PRiMER

Abdominal aortic aneurysms

Natzi Sakalihasan1,2*, Jean-​Baptiste Michel3, Athanasios Katsargyris4, Helena Kuivaniemi5,
Jean-​Olivier Defraigne1,2, Alain Nchimi2,6, Janet T. Powell7, Koichi Yoshimura8,9 and
Rebecka Hultgren10,11
Abstract | An abdominal aortic aneurysm (AAA) is a localized dilatation of the infrarenal aorta.
AAA is a multifactorial disease, and genetic and environmental factors play a part; smoking,
male sex and a positive family history are the most important risk factors, and AAA is most
common in men >65 years of age. AAA results from changes in the aortic wall structure, including
thinning of the media and adventitia due to the loss of vascular smooth muscle cells and
degradation of the extracellular matrix. If the mechanical stress of the blood pressure acting on
the wall exceeds the wall strength, the AAA ruptures, causing life-​threatening intra-​abdominal
haemorrhage — the mortality for patients with ruptured AAA is 65–85%. Although AAAs of
any size can rupture, the risk of rupture increases with diameter. Intact AAAs are typically
asymptomatic, and in settings where screening programmes with ultrasonography are not
implemented, most cases are diagnosed incidentally. Modern functional imaging techniques
(PET, CT and MRI) may help to assess rupture risk. Elective repair of AAA with open surgery or
endovascular aortic repair (EVAR) should be considered to prevent AAA rupture, although the
morbidity and mortality associated with both techniques remain non-​negligible.

*e-​mail: nsaka@
chu.ulg.ac.be
https://doi.org/10.1038/
s41572-018-0030-7
An aneurysm is a permanent and irreversible local­
ized dilatation of an artery. This abnormal dilatation
involves all three layers of the vascular wall: the intima
(which faces the lumen of the vessel), the media and
the adventitia (Fig. 1). By contrast, a false aneurysm or
pseudoaneurysm is a dilatation secondary to arterial
injury, in which the outer wall is made of a fibrous
material devoid of any organized vascular structure.
A false aneurysm can also be created by the infiltration
of blood through a dissection (longitudinal cleavage) of
the arterial wall at the level of the media, with a sub­
sequent enlargement of the external dimensions of the
artery. Morphologically1, aneurysms can be fusiform,
when the dilatation involves the whole circumference
of the artery, or saccular, when only a part of the circum­
ference is involved (Fig. 1). Most aneurysms are fusiform,
even though the dilatation of the dorsal side of the aorta
is often limited by the presence of the spine.
Aneurysms that form in the abdominal aorta dis­
tal to the renal arteries (the infrarenal aorta, the most
common site for aortic aneurysm development) are
called abdominal aortic aneurysms (AAAs). There
is no consensus on the definition of AAA. In 1991,
the Society for Vascular Surgery and the International
Society for Cardiovascular Surgery Ad Hoc Committee
on Standards in Reporting proposed that a dilatation is
an AAA if the diameter of the infrarenal aorta is 1.5 times
the expected normal diameter2. However, in clinical
practice, the infrarenal aorta is considered aneurysmal
if the diameter is ≥30 mm (ref.3), but this definition
might not be appropriate for women, who have smaller
diameter arteries than men4, and for individuals with
arteriomegaly, a condition of generalized arterial dilata­
tion. When reporting a dilatation of the diameter of the
infrarenal aorta in a patient, the diameter of the undila­
ted adjacent aorta should be taken into consideration,
although this is not always feasible in clinical practice5.
Thus, AAA should be diagnosed when the ratio of the
diameters of the infrarenal and undilated suprarenal
aorta is ≥1.5. On the basis of the diameter of the aorta,
AAA can be classified as small (not considered for repair,
<55 mm) or large (≥55 mm), when surgical repair can
be considered6.
Aneurysms result from progressive changes in the
arterial wall in response to multifactorial causes;
the resultant changes in wall structure and arterial pres­
sure lead to thinning of the wall, with the degradation of
extracellular matrix (ECM) in the adventitia and loss
of vascular smooth muscle cells (VSMCs) in the media
increasing the susceptibility to rupture7. Theoretically,
if an AAA is left untreated, its diameter increases grad­
ually; large AAAs are at increased risk of rupture. AAA
ruptures can occur intraperitoneally, retroperitoneally
or, rarely, in other organs such as the duodenum or the
inferior vena cava. Rupture usually leads to sudden-​
onset abdominal or back pain and haemorrhagic shock.

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The severity of shock varies with the location and extent
of the rupture. This condition, if left untreated, results in
almost 100% mortality6. In very rare cases, AAA rupture
causes a small loss of blood in the retroperitoneal space,
where it can become contained, causing pain but no
haemodynamic instability. As most patients with intact
AAA are asymptomatic, AAA is commonly an undiag­
nosed condition. Incidental or systematic screening of
at-​risk groups is the most effective approach to prevent
AAA-​related death. Because of the high mortality asso­
ciated with AAA rupture, most patients diagnosed with
large AAAs are offered either open repair surgery (to
support the aneurysmal infrarenal aorta with inlay tube-​
shaped or bifurcated prosthetic vascular grafts sewn into
the aorta) or endovascular aortic repair (EVAR), where
a stent graft is introduced and placed inside the aneu­
rysm via the iliac arteries. The success of EVAR depends
on the morphology of the aorta and associated arteries;
EVAR can be accomplished safely in those >80 years
of age8.
This Primer provides a contemporary overview of
the pathogenesis, diagnosis, treatment and outcome
of patients with AAA, focusing on fusiform AAA.
Epidemiology
Disease burden
Incidence and prevalence. Globally and in developed
countries, the prevalence and incidence of AAA have
decreased during the past two decades, but in some areas,
such as Latin America and high-income Asian–Pacific
countries, the prevalence is possibly increasing9. The
prevalence also varies worldwide between ethnic groups
and between sexes9. Of note, overall, there is a lack of
solid knowledge on the true prevalence of AAA world­
wide, as reports on the prevalence of AAA detected via
ultrasonography screening programmes in women and
men are available  from only a few countries (see below).
Most reports show regional variations in treatment rates,
which might reflect a selection bias, as access to afford­
able health care varies greatly in different populations.
Finally, temporal variations in prevalence trends might
actually reflect changes in sociodemographics in some
Author addresses
1
Department of Cardiovascular and Thoracic Surgery, CHU Liège, University of Liège,
Liège, Belgium.
2
Surgical Research Center, GIGA-​Cardiovascular Science Unit, University of Liège,
Liège, Belgium.
3
UMR 1148, INSERM Paris 7, Denis Diderot University, Xavier Bichat Hospital, Paris, France.
4
Department of Vascular and Endovascular Surgery, Paracelsus Medical University,
Nuremberg, Germany.
5
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences,
Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
6
Department of Medical Imaging, Centre Hospitalier de Luxembourg, Luxembourg,
Luxembourg.
7
Vascular Surgery Research Group, Imperial College London, London, UK.
8
Graduate School of Health and Welfare, Yamaguchi Prefectural University, Yamaguchi,
Japan.
9
Department of Surgery and Clinical Science, Yamaguchi University Graduate School
of Medicine, Ube, Japan.
10
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
11
Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden.
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countries. The variations in prevalence for men in devel­
oped countries are best observed in population-​based
screening programmes10–12.
The most recent ultrasonography-​based screening
studies diagnose AAA in 1–2% of all 65-year-​old men
and in 0.5% of 70-year-​old women9–12. However, some
persons are diagnosed outside of these programmes, are
treated before 65 years of age or are non-​participants,
and all these situations would slightly increase the true
prevalence in the general population10,12. In Denmark,
the AAA prevalence is slightly higher, at 2.6% in
65-year-​old men and 0.9% in 71-year-​old women13.
A recent population-​based report from Sweden includ­
ing untreated and treated women and men showed a
slight increase in individuals diagnosed with intact AAA
over time (from 46 per 100,000 people of >45 years of
age in 2001 to 51 per 100,000 people in 2015, with a peak
at 73 per 100,000 people in 2011)14. This increase is likely
due to the introduction of screening in men rather than
a true general increase in the incidence of AAA in the
population. The decline in cases of ruptured AAA from
22 per 100,000 people to 12 per 100,000 people during
the same time period could confirm this assertion14.
There has been a decline in the number of male smokers,
which could contribute to the decline in both the AAA
prevalence and rupture15.
Morbidity and mortality. During the past decade,
AAA-​related death has been the 12–15th leading cause
of death in persons of >55 years of age in the United
States, the United Kingdom and several European coun­
tries, as reported by the Centers for Disease Control
and Prevention’s Web-​based Injury Statistics Query and
Reporting System (CDC WISQARS; see Related links),
the UK Office for National Statistics (UK Office for
National Statistics; see Related links) and the Swedish
National Board of Health and Welfare (Swedish National
Board of Health and Welfare; see Related links). The
overall mortality in patients with AAA is high, in both
treated and untreated patient groups, when compared
with the general population, best shown by the excess in
observed mortality (standardized mortality rate (SMR)
1.71 for patients with AAA who have been treated),
mainly owing to the high co-​occurrence of atheroscle­
rotic disease, mostly cardiovascular disease13,16,17. Besides
cardiovascular causes of death, cancer is a common
cause of death in patients with AAA11,16–18. The true inci­
dence of deaths associated with ruptured AAA outside
of health-​care institutions is difficult to determine given
the decline in autopsy rates, but 50% of patients with
ruptured AAA have been reported to die before they can
be admitted to hospital19.
Although women are under-​represented in most
AAA studies, their outcomes are often reported to be
worse than those in men, including a higher rupture
risk of small aneurysms and more-​complicated aneu­
rysm morphology, which makes the AAA more difficult
to treat with standard surgical care20–22. Women with
AAA also seem to have a worse prognosis than men.
A 2017 meta-​analysis comparing the outcomes of AAA
repair (EVAR and open repair surgery) between men
and women showed that 30-day mortality was higher
 Primer

a b True aneurysms
Right carotid artery Saccular Fusiform False aneurysm
Subclavian Left carotid artery Anterior–posterior
artery
Aortic arch Adventitia diameter
Ascending aorta

Media
Transverse
Intima diameter
Descending
thoracic aorta A

Aortic annulus

Smooth
muscle cell C D
Diaphragm
Abdominal aorta

Coeliac trunk
Endothelial
Left renal cell
Superior artery
mesenteric Infrarenal aorta
artery B
Inferior
mesenteric Vertebra
Right common
artery
iliac artery
Intima Media Adventitia
Right external Left internal
iliac artery iliac artery Internal elastic membrane External elastic membrane

Fig. 1 | AAAs. a | Schematic of aortic anatomy. The descending thoracic aorta spans from distal to the origin of the left
subclavian artery to the diaphragm; the infrarenal aorta is the site where abdominal aortic aneurysms (AAAs) develop.
The average diameter of a normal, healthy infrarenal aorta is 1.80 ± 0.24 (s.d.) cm in men and 1.55 ± 0.19 (s.d.) cm in women226.
b | Morphological classification of aneurysms; inset shows details of the normal aortic wall. Regardless of the imaging
method, the dilatation of the aorta should be measured in both anterior–posterior and transverse directions. Measurement
could be based on inner-​to-inner, leading edge-​to-leading edge or outer-​to-outer boundaries; outer-to-outer boundary
measurements indicate the maximal diameter. Part a adapted from ref.227, Springer Nature Limited.

