Abstract
Atherosclerotic plaques are a feature of abdominal aortic aneurysms (AAAs). Atherosclerosis and AAA appear to share similar risk factors. These observations have led to the conclusion that AAAs are a consequence of advanced atherosclerosis.
This review explores current theories regarding the pathogenesis of AAA and their implications for treatment.
A systematic literature search was conducted using the search terms abdominal aortic aneurysm, atherosclerosis, pathogenesis, and systemic disease. Articles were categorized according to the association of AAAs with atherosclerosis, arteriomegaly, peripheral aneurysm, systemic expression, genetics, autoimmunity, oxidative stress, and systemic disease. Twenty-nine articles reporting changes in the systemic vasculature associated with AAA and 12 articles examining the shared risk factor hypothesis were identified.
There is insufficient evidence to confirm that AAAs are the result of advanced atherosclerosis. The bulk of evidence points to AAA disease being a systemic disease of the vasculature, with a predetermined genetic susceptibility leading to a phenotype governed by environmental factors.
Abdominal aortic aneurysm (AAA) is a permanent localized dilatation of the abdominal aorta encompassing all three layers of the vessel wall that exceeds the normal diameter by 50%. 1 The underlying problem is a weakening in the aortic wall that leads to progressive dilatation, which, if left untreated, may result in rupture and death. It is estimated to be the tenth most common cause of mortality and accounts for 2% of all deaths 2 ; up to 8% of men over 60 years are now affected. 3 The pathogenesis of AAA remains poorly understood; however, recent evidence has confirmed the significance of a chronic inflammatory process, particularly related to an upregulation of matrix metalloproteinases (MMPs). 4,5
Several significant risk factors for the development of AAAs have been identified. These include male sex, age, family history, and smoking. Whereas hypertension has been shown to increase growth rate in already established AAAs, 3,6 diabetes has been shown to be protective. 7 The incidence of AAA is increasing despite a reduction in tobacco use and an ever-increasing incidence of diabetes. This has led to uncertainty as to the significance of these risk factors in aneurysm pathogenesis. 8
The arterial wall is an organ capable of remodeling in response to hemodynamic, mechanical, and biochemical stimuli. 9 Throughout its lifetime, the living components of the arterial wall must regenerate and remodel continuously to maintain the integrity and function of the system and to withstand the repetitive wall stresses. 10
AAA formation appears to be a focal event, yet patients with AAAs often have aneurysms at sites remote from the abdominal aorta. This initially raised the suspicion that aortic aneurysms are a local representation of a systemic dilating diathesis.
There are three possible models of AAA pathogenesis. First, AAAs could be a purely local disease process confined to the abdominal aorta resulting from atherosclerosis. Second, aneurysms in the aorta may be representative of a systemic dilating diathesis primarily governed by genotype. Third, the changes in the abdominal aorta may be a demonstration of a globally sick or diseased vascular tree as a consequence of a chronic inflammatory process. The three proposed hypotheses are not mutually exclusive. The genotype may influence the inflammatory response, and, equally, the inflammatory cells and mechanical forces may modify gene expression. The evidence for a systemic process with focal manifestation in the abdominal aorta is diverse but as yet not categorical.
In this review, we examine the question of whether AAAs are a consequence of atherosclerosis and explore the argument that AAAs are actually a local representation of a systemic disease of the vasculature.
Literature Search
An initial systematic search strategy of the Medline and PubMed databases was used. The search terms abdominal aortic aneurysm and pathogenesis (limits: human, English, journal articles, within 5 years; articles identified = 1,324), atherosclerosis and abdominal aortic aneurysm (articles identified = 525), and abdominal aortic aneurysm and systemic disease (articles identified = 167). Abstracts were analyzed for relevance, and studies describing or comparing AAA pathogenesis with atherosclerosis were retrieved. Article references were hand-searched for relevant missed papers.
AAAs Secondary to Atherosclerosis
Atherosclerosis is an almost universal finding in the walls of aneurysms. 11 These two pathologies also share the same risk factors, including hypertension and cigarette smoking.
Risk Factors
Several recent studies have called into question the shared risk factor hypothesis linking AAAs to atherosclerosis. Smoking has a much stronger relationship with AAAs than atherosclerosis. 12 Hypercholesterolemia is not associated with AAAs but is strongly linked to atherosclerosis. 13 In the 12 studies, illustrated in Table 1, reporting the epidemiology of AAAs, only 5 identified an association with systemic atherosclerosis.
