Version May 2024
INTRODUCTION — An abdominal aortic aneurysm (AAA) is a permanent focal dilation 50 percent greater than the normal diameter of the adjacent healthy aorta (figure 1). The abdominal aorta is the most common site of true arterial aneurysm, affecting predominantly the segment of aorta below the renal arteries (infrarenal aorta) [1]. Well-defined risk factors are associated with the development of AAA and include advanced age, male sex, being from a White population, a positive family history, smoking, the presence of other large vessel aneurysms, and atherosclerosis [2,3]. While declining over the past twenty years, AAA-related mortality remains significant. Between 2018 and 2021 in the United States, AAA-related complications were responsible for 13,640 deaths, with a crude rate of 1 death per 100,000 [4,5].
AAAs progressively dilate over time. While expansion rates vary, large aneurysms generally expand at a faster rate than small aneurysms [2,3]. Mechanisms for the development, expansion, and rupture of AAA have been validated in animal models. However, the relative contribution of each mechanism in humans is unclear [6]. The main risk factors associated with expansion and rupture of AAA are somewhat different from those that contribute to the development of AAA and include large aneurysm diameter, rapid expansion, smoking, hypertension, elevated peak wall stress, a history of cardiac or renal transplant, decreased forced expiratory volume, and female sex [2,3]. While there is significant overlap, the epidemiology, risk factors, pathogenesis, and natural history of the development of AAA differ somewhat from the natural history of expansion and rupture and will therefore be discussed separately.
The epidemiology, risk factors, pathogenesis, and natural history of AAA are reviewed here. The diagnosis, management, and treatment of AAA are discussed in detail elsewhere. Definitions of aneurysms by their location relative to the visceral vessels, involvement of the vessel layer walls, morphology (saccular versus fusiform), and diameter (small versus large) are described in detail elsewhere. (See "Clinical features and diagnosis of abdominal aortic aneurysm", section on 'Aneurysm definition and anatomy' and "Management of asymptomatic abdominal aortic aneurysm", section on 'Introduction'.)
DEVELOPMENT OF AAA
Epidemiology — The prevalence of abdominal aortic aneurysm (AAA) is 4 to 8 percent in screening studies, affecting predominantly males [7-10]. However, AAAs found on screening are generally small; those measuring ≥5.5 cm or greater are found in only 0.4 to 0.6 percent of those screened [11]. Because the incidence of AAA rises sharply in individuals over 60 years of age, the future prevalence of AAA could increase substantially in association with the aging population [5]. On the other hand, some suggest that a reduction in the prevalence of smoking could have the opposite effect (figure 2), with several studies citing a lower prevalence of AAA in 65- to 80-year-old White adults [12-14].
The annual incidence of new AAA diagnoses is approximately 0.4 to 0.67 percent in Western populations. This equates to 2.5 to 6.5 aneurysms per 1000 person-years [15-18]. Age significantly impacts the incidence. As an example, in one study, among males aged 65 to 74 years, the incidence was 55 per 100,000 person-years, increasing to 112 per 100,000 person-years for males aged 75 to 85 years, and further increasing to 298 per 100,000 person-years for those older than 85 [19].
The incidence of AAA discovery may be decreasing, however. In a screening study that included 81,150 men, the overall prevalence of screen-detected AAA (diameter >3.0 cm) was 3.4 percent, decreasing from 5.0 percent in 1991 to 1.3 percent in 2015 [12]. AAA expansion rates were unchanged. Among males who initially had a subaneurysmal aorta (2.6 to 2.9 cm), 57.6 percent were estimated to develop an AAA of ≥3.0 cm within 5 years of the initial scan, and 28.0 percent to develop a large AAA (>5.5 cm) within 15 years.
Risk factors for the development of AAA — There is significant overlap between the risk factors that contribute to the development of AAA and the risk factors that contribute to the expansion and rupture of AAA. However, the relative contribution of each risk factor to either the development or the expansion and/or rupture of AAA varies. Tobacco abuse appears to be the main modifiable risk factor for the development of AAA. Protective factors for the development of AAA include female sex, not from a White population, diabetes, and moderate alcohol consumption [20]. (See "Management of asymptomatic abdominal aortic aneurysm", section on 'Therapies to limit aortic expansion'.)
Advanced age and male sex — The incidence and prevalence are not significant in populations aged less than 60 years [7-10,19]. Among males aged between 65 and 80 years, the prevalence of AAA is 4 to 8 percent, though this may be decreasing [7-10,12]. Aneurysms are rare in females less than 50 years of age. The prevalence of AAA in 65- to 80-year-old females is historically lower compared with males [21]. Screening data from the United Kingdom showed that the prevalence of AAA in females aged 65 to 75 years ranged from 0.43 to 1.15 percent [22]. In a systematic review of screening studies, the overall prevalence of AAA in females ranged from 0.37 to 1.53 percent [23]. Since prevalence studies have defined aneurysm as aortic diameter ≥30 mm, the true prevalence of AAA in females may be underestimated because of differences in body size [24].
White population — AAA occurs most frequently among non-Hispanic White populations including White Americans and White populations from, or with families from Europe. In a study from the United Kingdom, the incidence of AAA in males over 65was 10-fold lower in Asian populations at 0.45 percent [25]. Among Black Americans, AAA occurred one-half as frequently compared with White Americans [26]. The Life Line Screening cohort study also showed a reduced risk for the development of AAA among Hispanics Americans (odds ratio [OR] 0.69) and confirmed the decreased risk of AAA among Asian Americans and Black Americans [27].
