Expert Review of Cardiovascular Therapy

ISSN: 1477-9072 (Print) 1744-8344 (Online) Journal homepage: http://www.tandfonline.com/loi/ierk20

Understanding the pathogenesis of abdominal aortic aneurysms Helena Kuivaniemi, Evan J Ryer, James R Elmore & Gerard Tromp To cite this article: Helena Kuivaniemi, Evan J Ryer, James R Elmore & Gerard Tromp (2015) Understanding the pathogenesis of abdominal aortic aneurysms, Expert Review of Cardiovascular Therapy, 13:9, 975-987, DOI: 10.1586/14779072.2015.1074861 To link to this article: https://doi.org/10.1586/14779072.2015.1074861

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Published online: 25 Aug 2015.

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Understanding the pathogenesis of abdominal aortic aneurysms Downloaded by [University of New England] at 11:38 26 November 2017

Expert Rev. Cardiovasc. Ther. 13(9), 975–987 (2015)

Helena Kuivaniemi*1–3, Evan J Ryer4, James R Elmore4 and Gerard Tromp1,3 1 Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA 17822, USA 2 Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA 3 Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa 4 Department of Vascular and Endovascular Surgery, Geisinger Health System, Danville, PA 17822, USA *Author for correspondence: Tel.: +21 219 389 251 Fax: +21 219 389 863 [email protected]

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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 susceptibility

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. embryologic origin . epigenetics . extracellular matrix inflammation . matrix metalloproteinases . risk factors . smoking

The aorta is generally subdivided into its thoracic and abdominal components (FIGURE 1). The thoracic aorta is further classified into the ascending aorta, aortic arch and descending thoracic aorta, while the abdominal aorta spans the distance between the diaphragm and the aortic bifurcation. An aortic aneurysm is a permanent localized dilatation associated with a diameter ‡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. Rupture risk increases with increasing aortic diameter, and this catastrophic event is associated with a mortality of 50–80% [1]. Aortic aneurysms can develop in both the thoracic and the abdominal aorta (FIGURE 1), albeit more patients have and undergo surgery for aneurysms of the abdominal aorta [2,3]. Abdominal aortic aneurysms (AAAs) can be further categorized into supra-renal or para-visceral aneurysms if they involve the visceral arteries, para-renal if they involve the origins of the renal arteries or infra-renal if they begin lower than the renal arteries [4]. The majority of AAAs are infra-renal in extent [5]. Historically, thoracic

10.1586/14779072.2015.1074861

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genetic

aortic aneurysms (TAAs) and AAAs were thought to both arise from atherosclerotic degeneration of the aortic wall. More recent research, however, has demonstrated that these diseases are distinct disease entities [6]. Differences in the thoracic & abdominal regions of the human aorta

To better understand how the pathophysiology of thoracic aortic aneurysms (TAAs) and AAAs differs, it is helpful to begin by examining the embryology of the aorta. Different segments of the aorta are composed of cells originating from the neural crest, mesenchyme and splanchnic mesoderm, with a clear difference depending upon the segment (FIGURE 1). The early embryo develops a common set of precursor vessels that differentiate into arteries, veins and lymphatic vessels. Primitive arteries are surrounded by smooth muscle cells (SMCs) of mesodermal origin. Following extensive remodeling, the original primitive SMCs of the aortic arch and the thoracic aorta are replaced by a second wave of SMCs that migrate from the neural crest [7]. These neural crest-derived SMCs are likely better suited to

 2015 Informa UK Ltd

ISSN 1477-9072

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Kuivaniemi, Ryer, Elmore & Tromp

