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thoracic false lumen is converted to a long, inverted cul-de-sac, or
blind pouch. Then with flap pulsation limited by the buttressing
stent, blood in the false lumen becomes stagnant and prone to
thrombosis.
30–32
False lumen thrombosis is critical because the precise rupture
point in any individual patient is frequently unknown, and the
CH
breech may exist well below the entry tear. Simple coverage of
36
the proximal entry may then eliminate direct flow into the false
lumen, but if distal retrograde flow from abdominal sources persists, the risk of a continued leak exists and morbidity remains.
Although this strategy is associated with considerable mortality
and procedural complications, it represents an addition to the
existing treatment armamentarium.
Other Indications for Aortic Endografts
The question of unidentified patient subgroup(s) who present
with uncomplicated acute type B aortic dissection who may benefit from endograft placement remains. Some investigators have
identified certain high-risk features in patients with acute uncomplicated type B dissection that may portend an increased risk of
early aneurysm formation and increased mortality. These features
include measurements of various aortic dimensions at the time of
initial diagnosis. Initial attempts to propose high-risk criteria from
CT imaging considered descriptive features associated with a poor
prognosis and disease progression, such as a patent false lumen,
a gaping and circumferential entry tear with resultant small true
lumen, and a dominant false lumen with early fusiform expansion of the proximal descending aorta within 3 months of initial
symptoms.
Marui et al. proposed that patients with uncomplicated aortic
dissection and transaortic diameter greater than 40 mm were at
high risk of rapid aortic expansion.36 When applied to larger groups
of patients with dissection, this benchmark provided modest prognostic value. The poor results encouraged others to focus on the
issues and pursue more in-depth imaging analysis. Thereafter,
Marui et al. offered an improved prognostic factor that was based
on the extent of proximal descending aorta dilation at the time of
initial diagnosis
maximum transaortic diameter of the distal aortic arch divided by
the sum of the minimum diameter of the proximal aortic arch plus
the aortic diameter at the level of the pulmonary artery. A value
greater than 0.64 anticipates late aortic events in patients with
uncomplicated type B aortic dissection. The investigators recommended that patients with these predictors should undergo early
intervention with open surgery or stent graft implantation.
Immer et al. analyzed imaging studies (CT or MRI) over the
initial 18 months after diagnosis in 84 patients with acute type
A aortic dissection.
the time of the initial diagnostic scan is the strongest predictor of
subsequent downstream aortic enlargement. This was especially
true if the true lumen was less than 30% of the overall transaortic
area 6 months after aortic surgery for repair of type A dissection.
This concept of the initial false lumen diameter as a determinant
of late clinical deterioration was evaluated for type B disease in
2007 by Song et al.39 These authors studied 100 consecutive patients
with acute aortic dissection, including 51 with type A dissection and
49 with type B dissection. Over half of the patients underwent CT
imaging follow-up through 24 months. Of these, an aneurysm (diameter >
60 mm) was diagnosed in 28%, with the maximal aortic diameter
located in the proximal descending segment. A greater than 22-mm
initial false lumen diameter of the upper thoracic segment of the
descending aorta predicted late aneurysm formation with a sensitivity of 100% and a sensitivity of 76%. The 42 patients with an initial
false lumen diameter greater than 22 mm had a higher event rate
than the 58 with smaller false lumen aortic diameters (aneurysm,
42% vs. 5%; or death, 12% vs. 5%).
More recently, another predictive feature for early complication and clinical deterioration was described by Tsai et al.
after reviewing data from the International Registry of Aortic
37
: the fusiform index. This index is defined as the
38
They concluded that a large false lumen at
Dissection (IRAD).
40
They reviewed 201 cases of type B acute
aortic dissection. During the index hospitalization, 114 patients
(56.7%) had a patent false lumen, 68 patients (33.8%) had partial thrombosis of the false lumen, and 19 (9.5%) had complete
thrombosis of the false lumen. The mean 3-year mortality rate for
patients with a patent false lumen was 13.7%, for those with partial thrombosis was 31.6%, and for those with complete thrombosis was 22.6%. Although postdischarge mortality was high among
patients with acute type B aortic dissection, partial thrombosis,
as compared with complete patency, is a significant independent
predictor of postdischarge mortality (relative risk, 2.69; 95% confidence interval [CI], 1.45-4.98; P = 0.002).
In the future, it is likely that more sophisticated analysis will identify additional factors beyond simple dimensional aortic measurements to better predict patients with acute type B aortic dissection
who are at increased risk of disease progression, rapid deterioration, or acute rupture. As prognostic evaluation of aortic dissection
improves, the use of endovascular approaches will better target
and improve outcomes of this disease.
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thoracic aortic rupture: institutional experience and meta-analysis, Eur J Cardiothorac Surg
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repair for the ruptured descending thoracic aorta, J Vasc Surg 50:1265–1270, 2009.
30. Resch TA, Delle M, Falkenberg M, et al: Remodeling of the thoracic aorta after stent grafting of
type B dissection: a Swedish multicenter study, J Cardiovasc Surg (Torino) 47:503–508, 2006.
31. Kusagawa H, Shimono T, Ishida M, et al: Changes in false lumen after transluminal stent-graft
placement in aortic dissections: six years’ experience, Circulation 111:2951–2957, 2005.
32. Sayer D, Bratby M, Brooks M, et al: Aortic morphology following endovascular repair of
acute and chronic type B aortic dissection: implications for management, Eur J Vasc
Endovasc Surg 36:522–529, 2008.
33. Tsai TT, Fattori R, Trimarchi S, et al: Long-term survival in patients presenting with type B
acute aortic dissection: insights from the international registry of acute aortic dissections,
Circulation 114:2226–2231, 2006.
34. Nienaber CA, Rousseau H, Eggebrecht H, et al: Randomized comparison of strategies for
type B aortic dissection. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD)
trial, Circulation 120:2519–2528, 2009.
35. Nienaber CA, Kische S, Akin I, et al: Strategies for subacute/chronic type B aortic dissection:
the Investigation of Stent Grafts in Patients with Type B Aortic Dissection (INSTEAD) trial
1-year outcome, J Thorac Cardiovasc Surg 140:101–108, 2010.
36. Marui A, Mochizuki T, Mitsui N, et al: Toward the best treatment for uncomplicated
patients with type B acute aortic dissection: a consideration for sound surgical indication,
Circulation 100(Suppl II):II-275–II-280, 1999.
37. Marui A, Mochizuki T, Koyama T, et al: Degree of fusiform dilation of the proximal
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Cardiovasc Surg 134:1163–1170, 2007.
38. Immer F, Krahenbuhl E, Hagan U, et al: Large area of false lumen favors secondary dilation
of the aorta after acute type A aortic dissection, Circulation 112(Suppl I):I-249–I-252,
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39. Song JM, Kim JH, Kang DH, et al: Long-term predictors of descending aorta aneurismal
change in patients with aortic dissection, J Am Coll Cardiol 50:799–804, 2007.
40. Tsai TT, Evangelista A, Nienaber CA, et al: Partial thrombosis of the false lumen in patients
with acute type B aortic dissection, N Engl J Med 357:349–359, 2007.