Family history — A genetic predisposition for the development of AAA has been suspected since the first report of three brothers who each underwent surgery for ruptured AAA [28]. Since this report, multiple other familial clusters have been identified, further suggesting a genetic predisposition [29,30]. Family history appears to increase the risk of the development of AAA by twofold [30-33]. These are variable with polygenetic inheritance patterns [34]. Syndromic monogenetic disorders, such as Marfan syndrome (fibrillin-1 defect) (table 1) or Ehlers-Danlos syndrome type IV (abnormal type III procollagen), are more commonly associated with thoracoabdominal aortic aneurysm or dissection (table 2) [35,36]. No high-risk genes have been identified that are unique to the development of AAA in isolation [37]. Genes identified relate to processes regulating inflammation, smooth muscle cell apoptosis, and extracellular matrix degradation described below [37] (see 'Pathophysiology of AAA' below). Several genetic loci that have been identified via genome wide association studies (GWAS) that appear distinct from the genetic loci associated with thoracic aortic diseases. Further study will be required to identify the specific genes associated with the loci found on GWAS [38]. (See "Epidemiology, risk factors, pathogenesis, and natural history of thoracic aortic aneurysm and dissection", section on 'Genetic predisposition'.)
Tobacco use — Tobacco use is the modifiable risk factor most strongly associated with the development of AAA. 90 percent of all AAA patients have a history of tobacco use [2]. Only lung cancer has a stronger epidemiologic association with tobacco [2]. Among screened patients found to have small AAAs, 18 to 25 percent are current smokers [26,27,39]. Current smokers also initially present with larger aneurysms. The number of pack-years is positively associated with increased odds of AAA being found on screening [27,39]. Males who smoke over one pack per day also have a 15-fold increased risk of AAA compared with age-matched males who do not smoke [40]. Meta-analyses have shown that current smokers have a nearly five-fold increase in the risk of developing an AAA [41]. Smoking cessation decreases the subsequent odds of AAA being identified on screening, with the greatest benefit among those who have quit for more than 10 years. The risk of AAA after smoking cessation approaches that of never-smokers after 25 years of smoking cessation [41]. Unfortunately, the odds never return to the baseline of never-smokers, indicating that some degree of arterial damage inflicted by tobacco use is permanent [27].
Presence of other large vessel aneurysms — Patients with other large vessel aneurysms (eg, iliac, femoral, popliteal, or carotid artery aneurysms) have an increased risk for AAA. However, there are differences between AAA and other large vessel aneurysms with respect to inflammatory infiltrate and catalytic enzymatic activity [42]. Thus, while a risk factor, not all AAA are associated with other large vessel aneurysms, and vice versa.
Patients with a femoral artery aneurysm are found to have a concomitant AAA 85 percent of the time. Subjects with popliteal aneurysms have a concomitant AAA 60 percent of the time [43,44]. Up to 25 percent of subjects have combined thoracic and abdominal aortic aneurysms [45,46]. Compared with men, more women have combined thoracic aortic aneurysms and AAA (48 versus 28 percent) [45]. AAA has also been found to coexist with intracranial aneurysm. AAA screening is advocated by some for patients found to have intracranial aneurysm [47-49].
Atherosclerotic risk factors — Systemic atherosclerosis is present concurrently with AAA in multiple studies, corroborating the significant overlap in the risk factors between the two disease processes [26,27,50].
●Coronary artery disease is present in over 25 percent of individuals with AAA.
●Peripheral arterial disease is found in over 12 percent of those with AAA.
However, it is important to note that there are patients with aneurysmal disease with a low burden of peripheral artery disease (PAD). Moreover, the incidence of PAD is low in those with familial aortic aneurysm [51]. The pathophysiology responsible for AAA formation is thought to be distinct from atherosclerosis, but atherosclerosis may still play a role. (See 'Pathophysiology of AAA' below.)
With respect to the major risk factors associated with atherosclerosis, the roles of male sex and tobacco use are discussed above. Hypertension and hyperlipidemia are frequently cited as etiologic risk factors for the development of AAA [26,27,52,53]. Intuitively, chronically elevated blood pressure would weaken the aortic wall, as would lipid-laden atherosclerotic plaques.
Food and alcohol consumption — Data regarding moderate alcohol consumption are inconsistent, with several studies citing a moderate protective effect (hazard ratio [HR] 0.57 to 0.80) [54]. Conversely, with higher levels of alcohol intake (≥30 grams/day; ≥2 drinks/day) there appears to be an increased risk of AAA [40]. The decreased risk of AAA with modest alcohol intake seemed to be most pronounced with beer and wine. Meta-analyses also confirm that modest consumption was protective against the development of AAA; however, all effects were relatively modest. Thus, while alcohol consumption can independently modify the development of AAA, the magnitude of the effect of alcohol is small compared with the effect of other risk factors [55].
Fruit and vegetable consumption appears to be mildly associated with less AAA development [27,56]. The Lifeline Registry in the United States showed that individuals who adhered to a diet of fruit and nuts ≥3 servings/week decreased their odds of developing AAA by approximately 10 percent [27]. The effect appears stronger with higher fruit intake. In a Swedish cohort of 80,426 participants, when controlling for other confounders, namely tobacco use, higher consumption of fruits (>2 servings/day) was associated with a 25 percent decreased risk of AAA relative to those with lower fruit intake (0.7 servings/day) [56].
