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May 2015 | Volume 2 | Article 191
REVIEWS IN MEDICINE
published: 26 May 2015
doi: 10.3389/fcvm.2015.00019
Frontiers in Cardiovascular Medicine | www.frontiersin.org
Edited by:
Per Morten Sandset,
Oslo University Hospital
Rikshospitalet, Norway
Reviewed by:
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Cardiovascular Research Center
CSIC-ICCC, Spain
Alexandre Francois Roy Stewart,
University of Ottawa Heart Institute,
Canada
Gianmarco de Donato,
University of Siena, Italy
*Correspondence:
Christine Brostjan,
Medical University of Vienna,
Department of Surgery, Anna Spiegel
Center for Translational Research,
Vienna General Hospital AKH
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A-1090 Vienna, Austria
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This article was submitted to
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Frontiers in Cardiovascular Medicine
Received: 22December2014
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Published: 26May2015
Citation:
Piechota-PolanczykA, JozkowiczA,
NowakW, EilenbergW, NeumayerC,
MalinskiT, HukI and BrostjanC
(2015) The abdominal aortic
aneurysm and intraluminal thrombus:
current concepts of development and
treatment.
Front. Cardiovasc. Med. 2:19.
doi: 10.3389/fcvm.2015.00019
The abdominal aortic aneurysm and
intraluminal thrombus: current
concepts of development and
treatment
Aleksandra Piechota-Polanczyk
1,2, Alicja Jozkowicz
3, Witold Nowak
3, Wolf Eilenberg
1,
Christoph Neumayer
1, Tadeusz Malinski
4, Ihor Huk
1 and Christine Brostjan
1 *
1 Department of Surgery, Medical University of Vienna, Vienna, Austria, 2 Department of Biochemistry, Medical University of
Lodz, Lodz, Poland, 3 Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland, 4 Department of
Chemistry and Biochemistry, Ohio University, Athens, OH, USA
The pathogenesis of the abdominal aortic aneurysm (AAA) shows several hallmarks of
atherosclerotic and atherothrombotic disease, but comprises an additional, predominant
feature of proteolysis resulting in the degradation and destabilization of the aortic wall.
This review aims to summarize the current knowledge on AAA development, involving the
accumulation of neutrophils in the intraluminal thrombus and their central role in creating
an oxidative and proteolytic environment. Particular focus is placed on the controversial
role of heme oxygenase 1/carbon monoxide and nitric oxide synthase/peroxynitrite, which
may exert both protective and damaging effects in the development of the aneurysm.
Treatment indications as well as surgical and pharmacological options for AAA therapy
are discussed in light of recent reports.
Keywords: aortic aneurysm, abdominal, intraluminal thrombus in aortic aneurysms, neutrophils, heme
oxygenase-1, nitric oxide synthase
Epidemiology and Risk Factors
“Aneurysm” is dened as dilatation of an artery being at least 1.5 times larger than its expected normal
diameter (1). us, an abdominal aortic aneurysm (AAA) is given when the maximum diameter
is 30mm or more (2). Approximately, 80% of AAAs occur in the infrarenal aorta (3). In general,
“atherosclerotic” aneurysms represent the vast majority of AAAs (Figure1).
The prevalence of AAAs depends on patients’ age, gender, and geographical location (4).
Primarily, elder men are affected. Men’s prevalence of AAAs below 50mm in diameter increases
from 1.3% below 45years to 12.5% above 75years (2). For women, the prevalence ranges from
0 to 5.2%, respectively, but the risk of rupture is four times greater. The underlying mechanisms
of sex differences are not fully understood, although women seem to be protected by female
sex hormones (2). Smoking is another strong risk factor for the development of AAAs due to
its promoting effects on inflammation, proteolysis, and smooth muscle cell (SMC) apoptosis
(5). Enhanced aneurysm growth and an increased risk of rupture have been described (6).
Other risk factors comprise previous vascular aneurysms, coronary artery and cerebrovascular
disease, atherosclerosis, hyperlipidemia, and hypertension (4). An observational study recently
demonstrated that a low vitamin D status was associated with the presence of larger AAAs in
elder men (7). Moreover, various microorganisms have been associated with the pathogenesis
of AAAs (8).
FIGURE 2 | (A) CT axial image of an infrarenal AAA with intraluminal
thrombus. (B) Corresponding, massive, intraluminal thrombus removed
during open surgical repair.
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In addition to these environmental components, genetic aspects
play an important role. A positive family history for AAA especially
in male rst-degree relatives is associated with an increased risk for
AAA (9). Moreover, alterations on chromosome 9p21 are accom-
panied with a 20% increased risk of developing AAA (10). Other
genetic approaches suggested that aberrations of lipid metabolism
and proteolytic pathways are the key contributors to disease. Some
of these associations (e.g., lipoprotein receptor-related protein-1)
are not associated with atherosclerosis, indicating pathways unique
to AAA (11). Distinct connective tissue disorders such as Marfan
syndrome, Ehlers–Danlos syndrome, and Loeys–Dietz syndrome
also go along with an increased risk for AAAs (12).
The Intraluminal Thrombus
In 70–80% of AAA patients, the vessel wall is covered by an intralu-
minal thrombus (ILT, Figure2), which generally does not preclude
blood ow and shows little compression throughout the cardiac
cycle (13, 14). While mural thrombosis is frequently observed in
aneurysmal disease, the complete vessel occlusion is a comparably
rare event associated with a high rate of mortality (15).