Risk Factor Associations for Epidemiological Studies of Abdominal Aortic Aneurysm
ABPI = ankle-brachial pressure index; BP= blood pressure; CVD = cerebrovascular disease; HDL = high-density lipoprotein; IHD = ischemic heart disease; LDL = low-density lipoprotein; + = positive association; − = negative association; blank space = not mentioned.
*Refer to Comments column for more information regarding this positive association.
Medical management of hypertension and hypercholesterolemia has improved, and antismoking campaigns continue. Yet the incidence of AAAs continues to rise. This is in contrast to other smoking-related diseases, such as ischemic heart disease (IHD), which have seen a fall in incidence over a similar period. 14 Although it could be argued that the increased incidence of AAAs is due to more widespread intra-abdominal imaging, during this time period, public awareness of cardiac disease has increased, leading to a larger cohort of patients screened for IHD.
Diabetes, a risk factor associated with diffuse atherosclerosis, is inversely related to the presence of AAAs. 12 The Health in Men Study demonstrated an independent negative association between diabetes and AAA diameter in > 12,000 men aged 65 to 83 years (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.63–0.98; p < .05). 15 This finding is reproduced in other cohorts. 12,13
These findings emphasize that atherosclerosis in isolation is not an adequate explanation as the cause of AAAs.
Population
AAAs and atherosclerosis are both more prevalent in men than in women. 16 Aortic occlusive disease (AOD) affects younger men than aneurysmal disease. 1 7,18 Patients with AAAs are predominantly Caucasian and tend to have higher incomes than patients with AOD. 19
Pathology
Atherosclerosis is characterized by increased plaque volume owing to accumulation of a lipid core into the vessel lumen. Migration of smooth muscle cells (SMCs) and macrophages leads to endothelial dysfunction, an increase in intima media thickness, and overall vessel wall thickness. 20 In comparison, AAA involves dilatation of all layers of the arterial wall as a result of loss of elastin and SMC apoptosis. 16,21
The risk factor associations have suggested that AAAs are caused by atherosclerosis. 22 However, the pathobiology of the diseases differs. Symptomatic atherosclerosis preferentially affects muscular small arteries; aneurysms are more prevalent in large elastic arteries. Atherosclerosis is a disease of both the arterial intima and media; aneurysms are a disease of the media. SMC proliferation is typical in atherosclerosis, whereas SMC apoptosis is found in the aneurysmal wall. 23
The natural history of atherosclerotic arterial disease is progressive arterial stenosis leading to occlusion. If atherosclerosis is the initiating event in AAA pathogenesis, it is unclear why some individuals progress to an obliterative disease and others to aneurysmal disease. 24 This dichotomy emphasizes the role of immune or genetic factors in the AAA phenotype.
The finding of atherosclerotic plaques in aneurysm tissue has led to the hypothesis that plaque deposition with localized vessel dilatation and medial thinning predisposes to aneurysm formation. 25 This does not explain why some patients proceed to occlusive disease whereas others develop aneurysmal dilatation. One proposal is that regression of established atherosclerosis leads to aneurysmal enlargement of the aorta. This has been demonstrated in an experimental model of atherosclerotic disease using cynomolgus monkeys. 26 Three groups of animals underwent diet-induced atherosclerosis. After 6 months, one group had diet-induced regression of atherosclerosis. In this group, a twofold increase in abdominal aortic lumen was observed (10.0 ± 1.5 mm 2 vs 5.6 ± 0.7 mm 2 ; p < .05) compared with those animals with progressive atherosclerosis. This study had small numbers of animals and has not been reproduced. The evidence should be interpreted with caution. If regression of plaques predisposes to aneurysmal disease, atherosclerotic plaques may confer protection against aortic dilatation.
The initiating factor for AAAs remains unknown. The essential problem in assigning causality lies in the availability of aortic tissue for histologic analysis. At operation, the tissue represents end-stage disease. Expansive remodeling of peripheral arteries is seen in early atherosclerosis. This adaptive response preserves the luminal area for blood flow but is more pronounced in small peripheral arteries than in the aorta. 27 The adaptive changes are most evident when comparing AAA with AOD. It has been postulated that the difference between AAA and AOD patients lies in the response of both the SMC and neutrophil to early atherosclerosis. In contrast to the “normal” response of the AOD patients, the AAAs have an “abnormal response,” leading to chronic overproduction of elastase. The delivery of an increased amount of proteolytic enzymes to the atherosclerotic injury causes aneurysmal degeneration. 28
On a molecular level, the evidence for an association between AAA and atherosclerosis is mixed. In both aneurysmal and atherosclerotic aortas, type 1 pN-collagen has been shown to be present in the intima, suggesting an association. 29 An increase in type I, alpha I procollagen expression has been reported in AAA but not in atherosclerotic occlusive diseased or normal aortic tissue. 30
Atherosclerosis may lead to early expansive remodeling owing to protease and MMP secretion from an aortic plaque. Yet how this minimally dilated aorta undergoes translation to a clinically relevant AAA is unclear and not explained by atherosclerosis. 31 There is evidence that adventitial inflammation causes SMC apoptosis and proteolytic destruction of the elastic medial connective tissue, leading to AAA formation.
