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182 Coady and Elefteriades
approximately 10%. And, those with ASI above 4.25 cm/m
2
have yearly rates of
rupture, dissection, or death as high as 30% to 40% (35).
This data is summarized in Table 2. These differences in yearly rates were
reflected in the Cox proportional hazards regression, where the odds ratio for rup-
ture was more than 11-fold higher in patients with aortic size index >4.25 cm
/
m
2
.
Hypertension
Small abdominal aneurysms have been shown to rupture, with one study demon-
strating a 39% rupture rate during long-term nonoperative management of aneu-
rysms <6 cm in diameter (36). Cronenwett et al. (37) sought other factors important
in predicting rupture in small abdominal aortic aneurysms. Of the potential risk
factors studied, only diastolic blood pressure >100 mmHg, initial anteroposterior
diameter greater than 5 cm, and degree of COPD (FEV1 <50% of predicted) were
independently predictive of rupture. This study recognized the fact that small
aneurysms can rupture, that aneurysm expansion rate is not well correlated with
rupture, and that risk factors other than initial size may be of important prognostic
0
0.05
0.1
0.15
0.2
3456789
Aortic size (cm)
Growth (cm/yr)
Figure 4 Absolute change in growth as a function of aortic size.
Figure 5 Average yearly rates of negative outcomes (rupture, dissection and death). These
estimates represent the average rate during the first five years after presentation.
1.00
0.0%
5.0%
10.0%
15.0%
Yearly Rates
ASI (aortic size index)
20.0%
Rupture, Dissection or Death
Rupture or Dissection
Rupture Alone
25.0%
2.00 3.00 4.00 5.00 6.00
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Natural History of Thoracic Aortic Aneurysms 183
value. Predicted five-year rupture rates varied from 2%, when these risk factors
were absent to 100%, when all three risk factors were significant.
The law of Laplace states that as a cylinder increases in size, the wall ten-
sion also increases. Therefore, when hypertension is associated with larger aortic
diameters, it has been considered a risk factor for the development of aneurysm
rupture based on this law. Foster et al. (38) showed that rupture occurred in 72%
of patients with diastolic hypertension but in only 38% of the entire group. Szilagyi
et al. (31)
found hypertension (>150/100 mmHg) to be present in 67% of patients
who experienced aneurysm rupture, but in only 23% of those without rupture. For
TAAs, Dapunt et al. (32) reported that a history of hypertension correlated with a
greater thoracic aortic diameter at diagnosis, but did not significantly affect the
rate of enlargement. Masuda et al. (39) reported a positive association between
diastolic blood pressure and rate of expansion of TAA, which was statistically
significant in univariate but not in multivariate analysis.
Acute rupture and aortic dissection can also be linked to hypertension in
younger patients. In 2003, our group reported the occurrence of acute ascending
aortic dissection in five previously healthy young athletes who were lifting weights
at the time of onset of their aortic pain (40). We have now expanded this series to
31 young athletes (41). These are all tragic cases, often fatal if diagnosis is delayed
or immediate access to a major cardiac center is not effected.
We found that all these young athletes harbored unsuspected, moderate
dilatation of the aorta, in the range of 4 to 5 cm. Also, we found that weight
training produces dramatic rises in arterial blood pressure, up to 320 mmHg in
our studies (42).
Table 2 Risk of Complications by Aortic Diameter and Body Surface Area with Aortic
Size Index Given Within Chart
Aortic size (cm)
BSA 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
1.30 2.69 3.08 3.46 3.85 4.23 4.62 5.00 5.38 5.77 6.15
1.40 2.50 2.86 3.21 3.57 3.93 4.29 4.64 5.00 5.36 5.71
1.50 2.33 2.67 3.00 3.33 3.67 4.00 4.33 4.67 5.00 5.33
1.60 2.19 2.50 2.80 3.13 3.44 3.75 4.06 4.38 4.69 5.00
1.70 2.05 2.35 2.65 2.94 3.24 3.53 3.82 4.12 4.41 4.71
1.80 1.94 2.22 2.50 2.78 3.06 3.33 3.61 3.89 4.17 4.44
1.90 1.84 2.11 2.37 2.63 2.89 3.16 3.42 3.68 3.95 4.22
2.00 1.75 2.00 2.25 2.50 2.75 3.00 3.25 3.50 3.75 4.00
2.10 1.67 1.90 2.14 2.38 2.62 2.86 3.10 3.33 3.57 3.80
2.20 1.59 1.82 2.05 2.27 2.50 2.72 2.95 3.18 3.41 3.64
2.30 1.52 1.74 1.96 2.17 2.39 2.61 2.83 3.04 3.26 3.48
2.40 1.46 1.67 1.88 2.08 2.29 2.50 2.71 2.92 3.13 3.33
2.50 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20
= Low risk (∼2.5% per yr); = Moderate risk (∼10% per yr); = Severe risk (∼35% per yr).
