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172 Elefteriades
DISCUSSION AND COMMENTARY
Question for the Author
Is not your schema speculative?
Of course, you are correct, the schema we present for the causation and timing of
aortic dissection is an oversimplification, at least partially speculative. However,
we believe that this schema best represents the available evidence.
Specifically, there is no longer room for doubt about the genetic origin of
many, if not most, thoracic and abdominal aneurysms. While pointing to the MMPs
as the effector of the genetically-programmed aortic destruction is an oversimpli-
fication (see Chapter 17), the MMPs clearly play a major role. We have little doubt
about the importance of physical stress in bringing on an aortic dissection—as
evidenced in our reports of exercise-induced aortic dissection. Acute hypertension
makes great sense as the culprit in cases of extreme physical exertion. That blood
pressure rises astronomically with weight lifting is not disputable. We were
surprised to see just how large a proportion of patients and families interviewed
reported extreme emotional stress at the moment of onset of dissection pain. We
believe it is reasonable to speculate that severe hypertension accompanied these
episodes of extreme emotional stress.
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173
12
The Natural History of Thoracic Aortic
Aneurysms: Etiology, Pathogenesis,
and Evidence-Based Decision Making
for Surgical Intervention
Michael A. Coady
Harvard University, Landmark Hospital,
Boston, Massachusetts, U.S.A.
John A. Elefteriades
Section of Cardiothoracic Surgery, Yale University,
New Haven, Connecticut, U.S.A.
INTRODUCTION
Many clinicians hold a utilitarian view of the aorta, considering it merely a large
conduit through which blood travels to the vital organs of the body. For this reason,
the thoracic aorta may not capture the full attention that more elaborate functional
organs receive. Nevertheless, aneurysmal disease of the aorta is the thirteenth
most common cause of death in the United States (1).
With gradual dilation, the aortic wall becomes increasingly weakened, leading
to possible dissection, rupture, and even death. The incidence of thoracic aortic
aneurysm (TAA) is estimated to be 5.9 cases per 100,000 person-years (2). TAAs
have a mean age at the time of diagnosis between 59 and 69, with men predomi-
nating over women with a ratio of 2–4 to 1. Affected individuals often have
concomitant medical conditions including hypertension, coronary artery disease,
chronic obstructive pulmonary disease (COPD), and congestive heart failure.
The prevalence of aortic aneurysms appears to be increasing, which
may reflect improvements in imaging techniques as well as heightened clinical
awareness of the disease (3). At the Center for Thoracic Aortic Disease at the
SECTION IV: TREATMENT OF ACUTE AORTIC CONDITIONS
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174 Coady and Elefteriades
Yale University School of Medicine, we have examined the natural behavior of the
thoracic aorta both at the molecular level and in a robust clinical statistical analysis
in an effort to better understand the biological basis and natural history of this disease
process. It is hoped that these efforts may one day enable disease prevention and
refine current management. A further understanding of factors influencing aortic
growth, rupture, and dissection analyzed in a vigorous statistical model enables us
to develop strong, evidence-based indications for surgical intervention.
In this chapter, the etiology of TAA will be explored in detail. Second,
we will explore the pathogenesis and risk factors for development and expansion
of TAAs. Finally, we will review a sparsely studied area, namely, the appropriate
aortic diameters which necessitate surgical intervention. The current recommen-
dations for surgical intervention are based largely on clinical judgment, with a
paucity of hard scientific and statistical data regarding the appropriate size criterion
for surgical treatment. A recent MEDLINE search identified nearly 1000 articles
addressing the surgical treatment of TAAs, but less than 10 specifically examining
the natural risk of rupture or dissection in aneurysms not treated surgically.
In deciding whether or not to operate on the basis of the clinical characteristics
of patients, there has been little hard scientific guidance.
All patients discussed in this work were seen at Yale-New Haven Hospital
from October 1985 to May 2006. The insights into the behavior of the thoracic
aorta have been gleaned from our large, computerized database on thoracic aortic
diseases, which currently includes over 3000 total patients and over 9000 patient-
years of follow-up and 9000 catalogued imaging studies.
