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Preface
ix
milieu favorable to the release of MMPs. The MMPs cause massive destruction of elastin
fibers which significantly remodels the arterial wall, resulting in dilatation and AAA
formation. Reactive oxygen species play a role in the development of aneurysms. Increasing
the levels of TIMPs, proportional to the increased levels of ROS, was not sufficient to block
the formation of AAA. Further studies are being conducted to elucidate the role of
inflammatory cells and turbulent blood flow in the pathogenesis of AAAs in this experimental
model.
Chapter 4 Objectives: The aims of this study were to evaluate the morphometric and
structural characteristics of abdominal aortic aneurysms (AAA), and to form a morphometric
model of the AAA that could be applicable in the development of mathematical and
computation models for rupture risk assessment.
Material and Methods: The following morphometric parameters significant for
biomechanical stability and compliance of the aortic wall were analyzed: the thickness of the
wall, the thickness of the media and the thickness of the adventitia. Morphometry was
performed with the Olympus BX 41 microscope and the Olympus C 5060 wide zoom
digital camera with an application of the Olympus DP-soft Image Analyzer program. The
media-to-wall and adventitia-to-wall ratios were calculated. Parameters were correlated with
the diameters of the aneurysms (established by MSCT angiography and
gender, the presence of a thrombus and the grade of inflammation.
Results and Discussion: results showed that an increase in the AAA
diameter affected the structure of the aortic wall in the following ways: 1. the thickness of the
aortic wall significantly increased, with the greatest increase for aneurysms with diameters
between 41 and 60 mm (ANOVA F=268.561; p<0.001); 2. the thickness of the adventitia and
its proportion in the wall thickness significantly increased, in the same group (ANOVA
F=376.727, p<0.001); 3. the thickness of the media and its proportion in the wall thickness
significantly decreased, with the greatest increase for aneurysms with diameters >60mm
(ANOVA F=265.865; p<0,001). The supposed influence of the latter two factors reduced the
adaptability of the vascular wall and augmented the rupture risk since the aortic wall media is
responsible for the elastic properties of the blood vessels, while increased and fibrotic
adventitia did not provide sufficient compliance. The aithors confirmed, by means of the
Univariate Analysis of Variance, that the increase of the adventitia and destruction of the
media were even greater in aneurysms with inflammation and in patients over 65 years old.
Female patients with small aneurysms (d<40mm) are at a special rupture risk. They have a
significantly thinner wall (F=35.164; p<0.001), with a significantly thinner media (F=35.473;
p<0.001) and a significantly thicker adventitia (F=21.146; p<0.001) than male patients.
Small-diameter aneurysms with a thrombus are also under special rupture risk. Destruction of
the media was advanced in this group, with an exceptionally small medial thickness compared
to larger aneurysms with a thrombus (F=237.770; p<0.001).
Conclusions and Clinical Relevance: A correction of AAA computation models with
histomorphometric data is necessary for an accurate prediction of rupture risk. Parameters
used in computation models are based on CT scans, but not all parameters are easily assessed
with a CT scan (i.e., the wall thickness). Most of the computation models operate under the
assumption that aneurysms are homogenous structures, which is not the case. On the contrary,
aneurysms are heterogeneous, with extreme variations of structure among patients and in
different parts of the same aneurysm. Some data are not uniquely defined and recognized,
(i.e., the influence of a thrombus on the wall structure). Hence, the goal of morphometric
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Daniel Fischhof and Franz Hatig
x
models is to provide sufficient data for the construction of an improved and adjustable model
for rupture risk prediction that will combine many different factors and enable a tailored
decision making process for each patient.
Chapter 5 Over the past two decades, endovascular aneurysm repair (EVAR) has been
demonstrated to be safe and effective, and is nowadays a generally accepted alternative to
conventional open surgical aneurysm repair (OSAR). The landmark randomized controlled
EVAR-1, EVAR-2, OVER and DREAM trials have concluded that EVAR is associated with
reduced perioperative mortality, morbidity, blood loss and hospitalization, and provides
surgical treatment options for patients in a poor physical condition. Despite these convincing
short-term benefits of endovascular treatment, EVAR and OSAR have shown similar survival
rates at longer follow up.