Abbreviation: BSA, body surface area.
Source: From Ref. 35.
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184 Coady and Elefteriades
Smoking
In 1991, Strachan (43) published the Whitehall study, which examined 19,403 male
civil servants, and found 99 deaths attributed to aortic aneurysm during 18 years of
follow-up. Their results showed that fatal aneurysms were substantially increased in
current smokers, particularly in those who smoked hand-rolled cigarettes. Dapunt
et al. (32) in 1994, found smoking to be a significant risk for aneurysm expansion.
Presence of a Chronic Dissection
In our present series, we have demonstrated that the presence of a chronic dissection
was a significant predictor for more rapid aneurysmal growth (Fig. 6) (44).
Collagenase Activity
Busuttil et al. (45) reported increased collagenase activity in human aortic aneu-
rysm walls, particularly in larger or ruptured aneurysms. Collagenase functions
to break down collagen, thus weakening the arterial wall. Individuals with COPD
have been shown to have increased elastolytic activity in polymorphonuclear leu-
kocytes of patients with aortic aneurysmal but not occlusive disease (46). Not all
smokers develop elevated proteolytic activity after smoking, and the exact mecha-
nism of aneurysm formation is still being investigated (38).
Syphilis
The early studies by Boyd (47) in 1924, Colt (48) in 1927, Kampmeier (49) in 1938,
and Cranley (50) in 1954, detailed the influence of syphilis in generating aortic
aneurysms, with little information on aneurysms of arteriosclerotic origin.
Before antibiotics became prevalent, syphilis accounted for approximately 75% of
abdominal aortic aneurysms. Since the discovery of appropriate antibiotic treatment
for syphilis, the incidence of syphilitic aneurysms has dropped dramatically.
Figure 6 Risk factors for aneurysm growth rates. Bars shown in each group represent the
mean growth rate of each patient population ± the standard error. Note: *P < 0.04.
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
All Age
Renal
Disease
Smoking
History
Aortic
Dissection
Type A
Dissection
Location
cm/yr
<65 >65 no yes no yes no yes
Asc/Arch Desc/TA
yesno
*
*
*
*
*
*
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Natural History of Thoracic Aortic Aneurysms 185
Arteriosclerosis
Joyce et al. (51) in 1964 studied 107 patients who had nondissecting, nonsurgi-
cally treated TAAs. Approximately 73% were considered “arteriosclerotic” in
origin, and the incidence of syphilitic aneurysms at that time had fallen to 20%.
One of the reasons that the natural history of aortic aneurysms has been
difficult to record is the fact that arteriosclerosis is so prevalent in this population.
Joyce et al. (51) attributed the most deleterious effects on survival to the presence
of associated coronary, cerebral, or other peripheral arterial occlusive or aneurys-
mal disease. In their study, approximately 50% of patients with aortic aneurysms
were not alive at five years after diagnosis. Whether arteriosclerosis is a cause
of aortic aneurysm formation, or simply a coexisting disease process, is still a
matter of debate.
EVIDENCE-BASED CLINICAL DECISION-MAKING
FOR THORACIC AORTIC ANEURYSM
TAAs are serious conditions that frequently require surgical intervention due to
the threat of dissection or rupture. The natural history of aortic aneurysm is often
related to the specific location and the primary cause of the disease. The decision-
making process is further complicated by the greater risks of thoracic aortic
replacement compared to abdominal aortic replacement.
In developing management protocols for appropriate patient selection for
surgery, it is essential to study risk factors that may influence the natural history
of the disease. The specific objective is to select patients for whom the operative
risks are justified.