Overall, it appears that diets higher in antioxidants may help mitigate AAA. In an analysis of data from the Swedish Inpatient Register, the National Cause of Death Register, and the Register for Vascular Surgery, adherence to a diet with high anti-inflammatory potential (AIDI) was associated with a reduced risk for AAA and a reduced risk for AAA rupture [57]. The AIDI of diet was estimated using the Anti-inflammatory Diet Index (AIDI) based on 11 foods with anti-inflammatory potential (fruits, vegetables, whole grains, breakfast cereal, tea, coffee, low-fat cheese, nuts, wine, beer), and five with proinflammatory potential (unprocessed meat, processed meat, soft drink beverages, offal, chips) validated against high sensitivity C-reactive protein. The association was more pronounced among females than men. There was observed a significant interaction between the AIDI and sex, and an interaction between the AIDI and smoking status for AAA incidence was borderline significant.
Niacin administration may be one of the antioxidants to protect against the development of AAA. In angiotensin-II and calcium-chloride mouse models, niacin administration suppressed the development of AAA, specifically histologic examination of niacin-treated mice showed reduced adventitial immune cell infiltrate, inflammatory responses, and extracellular matrix degradation [58]. The association between niacin administration and decreased AAA and inflammation appeared to be mediated by increased levels of nicotinamide-adenine dinucleotide (NAD) in the niacin-fed mice. Validation of these findings is necessary within human populations. Further study into the mechanisms of NAD-mediated protection against AAA is also necessary to elucidate mechanisms of AAA development.
Increased salt intake is also associated with an increased risk of AAA in men. A dietary questionnaire from 11,472 older males found an increased risk of AAA with reported salt intake, even in the absence of arterial hypertension [59]. Moreover, aneurysms were larger in diameter compared with those in patients who denied significant salt intake.
There is inconsistency in the literature regarding the association of obesity with the presence of AAA [60-62]. If there is an association, it is mildly positive, increasing the odds of AAA by 22 percent in one large cohort from Australia [61]. Obesity may be more significant in conjunction with atherosclerotic disease, amplifying the odds of the development of AAA by twofold relative to nonobese individuals with atherosclerosis [62].
Negative risk factors — While diabetes mellitus is positively associated with the presence of atherosclerosis, most studies show that diabetes mellitus is negatively associated with AAA [26,27,53,63-65]. However, in one large population-based survey of over two million Polish individuals, diabetes mellitus was associated with a higher prevalence of AAA as well as AAA rupture [63]. Nevertheless, the general consensus within the literature remains that diabetes mellitus reduces the odds of the development as well as rupture of AAA [63]. Studies estimate the odds ratio of AAA among diabetics compared with nondiabetics to be between 0.52 and 0.75 [26,27,64]. One meta-analysis cited a 42 percent decreased risk of AAA among patients with diabetes mellitus [66].
The lack of association between diabetes and AAA supports the concept that the development of AAA and atherosclerosis may be distinct processes, despite the significant overlap of risk factors. Moreover, the medications used to treat diabetes mellitus may exert a potential protective effect with respect to AAA development. Metformin has been most consistently found to reduce the risk of AAA development in the literature [67]. Metformin has been shown to independently reduce inflammatory markers in mouse models, as well as rates of AAA growth in large human epidemiologic studies. Trials are ongoing to clarify the mechanisms and impact of metformin use upon AAA development and growth/rupture risk [68].
Pathophysiology of AAA — AAA is the focal manifestation of a systemic process highlighted by inflammation, smooth muscle cell apoptosis, and extracellular matrix degradation (figure 3). The embryologic origins of the infrarenal aorta may also play a role. Although there is significant overlap of risk factors and prevalence of disease with atherosclerosis, the etiology of most AAAs appears distinct from atherosclerosis. Some AAAs, however, remain strongly associated with an atherosclerotic origin. The processes driving the initiation of AAA, and the ultimate expansion and/or rupture of an AAA, are somewhat different and are discussed separately. (See 'Expansion and rupture of AAA' below.)
Much of the knowledge of the pathogenesis of human aortic aneurysms is extrapolated from animal models. No known treatment can induce regression once AAA has formed, and most therapies are aimed at limiting further expansion. (See "Management of asymptomatic abdominal aortic aneurysm", section on 'Therapies to limit aortic expansion'.)
Embryology and histology of the infrarenal aorta — The embryology and histology of the infrarenal abdominal aorta helps to explain the predisposition of this anatomic site to aneurysm formation (picture 1).
The smooth muscle cell composition of the infrarenal aorta is derived from the paraxial mesodermal somites, which is distinct from other parts of the aorta or iliac arteries. This is significant as areas derived from somites appear more susceptible to aneurysmal degeneration [69]. The thickness and number of elastic lamellae in the media gradually decrease along the length of the aorta from the aortic root to the iliac bifurcation such that at the level of the conus arteriosus to the bifurcation of the iliac arteries, there is a 10-fold decrease in the amount of elastin [70]. Transforming growth factor-beta (TGFB) appears critical to mediating the differences in the smooth muscle cell phenotype in different parts of the aorta due to differential responses depending upon the embryologic cell of origin [71,72]. There is also less collagen in the infrarenal aorta relative to other portions of the aorta [73]. Finally, the vasa vasorum is somewhat fragile, rendering the blood supply to the media relatively avascular compared to that of the thoracic aorta [38,74].