ETIOLOGY
Aneurysms of the ascending aorta are most commonly related to degenerative
changes in the medial layer of the aortic wall (Fig. 1A and B). These changes
within the muscular layers of the aorta may be associated with connective tissue,
disease acquired defects in the aortic media, annuloaortic ectasia, or idiopathic
causes (4). Atherosclerosis is less commonly seen in the ascending aorta, as
opposed to its frequency in descending and abdominal aortic aneurysms. Chronic
type A dissections are another potential cause of ascending aortic aneurysms.
Other more rare causes include poststenotic dilatation from aortic stenosis, trauma,
infections, mycotic aneurysms, and syphilitic aneurysms. Approximately 25% of
aortic aneurysms occur in the ascending aorta (5).
Annuloaortic ectasia, progressive dilatation of the sinuses of Valsalva and
the aortic annulus, is frequently associated with cystic medial necrosis (Fig. 2)
(6). As the media undergoes progressive degeneration, the aortic diameter under-
goes gradual fusiform widening. Progressively, the aortic root becomes widened,
and the annulus dilated, with resultant loss of coaptation of the valve leaflets and
regurgitation. Annuloaortic ectasia is commonly seen in individuals with Marfan’s
syndrome and true cystic medial necrosis. Cystic medial necrosis is, indeed, a rare
disease and should be differentiated from aortic medical degeneration, which is
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Natural History of Thoracic Aortic Aneurysms 175
seen in elderly patients (2). Aortic medial degeneration has been shown to occur
in most aneurysms regardless of cause or location (7).
Patients with Marfan’s syndrome and annuloaortic ectasia develop severe
aortic regurgitation. Patients without Marfan’s syndrome may also have annuloaor-
tic ectasia, however, those individuals with aortic regurgitation and annuloaortic
ectasia usually have some stigmata of Marfan’s syndrome (8).
Figure 1 (A) Elastic van-geison stained section of a normal ascending aorta (×40). Note the
uniform elastin fibers in the aortic media. (B) Hematoxylin and eosin stained section of an
ascending aortic aneurysm (×40). Note the disrupted elastin fibers in the media.
Figure 2 Hematoxylin- and eosin-stained section of an ascending aortic aneurysm (×40).
Cystic medial degeneration is seen here with focal degeneration of the elastic tissue in the
media and the presence of mucoid material in the media.
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176 Coady and Elefteriades
Aneurysms of the descending aorta most commonly arise at the level of the
left subclavian artery. Approximately 50% of TAAs are located in the descending
thoracic aorta (9). Historically, atherosclerosis has been linked to the development
of descending TAAs. Whether this represents a “cause and effect” is debatable.
Other causes of descending TAA may include chronic dissections, cystic medial
necrosis, aortitis, and traumatic transections.
Genetic Basis for Thoracic Aortic Aneurysms Formation
Marfan’s syndrome has been quite well characterized, and the gene has now been
isolated on the long arm of chromosome 15 (10). Any of a host of mutations on
the fibrillin gene can produce this phenotype, with its well-known skeletal, ocular,
cardiac, and aortic manifestations. However, Marfan’s syndrome is just the tip of
the aortic genetic iceberg, accounting for only 5% to 10% of TAAs.
NonMarfan’s related TAA and dissections are genetic diseases as well. Our
group has documented that TAAs run strongly in families (Fig. 3) (11). In fact, the
likelihood that a proband with aortic aneurysm has a first-order family member with
an aneurysm somewhere in the body is 21.5% (12). This percentage has remained
quite consistent as we have expanded our data to over 500 completed pedigree
charts. The predominant mode of inheritance appears to be autosomal dominant
(76.9%), but recessive and sex-linked patterns have been identified as well. We have
also demonstrated that probands with aneurysms in the thorax can have family
members with aneurysms in other locations as well, including the abdomen
and brain (12). Aortic growth rate is highest for nonMarfan’s patients who have
family members with aneurysms (0.21 cm
/
yr), as opposed to sporadic aneurysms
(0.16 cm
/
yr) and patients with Marfan’s symdrome (0.1 cm
/
yr) (p < 0.01) (12). This
suggests that familial patients harbor a more aggressive clinical entity and that
familial incidence represents an added risk factor for associated complications.
Relative to their sporadic TAA cohorts, familial TAA patients also tend to be younger
at presentation—again implying a more aggressive clinical entity.
