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Epidemiology, risk factors, pathogenesis, and natural history of thoracic aortic aneurysm

Authors: James H Black, III, MD, Christina L Greene, MD, Y Joseph Woo, MD
Section Editors: James Hoekstra, MD, Gabriel S Aldea, MD, Edward Verrier, MD
Deputy Editor: Kathryn A Collins, MD, PhD, FACS

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Jun 07, 2018.

INTRODUCTION — It is important to have a working knowledge of the risk factors, pathophysiology, and natural history of thoracic aortic aneurysm
(TAA) to aid with clinical decision making. Most thoracic aortic aneurysms (TAAs) identified in patients over age 65 years are degenerative and share
many of the same risk factors as abdominal aortic aneurysm (AAA); inflammatory disorders such as giant cell arteritis are also associated with TAA,
primarily in this age group. TAA identified in patients younger than 65 years is more often associated with a genetic predisposition that can be familial
or related to defined genetic disorders such as Marfan syndrome. Approximately 25 percent of patients with thoracic aortic aneurysm (TAA) will also
be found to have an AAA [1-3].

The natural history of TAA is one of slow expansion with a progressive increase in the risk of aortic dissection at larger aortic sizes. The rate of aortic
expansion depends upon aneurysm etiology, diameter, and location. Expansion rates for TAA are generally less than those of AAA. In addition, the
generally slow expansion of TAA means that most patients with TAA are asymptomatic and many patients will succumb to other disease processes
without being aware that TAA is present. Aneurysms that do produce symptoms are typically very large and at risk for rupture, which is associated
with high rates of morbidity and mortality.

This topic will review the etiology, risk factors, pathogenesis, and natural history of true thoracic aortic aneurysm. The clinical features, diagnosis,
and management of thoracic aortic aneurysm, including surgical and endovascular repair, are discussed elsewhere. (See "Clinical manifestations
and diagnosis of thoracic aortic aneurysm" and "Management of thoracic aortic aneurysm in adults" and "Overview of open surgical repair of the
thoracic aorta" and "Endovascular repair of the thoracic aorta".)

DEFINITION AND CLASSIFICATION — A true aneurysm is defined as a segmental, full-thickness dilation of a blood vessel having at least a 50
percent increase in diameter compared with the expected normal diameter [4-6]. The normal diameter of the thoracic aorta varies with location and
age. Normal average diameters are discussed separately. (See "Clinical manifestations and diagnosis of thoracic aortic aneurysm", section on
'Definition of TAA'.)

Pseudoaneurysm (false aneurysm) represents a collection of blood and connective tissue outside the aortic wall, which in the thoracic aorta can
result from a contained aortic rupture or from a variety of pathologic processes such as penetrating aortic ulcer, aortic dissection, trauma, or other
acute aortic syndromes. These disorders are discussed elsewhere. (See "Overview of acute aortic dissection and other acute aortic syndromes" and
"Clinical features and diagnosis of blunt thoracic aortic injury" and "Overview of acute aortic dissection and other acute aortic syndromes", section on
'Definition and pathophysiology'.)

Thoracic aortic aneurysms are classified by location within the aorta (ascending aorta, aortic arch, descending aorta), extent of aortic involvement,
and morphology [5]. These categories help to stratify the approach to management. (See "Clinical manifestations and diagnosis of thoracic aortic
aneurysm", section on 'Classification' and "Management of thoracic aortic aneurysm in adults".)

EPIDEMIOLOGY — It is difficult to assess the prevalence and incidence of thoracic aortic aneurysm (TAA) because TAA is a clinically silent disease.
Fatalities due to TAA complications (rupture, dissection) are likely to be attributed to other causes, such as acute myocardial infarction, in those who
do not undergo postmortem examination [5]. One population study that used chest computed tomography to screen for other conditions estimated
the prevalence of asymptomatic TAA at 0.16 percent [7]. Another study that sought to better define what constitutes a "normal" aorta found a
prevalence of 0.34 percent [8]. However, these studies likely underestimate the prevalence of asymptomatic TAA in the general population since TAA
was defined as aortic diameter >5 cm; thus, TAAs between 4 and 5 cm were not included.