An inhomogeneous thrombus structure was reported early on,
with a stier luminal side composed of a dense brin network
FIGURE 1 | CT recording of an infrarenal AAA with eccentric shape
and sites of calcication (atherosclerotic plaques highlighted in
white).
invaded by leukocytes and erythrocytes (16). By contrast, the
medial and abluminal ILT layers were found to be largely devoid
of cellular constituents and to exhibit progressive brinolysis and
hence decreased thrombus strength and stiness (17). Recent
reports have indicated that ILT structure may indeed be more
diverse than previously thought. When luminal, medial, and
abluminal ILT layers were evaluated for mechanical properties,
three subtypes of ILTs were identied (13). While the majority
of investigated thrombi displayed a multi-layered morphology
with gradually decreasing strength and stiness from the distinct
luminal to the thick medial/abluminal side (type 1), examples of
multi-layered ILTs with an abrupt loss of mechanical resistance
from luminal layers to rather thin and highly degraded medial/
abluminal layers were also observed (type 2). Of interest, a third
type of single-layered ILT of almost uid-like consistency was
reported for a limited number of cases (13). Future studies will
have to elucidate the pathogenesis and cellular/molecular com-
position of these distinct ILT variants. Importantly, based on the
possibilities of medical imaging, the potential correlation of ILT
subtype with disease progression and risk of rupture should be
evaluated.
Macromolecular transport is promoted by centrifugal convec-
tion from the luminal to the abluminal side of the brin network
and is further supported by the system of so-called “canaliculi”
(17). us, molecules released and activated within the thrombus
are readily transported to the vessel wall and aect aneurysm
growth. Animal models have shown that limiting thrombus devel-
opment with inhibitors of platelet activation strongly suppresses
aneurysm formation (18). e eect is accompanied by a reduction
in leukocyte inltration and lower release of proteases within the
mural thrombus, which results in decreased degradation of elastic
bers, and promotes thrombus colonization by SMCs. us, by
sequestering and activating platelets, erythrocytes, neutrophils,
and macrophages, the ILT exposes the vessel wall to a local milieu
of highly concentrated cytokines, proteases, and reactive oxygen
species (ROS) that promotes aneurysm development. In line, clini-
cal studies report that ILT thickness correlates with AAA diameter,
matrix metalloproteinase (MMP) levels, elastin degradation, and
SMC apoptosis (19, 20). Furthermore, the presence of a large
thrombus leads to localized hypoxia at the underlying aortic wall,
FIGURE 3 | Differential effects of heme oxygenase-1 (Hmox1) relevant
to AAA development. Hmox1 promotes endothelial cell proliferation and
inhibits their apoptosis, but has opposite impact on the proliferation and
apoptosis of smooth muscle cells. It can also modulate thrombus formation
by inhibition of platelet aggregation and promotion of brinolysis. cGMP,
cyclic guanosine monophosphate; PAI-1, plasminogen activator inhibitor-1;
SMC, smooth muscle cell.
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which triggers adventitial angiogenesis and aggravates inamma-
tory inltration from the outer vessel layers (21).
Despite this role in supporting the inammatory and proteo-
lytic mechanisms of AAA pathogenesis, the mural thrombus has
repeatedly been suggested to protect the aneurysm from rupture by
reducing the peak wall stress and altering wall stress distribution
(22). However, this protective role seems to depend on the degree
of thrombus attachment to the vessel wall (23). When bearing
in mind that large thrombi are reportedly associated with faster
AAA growth, the proteolytic weakening of the AAA wall may be
the more predominant ILT eect when compared to wall stress
relief (24).
Proteomics analysis of proteins sequestered by the ILT brin
network revealed the expected prevalence of platelet-derived
proteins such as clusterin and thrombospondin-1 (25), which are
likely to be subjected to proteolytic processing within the local
thrombus milieu thereby altering or activating protein function
(26). Furthermore, as the ILT constitutes a site of continuous
hemostasis and brin destruction, the respective coagulation and
brinolysis factors are detected in thrombus tissue and elevated
in AAA patients’ blood (27). Fibrinogen, D-dimer (a cross-linked
brin degradation product) and TAT (thrombin–antithrombin
complex) prevailed in meta-analysis as diagnostic markers (28).
Furthermore, circulating concentrations of hemostatic and brino-
lytic markers correlated with AAA and ILT size (29) and D-dimer
blood levels were suited to predict the AAA growth rate (30).
Importantly, large, population-based health screenings identied
elevated blood levels of brinogen and tissue plasminogen activa-
tor to be associated with the occurrence of AAA within the sub-
sequent 10–20years follow-up period. e fact that these plasma
proteins were elevated years before the clinical manifestation of
disease further supports the notion that deregulated hemostasis/
brinolysis is intricately involved in AAA pathogenesis – starting
at an early stage of disease (31).
e factors potentially protecting or predisposing an individual
to AAA development have been subjected to intense investigation.
Loss of endothelial homeostasis resulting in pro-inammatory
and pro-coagulant activation is proposed to trigger the onset of
disease. Two molecules that are central in regulating endothelial
homeostasis and may thus exert a protective function are carbon
monoxide (CO) and nitric oxide (NO) (32, 33). However, a more
complex picture has emerged with CO, NO, and their enzymatic
or reactive by-products exhibiting additional eects on, e.g., SMC
proliferation and survival, which may promote rather than inhibit
AAA development (34, 35). e loss of SMCs is a hallmark of the
weakening vessel wall. In addition, AAA pathogenesis involves the
destruction of elastic bers and other matrix components, which
seems to be vitally regulated by the accumulation of neutrophils
in the growing ILT (36). ese central mechanisms of disease
development are highlighted in the following review sections.
Role of Heme Oxygenase 1 in AAA and ILT
Heme oxygenase-1 (Hmox1) and products of its activity can aect
blood coagulation and formation of the thrombus. Hmox1 is an
enzyme degrading heme – as released by erythrocyte trapping and
hemagglutination in the thrombus – to carbon monoxide (CO),
ferrous iron (Fe2+), and biliverdin, which is subsequently reduced
by biliverdin reductase to bilirubin. Hmox1 has anti-oxidant, anti-
inammatory, and cytoprotective activity that is crucial for blood
vessel homeostasis (32) (Figure3). Carbon monoxide activates
guanylate cyclase, increases the level of cGMP (cyclic guanosine
monophosphate), and subsequently inhibits platelet aggregation
(37). Moreover, CO has been shown to suppress plasminogen
activator inhibitor-1 (PAI-1) in a lung ischemia-driven thrombosis
model (38) and subsequently aects brinolysis. Accordingly,
both CO and bilirubin suppress PAI-1 in Hmox1-decient mouse
embryonic cells (39).
e majority of studies characterizing the role of Hmox1 in
hemostasis and thrombosis have been performed on the occlusive
types of thrombosis as opposed to AAA. Lack of heme oxygenase-1
in Hmox1−/− mice leads to the faster occurrence of an occlusive
thrombus in the carotid artery aer photochemical injury (40).