in women than in men both for EVAR (2.3% and 1.4%,
respectively, OR 1.67, 95% CI 1.38–2.04) and open repair
surgery (5.4% and 2.8%, respectively, OR 1.76, 95% CI
1.35–2.30)22. Women were also less likely to be mor­
phologically eligible for EVAR and were less frequently
offered prophylactic repair than men. The authors
suggested that a smaller threshold for intervention for
women improves outcomes, as women have smaller aor­
tas than men4. However, the benefit of such a measure
could be hindered by the fact that women are reported
to have smaller general vascular dimensions and more
challenging morphology, both of which can complicate
all elective repair procedures.
Differences in outcomes following AAA repair
between different ethnicities have also been demon­
strated, with specific ethnic groups having worse short-​
term and mid-​term prognoses than others. Maori
patients in New Zealand had inferior mid-​term survival
after EVAR and open repair surgery compared with all
other ethnic groups in New Zealand23. Analysis of data
from the Vascular Quality Initiative demonstrated that
black patients in the United States have a higher risk of
developing postoperative renal failure and returning
to the operating room than white and Asian patients24.
Asian patients were more likely to experience post­
operative myocardial infarction than African-​American
and white patients24. Other studies have shown that
Hispanic individuals in the United States have higher
perioperative morbidity rates and mortality following
both EVAR and open repair surgery than other ethnic
groups25,26. Different factors have been suggested to
explain these differences in outcomes between ethnicities.
These factors include different access to high-​quality
health-​c are centres (for example, Afro-​C aribbean
patients are treated more often than other ethnic groups
in low-​volume centres); differences in the anatomical
extent of the AAA (for example, Afro-​Caribbean and
Asian patients seem to have concomitant iliac artery
aneurysms requiring more-​complex procedures more
often than patients in other ethnic groups); and differ­
ences in preoperative comorbidities (for example, black
patients have a higher incidence of hypertension than
non-​black patients).
Risk factors
The common fusiform AAA is a complex, multifactor­
ial disease with both genetic and environmental risk
factors that usually manifests at late age. The abdomi­
nal infrarenal aorta is a common site for atherosclerotic
non-​aneurysmal occlusive disease, and AAA is often
associated with atherosclerosis. AAAs and occlusive
atherothrombotic disease share several risk factors,
including smoking, older age, a positive family history
and male sex6,12,27–29.
However, current evidence based on molecular stud­
ies has demonstrated that atherosclerosis and AAA are
distinct disease entities30. Several at-​risk groups have a
very high prevalence of AAA, such as smokers, persons
with a family history of AAA and patients with coro­
nary heart disease, hyperlipidaemia, hypertension and
chronic obstructive pulmonary disease (COPD)15,18,31,32.
The prevalence of AAA among individuals with diabe­
tes mellitus is lower than in the general population, in
contrast to the prevalence in individuals with occlusive

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Table 1 | Genetic loci associated with abdominal aortic aneurysms

SNP Chromosome Nearest gene(s) Possible biological function MAF OR (95% CI) P value
rs602633 1 PSRC1, CELSR2 Mitosis (PSRC1), plasma membrane protein, 0.200 0.879 (0.842–0.918) 6.58 × 10−9
and SORT1 possibly a receptor (CELSR2), and lipid metabolism
(SORT1)
rs4129267 1 IL6R Inflammation 0.370 0.876 (0.846–0.908) 4.76 × 10-13
rs1795061 1 SMYD2 Gene regulation 0.333 1.131 (1.090–1.174) 8.80 × 10−11
rs10757274 9 CDKN2BAS1 Unknown, but a risk locus for many other diseases 0.457 0.806 (0.778–0.834) 1.54 × 10−33
including coronary artery disease, intracranial
aneurysms, several cancers, periodontitis,
Alzheimer disease, endometriosis, frailty in elderly
people and glaucoma
rs10985349 9 DAB2IP Tumour suppressor 0.193 1.171 (1.118–1.226) 2.40 × 10−11
rs9316871 13 LINC00540 Unknown 0.204 0.873 (0.837–0.911) 4.75 × 10−10
rs6511720 19 LDLR Lipid metabolism 0.097 0.804 (0.759–0.851) 7.90 × 10−14
rs3827066 20 PCIF1, ZNF335 Gene regulation (PCIF1 and ZNF335) 0.184 1.223 (1.168–1.281) 2.13 × 10−17
and MMP9 and protease (MMP9)
rs2836411 21 ERG Gene regulation 0.367 1.113 (1.074–1.154) 5.80 × 10−9
−8
The table summarizes the genome-​wide significant (P < 5 × 10 ) and validated associations. CDKN2BAS1, CDKN2B antisense RNA 1, also known as ANRIL; CELSR2,
cadherin EGF LAG seven-​pass G-​type receptor 2; DAB2IP, DAB2 interacting protein; ERG, v-ets avian erythroblastosis virus E26 oncogene homologue; IL6R, IL-6
receptor; LDLR, low-​density lipoprotein receptor; LINC00540, long intergenic non-​protein coding RNA 540; MAF, minor allele frequency (a measure of how
common the variant is in the population); MMP9, matrix metalloproteinase 9; PCIF1, PDX1 (pancreatic and duodenal homeobox 1) C-​terminal inhibiting factor 1;
PSRC1, proline and serine rich coiled-​coil 1; SMYD2, SET and MYND domain-​containing 2 (SET domain-​containing proteins, such as SMYD2, catalyse lysine
methylation); SNP, single nucleotide polymorphism; SORT1, sortilin 1; ZNF335, zinc-​finger protein 335. Data from ref.49.

atherothrombotic disease33. The AAA growth rate is also
slower in patients with diabetes mellitus. The possibility
that metformin, a commonly used drug used to manage
type 2 diabetes mellitus, inhibits AAA growth has been
addressed in several recent reports34,35.
The lower prevalence and later development of dis­
ease in women may be partly explained by sex-hormone-
related protection, equivalent to that observed in other
manifestations of cardiovascular disease20. The possible
protective effects of exogenous or endogenous female
sex hormones (such as oestrogen) on AAA develop­
ment have been investigated in some registry-​based
and questionnaire-​based studies, showing conflicting
results20. It is highly probable that smoking is a more
detrimental risk factor in women than in men, perhaps
modulated by the effect of smoking on reproductive func­
tion in women, such as premature menopause, and the
negative effects on lipid levels, lowering high-​density
lipoprotein (HDL) and increasing triglycerides15,20,36,37.
Genetic risk factors for AAA. Aortic aneurysms can
be found in patients with rare genetic diseases, such as
Ehlers–Danlos syndrome type IV (also known as the
vascular type), Marfan syndrome, Loeys–Dietz syn­
drome and fibromuscular dysplasia38. Most patients with
AAAs do not, however, have any of these rare genetic
diseases. Approximately 10–20% of patients with AAA
have at least one relative with this condition29,39, and
formal segregation analyses indicate that genetic mod­
els explain this familial aggregation40,41. On the basis of
two large twin studies from Sweden42 and Denmark43,
the phenotypic variance determined by genetics is esti­
mated to be 70–80%, whereas non-​shared environmen­
tal effects (such as smoking, infections or occupational
exposure) contribute to the remaining 20–30%. Having
a first-​degree relative with an AAA is a significant risk
factor (OR 1.96, 95% CI 1.68–2.28) for the person to
develop an AAA28. A positive family history for AAA has
been suggested to have clinical implications, as familial
AAA cases are reported to have increased growth rate44
or higher rupture risk29 than sporadic cases and possibly
also worse outcomes after EVAR45,46.
Family-​b ased genetic studies 47 are difficult to
carry out for AAA because it typically manifests at an
advanced age and is often a deadly disease; these factors
limit the number of patients available for such studies.
AAA is also usually asymptomatic, and ultrasonography
screening is required to detect AAA in family members.
Genetic association studies using cases and controls
have become the preferred method to identify genetic
risk factors for AAA48. The largest genome-​wide associ­
ation study (GWAS) for AAA included 4,972 AAA cases
and 99,858 controls in the discovery phase, followed
by genotyping in independent validation cohorts with
5,232 AAA cases and 7,908 controls49. The combined
analyses with the discovery and validation data sets iden­
tified nine AAA risk loci (Table 1), five of which were
previously known and four of which were new loci.
Despite their highly significant associations with
AAA (Table 1), these nine genetic loci explain only a small
proportion of the heritability of AAA. Furthermore, the
biology underlying these genetic associations still needs
to be defined. One study used VSMCs isolated from
patients with AAA and controls to assess DNA methyl­
ation in the genes found within the nine associated loci50.
Altered DNA methylation levels were found in three
genes (v-ets avian erythroblastosis virus E26 oncogene
homologue (ERG), IL-6 receptor (IL6R) and SET and
MYND domain-containing 2 (SMYD2)), suggesting
that epigenetic mechanisms such as DNA methylation
are implicated in AAA development. The proteins ERG
and SMYD2 are transcriptional regulators controlling