In two separate studies, the annual incidence of TAA was estimated to be 5.6 and 10.4 cases per 100,000 patient-years [3,9]. The incidence of TAA
appears to be increasing, though it is difficult to determine if this is related to increased detection through imaging or a true increase possibly related
to the aging population [10]. In studies performed where the population is stable and postmortem examinations are performed routinely, there
appears to be a real increase in the incidence of TAA over the past several decades [9-12]. The incidence of ruptured TAA also appears to be
increasing [13].

Thoracic aneurysms occur most commonly in the sixth and seventh decade of life and affect males approximately two to four times more commonly
than females.

ETIOLOGY AND RISK FACTORS — Most thoracic aortic aneurysms (TAAs) are degenerative (also termed sporadic) and occur in association with
risk factors for atherosclerosis. On occasion, a broad group of disorders classified under aortitis can also cause TAA in response to a systemic
autoimmune process [14,15]. TAA may also be acquired as a result of aortic infection.

TAA frequently occurs as a manifestation of known connective tissue disorders such as the Marfan, Loeys-Dietz, or Ehlers-Danlos syndromes
(syndromic TAA). However, it has been estimated that as many as one-fifth of patients with a TAA have a family history of aneurysmal disease
independent of known genetic syndromes (ie, nonsyndromic TAA) [16].

At risk for atherosclerosis — The majority of thoracic aortic aneurysms are degenerative and occur in association with risk factors for
atherosclerosis such as smoking, hypertension, and hypercholesterolemia [17,18]; however, it remains unclear what role atherosclerosis plays in
aneurysm formation [18,19]. (See 'Pathogenesis' below.)

Hypertension is an important risk factor that is present in over 60 percent of patients with TAA [3]. In the Hypertension Genetic Epidemiology
Network (HyperGEN) study, the estimated prevalence of aortic root dilation was 4.6 percent and was not significantly different between those with or
without hypertension; however, most patients with hypertension were receiving antihypertensive therapy [9,20].

Although diabetes is associated with atherosclerosis, similar to abdominal aortic aneurysm, diabetes is negatively correlated with TAA [21].

Presence of other aneurysms — Aneurysms of the large arteries are diagnosed in up to 13 percent of patients with TAA; approximately 20 to 25
percent of patients with a large thoracic aortic aneurysm also have an abdominal aortic aneurysm (AAA) [1-3]. Conversely, in patients with known
AAA, a study of 1305 patients found a high prevalence of dilatation/aneurysm of the ascending aorta and the aortic arch evaluated by transthoracic
echocardiography [22]. Using sex-specific criteria for aneurysm, 4 percent of the patients being evaluated prior to AAA repair had an ascending
aortic aneurysm and 6.5 percent had an aortic arch aneurysm. Furthermore, 2 percent of men had an ascending aortic aneurysm compared with
25.8 percent of the women, and 6.6 percent of men had an aortic arch aneurysm compared with 10.5 percent of the women. This study excluded
patients with other risk factors for the development of ascending TAA such as bicuspid aortic valve, previous aortic surgery, and other genetic
syndromes. (See "Clinical features and diagnosis of abdominal aortic aneurysm".)

Thoracic aneurysm and cerebral aneurysms can also coexist [23-25]. One radiologic study of 212 patients with a TAA who had undergone
concurrent brain imaging for clinical reasons found intracranial aneurysms in 9 percent of patients, with a higher prevalence of cerebral aneurysm in
patients with a descending versus ascending TAA [23]. Patients with bicuspid aortic valve, a known risk factor for TAA, have an increased risk for
developing intracranial aneurysm compared with the normal population [25]. Screening for brain aneurysm is also generally recommended in
patients with nonsyndromic familial TAA. (See "Screening for intracranial aneurysm" and "Management of thoracic aortic aneurysm in adults", section
on 'Identifying associated aneurysm'.)