Basal levels of carotid tissue factor, platelet counts, bleeding
time, and prothrombin time were not dierent in Hmox1+/+ and
Hmox1−/− mice. However, vascular injury induced higher levels
of arterial tissue factor and von Willebrand factor in Hmox1−/−
than in Hmox1+/+ mice. Also, photochemical injury led to the
endothelial damage only in Hmox1−/− mice. Finally, Hmox1+/+ mice
transplanted with Hmox1−/− bone marrow showed accelerated
thrombosis in comparison to the Hmox1+/+ mice that received
Hmox1+/+ bone marrow. Interestingly, faster occlusive thrombus
formation in Hmox1−/− mice could be rescued with biliverdin, or
when mice were inhaled with sublethal doses of CO (40).
Similarly, in the model of stasis-induced thrombosis in the
inferior vena cava (IVC), the clot was bigger in Hmox1−/− mice
(41). IVC ligation increased Hmox1 transcription and protein
levels in wild type endothelial and SMCs as well as in inltrating
FIGURE 4 | Schematic diagram showing the generation of NO and
ONOO− from a coupled eNOS and an uncoupled eNOS in a normal
and a dysfunctional endothelium, respectively. eNOS, endothelial nitric
oxide synthase; NAD(P)H, nicotinamide adenine dinucleotide (phosphate);
TDB, tetrahydrobiopterin.
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cells. It was demonstrated that IVC ligation in Hmox1−/− mice
induced a higher activation of nuclear factor kappa B (NF-κB)
transcription factor and increased the inammatory response
as reected by the expression of interleukin-6 (IL-6), monocyte
chemoattracting protein-1 (MCP-1), stromal cell-derived factor-1,
and KC (the murine homolog of interleukin-8) than in wild type
animals. Importantly, the activity and expression of MMP-9 were
also elevated in Hmox1−/− mice. Finally, similar to the model of
carotid artery injury in the work by True et al. (40), the vena
cava ligation led to the increased production of tissue factor in
Hmox1−/− mice (41).
Cobalt protoporphyrin IX (CoPP), a known inducer of heme
oxygenase-1, inhibits formation of the thrombus in response to
laser ablation of endothelium in cremaster arterioles, whereas tin
protoporphyrin IX (SnPP), a heme oxygenase-1 inhibitor, leads
to enhanced thrombus formation (42). Interestingly, in a murine
model of aorta allotransplantation, the thrombus was formed
when aortas from Hmox1−/− were graed (43). e eect of the
lack of Hmox1 was rescued with carbon monoxide releasing
molecule-2 (CORM-2) (43). Moreover, administration of hemin,
which not only induces Hmox1 but also promotes oxidative stress,
resulted in faster clot formation in response to ferric chloride in
Hmox1−/− mice than in Hmox1+/+ mice, which was not observed
under basal conditions (44). Noteworthy, in animals with a normal
level of Hmox1 hemin may have a protective activity. Prophylactic
treatment of Wistar rats with hemin reduced carotid thrombus
formation in response to the electric stimulation (45). A similar
observation was found in the mouse cremaster microvascular
circulation, where hemin delayed formation of the thrombus in
response to ferric chloride (46).
Despite the fact that the majority of functional studies regarding
the role of Hmox1 in thrombus formation were conducted in the
context of occlusive thrombosis, there are several ndings that
implicate Hmox1 in AAA pathobiology. Of note, expression of
Hmox1 is increased in rat aorta on days 7 and 10 aer AAA induc-
tion with elastase (47). Enhanced expression of Hmox1 prevents
endothelial cell apoptosis and facilitates endothelial proliferation
(32). By contrast, upregulation of Hmox1 in vascular SMCs
induces p53 expression and promotes apoptosis (48). Noteworthy,
increased SMC death and a high level of p53 is a common feature
of AAA lesions and the weakening vessel wall (49). Furthermore,
carbon monoxide inhibits the rat aortic SMC proliferation under
hypoxic conditions in response to endothelin-1 (34). Moreover,
probucol, which is used to prevent restenosis, increases Hmox1
levels in SMCs and therefore inhibits their proliferation (50). e
diverse eects that Hmox1 and its enzymatic products may exert
in the AAA setting (such as reducing thrombus formation, yet
increasing SMC apoptosis) are summarized in Figure3.
Importantly, the level of Hmox1 expression in humans is modu-
lated with the microsatellite polymorphism of the gene promoter
(51). Namely, a longer promoter with more guanidine–thymidine
(GT) repeats (n≥29) results in lower basal expression of Hmox1
and weaker upregulation in response to stimuli (52). It was shown
that human umbilical vein endothelial cells with a short Hmox1
promoter (n≤23) survive better under oxidative stress, proliferate
more eectively in response to vascular endothelial growth fac-
tor and produce less pro-inammatory cytokines such as IL-1β,
IL-6, and soluble intercellular adhesion molecule-1 (52). e
frequency of carriers of the short GT repeat allele of the Hmox1
promoter was signicantly lower in Austrian AAA patients than
in coronary or peripheral artery disease-matched controls (53).
Similarly, there was a higher frequency of the longer GT repeat
allele of the Hmox1 promoter in patients with cerebral aneurysms
(54). is may suggest that a higher expression or inducibility
of Hmox1 may play a protective role against AAA development.
By contrast, in a group of Croatian AAA patients, there was a
higher frequency of the carriers of short GT repeats in the Hmox1
promoter than in the non-AAA group (55). us, the relation
between AAA development and Hmox1 promoter polymorphism
requires further analysis.
Role of NO and Nitroxidative Stress in
Aortic Aneurysm Formation
Nitric oxide (NO) can be produced by three nitric oxide synthases
(NOS): endothelial – eNOS, neuronal – nNOS and inducible –
iNOS. In endothelium, NO is produced mainly by eNOS (Figure4).