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the expression of other genes, and IL6R is the receptor
for the inflammatory marker IL-6. Additional functional
studies will help to dissect the pathobiology leading to
AAA development, growth and rupture. Future studies
need to take into account these different stages of the
AAA disease, as the molecular mechanisms and genetic
factors probably differ in the initiation, growth and
rupture of AAA51.
Another important genetic finding for AAA comes
from a study that demonstrated that longer overall telo­
mere length was associated with reduced risk (OR 0.63,
95% CI 0.49–0.81) of AAA when compared with indi­
viduals without AAA. Interestingly, in the same meta-​
analysis, longer telomere length was associated with an
increased risk of several types of cancer52.
Finally, AAAs seem to differ genetically from thor­
acic aortic aneurysms and dissections, and these con­
ditions do not usually co-​occur in the same family53.
The overlap between the genetic loci currently known
to be associated with thoracic aortic aneurysms and dis­
sections and those associated with AAA is limited54,55,
suggesting that the pathobiology in the two aneurys­
mal diseases is distinct. For example, none of the nine
AAA loci have been associated with thoracic aortic
aneurysms and dissections, but interestingly, one of
them (rs10757274) has been associated with intracranial
aneurysms56. It is also worth noting that the embryolog­
ical origin of VSMCs in the abdominal aorta is splanch­
nic mesoderm, whereas VSMCs in the thoracic region
originate from neural crest54. VSMCs with different
embryo­logical origins respond differently to biolog­
ical stimuli such as cytokines and growth factors. The
best studied example is the response to transforming
growth factor-​β (TGFβ). TGFβ treatment of neural crest
VSMCs demonstrated increased DNA synthesis and
collagen production, whereas mesodermal VSMCs did
not respond57.
Growth and rupture risk of AAA
In the literature and in clinical practice, the continuous
enlargement of an AAA due to a degenerative weaken­
ing of the wall is called ‘growth’ of the AAA. The mean
growth rate is 2.5 mm per year in AAAs (39–49 mm in
diameter) and is 20–25% faster in current smokers and
25% slower in patients with diabetes mellitus, possibly
due to metformin treatment or to alterations in ECM
turnover34,58,59. A minority of patients diagnosed with
AAA do not have a detectable enlargement of their
AAA60. The majority of aneurysms enlarge over time in
a nonlinear mode, and the measurement methodology
influences the accuracy. Other factors that have been
inconsistently reported to be associated with increased
growth are hypertension, female sex and COPD34,60,61.
Individuals with an undiagnosed AAA who are not
under surveillance are at risk of AAA rupture, which
can lead to sudden death from massive intra-​abdominal
bleeding. Thus, patients diagnosed with AAA should be
surveyed. The most commonly reported factor influenc­
ing the risk of rupture is the size of the aneurysm. Size
is, therefore, the basis for all surveillance protocols of
patients with AAA6,62; however, contemporary reports
show that other factors (such as AAA morphology)
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influencing the risk could also be considered. The accu­
racy of predicting the risk of AAA rupture on the basis
of AAA diameter holds some weaknesses because in a
few patients, the AAA will rupture at <55 mm diameter
even under surveillance at a vascular clinic34. One of the
larger meta-​analyses in the field confirmed the higher
rupture risk in women than in men and an increased
risk in current smokers and those with untreated hyper­
tension20,34,61. Thus, precision medicine options to iden­
tify more patient-​specific rupture risk predictors are
under investigation, using factors such as aneurysm
volume, aortic size index (the association between
aortic width and body surface area), family history of
AAA, presence of diabetes mellitus and biomarkers,
such as circulating matrix metalloproteinases (MMPs)
or microRNAs22,63–69. The increased rupture risk reported
for women could be associated with the relatively larger
aortic size compared with the expected aortic diam­
eter; thus, the aortic size index could be a future tool
to consider for optimized individualized surveillance
of women69. Some registry-​based reports suggest that
the use of fluoroquinolones causes collagen breakdown
in the aortic wall, which could increase the risk of hos­
pital care or death from aortic disease (thoracic aortic
aneurysms, dissection or AAA)70.
The reported rupture risk, which varies as a function
of diameter, has been derived from studies of patients
with AAA who did not receive preventive repair surgery
owing to the presence of comorbidities62. However, the
2018 North American guidelines indicate that the rupture
risk, based on diameter alone, may be lower than previ­
ously reported62. Previously reported annual rupture risks
for patients with AAAs were negligible for AAA <40 mm,
0.7–1.0 per 100 person-​years for AAA 40–54 mm, 9 per
100 person-​years for AAA 55–59 mm, 10 per 100 person-​
years for AAA 60–69 mm and 33 per 100 person-​years
for AAA >70 mm (refs62,71). A contemporary pooled
analysis indicates that the annual rupture risk would
be 5.3 per 100 person-​years for AAA 55–70 mm and
6.3 per 100 person-​years for AAA >70 mm; this reduction
might be associated with the declining number of current
smokers among patients with AAA. Women with small
AAAs seem to have a higher rupture risk than men60,61.
Mechanisms/pathophysiology
Our knowledge of AAA pathobiology is mostly based
on histological and molecular evaluation of tissue sam­
ples of the abdominal aorta removed during open repair
surgery, mostly of large AAAs, compared with aortas
with occlusive disease and healthy aortas, although ani­
mal models are available (Box 1). AAA is characterized
by proteolytic fragmentation of the ECM, VSMC death,
immune cell infiltration of the adventitia and increased
oxidative stress in the aortic wall. Molecular studies
using high-​throughput microarray-​based genome-​wide
analyses have demonstrated that AAAs are character­
ized by a more important adaptive immune response
than occlusive atherothrombotic aortic disease 30.
Aneurysms are characterized by a more important
medial injury than intimal atheroma, mainly caused by
proteolysis and oxidative processes72. The ECM, with
its main fibrillar insoluble components, elastin and
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Box 1 | Animal models of AAA
A recent review summarized numerous publications on the experimental animal models
of abdominal aortic aneurysm (AAA)184. In animal models, only pharmacological
approaches that both degrade the arterial wall and maintain intraluminal thrombus (ILT)
biological activity would perpetuate the aortic injury212, thereby enhancing the
dilatation and possible subsequent rupture97. In this context, bacterial contamination of
the ILT by weak pathogens, such as Porphyromonas gingivalis, mainly from dental and
periodontal origin, in animals as well as in humans, may promote the progression of
AAAs97 via neutrophil recruitment and activation213. One of the common features
of experimental animal models is that the progression of the dilatation stops with the
cessation of the initial stimulus (elastase, angiotensin II or calcium chloride), initiating a
process of healing by mesenchymal cells (mainly vascular smooth muscle cells (VSMCs)).
This observation could suggest that, in human disease, the stimuli do not cease, as AAAs
progressively enlarge. It also supports the staccato evolution of AAA in humans, in which
latent (healing) phases are present between evolutionary phases (stimuli)214. However,
such comparisons between human and experimental models are confounded by three
important stimuli not found in most animal models: smoking, ageing and hypertension.
collagen, supports the haemodynamic load of the aortic
wall. The action of proteases that progressively degrade
the ECM is considered the most influential mechanism
for the development and progression of AAAs (Fig. 2).
Atherothrombosis and haemodynamics
Although AAA is a different disease entity from occlu­
sive atherothrombotic diseases, these two conditions
share common initial pathophysiological mechanisms.
In occlusive atherothrombotic diseases, the disruption
to the blood flow caused by atherosclerotic lesions
(also called atherosclerotic plaques or atheroma, that
is, subendothelial accumulations of fat (lipids including
low-​density lipoprotein (LDL)) is compounded by the
formation of a superimposed intraluminal thrombus
(ILT), a blood clot.
Atheroma begins with an outward convection of
plasma lipoproteins, mainly LDL, through the wall.
These initial fatty streaks evolve towards the forma­
tion of a plaque, and luminal intraparietal haemor­
rhage can lead to the formation of intraplaque and/or
luminal clots, forming the pathological substrate for
both occlusive atherothrombotic disease and AAA73.
Atherothrombotic diseases are specific to arteries,
with atheroma localizing preferentially to specific sites,
including those proximal to branching and bifurcations,
such as the infrarenal aorta.
The propensity of the infrarenal aorta for dilatation
associated with atherothrombotic disease is due to spe­
cific haemodynamic conditions associated with the iliac
bifurcation; these conditions promote pressure-​reflective
waves, owing to the impact of blood flow on a bifurca­
tion. Pressure-​reflective waves within the blood trans­
form kinetic energy into potential energy. This physical
phenomenon increases the outward radial transporta­
tion of plasma molecules and microparticles74 through
the wall and collisions of circulating cells between one
another and the aortic wall (Fig. 2). A study in the 1980s
showed that AAA was more frequent in men with above-​
knee amputation, and a greater curvature of the aorta
developed on the opposite side of the non-​amputated
leg75, suggesting that reflection waves on the remaining
limb bifurcation play an important part in the develop­
ment and lateralization of AAAs. Haemodynamics also
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contributes to the understanding of the different risks of
ILT at low blood pressure (embolic risk) or high blood
pressure (arterial wall degradation and rupture risk,
embolic risk not completely excluded). In the aorta,
where the blood pressure is high, radial convection (out­
ward mass transport through the wall generated by the
pressure gradient between the luminal blood pressure
(100 mmHg) and the interstitial pressure in the adventi­
tia (10 mmHg)) pushes the ILT components within the
wall, which may contribute to progressive dilatation and
risk of rupture76. In particular, changes in haemodynam­
ics within the ILT (bleeding within the ILT, the so-called
attenuating crescent sign) may indicate urgent appraisal
for intervention77. Thus, despite the ability of the ILT to
limit biomechanical wall stress owing to the increased
full thickness of the wall78, the outward convection of
proteolytic and oxidative activities from the ILT to the
wall outweighs its biomechanical protective advantage.
The role of the intraluminal thrombus during the devel-
opment of AAAs. The structure of AAAs is composed
of, starting from the aorta lumen, a multilayered ILT (in
the majority of cases); a thin, degraded media, with few
VSMCs and elastic components; and an inflammatory
and/or fibrotic adventitia, which can be thicker than nor­
mal owing to inflammation and oedema. However, the
ILTs associated with AAAs have different features than
the ILTs that form in occlusive atherothrombotic disease
(see below). Permanently renewed by circulating blood,
the ILT is a highly proteolytic and oxidative environ­
ment, and no cells (endothelial cells, SMCs or mesen­
chymal progenitors) can spread and pro­liferate in close
contact with the ILT. Thus, owing to the presence of the
ILT, there is neither endothelium nor intima in AAAs.
The role of the ILT is linked to its biological activities,
which are continuously renewed at the luminal inter­
face with blood. In AAAs, the ILT is a spatiotemporally
dynamic neo-​tissue that is able to degrade the underlying
aortic wall through one mechanism. First, the ILT tem­
porally recruits fibrinogen, circulating cellular elements
such as polymorphonuclear (PMN) leukocytes, includ­
ing neutrophils, platelets79 and red blood cells (RBCs)80,
and macromolecules such as HDL81, and it could thereby
deplete these elements from the circulation. Second, the
enzymes and other components released by the cells that
aggregate at the ILT and by fibrin (plasmin), spatially
convected outwardly through the wall, contribute to
ECM degradation and the adventitial immune response.
Of note, ILT development is also enhanced by trapped
bacteria (see below).
Rarely, patients with AAAs also develop (as a con­
sequence of ILT activities) consumptive coagulopathy.
These patients have increased risk of systemic bleeding,
owing to decreased platelet counts and plasma fibrino­
gen levels and associated increases in plasma D-​dimers
(a product of fibrin degradation)82. D-​dimers are the
hallmark of fibrinolysis and plasmin activation, which
have a major role in proteolytic injury of the wall. The
usual physiological healing response to this injury may
include the recruitment of stromal cells, VSMCs and cir­
culating mesenchymal cell progenitors to the damaged
tissue. However, the consumption of RBCs, neutrophils
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and fibrinogen by the ILT could hamper such cellular
responses83. These biological activities are not dependent
on the ILT volume but on its age: the fresher the ILT, the
more biologically active it is, particularly at the edges.
Extracellular matrix
The blood-​containing function of the arterial wall
mainly depends on the ECM, whose components are
synthesized by SMCs and processed by VSMCs. Lysyl
oxidase, synthesized and secreted by VSMCs, is the main
enzyme involved in the maturation of fibrillar struc­
tures (elastin and collagen), possibly rendering them
inso­luble. The ECM is constituted of macrofibrillar
and microfibrillar structures of crosslinked proteins
(macro: elastin and collagen; micro: fibronectin, fibril­
lin, and so on). In this context, elastin is reputed to resist
dilatation and collagen to resist rupture84.
The degradation of the ECM is largely due to out­
wardly convected proteases85. Because of pressure gradi­
ent between the circulating blood (≥80–120 mmHg in
older persons) and the interstitial pressure in the adven­
titia (10 mmHg), proteases released by neutrophils, or
directly plasma-​borne zymogens, are outwardly con­
vected through the wall, provoking ECM degradation
and progressive dilatation.
Elastin damage was preferentially associated with
progressive dilatation, whereas collagen damage led
to rupture84. Two protease families are predominantly
linked to AAA progression: serine proteases, which
degrade the ECM directly or indirectly, by degrading
adhesive proteins (such as fibronectin and fibrillin)
that are more sensitive to proteolysis than the macro­
molecular components, and activated MMPs67, which
can directly degrade the ECM (Fig. 2). Of note, these