Prior aortic dissection — Acute aortic dissection often involves the ascending and descending thoracic aorta. For patients who do not require
immediate operation and survive an acute aortic dissection, aneurysmal degeneration leading to progressive aortic expansion and late aortic rupture
can occur [26]. Although not a true aneurysm because the aortic wall is not full thickness in the dissected segment, this condition is frequently
referred to as a "dissecting aneurysm" or "aneurysmal dissection." Predictors of these complications include male gender, age of <60 years, type B
aortic dissection, Marfan syndrome, an initial postoperative aortic diameter of ≥40 mm, the presence of blood in the false lumen, a large false lumen,
the size and location of the intimal tear, elevated systolic blood pressure, and elevated pulse pressure [27]. (See "Clinical features and diagnosis of
acute aortic dissection".)

Chest trauma — Chest trauma is more likely to lead to a pseudoaneurysm of the descending thoracic aorta at the aortic isthmus due to deceleration
forces rather than a true full-thickness aneurysm. Blunt aortic injury is discussed in detail elsewhere. (See "Clinical features and diagnosis of blunt
thoracic aortic injury", section on 'Mechanism of injury' and "Clinical features and diagnosis of blunt thoracic aortic injury", section on 'Aortic injury
grading'.)

Aortitis — Aortitis refers to inflammation of the aortic wall, which can be due to infectious or inflammatory etiologies. Aortitis as a cause of TAA is
overall rare.

Infectious — Infection of the thoracic aorta leading to aneurysm is most commonly due to septic embolism, but direct bacterial inoculation,
bacteremic seeding, and contiguous infection can also occur. The infection weakens the constituents of the aortic wall, leading to rapid aneurysm
formation. The etiology and clinical features of infected aneurysms are reviewed separately. (See "Overview of infected (mycotic) arterial aneurysm".)

Inflammatory disorders — A broad group of inflammatory disorders are associated with the development of TAA, including giant cell arteritis,
Takayasu arteritis, rheumatoid arthritis, ankylosing spondylitis, Wegener's granulomatosis, reactive arthritis, and Behcet syndrome.

Giant cell arteritis is the most common inflammatory disorder leading to TAA formation. Thoracic aortic disease manifesting as thoracic aortic
aneurysm or aortic dissection will develop in as many as 11 percent of patients with giant cell arteritis [28]. TAA is usually a late manifestation
occurring in patients who had been previously treated a number of years [29]. The initial clue to the diagnosis may be based on pathologic review of
the explanted aortic tissue. (See "Clinical manifestations of giant cell arteritis", section on 'Large vessel GCA'.)

In one prospective study, among 788 patients requiring surgery for thoracic aortic disease (aneurysm or dissection), 39 (4.9 percent) were due to
histologically proven aortitis [30]. The distribution of etiologies in the patients with an inflammatory cause was as follows:

● Takayasu/giant cell aortitis (n = 31)

● Inflammatory aneurysm (n = 3)

● Nonspecific lymphoplasmacellular aortitis (n = 2)

● Systemic lupus erythematosus aortitis (n = 1)

● Behcet disease (n = 1)

In a separate review of pathology specimens from 684 patients who underwent surgical repair of ascending thoracic aortic aneurysm, aortitis was
identified in 47 (6.9 percent) [31]. Among these, 32 of the cases of aortitis were deemed idiopathic. Aortic aneurysms associated with idiopathic
aortitis are reported to be limited to the thoracic aorta in >90 percent of patients [31-33].