A disadvantage of EVAR is the continuous risk of device-related complications, such as
migration and endoleaks, and so persisting risk of aneurysm rupture. The landmark trails
mention the higher rate of complications and secondary interventions associated with EVAR.
Furthermore, these possible complications necessitate a life-long follow-up in EVAR-
patients. The more recent OVER trial showed a similar reintervention rate after two years,
probably due to the use of later generation devices and a changed approach towards Type-II
endoleaks.
Despite the lack of consensus, patients seem to prefer endovascular repair rather than
open repair. Even in cases where, according to the instructions for use, patients are not
eligible for endovascular repair. Severely angulated or short infrarenal aortic necks are
associated with the occurrence of adverse EVAR outcomes. To ensure limited risk on
possible complications, only those with ideal anatomy are considered candidates for EVAR.
Probably the significantly higher rate of secondary interventions in the EVAR-1 and DREAM
trials was partly due to the use of older-generation devices, less knowledge about aneurysm
morphology, and less sophisticated intraoperative fluoroscopic imaging. The evolution of
stent-grafts and endovascular delivery systems has improved the application of EVAR with
less technical complications and re-interventions, which results in more extensive eligibility
criteria for safe endovascular treatment. The EUROSTAR and Lifeline registries have proved
this.
The Endurant Stent-Graft System is a new generation stent-graft with increased
performance in sealing and fixation, durability, conformability in tortuous vessels, and
delivery profile. The ENGAGE registry, initiated to evaluate the Endurant Stent-Graft
System, shows promising results with less aneurysm-related mortality, technical
complications and re-interventions in the long term. The recently launched EAGLE registry
looks at the clinical success of more challenging anatomy cases. The aim of this registry is to
collect clinical information on the performance of the Endurant Stent-Graft System in
anatomically challenging aneurysms, and to critically assess whether the current guidelines
for anatomic eligibility to endovascular treatment with this system can be expanded even
more.
Chapter 6 Abdominal aortic aneurysm (AAA) ruptures cause 16,000 deaths a year.
Randomized clinical trials on AAA screening in Europe demonstrated ultrasonography
significantly reduces AAA-related mortality. As a result, AAA screening programs were
developed to prevent AAA ruptures by identifying and treating patients with AAA. An AAA
is defined as an aortic diameter about 1.5 times greater than a normal aortic diameter,
, the diagnosis of AAA is made
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Preface
xi
in 4-8% of males 65-75 years of age. Much research has been invested into determining the
causes of AAA development and expansion, so that screening yield of patients and
management protocols for patients with AAA can be improved. This chapter discusses the
screening parameters for the diagnosis of AAA, the evolution of AAA screening from the
randomized screening trials to current AAA screening programs, as well as new research
improving AAA screening yield and diagnosis.
Chapter 7 An aortic aneurysm is a focal dilatation of the aorta that can be life-
threatening if it leads to a dissection or rupture of the degraded aortic wall. The disease occurs
most often in the ascending and abdominal aorta, an observation that cannot be fully
explained by the current medical knowledge of its pathophysiology. This review paper first
provides an argument as to why aortic hemodynamics might be an important factor in the
onset of the disease, and discusses previous studies focusing on the flow field in (already
developed) human aneurysms. Human studies are, however, hampered by the asymptomatic
nature and slow time course of the disease, which makes inclusion of baseline data in follow-
up studies on aneurysm formation a difficult task. A second part of the review therefore
focuses on different mouse models of aneurysm formation, and explains why the angiotensin
II-infused ApoE
-/-
mouse model has become the model of choice to study the disease. An
overview of studies on aortic hemodynamics in mice is presented, and the most important
technical limitations are discussed. Finally, a novel methodology is presented in which in
vivo measurements of the aortic geometry (using contrast-enhanced micro-CT) and aortic
flow velocities (using high-frequency ultrasound) are combined to obtain entirely mouse-
specific simulations of the flow field in the murine aorta. The outcome of these simulations
can be related to the location of the aneurysm in the same animals, and might in the future
provide more insight into the initial phase of the disease.