when continuously infused led to aneurysms of the suprarenal abdominal aorta in mice deficient in the gene for apolipoprotein E (Apoe–/–) without effect on the thoracic aorta [13]. This study, too, highCharacteristics lights the differential response of the cells Aneurysm sites comprising the thoracic aorta when compared with the abdominal aorta. A final example is TGF-b, which is an estabAortic arch lished contributor to vascular development and regulator of cell growth and More distensible Elastin:Collagen 2:1 differentiation. When treated with Vascular outer media TGF-b, neural crest VSMCs demonstrated increased DNA synthesis and colDescending lagen production, while mesodermal thoracic aorta VSMCs did not respond [14]. This may explain why mutations in the TGF-b receptor may lead to TAA but have little effect on the abdominal aorta. Abdominal Less distensible Corresponding to their differing aorta Fewer lamellae embryology, the thoracic and abdominal Elastin:Collagen 1:2 aortas are also structurally very different Avascular media Persistent from one another. Both the thoracic and Greater plaque sciatic artery deposition abdominal aortas are elastic arteries that consist of an intimal, medial and adventitial layer. The intima is a single layer of endothelial cells upon connective tissue, the media consists of SMCs embedded in structural proteins (elastin and collagen), Popliteal Embryologic artery while the adventitia is composed of fibrosciatic artery blasts and collagen fibers [15]. The aorta, regardless of the location, is dependent Figure 1. Regional variation in the aorta of embryologic origin, structure and upon distinct fibromuscular layers (sodisease susceptibility. Different parts of the aorta are from different embryologic origin. Disease susceptibility also varies, with the infrarenal abdominal aorta being more called lamellar units) to distribute stress prone to atherosclerosis and aneurysm formation than the thoracic aorta. and provide elasticity. The media of the VSMC: Vascular smooth muscle cell. thoracic aorta comprises ~60 units Modified and reproduced with kind permission from Springer Science+Business Media: divided into avascular and vascular Tromp et al. [6]. regions. On the other hand, the abdominal aorta consists of ~30 units and is adaptively remodel the thoracic aorta to withstand the higher entirely avascular. In addition to being less substantial with pulse pressure and ejection volume by laying down more elastic regard to the number of fibromuscular layers, the media of the lamellae during development and growth. In contrast, the epi- abdominal aorta is completely dependent on transintimal diffugenetic programming of the SMCs in the abdominal aorta sion of nutrients for survival of SMC [16]. It is likely that the remains more similar to that of the original primitive arterial fewer lamellar units and avascular nature make the abdominal SMCs [6]. Moreover, the neural crest cell precursors of the tho- aorta more prone to aneurysmal degeneration. racic aorta respond differently to various cytokines and growth Finally, there are genetic differences in underlying aneurysms factors than the mesodermal precursors of the abdominal of the thoracic and abdominal aortas (FIGURE 2; SUPPLEMENTARY TABLE aorta [8]. One well-known example is homocysteine, a sulfur- [supplementary material can be found online at www.informacontaining amino acid involved in atherosclerosis, elastolysis, healthcare.com/suppl/14779072.2015.1074861]). While there collagen deposition and aortic compliance [9,10]. Homocysteine is a 10–15% chance of an individual with an AAA having a has been found to stimulate the proliferation and synthetic metachronous or synchronic TAA [17], most family-based studactivity of neural crest vascular smooth muscle cells (VSMCs), ies have demonstrated a predisposition for either aneurysmal while those of mesodermal origin are unaffected [11]. Another involvement of the thoracic or abdominal aorta, but not example is angiotensin II (Ang II), a vasoactive peptide associ- both [18]. Indeed, most recent genetic studies show no genetic ated with vascular remodeling and atherosclerosis [12], which overlap between AAA and TAA.

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Embryologic origin of VSMC Neural crest Somites Splanchnic mesoderm Adaptively remodeled

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Understanding the pathogenesis of abdominal aortic aneurysms

Clinical features of AAA

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Clinical picture & risk factors for AAA

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Genetic loci Thoracic aortic aneurysm Abdominal aortic aneurysm Vascular disease risk locus

The main risk of an untreated AAA is progressive expansion, rupture, hemorrhage and death. Despite advances in screening and treatment, AAA rupture remains a major cause of death in the elderly. A recent review of 3 million patients undergoing a medical and lifestyle questionnaire prior to ultrasound screening found that smoking is by far the strongest modifiable risk factor for AAA [19]. In addition, other important risk factors including age, male sex and family history were confirmed [19]. In this 1 2 3 4 5 6 9 10 11 12 15 16 17 19 study, Kent et al. [19] went on to construct a predictive scoring system to idenFigure 2. Genetic map of non-syndromic thoracic and abdominal aortic tify AAA. Applying this model to US aneurysms. Underlying genetic factors contributing to the aneurysmal diseases differ based on the site of the clinical manifestation. Vertical lines adjacent to the chromosome population statistics, these investigators ideograms indicate regions identified by DNA linkage studies, and round symbols indiestimated that there are ~1 million AAAs cate locations of SNPs found in genome-wide (GWAS) or candidate gene association in the USA, of which half were women, studies. See Supplementary Table for details on the studies. The ideograms can be nonsmokers and those less than 65 years obtained from “Idiogram Album: Human”. of age. This translated to an overall prev 1994 David Adler, University of Washington, Department of Pathology) at www.pathology.washington.edu/research/cytopages/idiograms/human/. alence of AAA of 2.8% for men aged 65–79 years. These numbers advocate for a broader application of AAA screening to reduce mortality prevalence of AAA in those with a family history, patients with from ruptured AAA. In contrast, an AAA screening program in a positive family history had a significantly larger mean aortic Sweden found a lower prevalence of AAA, suggesting that there diameter (20.5 mm) compared with those without a family hishas been a change in AAA epidemiology [20]. In this study, tory (p < 0.001). A unique finding of this family history study Svensjo et al. [20] examined all 65-year-old males, identified was that a positive family history with female relatives with an through a National Population Registry, who underwent ultra- AAA had a more than a twofold increase in the prevalence of sound screening for AAA. In total, 22,187 patients were AAA when compared with those who had a positive family hisscreened and 373 AAAs (1.7%) were identified. When account- tory with male relatives with AAA (odds ratio [OR] = 2.65, ing for 127 known AAAs undergoing surveillance, the 95% CI: 1.37–5.13). In addition to an increased AAA prevainvestigators calculated an AAA prevalence of 2.2%. Similar to lence in those with a positive family history, a positive family the study by Kent et al. [19], smoking was again the most history may also be responsible for accelerated growth, and posimportant risk factor for AAA. In contrast to the study by sibly rupture, of small (

Understanding the pathogenesis of abdominal aortic aneurysms.

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 ...
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