Genetic predisposition — Genetic defects that lead to abnormalities in connective tissue metabolism predispose to thoracic aortic aneurysm and
dissection (TAAD) [34-39]. Genetically mediated TAA accounts for approximately 5 percent of TAAs. Approximately 20 percent of patients with a
TAAD have a family history of aneurysmal disease that is independent of any known genetic tissue syndrome (nonsyndromic TAAD) [16]. A strong
personal or family history of dissection or aneurysm in young (<50 years old) individual may be an indication for genetic testing for inherited
aortopathy [40]. (See "Management of thoracic aortic aneurysm in adults", section on 'Identifying associated genetic conditions'.)
 Syndromic connective tissue disorders — Genetic syndromes (syndromic TAAD), such as Marfan syndrome, vascular Ehlers Danlos
syndrome, Loeys-Dietz syndrome, and Turner syndrome, have more aggressive rates of aortic expansion and are more likely than sporadic TAA to
require intervention. Furthermore, if a patient with an underlying connective tissue disorder undergoes intervention for a type A aortic dissection as
his/her index aortic operation, those portions of the aorta with residual chronic dissection in the more distal aorta are at very high risk for
degeneration to thoracoabdominal aortic aneurysm and must undergo postoperative surveillance. (See "Overview of open surgical repair of the
thoracic aorta", section on 'Follow-up imaging'.)

Marfan syndrome — The Marfan syndrome is associated with mutations in the FBN-1 gene. The aneurysm in Marfan syndrome is typically
located in the aortic root but may extend to the ascending aorta. These aneurysms are associated with accelerated expansion compared with
degenerative aneurysms and a high risk of aortic complications at a relatively young age [5,41-43]. Aortic root dilatation, aortic regurgitation, and
aortic dissection are the main causes of morbidity and mortality in patients with Marfan syndrome [44]. Marfan syndrome is discussed in detail
elsewhere. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders" and "Pregnancy and Marfan syndrome" and
"Management of Marfan syndrome and related disorders".)

Ehlers-Danlos syndrome — Ehlers-Danlos syndrome is a group of conditions due to defects in type III procollagen that cause hyperelasticity
and fragility of the skin and hypermobility of the joints. Most types of Ehlers-Danlos are not associated with aortic dilation, although mild mitral valve
prolapse is often present. However, in the vascular type (previously Type IV) Ehlers-Danlos syndrome, vascular and connective tissue integrity is
markedly impaired and spontaneous rupture of large and medium-sized arteries can occur [45]. (See "Joint hypermobility syndrome", section on
'Ehlers-Danlos syndrome'.)

Loeys-Dietz syndrome — Loeys-Dietz syndrome is an autosomal dominant condition due to mutations in transforming growth factor beta
receptor gene (TGFBR1, TGFBR2) [46]. Patients with Loeys-Dietz syndrome have some clinical features in common with patients with Marfan
syndrome and are also at high risk for aortic or other vascular dilation, rupture, or dissection at a young age [5,47]. (See "Genetics, clinical features,
and diagnosis of Marfan syndrome and related disorders", section on 'Spectrum of phenotypes and differential diagnosis' and "Management of
thoracic aortic aneurysm in adults".)

Turner syndrome — Turner syndrome is a gonadal dysgenesis syndrome characterized by a 45X female with ovarian failure and characteristic
features such as a webbed neck, short stature, and low-set ears. Congenital heart defects, diabetes, and hypothyroidism are also associated with
the syndrome. Approximately 10 to 25 percent of patients have bicuspid aortic valves, 8 percent will have coarctation, and approximately 33 percent
will have aortic dilatation. Most Turner syndrome patients who develop aortic dissection have bicuspid valves, coarctation, or risk factors like
hypertension. Although Turner syndrome patients have an increased risk of aortic dissection compared with the normal population, this risk is viewed
to be much lower compared with Marfan syndrome or Loeys-Dietz syndrome [48,49]. (See "Clinical manifestations and diagnosis of Turner
syndrome".)

Nonsyndromic disorders — Patients who have thoracic aortic disease but who do not meet strict criteria for known connective tissue syndromes
are grouped as nonsyndromic. The most common of these is likely familial thoracic aortic aneurysm and dissection, for which clinical studies have
found a strong genetic component [16,50]. Genetically mediated conditions present at birth can also predispose to thoracic aortic aneurysm later in
life, such as bicuspid aortic valve [51-54]. (See "Clinical manifestations and diagnosis of coarctation of the aorta" and "Clinical manifestations and
diagnosis of Turner syndrome", section on 'Cardiovascular disease'.)