Chapter 8 The Endovascular Aneurysm Repair (EVAR) is a minimal invasive
alternative to open surgical therapy. From a long term perspective, complications such as
prostheses displacement or leaks inside the aneurysm sac (endoleaks) could appear
influencing the evolution of treatment. The objective of this work is to develop a decision-
support preliminary system for the diagnosis of EVAR progression from computed
tomography angiography CTA images. The system is based on the extraction of texture
features from thrombus aneurysm samples and a posterior classification. Regions of interest
(ROIs) from patients with different post-EVAR evolution were extracted by experienced
radiologists. Three conventional texture-analysis methods such as the gray level co-
occurrence matrix (GLCM), the gray level run length matrix (GLRLM), and the gray level
difference method (GLDM), were applied to each ROI to obtain texture features. In order to
evaluate the discrimination ability of textures features several classification schemes based on
multilayer perceptron neural network (MLP-NN), and support vector machine (SVM)
classifiers were experimented. The performance of classifiers was evaluated using 10-fold
cross validation with the entire dataset. The average of accuracy, sensitivity, specificity,
receiving operating curves (ROC) and area under the ROC curves (AUC) were calculated for
the classification performances of each texture-analysis method. The study showed that the
textural features could help radiologists in the classification of abdominal aneurysm evolution
after EVAR.
Chapter 9 Aortic aneurysm (AA) is a pathologic entity defined by a localized dilatation
in the thoracic (TAA), abdominal (AAA) or thoracoabdominal (TAAA) aorta. Aneurysms
rupture is an unexpected and usually fatal event, which usually leads to death due to
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Daniel Fischhof and Franz Hatig
xii
exsanguination. Another significant complication of AA is thromboembolism due to poor
hemodynamics, which is characterized by disturbed flow and circulation zones.
The first section of the chapter discusses the flow regimes of healthy and aneurysmatic
aorta from hemodynamic point of view using computational fluid dynamics (CFD) methods.
For both aortic arch and abdominal aorta, the aneurysm provokes a highly disturbed flow and
large recirculation regions in comparison to the cases without aneurysms.
The disturbed flow observed in the aneurysm sacs, especially during diastole, imply poor
particle washout from the aneurysm sac and regions of stagnation in the center of the
circulation zones. In addition, poor hemodynamics towards the iliac arteries might impair
perfusion.
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In: Aortic Aneurysms ISBN: 978-1-62618-458-9
Editors: Daniel Fischhof and Franz Hatig © 2013 Nova Science Publishers, Inc.
Chapter 1
GENETIC RISK FACTORS FOR ABDOMINAL
AORTIC ANEURYSMS (AAA)
Helena Kuivaniemi
*
, Evan J. Ryer, H. Richard Yoon
and James R. Elmore
Sigfried and Janet Weis Center for Research (HK), and
Department of Endovascular and Vascular Surgery (EJR, HRY, JRE),
Geisinger Clinic, Danville, Pennsylvania, US
ABSTRACT
Abdominal aortic aneurysm (AAA) is a complex, multifactorial disease with a strong
genetic component. About 20% of AAA patients have at least one relative with this
condition. Since the first candidate gene studies were published 20 years ago, nearly 100
genetic association studies using single nucleotide polymorphisms (SNPs) in biologically
relevant genes have been reported on AAA. The most significant results from candidate
gene studies are for sortilin-1 (SORT1), interleukin 6 receptor (IL6R), and
apolipoprotein(a) (LPA). Unbiased genome-wide approaches such as family-based DNA
linkage studies and genome-wide association studies have been carried out by
international consortia to identify susceptibility loci for AAA. The chromosomal regions
in the human genome with the strongest supporting evidence of contribution to the
genetic risk for AAA are: 1) CDKN2BAS gene (located on chromosome 9p21), also
known as ANRIL, which encodes an antisense RNA that regulates expression of the
cyclin-dependent kinase inhibitors CDKN2A and CDKN2B; 2) DAB2 interacting protein
(DAB2IP; located on chromosome 9q33), which encodes an inhibitor of cell growth and
survival; 3) low density lipoprotein receptor-related protein 1 (LRP1; located on
chromosome 12q13.3), a plasma membrane receptor involved in vascular smooth muscle
and macrophage endocytosis, and 4) contactin-3 (CNTN3; located on chromosome
3p12.3), which demonstrated the strongest association in smokers and yet its function
remains unclear. These four loci were identified in genome-wide association studies.
