.1203410.