Association of AAAs with Systemic Arteriomegaly
Arteriomegaly was initially deemed a separate entity to aneurysmal disease 32 ; however, now it has become clear that this may be representative of a predisposition to aneurysm formation. 33 Two historical small studies described a 57 to 60% incidence of aneurysms in arteriomegalic patients. 34,35 In both series, popliteal and aortic aneurysms predominated. The risk factors, or associations, for diffuse arteriomegaly include male sex (100%), smoking (76%), ischemic heart disease (60%), and hypertension (59%) 32 -remarkably similar to current known risks for AAAs.
Peripheral arteries are reported to be dilated in aneurysmal disease relative to controls. These included the brachial and distal external carotid arteries, vessels usually immune from atherosclerosis. 36 The findings do lend support to the view that there is a generalized dilating diathesis in aortic aneurysmal disease that may be independent of atherosclerosis.
The alterations in peripheral arteries distant from the aorta may be slight yet significant. The carotid artery is elastic and although exposed to different hemodynamic stresses may be a more sensitive measure of this concept of arteriomegaly. Three studies have reported statistically significant common carotid enlargement in patients with AAAs compared with controls. 37–39 Following adjustment for blood pressure, carotid luminal diameter remained significantly greater in aneurysm patients. Interestingly, a subgroup analysis of patients with ruptured AAA versus nonruptured AAA demonstrated that patients with ruptured AAA had severely reduced carotid distensibility; this was independent of intimal disease or aortic aneurysm size. 37 Reduced AAA wall compliance has previously been shown to relate to aneurysm rupture. 40
Systemic changes in vascular compliance are evident in aneurysmal disease. Common carotid artery stiffness, assessed ultrasonographically, was found to be increased in men (p = .027) and in women (p = .0001) with AAAs to a mean of 131% and 149% of the normal predicted values, respectively. This corresponded with increased aortic stiffness in the aneurysm wall itself. 41 An in vitro study by Goodall and colleagues compared the tensile strength of the inferior mesenteric vein (IMV) in patients with AAAs and controls. 42 The authors found that the IMVs of patients with AAAs exhibited less strength and stiffness than veins from control subjects. Young's modulus of elasticity in the AAA group was 2.72 MPa, compared with 5.36 MPa in the control group (p = .0005). The findings correlated with histologic evidence of reduced volume and integrity of medial and adventitial elastin in the venous tissue from the AAA patients. The medial elastin content determined by stereologic analysis 4 from the AAA group was 19.4% compared with 26.8% in the control group (p = .018). The observed changes were analogous to those in the arterial aneurysmal wall.
Systemic morphologic variations in the vasculature may present as increased vessel tortuosity. An association between the tortuous internal carotid artery and AAA has been found independent of other risk factors. 43
Arteriomegaly, carotid arteriomegaly, carotid tortuosity, and AAAs all share the same risk factors. They are all primarily found in men, are associated with smoking and hypertension, and have increased incidence with age. 32,38,43,44 These pathologies are all characterized by altered remodeling of the vessel wall leading to distorted structural integrity and mechanical properties. It is likely that they are all representative of the same systemic disease of the vasculature with variation in the phenotypic expression.