Using a different approach, DNA linkage analysis with affected relative-pairs, two
additional loci containing several plausible candidate genes, located on chromosomes
*
Corresponding author: Helena Kuivaniemi, Tel.: (570) 271-5593, FAX: (570) 271-6701, E-mail:
shkuivaniemi@geisinger.edu.
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Helena Kuivaniemi, Evan J. Ryer, H. Richard Yoon et al.
2
4q31 and 19q13, were discovered. On-going and future studies to find additional risk loci
include large meta-analyses and whole genome sequencing. Furthermore, functional
studies are needed to establish the mechanisms by which these genes contribute to AAA
pathogenesis. In the long-term, these discoveries will result in important translational
applications to the prevention, diagnosis and management of AAAs.
1. INTRODUCTION
An abdominal aortic aneurysm (AAA) is a permanent localized dilatation of a weakened
aortic wall with a diameter greater than 3.0 cm [1]. The main risk of an untreated AAA is
progressive expansion, rupture, hemorrhage and death. AAA rupture is the 16th leading cause
of adult death in the Unites States and accounts for more than 10,000 deaths in the USA
annually [
2]. AAA rupture risk increases with increasing aortic diameter and this catastrophic
event is associated with a mortality of 50 to 80% [3-5]. The most important risk factors for
the development of a AAA are smoking, advanced age, male sex and a family history of AAA
[6-8]. Over the last 50 years, there is an increasing amount of evidence supporting the
substantial genetic contribution to the risk of AAA. The goal of this review article is to
summarize the current knowledge on the contribution of genetic factors to AAA.
2. HISTORICAL PERSPECTIVE
In 1951, Griffiths et al. [9] reported a case involving a mother and son, both of whom
died as a result of ruptured dissecting aortic aneurysms. In this report, the possibility of a
hereditary predisposition to aortic aneurysm formation, albeit in association with aortic
familial nature of dissecting aneurysms of the aorta [10-13]. The first report of familial
clustering of a non-dissection related abdominal aortic aneurysm was by Clifton in 1977 [14]
who reported three brothers, the only siblings of one family, all of whom underwent surgery
for rupture of a previously asymptomatic AAA. This was followed by reports from Norrgård
et al. [15] and Tilson and Seashore in 1984 [16, 17], as well as from Kuivaniemi et al. in 2003
[18], which further described familial clustering of AAA. The first studies on the genetic
basis of AAA were reported in 1984 and compared the frequencies of blood groups or allelic
variance in class I human leukocyte antigens (HLA) in AAA patients and controls [19]. This
was shortly followed by candidate gene studies in AAA families. These investigations [20-
23] outlined specific mutations in connective tissue genes, however, these mutations were not
seen in sporadic AAA patients and therefore alternative approaches were needed. In this
review, we summarize these alternative techniques including genome-wide DNA linkage
analysis, candidate gene analysis, and genome-wide association studies (GWAS).
3. MONOGENIC, RARE, SYNDROMIC FORMS OF AORTIC ANEURYSMS
Fifteen distinct genetic diseases with arterial tortuosity, dilatation or dissection have been
identified (Table 1). In most of these rare syndromes, aneurysmal degeneration does not
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Genetic Risk Factors for Abdominal Aortic Aneurysms (AAA)
3
involve the abdominal aorta and most commonly vascular manifestations occur in the aortic
arch or the thoracic aorta. Thirteen different genes harbor mutations causing these 15
syndromic forms of aortic aneurysms and dissections (Table 1) [24-37]. While mutations in
most of these 13 genes lead to one distinct phenotype, mutations in ACTA2 can lead to either
the multisystemic smooth muscle dysfunction syndrome or the type 5 subtype of the
Moyamoya disease [
33]. Similarly, mutations in the genes for transforming growth factor,
beta receptors 1 (TGFBR1) and 2 (TGFBR2) can lead to phenotypic heterogeneity and
classification of the patient into different subtypes of the Loeys-Dietz syndrome [32]. Since
the number of patients studied for each of these conditions is small, it is difficult to make
generalizations about genotype-phenotype correlations. What can be concluded, however, is
that many of the genes encoding members of two biological pathways, the TFGB-signaling
and the contractile apparatus of the smooth muscle cell, are mutated in these patients. The
third important category of proteins defective in some of the patients is the proteins of
extracellular matrix (ECM) (Table 1).