Hemodynamic susceptibility — The unique hemodynamic pressures exerted on the infrarenal aorta upregulate proteins that are important in the development of AAA. As the aorta tapers and gives off its major branches, the pulse wave amplitude increases from the heart toward the infrarenal aorta [75]. The bifurcation of the aorta also results in turbulence and areas of high and low shear stress [76]. In regions of high shear stress, endothelial cells increase the production of endothelial nitric oxide, and production of matrix metalloproteinase-2 and -9 and TGFB are upregulated [77]. In areas of low stress, endothelial cells produce nuclear factor kappa-light-chain-enhancer of activated B cells (ie, nuclear factor-KB) and endothelin-1 [78]. Areas of low-shear stress have generated interest as a predictor of AAA growth and rupture, though external validation with larger datasets are required to validate preliminary findings [79].
Inflammation and the Th2 response — CD4+ helper cells are responsible for mediating two distinct immune-mediated responses, the T-helper type 1 (Th1) response and the T-helper type 2 (Th2) response. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets'.)
●The Th1 response is responsible for clearing intracellular pathogens and is mediated by the secretion of cytotoxic cytokines, namely interferon-gamma (IFN-γ), interleukin-2 (IL-2), and lymphotoxin. The Th1 response results in macrophage-mediated cellular immunity.
●The Th2 response of CD4+ helper cells secretes IL-4, IL-5, IL-9, IL-10, and IL-13. The Th2 response results in a vigorous antibody response, eosinophil promotion, and inhibition of macrophage-mediated immunity [80,81].
With respect to AAA, there is evidence of transmural infiltration of inflammatory cells in AAA, such as polymorphonuclear neutrophils, T-cells, B-cells, macrophages, mast cells, and natural killer cells [82-85]. The predominant cell types are CD4+ T-cells, B-cells, and macrophages [80], indicative of a shift toward a Th2 inflammatory response. Moreover, AAAs demonstrate a shift towards the secretion of Th2 cytokines, predominantly IL-4, and inhibition of IFN-γ [81]. The Th2 cytokines have pleiotropic effects upon smooth muscle cells, extracellular matrix, and other inflammatory cells that mediate the development of AAA [81,86,87]. Much of Th2 response is associated with Gata-3, a key transcription factor [88]. By contrast, the T-helper type 1 (Th1) response is more frequently found in atheroma and is characterized by overexpression of Th1 cytokines, namely IL-2 and IFN-γ [81]. The Th1 response is associated with T-bet, a key transcription factor [88].
Reactive oxygen species (ROS), particularly superoxide anion (O2-), are significantly increased in aneurysmal tissue. ROS are especially important in the pathogenesis of AAA in the presence of tobacco abuse. These species are produced by the inflammatory cell infiltrate and appear to predispose toward the Th2 inflammatory phenotype [89]. The effects of ROS are mediated via nicotinamide adenine dinucleotide phosphate-oxidases and contribute directly to smooth muscle cell degeneration as well as to amplify the Th2 inflammatory response that mediates AAA development [90]. Other mechanisms of ROS production include uncoupled endothelial nitric oxide synthase, myeloperoxidase, xanthine oxidase, cyclo-oxygenase, and mitochondrial metabolism [91]. Moreover, ROS upregulates enzymes such as matrix metalloproteinases (MMPs), which enhance the degradation of the extracellular matrix [92].
While we know that inflammation helps to mediate AAA, we do not have radiographic modalities that reliably predict AAA development, growth, and/or rupture [93]. Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging is one modality that can identify aortic wall cellular inflammation in those with AAA [94,95]. In a multicenter cohort study that monitored 342 individuals with AAA ≥4 cm for over two years, USPIO enhancement was identified in 42.7 percent of participants, absent in 55.8 percent, and indeterminant in 1.5 percent [95]. Compared with those without uptake, patients with USPIO enhancement had higher rates for the primary outcome of aneurysm rupture or repair (47.3 versus 35.6 percent). Patients with USPIO enhancement also had increased rates of aneurysm expansion compared with those without uptake (3.1 versus 2.5 mm/year), although this was not independent of current smoking habit. Baseline AAA diameter and current smoking also predicted the primary outcome. The addition of USPIO enhancement to the multivariate model did not improve prediction of adverse AAA-related events over clinical features alone. The use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is promising but inconsistent for predicting AAA expansion or rupture [93,94]. A systematic review revealed that FDG-PET showed that standardized uptake values (SUVs) either had a negative association with AAA growth, or nonstatistically significant associations with AAA expansion [93]; other studies have shown a positive association [96]. Further study is needed to more accurately quantify associations between inflammation within AAA on imaging and subsequent expansion or rupture before these become clinically useful.
Smooth muscle cell apoptosis — The Th2 inflammatory cells also secrete Fas ligand and Fas-associated phosphatase-1 (FAP-1). These mediate apoptosis of vascular smooth muscle cells as well as the Th1-lymphocytes [81,97]. IL-4 will also accelerate the Th2 inflammatory phenotype as it promotes the survival of Th2 lymphocytes while failing to rescue Th1 lymphocytes. This favors the cytokine environment further toward the Th2 phenotype, which then accelerates vascular smooth muscle cell apoptosis (picture 2) [98]. Potential mechanisms of smooth muscle cell apoptosis include long non-coding RNA segments, which have been linked with AAA development in mouse models [99].
