Literature Review
Literature Search Strategy
Electronic searches were performed on PubMed and Cochrane databases with no limits
placed on dates. Search terms included natural history, thoracic aortic aneurysms,
aneurysm size, risk factors, survival rates, medical therapy, aneurysm growth, dissection,
rupture, and mortality. Search terms were charted to MeSH terms and combined using
Boolean operations, and also used as key words. Papers were selected on the basis
of title and abstract. The reference lists of selected papers were reviewed to identify
any relevant papers that might be suitable for inclusion in the study.
Selection Criteria
Research papers were not excluded based on study design except for case reports. Comments,
opinions, or editorials were not included in our selection, so as to provide an unbiased
view. Papers were selected based on providing primary end points of death, rupture,
or dissection and/or information regarding aortic aneurysm growth. Papers were not
excluded based on patient population age.
Survival
An Overview
There is unarguable evidence that a diagnosis of TAA carries with it a dismal prognosis.
This is well described by Crawford and DeNatale[3], in an observational study of unoperated thoraco-abdominal aneurysm patients published
in 1986. This observation has since been repeated in much larger cohorts that also
include TAAs of the ascending and descending portions of the aorta. This is visibly
demonstrated in [Figure 1], a Kaplan-Meier plot displaying the starkly poor 10-year survival in a group of
170 patients from 1984 to 1993[4], which compares TAAs, thoraco-abdominal aneurysms, and abdominal aortic aneurysms.
Figure 1. Kaplan-Meier cumulative survival displaying the dismal prognosis of unoperated patients
with thoracic aortic aneurysms (TAA), thoraco-abdominal aneurysms (T-AAA), and abdominal
aortic aneurysms (AAA). From Perko et al.[4].
A report of 107 patients with TAAs attending the Mayo Clinic between 1945 and 1955
describes 1- and 5-year survival rates of 87% and 50%, respectively[5]. It is pertinent to consider that these observations were reported more than 5 decades
ago, and advances in conservative management may have improved prognosis, although
even this is currently debated. The advent of large databases, specifically designed
for thoracic aortic aneurysms, has allowed for more recent estimates of survival.
Coady et al.[6] report overall survival in 230 patients at 1 and 5 years from diagnosis to be 85%
and 64% respectively, during the period 1985 to 1996. To date, this database has now
recruited 721 patients and reports that 5-year survival in medically treated patients
is approximately 66%[7].
What are the specific pertinent factors that we need to consider when dealing with
an aortic aneurysm?
Etiology
The prevailing consensus, reflected in the most recent guidelines for thoracic aortic
disease, cites medial degeneration as the primary causative factor for the majority
of TAAs[8]. Historically, atherosclerosis was credited as the main cause for aortic aneurysms,
which was based on findings from postmortem examinations[9]
[10]. Although atherosclerotic lesions are commonly associated with thoracic aneurysms,
typically they are preceded by medial degeneration[1]. In the past, the majority of cases could be attributed to syphilitic infection;
however, with the modern era of screening and antibiotics, this is now a rarity.
Classically, Marfan syndrome has been the most extensively studied connective tissue
disorder in relation to thoracic aortic disease. It is well documented that approximately
50-80% of these patients will develop aortic dilation. Because of this predictable
progression, Marfan syndrome has been used to extrapolate clinical findings and practice
to TAA of different etiologies[2]
[11]. Recently, these observations have been challenged, in part due to the obvious differences
in etiology and varied clinical findings; it is now realized that substantial variation
exists among aneurysms of different etiologies. Because patients with Marfan syndrome
and other genetic diseases related to TAA often exhibit symptoms earlier in their
course, this has allowed for study of the natural history in those disease groups.
Because of this, earlier surgical intervention is advocated for Marfan's disease and
other genetic syndromes compared to TAA of other etiologies, as aneurysms in these
patients tend to rupture or dissect earlier[12].
Coady et al.[13] have reported an extensive database of approximately 1200 patients who were diagnosed
with TAA in Connecticut. Their analysis of this database identified 21% of this cohort
who had a first degree relative with known or likely aortic aneurysm, in the absence
of a known connective tissue syndrome (affecting multiple organ systems). Among these
familial patients, an autosomal dominant pattern of inheritance, with incomplete penetrance,
was displayed. The Yale group notes that the actual percentage of inheritance is likely
to be higher, as these results were based on family interview and are subject to bias
due to nonimaged family members.
In the absence of connective tissue disease syndrome, current evidence points toward
a strong inherited genetic phenotype of accelerated medial degeneration as the primary
culprit for TAA. However, there are many risk factors that contribute to formation
of a TAA. Therefore, the likelihood that this is a multifactorial disease is the consensus
of most papers.