Its release depends on the velocity of blood ow and the diameter of
the vessel. In the cardiovascular system, NO regulates the blood ow
as well as prevents platelet and leukocyte adhesion and aggregation
(33, 56, 57). Under laminar ow, there is a homogeneous thin
layer (about 1–3μm) of NO in close proximity to the arterial wall.
However, under turbulent or semi-turbulent ow, the NO layer can
be depleted (58). erefore, NO production from the endothelium
under turbulent ow is signicantly higher than under laminar
ow. Under this turbulent ow and under intensive production
of NO, eNOS can become uncoupled, which leads to dysfunction
of the endothelial cells (58, 59). is process is observed in many
cardiovascular diseases including atherosclerosis, hypertension,
stroke, diabetes, and aneurysm. e uncoupling of eNOS can be
attributed to a shortage of substrates of eNOS (L-arginine and/
or oxygen) as well as cofactors of eNOS like tetrahydrobiopterin
(THB) (60, 61). Uncoupled eNOS can concomitantly generate NO
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and superoxide
()O2
-
. NO can react rapidly in a diusion controlled
reaction with
O2
-
to produce peroxynitrite (ONOO−). Peroxynitrite
is a short lived (t1/2<1s) molecule with an oxidation power that is
much higher than that of NO or
O2
-
. erefore, high concentrations
of ONOO− can cause signicant damage to proteins, enzymes, and
DNA in a biological milieu (62, 63).
e role of NO in the development of aneurysm is ambiguous
and unclear. ere are several studies concerning eNOS- and iNOS-
derived NO in the pathology of aneurysms performed on animal
models and human beings (64–68). However, the results produced
by these studies are very oen contradictory. Aneurysmal degen-
eration is a result of biochemical and biomechanical processes,
which nally lead to the partial destruction of the aortic wall (49).
Nitric oxide and peroxynitrite may be involved in many of these
processes. e eect of turbulent ow will be more pronounced with
the increase in diameter and asymmetry of aneurysms (69). Based
on our studies, the change of ow from laminar to turbulent would
lead to a higher level of NO concentrations and a higher expression
of eNOS (62, 63). However, an increase in eNOS expression does
not always produce a higher level of bioavailable NO (diusible
NO, which can be involved in cellular signaling), because it is not
usually accompanied by an increase in the levels of L-arginine
or cofactors like THB. At an insucient level of substrates and
cofactors, the dimeric form of eNOS enzyme can be uncoupled
and the net eect of uncoupled eNOS correlates inversely with the
level of bioavailable NO and directly with ONOO− concentrations.
us, while NO production by eNOS is known to play a protective
role in the cardiovascular system by its vasodilatory eect, Gao
etal. found that eNOS uncoupling/THB deciency accelerated the
formation of AAA in mice (64). Comparably, it has been suggested
that eNOS deciency increased in atherosclerosis in Western-type
diet-food apoE knock-out mice and triggered spontaneous aortic
aneurysms (66). Furthermore, NO may play a role in the MMP
regulation in AAA: NO produced via eNOS inhibits MMP activity
and inhibits SMC migration (65, 68).
Animal models demonstrated that inhibition of iNOS decreased
NO generation and inhibited aneurysm formation. However, the
opposite eect was also reported. Lee etal. demonstrated in animal
models that iNOS does not play a requisite role in the process of
elastase-induced experimental aneurysmal degeneration in mice
(67). e authors also suggested that therapeutic treatment of
aneurysms by inhibition of iNOS may have a deleterious eect.
Most published studies on models of aneurysm indicate that iNOS
expression increases while eNOS decreases during aneurysmal
degeneration.
We believe that a likely reason for these confusing results is due
to the heterogeneous distribution of NOS along the wall of an aneu-
rysm. In our opinion, the type of ow (laminar versus turbulent)
could be a determining factor, which will inuence the kinetics of
NO release, expression of eNOS and iNOS, and NO bioavailability
in dierent segments of aneurysmal tissue. erefore, one can
assume that it is highly unlikely that a lateral NO distribution in the
aneurysm will be homogeneous, but it will not be. us, analysis
of a sample of aneurysm without information providing specic
locations (coordinates) of the aneurysmal tissue may be awed. An
indication of NO production by iNOS has been closely associated
with inammation, which follows an increase in the dysfunction
of the endothelium, the increase in eNOS uncoupling, and an
increase in peroxynitrite and nitroxidative stress. It is well accepted
that ON OO− is directly involved in the triggering of inammation.
Endothelial, bioavailable NO is cytoprotective, while peroxynitrite
is cytotoxic. e balance between the concentrations of these two
molecules has to be measured along the arterial wall at well-dened
coordinates. ese kinds of measurements have never been done
and this is likely the reason for the very conicting picture seen
for the role of NO in the development of aneurysms. Recently,
our laboratory developed a system of nanosensors (diameter of
lower than 300nm), which can be placed near the endothelium
of an aortic aneurysm for the simultaneous, insitu measurements
of NO, ONOO−, and
O2
-
(62, 63). e preliminary data obtained
from these experiments indicate a substantial dierence in the
kinetics and concentration of the release of NO, as well as the
release of the other components of nitroxidative stress at dierent
segments of aneurysms. NO plays a signicant role in the early
events in aneurysm formation and this mechanism may not be
related to hypertension. During this early event, uncoupled eNOS
starts to produce signicant concentrations of ONOO−, changing
the balance between the cytoprotective NO and the cytotoxic
ONOO− (70). e NO/ONOO− imbalance stimulates iNOS, which
starts to produce uncontrollably high levels of NO, as a protec-
tive measure. However, this increase in NO production by iNOS
causes further uncoupling of eNOS due to local consumption of
L-arginine. e net eect of these processes (nitroxidative stress)
stimulates a cascade of events, which lead to the elevated genera-
tion of additional oxidative and nitroxidative species, including
O2
-
, ONOO−, and H2O2. e stimulation of NAD(P)H, under this
condition, contributes to the elevation of
O2
-
, oxidation of THB,
and the further enhancement of ONOO− levels (62, 64).
erefore, the low level of bioavailable NO and the high level of
nitroxidative and oxidative stress can be considered as important
factors in the initial stage of aneurysm development. is process
can be similar to that observed in atherosclerosis. Nitroxidative
stress can trigger several processes leading to the injuring of
endothelial cells and SMCs, upregulation of chemotactic cytokines,
upregulation of NAD(P)H and adhesion molecules, as well as
activation of MMPs (71). All of these processes can contribute to
vessel wall remodeling and breakdown. As the aneurysm devel-
ops further, NO is involved in the inhibition of smooth muscle
proliferation, nitroxidative stress, and the change of angiogenic
activities (35, 72). is may result in the serious destruction of
extracellular matrix and elastic bers. e net eect of NO and
ONOO− action can be the thickening and weakening of the arte-
rial wall and nally its rupture. We believe that the ratio of NO
concentration to ONOO− concentration and non-homogenous
distribution of oxidative/nitroxidative stress plays a crucial role
in the development of the aneurysm.