455
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36
EndovAsCulAR THERAPy foR AoRTiC dissECTion
PA RT X
AORTIC ANEURYSM
CHAPTER
37 Pathophysiology, Epidemiology, and
Prognosis of Aortic Aneurysms
Reena L. Pande, Joshua A. Beckman
Aortic aneurysms result in significant morbidity and mortality,
accounting for nearly 13,000 deaths and 55,000 hospital discharges
per year in the United States.
part of the aorta from the aortic root down to the abdominal aorta,
the prognosis and outcome in patients with aortic aneurysms vary
based on location and underlying etiology. Timely and appropriate intervention may improve the natural history of the disease
process. This chapter reviews the pathophysiology, epidemiology,
and prognosis of aortic aneurysms.
The Normal Aorta
The aorta is the large conduit vessel through which the heart delivers blood to the entire body. It courses from the heart through the
thorax and abdomen, and ultimately bifurcates into the common
iliac arteries (CIAs) in the abdomen. In the thorax, the aorta can
be subdivided into three segments: ascending aorta (from the
base of the heart to the innominate artery), transverse aorta or
aortic arch (including the great vessels and extending to the left
subclavian artery), and descending aorta (from the distal edge of
the subclavian artery to the level of the diaphragm) (Fig. 37-1).
Like other arterial structures, the aorta is composed of three
layers: tunica intima, tunica media, and adventitia. The innermost
surface of the tunica intima is lined by a single-cell-thick layer
of endothelial cells (ECs). The intima is bound by the internal
elastic lamina. The tunica media is composed of smooth muscle
cells (SMCs), collagen, fibroblasts, elastin fibers, and ground substance, which together control the degree of vessel constriction
and vasodilation. The presence of elastin fibers in the media
defines the aorta as an elastic artery and provides the tensile
strength that permits the aorta to withstand pulsatile delivery of
blood from the heart. Elastin content gradually decreases with
distance from the heart.
a thin layer that contains connective tissue, fibroblasts, and the
nutritive vasa vasorum.
Definition of Aortic Aneurysm
In adults, the normal diameter of the aorta is approximately 3 cm
at the origin, 2.5 cm in the descending thoracic aorta, and 1.8 to
2 cm in the abdominal aorta. Aortic aneurysm is defined as a maximal aortic dimension greater than 3.0 cm, or a 50% increase in
size compared with the normal segment proximal to the aneurysm. Mild expansion that does not meet these criteria may be
referred to as aortic ectasia. True aneurysms are classified into two
major groups on the basis of morphology: (1) fusiform (
and 37-3), defined as a circumferential expansion of the aorta, and
(2) saccular, representing a focal outpouching of a segment of the
aorta (
Fig. 37-4). Fusiform aneurysms are the most common mani-
festation. In contrast to true aneurysms, which involve expansion
of all three layers of the aortic wall, a pseudoaneurysm, also known
1
Although aneurysms may affect any
2
The outermost layer, the adventitia, is
Figs. 37-2
as a false aneurysm, results from a disruption of the aortic wall and
essentially represents a contained rupture of the aorta.
Pathophysiology of Aortic Aneurysms
A wide variety of pathological states are associated with aortic
aneurysms (
ited disorders, infections, inflammatory conditions (i.e., vasculitis),
and trauma. Specific disorders associated with aortic aneurysms
are discussed later in this chapter. Important determinants of aortic
aneurysm formation include inflammation, proteolysis of the structural components of the aortic wall, and abnormal biomechanical
forces
ogy of aneurysm formation is critical not only for prevention of
initial aneurysm formation but also for limiting aneurysm growth
and expansion.
Traditionally, pathological aortic aneurysm formation was
ascribed to a process akin to atherogenesis. Although advances in
basic and clinical investigation in both lesion types have revealed
some common themes, newer studies suggest that aneurysm formation is fundamentally different from atherosclerosis. Preferential
weakening of the adventitia and media—rather than an intimal
proliferative process, as in atherosclerosis—results in diminished
aortic resilience and tensile strength, culminating in aortic wall
thinning, dilation, and increased wall stress, all of which may result
in rupture. Although atherosclerotic changes may be seen in the
wall of aneurysms, these changes may be a consequence of local
turbulent flow as opposed to a cause of aneurysm formation.
Moreover, the degree of systemic atherosclerosis does not correlate
well with the degree of aneurysm formation.
Development of aneurysms is associated with loss of two critical
structural elements in the aortic wall: elastin and collagen. Elastin
provides radial and longitudinal support, enabling the aorta to
respond to pulsatile flow while maintaining normal arterial dimensions. The importance of elastin in maintaining aortic structure is
highlighted by animal models where elastase infusion results in
elastin breakdown and experimental aortic aneurysm formation.
However, breakdown of elastin alone appears insufficient to cause
aneurysmal expansion and rupture. Loss of collagen, another
important structural element, is an additional contributor, and the
relative balance of elastin and collagen deposition, among other
factors, may be critical for determining aneurysm formation.
Early in aneurysm formation, the aorta compensates for loss of
elastin by increasing production of collagen,
tent decreases, collagen (as the major source of tensile strength)
is overwhelmed, and aortic expansion occurs. This is exacerbated
by up-regulation of collagenases, resulting in further collagen
degradation as described later.9 Structural changes in each layer
of the aortic wall develop that together promote aortic stiffness.
As a consequence, decrease in the vessel's ability to distend normally with left ventricular (LV) contraction, weakening of the
Box 37-1). These include degenerative diseases, inher-
3
(see Fig. 37-2). Understanding the underlying pathophysiol-
6
8
but as elastin con-
4,5
7
8
457
458
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CH
37
FIGURE 371 Magnetic resonance angiography (MRA) of the thoracic
aorta. Note the different aortic segments: ascending aorta, aortic arch, and
descending aorta. Left subclavian artery separates the aortic arch from the
descending aorta.
FIGURE 372 Three pathophysiological mechanisms that best
characterize the process of aneurysm formation. Aortic aneurysm
specimens reveal increases in leukocyte infiltration, cytokine concentration,
and leukocyte adhesion molecules. Both elastin-related and collagenrelated autoantigens have been identified and may participate in initiation
of process. Once process has begun, proteolytic enzymes, particularly matrix
metalloproteinase (MMP)-2 and -9, increase in concentration and break
down elastin and collagen. Increases in enzyme coactivators (e.g., urokinase
plasminogen activator [uPA], tissue plasminogen activator [tPA]) further
augment matrix breakdown. Increase in proteolysis is not accompanied
by change in inhibitors of process, yielding a degenerative environment.
Abdominal aorta is predisposed to aneurysm formation because of adverse
blood flow patterns and its relative lack of elastin and vascular smooth muscle
compared with thoracic aorta. (Volume-rendered computed tomography image of
abdominal aortic aneurysm used with permission of Joseph Schoepf, MD.)
FIGURE 373 Computed tomographic angiogram (CTA) of ascending
aortic aneurysm. Notice that proximal descending portion of aorta is ectatic
as well. Aneurysm involves entire circumference of aorta and is thus fusiform.
Normal ascending aorta size is less than 3 cm.
vessel wall, and increase in the tendency for dilation and ectasia follow.
10
Some of the changes in aortic structure that promote
aneurysm formation may arise as a result of the normal aging process. With normal aging, aortic stiffness due to fragmentation of
elastin fibers, deposition of glycosaminoglycans, fibronectin (FN),
and collagen, and reduced bioavailability of endothelium-derived
nitric oxide (NO) occurs.