Size of Aneurysm
TAA size is currently utilized as the primary marker for surgical indication in asymptomatic
patients. The Yale group was among the first to provide evidence-based data supporting
aortic size as a predictor of rupture and mortality[6]. Their initial work encompassed clinical and radiological data of 370 patients with
TAAs from 1985 to 1997. This produced a striking graph depicting how survival significantly
decreases over time with increasing aortic aneurysm diameter ([Fig. 2]). Please note that small aneurysms take years to produce mortality: this is a virulent
but indolent disease. Furthermore, the incidence of rupture and dissection as a function
of initial aneurysm size increases with greater aneurysm diameter ([Fig. 3]). Statistical analysis reveals odds of rupture or dissection to be 8.84 times greater
for an aneurysm of 6-6.9 than that of an aneurysm of 4.0-4.9 cm. Critically, this
paper demonstrates how aneurysm size significantly relates to probability of rupture,
dissection, and death. These data have since been the foundation of current recommended
guidelines for surgical intervention based on size, and these evidence-based paradigms
are used internationally[8].
Figure 2. Kaplan-Meier cumulative survival for 5-year survival in TAAs of varying size between
4 and 6 cm. From Coady et al.[6].
Figure 3. Cumulative incidence of rupture and/or dissection displayed as a function of initial
aortic size. From Davies et al.[7].
Other groups as well have published results pertaining to aneurysm size, morbidity,
and mortality which show similar results, strengthening the evidence in favor of using
size as a predictor of rupture or dissection[4]
[5]. Perko et al.[4] report a 5-fold increase in cumulative hazard of rupture in aneurysms greater than
6 cm compared to those below this threshold, and a 66% probability of rupture. Further
analysis of size, from the Yale group, reveals a statistically significant increase
in the incidence of rupture, mortality, and dissection with increasing size[14].
Certainly, there is powerful evidence that initial measured aortic size accurately
predicts prognosis with regard to mortality, rupture, and dissection. Furthermore,
documented analysis shows these risks increase with increasing aortic size, and maximal
risk is realized in aneurysms > 6 cm. Analysis from the Yale database in 2002, that
includes data prospectively collected from 1600 patients, demonstrates that even in
aneurysms categorized to the smallest diameter (3.5 cm-3.9 cm) have a yearly risk
of rupture, dissection, or death of 7.2% (see [Fig. 7])[15], the majority representing dissection rather than rupture. Rupture is reported at
a 0% rate in aortic sizes of 3.5-4.0 cm[15].
However, size as a model of prediction of the natural history is not perfect. It could
be argued that information derived from large groups and data sets do not accurately
predict the behavior of the individual patients. The ideal would be a move toward
a personalized medical model, however to achieve this, the complete understanding
of the natural history of the disease is a necessity.
Location
The thoracic aorta is a complicated structure that has been shown in mechanical ex
vivo modeling to display different characteristics on both a macroscopic and microscopic
level in different anatomical locations along the aorta[16]
[17]. Clinically, aneurysms located in the ascending, descending, and thoraco-abdominal
aorta vary in terms of prevalence, management, and prognosis. Elefteriades and Farkas[2] differentiate two different diseases, separated at the ligamentum arteriosum. Ascending
aortic aneurysms are rarely calcified, almost never contain thrombus, and are not
as strongly correlated with traditional arteriosclerotic risk factors. On the other
hand, descending and thoraco-abdominal aneurysms are almost invariably calcified,
contain generous thrombus, and correlate well with traditional arteriosclerotic risk
factors.
It is recognized that descending aneurysms are less prevalent than ascending aneurysms,
but are associated with a poorer prognosis, starkly demonstrated in [Figure 4]
[6]. The Yale group report 5-year survival in ascending and descending aneurysms as
77% and 39% respectively, in a cohort of 153 patients. In this study the prevalence
of ascending and descending aortic aneurysms was 64% and 24%, respectively. Other
groups report similar figures and a similar difference in survival among ascending
and descending aortic aneurysms[18]. The postulated reasons why descending aneurysms are more deadly than ascending
aneurysms are speculative and not conclusively proven.
Figure 4. Kaplan-Meier cumulative survival displaying 5-year survival for patient suffering
from ascending and descending thoracic aortic aneurysms. From Coady et al.[6].
A further critical observation of aneurysm location regards the mean aortic diameter
for rupture. Coady et al.[6] report significantly different probabilities in the complications from aneurysms
with similar aortic sizes in the ascending and descending aorta. They describe these
sizes for which the risk dramatically increases as “hinge points,” which are 6 cm
and 7 cm in the ascending and descending aorta, respectively ([Fig. 5A] and [5B]). This observation has influenced recent aortic aneurysm surgical guidelines insofar
as it is recommended to operate on ascending and descending aneurysms at different
sizes[8].
Figure 5. The percentage risk of complications for (A) ascending and (B) descending aortic
aneurysms according to aneurysm size. From Coady et al.[6].