Cyclic stretching
Blood flow

Mast cell
ILT

Fibrinogen Antibody
Plasminogen TLO
VSMC
Fe ++

Oxidation Adventitia
angiogenesis
Myeloperoxidase

Pro-MMPs MMP8 Elastin and collagens

MMP9

RBC Plasmin Adhesive glycoproteins

Activated u-PA
platelet
Leukocyte elastase Elastin

Neutrophil
Proteolysis VSMC disappearance ECM breakdown
Inward injuries
• Cell collision
• Plasma protein convection

Media Adventitia
Internal elastic membrane External elastic membrane
Fig. 2 | A speculative model of AAA progression. As in the progression of other forms of atherothrombosis, interactions
with various blood components, soluble plasma molecules and circulating cells can possibly result in an injury in the aortic
wall. These interactions promote the formation of an intraluminal thrombus (ILT) that has proteolytic and oxidative
activities. These processes facilitate breakdown of the extracellular matrix (ECM), apoptosis of vascular smooth muscle
cells (VSMCs) and activation of immune responses80. Leukocyte elastase (a serine protease) can degrade the fibrillar ECM.
Plasmin (another serine protease) can degrade the intermediate adhesive proteins, provoking VSMC detachment and
apoptosis228, and activate the pro-​matrix metalloproteinases (MMPs; the inactive precursors of MMPs). Plasminogen is
activated into plasmin on ILT fibrin by tissue-​type or urokinase-​type plasminogen activator (t-​PA or u-​PA, respectively,
both serine proteases). u-​PA and leukocyte elastase are released by neutrophils. Elastase is also able to degrade fibrin,
generating fibrinopeptides differing from D-​dimers, which could serve as biomarkers in abdominal aortic aneurysm (AAA)
evolution229. MMP9 is released in association with neutrophil gelatinase-​associated lipocalin (NGAL) by neutrophil
activation and death230, and acts directly on elastin. MMPs are synthesized as inactive precursors and must be locally
activated by partial plasmin proteolysis and/or by reactive oxygen species. The adventitia of AAAs is also enriched by mast
cells containing tryptase and chymase in relation to adventitial neoangiogenesis231. Mast cells are activated by IgE binding
and clustering, which triggers degranulation, releasing different vasoactive factors (serotonin, histamine, heparin, tumour
necrosis factor and prostaglandins). RBC, red blood cell; TLO, tertiary lymphoid organ.

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proteolytic mechanisms potentially underlie the oppo­
site effects that smoking and diabetes mellitus have
on AAA expansion, as smoking is associated with
increased proteolytic activity, whereas diabetes mellitus
is associated with reduced sensitivity to proteolysis due
to glycation crosslinking of the ECM macromolecules
and microfibrils.
The partial disappearance of VSMCs is mainly due
to the proteolytic and oxidative environment in the aor­
tic wall. The serine proteases plasmin and elastase can
provoke VSMC detachment and death86,87. In parallel,
intense oxidative stress can also provoke VSMC death.
For instance, ceroids (yellow-​brown polymers com­
posed of oxidized lipids and proteins) are a hallmark of
oxidation, are highly toxic for VSMCs and are present
in the AAA wall87,88.
All these proteases are regenerated and activated in
the most luminal layer of the ILT and are then outwardly
convected and percolate through the wall, provoking
ECM degradation and VSMC loss89. The proteolytic
injuries are partly limited by antiproteases, including
tissue serpins and tissue inhibitors of MMPs (TIMPs).
Thus, such plasma protease–antiprotease complexes
could hypothetically serve as circulating markers of
AAA progression, but the evidence for their use in
clinical practice has not been substantiated. The most
sensitive and accessible biomarkers for measurement
would potentially be plasma MMP9 (ref.90), leukocyte
elastase–antitrypsin complexes, D-​dimers91 and ECM
degradation products.
Calcification. Calcification (precipitation of ionized
calcium in soft tissue) appears very early in the evolu­
tion of aortic atherothrombosis and AAAs. Calcification
depends on the presence of inorganic phosphates.
Box 2 | Mycotic AAA
Mycotic abdominal aortic aneurysm (AAA) is not entirely an accurate term, as fungal
infections rarely cause or contribute to aneurysms, and mycotic (or rather infectious)
aneurysms are predominantly caused by bacteria. It is more common in Asian
populations than in Western populations215. A mycotic AAA occurs as commonly in
the thoracic as in the infrarenal aorta and is more often saccular than fusiform. The
pathogenesis of mycotic AAA is not completely understood; there might be an
underlying vulnerable lesion or plaque in the aortic wall that makes the wall susceptible
to colonization by circulating bacteria (for example, from endocarditis or urinary tract
infections216,217), which triggers AAA development. The type of bacterium differs based
on geographical location, with a more diverse pattern in Europe and the United States
(30% Staphylococcus spp., 11% Streptococcus spp. and 7–10% Escherichia coli) than in
Asia (60% Salmonella spp.)218–222. In 20–30% of patients, the pathogen has not been
determined218,219. The patients are often elderly and have several other comorbidities,
such as diabetes mellitus, renal insufficiency or HIV infection219–222. Patients with
mycotic AAA have a high mortality, and they can develop a fistula, an erosive process
between their aorta and bowel (aortoenteric fistula) that commonly causes
gastrointestinal bleeding, anaemia and an extremely poor prognosis223.
The only curative treatment for mycotic AAAs is surgical, by local resection of the
aneurysm, and commonly an extra-​anatomical bypass. Antibiotic therapy is important
preoperatively and postoperatively, but there are few reports on this as a sole curative
treatment222,224. A 6–12-month period of antibiotic therapy is recommended in patients
successfully treated with open repair surgery. In a large multicentre series, 132 patients
were treated for mycotic AAA over 20 years, with 30-day and 1-year survival of 86% and
79%, respectively225. The increasing use of endovascular aortic repair (EVAR) in patients
with mycotic AAA is debated and should probably be accompanied by a longer
preoperative and postoperative use of antibiotics219–221.
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Sources of inorganic phosphates in arterial tissue are
intracellular energy metabolism (ATP recycling), extra­
cellular lipoproteins, cell membrane phospholipids, free
extracellular DNA (via the backbone phosphates) and
the products of alkaline phosphatase. Calcification has
been observed in the AAA wall, potentially associated
with VSMC death and release of free DNA92. There is
conflicting evidence regarding the role of aneurysmal
aortic wall calcification in disease progression93,94.
Innate and adaptive immunity
AAA progression involves both innate and adaptive
immunity. Under physiological conditions, the media
of the infrarenal aorta is an avascular tissue and an
immune-​privileged site devoid of capillaries. Thus,
the diapedesis (the passage of blood cells through the
intact walls of the capillaries) of circulating leukocytes
to the media depends on neoangiogenesis95. By con­
trast, the external adventitia of the aorta is fully vas­
cularized, enabling leukocyte diapedesis, innate and
adaptive immunity and inward sprouting of new ves­
sels in response to growth factors. The inner layer of
the adventitia is the preferred, and commonly the only,
site for the development of intense neoangiogenesis. In
the AAA context, relative hypoxia and phospholipid
metabolism producing eicosanoids could trigger neo­
angiogenesis by induction of vascular endothelial growth
factor (VEGF) overexpression in macrophages and
VSMCs. This neo­angiogenesis includes dense arterioles,
capillaries, venules and lymphatic vessels96.
Innate immune activities involve the diapedesis of
PMN leukocytes in the ILT, mainly by interaction with
activated platelets, exposing P-​selectin, which binds
to PSGL1 expressed on neutrophils and macrophages
in the adventitia. PMN leukocyte activation and
death result in a release of granule contents, including
proteases, oxidant peptides, myeloperoxidase and pro-​
inflammatory mediators such as IL-8. The outward
radial convection of degradation products and medi­
ators results in endocytosis, whereas phagocytosis mainly
takes place in the inner adventitia, where macrophages
predominate. The principal endocytic and/or phago­
cytic activity detected is the storage of ferric iron (the
storage and recycling of the redox-​active ferrous iron
from haem) from RBCs within CD68+ cells (CD68 is
a marker of phagocytic functions but not of a specific
cell lineage), including macrophages and fibroblasts.
Ferric iron deposits can also be observed in periaortic
lymph nodes7.
Bacteria circulating in vessels have a high affinity for
thrombi. In AAAs, the ILT fosters compartmentaliza­
tion of pathogens and promotes local innate immunity97.
In response to bacterial infiltration, neutrophils are
recruited to the ILT and release neutrophil extracellu­
lar traps (NETs); NETs are highly charged networks of
chromatin (DNA and histones) able to retain proteases
and oxidant molecules in the ILT milieu, potentially
promoting aneurysmal growth and risk of rupture.
Thus, viral and bacterial breakdown products further
trigger innate and adaptive immunity, contributing to
AAA pathogenesis. Bacterial infection can also cause a
subtype of AAA, called mycotic AAA (Box 2).
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a Ultrasonography b CT c MRI

*
*
*

Fig. 3 | Conventional imaging of AAA. a | Ultrasonography sagittal section of an infrarenal abdominal aortic aneurysm
(AAA; indicated by arrows) with parietal thrombus (asterisk) in a man. b | CT sagittal image of the AAA (arrows) with
parietal thrombus (asterisk) in the same patient. c | 2D T1-weighted post-​contrast MRI sagittal image in the same patient.
Images courtesy of N. Sakalihasan, University of Liège, Belgium.

Adaptive immune responses to the proteolytic
and/or oxidative injuries of the wall also take place in
the adventitia95. This immune response is character­
ized by the development of adventitial tertiary lym­
phoid organs (TLOs), which are organized lymphocytic
neo-​granulomas with a germinal centre composed of
B cells and can mature the adaptive immune response
towards antibody production. These germinal centres
are surrounded by endothelial venules, follicular den­
dritic cells and T follicular helper cells, which stimulate
immunoglobulin switching through a specific and com­
plex cytokine network98. This adaptive immune response
depends on two main conditions: a specific inter-​T cell
and interleukin network to organize the TLO struc­
ture and outwardly convected neo-​antigens to drive anti­
body maturation. Neo-​antigens are self-​molecules with
oxidative or proteolytic modifications that reveal new
modified epitopes that could stimulate the immune sys­
tem. TLOs produce polyspecific antibodies against these
neo-​antigens (Fig. 2). There is no direct retro-​diffusion
of antibodies to the media or the ILT; the antibodies
are released into the general circulation and reach their
molecular targets from the arterial circulation.
There is evidence that complement pathways are
activated in AAA99. In humans, molecular elements
of the complement cascade predominate in the ILT99.
Nevertheless, the exact pathophysiology of complement
activation in human AAA remains to be more clearly
defined. Current data support the hypothesis that the
adventitial immune adaptive response in AAAs might
be more an active participant than a bystander in AAA
growth and rupture risk.
Inflammatory AAA. An inflammatory AAA is a clinical
diagnosis based on thickened anterior and lateral aortic
wall, including ILT observed in radiological examina­
tions and confirmed during open AAA repair surgery100.
Inflammatory AAAs are rare and are associated with
the exacerbation of the adventitial immune response,
involving oedema, porosity, phagocytosis and a fibrotic
healing process. The adventitial inflammatory reaction
creates a close adhesion between the aortic wall and the
neighbouring organs: the duodenum, small intestine,
sigmoid colon, ureters and even rectum. Pathological
examination of these adhesions shows dense fibrosis
with an intense infiltration of lymphocytes101. In this
context, the IgG4 immune response could play a specific
part in this inflammatory form102,103.
Oxidative stress
Oxidative stress is present in a tissue when the free rad­
ical production exceeds the capacity of the antioxidant
defence. This imbalance leads to cell death as a conse­
quence of the production of oxidized proteins, peroxides
and DNA damage73. It also activates pro-​MMP2 and pro-​
MMP9, which degrade the collagen fibres in the arte­
rial wall104. By modifying protein antigenicity, oxidative
stress is the main determinant of the immune adaptive
response in AAA. Interestingly, smoking potentially acts
by increasing oxidative stress. The two main sources of
oxidative stress in human AAA are oxidases from PMN
leukocytes (NADPH and myeloperoxidase) and redox-​
active ferrous iron (Fe2+) as a catalyst of oxidase activi­
ties (Fenton reaction) released by trapped RBCs in the
luminal layer of the ILT. In this context, the trapping of
RBCs by the luminal ILT could be so important that it
creates a perturbation of iron metabolism and consump­
tive anaemia80. Myeloperoxidase and iron metabolism
markers can be detected in patient plasma as oxidative
stress markers produced by neutrophils and RBCs. Free
radical production has also been correlated with clinical
features and the overall mortality risk105.
Circulating HDL particles are dysfunctional in
patients with AAA106, and AAA growth has been asso­
ciated with a decrease in circulating APOA1 (the major
protein component of HDL) and HDL81. The decrease in
HDL levels is directly linked to their convection through
the highly oxidative environment of the ILT, the oxi­
dation of APOA1 and the dissociation of APOA1 and
release of its lipid cargo107.
Diagnosis, screening and prevention
Clinical diagnosis of AAA
In countries with no population-​based screening pro­
grammes, most individuals with an intact, asymptomatic
AAA referred to vascular departments are diagnosed
incidentally with AAA when a radiological or ultrasono­
graphy examination is performed for another medical
condition. This situation changes; where population-​
based screening in men has been introduced, screening