11–14
FIGURE 374 Maximal intensity projection (MIP) of magnetic
resonance (MR) image of saccular aneurysm. Note outpouching of an
otherwise normal descending aorta (arrow). This pattern of aneurysm is more
common in infectious aneurysms.
Box 37-1 Disorders Associated with
Aortic Aneurysms
Degenerative
Cystic medial necrosis
Aortic dissection
Developmental
Marfan's syndrome (MFS)
Loeys-Dietz's syndrome
Ehlers-Danlos' syndrome (EDS)
Bicuspid aortic valve (BAV)
Turner's syndrome
Aortic coarctation
Infectious
Tuberculosis
Syphilis
Staphylococcus
Salmonella
Vasculitis
Takayasu's arteritis (TA)
Giant cell arteritis (GCA)
Behçet's disease
Rheumatoid arthritis
Systemic lupus erythematosus (SLE)
Sarcoidosis
Ankylosing spondylitis
Reiter's syndrome
Relapsing polychondritis
Cogan's syndrome
Trauma
Pathophysiologically, the major determinants of aortic aneurysm formation include proteolysis of the structural components
of the aortic wall, inflammation, and abnormal biomechanical
3
forces
(see Fig. 37-2). Pathology of aortic aneurysms varies in
different segments of the aorta and in different predisposing diseases. Frequently observed histological features include cystic
medial necrosis, mucoid infiltration, and cyst formation in the
setting of elastin necrosis and vascular smooth muscle apoptosis. In patients with Marfan's syndrome (MFS), bicuspid aortic
valve (BAV), or Turner's syndrome, cystic medial necrosis is a
common feature, but in contrast, inflammation is less prominent
than in abdominal aortic aneurysms (AAAs).
15,16
On the other
hand, cystic medial necrosis is less likely to be observed in AAAs.
Instead, AAAs typically have disrupted elastin fibers, inflammation, greater vascular smooth muscle cell (VSMC) apoptosis, and
deficient glycosaminoglycan production.
17
Elastin fragmentation
occurs adjacent to the inflammatory cells. Despite differences in
pathophysiology due to location and underlying etiology, formation of all aortic aneurysms involves to some degree the processes described in the following discussions (i.e., proteolytic
degradation, inflammation, changes in biomechanical forces)
that together facilitate aneurysm formation.
Proteolytic Degradation
Several proteolytic enzymes contribute to degradation of structural
components of the arterial wall, ultimately increasing risk of aneurysm formation. Matrix metalloproteinases (MMPs) are endopeptidases that degrade one or more components of the extracellular
matrix (ECM). Thus far, several classes of MMPs, comprising nearly
30 individual proteinases, have been characterized. They include
collagenases, gelatinases, stromelysins, matrilysins, membrane-type
(MT)-MMPs, and other MMPs.
MMPs may be activated both intracellularly and extracellularly, and
may be secreted by endothelial cells, vascular smooth muscle cells,
or adventitial fibroblasts. Extracellular regulation of activation may
occur as a result of an MMP–MT-MMP interaction or via interaction
18
Typically produced as proenzymes,
with plasmin or reactive oxygen species (ROS).
of MMPs are the tissue inhibitors of matrix metalloproteinases
(TIMPs) and plasminogen activator inhibitors (PAI) 1 and 2.
Increased local production of MMPs in aortic aneurysms was
first reported nearly 20 years ago.
22–24
19–21
The inhibitors
18
Although elevations of
several MMPs have been noted, MMP-1 (collagenase) and MMP-3
(stromelysin), MMP-2 (gelatinase A), and MMP-9 (gelatinase B)
represent the principal proteinases in aortic aneurysms that result
in elastin and collagen degradation.
25,26
MMP-2 and MMP-9 gelatinases specifically break down collagen. They are synthesized by
local cells in the aortic wall, including infiltrating macrophages
and resident aortic VSMCs.
adventitia near the vasa vasorum, localizing to infiltrating macro-
29
phages.
MMP-2 is synthesized constitutively by VSMCs30 but can
also be synthesized by infiltrating leukocytes.
27,28
MMP-9 is typically found in the
31
Interestingly, MMP-2
production is increased in the vasculature remote from the aorta,
suggesting a systemic underlying disease process that manifests
with aortic aneurysmal disease.
32
The centrality of these enzymes in aneurysm formation is supported by several lines of evidence. Studies have demonstrated
that MMP-2 and MMP-9 levels are higher in tissue obtained from
aortic aneurysms than in atherosclerotic plaque or normal arterial tissue.
not form aortic aneurysms in experimental models.
competent macrophages from wild-type mice into MMP-9 knockout mice enables aneurysm formation.
30,31
Furthermore, MMP-9 and MMP-2 knockout mice do
33
In addition, elevated lev-
33
Reinfusion of
els of MMP-1, MMP-8 (a neutrophil collagenase), and MMP-9 have
been associated with aneurysm rupture, and levels of these MMPs
may vary with aneurysm size.
less clear for MMP-2.
37–40
34–36
Relationship to aneurysm size is
Elevated levels of other proteolytic enzymes such as human
macrophage metalloelastase (MMP-12) and membrane type-1
metalloproteinase (MT1-MMP) have also been demonstrated in
aortic aneurysms.
41
Expression of MMP-12 is increased in aortic
aneurysms as a result of macrophage infiltration. However, the
relevance of MMP-12 to aneurysm formation is less clear, based
on the finding that MMP-12 knockout mice are not completely
protected from aneurysm formation.42 MT1-MMP, a collagenase
produced by macrophages and increased in aortic aneurysms,
likely has its greatest effect as an activator of the proenzyme form
of MMP-2.
43,44
In addition to increased expression of MMPs, aneurysm formation is associated with abnormal regulation of MMP levels in tissues.
Matrix metalloproteinase levels are increased in states of inflammation and oxidant stress, both known to play a role in aneurysm
formation. Compared with nonaneurysmal sections of aorta, superoxide anion and markers of oxidative stress are increased in aneurysmal segments, and ROS can convert proenzymes of MMPs to
their active form.
45–47
In addition, MMP levels can be augmented by
plasminogen activators, such as urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), which are
specific physiological regulators of MMP-2 and MMP-9 activation
and overexpressed in aortic aneurysms but not in healthy aortic
specimens.
48
Matrix metalloproteinase levels are also normally regulated
by TIMPs. Although early work reported decreased concentrations of TIMPs in aneurysmal tissue,
less clear, showing no difference in certain TIMP levels between
aneurysmal and healthy aortic tissue.
imbalance in MMPs to TIMPs may be the more relevant factor.
49
more recent data have been
36,43,50,51
However, the relative
41
Nonetheless, experimental data have clearly demonstrated the significance of TIMPs to aneurysm formation. Local overexpression
of TIMP-1 prevented aneurysm formation in a rat model of aortic
aneurysm,
ity and greater aneurysm formation.
of PAI-1, a regulator of plasminogen activator activity, has been
reported in aneurysmal disease.