Role of Neutrophils in Aortic Aneurysm
Formation
e bulk amount of ROS and reactive nitrogen species (RNS) in
AAA and ILT is produced by activated polymorphonuclear cells
like neutrophils. Neutrophils have pro-oxidant activities via, e.g.,
NADPH oxidase and myeloperoxidase. Myeloperoxidase is a
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heme enzyme, which is expressed in 95% of polymorphonuclear
neutrophils (PMNs). Both myeloperoxidase and NAPDH oxidase
are primarily involved in the generation of ROS/RNS (73). Ramos-
Mozo etal. showed a decreased catalase activity in circulating
PMNs as well as in plasma from AAA patients, indicating that
neutrophils of AAA patients have a reduction in anti-oxidant
enzymes (74). By contrast, H2O2 levels and MPO levels in isolated
PMNs were signicantly higher than in controls. erefore, a redox
imbalance toward increased oxidative stress in AAA patients could
be a key factor in AAA formation (74). However, PMNs do not only
contribute to oxidative stress but also to proteolytic degradation of
the aortic media and to adventitial inammation (75). Important ly,
PMN depletion showed a signicant inhibition of experimental
AAA formation thus pointing to the central role of neutrophils in
AAA pathogenesis (76).
e luminal layer of the ILT is the predominant site of leuko-
cyte retention. In the luminal ILT IL-8, a neutrophil chemotactic
factor is released four times higher than in the AAA wall (77).
Leukotriene B4 (LTB4) is another potent leukocyte chemoat-
tractant and mediator of inammation. Houard etal. showed
thrombus-derived LTB4 as a mediator of neutrophil chemotaxis
(78). Again, the luminal layer of the ILT had the highest activity.
Furthermore, the alternative complement pathway was found to be
activated in the AAA setting (79) and C5a had the specic ability to
chemoattract neutrophils and trigger oxidative burst by inducing
the release of CXC chemokines (80). Pagano etal. showed in a
murine model that elastase-induced AAA is indeed complement
(C3a, C5a) dependent (79). Neutrophils are 12 times more numer-
ous in clots than in blood because these cells have a high anity
for the brin–bronectin network. ey bind to brin via integrins
and to platelet-exposed P-selectin via the expression of the sialyl
Lewis-X-containing polysaccharide ligand (81). Neutrophils are
terminally dierentiated cells, which undergo constitutive apopto-
sis aer binding; this process is postponed upon NF-κB activation
in neutrophils (82) as facilitated in the context of the ILT.
e presence of an ILT has been associated with a thinner
arterial wall (21), more extensive elastolysis, a lower density of
SMCs in the media, and a higher level of immuno-inammation
in the adventitia (19). is suggests that an important part of
the protease activity originates from the ILT in contrast to the
previously suspected direct generation within the AAA wall.
e ILT is particularly rich in pro- and active forms of MMP-9
(83), and MMP-9–lipocalin complexes, which are of neutrophil
origin (84). Localization of neutrophils in the luminal part of the
thrombus is associated with increased levels of MMP-8, MMP-9,
and elastase compared with other (medial and abluminal) layers
of the ILT (36). Neutrophils release granular serine proteases such
as urokinase plasminogen activator, elastase, proteinase 3, and
cathepsins from their azurophilic granules. MMP-9 and MMP-8
are released from gelatinase granules. e cysteine proteases are
also potent elastolytic and collagenolytic enzymes associated
with AAA development. Several cathepsins (85) and dipeptidyl
peptidase I (86) have been reported to be elevated in AAA tissue,
combined with a decrease in their cystatin inhibitors. Dipeptidyl
peptidase I is a lysosomal cysteine protease, which is of central
importance, as it promotes the activation of granule-associated
serine proteases, including neutrophil elastase, cathepsin G, and
proteinase 3 (87). Neutrophil proteases may essentially degrade all
types of matrix brillar proteins and thus promote AAA progres-
sion and ultimate wall rupture. e site of nal adventitial rupture
is characterized by a high level of protease expression (88) and a
prominent enrichment of leukocytes and focal neovascularization
(89). Of interest, Lindholt etal. have reported a protective eect of
calcication in the evolution of AAA, probably explained by the
greater resistance of calcied tissue to proteolysis (90).
Abdominal aortic aneurysm biomarkers are of great scientic
interest, as a specic biomarker for prediction of AAA rupture is
urgently needed. ere are no AAA-specic laboratory markers;
however, neutrophil-related factors may have future prospects.
Ramos-Mozo et al. showed that plasma levels of neutrophil
gelatinase-associated lipocalin are increased in AAA patients and
correlate with AAA growth, reecting the potential activation of
both resident and circulating neutrophils (91). Despite the fact that
AAA-related biomarkers have the limitation of not being disease
specic due to a strong connection to general atherosclerosis,
MMP-9 levels were found to have a signicant correlation with
AAA diagnosis (92). In addition to the marker potential, neutro-
phils (and PMN-related factors) constitute a therapeutic target
in AAA patients. Doxycycline can directly inhibit MMP activity,
and it eectively suppresses the development of elastase-induced
AAAs in preclinical models (93). In clinical trials, preoperative
doxycycline therapy improved the proteolytic balance in human
AAA by reducing aortic wall neutrophil content (94). Doxycycline
treatment resulted in a 2.5-fold decrease of MMP-9 protein levels
(95). Lindeman etal. could show a strongly reduced PMN and
cytotoxic T-cell content of the aortic wall aer a 2-week doxycy-
cline treatment of AAA patients indicating that the doxycycline-
mediated eects are not restricted to neutrophils (96).