Familial TAAD — Familial thoracic aortic aneurysm and dissection (TAAD) refers to patients who have thoracic aortic disease associated with
a family history of aneurysmal disease but who do not meet strict criteria for known connective tissue syndromes. Familial TAAD is increasingly
being recognized and can include patients with a dilated aorta or aneurysm affecting other vessels, and a family history of dissection, rupture, or
sudden unexplained death. The ascending thoracic aorta is involved in approximately 80 percent and the descending aorta is affected in the
remaining 20 percent [15]. Patients with familial TAAD generally present at an earlier age (56.8 years) compared with patients with sporadic TAA (57
versus 64 years in one study) and also have faster rates of aortic expansion [16]. (See 'Natural history' below and "Management of thoracic aortic
aneurysm in adults", section on 'Diameter criteria'.)

Studies of the family trees of patients with isolated TAA or dissection have found that 21 percent of proband have at least one family member with a
known arterial aneurysm [16,50]. The rate of inheritance may be higher, since many family members may not be aware that an aneurysm is present.
Approximately 80 percent of familial TAAs appear to be inherited in an autosomal-dominant manner, but other genetic patterns are also expressed
[16,50]. The variable penetrance and expression of the genetic mutations make obtaining a definitive diagnosis difficult [37,38]. Mutations in the
transforming growth factor beta receptor 2 gene (TGFBR2) may be responsible for approximately 5 percent of familial cases [36,55,56]. Other
mutations include ACTA2 and MYH11 [5]. ACTA2 may account for up to 14 percent of genetic mutations associated with familial syndromes. Each
year, new gene mutations are identified in families with familial TAAD. It is therefore suggested that patients with familial TAAD without an identified
gene mutation be reassessed by a genetic specialist periodically.

The location of the TAA in the proband closely mirrors aneurysm location in family members [50], supporting the notion that the etiology of
aneurysmal disease is differentiated proximal and distal to the ligamentum arteriosum. Disease proximal to the ligament is predominantly
nonatherosclerotic in nature, whereas disease distal to it is strongly associated with atherosclerosis [10].

Bicuspid aortic valve — There is an association between bicuspid aortic valve, which is the most commonly recognized congenital
abnormality in adulthood, and thoracic aortic aneurysm [57,58]. Approximately 25 percent of patients with a bicuspid aortic valve required an
intervention to treat abnormalities of the aortic valve, aorta, or both during their lifetime. A heritable tendency, likely autosomal dominant, is supported
by family studies that have identified features of aortopathy in otherwise normal (ie, three-leaflet valve) first-degree relatives of patients with bicuspid
aortic valves [5,59,60]. The reported prevalence of dilation of the ascending aorta among persons with a bicuspid aortic valve ranges from 20 to 84
percent [57]. In a study of young men with normally functioning bicuspid aortic valves, enlargement of the aortic root and/or ascending aorta was
noted in 52 percent; this finding was independent of hemodynamic abnormalities, age, or body size [61]. The risk of aortic dissection in patients with
a bicuspid valve is also higher than in the general population. In a cohort of 416 bicuspid aortic valve patients in Olmsted county, Minnesota, aortic
dissection occurred in 2 of 416 patients over a mean follow-up of 16 years (6530 patient-years), corresponding to an incidence of 3.1 (95% CI 0.5-
9.5) cases per 10,000 patient-years (age-adjusted relative risk of 8.4; 95% CI 2.1-33.5) [62]. (See "Clinical manifestations and diagnosis of bicuspid
aortic valve in adults", section on 'Associated cardiovascular lesions'.)

Aneurysm-osteoarthritis syndrome — Aneurysm osteoarthritis syndrome, caused by pathogenic variants of "mothers against
decapentaplegic homolog 3" (SMAD3), is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity that
may occur in combination with early-onset osteoarthritis [63,64]. Aneurysms are most frequently localized to the aortic root but can be found
throughout the arterial tree, including the iliac, visceral, and intracranial arteries [64]. In one review of 38 patients, 71 percent had aortic root dilation
[65].