Our team at the Yale Center for Thoracic Aortic Disease has developed and
maintained a robust clinical database to:
1. Further define the natural history of TAAs in terms of thoracic aortic
growth, incidence of complications (dissection and rupture), and
survival;
2. determine risk factors for thoracic aortic growth, dissection, and
rupture; and
3. define scientific criteria for surgical intervention based on the natural
history available from these patients.
The Yale observations confirm that TAA is, over the long term, a lethal
disease. Figure 7A illustrates that patients with TAA do, indeed, have a dramati-
cally poorer natural outlook than an age and sex-matched general population.
Figure 7B illustrates that patients with descending aneurysms do have a poorer
outlook than those with ascending aneurysm. Figure 7C illustrates that patients
with dissection fare more poorly than patients free of dissection. And, Figure 7D
shows that prognosis depends on size of the aortic aneurysm: patients with larger
aneurysms do more poorly. Careful scrutiny of Figure 7D reveals that that TAA is
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186 Coady and Elefteriades
indeed a lethal disease, but that it takes years for this lethality to express itself.
Please note that it is not until after three years of follow-up, even in the largest
aneurysms, that the survival curve drops significantly. Figure 7E demonstrates
the excellent survival after elective surgical therapy for TAA. Note that emergent
surgical therapy leads to much poorer long-term survival.
These graphs argue strongly for elective, prophylactic surgical extirpation
of the aneurysmal thoracic aortic aorta, before rupture or dissection—which either
result in death or require emergent surgery—have a chance to occur.
Aortic Growth
Our team has found that calculation of growth rate is more complicated than simply
subtracting original size from current size and dividing by time. Rizzo (52), from
the Yale School of Public Health, has developed exponential equations that permit
rigorous calculation of growth rates for large populations of TAA patients.
Growth rate estimates were obtained for our entire population and for sub-
groups with specific risk factors by means of a multivariable regression analysis
in which aneurysm growth followed an exponential path. In particular, the natural
logarithm of the difference between the last measured size and the first measured
Figure 7 Key natural history graphs from the Yale database. (A) Survival of patients with
unrepaired thoracic aortic aneurysm compared to that of the age and sex-matched general
population. (B) Poorer outlook of patients with descending compared to ascending thoracic
aortic aneruysm. (C) Adverse impact of aortic dissection on outlook. (D) Larger aneurysms
do more poorly in the long run. (E) Elective surgical therapy is very safe, and restores
excellent long-term prognosis. Source: From Ref. 1.
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Natural History of Thoracic Aortic Aneurysms 187
size was related to the time interval between the two tests and interactions between
this time variable and risk factors. This statistical method was previously described
in detail by our team (52).
The growth rates for TAA are displayed in Table 3. The overall growth rate
is approximately at 0.17 cm
/
yr (range 0.136 and 0.306 cm
/
yr). Risk factors that
increase aortic growth include advancing age, smoking, and progressive aortic size.
The slowest mean growth rate represents patients younger than 45 years
and the fastest estimated growth rate is seen in patients with initial aortic size
greater than 7.5 cm (Table 3) (44).
Table 3 Analysis of the Relationship of Different Variables on Thoracic Aortic
Aneurysm Growth
Variable Number (%) Growth rate (cm/yr) 95% CI P value
Overall 493 0.170 0.151–0.189
Gender
Male 317 (64.3) 0.170 0.093–0.247 0.9688
Female 176 (35.7) 0.170 0.135–0.206
Age
<65 252 (51.1) 0.149 0.078–0.222 0.0020
a
≥65 241 (48.9) 0.212 0.180–0.245
Non-Marfan family
history
(−) 290 (83.6) 0.177 0.153–0.201 0.8074
(+) 57 (16.4) 0.170 0.087–0.253
Marfan syndrome
(−) 453 (91.9) 0.174 0.153–0.195 0.4395
(+) 40 (8.1) 0.156 0.089–0.223
Hypertension
(−) 149 (32.9) 0.186 0.117–0.255 0.1272
(+) 303 (67.0) 0.155 0.126–0.183
Renal disease
(−) 375 (87.0) 0.168 0.146–0.190 0.0348
a
(+) 56 (13.0) 0.243 0.151–0.337
Pulmonary disease
(−) 334 (75.9) 0.173 0.150–0.196 0.8245
(+) 106 (24.1) 0.179 0.103–0.256
Smoking history
(−) 264 (61.8) 0.158 0.133–0.183 0.0079
a
(+) 163 (38.2) 0.220 0.148–0.292
Initial aortic size (cm)
<4.5 204 (41.9) 0.171 0.100–0.243 0.9402
4.5–5.4 187 (38.4) 0.179 0.111–0.243 0.6986
5.5–6.4 54 (11.1) 0.137 0.049–0.227 0.2991
6.5–7.4 28 (5.8) 0.219 –0.003–0.452 0.6420
(Continued )
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188 Coady and Elefteriades
The presence of a chronic aortic dissection was associated with a faster growth
rate, as was the presence of TAAs in the descending thoracic and thoracoabdominal
aortas compared to ascending aneurysms and aneurysms of the aortic.