Thus, location of an aortic aneurysm plays a decisive role in the natural history
of the disease. There is a significant difference in the prognosis of ascending and
descending aortic aneurysms. Furthermore, the ascending aorta has a susceptibility
to rupture at smaller diameters in comparison to the descending aorta. However, it
is pertinent to consider aortic arch involvement, which has not yet been discussed.
Involvement of the arch is not uncommon in TAA disease, and considering its added
complexity, it is natural to question whether aortic arch involvement can influence
the natural history of the disease. This is a question that has not been thoroughly
investigated, and our future research will address this.
Dissection
The presence of an aortic dissection negatively impacts prognosis in TAAs, as demonstrated
in the Kaplan-Meier survival curves reported by Coady et al. ([Fig. 6])[6]. Dissection can present itself in either an acute or chronic fashion, and also in
two locations (ascending and descending): these distinctions all herald different
prognoses. The International Registry of Acute Aortic Dissection (IRAD) is able to
provide insight into these differences. Acute Type A dissections incurred an in-hospital
mortality, in those not surgically treated, of 58%. Acute Type B dissection medically
managed yielded an in-hospital mortality of 10.7%[19]. Chronic dissections have not been thoroughly researched, but evidence suggests
that chronic dissections are quite vulnerable to progression, via additional dissection,
enlargement, and aneurysmal dilatation, rupture, and death[20]
[21]
[22]
[23]. Future clinical investigation from our center will examine chronic behavior of
the dissected aorta more fully.
Figure 6. Kaplan-Meier cumulative survival demonstrating 5-year survival in TAA patients with
or without a dissection present[6].
In the context of aortic size, dissection holds an interesting position. It is true
that an aortic size greater than 6.0 cm carries a much greater risk of dissection
than diameters below that level. However, unlike rupture, which positively correlates
with increasing aortic size, dissection does not hold entirely true in this concept.
In fact, Elefteriades and Farkas[2] observed a 2.2% yearly risk for dissection in aneurysms between 3.5 and 4.0 cm,
which only increased to 3.6% in those greater than 6 cm ([Fig. 7]). It is well known that, on occasion, dissection can indeed occur at small sizes.
Figure 7. Cumulative risk of rupture, dissection, or death graphically represented as a function
of initial aortic size. From Elefteriades et al.[15].
Trimarchi et al.[24] used the IRAD database to look at 613 patients with acute Type B aortic dissections
between 1996 and 2009. In this study the mean aortic size at time of dissection was
4.1 cm and, furthermore, only 18.4% of patients in this cohort had an aortic diameter
equal to or greater than 5.5 cm, the current recommended surgical intervention size.
However, the study reports a mortality rate of 6.6% and 23.0% in aortic diameters
less than 5.5 cm and greater than 5.5 cm, respectively (P < 0.001). This paper further demonstrates that risk of dissection is not entirely
dependent on aneurysm size. However, the IRAD study had no information regarding the
denominator of patients at risk with small aneurysm. Because of the bell-curve distribution
of aortic size, many millions of patients have aortas in the 4- to 5-cm range, so
that the actual likelihood of dissection is indeed small[2]. Thus, the IRAD study recommended no change from current intervention criteria.
Interestingly, a report of 100 consecutive acute descending aortic dissections, presenting
between 1988 and 1998, revealed the mean aortic size at the time of dissection to
be 5.05 cm[25].
Growth Rate
TAA growth rate is an important factor to consider in the natural history of the disease.
[Figure 3] demonstrates that with increasing aortic size, the risk of rupture, dissection,
or death is increased. Accurate predictions of aneurysm growth would significantly
add to the surgeon's armamentarium to predict the opportune time for surgical intervention.
Such ability would enhance decision making, which is currently based on current indications
of aneurysm size[8].
Calculation of growth rate exhibits controversy in the aortic world[26]. In particular, many studies ignore the fact that measurements vary about a mean,
and that specific aortic measurements may be lower than a prior measurement in the same patient. To discard such measurements leads
to an erroneously high calculated rate of growth. Accordingly, some experts argue
that such measurements should not be discarded. Such issues contribute to the much
varied reported aneurysm growth rates in different centers[2]
[26].
Bonser et al.[10] described a mean aneurysm expansion rate of 1.43 mm/yr. This expansion rate was
significantly different by anatomical location of the aneurysm and aneurysm size.
The ascending aorta experienced the lowest expansion rate, with the highest rate of
expansion observed in the midportion of the descending aorta. In all segments, increasing
aortic size was associated with increasing rate of aneurysm expansion. Aneurysm growth
was not affected by the presence of a dissection in this study. Hirose et al.[27], in Japan, observed in a case series of 82 TAAs that aneurysms of the arch grew
at a faster rate than at any other location (0.56 cm/yr, n = 34).