Treatment Indications
Biodegradation of the abdominal aortic wall determines aneurys-
mal growth. Average growth rates of AAAs below 55mm in size
range from 2 to 3mm per year. Larger AAAs are associated with
higher growth rates (4). Most AAAs are asymptomatic, and the vast
majority is detected occasionally during routine investigations.
Risk factors for progression to rupture comprise hypertension, age,
female sex, and persistent smoking (4). Finally, the life-threatening
risk of rupture has to oset the operative mortality for aneurysm
repair. For small fusiform AAAs (AAA diameter 30–39mm),
the 12months risk of rupture is 0%, and it is still about 1% in
those cases when the AAA diameter ranges between 40–49mm
(4). As a consequence, several studies recommended pursuing a
surveillance policy in these cases (97). However, the 12months risk
of rupture rises exponentially with further increase of the aortal
maximum diameter. Consequently, the threshold for aortic repair
is 50mm for women and 55mm for men (4).
Besides the diameter of the AAA, its morphology plays another
important role in the decision for repair. Fusiform AAAs are
thought to be less prone to rupture than saccular AAAs, or those
with eccentric components (Figure1). Peak wall stress, presence
of an ILT (Figure2), and AAA wall mechanics are the factors
most implicated with rupture risk. erefore, early repair has been
advised in these cases (98).
FIGURE 5 | (A) Successful exclusion of an infrarenal AAA by a tube graft.
Iliac bifurcation intact. (B) Successful exclusion of an infrarenal AAA by a
bifurcated stent graft.
FIGURE 6 | (A) Invasive angiography prior to endovascular repair (EVAR):
rupture of an infrarenal AAA. (B) Final angiography after EVAR: successful
exclusion of the ruptured AAA by a bifurcated stent graft; no endoleak visible.
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Symptomatic AAA is characterized by abdominal, back, or
chest pain (99). Peripheral embolization with subsequent ischemia
may be another sequel of AAAs with intraluminal thrombus (4).
Peak wall stress is signicantly greater in symptomatic or ruptured
AAAs compared to asymptomatic AAAs according to a recent
meta-analysis (98). As a consequence, early repair has been recom-
mended in symptomatic patients (4, 98). Likewise, rapid aneurysm
growth with more than 10mm per year represents another indica-
tion for early repair (4). In conclusion, these recommendations aim
to prevent AAA rupture, a life-threatening event with mortality
rates of approximately 65–85% (100).
Surgical Repair
orough preoperative evaluation of the patient’s comorbid
diseases is a prerequisite for any type of surgical repair as its
outcome essentially determines the decision between open or
endovascular repair. Second, optimization of the treatment for
various comorbidities should be obtained (4). Moreover, computed
tomography (CT) or magnetic resonance angiograms are necessary
to outline the morphological characteristics of AAAs for devising
the operative strategies in open surgical repair (OSR) as well as
for selection of the appropriate stent gra for endovascular aortic
repair (EVAR). OSR is the mainstay in elective AAA cases. In
general, tube gras (Figure5A) are preferred to bifurcated gras,
due to reduced dissection with less risk of injury to adjacent
structures and consecutively shorter operating time (4). In case
of additional iliac artery aneurysms or concomitant iliac arte-
rial occlusive disease, indication for a bifurcated gra is given
(Figure5B). Since the introduction of EVAR via a transfemoral
approach by Volodos in 1984 (101), this technique has become of
wide-spread use (Figure6).
An advantage of EVAR over OSR is less surgical trauma.
Moreover, general anesthesia can be avoided. EVAR, however,
requires adequate aortic and iliac xation sites for eective seal-
ing and xation (4). Tortuous iliac arteries or extreme kinking of
the aorta may prevent from adequate insertion or xation of the
stent gra in up to 40% of the patients. Endoleak aer EVAR is
a common complication in up to 25% of patients (4). In general,
AAA patients suer from a pro-thrombotic tendency. While the
incidence of AAA-related disseminated intravascular coagulation
(DIC) prior to surgery is rare and may be resolved upon AAA
repair, the occurrence of DIC as a perioperative coagulopathy is
a more frequent complication (102). In addition, a high incidence
of venous thrombosis is observed aer elective AAA repair despite
systematic heparin application (103) and both coagulopathy as well
as a hyperbrinolysis are similarly encountered in ruptured AAA
repair (104). It has been subject of investigation whether the two
types of surgical intervention (OSR versus EVAR) dier in their
hemostasis eects (27). Both were found to further aggravate the
pro-coagulant and hyperbrinolytic state of AAA patients in the
initial post-operative period (105, 106) while reducing the circulat-
ing markers of deregulated hemostasis/brinolysis several months
aer AAA repair (107). Despite the fact that EVAR represents a
smaller surgical trauma, a number of studies observed that EVAR
as compared to open surgery led to higher marker levels in the
immediate perioperative phase as well as the long-term period
(108). is indicates that the inherent procedure and materials
of EVAR may extend the hemostatic imbalance aer AAA repair.
With respect to overall outcome, meta-analyses of prospective,
randomized, controlled trials showed that 30-day mortality was
higher in OSR (3.2–4.2%) versus EVAR (1.2–1.4%) in elective
AAAs (109–111). However, there were no dierences in the
long-term (>4years) all-cause mortality between EVAR (37.3%)
and OSR (37.8%) (109, 110, 112). Causes of deaths were primarily
cardiovascular events with similar incidences of cardiac death and
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fatal stroke, and malignant diseases (109, 112). Moreover, there
were no signicant dierences in aneurysm-related mortality.