Table 1. Monogenic, Rare, Syndromic Forms of Aortic Aneurysms
Disease Phenotype
Phenotype MIM ID
Inheritance
Gene
Gene MIM
ID
Chromosomal Region
Arterial tortuosity syndrome
208050
AR
SLC2A10
606145
20q13.12
Ehlers-Danlos syndrome,
vascular type
130050
AD
COL3A1
120180
2q31
Cutis laxa
123700
AD
ELN
130160
7q11.2
Cutis laxa, type 1A
219100
AR
FBLN5
604580
14q32.12
Cutis laxa, type 1B
614437
AR
EFEMP2
604633
11q13
Loeys-Dietz syndrome, type
1A
609192
AD
TGFBR1
190181
9q22
Loeys-Dietz syndrome, type
1C
613795
AD
SMAD3
603109
15q22.33
Loeys-Dietz syndrome, type
2A
608967
AD
TGFBR1
190181
9q22
Loeys-Dietz syndrome, type
2B
610380
AD
TGFBR2
190182
3p22
Loeys-Dietz syndrome, type
4
614816
AD
TGFB2
190220
1q41
Marfan syndrome
154700
AD
FBN1
134797
15q21.1
Multisystemic smooth
muscle dysfunction
syndrome
613834
ACTA2
102620
10q23.3
Moyamoya disease, type 5
614042
AD
ACTA2
102620
10q23.3
Periventricular heterotopia
300049
X
FLNA
300017
Xq28
Shprintzen-Goldberg
craniosynostosis syndrome
182212
SKI
164780
1p36.33
MIM, Mendelian Inheritance in Man database available at http://omim.org; AD, autosomal dominant;
AR, autosomal recessive; X, X-linked; SLC2A10, solute carrier family 2, member 10; COL3A1,
type III procollagen; ELN, elastin; FBLN5, fibulin 5; EFEMP2, EGF containing fibulin-like
extracellular matrix protein 2; TGFBR1 and 2, transforming growth factor receptors 1 and 2;
SMAD3, SMAD family member 3; TGFB2, transforming growth factor 2; FB1, fibrillin 1;
ACTA2, smooth muscle alpha-actin 2; FLNA, filamin A; SKI, v-ski sarcoma viral oncogene
homolog. Official approved gene symbols for this table and throughout the Chapter were obtained
from www.gene.ucl.ac.uk/nomenclature.
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Helena Kuivaniemi, Evan J. Ryer, H. Richard Yoon et al.
4
4. FAMILY HISTORY AS AN IMPORTANT RISK FACTOR FOR
ABDOMINAL AORTIC ANEURYSM
Family history plays a critical role as a risk factor for the development of AAAs and can
be utilized to help identify patients at high risk for AAA development. A positive family
history can increase the risk for AAA in a first degree relative by 10-fold compared to a
person who does not have any affected first degree relatives [38]. The aggregation of AAA in
families was first reported primarily as case reports in the 1970s-1980s [14-17]. In 2003, the
largest collection of 233 AAA families was reported [18]. In this collection 72% of the AAA
families were consistent with an autosomal recessive pattern, while 25% showed an
autosomal dominant pattern of inheritance.