Extracellular matrix degradation — Further degradation of the extracellular matrix contributes to the development of AAA. In particular, MMPs and elastases are critical to degrade and fragment the medial elastic lamellae and type I and III collagen. This is accompanied by a decrease in the tissue inhibitors of MMPs [91]. These are secreted by the inflammatory cell infiltrate, smooth muscle cells, and endothelial cells of the aorta.
The most important inflammatory cell appears to be the macrophage, which is particularly vital for the production of MMP-9 [84,100]. MMP-9 knockout mice appear resistant to AAA formation in elastase-infusion mouse models. MMP-12 production is augmented by IL-4 and gamma interferon blockade and appears to be important for potentiating other MMPs in the early stages of AAA development [87,91].
The proteases found most frequently in AAA are MMP-1, -2, -3, -8 -9, -12, and -13; serine proteases (tissue-type plasminogen activator [t-PA], urokinase [u-PA], plasmin and neutrophil elastase); and cysteine proteases (cathepsin D, K, L, and S). MMP-1 (collagenase 1) and MMP-13 (collagenase 3) levels are elevated in AAA and especially in symptomatic AAA [91]. Elastin has a long half-life and decreases with aging and in aneurysms. These are responsible for the destruction of type I and III collagen and elastin and the elastic lamellae, which are the hallmark of histological specimens of AAA [101,102].
Role of the renin-angiotensin system — The significance of the renin-angiotensin system was initially shown in the mouse elastase model, where administration of angiotensin-converting enzyme (ACE) inhibitors mitigated the development of AAA. Since then, angiotensin-II infusions in apolipoprotein E/low-density lipoprotein receptor knockout mice have been used to create AAA in mice.
Angiotensin-II alone does not appear to increase AAA. Angiotensin-II seems to serve as a cofactor and requires mast cell production of chymase to activate MMPs and effect smooth muscle cell apoptosis. Unfortunately, exogenous ACE inhibitor administration has not been shown to limit AAA growth in humans. This may be because mast cell-activated chymase may still occur in in vivo, mitigating the effect of ACE inhibitors [91].
Atherosclerotic remodeling and aneurysm formation — Inflammation is the main pathophysiologic process driving AAA development, expansion, and rupture. However, atherosclerosis may still contribute to the development of AAA [103]. Atherosclerotic plaque induces stenoses. The body therefore remodels arteries to dilate to compensate for stenosis so that the plaque-free lumen remains largely unchanged (at least for a time) [103-105]. Theoretically, flow-related shear stress induced by atherosclerotic plaque stimulates the production of matrix metalloproteinases, resulting in the necessary changes in the extracellular matrix, vascular smooth muscle cells, and endothelium [104,105]. This theory has been difficult to prove consistently in the literature [103]. Due to the overlap of risk factors between AAA and atherosclerosis, it is difficult to distinguish AAAs that are caused predominantly due to atherosclerotic-related processes.
Comparisons of AAA and atherosclerotic aortic tissue may help to clarify differences between atherosclerosis and AAA development in spite of the significant overlap of risk factors for their development. In a study that examined aortic biopsies of patients undergoing open aortic repair for either AAA (n = 12) or aortoiliac occlusive disease (n = 7), pathways that were differentially expressed included inhibition of bone morphogenic protein and upregulation of transforming growth factor (TGF) beta [106]. Moreover, inflammatory signaling was markedly deranged in the AAA relative to the occlusive biopsy specimens. In contrast, mouse models show an association between microcalcifications and the development of AAA suggesting shared pathways between atherosclerotic and AAA manifestations [107]. These data further corroborate the usually distinct, but sometimes overlapping pathogenesis of AAA versus atherosclerosis and help to identify pathways for future investigation.
EXPANSION AND RUPTURE OF AAA — The risk factors associated with expansion and rupture of abdominal aortic aneurysm (AAA) overlap somewhat with those associated with the development of AAA, though there are some significant differences. These risk factors include large baseline aneurysm diameter, rapid expansion, tobacco use, hypertension, elevated peak wall stress, a history of cardiac or renal transplant, decreased forced expiratory volume (FEV1), and female sex [2,3]. Most of these risk factors are intuitive, though the role of female sex requires further explanation. While the most validated metric, baseline diameter is imperfect at predicting aneurysm expansion or rupture, with a significant minority of patients rupturing their aneurysm with a diameter that is <5.5 cm [108]. Thus, other risk factors have been proposed to help predict which AAAs will rapidly expand/rupture.
Epidemiology of AAA rupture — In 2015, statistics compiled by the United States Centers for Disease Control found that aneurysmal disease (including dissection) is the 15th leading cause of death among adult Americans (males or females) aged 85 to 89 years of age [4]. Aneurysmal disease is the cause of death in 0.13 percent of males, compared with 0.07 percent of females. The rates of rupture per 100,000 appear to be declining [4], but may in fact be increasing in some subpopulations [109].