Re-intervention rates, however, were signicantly higher and more
aortic related aer EVAR (18.9%) compared to OSR (9.3%) (110).
e incidence of ruptured AAAs ranges between 6 and 18
per 100 000 person-years in Western countries (4). e overall
mortality rate is extremely high with up to 80–90%. AAA rupture,
dened as bleeding outside the adventitia of the dilated aortic
wall, is classied into free rupture into the peritoneal cavity with
extremely poor outcome or retroperitoneal rupture. Treatment
strategies are of importance in aortic surgery, as clamping of the
aorta is connected with a massive lower torso ischemia. Pre- (113)
and post-conditioning (114) should activate the endogenous
anti-oxidant defense mechanisms. Additionally, early infusion of
radical scavengers plus L-arginine and cofactors (59, 61, 115, 116)
play an important role to ameliorate deleterious consequences.
Following these strategies, a reduction of 30-day mortality rates
(52%) was noticed (117). In our own studies, the 90-day mortality
rate for patients receiving OSR was 29% (118). In the last decade,
a progressive increase in the proportion of patients managed by
EVAR in case of ruptured AAAs was observed. Importantly, it has
been shown that successful exclusion of ruptured AAAs by EVAR is
feasible. Several studies showed signicantly lower 30-day mortal-
ity rates aer EVAR (24%) compared to OSR (52%) (111, 117).
e survival advantage for EVAR aer ruptured AAA persisted
during the rst 5years aer repair, but was lost aer that period.
e estimated 5-year survival was 44 and 39% for EVAR and OSR,
respectively (117). By contrast, a recent meta-analysis including
only randomized controlled trials failed to show superior outcome
aer EVAR compared to OSR (119). Moreover, long-term data are
lacking for both survival and complications (119).
In conclusion, evaluation of the literature on OSR versus EVAR
in both elective and ruptured AAAs failed to show superiority
of one of these treatments in the long run, because randomized
controlled trials do not consider the various risk factors, which
account for the nal outcome. erefore, the tailored approach
attributing geriatric patients with multiple morbidities to EVAR
resulted in better outcome rates – at least initially (120, 121). In
individuals considered unt for OSR, no dierence between EVAR
and the non-intervention group with regard to all-cause mortality
(21% in each group), with higher aneurysm-related deaths in the
non-intervention group have been described (109). is nding
may prompt us to avoid excessive surgery in geriatric and high-risk
patients with multiple comorbidities. Future research, however,
should aim at predictors for AAA growth and rupture. New
biochemical markers along with functional imaging may help to
select patients who are at risk at an early stage.
Pharmacological Treatment Options
Based on the outlined pathomechanism of disease, various
pharmacological treatments are oered to AAA patients in addi-
tion to surgical intervention, which is limited to the progressed
state (Figure7). According to the European Society for Vascular
Surgery guidelines for the management of AAA, statins and
anti-platelet drugs should be used in patients diagnosed with
AAA (4). Statins should be started 1month before intervention
to reduce cardiovascular morbidity and should be continued in
the perioperative period for an indenite duration; while aspirin
at low doses should be prescribed on diagnosis and continued
through the perioperative period unless a contradiction exists (4).
However, only statins were indicated to both reduce cardiovascular
mortality in AAA patients and to slow the rate of AAA growth. On
the contrary, among the drugs that do not aect AAA growth but
may be indicated for comorbidities are beta-blockers, angiotensin-
converting enzyme (ACE) inhibitors, and AT1-receptor antago-
nists (122).
Abdominal aortic aneurysm is thought to be an inammatory
disease as patients with AAA exhibit increased values of inamma-
tory parameters such as C-reactive protein (123), or cytokines like
tumor necrosis factor alpha (TNF-α) (77). Indeed, AAA and ILT
are sources of physiologically active cells, including macrophages,
T-cells, B-cells, and neutrophils that produce large amounts of
messenger molecules (124). SMCs and endothelial cells in the AAA
wall as well as red blood cells and platelets in the intraluminal
thrombus are a source of free oxygen and nitrogen radicals.
When activated platelets produce intracellular superoxide anion
via NADPH oxidase, it conversely increases platelet recruitment
favoring thrombus formation (125).
Statins
e guidelines are based on experimental and clinical evidence
of the positive eect of statins in AAA prevention and treatment.
It was reported that statins may prevent aneurysm formation
in animal models (126). Moreover, some observational studies
in humans presented a 50% reduction in AAA expansion rate
(127), and an association between statin therapy and a risk of
AAA rupture (6). Also, a randomized trial reported that uvastatin
(80mg daily for 30days before surgery and continued until at least
30days aer surgery) halved both the primary 30-day outcome of
post-operative myocardial ischemia and the secondary outcome
of non-fatal myocardial infarction and cardiovascular death (128).
A recent large meta-analysis showed that statins reduce the rate of
progression of AAA (129). e meta-analysis by Galinanes etal.
(130) reported that 1 week of statins administered to patients
undergoing OSR or EVAR was associated with improved survival
during 1year aer surgery and a decreased incidence of lower
extremity embolic complications aer EVAR.
In our previous report, we showed that simvastatin decreased
the rate of free radical formation and the content of pro-inamma-
tory molecules like TNF-α in the aneurysmal wall (131). erefore,
protection of the AAA wall from ROS may be an important factor
in the reduced AAA rupture risk. Furthermore, patients with a
higher baseline C-reactive protein level respond better to statin
therapy and have a lower absolute vascular risk than those without
statins, as the ndings of the JUPITER trial documented (132).
e anti-inammatory eect of statins may be in part connected
with their inuence on pro-inammatory signaling pathways.