Complications: Rupture and Dissection
The incidence of adverse events (rupture and dissection) increases with faster growth
rates, as illustrated in Figure 8. When the growth rate was less than 0.05 cm
/
yr the
incidence of a negative event was 24% compared to 45% with a growth rate above
0.20 cm
/
yr (44).
Figure 9 illustrates the estimated increase in the probability of incurring a
dissection or rupture as a function of ascending aneurysm size. On the y-axis is
displayed the likelihood of natural complications of the aortic aneurysm, namely
rupture or dissection. On the x-axis is the size of the aneurysm. These curves pres-
ent the cumulative risk, over the patient’s lifetime in achieving a certain current
aortic size, of rupture or dissection. It can be seen that there are discrete “hinge
points” in the behavior curves for the ascending and the descending aortas. For the
ascending aorta, the hinge point occurs at 6 cm. Relative to the 4.0 to 4.9 cm
cohort, the probability of incurring a dissection or rupture is 32.1 percentage
points higher in the 6.0 to 6.9 cm cohort (p < 0.01). This is a sobering statistic,
expressing once again the virulence of this disease over time.
Similarly, Figure 10 shows that the rate of dissection or rupture increases
by 43.0% points in descending aneurysms ≥7 cm in diameter (p < 0.01). For the
descending aorta, the hinge point occurs at 7cm.
Note that the descending aorta does not rupture or dissect until a somewhat
larger size is attained. This is not an intuitive finding, as the descending aorta has
Table 3 Analysis of the Relationship of Different Variables on Thoracic Aortic
Aneurysm Growth (Continued)
Variable Number (%) Growth rate (cm/yr) 95% CI P value
≥7.5 14 (2.9) 0.306 –0.088–0.733 0.4887
Aneurysm location
Ascending/arch 369 (74.9) 0.161 0.078–0.246 0.0898
Descending/TA 124 (25.2) 0.226 0.158–0.296 0.0041
a
Chronic aortic dissection
(−) 362 (73.4) 0.155 0.134–0.177 0.0081
a
(+) 131 (26.6) 0.214 0.149–0.279
Type A dissection
(−) 433 (87.8) 0.158 0.139–0.178 0.0003
a
(+) 60 (12.2) 0.269 0.189–0.352
Type B dissection
(−) 406 (82.4) 0.163 0.142–0.184 0.1520
(+) 87 (17.7) 0.197 0.130–0.265
Source: From Ref. 44.
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Natural History of Thoracic Aortic Aneurysms 189
Figure 8 The incidence of negative events (rupture, acute dissection, and death) as a func-
tion of growth rate. Source: From Ref. 44.
0%
20%
40%
60%
< 0.05 0.05 to 0.1 0.1 to 0.14 0.15 to 0.19 = 0.20
cm/yr
Incidence of Negative Events (%)
Figure 9 Regression analysis for the ascending aorta.
-10
0
10
20
30
40
4
5678
Aortic size (cm)
% increased risk of complication
* Hinge point at
6.0 cm (p<0.01)
*
Figure 10 Regression analysis for the descending aorta.