PATHOGENESIS
The Aortic Wall and Aneurysm Formation
Aneurysm formation involves alterations in structural proteins of the aorta in addition
to modifications in other extracellular matrix proteins, such as laminin, glycosamino-
glycans, proteoglycans, and fibronectin. These are regulated in part by alterations in
matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs).
Collagen and elastin are the major structural proteins of the aorta. Decreases
in aortic content of these structural proteins were initially reported by Sumner et al.
(13) in 1970. Decreased elastin content has been confirmed by a number of groups
(14–16); however, collagen content appears to be more variable, with some groups
reporting elevated levels (17). Cells of the connective tissue matrix have potential
for synthesis of new collagen after injury; however, the capacity for generation of
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Natural History of Thoracic Aortic Aneurysms 177
new elastin is limited. In the aortic wall, collagen is responsible for the tensile
strength of the vessel, whereas elastin is responsible for its recoil capacity.
Fibrillin is another structural protein that contributes to the microfibrillar
organization of the extracellular matrix. The microfibrillar construction functions
as scaffolding for the deposition of elastin during elastogenesis. A mutation in
fibrillin has been demonstrated in patients with Marfan’s syndrome.
The aorta is categorized as an elastic artery with three defined layers—the
intima, media, and adventitia. The intima consists of single layer of endothelial cells
that rest on a basal lamina. The intimal cells rest on a subendothelial tissue com-
prised of collagen and elastin fibers, fibroblasts, and a mucoid ground substance.
P007
P042
P145
P188
P286
P470
P518
P557
P571
P027
P141
P184
P284
P422
P547
P565
P580
P588
P518
P572
P563
P546
P511
P330
P271
P167
Figure 3 Thoracic aortic aneurysm (TAA) family pedigrees selected from over 500
family pedigrees. Squares represent men and circles, women. An arrow indicates the
proband with a TAA. Blackened circles or squares represent affected patients with aortic
aneurysms.
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178 Coady and Elefteriades
The internal elastic lamina separates the intimal layer from the media. The inter-
nal elastic lamina, composed primarily of elastin, has fenestrae that allow sub-
stances from the lumen to diffuse to nourish cells within the aortic wall.
The media is composed of smooth muscle cells within a matrix of elastin,
collagen, and ground substance. The elastic fibers in the aortic wall are arranged in
the media as circumferential lamellae. The thoracic aorta consists of 45 to 56 lamellar
units (concentric elastic lamellae with smooth muscle cells, collagen, and ground
substance); the abdominal aorta contains only 28 units (18). The number of lamallar
units is preserved throughout the mammalian species, with the exception of the
human abdominal aorta, which consists of fewer units than expected given the load
it bears. This may be a contributing factor in the prevalence of abdominal aorta
aneurysm (AAA) compared to aneurysms in the thoracic aorta.
The lamallar units provide a structural framework for the media. These
elastic lamellae serve to maintain the forward flow of blood during diastole:
during systole, the diameter of these lamellae increases; the elastic fibers recoil
during diastole (19). Smooth muscle cells within the medial layer maintain vascu-
lar resistance, serve a macrophage-like function, and are capable of collagen
synthesis when stimulated (20). Humans lose the ability to produce elastic fibers
in early life, and little elastin synthesis can be detected within the aortic wall
beyond infancy (21).
In most patients with aortic aneurysm, histology examination reveals loss of
elastic fibers—so called “medial degenerative disease.” The mechanisms for this
degeneration are not known, but fragmentation and retrogression of elastic fibers
within the aortic media are clearly evident. More advanced medial degeneration
(as in Marfan patients) leads to loss of smooth muscle cells. Histologic examina-
tion reveals significant reduction in the number of smooth muscle cells within the
tunica media, and multiple interspersed lakes of mucopolysaccharide (“cystic
medial necrosis”).
White et al. (22) however, emphasize that loss of smooth muscle cells of the
media should not directly affect the maximal outer diameter of the aorta. They and
other others believe that loss of smooth muscle cells may play an important role
in the formation of aortic aneurysm and growth through their degradative and
synthetic functions but not through loss of contractile function (23). Loss of struc-
tural integrity of the adventitia, not the media, is required for aneurysm formation
(24). The biomechanical function of the adventitia is the maintenance of the maxi-
mal aortic outer diameter (23). Destruction of elastin within the aortic wall results
in pathologic dilation of the vessel, whereas destruction of the collagen within the
vessel has been shown to cause rupture (23). Therefore, at least in AAA, it is
presently believed that maintenance of adventitial elastin is critical for sustaining
the integrity of the aortic wall.
