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Abdominal Aortic Aneurysm Screening
147
AAA screening programs become more cost-effective the longer they are active. A
decision analytical model on AAA screening using 2012 clinical data [34] revealed that an
AAA screening program versus the absence of an AAA screening program is more cost-
effective in clinical practice when managing treatment options for patients with AAA.
Specifically, the expected cost of an abdominal ultrasound screening for AAA would
generally be less than $50,000 per quality-adjusted life-year (QALY) saved [34].
Additionally, the cost-effectiveness is predicted to increase substantially over time. The
MASS trial reported a cost effectiveness ratio of £7600 in 2008-2009 over a 10-year period
per life gained [31]. The Viborg Study also found screening to be very cost-effective, and the
amount spent on screening is well below the ideal amount set by the National Institute of
Clinical Excellence for acceptance of interventions in the National Health Service of
Denmark [35]. In the United States, the VANCHCS AAA screening program was determined
to be more effective in the later years by a significant decline in ultrasound costs and the
number of inappropriate screenings that did not meet USPSTF guidelines [22]. Therefore, the
cost-savings of long-term AAA screening in health care systems are the result of a reduction
in emergent repairs and inappropriate screenings, as well as an increase in elective AAA
repairs and screening yield over time.
VIII. IMPROVING AAA DIAGNOSIS AND SCREENING YIELD
Clinical and experimental research is ongoing to advance our understanding of AAA
disease to further improve AAA screening. For instance, there are clinical studies determining
which risk factors are prevalent with the AAA diagnosis, which will help clinicians identify
the most at-risk patients for AAA. Furthermore, experimental studies entail formulating how
the aorta expands from a normal diameter to a pathologic one. The knowledge gained will
ultimately improve AAA screening yield.
A. Risk Factors
Evaluating which risk factors are prevalent in patients with AAA should increase
screening yield of detected AAA. This would identify patients with the most risk for the AAA
diagnosis. Patients of high cardiovascular risk factors are typically at risk for AAA disease.
Notably, the AAA disease is indicative of increased atherosclerosis and cardiovascular risk
[36, 37]. The literature describes older age, male gender, and previous smoking history as the
most linked risk factors to the AAA diagnosis [4, 5, 12, 13]. Other studies include
hypertension, coronary artery disease (CAD), peripheral vascular disease (PVD), and chronic
obstructive pulmonary disease (COPD) as risk factors associated with AAA disease [38-40].
Importantly, elastin and collagen breakdown of the aorta is a hallmark of AAA disease, [5,
39] and aging is linked to aortic elastin breakdown
[40]. Therefore based on current clinical
evidence, many AAA screening programs utilize the age range of 65-75 years when inviting
subjects to participate in screening.
The presence of diabetes is associated against the AAA diagnosis. This seems
counterintuitive because the AAA diagnosis is associated with high cardiovascular risk, and
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having diabetes increases cardiovascular risk. However, there is evidence determining
diabetes does protect against AAA development [5, 41]. However, the mechanisms on how
diabetes prevents AAA development have yet to be elucidated. What is physiologically
known about diabetes on aortic expansion is that diabetic patients have thicker aortic walls
[42] and reduced serum matrix metalloproteinase (MMP) activity [43] when compared to
controls. Some physicians argue that investigating the nature of diabetes on aortic expansion
should be a new direction for experimental research [44]. Thus, future prospective studies are
warranted to determine whether diabetes should be utilized as exclusion criteria for AAA
screening to improve screening yield.
B. Research on AAA Development and Expansion
Muscular deterioration of the aortic wall is a hallmark feature of AAA disease. Why this
deterioration becomes pathologic to some individuals, despite being a normal occurrence with
aging, remains to be elucidated. To date, systemic inflammation is known to play a large role
in developing AAA [45-47]. Research is ongoing on discovering specific inflammatory
mechanisms on the development of AAA disease. For instance, there is evidence that
increased MMP-9 activity [48, 49] and monocytes are involved with endothelial permeability
dysfunction of the aortic wall in AAA patients [50]. Additionally, statins are acknowledged to
decrease AAA expansion from their pleiotropic effects on reducing inflammation [51-53].
Furthermore, there are other studies that observe the role of various inflammatory factors on
AAA pathophysiology, such as vascular endothelial growth factor [54],
hyperhomocysteinemia [55], uncoupled nitrous oxide synthase [56], mast cell tryptase
deficiency [57], as well as plasma cathepsin S and cystatin C levels [58]. Research on
pharmacological associations with AAA disease may help clinicians identify more patients at
risk for the AAA diagnosis and create better medicines to reduce aortic expansion.
While using pharmacological intervention to reduce systemic inflammation and aortic
expansion in patients with AAA disease is recommended [59-61], there is no standard course
of treatment for aneurysms not requiring surgical repair. These aneurysms are typically < 5.5
cm. Within the last couple of years, novel drug therapies are being investigated to diminish
AAA expansion, such as statins [51-53], beta-blockers [60, 61], MMP inhibitors [63, 64], the
antibiotics doxycycline [65] and roxithromycin [66], as well as angiotensin-converting
enzyme (ACE) inhibitors [67, 68]. A meta-analysis concluded that antibiotics reduce
expansion rates of aneurysms [69]. However, a recent Cochrane review [70] of current
treatments for AAA < 5.5 cm determined antibiotics and beta-blockers offer little protection
to AAA expansion. This review also suggested clinicians should focus more on identifying
risk factors associated with AAA expansion and using other non-pharmacological treatments
to reduce AAA expansion. For instance, exercise training [71] and stem cell therapy [72-74]
were proposed as other methods to inhibit AAA expansion.