Table 2. Family History of AAA Patients Based on Interviews and National Registries
Study
Country
Study
Design
Patients (N)
Studied
Positive
History
Familial
Prevalence (%)
Norrgård et al. 1984 [15]
Sweden
Interview
1
87
16
18
Johansen and Koepsell 1986 [38]
USA
Interview
1
250
48
19
Powell and Greenhalgh 1987 [71]
UK
Interview
1
56
20
36
Johnston and Scobie 1988 [39]
Canada
Interview
1
666
41
6.1
Cole et al. 1989 [139]
Canada
Interview
1
305
34
11
Darling et al. 1989 [140]
USA
Interview
1
542
82
15
Majumder et al. 1991 [70]
USA
Interview
1
91
13
14
Verloes et al. 1995 [72]
Belgium
Interview
1
313
39
13
Lederle et al. 1997 [40]
USA
Interview
1
985
91
9.2
Lawrence et al. 1998 [141]
USA
Interview
1
86
19
22
Salkowski et al. 1999 [142]
USA
Interview
1
72
19
26
Rossaak et al. 2001[143]
New Zealand
Interview
1
248
48
19
Larsson et al. 2009 [144]
Sweden
Registry
2
3,183
268
8.4
Combined
6,884
738
11
1
Family history information was collected by interviewing the AAA patients or sending a family history
questionnaire via mail.
2
AAA patients were identified from the National Hospital Discharge Registry of Sweden and their
relationships were obtained in the Multigenerational Registry of Sweden [144].
The estimates of prevalence of AAA among family members of AAA patients depend on
the type of approaches used to obtain this information. Two different approaches have been
used: 1) collect family information from the patient using interviews and family history
questionnaires (Table 2), and 2) screen the family members with aortic duplex imaging for
detection of asymptomatic AAAs (Table 3). Both approaches have been used extensively (see
Tables 2 and 3). Although there are large variations between studies, when the results are
combined from all studies using the same techniques, the estimates of prevalence of AAA
among family members are very similar between studies using interview method (11%) and
those carrying out screening by imaging (12%).
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Genetic Risk Factors for Abdominal Aortic Aneurysms (AAA)
5
Studies using interviews (Table 2) were performed in the last 30 years and revealed an
overall AAA prevalence of 11% (range 6 36%) among relatives of AAA patients.
Interviews allow inclusion of family members that may not be able to attend an ultrasound
screening examination but the study relies on the patient or relative to provide accurate
medical information of the family. It also requires that the relatives must already have a
diagnosis of AAA leaving out asymptomatic undiagnosed AAA cases.
One of the earliest interview studies, carried out by Johansen and Koepsell in 1986, found
that 19.2% of the AAA patients interviewed had relatives who were also diagnosed with
AAA [38]. In contrast, only 2.4% of individuals without AAA knew of any relative with
AAA in their families. Johnston and Scobie [39] reported on 666 patients that underwent
surgery for non-ruptured AAA and found positive family history for AAA in only 6.1% of
these patients. Slightly higher proportion (9.2%) of 985 aneurysm patients (with at least a 4
cm aneurysm) studied by Lederle et al. [
40] reported a positive family history for AAA.
Table 3. Prevalence of AAA among First-Degree Family Members Based on
Ultrasonography Screening
Study
Country
Brothers
Sisters
Total
1
N
screened
% with
AAA
N
screened
% with
AAA
N screened
% with
AAA
Bengtsson et al. 1989
[145]
Sweden
35
28.6
52
5.8
87
15
Collin & Walton 1989
[146]
UK
16
25.0
15
0
31
13
Webster et al. 1991 [147]
USA
24
20.8
30
6.7
157
8.9
Adamson et al. 1992
[148]
UK
25
20.0
28
10.7
53
15
Bengtsson et al. 1992
[149]
Sweden
62
15
van der Lugt et al. 1992
[150]
Netherlands
56
28.6
52
5.8
108
18
Adams et al. 1993 [151]
UK
23
17.4
28
3.6
74
15
Moher et al. 1994 [152]
Canada
48
18.8
48
19
Fitzgerald et al. 1995
[153]
Ireland
60
21.7
65
3.1
125
12
Larcos et al. 1995 [154]
Australia
52
0
Baird et al. 1995 [155]
Canada
26
26.9
28
10.7
54
19
Jaakkola et al. 1996 [156]
Finland
45
8.9
78
1.3
123
4.1
van der Graaf et al. 1998
[157]
Netherlands
210
12.4
210
12
Salo et al. 1999 [158]
Finland
238
4.6
Rossaak et al. 2001 [143]
New
Zealand
49
8.2
Frydman et al. 2003 [159]
Australia
150
42.7
126
15.9
276
30
Ogata et al. 2005 [160]
Canada
98
11.2
147
2.7
276
5.4
Badger et al. 2007 [161]
Northern
Ireland
136
5.8
122
1.6
300
3.3
Linne et al. 2012 [162]
Sweden
66
17
84
6
150
11
Combined
1,018
20
855
5.8
2,473
12
1
Total refers to all screened relatives (sisters, brothers and other relatives of the AAA-patient). Some
reports did not specify which relatives were screened.