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a PET with 18F-FDG b Fused PET–CT with 18F-FDG c Fused PET–CT with 18F-FDG

Fig. 4 | Functional imaging of AAA. PET coronal section (part a) showing increased 18F-​FDG uptake in the abdomen of a
man with a symptomatic but intact abdominal aortic aneurysm (AAA; arrow). Fused PET–CT images (coronal section,
part b, and sagittal section, part c) show increased 18F-​FDG uptake in the anterior wall of the AAA (arrow) in the same
patient. Images courtesy of N. Sakalihasan, University of Liège, Belgium.

programmes are also reported to be associated with a
decline in the incidence of ruptured AAA in men11,108–110.
Only a very small fraction of patients with intact asymp­
tomatic AAA are diagnosed at a clinical examination
because the AAA presents as a pulsatile mass or because
a large AAA compresses other intra-​abdominal organs.
Patients with ruptured AAA who are admitted to the
emergency department usually present with abdominal
pain. However, the classic triad of clinical signs (abdom­
inal or back pain, hypotension or shock, and abdominal
pulsatile mass)111,112 does not always lead to an accurate
diagnosis of AAA, as only 25–50% of patients with
ruptured AAA demonstrate all signs111,112. Today, most
patients admitted to the emergency room with severe
abdominal pain undergo ultrasonography (Fig. 3) to con­
firm or exclude the existence of an AAA; if an AAA is
detected, a CT angiogram is performed. The most com­
mon differential diagnoses include acute myocardial
infarction, kidney stone, backpain and gastrointestinal
diseases such as perforated ulcers.
CT increases the specificity of the diagnosis of
rupture (to ~85%), evaluates morphological suitabil­
ity for EVAR and also improves the quality of open
repair surgery.
Conventional imaging
Ultrasonography of the abdomen is generally considered
the gold standard for AAA diagnosis and monitoring
in asymptomatic patients, as it has a nearly 100% diag­
nostic accuracy113, and is harmless, non-​invasive and
affordable, with portable scanners being widely availa­
ble. Patients with an intact large (>55 mm) AAA or those
with a symptomatic or ruptured AAA, regardless of the
size, usually also undergo CT imaging. CT angiograms
should preferably be performed with a <0.5–1 mm slice
thickness and with contrast in the arterial phase. CT is the
imaging standard of reference for AAA62, can additionally
detect possible concurrent aneurysmal disease in other
vessels and enables the planning of surgical intervention.
MRI cannot be performed in emergency situations but is
important as an adjunct imaging method, specifically in
patients with contraindications to iodinated CT contrast
agents, such as renal insufficiency and allergy.
Functional imaging
Functional imaging refers to the assessment of patho­
physiological pathways involved in diseases; PET is the
flagship method for metabolic and molecular imaging in
clinical practice. A radionuclide, also known as a tracer,
that often specifically tracks physiological processes or
tissues is injected, and PET produces 3D images based
on the tracer concentration in the tissues and organs.
18
F-​FDG, a glucose analogue, is one of the most widely
used tracers; it enters cells and is phosphorylated to
18
F-FDG-6-phosphate. As 18F-FDG-6-phosphate can
neither enter the glycolytic cycle nor exit the cell, its accu­
mulation identifies sites of increased glycolysis, such as
inflammatory foci and cancer114. Some models of scanner
combine PET and CT within the same gantry, enabling
the co-registration of PET and CT data and accurate
anatomical localization of the tracer uptake (Fig. 4).
Imaging AAA using PET is challenging, as 18F-​FDG
uptake in AAA is nonspecific115. In addition, a marked
decrease in cell density in AAAs 116 and substantial
background noise on PET images decrease the chance
of observing 18F-​FDG uptake117,118. Nevertheless, sev­
eral studies have shown that 18F-​FDG uptake in AAA
is associated with inflammatory and phagocytic cell
infiltrates119–123, proteolytic activity by MMPs120,124 and
cellular and molecular signalling preceding rupture125.
The ability of iron oxide tracers to alter the MRI
signal provides another option for functional imaging
in AAA, as iron oxides are specifically phagocytized
by the reticulo-​endothelial system (mainly by macro­
phages)126,127. Diffusion-​weighted imaging (DWI) is a
type of MRI sequence that evaluates the movement of
water molecules in tissues; similarly to 18F-​FDG–PET,
DWI MRI is sensitive to cellular density and can, there­
fore, contribute to the functional assessment of AAA.
The expected correlation between DWI MRI and
18
F-​FDG–PET has thus far been reported only once in a
patient with an aortic arch aneurysm128. MRI can also be