Other quoted rates of aneurysm growth vary between 0.07 and 2.0 cm per year, but on
average are about 1 mm per year[6]
[10]
[26]
[28]. TAA growth rate is often described as indolent, and thus it is recommended that
asymptomatic TAAs that have yet to reach the appropriate size for intervention be
imaged yearly (or even less frequently). However, it is generally accepted that rapid
expansion of TAAs is a criterion for surgical intervention. Clinical practice tells
us that these patients are likely to suffer an acute aortic dissection or rupture,
although documented evidence supporting this is limited[1]
[29].
Risk Factors
There is increasing recognition that numerous modifiable and nonmodifiable risk factors
contribute, not only to the development of TAAs, but also to the risk of rupture of
established TAAs, as well as to the rate of growth of an aneurysm. Bonser et al.[10] evaluated 87 TAA patients who underwent serial imaging at their clinic. Univariate
analysis revealed that the presence of thrombus, transient ischemic attack (TIA)/stroke,
smoking, or peripheral vascular diseases were all factors that statistically accelerated
aneurysm growth. The median difference of expansion varies from 0.82 to 2.10 mm/yr
according to risk factors, with TIA/stroke causing the greatest increase in growth.
Further analysis in this study reveals factors that have no effect on aneurysm growth,
including sex, dissection, calcification, β-blockers, ischemic heart disease, or hypertension.
It is interesting to see that β-blockade and hypertension have no effect on aneurysm
growth, although this should be interpreted with caution due to the small number of
patients. It should be noted that this study looks at aneurysm growth but does not
assess risk of rupture or death. The study begs the question: does rupture occur earlier
in patients when these risk factors are present?
Large-scale prospective controlled trials, specifically designed to assess impact
of risk factors on aneurysmal growth, have not been performed. Hypertension prevails
as a modifiable risk factor that can be stringently controlled in TAA patients[8]. This stems mainly from work with Marfan patients, where β-blockade and angiotensin
receptor blockade significantly reduce the rate of aortic dilation[30]
[31]. Although studies prospectively analyzing smoking and TAAs have not been performed,
it is reasonable to advise smoking cessation because of its significant links with
hypertension and atherosclerosis.
Statin use was recently evaluated by the Yale group[32], who examined 649 patients, among whom 147 were taking statins at first presentation,
compared to 502 who were not. Analysis revealed a statistically significant improved
freedom from death, rupture, or dissection in patients taking statins compared to
those who were not, depicted in [Figure 8].
Figure 8. Kaplan-Meier survival demonstrating survival free of death, rupture, dissection,
or operative repair in TAA patients who were prescribed a statin and those who were
not. From Jovin et al.[32].
What's on Medical Management?
Medical management in TAAs is the mainstay treatment in asymptomatic aneurysms that
do not reach the required size for surgical intervention. The main objectives of medical
management are to reduce aneurysm growth, risk of rupture or dissection, and ultimately
death. Thus, medical management can play a pivotal role in modifying the natural history
of TAAs. There is good evidence to show that statin therapy does not increase risk
of growth, but rather significantly reduces risk in the long term ([Fig. 8])[32].
β-Blocker therapy enjoys its position as the drug of choice in the medical management
of TAAs. The evidence underpinning this stems from studies of Marfan patients and
mechanical modeling of the aorta in relation to blood pressure. However, recently,
it has become increasingly recognized that this evidence is not applicable to the
majority of TAAs that are degenerative in origin. Currently, no randomized controlled
trials exist assessing this, which is understandable considering the lethality of
the disease; ethically, it would be challenging to conduct such a trial. However,
a recent meta-analysis of β-blocker therapy in TAAs of Marfan patients concluded that
there was no clinical benefit[33]. The study included 802 patients over 6 studies; however, it lacked high-quality
randomized trials in its analysis, reducing the power of the results. Bonser et al.[10] describe β-blocker therapy and hypertension to have no significant effect on aneurysm
growth. Again, this must be interpreted carefully, considering that in their study,
only a small group of patients were not taking β-blockers, and of these, all were
having their blood pressure controlled with other medications.
β-Blocker trials in TAA are limited, and currently, the aneurysm world can only glimpse
the potential benefits of β-blockers by assessing clinical outcomes of patients who
are unable to take β-blockers due to adverse effects. Genoni et al.[34] retrospectively evaluated 71 patients with medically treated chronic Type B aortic
dissection, and of these, 51 were prescribed β-blockers, and the remaining 20 were
prescribed other antihypertensives. In this study, freedom from subsequent aortic
operation was 80% and 47% in those prescribed β-blockers and those prescribed other
antihypertensives, respectively (P < 0.001); the study also found that aortic aneurysm growth was significantly reduced
in the β-blocker therapy group.