52
but TIMP knockout mice have increased MMP activ-
53
Similarly, lower expression
49,54
Increased expression of plasminogen activators without reciprocal changes in their inhibitors
alters the balance toward fibrinolysis, MMP activation, and tissue degradation. Experimental overexpression of PAI-1 prevents
459
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37
PATHOPHYSIOLOGY, EPIDEMIOLOGY, AND PROGNOSIS OF AORTIC ANEURYSMS
460
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aneurysm formation in a rat model of aortic aneurysm,55 confirming the importance of relative rather than absolute concentrations.
The contribution of MMPs to the pathophysiology of aortic
aneurysms is highlighted by the beneficial effect of medications
known to reduce MMP levels on aneurysm expansion. For example, tetracyclines (e.g., doxycycline) have long been recognized
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as generalized inhibitors of metalloproteinases.56 Their poten-
37
tial value in aortic aneurysmal disease has been demonstrated
in both organ culture and rodent models of aneurysm forma-
36,57–59
tion.
In humans, doxycycline limits the activity of both
MMP-2 and MMP-9 in aortic wall specimens, both by reducing
macrophage MMP-9 messenger ribonucleic acid (mRNA) expression and diminishing activation of the proenzyme form of MMP-
60–62
2.
In a few small randomized phase 2 trials, doxycycline has
been shown to decrease aneurysm expansion rate.
63,64
these data await confirmation in larger trials, they do support the
conceptual framework of the importance of proteolytic enzymes
in aortic aneurysm formation and expansion.
By reducing levels of proteolytic enzymes, several other therapies
may potentially be of therapeutic benefit in aneurysmal disease.
HMG-CoA reductase inhibitors, or statins, have antianeurysm
properties in experimental models by virtue of reducing oxidant
stress and macrophage production of MMPs.
65–67
However, data
in humans have been inconsistent. A meta-analysis of five studies
including 697 patients with small aortic aneurysms (<55 mm)
treated with or without statins suggested that statin therapy was
associated with lower rates of expansion.
68
On the other hand, other
human studies have not shown a benefit of preoperative statin treatment on MMP or TIMP levels in aneurysm specimens, and no difference in aneurysm expansion rate.
69–71
Indomethacin also appears
to prevent aortic aneurysm formation in a rat model,
mechanism may be related to inhibition of cyclooxygenase (COX) 2,
prosta glandin E2 (PGE2), and reductions in MMP-9.
PGE2 expression is up-regulated more than 30-fold in aortic
aneurysms.76 Prostaglandin E2 localizes to infiltrating macrophages,
and its expression is dependent on COX activity.77 Prostaglandin E2,
through activation of interleukin (IL)-6, may increase VSMC apoptosis, further weakening the structural elements of the aorta.
Inflammation
The contribution of inflammation to many pathological arterial processes has been well established.
80
Dent
reported mild chronic inflammation in 72.5% and moderate inflammation in 15.7% in 51 consecutively resected AAAs.
Subsequently it was discovered that lymphocytes and macrophages are found in greater quantity in the adventitia and media
of AAAs than of atherosclerotic or normal aortas.81 In addition,
surgical explant specimens from patients with aortic aneurysms
demonstrated higher levels of adhesion molecules, including intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion
molecule (VCAM)-1, than seen in atherosclerotic and normal
aortas. Similarly, tissue levels of proinflammatory cytokines, such
as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, monocyte chemoattractant protein (MCP)-1, interferon (IFN)-γ, and IL-6,
have all been noted to be elevated in patients with aneurysms
compared with control subjects.
82
Some studies have even suggested cytokine levels are higher in ruptured aortic aneurysms
than in asymptomatic aortic aneurysms,
been inconsistent.
84
Finally, other acute-phase proteins, including
C-reactive protein (CRP), D-dimer, and ceruloplasmin, are also
present at increased levels in plasma and in the vessel wall.
These inflammatory mediators largely derive from infiltrating
macrophages, but lymphocytes and aortic ECs and SMCs also contribute to the inflammatory milieu. The presence of inflammation in
aortic aneurysms is supported by positron emission tomographic
imaging with
18
fluorodeoxyglucose (FDG-PET) showing greater
FDG uptake in aneurysmal compared to nonaneurysmal aortic
segments from matched control subjects, and by advanced magnetic resonance imaging (MRI) techniques.
79
In 1981, Rose and
83
although the data have
88,89
Thus, immune cells
Although
72
and the
73–75
Indeed,
75,76,78
82,85–87
invade the aortic wall, become activated, and create an inflammatory environment that engages the activity of local stabilizing cells,
initiating the process of elastin and collagen breakdown and aneurysm formation. However, the initial signals that drive inflammatory
cell recruitment remain unclear. Animal studies with experimental aneurysm models have confirmed the human studies and
demonstrated that increased inflammation promotes aneurysm
formation.
90
Given the contribution of inflammation to aortic aneurysms, it
follows that strategies to reduce inflammation might reduce aneurysm formation or limit aneurysm growth. Indeed, as mentioned
previously, some data suggest that statins, known to have beneficial antiinflammatory properties beyond their effect on cholesterol lowering, may limit aneurysm growth and expansion.
Recent studies have also shown that limiting inflammation can
reduce aneurysm formation in animal models.
93–97
Future studies
67,91,92
will be required to clarify whether strategies to target inflammation
can prevent formation of aortic aneurysms or limit expansion in
humans.
Increases in Biomechanical Wall Stress
The frequency of aneurysm formation in the abdominal aorta
compared to other vascular locations suggests a predisposition
in this area. Variations in biomechanical factors have been noted
in the differing regions of the aorta. Relative deficiencies in structural elements combined with adverse blood flow patterns predispose the abdominal aorta to aneurysm formation. Compensatory
mechanisms occur after aneurysm formation have developed, but
they do not stop the process. Thus, aneurysm expansion is promoted by an imbalance of biomechanical forces and compensatory mechanisms.
Several specific structural changes may predispose the abdominal aorta to aneurysm formation. For example, elastin within
the aortic wall is organized into circumferential plates, or lamellae, that respond to the pulsatile load created by the heart. Each
lamellar unit consists predominantly of two elastin bundles and
vascular smooth muscle. However, deposition of elastin is not uniform along the aorta, with the thoracic aorta incorporating 35 to
56 lamellar units compared to only 28 in the abdominal aorta.
The abdominal aorta may therefore be more susceptible to elastin breakdown due to a relative increase in pressure withstood
per lamellar unit, compared with the rest of the vessel. In addition, the abdominal aorta has a decreased concentration of nutritive vasa vasorum compared to more proximal aortic segments.
Reductions in aortic tissue perfusion stiffen the vessel, reducing
compliance and ability to withstand pulsatile stress.
100
Vascular cells in the aorta attempt to restore elastin content
in the setting of elastin degradation to compensate for reductions
in tensile and radial strength. Human AAA samples show a fourto sixfold increase in tropoelastin protein compared with control arteries.
101,126
Elastin is produced by SMCs and macrophages.
In areas of macrophage infiltration, elastin deposition is not organized into mature effective bundles. Indeed, compared with normal specimens, aneurysm specimens have a ninefold reduction in
desmosine, a marker for mature elastin cross-linking.
101
Thus, compensatory elastin replacement is disordered and does not improve
aortic compliance.
Another factor that may make the abdominal segment of the
aorta more prone to aneurysm formation is blood flow patterns
specific to that segment. In experimental models, the infrarenal
segment of the aorta is subject to much higher levels of oscillating flow and reflected pressure waves compared with the suprarenal segment,
102
resulting in higher levels of aortic wall tension.