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used to evaluate periaortic neoangiogenesis as a marker
of instability129,130.
The relationship between functional imaging find­
ings and patient outcomes is supported by animal mod­
els of AAA131,132. Nevertheless, a meta-​analysis133 found
conflicting results when predicting AAA growth rate or
rupture using functional imaging. Interestingly, 18F-FDG
uptake seemed to be an indicator of AAA growth only
in subgroups of patients in whom AAA growth was
rapid134. Furthermore, in studies reporting rupture as
the end point, the site of rupture almost always spatially
colocalized with increased 18F-​FDG uptake119,135.
Computational analyses
3D anatomy provided by imaging techniques (CT, MRI
and ultrasonography, in decreasing order of relevance)
may offer an alternative assessment of the risk of rup­
ture via finite element analysis (FEA) (Fig. 5). FEA esti­
mates the pressure acting on the aortic wall (that is, the
wall stress) and promoting dilatation and rupture risk
on the basis of computational models obtained from
3D images.
A meta-​analysis compiled nine studies (348 patients)
that retrospectively evaluated whether FEA differenti­
ated between intact (or asymptomatic) and ruptured (or
symptomatic) aneurysms136. The maximal wall stress was
significantly higher in ruptured or symptomatic aneu­
rysms than in intact or asymptomatic aneurysms in seven
of the nine studies137,138. In addition, wall stress estimates
better differentiate ruptured and intact AAAs than the
maximal aortic diameter. There have also been prelim­
inary studies on the association between wall stress and
AAA growth rate139,140. Wall stress estimates from images
can be correlated to the wall resistance obtained from in
vitro biomechanical testing of aortic tissues to provide
a b
Fig. 5 | Finite element analysis of AAA. Finite element analysis (FEA) of ruptured
(part a) and unruptured (part b) abdominal aortic aneurysm (AAA). These images are
computational models based on CT scans, which can analyse baseline data such as
diameter, aortic volume and thrombus volume, as well as arterial wall strength and
stress. The model includes patient-​specific data such as sex and blood pressure.
The mathematical findings are presented as tables for the individual patient but also as
visual interpretations of vulnerable areas or less-​vulnerable areas of the AAA. The peak
wall rupture index (PWRI) is reported to be a possible predictor of poor wall strength
and could be one of the future modalities for individualized surveillance protocols.
Part a is an FEA of a 60 mm ruptured AAA with a PWRI of 0.631; part b is a 60 mm
non-ruptured asymptomatic AAA with a PWRI of 0.206, indicating a lower index, that
is, a stronger wall136. Images courtesy of R. Hultgren, Karolinska Institutet, Sweden.
Nature Reviews | Disease Primers | Article citation ID: (2018) 4:34 11
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a biomechanical relative rupture risk index, which dis­
criminates symptomatic versus asymptomatic aneurysms
better than wall stress; however, there is no prospective
validation of this relative rupture risk index141.
Despite the ongoing refinements of computational
analyses, their widespread use in AAAs is limited
by the availability of technical resources and concerns
that the generalized assumptions on which these ana­
lyses are based (for example, regarding haemodynam­
ics and the structural properties of the AAA wall) may
not apply to specific cases142. Thus, the role of compu­
tational analyses in predicting the rupture site in AAA
is debatable143. Several investigations have reported a
spatial colocalization of the maximal wall stress and
the rupture site135,141, and areas under high wall stress
exhibited histopathological features of aneurysmal wall
weakening compared with areas under low wall stress
on the same aneurysm144,145. However, the relationship
between elevated wall stress estimates and other haemo­
dynamic parameters and rupture is not established.
Indeed, areas of high wall stress spatially colocal­
ize poorly with aortic wall blebs (localized bulges)146
or inflammation, as determined by either uptake of
18
F-​FDG on PET imaging or iron oxide contrast agent
on MRI147,148. Thus, inflammation and wall stress may
represent different but complementary features of
AAA progression.
Screening
Knowledge of the natural history of AAA has vastly
improved from the large AAA screening and surveil­
lance trials11,108,109. Population-​b ased screening has
been shown to reduce AAA-​related mortality in men;
such screening programmes have been implemen­
ted nationally in the United Kingdom and Sweden,
inviting all 65-year-​old men to a one-​time ultrasono­
graphy scan11,17,108,110. The participation rate in the United
Kingdom and Sweden is 75–85%, and the prevalence of
AAA in the target population was 1–2%. However, large
regional variations are often found both in prevalence
and participation rates9,11,13,17,108,110. These variations
could depend on risk factor distribution, such as smok­
ing habits, and differences in the development of AAA
exist for different ethnic groups, as, for example, white
individuals are more prone9.
The maximum aortic diameter at the latest control
will influence the surveillance interval. Structured sur­
veillance protocols are commonly used at most vascular
departments for patients with asymptomatic AAA and
also indicate when patients should be evaluated for aor­
tic repair — approximately at 55 mm, see below73 (Fig. 6).
The majority (70%) of men who are diagnosed with AAA
in screening programmes have AAAs <45 mm in diam­
eter; thus, this patient group will be observed for a long
time with consecutive ultrasonography examinations
before treatment is considered108–110.
As the prevalence of AAA is expected to decline, the
cost–benefit balance of AAA screening in men has been
re-​evaluated in several cost-​effectiveness models. If the
AAA prevalence falls below 0.35–0.5% and the inciden­
tal detection rates increase further, the cost-​effectiveness
will decrease, and the programmes will need to be
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re-evaluated110,149,150. A summary of the first 10 years of
screening programmes in Sweden confirmed the bene­
fit of screening men in population-​based programmes,
and this benefit is similar to that reported from previous
large randomized clinical trials of AAA screening108,110.
The introduction of screening was associated with a
reduction in AAA-​specific mortality in men (mean:
4.0% per year of screening; P = 0.020). After a mean of
4 years, 29% of patients with AAA had received aortic
repair, with a 30-day mortality of 0.9%, which is com­
parable to the 26% of patients who had received surgery
in the MASS (Multicentre Aneurysm Screening Study)
trial at 4 years follow-​up108,110. Screening also decreases
all-​cause mortality in screened men compared with
an unscreened population151. In recent years, there
has been some debate, opposing population-​b ased
screening programmes in general. Some groups have
suggested that the screening programmes diagnose
men who will never be treated for their AAA, thereby
over-​diagnosing the condition. However, the effects of
the programmes on the decrease in aneurysm-​related
mortality and also on all-cause mortality are clear when
popu­lation-​based screening programmes within 7 years
are analysed11,110,151,152. The quality of life (QOL) aspects
are discussed below.
There is no evidence that supports the implementa­
tion of population-​based screening in women, mainly
owing to the lower prevalence and later onset of disease
than in men10,36. Targeted screening of patient groups
with specific risk factors (for example, subaneurysmal
aorta (2.5–2.9 cm in diameter), smoking or family his­
tory) could prove to be efficient and would also include
women at risk; however, the practical implementation
and cost-​effectiveness remain uncertain62.
Management
A ruptured AAA is a surgical emergency, and immediate
treatment is required. Patients who present with a symp­
tomatic but non-​ruptured AAA can also require prompt
treatment. Contemporary management of patients with
ruptured AAAs can be performed either by EVAR or
open repair surgery153–155.
AAA size
2.5 3.0 3.5 4.0 4.5 5.0 5.5
(cm)
Every Every
Women
Every Every
6–12 3
Consider
5 years 2–3 years surgery
months months
Every Every
Every Every Every
Consider
Men 6–12 6 3–6
5 years 2–3 years surgery
months months months
Consider Follow-up
follow-up
Fig. 6 | Proposed surveillance protocol for patients with AAAs. Intervention may be
considered earlier than the protocol suggests for patients with rapidly growing
abdominal aortic aneurysms (AAAs; 10 mm per year), an AAA with increased PET signals,
saccular AAAs, mycotic AAAs, inflammatory AAAs or family history of AAA rupture. If the
patient is not fit for surgery, the lower threshold for surgery is re-​evaluated and increased
(>6 cm). Follow-​up for AAAs 2.5–2.9 cm in diameter is debated but can be considered in
women and younger patients.
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In most modern vascular services, 75–85% of
AAA repairs are performed electively for intact aneu­
rysms155,156. Patients with an asymptomatic fusiform
AAA ≥5.5 cm in diameter should be considered for elec­
tive repair. Of note, elective repair is also recommended
for patients with a saccular AAA, which generally has
a smaller diameter than fusiform AAAs, although speci­
fic guidelines for saccular AAAs are lacking owing to
the infrequent presentation of this type of AAA 62.
Early elective repair can occasionally be considered for
patients with AAAs of small diameter (≤5.5 cm) but
rapid expansion rate and for young and healthy patients,
particularly women, with AAAs 5.0–5.4 cm. By con­
trast, in patients with AAAs ≥5.5 cm but of advanced
age or with substantial comorbidities and risk factors,
elective repair may be delayed or inappropriate62.
The management of AAAs has improved substan­
tially since the first resection was performed (Fig. 7). In
a modern vascular service, two treatment options are
available for elective repair: open surgery or EVAR.
Several randomized controlled trials have analysed
the differences in long-​term outcomes between EVAR
and open repair surgery (see below). Several factors,
on different levels, will influence the choice between
the two procedures, including reimbursement issues
and factors related to the hospital, surgeon and patient.
Reimbursement, mainly depending on the possibility
of patients having their AAA repair tax-​funded or fee-​
for-service, can often explain the major differences in
the rates of EVAR and open repair surgery between
countries and continents. EVAR is rarely used in
most countries in Africa or Southeast Asia9. The pre­
ferred use of certain techniques by hospitals and sur­
geons, or the availability of access to hybrid operating
suites and grafts can commonly influence regional dif­
ferences, even in countries with tax-​funded repair. The
AAA morphology and the patient’s ability to adhere to
postoperative radiological controls after EVAR often
influence choices on a local or regional level. In all
surgical specialties, the introduction and widespread
use of a new surgical technique will decrease the use
of the surgical technique that was previously the
standard of care and thereby the related skills of
health-​care workers; this phenomenon was reported
for open cholecystectomies (surgical removal of the
gall bladder), which was replaced by laparoscopy in
the 1990s. A similar development is also observed now,
as open repair surgery is replaced by EVAR in many
vascular centres worldwide. This will have clinical
implications for patients who require complex open
aortic procedures in the future, for example, patients
who need explantation of failing EVAR grafts or
experience graft infections.
The annual number of treated patients, as well as
the distribution between interventions for ruptured
and intact AAAs, varies between regions and coun­
tries, and the screening activity in the population will
influence the proportion of elective repair. The inter­
vention rate is much higher in the United States than in
the United Kingdom or Sweden (64 per 100,000 indi­
viduals in the United States versus 32–42 per 100,000
individuals in the United Kingdom and Sweden),
 Primer

First clinical description of an
AAA by Andreas Vesalius
First case of ligation
of the human aorta to
repair a ruptured AAA
by Astley Cooper
First successful resection of an AAA Emergency endovascular repair of Chimney graft for AAA
followed by the implantation of a leaking aortic aneurysm by Brian Hopkinson
homograft by Charles Dubost Endoanchor system for
transmural fixation of
First use of temporary polythene shunts The world’s first EVAR procedure an aortic stent graft
to permit occlusion, resection and for the treatment of AAA by
frozen homologous graft replacement Nicholay Volodos

1557 1719 1817 1903 1951 1953 1987 1991 1994 1999 2008 2011

Obliterative surgery and

Surgical treatment
endoaneurysmorrhaphy Endovascular graft repair of
of aneurysm by
First description by Rudolph Matas ruptured aortoiliac aneurysm
resection and Transfemoral
of the rupture restoration intraluminal graft by Takao Ohki and Frank J. Veith Sac-anchoring
of an AAA by Internal reinforcement of continuity implantation endoprosthesis
Giovanni Battista of the AAA wall by with graft by for AAA by First fenestrated and branched for aortic
Morgagni copper rods Michael De Bakey Juan Carlos Parodi stent graft implantation aneurysm repair

Fig. 7 | History of the treatment of AAA. In 1817, Astley Cooper performed the first ligation of the aorta on a ruptured
aneurysm, and in 1903, Rudolph Matas performed an obliterative surgery (ligature of the aneurysmal sac) based on
arteriorrhaphy (the opening and suturing of the aneurysmal sac to reduce its volume), but the modern history of the
treatment of abdominal aortic aneurysms (AAAs) started on 29 March 1951, when Charles Dubost successfully carried out
the resection of an AAA followed by the implantation of a homograft232. Less than 1 month earlier, Schaffer and Harding233
performed the same intervention, but their patient died on the 29th day following the operation. In 1951, temporary
polythene shunts were used to permit occlusion, resection and frozen homologous graft replacement of vital vessel
segments. Two years later, De Bakey popularized AAA resection using a textile graft to replace the aneurysmal section
of the aorta234. Endovascular aortic repair (EVAR) was first performed in 1987 by Volodos et al.235 for the treatment of an
AAA. In 1991, Parodi et al.236 reported their initial experience with the use of stent grafts to treat AAA. Since the 2000s,
different types of stent graft have been developed. Owing to space limitiations, this is a selection of key events and not
an exhaustive list.

likely reflecting the fee-​for-service health-​care sys­
tem in the United States rather than the general gov­
ernmental reimbursement systems commonly used
in Europe13,155,157. The mean aortic diameter in treated
patients is also a marker that reflects the diversity in
treatment regimens. There is a trend towards an increas­
ing proportion of patients with small-​diameter AAAs
being treated in many countries, especially within
fee-​for-service systems155,157,158.
Open repair surgery
Open repair surgery consists of the interposition of an
arterial prosthesis during an open surgery. The goal is to
avoid AAA rupture by replacing the aneurysmal sac with
a vascular synthetic graft (Fig. 8). Open repair surgery
is usually performed with laparotomy, either through
a long transperitoneal midline or a wide transverse
incision. Alternatively, a left retroperitoneal approach
can be used.
Open AAA repair surgery continues to be used for
patients whose vascular anatomy is not suitable for EVAR
(for example, with short sealing zones, multiple acces­
sory renal arteries or no suitable access vessels) and in
regions or countries with limited resources for health
care. Open repair surgery may also be offered to young
and healthy individuals who are also suitable for EVAR,
given that open repair surgery likely has better long-​term
durability and a reduced need for long-​term surveil­
lance and reinterventions compared with EVAR. Open
repair surgery may also be required for the treatment
of complications after EVAR (for example, persistent
endoleak (persistent blood flow in the aneurysmal sac
after deployment of the stent graft) or aneurysmal
sac growth) or for the treatment of a mycotic AAA or
graft infection62.
EVAR
EVAR consists of the implantation of a bifurcated graft
via the femoral and iliac arteries; the graft is anchored
with stents at the normal, non-​aneurysmal aorta at the
level of the renal and iliac arterial walls, and the aneu­
rysmal sac is left in situ. EVAR aims to exclude the
AAA from the systemic circulation instead of replacing
the damaged aorta. Several factors must be considered
when assessing the feasibility of EVAR. The access ves­
sels should be of adequate quality to enable the introduc­
tion of the stent graft. Furthermore, to achieve complete
sealing, healthy (non-​aneurysmal) proximal and distal
zones are required for anchoring of the stent graft. In
cases of inadequate proximal anchoring zones below the
renal arteries, the suprarenal part of the aorta can be used
for sealing using advanced EVAR techniques, such as
fenestrated grafts (stent grafts with fenestration-​holes to
accommodate the renal arteries and the superior mesen­
teric artery and coeliac trunk if needed) or the chimney
technique159. Aortic morphology influences EVAR out­
comes. The performance of EVAR in patients who do not
have the necessary features for this procedure is associ­
ated with inferior long-​term outcomes160,161. Thus, a strict
indication should be followed to achieve safe long-​term
EVAR outcomes. In cases of questionable anatomical
suitability, alternative treatment strategies (for example,