PATHOGENESIS — Aortic disease distal to the ligamentum arteriosum is predominantly strongly associated with atherosclerosis, whereas aortic
disease proximal to it is predominately nonatherosclerotic in nature [10]. These differences may be related to the differing embryologic origins of
ascending aorta and descending aorta smooth muscle cells (SMCs), which are responsible for secreting many of the proteolytic factors implicated in
aneurysm formation. The ascending aorta and great vessel SMCs arise from neural crest cells, whereas the descending aorta arises from paraxial
mesoderm [66,67]. The aortic valve arises from the lateral plate mesoderm [66]. Abnormalities of the aortic valve (eg, bicuspid aortic valve) are
highly associated with coarctation of the aorta, suggesting that the abnormal aortic tissue may extend into the distal arch or the proximal descending
aorta [68].

Most thoracic aortic aneurysms (TAAs) are degenerative (ie, sporadic), resulting from alterations in vascular wall biology that lead to loss of structural
integrity and aortic wall strength [17,19,69]. The underlying triggers for degenerative TAA are not known for certain, but similar processes appear to
be responsible for degenerative abdominal aortic aneurysm (AAA). The combination of protein degradation and mechanical factors are thought to
cause medial degeneration, which has the appearance of smooth muscle cell necrosis and elastic fiber degeneration with cystic spaces in the media
filled with mucoid material [70]. Cystic medial degeneration of the aorta occurs normally with aging but is accentuated by hypertension and other
factors.

Most theories emphasize the primary role of breakdown of extracellular matrix proteins (ie, elastin and collagen) by proteases such as elastase,
collagenase, various matrix metalloproteinases (MMPs) [71-73], and plasmin [74]. These proteolytic factors are derived from endothelial and smooth
muscle cells and also from inflammatory cells infiltrating the media and adventitia [74]. The following observations in animal models are consistent
with the importance of plasmin and MMPs in aortic aneurysm formation:

● Blockade of plasmin formation by overexpression of plasminogen activator inhibitor-1 prevents the formation of aneurysms and rupture by
inhibiting metalloproteinase activation [75].

● Aneurysm rupture correlates with an increase in metalloproteinase (gelatinase A and B) levels; local overexpression of tissue inhibitor of matrix
metalloproteinases, produced by retrovirally infected smooth muscle cells, can prevent aneurysmal degeneration and rupture [76].

Familial TAA and TAA associated with genetic syndromes share similar pathogenic pathways with degenerative aneurysms, but with some unique
differences related to the known genetic defects [77-79]. Specifically [77]:

● The ACTA2 gene encodes a protein called smooth muscle alpha (α)-2 actin, which is part of the actin protein family. Deficiency in patients with
familial TAA leads to decreased numbers and disorganization of vascular smooth muscle cells [80].

● The TGFBR1 gene encodes a protein called transforming growth factor-beta (TGF-β) receptor type 1, which transduces signals from the cell
surface into the cell. TGFBR1 gene mutations that cause Loeys-Dietz syndrome change single amino acids in the TGF-β receptor type 1,
resulting in a nonfunctional receptor protein. The signaling pathway is overactive even though the receptor proteins are nonfunctional, which
indicates that other, unknown mechanisms compensate for the lack of receptor activity. This overactivity disrupts connective tissue development.

● The TGFBR2 gene encodes a protein called transforming growth factor-beta (TGF-β) receptor type 2, which transduces signals from the cell
surface into the cell. The pathogenetic mechanism is similar to TGFBR1 as described above. More than 70 mutations in the TGFBR2 gene have
been found to cause the Marfan syndrome and Loeys-Dietz syndrome types. At least two TGFBR2 gene mutations have been identified in
people with familial thoracic aortic aneurysm.