Turbulence and pressure are exacerbated by the aneurysm's
morphology, which promotes development of local vortices and
turbulent flow patterns.
aneurysm by placing an aortic endograft rapidly reduces plasma
MMP-9 levels in patients.
103
Excluding these flow patterns from the
104,105
In a rodent elastase infusion model
of aortic aneurysm, flow conditions were examined by creating
98
99
a left femoral arteriovenous fistula (AVF) or left iliac artery ligation. Increases in shear stress due to fistula formation resulted in
a more stable aortic phenotype with decreased oxidative stress,
decreased macrophage density in the media, increased aortic
ECs and vascular smooth muscle cells, and reduced apoptosis
compared to the lower shear stress introduced by femoral artery
ligation.
26%.
4,106,107
106
Improved flow decreased aortic expansion by
In addition to adverse biomechanical forces creating an environment permissive for aneurysm formation, the role of intraluminal thrombus on wall stress and aneurysm expansion has recently
been a focus of much study. Using finite element analysis in a threedimensional (3D) model of the aorta derived from computed
tomography (CT) scans, intraluminal thrombus was found to lower
peak wall stress by up to 38%
bus constituents.
109
Thrombus decreases transmission of luminal
pressure to the aneurysm wall and may prevent aneurysm rupture by reducing wall strain.
thrombus may also contribute to further aneurysm formation,
108
relatively independent of throm-
110–115
On the other hand, intraluminal
111
given that thrombus has been demonstrated to have higher levels
of proteolytic enzymes and enzyme activators than the aneurysm
116
itself.
Intraluminal thrombus may act as a proteolytic enzyme reservoir through polymorphonuclear leukocytes, and enzyme accumulation provides a ready source of destructive elements for the
adjacent aneurysm.
116
Understanding biomechanical factors may help improve assessment of risk of aneurysm growth and rupture above and beyond the
predictive value of lumen diameter alone.
117
Several studies have
used novel computational models to incorporate biomechanical
factors such as wall stress, wall strength, and extent of intraluminal
thrombus for assessment of abdominal aneurysms.
112,118–123
Some
studies have suggested that assessment of wall stress, wall strength,
and the ratio of wall stress to wall strength may be better predictors
of rupture risk than diameter.
124,125
Epidemiology and Prognosis of Aortic
Aneurysms
Abdominal Aortic Aneurysms
Aortic aneurysms are typically defined as an increase in diameter
of 50% compared to the adjacent normal segment of the aorta; the
upper limit of normal for the abdominal aorta is 3 cm. The absolute
size definition for AAA is preferable, given that body size and baseline diameter may vary on the basis of height, sex, weight, and presence of a thoracoabdominal aortic aneurysm (TAAA). However, all
these factors should be taken into consideration when considering
risk in any given individual.
PREVALENCE
The prevalence of aneurysms of the abdominal aorta has been
determined on the basis of several large screening studies and
autopsy series (
tive autopsies performed over 23 years, 1.97% of the subjects were
found to have an AAA.
Table 37-1). In an early series of 24,000 consecu-
126
Of the 473 aneurysms found, 58% were
larger than 4 cm in diameter, nearly three quarters of the patients
were men, and one fourth of the aneurysms had ruptured. More
recent large screening programs in targeted populations have further evaluated the prevalence of AAA. The largest screening program performed was the Aneurysm Detection and Management
(ADAM) Study Screening Program, which studied 126,196 veterans 50 to 79 years of age.
127
In this cohort of predominantly male
American veterans, 3.6% of subjects had an infrarenal aortic diameter greater than 3 cm, and an AAA 4 cm or larger was found
in 1.2%. The Multicentre Aneurysm Screening Study (MASS) also
screened 27,147 of 33,830 invited men aged 65 to 74 and reported
a 4.9% prevalence of AAA 3 cm or larger.
128
Several studies have demonstrated lower prevalence of AAA
in women. The largest and most recent of these studies screened
nearly 10,012 women (mean age, 69.6 years) and found an AAA
prevalence rate of 0.7%, with only 4 of 74 detected aneurysms measuring larger than 5 cm.
129
These low prevalence rates were consistent with findings from earlier studies. Among 4237 subjects
aged 65 to 80 who participated in a screening study among general practitioners in West Sussex, United Kingdom, 2290 women
agreed to undergo abdominal ultrasonography.
130
Only 1.4% of
the women had an AAA 3 cm or larger, and only 0.3% had an AAA
4 cm or larger. This dramatically lower prevalence in women has
been confirmed in subsequent studies. In the Norwegian Tromso
study, 2% of 2943 women aged 55 to 84 had an AAA 3 cm or larger,
and 0.5% had an abdominal aneurysm 4 cm or larger.
among female American veterans, the prevalence of an AAA 3 cm
or larger was just 1%.
132
However, an increasing number of cardiovascular risk factors does increase the risk of AAA in women, with
a prevalence rate as high as 6.4% in this higher-risk group.
RISK FACTORS
Three risk factors predict the vast majority of AAAs: age, gender, and
cigarette smoking. Aneurysms usually affect the elderly, seldom
occurring in those younger than 60 years of age, and there is a clear
increase in incidence with increasing age, even when limiting the
studies to older individuals.
133–135
In a Norwegian population-based
study of 6386 men and women aged 25 to 84, the incidence of AAA
in men increased from 0% in those aged 25 to 44, to 6% in those
aged 55 to 64, and to 18.5% in those aged 75 to 84.
131
Large North
American epidemiological studies have demonstrated an increase
in AAA risk ranging from 58% to 300% with each additional decade
136
of life.
in all age groups, risk of AAA is two- to sixfold higher in men than
women.
Gender is also an important predictor of AAA formation;
131,132,137–140
Cigarette smoking is the most potent modifiable risk factor and increases the risk of AAA by 60% to 850%.
In the ADAM study and the Edinburgh Artery Study, risk of an
aneurysm increased threefold with any smoking history.
of AAA development further increases with number of cigarettes
smoked, duration of smoking, and lack of filtration, indicating a
dose-response relationship.
149
In the Whitehall study of 18,403 male
civil servants examined at age 40 to 64 years, aneurysm frequency
increased from sixfold with manufactured cigarettes with filters
to 25-fold with hand-rolled cigarettes.
150
Smoking cessation can
131
Finally,
129
127,148
141–147
Risk
461
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37
PATHOPHYSIOLOGY, EPIDEMIOLOGY, AND PROGNOSIS OF AORTIC ANEURYSMS
TABLE 37-1 Prevalence of Aortic Aneurysm in Large Epidemiological Studies
AUTHOR NO. GENDER AGE YRS ANEURYSM FREQUENCY % NATION
Pleumeekers
127
Lederle
128
Ashton
131
Singh
132
Lederle
139
Scott
F, female; M, male.
137
5419 42% M >55 4.1 M, 0.7 F Netherlands
126,196 97% M 50-79 1.3 United States
27,147 M 65-74 4.9 United Kingdom
2998 F 25-84 2.2 Norway
3450 F 50-79 1.0 United States
9342 F 65-80 1.3 United Kingdom
462
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reduce the risk of aneurysm formation, with former smokers having a lower AAA risk than current smokers.