Nature Reviews | Disease Primers | Article citation ID: (2018) 4:34 13

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a b
Aorta
Renal arteries
Clamp
Aortic
wall
Vascular
graft
Iliac
arteries
Fig. 8 | Open AAA repair surgery. a | A vascular graft
from the aorta to both common iliac arteries is used to
replace the aneurysmal aorta. Aortic cross-​clamping
should be performed below the renal arteries if possible.
If the abdominal aortic aneurysm (AAA) extends above the
renal arteries, suprarenal clamping may be preferred,
which could yield an increased rate of renal dysfunction
and perioperative morbidity. b | Once the graft is in place,
the aortic wall is wrapped around the graft to protect it
from exposure to intestines. Part a courtesy of P. Bonnet,
University of Liège, Belgium.
open repair surgery or advanced EVAR with fenestrated
or chimney grafts) should be considered162.
In 2013, endovascular aneurysm sealing (EVAS),
a new concept of endovascular AAA repair, was intro­
duced163. EVAS consists of a combination of stent grafts
and polymer-​filled endobags that fill the aneurysmal sac
to minimize the risk of endoleaks. Clinical experience
with EVAS to date has shown that endobags can help to
reduce type II endoleaks (back bleeding in the aneurys­
mal sac from lumbar arteries or other side branches of
the aorta) and associated reinterventions. Nevertheless,
anchoring of the endobags to the aneurysmal sac may
sometimes be unstable, owing to the presence of ILTs
(especially in AAAs with an increased ILT burden), and
in very large AAAs, the small size of the endobags can
lead to stent graft migration owing to loose fit of the
endobags in the aneurysmal sac. Migration following
EVAS proved to be a major issue that led to the revision
of the instructions for use in 2016, excluding AAAs with
a specific amount of sac ILT and also with a blood lumen
diameter >70 mm (ref.164). Unfortunately, only mid-​term
follow-​up data are available for EVAS, and before fur­
ther widespread use is recommended, long-​term data
must be reported165. On the basis of what we learned
from the long-​term follow-​up of the EVAR trials, the
long-​term durability of a treatment modality may be
more important than early technical success.
When it was first introduced, EVAR was considered
only for frail patients who were not fit for open surgery.
Gradually, the indications expanded to include low-​risk
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patients. Currently, EVAR is considered a safe alterna­
tive to open repair surgery for anatomically suitable
AAAs and is actually the preferred approach in most
centres166 (Fig. 9). Table 2 summarizes the most common
complications that can occur after EVAR and open AAA
repair surgery.
Comparing open repair surgery and EVAR
Several randomized and observational studies have com­
pared EVAR with open AAA repair surgery167–173. The
DREAM (Dutch Randomized Endovascular Aneurysm
Management) trial showed a benefit of EVAR compared
with open repair surgery with regard to 30-day mortal­
ity (1.2% and 4.6%, respectively; P = 0.10), complication
rates (11.7% and 26.4%; P < 0.001) and length of hospi­
tal stay (6 days and 13 days; P < 0.001)167. Nevertheless,
the early perioperative survival advantage of EVAR
was not sustained after the first postoperative year, and
EVAR was associated with higher reintervention rates
than open repair surgery during 6 years of follow-​up
(29.6% and 18.1%; P = 0.03)168,169.
Similarly, the UK EVAR 1 (UK Endovascular
Aneurysm Repair 1) trial showed an early survival
advantage for EVAR, which, however, was not sustained
at the 4-year follow-​up170,174. At 15 years of follow-​up,
EVAR was associated with lower survival than open
repair surgery, mainly owing to increased second­
ary aneurysmal sac rupture but also increased cancer
mortality in the EVAR group173.
There have been substantial improvements in stent
graft technology that may have a positive effect on
EVAR durability171,172,175. Materials have been improved
(for example, grafts have lower permeability and stent
designs are more flexible), and deployment mechanisms
have also been revised to enable more-​precise proximal
deployment. Consequently, the long-​term outcomes of
EVAR with current stent graft technology may improve
compared with those reported in the existing studies
evalu­ating EVAR with previous-​generation stent grafts.
The more recent trials comparing open repair surgery
and EVAR for ruptured AAAs show that EVAR has better
patient outcomes in up to a 3-year follow-​up, including
cost-​effectiveness and QOL153. However, neurological
and erectile complications can rarely be observed imme­
diately and/or during the follow-​up after EVAR and open
repair surgery. The incidence of spinal cord ischaemia
after EVAR or open repair surgery has been reported to be
0.21% and 0.25–0.9%, respectively176,177. A meta-​analysis
showed that the prevalence of postoperative erectile
dysfunction varies from 7.4% to 79% following open
repair surgery and from 4.7% to 82% following EVAR178.
In the long term, the higher mortality but good
durability associated with open repair surgery has to be
balanced against the lower early mortality but inferior
durability of EVAR179.
Non-​surgical treatment
Without elective repair, AAAs usually continue to
enlarge, and increasing diameter also increases the risk
of rupture. Medical treatment to prevent AAA progres­
sion could substantially improve the management of
patients with AAA180–182.

Non-​surgical therapy in experimental studies. The pro­
gression of an already developed AAA in small animal
models can be suppressed by pharmacological interven­
tion182–184. Interventions to regulate pro-​inflammatory
mediators, the renin–angiotensin system and prostaglan­
din metabolism have been demonstrated to be effective in
reducing the progression of already developed AAAs182.
Interventions to inhibit inflammatory signalling path­
ways and treatments with immunosuppressive agents
are also effective in halting AAA progression182. Notably,
treatment with JUN N-​terminal kinase (JNK) inhibitor
after the establishment of AAA formation resulted in
a reduction of the aneurysmal diameter185. Abrogating
ECM degradation using MMP inhibitors can also be
effective in preventing AAA progression186.
Because of the considerable differences in the AAA
pathophysiology of humans and animal models (Box 1),
the effectiveness of these pharmacological interventions
has also been studied using cultures of human AAA
explants. Indeed, interventions to regulate inflamma­
tory responses and treatments with MMP inhibitors are
reported to be effective in ex vivo culture of human AAA
tissues182. Treatment with HMG-​CoA reductase inhibi­
tors (statins) or angiotensin-​converting enzyme (ACE)
inhibitors was also effective in reducing inflammatory
responses in human AAA tissue culture182.
In addition, cell therapy has also been suggested to
be useful in preventing AAA progression. Local infu­
sion of bone-​marrow-derived mesenchymal stem cells
(BM-MSCs), endothelial cells or VSMCs, as well as sys­
temic injection of BM-​MSCs, was shown to be effective
in suppressing the progression of already developed
AAAs in animal models187–189.
a an AAA show a temporary reduction in mental QOL
b
Renal
arteries
Stent
graft
Intraluminal
thrombus
Catheter
Iliac
artery
Fig. 9 | Endovascular aortic repair. a | Schematic representation of the first moments of
the endovascular aortic repair (EVAR) procedure: a catheter is inserted through the iliac
artery, the upper proximal part of the stent graft is opened and the main upper body
of the stent graft is shown in the aorta below the renal arteries, sealing the neck above
the aneurysmal bulge. b | CT image of the EVAR stent graft with the two prolonged stent
grafts elongating into the common iliac arteries. The part of the stent not covered
with graft is fixed appropriately above the renal arteries. Image in part b courtesy of
N. Sakalihasan, University of Liège, Belgium.
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Pharmacotherapy in clinical trials. The β-adreno­
receptor blocker propranolol was one of the first drugs
to inhibit the development of AAAs in animal models190.
However, in a randomized trial, it was not well tolerated
by patients with AAAs and did not affect the growth rate
of AAAs182.
Chlamydia pneumoniae, unlike other bacteria, has been
detected at a higher frequency in the wall of AAAs than
in the normal aortic wall from cadavers191 and is, there­
fore, suspected to have a pathogenic role in AAA devel­
opment, although this has not been formally proven180,181.
Randomized clinical trials of antibiotics, including doxy­
cycline and azithromycin, were conducted in patients
with AAAs but did not clearly demonstrate an effect of
antibiotics in reducing the AAA growth rate182,192,193.
Doxycycline was expected to act as an MMP inhib­
itor 181 and was administered to a large number of
patients for longer periods than the first trial192 at the
dose expected to inhibit MMPs, but doxycycline treat­
ment did not reduce AAA growth58. Recently, two ran­
domized trials with pemirolast, a mast cell inhibitor,
and perindopril, an ACE inhibitor, have been reported,
but neither drug reduced the AAA growth rate59,182,183.
Several small observational studies demonstrated an
association between statin administration and decreased
AAA growth, although the beneficial effect of statins has
not been confirmed in larger clinical trials182,183,193. Thus,
there is currently no strong scientific evidence that sup­
ports pharmacological treatment to reduce AAA growth
in humans62,194,195.
Quality of life
Both the diagnosis and treatment of AAAs have an
effect on patients’ QOL. Men recently diagnosed with
during the first year, but then they tend to think pro­
gressively less about their condition196. By contrast,
the effect on physical QOL seems to be more perma­
nent, and men diagnosed with AAAs have a consist­
ently lower physical QOL than men without AAAs196.
Vascular surgeons and patients evaluate the success of
AAA repair differently. Traditional end points that sur­
geons use to evaluate outcomes after a surgical proce­
dure include mortality and morbidity. Patients evaluate
the success of their operation based on QOL, physical
functioning and ability to be discharged from hospi­
tal to home and to resume their pre-​surgery lifestyle.
Indeed, there is increasing recognition that QOL and
patient satisfaction should be considered when evalu­
ating outcomes of a specific treatment197. Particularly
for AAA repair, the risks of perioperative mortality
and morbidity increase the relevance of evaluating
QOL198–201. Vascular surgeons should, therefore, aim to
include evaluations of QOL and to improve patient satis­
faction rather than merely measuring adverse events
as end points202. For both AAA surveillance and repair,
the assessment of QOL and other patient-​focused out­
comes should be evaluated in the longer term. Such
longer-​term follow-​up (up to 10 years) is rare and
might be particularly relevant for patients entering
surveillance programmes after EVAR. Forthcoming
guidelines from the European Society for Vascular
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Table 2 | Complications of surgical and endovascular treatment of AAA
Complication Incidence (%)
EVAR
Access site problems 9–15 (refs168,237)
Endoleaks (all types) 20–50 (ref.238)
Endoleak type I Up to 10 (ref.241)
Endoleak type II 10–25 (ref.244)
Endoleak type III Up to 4 (ref.247)
Endoleak type IV Rare with the new-​generation
devices but can be detected
in low-​profile stent grafts
Stent graft migration Stent graft migration after
endovascular aneurysm repair
was reported to occur in 8%,
emphasizing the importance
of proximal fixation249
Graft limb occlusion 1.7–3.7 (ref.251)
Stent graft infection <1 (ref.251)
Sac expansion and Schanzer et al.256 reported
secondary rupture that the rate of AAA sac
expansion after EVAR may
be as high as 41% at 5 years,
whereas other authors report
a lower incidence
Open repair surgery
Graft limb occlusion Up to 2 (ref.258)
Para-​anastomotic Up to 3 (ref.258)
aneurysm
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Description
Problems include haematoma, arterial
thrombosis, distal embolization,
pseudoaneurysm and arteriovenous fistula
Persistent blood flow in the aneurysmal sac
after deployment of the stent graft
Insufficient sealing at proximal (type Ia) or
distal (type Ib) attachment sites of stent graft
Backflow via lumbar arteries and patent
inferior mesenteric artery
Separation of stent graft components
Depend upon porosity in the graft material
Caudal movement of the stent graft due
to insufficient proximal attachment, more
common in first-​generation and second-​
generation devices. Can lead to proximal
type Ia endoleak
Thrombosis of the iliac graft limb
Infection of the implanted stent graft based
on clinical, radiological and laboratory
criteria
• Sac expansion may occur during follow-​up
as a result of an endoleak
• If left untreated, sac expansion may result
in late AAA rupture despite previous
EVAR. A recent meta-​analysis of 16,974
procedures reported a late rupture rate of
0.9 per 100 person-​years after EVAR257
May cause symptoms of acute or chronic
limb ischaemia
Either true aneurysm due to progression
of disease or pseudoaneurysm caused
by destruction of the anastomosis line
between the graft and the native aorta.
Pseudoaneurysms may indicate graft
infection259,260
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Treatment
Surgical revision
• Treatment is type-​specific (see below)
• If endovascular techniques fail, open
repair surgery is required to definitively
treat endoleaks239,240
Implantation of additional stent grafts
more proximally (for Ia) or distally (for Ib); in
cases with a limited landing zone, advanced
endovascular techniques (fenestrated and
branched stent grafts) can be used242,243
Type II endoleaks can be treated
conservatively (only surveillance), but in the
case of substantial aneurysmal sac expansion
during follow-​up, embolization of the
feeding vessels should be considered245,246
Management includes the use of a bridging
stent graft248
Relining with placement of a second stent
graft inside the first stent graft
Management can include placement of
additional stent grafts proximally; increasing
fixation of the stent graft to the aortic wall
with the use of endoanchors can also be
considered250
Treatment includes thrombectomy with
adjunct stenting if needed; if thrombectomy
fails, blood flow can be re-​established with
an open surgical procedure (femoral–femoral
artery crossover surgical bypass)252
Although conservative treatment with
lifelong antibiotics has been sporadically
reported to be successful, definitive
treatment requires explantation of the
infected graft253. Revascularization of
the lower limbs can be achieved with
different options: ligation of the aorta and
axillobifemoral bypass; in situ use of cryo-​
preserved aortic homografts; antibiotic-​
soaked prosthetic grafts; and autologous
reconstruction using femoral veins254,255
Treatment includes a second endovascular
repair or open surgical conversion with
removal of the stent graft. Both operations
are associated with higher morbidity rates
and mortality than with primary EVAR or
open repair surgery
Treatment includes thrombectomy with
adjunct stenting if needed; if thrombectomy
fails, blood flow can be re-​established with
an open surgical procedure (femoral–femoral
artery crossover surgical bypass)252
Conventional treatment of para-​anastomotic
aneurysms includes surgical revision,
especially in the case of infection; if graft
infection is excluded, relining and extension
of the repair with a stent graft can offer a
less-​invasive treatment261