● The FBN1 gene encodes for a large protein called fibrillin-1, which is transported out of cells into the extracellular matrix. More than 1000 FBN1
gene mutations have been identified in Marfan syndrome. Most of these mutations alter a single amino acid in the fibrillin-1 protein, reducing the
amount of fibrillin-1 produced by the cell, altering the structure or stability of fibrillin-1, or impairing the transport of fibrillin-1 out of the cell. These
mutations lead to a severe reduction in the amount of fibrillin-1 available to form microfibrils. Without enough microfibrils, excess TGF-β growth
factors are activated and elasticity in many tissues is decreased, leading to instability of tissues.

NATURAL HISTORY — The natural history of thoracic aortic aneurysm (TAA) is one of slow expansion with an increasing risk of sudden aortic
dissection as the aorta enlarges. Expansion rates range from 0.1 to 1.0 cm per year, depending upon TAA etiology, diameter, and location within the
aorta [10,81-87]. Although rapid expansion can occur in a TAA, most reports of rapid growth usually reflect measurement errors; however, when
rapid expansion is seen, it raises concern for aortic dissection or aortic infection [10].

Expansion — In general, isolated sporadic (ie, degenerative) ascending aortic aneurysms have an average expansion rate of 0.1 cm per year,
whereas descending TAAs expand by approximately 0.3 cm per year [16,88]. Patients with familial TAAs have faster average rates of expansion at
0.2 cm per year (combined ascending and descending TAA) compared with patients with sporadic TAAs [50]. TAA associated with genetic
syndromes can expand more rapidly. Aneurysms associated with bicuspid aortic valve expand up to 0.2 cm per year [57,89,90]. Marfan syndrome is
associated with expansion rates up to 0.3 cm per year. TAAs associated with the particularly aggressive Loeys-Dietz syndrome can expand very
rapidly at up to 1.0 cm per year [47,50]. (See 'Genetic predisposition' above.)

Similar to abdominal aortic aneurysm, larger-diameter TAA expands more rapidly than smaller-diameter TAAs [16]. This was illustrated in a study of
67 patients with thoracic aortic aneurysm who underwent serial computed tomography (CT) imaging [87]. The rate of expansion for aneurysms >5.0
cm in diameter was approximately 0.8 cm per year, but approximately 0.2 cm per year for aneurysms <5.0 cm. A history of hypertension did not
affect the rate of aneurysm expansion. However, these studies are older, and the location and specific etiology of the aneurysm may not have been
taken into account.

The anatomic location of the aneurysm is another factor associated with the rate of expansion. In a series of 87 patients who underwent serial CT or
magnetic resonance (MR) imaging, aneurysms located within the middescending aorta showed the most rapid expansion, while those in the
ascending aorta had the slowest rate, despite having a larger initial diameter [86].

Aneurysm morphology, specifically saccular versus fusiform, is thought to increase expansion rates and rupture risk. Saccular aneurysms are
associated with aortic infection and as such are often treated more aggressively. In a review of 153 saccular aneurysms, 2 were in the ascending
aorta, 23 were in the aortic arch, and 219 were in the descending thoracic aorta [91]. The expansion rate of saccular aneurysms that were
conservatively managed was 0.28 cm±0.29 cm/year. (See "Overview of infected (mycotic) arterial aneurysm".)

Rupture/dissection — The risk of complications of TAA (rupture, dissection) increases with larger aortic diameter. In several series, aneurysm
rupture occurred in 32 to 68 percent of medically treated patients and accounted for 32 to 47 percent of deaths [3,92-95]. The one-, three-, and five-
year survival rates of unoperated thoracic aneurysms were 65, 36, and 20 percent, respectively. Concomitant cardiovascular disease is the second
most common cause of death in these patients.

The most important determinant of rupture is the diameter of the aneurysm and the underlying cause [9,96-101]. Other factors, such as the presence
of acute symptoms, a concomitant bicuspid aortic valve, a connective tissue disease, or a rapidly expanding aortic diameter also increase the risk for
rupture [102].