0
10
20
30
40
50
345678
Aortic size (cm)
% increased risk of complication
* Hinge point
at 7 cm (p<0.01)
*
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190 Coady and Elefteriades
fewer lamellae than the ascending and is normally smaller in the preaneurysmal
state (53). We would expect the descending aorta to rupture earlier, but this does
not appear to be the case. Fluid dynamics, flow patterns, wall stress, and the like
may underlie this observation.
A “Holy Grail” has been to make predictions of specific yearly dissection,
rupture, and mortality rates for each size of the thoracic aorta. We were not able to
do this until relatively recently, as this requires extremely robust data, with many
“hard end-points” for each aortic size. Our database has recently reached a size
where such calculations have become possible. As can be seen in Figure 11, the
risks of rupture, dissection, and death increase in stepwise fashion as the aorta
dimension, yearly risk of rupture is about 4%, dissection is about 4%, death is
about 10%, and risk of rupture, dissection, or death is about 14%.
Surgical Decision Making for Prophylactic Resection
of the Thoracic Aorta
We believe that these observations permit evidence-based conclusions regarding
when the asymptomatic aneurysmal thoracic aorta should be resected, to prevent
rupture, dissection, and death. Recommendations are indicated in Figure 12 (54).
This data indicates that replacement of the ascending aorta at about 5.5 cm will
preclude most ruptures and dissections, while not exposing affected patients
unduly early to the risks and discomforts of surgery. For the descending aorta,
surgery at about 6.5 cm will, similarly, pre-empt most adverse aortic-related events.
We apply more stringent criteria for patients with Marfan’s disease, whose disease
is more aggressive. We intervene prophylactically at 5.0 cm for the ascending
Figure 11 Probabilities that rupture or dissection will occur have been calculated for
aortic aneurysms in the chest. There is a dramatic surge in danger when aneurysms reach 6
cm. Based on this information, we conclude that many patients with aneurysms in the
range of5.5 cm should undergo elective, pre-emptive aortic replacement to prevent aortic
rupture. Such a criterion spares most patients from naturally occurring rupture, dissection,
or death, P. Source: From Ref. 42.
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Natural History of Thoracic Aortic Aneurysms 191
aorta and 6.0 cm for the descending aorta in Marfan’s patients. We, and others,
have observed that even for patients without a recognizable connective tissue
syndrome like Marfan’s disease, aortic aneurysm and dissection the run in fami-
lies (11). We found that these familial aortas grow relatively rapidly. We tend to
intervene at the Marfan’s criteria, namely 5.0 cm for the ascending and 6.0 cm for
the descending aorta, in patients with this type of familial (non-Marfan’s) aortic
aneurysm or dissection. If there is a family history of aortic dissection or aortic-
related death, we are especially inclined to move at these “early” criteria. Similarly,
because bicuspid aortic valves are also virulent in inducing aortic dissection, we
tend to operate sooner than in other patients.
It cannot be emphasized too strongly that these size criteria apply for the
asymptomatic TAA. Any symptomatic aneurysm must be resected, regardless of
size. It is an unfortunate characteristic of this disease that only a small proportion
of patients are symptomatic—with pain, tracheal or esophageal compression, or
vocal cord paralysis. For most patients, their first symptom is an acute aortic event.
However, if a patient is symptomatic, his aorta must be resected, even if it does not
meet traditional size criteria.
It is, of course, a matter of clinical judgment whether the pain symptoms
experienced by an individual patient are of aortic origin. Unless we can demonstrate
Figure 12 Recommended surgical intervention criteria for thoracic aortic aneurysms.
a
The Marfan’s intervention criteria should also apply if there exists a family history of
aortic disease other than Marfan’s syndrome.
1. Rupture
2. Symptomatic states
a. Pain consistent with rupture and unexplained by other causes.
b. Compression of adjacent organs, especially trachea, esophagus, and
left main stem bronchus.
c. Significant aortic insufficiency in conjunction with ascending aortic aneurysm
3. Absolute size
Marfan’s syndrome patients
a
NonMarfan’s
patients
Ascending 5.0 cm 5.5 cm
Descending 6.0 cm 6.5 cm
4. Documented enlargement
a. Growth ≥ 1 cm/yr or substantial growth, and aneurysm is rapidly
approaching criteria in number 3 above.
5. Acute aortic dissection
a. Ascending requires urgent operation
b. Descending requires “complication-specific approach”
116
syndrome
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