Table 2 (cont.) | Complications of surgical and endovascular treatment of AAA
Complication Incidence (%) Description
Open repair surgery (cont.)
Graft infection 0.2–1.3 (ref.258) Infection of the implanted stent graft based
(with or without on clinical, radiological and laboratory
concomitant criteria
aortoenteric fistula)
Incisional hernia 12.8 (ref.262), but this is often Development of the hernia at the level of the • Commonly conservative treatment if
based on ultrasonography midline laparotomy
detection; many hernias are
asymptomatic
Sexual dysfunction 7.4–79 (incidence of erectile Erectile and/or ejaculation problem
dysfunction178)
AAA, abdominal aortic aneurysm; EVAR, endovascular aortic repair.
Surgery suggest the use of duplex ultrasonography as
the gold standard for long-​term EVAR surveillance in
patients without sac expansion or other complications,
rather than annual CT scans. CT is more expensive,
incurs radiation burden and could, in the long term,
affect QOL.
Doubts and fears about the durability of EVAR
remain and have been exacerbated by reports about low-​
profile devices (in which the fabric is thinner such that
the device can fit in smaller delivery catheters)203. These
fears, together with the continuing threat of reinter­
vention (much more common after EVAR than after
open repair surgery), may affect patients’ QOL as well
as patient anxiety and depression (which are almost
never assessed). One of the few examples of long-​term
QOL follow-​up comes from the DREAM trial, which
showed that although EVAR was associated with less
reduction in QOL in the short term (3 months) com­
pared with open repair surgery204, in the longer term (up
to 5 years), QOL measures favoured open repair sur­
gery. Meta-​analysis data have shown that elective AAA
repair (by either open repair surgery or EVAR) results
in a significant deterioration of QOL (both physical and
mental) that is more evident in the first 3–6 months
after treatment205. A meta-​analysis of five randomized
trials for intact AAA compared QOL outcomes between
EVAR and open AAA repair surgery206: EVAR provided
better QOL than open repair surgery for up to 1 year
postoperatively. This advantage of EVAR was, however,
lost at 2 years of follow-​up. Similar results apply after
repair of ruptured AAA, in which EVAR is associated
with large gains in QOL during the first year153.
Reported QOL outcomes should be interpreted with
caution, owing to the inherent subjectivity of patient-​
reported outcomes. After open AAA repair surgery,
patients are more willing to accept perioperative com­
plications and discomfort, whereas after EVAR, patients
expect to recover quickly without major problems. Any
deviation from such preoperative expectations can bias
patient-​reported QOL outcomes204. However, the sur­
gical trend towards defining core outcome data sets
mandates patient participation in defining the key out­
comes reported; thus, in the future, we can expect to see
patient-​focused outcomes more widely reported.
Nature Reviews | Disease Primers | Article citation ID: (2018) 4:34 17
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Primer
Treatment
• As for stent graft infection
• For concomitant aortoenteric fistula,
additional reconstruction of the enteric
lesion is required
diagnosed at follow-​up
• Mesh reinforcement of fascia closure can
be scheduled in fit patients
Preventive careful dissection and
management of the pelvic circulation during
repair to avoid development of sexual
dysfunction; pharmaceutical therapy can be
considered
Outlook
AAA remains an important disease, as smoking remains
rife in developing countries, and a growing number of
elderly patients are diagnosed with AAA in developed
countries. This observation depends on the ageing popu­
lation, with AAA becoming diagnosed at older ages, while
the advent of EVAR has also extended the number of
patients, even elderly ones, who are eligible for elective
AAA repair.
Since 2000, there have been several developments in
the management of AAA. Furthermore, a large body of
research has been accumulated on the risk factors and
pathophysiology of AAA and potential non-​surgical
therapies. The effectiveness of minimally invasive EVAR
for both elective and emergency cases has been substan­
tiated by several randomized trials and meta-​analyses
of these trials. These same trials, together with other
evidence, have also exposed some of the weaknesses of
EVAR, the rather poor long-​term durability compared
with open surgical repair, the potential need for lifelong
surveillance and the limited applicability of this newer
technique to women207,208. Ongoing research and devel­
opment programmes are addressing these issues, using
advances in materials science, including the avoidance
of metallic components in endografts. The alternative
approach of EVAS remains under evaluation, and as
new data emerge, additional morphological restric­
tions are being placed on the use of EVAS. Controversy
is widespread concerning the operative management
of aneurysms that extend close to or above the renal
arteries, including how endovascular techniques should
be modified or adapted for these complex aneurysms.
Other problems that remain to be addressed include
reducing the morbidity and mortality from AAA in
women and ethnic minorities. Patients diagnosed with
AAAs will require continuous surveillance, commonly
with ultrasonography, to determine whether it is time
to consider elective repair. As small AAAs are common
and readily detected by non-​invasive, low-​cost ultra­
sonography screening, finding therapeutic agents that
will prevent further AAA growth and the need for any
future operative repair remains a major goal.
Experimental animal studies have provided many
new leads (potential targets for future pharmaceutical
Primer

therapies), particularly in cell signalling pathways,
often with very effective functional imaging modali­
ties and targeted treatments in these animal models.
However, most of these studies were performed in small
animal models, where AAA induction is rapid and not
dependent on smoking, in sharp contrast to the indo­
lent course of small AAA in humans, where smoking
remains the most important risk factor. In addition,
bias might have been introduced by the lack of adequate
observer blinding, insufficient number of animals in
experimental groups or use of only one of the available
animal models209.
Although GWAS and other molecular studies have
identified genetic variants and genetic loci associated
with the development of AAA, translational research
aimed at producing effective drugs to limit AAA growth
is limited. New epidemiological studies have suggested
other new therapeutic targets or drugs to limit the pro­
gression of AAAs, but none of these therapies has yet
been shown to be effective in properly conducted ran­
domized trials58,59,182,185,210,211. For AAA, the field of trans­
lational biology, together with other technologies, for
example, nanotechnology (target drug release), remains
wide open. The success of such approaches in thoracic
aortic aneurysms and dissections provides insight into
why genetic and basic science research on AAAs in
humans must continue. For thoracic aortic aneurysms
and dissections, major causal genes have been identi­
fied together with associated pivotal signalling pathways,
which have allowed effective targeted pharmacological
therapies to be developed and validated in randomized
trials. Monogenic disorders are rare in AAA, perhaps
emphasizing the different embryological derivation of
the thoracic and abdominal aorta. However, AAAs are
much more common than thoracic aortic aneurysms and
dissections, and the need for further genetic and basic
science research to identify pivotal cell signalling path­
ways and to develop other effective novel therapeutic
approaches for AAA remains urgent. Pharmacological
therapy for AAA should not be limited to preventing
aneurysmal growth. Additional targets include prevent­
ing distal and proximal aneurysmal extension following
surgical correction and reducing the risk of aneurysmal
rupture in those with large AAAs who are not consid­
ered candidates for AAA repair. In summary, present-​
day interventions to prophylactically repair AAAs still
have a certain early mortality (at best 1–2%), morbid­
ity and consequences for long-​term health and health
costs. In developed countries, a better knowledge of the
epidemiology of AAAs in ageing populations, the AAA
growth rate and the true incidence of rupture, together
with a demonstration of genetic mechanisms and the
elucidation of the biochemical, cellular and immuno­
logi­cal pathways involved in genetic and environmen­
tal risk factors, will provide us with a comprehensive
approach for better management of those with AAAs.
The immuno­logical pathways may have particular
relevance for the AAAs of infectious aetiology, which
may be most common in developing countries. Such
knowledge will enable us to achieve better outcomes for
AAA repair and to develop new, effective, prophylactic
pharmacological therapies.
Published online xx xx xxxx

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Acknowledgements
The authors thank A. Courtois for her help during the prepar­
ation of this manuscript, J. Roy, M. L. Liljeqvist and C. Gasser
for their contribution to Fig. 5 and P. Bonnet for providing the
figure on the surgical management of AAAs.
Author contributions
Introduction (N.S. and J.T.P.); Epidemiology (R.H. and H.K.);
Mechanisms/pathophysiology (J.-O.D., H.K. and J.-B.M.);
Diagnosis, screening and prevention (N.S., A.N. and R.H.);
Management (N.S., A.K., K.Y. and R.H.); Quality of life (A.K.
and J.T.P.); Outlook (N.S., H.K. and J.T.P.); Overview of Primer
(N.S. and R.H.).
Competing interests
All authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Disease Primers thank H.-H. Eckstein,
S. Haulon, F. Moll, C. A. Nienaber, P. Norman, C. Zarins and
the other anonymous reviewer(s) for their contribution to the
peer review of this work.
Related links
CDC WiSQArS: http://www.cdc.gov/injury/wisqars/index.html
Swedish National Board of Health and Welfare: https://
www.socialstyrelsen.se/publikationer2017/2017-9-11
UK Office for National Statistics: https://www.ons.gov.uk/
peoplepopulationandcommunity/healthandsocialcare/
causesofdeath