Simvastatin taken for at least 6months decreased the activity of
NF-κB and ERK1/2 signaling pathways in the aortic wall of AAA
patients (131, 133). A reduction in NF-κB activity under statins
may be in part related with modulation of NF-κB in inltrating
T helper cells and CD40 signaling in SMCs and mononuclear
cells (134), resulting in lower synthesis and release of IL-6 and
FIGURE 7 | Molecular changes in the aneurysmal wall, which may be
targeted by pharmacological treatment. Compounds generated in the
extracellular matrix (ECM) like free oxygen or nitrogen species (ROS/RNS),
inammatory cytokines, e.g., tumor necrosis factor alpha (TNF-α) or cyclophilin
A, and angiotensin II (through angiotensin receptor 1; AT1) stimulate
inammatory cells like macrophages or neutrophils, and platelets inside the
AAA wall. Next, macrophages/neutrophils act on T and B lymphocytes
initiating humoral and cell-mediated immune responses and leading to
inammation. As a consequence, pro-inammatory signaling pathways
involving NF-κB, T-bet, STAT-4, STAT-6, or GATA-3 are activated and a large
amount of pro-inammatory cytokines is released. Moreover, activated
leukocytes produce matrix metalloproteinases (MMPs), which degrade elastic
bers inside the AAA wall. The activation of AT1 receptor and increased
production of ROS/RNS by leukocytes activate platelets that form the
intraluminal thrombus. Those changes, however, may be slowed down or
eliminated by statins, anti-platelet drugs, or ACE inhibitors. ACE inhibitors,
angiotensin-converting-enzyme inhibitors; Ang II, angiotensin II; AT1,
angiotensin II receptor type 1; GATA, trans-acting T cell-specic transcription
factor; MMP, matrix metalloproteinase; ROS, reactive oxygen species; RNS,
reactive nitrogen species; STAT, signal transducer and activator of
transcription; TGF-β, transforming growth factor beta; Th, T helper cell; TNF-α,
tumor necrosis factor alpha.
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IL-8 (135). Recently, van de Meij etal. (124) conrmed previous
ndings that patients who underwent AAA repair treated with
simvastatin and atorvastatin at clinical doses had a reduced tissue
content of macrophage-related markers and NF-κB dependent
inammatory molecules such as IL-6 and MCP-1, however,
without a decrease in macrophage content.
Furthermore, inammatory mediators regulate the expression
and activity of MMPs released mainly by activated neutrophils
and macrophages. In animal models, statin therapy suppressed the
extent of AAA formation by 25%, and the incidence of AAA by 30%
(136). e eect was associated with a reduction in MMP-9 protein
and gene expression. In clinical trials, simvastatin was found to
signicantly lower MMP-9 concentrations by 40% within the
aneurysm wall compared to placebo (137). Importantly, MMPs are
inhibited when complexed with tissue inhibitors of MMPs (TIMPs).
It was reported that MMP-9 and TIMP-1 as well as MMP-2 and
TIMP-2 correlate with ILT thickness in patients with AAA (20).
erefore, statins may have benecial eects to slow AAA growth.
Anti-Platelet Therapy
Meta-analyses of randomized trials on primary and secondary
prevention of AAA with anti-platelet therapy suggested that all
patients diagnosed with AAA should be started on aspirin therapy
at the time of AAA diagnosis as the use of low-dose aspirin may
be associated with a reduction in all vascular deaths (138). Recent
epidemiologic data indicate that the initiation of lifelong aspirin
therapy should be considered as soon as a diagnosis of AAA is
made (139). However, a retrospective study, which investigated
aortic aneurysm cases between 1999 and 2006 from the National
Health Insurance Research Database found no association between
low-dose aspirin exposure and mortality or exacerbation in dif-
ferent types of aortic aneurysms (140).
Animal studies also showed that aspirin may signicantly
reduce both aortic plaque size and thrombus formation aer vessel
injury (141). ose eects may be in part mediated by the anti-
oxidant eect of aspirin in atherosclerotic vessels (142). Aspirin
treatment also leads to a reduction in free radical stress evident by
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decreased lipid peroxidation and signicantly prevented reduction
in glutathione content in endothelial cells of hypercholesterolemic
animals (143). erefore, based on animal models, anti-platelet
therapy is expected to be benecial to AAA patients.
ACE Inhibitors
Activation of the renin–angiotensin system has been implicated
in the genesis of several cardiovascular disorders including AAA
(144). Angiotensin II (Ang II) is strongly upregulated in human
aortic aneurysms, and the Ang II increase is mediated by pathways
dependent on ACE and chymase (145). In experimental studies,
ACE inhibitors were found to reduce AAA rate (146), and in a
retrospective clinical study, they were associated with a reduction
in the risk of AAA rupture (147). However, there are controversial
data. Some studies indicated that AAA patients treated with ACE
inhibitors, but not those treated with other anti-hypertensives,
seemed to be less likely to present with ruptured AAA as a recent
Canadian study showed (147). By contrast, Wilmink etal. did not
conrm the benecial eect of ACE inhibitors on AAA progres-
sion (148), while others found a reverse, negative eect of ACE
inhibitors on AAA (149).
Recently, Kortekaas eta l. (150) presented results where patients
treated with the ACE inhibitor ramipril (5mg/day, for 4weeks)
had signicantly lower levels of NF-κB and Ang II activity in AAA
tissue and a lower content of IL-8 and MCP-1. e eect of ACE
inhibitors on inammatory mediators may result in a change of
cell activation and, for instance, a shi in macrophage signature
toward a predominance of alternatively activated macrophages.
is may at least in part, account for the reduced expression of
the proteases MMP-9, cathepsin L, and S, which are all considered
instrumental in the process of AAA growth (85). Moreover, ACE
inhibitors inuence elastolytic MMP levels in the AAA wall to
reduce elastin degradation within the vessel (146).
Conclusion
Substantial progress has been made in recent years in understand-
ing the process of AAA development and progression. e ILT
has emerged as a major player, which “entraps” leukocytes, in
particular neutrophils, to create a pro-oxidant and proteolytic
environment that leads to vessel wall destabilization. e early
processes of aneurysm development may be particularly sensitive
to changes in the pathways controlling oxidative or nitroxida-
tive stress where localized deregulation may induce endothelial
and SMC dysfunction and promote thrombus formation. us,
pharmacological treatment options for AAA patients progres-
sively incorporate anti-oxidant, anti-inammatory, and anti-
proteolytic drug eects in addition to cholesterol, hemostasis,
or blood pressure control. e need for surgical repair is carefully
evaluated based on disease progression, morphological AAA
characteristics, and patient comorbidities to avoid unnecessary
risks. Predictive markers such as D-dimer for AAA growth are
required to evaluate the risk for imminent rupture and further
improve disease control.
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