Association of AAAs with Peripheral and Visceral Vascular Dilatation
AAAs are associated with aneurysms peripheral in the vasculature. 45 Clinical detection of popliteal or femoral artery aneurysms has been reported to be associated with 14 to 85% incidences of AAAs. 46–49
Equally, up to 70% of patients with a popliteal aneurysm will have an AAA, 50,51 and popliteal aneurysms are bilateral in 50 to 70% of cases. 52 The incidence of isolated popliteal aneurysms in the healthy population is rare, between 0.1 and 3%, 53 whereas a 55% incidence of popliteal aneurysms in patients with angiographic arteriomegaly is reported. 54
Cerebral Aneurysms
Cerebral aneurysm (CA) and AAA are both chronic degenerative diseases of the vasculature. Hemodynamic forces alone are not sufficient to produce either pathology. 55 They both share evidence of increased proteolytic activity, specifically increased expression of MMP-2, when compared with normal arteries. 56 Hypertension has been shown to be an independent risk factor in both pathologies. 12,57 The association of CAs and AAAs was first highlighted in a series of case reports. 58,59 An observational study has shown the incidence of AAAs in patients with CAs to be 7.2%. 60 A genetic variant, known as rs10757278, on chromosome 9p21 has been shown to affect the risk of both AAAs and CAs. This variant was found to be associated with AAA (OR 1.31, 95% CI 1.22–1.42) and CA (OR 1.29, 95% CI 1.16–1.43). 61
Aneurysms in Allografts
Vein bypass grafts in patients with popliteal aneurysms have been shown to have greater diameters than those for occlusive disease (6.24 mm vs 5.73 mm; p < .02). 62 Grafts in patients with aneurysmal disease have been shown to have altered remodeling relative to occlusive disease. Marked expansive remodeling has been reported in vein grafts for aneurysmal disease; the diameter of bypass grafts for occlusive disease remains static. 63
Aneurysm formation in these grafts is very rare, with an overall incidence estimated at 1%. 64,65 Loftus and colleagues interrogated their prospective database of infrainguinal vein bypass procedures looking specifically for any association between vein graft aneurysms and popliteal aneurysms. They identified a 42% incidence of vein graft aneurysm in bypasses performed for popliteal aneurysm disease compared with a 2% incidence in occlusive disease. Multiple logistical regression analysis confirmed that the presence of a popliteal aneurysm was the only significant risk factor in this group. 66
Coronary Artery Ectasia and AAAs
Coronary artery ectasia (CAE) and AAA share similar histologic features. They both occur in saccular and fusiform configurations, have a strong association with atherosclerotic disease, and are the result of vessel medial elastin degeneration. 67,68 On these grounds, a theoretical association between these two pathologies is attractive.
Historical studies have reported an increased incidence of AAAs in patients with CAE, ranging between 24 and 80%. 69,70 Conversely, the incidence of CAE in AAA patients has been described as approximately 20%. 71,72 Overall, there appears to be an increased incidence of CAE with AAA.
Venous Changes Associated with Aneurysms
Venous aneurysms (VAs) are rare, and the pathogenesis is poorly understood. Varicose veins (VVs) are more common and may share a similar pathogenesis. 73 An association between VAs and increased expression of MMP-2, -9, and -13 has been shown. 74 MMP-2 has also been implicated in VV pathogenesis. 75 The populations at risk of AAAs and VVs vary chronologically. There are no studies reporting the prevalence of VAs or VVs in AAA patients. However, the association of all of these diseases of the vasculature with increased MMP expression proposes a possible systemic process with differential susceptibility related to age and genetics.
Genetic Predisposition
Family history is a risk factor for AAA independent of risk factors for atherosclerosis. 13 Siblings of AAA patients, especially brothers, are significantly more affected, supporting the theory that AAA can be an inheritable disease. 76
The relative risk of having an AAA if a sibling is affected is 4.33. Atherosclerotic disease is more common in black than white American populations. AAAs are more common in white populations. 19 These two findings provided evidence that aneurysms are familial and not simply explained as an advanced form of atherosclerosis.
Little is known about the initial formation of AAA. Results of global gene expression analysis demonstrated that over 3,000 genes are differentially expressed between aneurysmal and nonaneurysmal aortic tissue. 77 Interpretation of these pathways points to an immune response. There is no genetic evidence that AAAs are a natural progression from advanced atherosclerosis.
Systemic Expression in AAAs
MMPs play an important role in the vascular remodeling process, and in healthy tissue, MMP activity is tightly regulated by tissue inhibitors of metalloproteinases (TIMPs). The pathologic significance of an imbalance of MMP/TIMP in aneurysmal disease has been demonstrated. 78,79 The MMP/TIMP imbalance has been shown to be expressed in serum from a peripheral blood sample and to correlate inversely with distensibility (r = −.74, p = .002) and compliance (r = −.58, p = .024) of the suprarenal aorta. 39 In the same group of patients (n = 34), mean common carotid artery diameter was 9.1 (± 1.3) in AAA patients versus 7.8 (± 1.4) in controls, with statistical significance remaining following correction for age and sex (p = .022).