Since it is well recognized clinically that it is unusual for aneurysm formation
to occur after an endarterectomy if the adventitia remains intact, White et al. (24)
believe that aneurysmal disease must be a disorder of the adventitia. The integrity
of this layer is critical for maintenance of aortic wall integrity under wall stress
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Natural History of Thoracic Aortic Aneurysms 179
and high intraluminal pressure. Elastin degradation of the aortic wall manifests
first in the intima and media (medial degenerative disease), causing deterioration
of these layers (23).
Disruption of the medial architecture does not directly result
in the loss of biomechanical function of the aortic wall or in clinically detectable
aortic dilation.
Elastin disruption and depletion is complete at the stage of relatively
small aneurysms, implying that loss or reorganization of the additional structural
components is important (24). Ultimately, the forces that lead to medial elastin
degradation also cause degradation of the elastic lamellae within the inner third of
the adventitia. This allows for damage to the collagen within the adventitial layer,
resulting in aneurysm formation. Since the strength of collagen is significantly
greater than elastin, degeneration, synthesis, and redeposition of poorly organized
collagen may account for the maintenance of collagen content in aneurysms
despite the significant elastin degradation.
Recent investigations at our own and other institutions have shed light on
certain additional cellular mechanisms that underlie aneurysm formation and
expansion. It has become clear in both the abdomen and the thorax that MMPs
participate in the destruction of the structural components of the aortic wall. These
proteolytic enzymes were discovered in tadpole tails, where they play a role in the
regenerative capacity of that organism.
MMPs initiate tissue remodeling by degradation of existing extra-cellular
macromolecules such as collagens and proteoglycans. Over 20 different MMPs
have been identified, with additional identifications occurring with regularity.
There is considerable consistency between species in the importance of these
enzymes. The MMPs are held in check in a homeostatic balance by the tissue
inhibitors of MMPs, or TIMPs.
Our group has demonstrated that in both aortic aneurysm and dissection
patients, the levels of certain key MMPs, including MMP-1 (collagenase) and
MMP-9 (gelatinase B), are elevated in the aortic wall, compared to control aortas
(25). In addition, the ratio of MMPs to TIMPs, a measure of the proteolytic state,
is also elevated. Those patients who had an aortic dissection had even higher levels
of MMPs than the aneurysm patients. In patients with bi-leaflet aortic valves, these
levels are also elevated compared to tri-leaflet aortic valves—perhaps explaining
the close relationship between bi-leaflet aortic valve and aortic dissection (26).
In our laboratories, we have also been analyzing the molecular biologic
events occurring during aneurysm formation and expansion (27–29). Specimens
of aortic aneurysms from various thoracic locations were harvested. These inves-
tigations have shown that: (i) Although the aortic media becomes thinner, the total
amount of aortic medial tissue increases, due to the much larger diameter that the
aorta attains. (ii) An intense inflammatory process is involved in aneurysm
formation. There is prominent infiltration by interferon-
γ
-producing T-cells. (iii)
Programmed cell death, with apoptosis of vascular smooth muscle cells is not
seen, in contradistinction to findings in abdominal aortic aneurysms. This funda-
mental difference in the biological response in thoracic compared to abdominal
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180 Coady and Elefteriades
aneurysms may be reflective of the difference in embryologic origin between the
ascending aorta, originating from ectoderm, as opposed to the abdominal aorta,
arising from mesoderm.
Risk Factors for Aneurysm Growth
Size
The natural history of TAA, as in any aneurysm, is related to size. Since the initial
studies in 1966 by Szilagyi et al. (30), size has been shown to be a significant risk
factor for aortic rupture. Survival expectancy in untreated small abdominal aortic
aneurysms (<6 cm) was shown to be better than for larger aneurysms (>6 cm). For
nonsurgical aneurysms over a 10-year period, the risk of rupture was 19.5% for
small aneurysms and 43% for larger aneurysms. Removal of the aortic aneurysm
was shown to double the patient’s survival expectancy (31).