Risk factors for AAA rupture
Baseline aortic diameter — Baseline diameter is the most validated parameter associated with AAA rupture (table 3). Rupture risk cited from randomized trials is higher than rupture risk determined from epidemiologic studies [2,3,110]. Relative to other methods of diagnosis (eg, clinical evaluation, incidental imaging finding), only a small fraction of AAAs are identified as the result of screening programs. Interestingly, for those AAAs identified by screening, the overall risk of rupture is low [111]. In a population screening study that followed over 18,000 males identified with AAA <5.5 cm using surveillance ultrasound (figure 4), the risks for rupture per year were as follows [108]:
●0.03 percent (95% CI 0.02-0.05 percent) for small (3 to 4.4 cm) aneurysm
●0.28 percent (95% CI 0.17-0.44 percent) for medium (4.5 to 5.4 cm) aneurysm
●0.40 percent (95% CI 0.22-0.73 percent) for AAA just below (5.0 to 5.4) the threshold for repair
Rapid expansion — While the expansion of aneurysms is largely predictable, individual aneurysms may undergo unpredictable stochastic expansion (eg, expanding for a time, then not expanding, then expanding again). Larger aneurysms expand at more rapid rates compared with smaller aneurysms [12,112-114]. In the United Kingdom Small Aneurysm Trial, the mean expansion rates were as follows [114]:
●1.9 mm per year for AAA baseline diameter 2.8 to 3.9 cm
●2.7 mm per year for AAA baseline diameter 4.0 to 4.5 cm
●3.5 mm per year for AAA baseline diameter 4.6 to 8.5 cm
Rapid expansion has been defined as aneurysms that increase in size ≥5 mm over a six-month time-period or ≥10 mm over a 12-month period [2]. It is unclear whether rapidly expanding aneurysms increase the risk of rupture independent of the diameter of the aneurysm. As an example, a 3.0-cm aneurysm that increases to 3.5 cm may be "rapidly expanding" but may not have increased risk of rupture. This is because aneurysms grow at nonlinear rates, such that an aneurysm that grows 5 mm in the preceding year may not grow substantially for the next two years [12,112-114].
On the other hand, natural history studies have confirmed that larger aneurysms expand more quickly than smaller aneurysms. One longitudinal study followed over 80,000 men screened for AAA over a 25-year period. Among those who initially had a subaneurysmal diameter aorta (2.6 to 2.9 cm), the rate of expansion increased from 0.5 mm/year in the first 5 years of follow-up to 3.6 mm/year after 15 to 19 years [12]. The mean expansion rate for a larger initial diameter aorta measuring 3.0 to 5.4 cm was 2.6 mm/year in the first five years of follow-up, increasing to 8.0 mm/year after 15 to 19 years.
Tobacco use — Tobacco use is associated with the development of AAA, more rapid expansion, and increased risk of AAA rupture [112-114], and smoking cessation represents the single most effective nonsurgical intervention to reduce the risk of aneurysm-related complications and/or death [115]. Data from the Aneurysm Detection and Management (ADAM) Study Group suggest that current smoking increases the mean expansion rate of AAA by an additional 0.05 cm/year [112]. A meta-analysis found that current smoking increased the AAA expansion rate by 0.35 mm/year and was associated with a twofold increased risk of rupture [116].
Hypertension — Data regarding the role of hypertension in AAA expansion are somewhat inconsistent. Elevated diastolic blood pressure is associated with a 0.02 cm/year increase in diameter for every 10 mmHg in the Aneurysm Detection and Management Study [112]. Data from the United Kingdom failed to show an association between hypertension and aneurysm enlargement [114] but did show an association between hypertension and AAA rupture [117]. Overall, the data most consistently support the association between AAA rupture and hypertension. The association between AAA expansion and hypertension is less clear.
Elevated peak aortic wall stress — Unfortunately, there are limits to using baseline AAA diameter to predict rupture risk [118]. In one review of 24,000 consecutive autopsies performed over 23 years, 473 AAAs were identified, of which 118 were ruptured, but 40 percent of AAAs with a diameter between 7 and 10 cm were not ruptured. Moreover, 13 percent of aneurysms <5 cm had ruptured. These data have led investigators to seek other factors associated with AAA rupture.
One of the more popular investigational methods uses finite element analysis to quantify peak wall stress at given points of an aneurysm based upon computed tomographic (CT) images [119]. Later iterations of these analyses have become more complex and incorporate the peak wall stress with wall stiffness, the patient's diastolic pressure, morphology of the aneurysm, diameter, expansion rate, and sex to improve the precision of the predicted models [120,121]. Interestingly, areas of inflammation do not consistently correspond to areas of maximal peak wall stress. This suggests that there are some aneurysms that rupture due to elevated peak wall stress, whereas others rupture due to focal areas of excessive inflammation [121].
Further research into this area is necessary, however, and these methods are not yet available for generalized clinical use.
History of cardiac or renal transplant — Cardiac and abdominal organ transplant appears to increase the prevalence of AAA, the rate of expansion, and the risk of rupture post-transplantation [122,123]. Immunosuppressant and corticosteroid treatment have been associated with AAA development, expansion, and rupture in animal models, though more study is required to clarify the mechanisms of AAA expansion and rupture after transplantation [122,123].
For heart transplant patients, 10 percent of subjects were found to have AAA. Among those heart transplant recipients without preexisting aneurysms, the diagnosis of AAA was made at a mean of six years after transplantation. Older age at the time of transplantation, male sex, and ischemic heart disease prior to transplantation were positively associated with the development of AAA [122]. In a large series of liver and/or kidney transplant patients, the prevalence of AAA was approximately 1 percent. AAA expansion rates were higher relative to pretransplantation rates, with rupture occurring only post-transplantation [123].