Although a more thorough discussion on the development, expansion, and management
of AAA is not the scope of this chapter, research studies conducted in these areas are essential
for our understanding of AAA pathophysiology and improving the AAA diagnosis. Hence,
the screening yield and the effectiveness of current AAA screening programs would be
maximized. If AAA screening programs are given enough time to remain active, they may
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Abdominal Aortic Aneurysm Screening
149
one day reduce all-cause mortality in screened subjects, as revealed in the final report of the
MASS trial [75].
Table 4. Summary of various therapies used to reduce AAA expansion
Intervention
Type
Surgery
Open repair
EVAR
Drugs
ACE inhibitors
Antiobiotics
Beta-blockers
MMP inhibitors
Statins
Other
Exercise
Stem cell therapy
AAA, Abdominal aortic aneurysm ;ACE, Angiotensin-converting enzyme; EVAR, Endovascular
aneurysm repair; MMP, matrix-metalloproteinase
CONCLUSION
AAA screening via ultrasonography is a non-invasive method used to identify patients at-
risk for AAA. Much of our current information on AAA screening originates from the
European and Australian randomized trials. Long-term analysis of AAA screening revealed a
substantial decrease in AAA-related mortality in screened patients compared to controls, and
increased cost-effectiveness the longer AAA screening programs are active. Despite our
unfamiliarity with AAA pathophysiology, clinical and experimental research is ongoing. This
includes identifying unique risk factors associated with the AAA diagnosis and observing the
pharmacological effects on aortic expansion to better understand AAA disease. Therefore, the
AAA diagnosis and screening yield of detected AAA may improve.
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https://t.me/med1917
In: Aortic Aneurysms ISBN: 978-1-62618-458-9
Editors: Daniel Fischhof and Franz Hatig © 2013 Nova Science Publishers, Inc.
Chapter 7
AORTIC HEMODYNAMICS AND THEIR ROLE IN
ANEURYSM LOCATION:
CAN MICE PROVIDE MORE INSIGHT?
Bram Trachet
1,*
, Stefaan Vandenberghe
2
, Bart Loeys
3,4
and Patrick Segers
1
1
IBiTech - bioMMeda, Ghent University, Ghent, Belgium
2
IBiTech - Medisip, Ghent University - IMinds, Ghent, Belgium
3
Centre for Medical Genetics, Ghent University, Ghent, Belgium
4
Centre of Medical Genetics, Antwerp University Hospital, Antwerp, Belgium
ABSTRACT
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
*
IBiTech bioMMeda, Ghent University, De Pintelaan 185, Block B, BE-9000 Gent (Belgium). Tel: +32 9 332 33
79; Fax: +32 9 332 41 59; bram.trachet@ugent.be.
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Bram Trachet, Stefaan Vandenberghe, Bart Loeys et al.
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aneurysm in the same animals, and might in the future provide more insight into the
initial phase of the disease.
INTRODUCTION
An aortic aneurysm is a pathological condition of the aorta which, on morphological
grounds, can be defined as a focal loss of parallelism of the arterial wall, leading to a
progressive dilatation and finally to dissection or rupture of the aortic wall [1]. The
consequences depend on the size of the rupture, where a large rupture is most often followed
by a rapid death caused by internal bleeding while a small one (sometimes termed a leak) may
produce warning symptoms that allow to seek medical care. A more pathophysiological
definition defines aortic aneurysm as a progressive loss of the capacity of the aorta to resist a
high intraluminal pressure, related to the degradation of the arterial wall
[2].
Aortic aneurysm occurs with increasing frequency in our aging population, and has been
estimated to account for 1-2 % of all deaths in industrialized countries [3]. It can develop
anywhere along the aorta, but is reported to be more frequently at some distinct aortic
locations such as the (infrarenal) abdominal and (ascending) thoracic aorta. Furthermore,
aneurysms occur in the cerebral arteries and, albeit much less frequently, also in the popliteal,
femoral, carotid and coronary arteries [4]. Aneurysms may be saccular or fusiform, but the
saccular shape is in almost all cases restricted to cerebral aneurysms. Both the
pathophysiology and physical appearance of cerebral aneurysms are considered to be
different from other aortic aneurysms [5]. Within this review, we will focus on the two most
abundant types of (fusiform) aortic aneurysm: ascending and abdominal aortic aneurysms
(AAA).
ANEURYSM LOCATION: WHY HEMODYNAMICS?
A lot of research has been dedicated to study the progression and pathophysiology of
existing aneurysms. However, little is known about the initial step, the local trigger causing
the cascade of events that lead to aortic dilatation. Many of the known risk factors (including
age, smoking and hypertension) are systemic and do not differ along the arterial wall. Some
hypotheses have been put forward to explain the increased incidence at the abdominal and
ascending aorta, such as the low amount of elastin present in the infrarenal abdominal aorta
[6], and the different embryonic origin of vascular smooth muscle cells (VSMCs) and their
response to the cytokine TGF- [7]. This review focuses on hemodynamic wall shear stress
(WSS), another factor that varies along the aorta. Wall shear stress is the tangential stress
exerted by the blood on the aortic wall. Endothelial cells are known to sense (changes in)
shear stress [8] and respond to them by activating shear-responsive genes that ultimately
mitigate inflammation and oxidative stress [9, 10]. This suggests that regional differences in
aortic hemodynamic conditions may account for differential aneurysm risk [11], similar to
what has already been shown for atherosclerosis [12, 13]. Several studies support this view.
A significantly higher prevalence of AAA has been reported in patients with one amputated
leg [14] and in patients with peripheral vascular occlusive disease or spinal cord injury (SCI)
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