The annual risk of rupture or dissection is <2 percent for TAAs between 4.0 and 4.9 cm but nearly 7 percent for TAAs >6.0 cm [85]. There is a
significant increase in the risk of rupture or dissection for a diameter greater than 6.0 cm for an ascending TAA and 7.0 cm for a descending TAA
[103]. In another series of 370 patients, the median diameter at the time of rupture or dissection was 5.9 cm for ascending aneurysms and 7.2 cm for
descending aneurysms [97]. One group has shown that the clinical threshold for rupture mirrors the innate physical limits of the aortic wall. As the
aorta approaches 6.0 cm, its distensibility rapidly falls [104]. At this diameter, the aorta loses its natural elasticity and effectively becomes a rigid
tube. At a blood pressure of 200 mmHg, easily achieved through strenuous exercise or emotional distress, the stress generated in the wall of a 6.0-
cm aorta can attain or exceed the maximum tensile strength of aortic tissue [104].

Even though the risk of dissection/rupture increases with aortic diameter, most patients who present with dissection have smaller aneurysms,
probably because many more individuals in the population with thoracic aortic aneurysm have thoracic aortic diameters between 4.0 and 5.5 cm,
which have a low risk for rupture. In a review of 591 patients with type A dissection enrolled in the International Registry of Acute Aortic Dissection
(IRAD), the mean diameter was 5.3 cm. Nearly 60 percent of patients had aortic diameter<5.5 cm, and 40 percent had aortic diameter <5.0 cm [105].

SUMMARY AND RECOMMENDATIONS

● A thoracic aortic aneurysm (TAA) is defined as a permanent localized dilation of the thoracic aorta, having at least a 50 percent increase in
diameter compared with the expected normal diameter for that aortic segment.

● True aneurysms include all three layers of the vessel, including the intima, media, and adventitia. A pseudoaneurysm, or false aneurysm, is a
collection of blood and connective tissue outside the aortic wall, usually the result of a focal rupture.

● Aneurysms of the thoracic aorta are classified by the segment of the aorta that is involved. (See 'Introduction' above.)

● The incidence of TAA is estimated to be 6 to 10 cases per 100,000 patient-years. TAA is more common in men. The majority of TAAs are
degenerative (sporadic) and associated with risk factors similar for atherosclerosis (eg, hypertension, hypercholesterolemia, smoking). TAA is
also associated with inflammatory disorders/vasculitis (eg, giant cell arteritis, mycotic aneurysm, Takayasu's aortitis), bicuspid aortic valve
disease, and genetically triggered connective tissue disorders such as Marfan, Loeys-Dietz, or vascular type Ehlers-Danlos syndromes. There
are also familial associations with thoracic aneurysms, and it has been estimated that as many as 21 percent of patients with a thoracic aortic
aneurysm/dissection have a family history of this disorder independent of those with Marfan syndrome or a bicuspid aortic valve. (See
'Epidemiology' above and 'Etiology and risk factors' above.)

● Most TAAs result from alterations that lead to loss of structural integrity and aortic wall strength. A combination of breakdown of extracellular
matrix proteins and mechanical factors are thought to cause medial degeneration, which occurs normally with aging but is accentuated by
hypertension and other factors. Most theories emphasize the primary role of breakdown of the extracellular matrix proteins elastin and collagen
by proteases such as collagenase, elastase, various matrix metalloproteinases, and plasmin (formed from plasminogen by urokinase
plasminogen activator and tissue type plasminogen activator). Additional pathogenetic mechanisms involving abnormalities in cell signal
processing occur in patients with genetically mediated TAA. (See 'Pathogenesis' above.)

● The natural history of TAA is generally one of slow expansion but with an increasing risk of dissection as aortic size increases. The rate of
increase in aortic diameter ranges from 0.1 to 1.0 cm per year, depending upon TAA etiology, diameter, and location within the aorta. (See
'Natural history' above and "Management of thoracic aortic aneurysm in adults", section on 'Diameter criteria'.)

ACKNOWLEDGMENT — We are saddened by the death of Emile R Mohler, III, MD, who passed away in October 2017. UpToDate wishes to
acknowledge Dr. Mohler's past work as an original contributor for this topic, as well as his work as our Section Editor for Vascular Medicine.

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