Decreased forced expiratory volume (FEV1) — Individual studies suggest that subjects with severe chronic obstructive pulmonary disease (COPD) may have an elevated risk of AAA rupture [117,124]. A lower FEV1 was independently associated with an increased risk of aneurysm rupture after three years of surveillance of AAA in one study [117]. This association remained significant independent of the patients' smoking status [117]. Another study similarly found that those with severe chronic obstructive pulmonary disease (COPD) had an increased risk for ruptured AAA [124]. Data are mixed as to whether mild-to-moderate disease increases the risk of rupture.
Female sex — Although the prevalence of AAA is lower among females, multiple studies have quantified that female sex is one of the strongest predictors of AAA rupture [2,3,110,117,125,126]. Data from the United Kingdom Small Aneurysm trial suggest that the risk of death from rupture in females may be four times higher compared with males with similar-diameter aneurysms during surveillance [117].
AAAs in females also expand more rapidly, and rupture occurs at AAA diameters that are 5 to 10 mm smaller compared with males when controlling for other known covariates known to influence rupture risk [125,126]. This may be due to a decreased tensile strength in female aortas as well as due to increased peak wall stress within female AAA [127,128]. Differentiating sex from effect of a smaller body habitus has been difficult and requires further research to develop a nomogram to predict rupture risk adjusted for body size, similar to that which is being developed for thoracic aortic aneurysms [129].
Other possible factors
Aneurysm intraluminal thrombus — Observational studies have suggested a potential role for intraluminal thrombus as a mediator of AAA expansion and rupture risk. Most AAA have some degree of intraluminal thrombus. Some imaging studies quantifying the volume of intraluminal thrombus have identified faster expansion and increased risk for rupture for those with larger thrombus burden [103,130-138]. Unfortunately, larger aneurysms tend to have increased amounts of intraluminal thrombus, which confounds the analysis. Furthermore, there is not a validated methodology to accurately measure the volume of intraluminal thrombus. Moreover, data are somewhat conflicting regarding the role of intraluminal thrombus, with some data from animal models suggesting that AAA with thin layers of thrombus may exhibit higher levels of oxidative stress and enzymatic degradation of the extracellular matrix [92]. This could hypothetically correlate with increased expansion and rupture risk for AAA with thin layers of intraluminal thrombus. Thus, further study is needed to accurately measure the impact of intraluminal thrombus upon subsequent AAA rupture/growth risk.
Saccular aneurysm morphology — Saccular aneurysms have been posited to be at an increased risk of rupture. This is based on the theoretical increased risk of rupture in the transition zone between healthy aorta and the aneurysm itself, which is more pronounced in saccular aneurysms. This risk has not been well quantified in the literature. One study failed to find an association between peak wall stress and saccular aneurysms [139].
Recent surgery — The influence of recent surgery upon AAA rupture has also been reported in small series. In a small series of 33 patients with a known AAA who underwent a variety of unrelated operations, 3 percent of AAA >5 cm ruptured postoperatively [140]. The risk may be higher with cardiac surgery [141]. The mechanisms of this increased risk are unclear, though they may be related to the stress of surgery.
Fluoroquinolones and other antimicrobials used to treat infection — Antimicrobial agents used to treat infection, or infection itself, may be associated with the development of AAA [142-144]. A database review estimated the risk of aortic aneurysm/dissection and infection as well as compared the risk for various antibiotics with similar indication profiles among a matched cohort of patients with the same types of infections. The adjusted odds ratio (OR) of aortic aneurysm/dissection with any indicated infection was 1.73 (95% CI 1.66-1.81) [143]. Sepsis (OR 3.16, 95% CI 2.63-3.78) and intra-abdominal infection (OR 2.99, 95% CI 2.45-3.65) had the highest increased risk.
Clinical studies have implicated fluoroquinolone use with an increased risk of aortic aneurysm/dissection [143,145-151]. This was because fluoroquinolones have nonantimicrobial properties that may compromise the integrity of the vascular wall. Fluoroquinolones alter expression of matrix metalloproteinases (MMPs) in animal experiments and, in in vitro studies, have effects on connective tissues [152-155]. Ciprofloxacin inhibits lysyl oxidase activity and increases MMP activity [152,153]. The impairment of lysyl oxidase results in increased elastin fragmentation, which represents a plausible mechanism by which AAA/aortic dissection risk is increased. (See "Fluoroquinolones", section on 'Musculoskeletal'.)
●In a nationwide propensity matched cohort study from Sweden, fluoroquinolone use (360,088 fluoroquinolone treatment episodes) increased the risk of aortic aneurysm or dissection events (defined as hospital or emergency department admission within 60 days from the start of treatment) compared with reference amoxicillin use (1.2 versus 0.7 cases per 1000 person years; hazard ratio [HR] 1.66, 95% CI 1.12-2.46). The estimated absolute difference was 82 cases of aortic aneurysm or dissection per 1 million treatment episodes [146]. Among the cases that occurred among fluoroquinolone users, most were AAA, followed by thoracic aortic aneurysm or thoracoabdominal aneurysm. In a case crossover study of 1213 patients, the risk of fluoroquinolone exposure of 3 to 14 days increased the risk of AAA by over twofold, though the precise dose toxicity remains unclear [147].