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Helena Kuivaniemi, Evan J. Ryer, H. Richard Yoon et al.
6
Due to the potential limitations of interviews, research on the prevalence of AAA among
family members in more recent years has focused on the use of aortic duplex screening.
Aortic duplex will allow for the accurate determination of an AAA in asymptomatic family
members. Studies to screen family members with an aortic duplex for an AAA are presented
in Table 3. The overall prevalence of AAA in these studies was 12% (range 3.330%). The
large range of prevalence seen in these studies most likely reflects the study group analyzed.
For example, if a group had a larger percentage of smokers, the incidence would be increased
due to the additive risk factor of smoking [
41]. Because of the associated costs, most of these
studies are relatively small with 300 or fewer participants.
The risk of AAA depends greatly not only on smoking but also on sex as displayed in
Table 3. Based on aortic duplex screening studies, a brother of an AAA patient has a 20%
overall risk of developing an AAA as compared to an overall risk of 5.8% in a sister.
Regardless of sex, the rates of AAA in relatives of AAA patients are greatly increased over
the baseline general population.
These prevalence rates of AAA must be compared to the baseline rates of the disease.
Baseline rates of AAA can be based on necropsy studies as analyzed by Bengtsson et al. [42]
from Malmö, Sweden. In this classic publication of 45,838 autopsies performed from 1958-
1986, the overall prevalence of AAA was 3.2% with a rate of 4.3% in males and 2.1% in
females. One of the largest screening studies using aortic duplex was by Lederle et al.
published in 1997 [40]. Aortic duplex was used to screen 73,451 United States military
veterans identifying 3,366 aneurysms that were 3 cm or larger giving an overall prevalence
rate of 4.6%. About 76% of these veterans were ever smokers leading to a group of patients
that would be at high risk for aneurysm development. In 2010, Palombo et al. [43] screened
8,234 Italian participants, age 65 years or greater, with an aortic duplex and found a 6.2%
prevalence of AAA. These authors concluded that the high prevalence rate in this particular
study was due to the advanced age of the screening participants.
Familial clustering of AAA has been well documented in twin studies. One of the more
notable is the Swedish Twin Study. This study contains data on all twins born in Sweden
since 1886 with 172,890 twins registered as of 2010. This registry identified 265 twins with
an AAA [44]. Using this large collection of patients, the investigators determined that a
monozygotic (identical) twin has a 24% probability of having an aneurysm given an
aneurysm in the other twin, whereas the probability is only 4.8% in dizygotic twins. Put more
simply, a monozygotic twin with an affected sibling is 71 times more likely to develop an
AAA. Not surprisingly, the overall prevalence of AAA in twins is similar to baseline rates
noted above (monozygotic twin 1.2% and dizygotic twin 1.4%).
The Swedish Twin Study was also able to estimate the genetic and environmental
contributions to AAA formation. Phenotypic variance determined by genetics was 70% and
non-shared environmental effects 30% [44]. Environmental effects were defined as factors
causing differences between twins such as smoking, infections, or occupational exposure. No
effect was seen due to shared environmental effects which are those factors shared by both
twins such as would be seen during their youth with dietary habits or passive smoke
exposure.
Family and twin studies have documented the crucial importance of family history to
AAA. These studies have paved the way for research into the genetics of AAA. The classic
description that a male relative of an aneurysm patient has a one in five chance of having an
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