Risk factors for cardiovascular disease in general (e.g., hypertension, hyperlipidemia) also increase the risk of AAA formation but are less potent risk factors than age, gender, and
smoking.
CH
modest association of both hypertension and hyperlipidemia
37
with AAA.
tionship with hypertension,
to correlate best with diastolic blood pressure
hypertensive medication.
may be a greater risk factor for aneurysm rupture than for initial
aneurysm formation.
AAA is clear, although hyperlipidemia is a less potent risk factor
than those mentioned previously.
127,136,152–154
155
In the REACH registry, there was a clear
Earlier studies had suggested a less consistent rela-
138,156
but aneurysm formation seems
140
Some data suggest that hypertension
158
The association between cholesterol and
135,137,159
increased 30% per 40 mg/dL total cholesterol in the Chicago
Heart Association Detection Project in Industry cohort.
cific components of the lipid profile, higher levels of low-density
lipoprotein (LDL) and lower levels of high-density lipoprotein
(HDL) cholesterol are both associated with aneurysm forma-
133,159
tion.
of aneurysm formation,
Similarly, the presence of atherosclerosis increases risk
133,134,137
although as mentioned previously,
aneurysm formation is likely a process distinct from atherosclerosis. In the ADAM study of more than 100,000 subjects, hypertension, elevated cholesterol, and presence of other vascular
disease increased risk of aneurysm formation by 15%, 44%, and
66%, respectively.
127
In contrast, diabetes and black race appear
protective against formation of an aneurysm.
decreases risk of aneurysm formation by 30% to 50%.
A dramatic increase in frequency of AAA formation in relatives
of patients with aortic aneurysm suggests a genetic component
to the disease. Although cigarette smoking numerically accounts
for the vast majority of AAAs in the population,
risk factor for aneurysm formation is a history of aneurysm in
a first-degree relative. Norgaard et al.
dence of aneurysms in first-degree relatives of patients with AAA.
In the ADAM study, a family history doubled the risk of AAA, but
was reported in only 5.1% of more than 100,000 participants.
Investigations specific to the impact of family history demonstrate a larger risk. Several studies have demonstrated that a family history of AAA increases the risk of AAA four- to fivefold.
Family history of AAA was also related to earlier AAA formation
and rupture by nearly a decade.
fold higher in patients with a family history than in sporadic AAA
patients. Frydman et al.
165
164
Rate of rupture was nearly four-
screened the siblings of 400 AAA patients
and found an AAA in 43% of male siblings and 16% of female siblings. More specifically, the risk of AAA formation consistently rises
above 20% for men older than 50 who have a first-degree relative
with AAA.
161,166–169
Using segregation analysis, Majumder et al.
reported that the relative risk of developing an AAA is 3.97 and
4.03 with paternal and maternal history, respectively. Risk increases
to nearly 10-fold with an affected male sibling and 23-fold when a
female sibling is affected.
170
Twin studies further support a genetic
component to AAA formation, with one study reporting an odds
ratio (OR) of 71 (95% confidence interval [CI], 27-183) for monozygotic twins and 7.6 (95% CI, 3.0-19) for dizygotic twins.
Despite the wealth of data supporting a genetic component to
AAA formation, no clear mode of inheritance and no single candidate gene has been identified. Early studies suggested evidence
of both sex-linked and autosomal dominant patterns of inheritance. Associations have been made with blood types, haptoglobin variations, α
II (HLA-II) immune response genes.
-antitrypsin, and human leukocyte antigen class
1
genetic associations with AAA have appeared in the literature,
including genes related to cardiovascular disease, inflammation,
and related signaling pathways. One study suggested an association between reduced AAA growth and five single-nucleotide
polymorphisms (SNPs) in latent TGF-β binding protein (LTBP4),
as well as an allelic variant of TGFB3.
showed no association between genetic polymorphisms in the
136,149,151
157
or use of an anti-
Risk of AAA formation
127,132,136,160
136
the most potent
161
identified an 18% inci-
172–174
More than 100 reports on
176
However, another study
138
For spe-
Diabetes
136,157
171
157,163
main receptors for TGF-β and AAA formation.
177
Two genomewide association studies (GWAS) have suggested an association
between AAA and a SNP located on chromosome 3p12.3 in a
region near the gene CNTN3 for contactin-3, a lipid-anchored
cell adhesion molecule.
178
Another GWAS in a population from
Iceland and the Netherlands found a SNP on 9q33 associated
with AAA with an OR of 1.21. The same SNP has been associated
with coronary artery disease (CAD), peripheral artery disease
(PAD), and pulmonary embolism (PE).
179
The SNP resides in the
gene coding for DAB2IP, a gene encoding a cell growth and survival inhibitor. In addition, the same gene variant associated with
myocardial infarction (MI) at locus 9p21 has been associated
with AAA.
association between telomere length and AAA in a small cohort
in the United Kingdom.
180,181
Finally, of interest but of unclear significance is the
182
This may represent the association of
aging, telomere length, and aneurysm formation, but the direct
pathophysiological link remains unclear.
PROGNOSIS
The natural history of AAA is one of silent coexistence and sudden
lethal rupture. In a large autopsy study performed over a quarter
of a century, one fourth of abdominal aneurysms were ruptured
on postmortem examination.
126
The frequency of rupture was
dependent largely on size in this study population, ranging from
9.5% in aneurysms smaller than 4 cm to 45.6% in aneurysms 7.1 to
10 cm in diameter. In a comparison of patients with aortic aneurysms divided into two groups at a cutoff point of 6 cm, survival
was markedly decreased in the patients with larger aneurysms.
In a single-center study that included 60 AAA ruptures over a
30-year period, only 2 occurred in patients with an aneurysm
diameter smaller than 5 cm.
184
Similarly, in a study in Rochester,
Minnesota, no ruptures occurred in aneurysms smaller than 5 cm,
whereas rupture occurred in 25% of AAAs larger than 5 cm.
In 198 patients with aneurysms 5.5 cm in diameter or larger, but
who were deemed too risky for surgery, 23% had presumed rupture over a mean follow-up of 1.6 years.
162
64% are observed in patients who present with a ruptured aortic
aneurysm.
187
186
Mortality rates as high as
On the basis of these data, two large trials have been conducted
to determine whether early recognition and treatment can
alter the natural history of AAA. The U.K. Small Aneurysm Trial
randomized 1090 patients aged 60 to 76 years with asymptomatic
AAAs 4 to 5.5 cm in diameter to undergo early elective open
surgery or ultrasonographic surveillance.
188
In the surveillance
group, surgery was performed when the aneurysm reached
5.5 cm. Early surgery did not affect overall mortality. At 3 years,
nearly 20% of both groups had died, although abdominal
170
aneurysms accounted for only a quarter of the deaths in both
groups. Cardiovascular mortality unrelated to the aneurysm
accounted for 40% of total mortality, and cancer caused slightly
more than 20% of the deaths. In a similar study performed by
the U.S. Veterans Administration, 1136 subjects aged 50 to 79 years
with asymptomatic AAA 4 to 5.5 cm in diameter were randomized
to undergo either early elective open surgery or ultrasonographic
surveillance
153
(Fig. 37-5). After 5 years, there was no significant
difference in survival between the groups, each with a near 25%
mortality rate. In this study, aneurysm-related deaths accounted
for only 3% of total mortality. More recently, the PIVOTAL study
demonstrated no difference between surveillance and early
endovascular repair in patients with small aneurysms (measuring
4-5 cm), and no difference in aneurysm-related death in the two
groups after 3 years of follow-up.