●In a cohort study of 47,596,545 antibiotic prescriptions in the United States, fluoroquinolone use (9,053,961 prescriptions; 19 percent) increased the risk of AAA and iliac artery aneurysm diagnoses within 90 days of the prescription compared with other antibiotic prescriptions [148]. The risk appeared age related, with the most pronounced increased hazard of aneurysm formation occurring in patients 50 to 64 years of age. These results suggest that caution over fluoroquinolone use should perhaps be extended to all adults and not simply those with risk factors for aortic aneurysm.
However, later studies did not find an independent association of fluoroquinolone use and increased risk of AAA and/or aortic dissection. Compared with other antibiotic combinations, the risk of aortic aneurysm/dissection may be similar, leading many to conclude that the nature of the infection, not the antimicrobial agent is the primary cause of increased risk.
●In the database study described above, the use of fluoroquinolones was not associated with an increased risk of aortic aneurysm/dissection compared with combined amoxicillin-clavulanate, combined ampicillin-sulbactam, or with extended-spectrum cephalosporins among patients with indicated infections [143].
●In another nationwide population-based study from Korea, the incidence of aortic aneurysm/dissection was compared among propensity score matched adults ≥20 years who received an oral fluroquinolone or third generation cephalosporin from 2005 to 2016 [145]. Both antibiotics were associated with an increased risk of aortic aneurysm/dissection. The overall incidence of aortic aneurysm/dissection among the patients who received a fluoroquinolone was 5.4 per 100,000 years and for the cephalosporin was 8.47 per 100,000 person-years. The adjusted risk of aortic aneurysm/dissection was similar between the groups (adjusted HR 0.75, 95% CI 0.52-1.1).
Much of the data show an independent association with fluoroquinolone use and increased risk of AAA/aortic dissection. Because of the association with AAA, aortic dissection, and other connective tissue pathologies associated with fluoroquinolone use [146,148], the US Food and Drug Administration attached its strongest warning label on the packaging of fluoroquinolones in December 2018 stating that fluoroquinolones may increase the occurrence of aortic aneurysm/dissection, and their use should be avoided in patients with or at risk for aortic aneurysm/dissection [156]. Further study, including metaanalyses and appropriately powered prospective analyses, will be required to definitively quantify the effect of fluoroquinolone use and AAA/aortic dissection risk. (See "Management of asymptomatic abdominal aortic aneurysm", section on 'Fluoroquinolone use'.)
Negative associations — When AAA occurs in patients with diabetes mellitus, diabetes appears to protect against expansion of AAA [112,116]. The expansion rate in patients with diabetes is 25 to 40 percent that of patients without diabetes [112,116]. The mechanisms for this remain unclear, but this is consistent also with the protective effect of diabetes upon the development of AAA. Some authors posit that the protective effect may be mediated by the increased arterial stiffness induced by diabetes upon the aorta [157]. It is unclear whether diabetes decreases rupture risk when controlling for aneurysm diameter. (See 'Negative risk factors' above.)
Although coronary artery disease and systemic atherosclerosis appear to be associated with the development of AAA, coronary artery disease may not be associated with expansion or rupture of AAA. A meta-analysis found a negative association between a history of coronary artery disease and AAA expansion [158]. Future appropriately powered studies that clearly define the severity of systemic atherosclerosis will be required to quantify the true role of atherosclerosis upon AAA expansion and rupture.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Aortic and other peripheral aneurysms".)
SUMMARY AND RECOMMENDATIONS
●Abdominal aortic aneurysm – Abdominal aortic aneurysm (AAA), which is a focal dilation more than 50 percent greater than the normal diameter of the aorta (figure 1), is a common but potentially lethal condition. The abdominal aorta is the most common site of true arterial aneurysm, affecting predominantly the segment of aorta below the renal arteries (infrarenal aorta). (See 'Introduction' above.)
●Prevalence – Ultrasound screening studies have found that 4 to 8 percent of older males have an occult AAA, though this rate may be declining. Although the prevalence of AAA is four to six times lower for females compared with males, females present with rupture more often than men. (See 'Epidemiology' above and 'Epidemiology of AAA rupture' above.)
●Risk factors – The main risk factors for developing AAA include advancing age, male sex, being from a White population, family history, smoking, the presence of other large vessel aneurysm, and atherosclerotic risk factors. Although diabetes mellitus is a strong risk factor for atherosclerosis, it is negatively associated with the development of AAA. (See 'Risk factors for the development of AAA' above.)
●Pathophysiology – Aneurysmal degeneration of the abdominal aorta is a multifactorial systemic process due to alterations in vascular wall biology. AAAs are characterized by transmural inflammatory changes, abnormal collagen remodeling and cross-linking, reactive oxygen species, and loss of elastin and smooth muscle cells, which results in progressive thinning and weakening of the aortic wall and enlargement of the aortic diameter. (See 'Pathophysiology of AAA' above.)
●Expansion and rupture – Multiple factors influence aortic expansion and the risk of rupture, the most important of which are aortic diameter and ongoing smoking. Small- and medium-sized AAAs (<5.5 cm) expand at an average rate of 2 to 3 mm/year while larger AAAs expand at approximately 3 to 4 mm per year. AAAs that exhibit rapid diameter expansion ≥5 mm over six months or >10 mm over one year of follow-up have an increased risk for rupture. (See 'Expansion and rupture of AAA' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.
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