MMP-2 has been postulated as a significant elastase in early aneurysm formation. 5 Increased local expression of MMP-2 in aneurysm tissue has been reported, and SMCs derived from aneurysmal aortas produced threefold higher levels of MMP-2 than cells from atherosclerotic controls. 78 The elevation of MMP-2 expression in patients with aneurysms has been isolated in vascular tissue remote from the abdominal aorta. MMP-2 levels were significantly increased in the AAA group (36.3 ng/mL vs 17.1 ng/mL, p = .0018), with a similar decrease in elastin (19.4% vs 26.8%, p = .018) in that group. The combination of morphologic changes and tissue protease expression distant from the aorta supports the systemic nature of aneurysmal disease. 80
There is emerging evidence for circulating markers of AAA presence and progression. 81,82 The aneurysm itself may be the source of the cytokine, as has been shown for interleukin-6. 83 There are biomarkers that are produced distant from the aneurysm. Levels of C-reactive protein, a protein manufactured in the liver, are elevated in larger aneurysms. 84 Serum osteopontin (OPN), a glycoprotein involved in maintenance of tissue integrity in inflammation, is elevated in AAA patients compared with controls. 85 In humans, common variants in the OPN gene have been associated with immunologic diseases and related to the serum concentrations of the protein.
Autoimmunity
There is serologic and histologic evidence that autoimmunity may play a role in the pathogenesis of AAAs. 86 Substantial evidence has accumulated to suggest that AAA is a specific antigen-driven T-cell disease. Mononuclear cell infiltrates containing CD3+ T cells are present in AAAs. 87 Autoantibodies are present in AAA patients. 88 Analysis of AAA tissue for gene expression profiles shows an overexpression of pathways involved in immune response, 77 whereas immunosuppressive drugs reduce the rate of aneurysm expansion in animal models. 89,90
The mechanism of autoimmunity has been proposed as a breakdown of the immunoregulatory mechanisms and tolerance in general, or a molecular mimicry. An example of this could be the association of Chlamydia pneumoniae with initiation or acceleration of AAA growth. 91 C. pneumoniae is often identified in the vessel wall of AAA patients, and C. pneumoniae–specific T lymphocytes have been found in the mononuclear cell infiltrates of AAAs. These microorganisms may initiate an immune response, which is then propagated by the host cross-reacting determinants leading to clinical disease, long after the microorganism is cleared. 92
C. pneumoniae infection is also associated with atherosclerotic disease. Systemic manifestations of infection can influence atherogenesis through promoting cytokine production. The role of antibiotics has been explored in both AAA and atherosclerosis. Doxycycline has been shown to stabilize atherosclerotic plaques in humans by decreasing MMP-1 expression 93 ; it has also been shown to reduce plasma MMP-9 in patients with AAAs but has no impact on AAA expansion rate. 94 The systemic inflammatory burden can influence the extent of both AAAs and atherosclerosis.
Oxidative Stress
AAAs exhibit features of inflammation and tissue degeneration common to many chronic disease states. There is increasing evidence that reactive oxygen species (ROS) and reactive nitrogen species (RNS) may cause the progressive cell and tissue damage (eg, oxidative stress) implicit in AAA pathogenesis. 95
The evidence implicating MMPs in AAA formation has been described. 5,44 One of the main modulators of MMP activity is oxidative stress. ROS have been reported to activate MMPs, leading to extracellular matrix degradation. 96 ROS and RNS can potentially modulate proteases to induce vascular remodeling.
The evidence for a pathologic role for oxidative stress independent of atherosclerosis has been presented. Segments of infrarenal AAA and adjacent normal aorta harvested at elective AAA repair have been compared. Histology of both samples showed atherosclerosis. Significantly, superoxide levels were 2.5-fold higher in the AAA segments compared with the adjacent atherosclerotic nonaneurysmal aorta.
Antioxidant therapy has not proven effective at preventing or treating atherosclerosis in humans. Vitamin E, an oxidant species scavenger, has been shown to reduce the size of AAA and the incidence of rupture in an animal model. The vitamin E treatment had no effect on the extent of atherosclerosis. 97
AAAs' Association with Extravascular Connective Tissue Deficiency
AAAs are associated with genetic diseases, for example, Marfan and Ehlers-Danlos syndromes. 41 They are also linked to acquired diseases of connective tissue.
Associations with Inguinal and Incisional Hernias
Patients with AAAs have an increased incidence of inguinal herniation, 98 incisional herniation, 99 and diastasis recti. 100 This finding is thought to represent systemic collagen fiber degradation and was initially demonstrated in patient groups matched for hypertension and smoking.