Size has also been considered a major risk factor for complications (dissec-
tion and rupture) and is perhaps the single most important factor in the decision
to intervene surgically on a nonemergent basis. The empirical evidence on the
influence of size on rate of growth, however, is mixed. Dapunt et al. (32) note, for
example, that a higher rate of expansion was found in those patients with a larger
aortic diameter (>5 cm) at diagnosis. In contrast, Hirose et al. (33) find no signifi-
cant effect of size on aortic growth.
Table 1 shows the estimated aneurysm growth rates from our own institu-
tional data in relation to initial aneurysm size, chronic dissection, and location.
Annual growth varied from 0.10 cm
/
yr for small (4.0 cm) aneurysms to 0.19 cm
/
yr
for large (8.0 cm) aneurysms. This relationship is depicted graphically in Figure 4.
Also seen in Table 1, dissected aortas grow more rapidly than non dissected aortas,
and descending aneurysms grow more rapidly than ascending aneurysms physicians
must remember to compare to the patient’s earliest study—not the most recent prior
study—in order to asses growth rate properly in a particular patient (34).
Females are at higher risk than males at relatively similar aortic sizes for the
combined endpoint of rupture or dissection (35). We hypothesize that this may be
due in part to differences in mean body size between males and females, with a
given aortic size representing a proportionally greater diameter in smaller women.
In a recent manuscript, we demonstrated that, at any given aortic size, lower body
surface area (BSA) is associated with a higher incidence of complications—
including rupture, dissection, and death. In order to more accurately assess the
risk of aneurysm complications, we developed a new measurement, aortic size
index (ASI), which takes into account both aortic diameter and BSA. ASI is
simply aortic diameter divided by BSA. Throughout all methods of analysis,
ASI was a better predictor of complications than maximal aortic diameter.
In particular, we found that using ASI, patients could be stratified into three
categories of risk (Fig. 5). Those with ASI <2.75 cm
/
m
2
are at low risk for rupture
or dissection, with a yearly incidence of approximately 2.5%. Those with ASI
between 2.75 and 4.25 cm
/
m
2
are at moderate risk, with yearly incidence of
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Natural History of Thoracic Aortic Aneurysms 181
Table 1 Multivariable Estimates of Aneurysm Growth Rates—Annual Growth Rates According to Intial Aneurysm Size
a
Patient <4.0 cm 4.0–4.9 cm 5.0–5.9 cm 6.0–6.9 cm 7.0–7.9 cm >8.0 cm 5.0 cm
category (n = 84) (n = 220) (n = 106) (n = 42) (n = 19) (n = 7) (sample mean)
All (n = 478) 0.12 cm/yr 0.16 cm/yr 0.19 cm/yr 0.21 cm/yr 0.24 cm/yr 0.40 cm/yr 0.16 cm/yr
(0.09–0.14) (0.13–0.18) (0.15–0.24) (0.10–0.32) (−0.06–0.55) (−0.18–1.02) (0.15–0.18)
Dissection status
Chronic dissection 0.12 cm/yr 0.20 cm/yr 0.25 cm/yr 0.83 cm/yr 0.08 cm/yr N/A 0.21 cm/yr
(n = 123) (0.07–0.17) (0.14–0.27) (0.10–0.43) (0.57–1.10) (−0.16–0.34) (0.17–0.25)
No dissection 0.11 cm/yr 0.14 cm/yr 0.18 cm/yr 0.15 cm/yr 0.71 cm/yr 0.39 cm/yr 0.15 cm/yr
(n = 355) (0.08 –0.15) (0.11–0.17) (0.14–0.23) (0.04–0.27) (−0.04–1.55) (−0.13–0.94) (0.13–0.17)
Location of aneurysm
Ascending or 0.12 cm/yr 0.14 cm/yr 0.18 cm/yr 0.52 cm/yr 0.18 cm/yr N/A 0.15 cm/yr
Arch (n = 358) (0.08–0.14) (0.11–0.17) (0.12–0.22) (0.33–0.73) (−0.19–0.57) (0.13–0.17)
Descending or 0.10 cm/yr 0.20 cm/yr 0.24 cm/yr 0.13 cm/yr 0.98 cm/yr 0.41 cm/yr 0.21 cm/yr
TA (n = 120) (0.00–0.21) (0.13–0.27) (0.14–0.34) (−0.02–0.28) (0.24–1.78) (−0.32–1.20) (0.16–0.26)
a
95% Confidence intervals in parentheses.
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