175
that early repair of small aneurysms does not alter outcomes.
189
Together, these data suggest
Several factors can predict the likelihood of expansion and rupture of AAAs and can help identify which patients require intervention. The factor most predictive of rupture is initial size of the
aneurysm. In one study of patients too ill for surgery, aneurysm
rupture rates ranged from 9.4% for AAA of 5.5 to 5.9 cm to 32.5%
for AAA of 7 cm or more.
186
In the U. K. Small Aneurysm Study, rate
183
185
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Cumulative survival
0.2
0.1
0
0
No at risk
Surveillance
Immediate repair
FIGURE 375 Survival curves in early surgery group compared with
ultrasound surveillance group in Aneurysm Detection and Management
(ADAM) Veterans Affairs Cooperative Study. No significant difference in
mortality was found between the two groups. (From Lederle FA, Wilson SE, Johnson
GR, et al: Immediate repair compared with surveillance of small abdominal aortic
aneurysms. N Engl J Med 346:1437, 2002.)
567
569
552
545
Immediate-repair group
Year of study
513
530
502
526
153
of rupture was 0.9% in aneurysms 3 to 3.9 cm, 2.7% in aneurysms
4 to 5.5 cm, and 27.8% in aneurysms 5.6 cm and larger.
Surveillance group
274
264
183
172
393
383
158
aneurysm size also predicted a more rapid increase in diameter.
Similar to factors that predispose to initial development of AAA,
cigarette smoking and higher blood pressure increase the risks
of rapid expansion and rupture. In contrast to the decreased risk
of AAA development in women, being female actually increases
risk of rupture and death after rupture in those with established
158,191,192
AAA.
threefold higher risk of AAA rupture than men.
In the U.K. Small Aneurysm Study, women had a
158
As mentioned
previously, some have advocated use of biomechanical factors
(wall stress, wall strength) to help with risk prediction. Prospective
studies will be required to determine whether these factors can
improve assessment of patients at high risk for aneurysm rupture
and can improve selection of patients for aneurysm repair.
Thoracic and Thoracoabdominal
Aortic Aneurysms
PREVALENCE
The most common location of involvement of thoracic aortic aneurysms (TAAs) is the ascending aorta and/or aortic root (noted in 60%), with the descending aorta affected
in approximately 40% of cases and the aortic arch in 10%.
Thoracoabdominal aortic aneurysms are defined by contiguous
involvement of the descending thoracic aorta and abdominal
aorta and account for 5% to 10% of all aortic aneurysms.
The prevalence of isolated TAA is poorly defined but estimated
at 6 persons per 100,000 per year.
from 63% of 70,368 deaths between 1958 and 1985 in the city of
Malmo, Sweden, TAAs were diagnosed in 205 of the deceased,
53% of whom were men.
196
63 individuals (0.14%) had died of a ruptured TAA. The relative
infrequency of TAA is confirmed by a retrospective analysis in Rochester, Minnesota.
45,000 residents, 72 (0.16%) were diagnosed with a TAA; 61%
were women, and 67 patients had thoracic aortic involvement
only. Most studies, however, suggest that men are twice as likely
to develop a TAA as women.
aneurysms occur even more infrequently. Of the 44,332 people
to undergo necropsy in Malmo, Sweden, a mere 10 had TAAA.
195
In autopsy records reported
Of the 44,332 autopsies performed,
197
Over 30 years, of approximately
197,198
Thoracoabdominal aortic
87654321
76
67
Larger
190
193
193,194
196
In the Rochester, Minnesota, experience the incidence was 0.37
per 100,000 person-years of follow-up.
197
Because of the relatively
small sample sizes reported in the literature, risk factors for TAAA
development are less well defined. Risk factors currently associated with development of TAAA include smoking, hypertension,
and atherosclerotic vascular disease.
193
ETIOLOGY AND PATHOPHYSIOLOGY
Aneurysms involving the thoracic aorta commonly develop as a
result of cystic medial necrosis, a degenerative process that histologically involves degeneration of elastic fibers and SMCs. Cystic
medial degeneration can arise as an isolated abnormality or as a
result of an underlying connective tissue disease, such as MFS or
Ehlers-Danlos' syndrome (EDS). Degeneration of the media within
the arterial wall results in impaired structural integrity of the aorta,
leading to eventual aortic dilation, aneurysm formation, and risk
of rupture.
As with AAA, age is a significant risk factor for development
of TAA; median age for presentation varies from 64 to 69 years.
Cystic medial necrosis develops to some degree as a natural
consequence of aging and may be accelerated by comorbid
conditions such as hypertension.
199
Although a degenerative
aneurysmal process is found in the majority of patients with TAAA,
several other etiologies should be considered, including inherited collagen vascular disorders (e.g., MFS), BAV disease, aortic
dissection, infection, and vasculitis (e.g., giant cell or Takayasu's
arteritis). Rarer causes of TAA include coarctation of the aorta
and trauma. Finally, some aneurysms develop because of a familial predisposition termed familial thoracic aortic syndrome.
NATURAL HISTORY AND PROGNOSIS
The natural history and prognosis for TAAs and TAAAs remain poor
but not completely defined, in part because modern imaging techniques now allow for early detection and intervention of aneurysm before rupture, and because the natural history is dependent
in large part on underlying etiology. However, in a study accumulated over 25 years that followed 94 patients with TAAAs who did
not undergo operative repair, 76% died within 2 years of follow-up,
with half of the deaths resulting from aneurysm rupture.
recent experience with 57 TAAA patients managed without operation revealed a 69% 2-year survival, with aneurysm rupture as
the cause of death in 19%.
expansion and rupture include smoking, chronic obstructive pulmonary disease (COPD), and renal insufficiency.
201
Features associated with aneurysm
202
Dissection as
an underlying cause of aneurysm formation is also associated with
a greater risk of rupture compared with degenerative causes.
Extension of a TAA into the abdomen is associated with a 50% relative increase in risk of rupture, compared with those limited to the
thoracic aorta alone.
204
The natural history of TAA depends in large part on rate of expansion. Initial aneurysm size at the time of diagnosis is the most
important predictor of thoracic aneurysm growth.
data have suggested that the mean rate of growth of thoracic aneurysms averages 0.1 cm/yr.
rate of growth. Growth rate is increased in the setting of an aortic dis-
205
Several factors also contribute to the
section. In one study, presence of a chronic aortic dissection was
associated with a 0.37 cm/yr rate of growth.
193
Longitudinal
205
Descending TAAs
tend to increase in size more rapidly than ascending TAAs.
Those who smoke have a twofold increased rate of growth over
nonsmokers.
Survival rates for TAA range from 39% to 87% at 1 year and from
13% to 46% at 5 years.
207
201,207,208
In a study of 67 patients with TAA
(mean age, 65 years), those with an aortic diameter less than 5 cm
had a 90% 3-year survival rate, compared to 60% for patients with
a TAA larger than 5 cm.
with TAAs 6 cm or larger had a higher mortality rate than those
with smaller aneurysms.
is recommended when the aneurysm reaches 5.5 cm or greater in
the ascending aorta.