Associations with Emphysema
Patients with emphysema (chronic obstructive pulmonary disease [COPD]) have a higher incidence of AAAs than the normal population 101 ; they also have an increased risk of ruptured AAA. 102 In both COPD and AAA, the elastin content in the aortic wall and lung is decreased. 103,104 This association may be due to a number of factors. It may represent a systemic phenomenon of increased proteolysis. Cigarette smoking may enhance elastase activity or upregulate the individual's susceptibility to its effects. Chronic treatment of COPD with systemic corticosteroids may impair the quality of connective tissue, although in an animal model, it has been shown that the aorta is unaffected by this medication. 105
Smoking is a strong risk factor for both diseases, 106,107 but as yet, no one has proven a causative link between smoking and AAA formation. 108 A dermatologic study examined the effect of smoking on cutaneous collagen synthesis. 109 It showed that the skin of smokers had lower rates of collagen synthesis, lower levels of TIMP-1, and higher levels of MMP-8.
Implications for Treatment
The knowledge that aneurysmal disease is systemic has implications for screening practice. There is evidence that screening for AAAs during lower extremity arterial evaluation is cost-effective and an appropriate and valuable contribution to the examination protocol. 110 Screening for popliteal aneurysms in patients with small AAAs is not cost effective. 111 However, as part of the AAA preoperative assessment, clinical examination of the popliteal vessels is mandatory.
AAAs represent a systemic dilating diathesis. The tendency toward aortic dilatation is not arrested at repair. This makes continued surveillance of the arterial tree obligatory in young patients having aneurysm repairs and all patients following endovascular repair. Current surveillance protocols are in place to identify endoleaks and graft movement. Understanding the disease pathogenesis highlights the need for continued screening of the aorta above and below the endograft.
The value of early endovascular intervention, for aneurysms of 4 to 5.4 cm, is currently under investigation. The PIVOTAL study (Positive Impact of endovascular Options for Treating Aneurysms early) will explore the value of endovascular aneurysm repair for small aneurysms. 112 If this early treatment becomes the gold standard, close, lifelong surveillance will be necessary to identify continued aneurysm neck dilatation and subsequent endoleak owing to the greater potential for aortic diameter expansion.
Endovascular graft fixation depends on the integrity and long-term structural stability of the aorta at the sites of deployment. Gradual dilatation and elongation of the residual infrarenal aortic segment have been described following open AAA repair. 113 At a median 42 months of follow-up, 25% of patients had > 10 mm aortic neck elongation and 8% of patients had a > 5 mm neck diameter increase. The infrarenal aortic neck dilates at 0.5 to 0.7 mm/yr. 114,115 These findings dictate the necessity for lifelong endovascular graft surveillance. The optimal modalities of surveillance are currently topics of research. 116,117 The systemic tendency toward dilatation sustains the risk of endoleak, mandating close surveillance.
The systemic nature of AAAs makes it likely that a biomarker of this process will be discovered. Altered genetic or proteomic expression must be associated with aneurysm growth or rupture. These are areas of research that may lead to greater understanding of aneurysm pathobiology and identify bloodborne markers of aneurysm growth or rupture. This may provide another tool of risk stratification alongside AAA size.
Conclusion
AAAs appear to be local manifestations of a systemic tendency toward vessel dilatation. The pathophysiology remains unclear yet is likely due to a genetic predisposition combined with environmental factors contributing to the formation of aneurysms in anatomically vulnerable vessels.
The association with vascular and biochemical changes distant from the aorta supports the argument that AAAs are a systemic disease of the vasculature. The link with pulmonary and musculoskeletal elastin loss demonstrates that the vulnerability of the connective tissue reaches beyond the vascular tree. AAAs are a prevalent presentation of this weakness as a result of aging, predisposed abdominal aortic deficits, and biomechanical forces.
Atherosclerosis appears to contribute to AAA development. However, the finding that risk factors such as smoking maintain the strength of their association with AAAs independent of atherosclerosis suggests alternate pathways down which smoking and other risk factors act.
Insufficient evidence remains to prove that AAAs are the result of advanced atherosclerosis. The bulk of evidence points to AAA disease being a systemic disease of the vasculature, with a predetermined genetic susceptibility leading to phenotype governed by environmental factors. The implications of this are relevant to research into aneurysmal disease, aneurysm screening, postoperative aneurysm surveillance, systemic biomarkers, and future pharmacotherapy.
Footnotes
Acknowledgment
Financial disclosure of authors and reviewers: None reported.