207
Similarly, in two other studies, patients
206
Based on these data, referral for surgery
209
200
A more
205,206
463
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37
PATHOPHYSIOLOGY, EPIDEMIOLOGY, AND PROGNOSIS OF AORTIC ANEURYSMS
193
203
464
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However, several factors increase risk of aneurysm rupture
and may prompt earlier referral for intervention. Guidelines recommend that patients with MFS or other genetic disorders (e.g.,
vascular Ehlers-Danlos', Loeys-Dietz's, and Turner's syndromes,
BAV disease, or familial aortic aneurysm) may require intervention at smaller diameters, such as 4.0 cm to 5.0 cm, depending
CH
on clinical circumstances.
37
rapid rate of growth than expected (i.e., ≥
increased risk of rupture and require repair at diameters less
than 5.5 cm.
209
Finally, repair should be considered in patients
with ascending aortic diameter greater than 4.5 cm if undergoing aortic valve surgery.
209
206,209–214
In addition, those with a more
0.5 cm/yr) may be at
For aneurysms involving the aortic arch, surgery should be
considered when the diameter reaches 5.5 cm or greater.
degenerative descending TAAs, repair is recommended when the
diameter exceeds 5.5 cm, although in individuals with TAAAs or
those with high surgical risk, elective surgery is recommended
when the diameter exceeds 6.0 cm.
209
Other factors reported to
significantly increase rate of rupture or need for surgery include
older age, history of COPD, pain possibly related to the aneurysm,
higher blood pressure, and extension of the aneurysm into the
abdomen.
202,204
Inherited and Developmental Disorders
Marfan's Syndrome
Marfan's syndrome is an autosomal dominant inherited disorder of connective tissue arising from mutations in FBN1, a gene
on chromosome 15 encoding the ECM protein fibrillin-1 (FBN1).
Abnormalities in fibrillin synthesis may affect multiple tissues
in patients with Marfan syndrome, including the cardiovascular,
skeletal, and ocular systems. Excessive signaling through the
TGF-β cascade has been suggested as a contributing factor. This
is supported by experiments showing that TGF-β-neutralizing
antibodies reverse aortic disease in a mouse model of Marfan
syndrome, and by the demonstration that losartan, an angiotensin
receptor blocker (ARB) with anti-TGF-β properties, can partially
reverse aortic wall defects in these mice.
tions of MFS include ectopia lentis, hyperelasticity and ligamentous redundancy, valvular heart disease, and abnormalities in skin,
fascia, skeletal muscle, and adipose tissue.
However, potentially the most lethal complication in MFS is disease of the ascending aorta resulting in aneurysm, dissection, and
rupture. Dilation of the aortic root has been demonstrated early
in childhood in patients with Marfan syndrome. Histologically,
changes in the media seen in patients with MFS include cystic
medial necrosis with fragmentation and disarray of elastic fibers,
a paucity of smooth muscle cells, and separation of muscle fibers
by collagen and glycosaminoglycans.
Ehlers-Danlos' Syndrome
Ehlers-Danlos' syndrome type 4 (vascular type) is a rare congenital defect in the synthesis of type 3 collagen resulting from a
mutation in the COL3A1 gene.
ent with acrogeria (distinctive facial appearance), bruising, thin
skin, and vascular or visceral rupture. Histological examination
reveals a thinned, fragmented internal elastic lamina.
deposition of glycosaminoglycans in the media of major arteries
and intima of smaller arteries, with intimal thickening, has been
219
noted.
stability or prevent formation of collagen, decreasing vascular
wall stability.
Abnormalities in type 3 collagen fiber formation reduce
218
In a study of 199 patients with confirmed EhlersDanlos syndrome, 25% of patients suffered a ruptured vessel or viscus by age 20 and 80% by age 40.
There were 131 deaths, 103 of which were due to vascular rupture. Complications of pregnancy caused the death of 15% of the
women who became pregnant.
217
Patients with EDS typically pres-
220
215
Clinical manifesta-
216
Mean survival was 48 years.
209
218
Moreover,
For
Loeys-Dietz's Syndrome
Loeys-Dietz's syndrome is an autosomal dominant condition arising from mutations in either the type I or type II receptor for TGFβ (TGFBR1 or TGFBR2). Individuals with Loeys-Dietz's syndrome
have several characteristic features, including abnormal uvula,
hypertelorism (increased space between the eyes), and arterial
aneurysms, among other abnormalities, some of which are similar to Marfan syndrome.
214
The syndrome is characterized by
particularly aggressive arterial disease manifested as aortic aneurysm with high risk of aortic dissection and rupture. As such, the
average age of death of 26 years. Because of the high morbidity
and mortality and the high rate of aortic dissection, even with
aneurysms of less than 5.0 cm in size, early repair at smaller diameters is recommended.
209,214
Bicuspid Aortic Valve
Presence of a BAV increases the risk of ascending aortic aneurysm
formation.
dilation was a “post-stenotic” phenomenon arising secondary to
abnormal flow through a diseased aortic valve, more recent data
support the notion that aortic expansion occurs independently
of valvular dysfunction, severity, age, and body size.
dence that aortic dilation is not dependent on valve dysfunction
is found in a study of 118 consecutive patients with BAV in whom
the diameter of the ascending aorta was not correlated with severity of aortic stenosis.
can arise even when there is no hemodynamically significant aortic valve disease, and replacement of a diseased valve does not
change the rate of aortic expansion.
In one study comparing aorta and pulmonary artery specimens
in patients with BAV and tricuspid aortic valve disease, those
with BAV had decreased FBN1 concentrations in both the aortic and pulmonary specimens, suggesting a systemic disorder.
Vascular smooth muscle cells from patients with BAV show intracellular accumulation and reduction of extracellular distribution
of several structural elements including fibrillin, fibronectin, and
tenascin.
inflammation and increased expression of MMP-2 and MMP-9 in
patients with BAV compared to those with tricuspid aortic valve
disease.
risk of developing BAV, also exhibit an increased rate of aneurysm
formation.
193
Although it was once thought that the aneurysmal
221
Further evi-
222
Moreover, abnormalities in the aortic wall
223
16
Surgical specimens demonstrate greater amounts of
225,226
Patients with Turner's syndrome, who are at increased
227
224
Aortic Coarctation
Coarctation of the aorta represents 5% of congenital heart disease.
The clinical consequences of aortic coarctation are varied, ranging from being life-threatening in infancy to remaining unappreciated until adulthood.
228
Coarctation has long been recognized
as associated with de novo aortic aneurysm development, and
aneurysms can also develop at the site of coarctation repair—
specifically patch angioplasty repair—in up to 20% of patients.
229,230
Some reports indicate aneurysm formation can even occur several decades after initial repair. Intermediate follow-up studies
suggest that percutaneous balloon angioplasty repair results in
a 2% to 5% rate of repair-site aortic aneurysm formation.
231,232
A
potential explanation for the relationship between coarctation and
aortic aneurysm is the common link with the presence of BAV in
approximately 15% of patients with aortic coarctation.
212
Other Conditions Associated
with Aortic Aneurysm
Although most aortic aneurysms occur as a result of degenerative
processes in the aortic wall as described earlier, certain disease
states including vasculitis, infection, and inherited abnormalities of
structural proteins predispose patients to aortic aneurysm formation (see
Box 37-1).
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