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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3616_Библиотеки_им_академика_М_И_Перельмана
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Chapter 10
https://t.me/med1917
Guilt by Association: Paradigm for
Detection of Silent Aortic Aneurysms
Ross Findlay, Oliver Thompson, Bulat A. Ziganshin, John A. Elefteriades
Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT, United States
Chapter Outline
Introduction 107
Intracranial Aneurysm 108
Aortic Arch Anomalies 109
Abdominal Aortic Aneurysm 111
Bicuspid Aortic Valve 111
A Positive Thumb–Palm Sign 112
INTRODUCTION
Family History of Aortic Disease 113
Simple Renal Cysts 115
Giant Cell Arteritis (and Other Autoimmune Disorders) 115
Other Conditions—Ongoing Research 116
References 117
Thoracic aortic aneurysms (TAAs) have been a leading cause of sudden death in developed countries for some time.
Nicknamed the “silent killer,” TAAs grow asymptomatically before producing a devastating complication: aortic dissection
or rupture. Indeed, often, the first symptom of a TAA is death or an aortic complication that threatens to produce death.
Despite their lethal potential, TAAs grow slowly and have a good prognosis if they are repaired before rupture. Early diagnosis is, therefore, essential. Historically, this has been left to chance—a patient has a computer tomography (CT) scan or
echocardiogram for another reason and a dilated aorta is found. This unsatisfactory situation has led clinicians to search for
other method to identify those at risk of harboring a silent TAA.
Recently, the concept of Guilt by Association has been described [1,2]. Guilt by Association refers to a series of seem-
ingly unrelated clinical markers, which all point to thoracic aortic disease:
1. Intracranial aneurysms (ICAs)
2. Aortic arch abnormalities
3. Abdominal aortic aneurysms (AAAs)
4. Bicuspid aortic valve (BAV)
5. Positive thumb–palm sign
6. Family history of thoracic aortic disease
7. Simple renal cysts
8. Giant cell arteritis (GCA)
Research has shown that the presence of one or more of these markers in a patient can indicate the existence of a TAA
(Fig. 10.1). This novel paradigm for diagnosis can predict individuals who harbor or are at risk of developing a TAA and
thus allow early detection and repair [1,2].
The matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of thoracic aortic disease. MMPs
are a family of proteases responsible for cleaving matrix-forming proteins such as collagens, elastin, and gelatin. One such
substrate, collagen type I, constitutes 60% of the aortic wall [3]. An increase in MMP activity results in an excessively proteolytic state, causing a loss of integrity of the extracellular matrix (ECM). This leads to a decrease in aortic wall elasticity and
a corresponding circumferential weakness in the vessel wall, thereby making aneurysm formation and aortic dissection more
likely. High levels of MMPs (specifically MMPs 2 and 9) have been found in the wall of the aneurysmal thoracic aorta [4,5].
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00010-9
Copyright © 2018 Elsevier Inc. All rights reserved.
107
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FIGURE 10.1 Paradigm of “Guilt by Association” for the detection of silent thoracic aortic aneurysms. Modified with permission from Elefteriades
JA, Sang A, Kuzmik G, Hornick M. Guilt by association: paradigm for detecting a silent killer (thoracic aortic aneurysm). Open Heart 2015;2:e000169.
Activity of MMPs is partly counteracted by a family of endogenous protease inhibitors known as tissue inhibitors of
metalloproteinases (TIMPs). TIMPs bind to the C-terminal domain of MMPs and reduce their activity [6].
Although an association between an increase in MMPs and TAAs has been demonstrated [4,5], it is not yet clear
whether MMPs are the driving force behind the macroscopic changes or whether they are released in response to them.
However, MMP inhibitors such as doxycycline have been shown to slow TAA progression [6]. This supports the hypothesis
that MMPs are a driving force behind aortic disease. As we shall see, MMPs are also excessively active in many of the
“guilty associates.”
INTRACRANIAL ANEURYSM
ICAs (Fig. 10.2) vary in size and location; however, they are susceptible to rupture, causing subarachnoid hemorrhage.
Ruptured ICAs and subarachnoid hemorrhage confer a high morbidity and mortality: 1-month mortality is 40%, and many
patients are left with lifelong neurological impairments [7]. The documented associations of ICAs are myriad, including:
hypertension, smoking, connective tissue disorders and family history—similar to the risk factors for development of TAAs
[7–9].
Recently, an association between ICAs and TAAs has been shown; patients with a TAA are nine times more likely to
have a concurrent ICA than the general population [10]. In addition to this, data have been published showing that the converse relationship is also true: patients with an ICA have a 5% likelihood of concomitant TAA [11,12].
The association of intracranial and TAAs is scientifically plausible, as these two conditions are thought to share a common pathogenesis. High levels of MMPs (specifically MMPs 2 and 9) are found in the walls of both ICAs and TAAs [4,5].
The resulting proteolytic state makes aneurysm formation more likely.
Strong additional evidence for the association between TAAs and ICAs is provided by the discovery of a genetic link
between the two diseases. Mutations (following an autosomal dominant pattern of inheritance) in the genes TGFBR1,
TGFBR2, and ACTA2 have been found in families with a strong family history of TAAs and also in those with history of
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(A)
(B)
(C)
FIGURE 10.2 Cerebrovascular images from a patient with a thoracic aortic aneurysm and a concurrent typical intracranial aneurysm (ICA). Arrows
indicate the location of the ICA. (A) Three-dimensional reconstruction (oblique cutaway, view from right). (B) Three-dimensional reconstruction (coronal
cut, anterior view). (C) Computed tomographic angiogram showing 7-mm aneurysm in middle cerebral artery. Reprinted with permission from Kuzmik GA,
Feldman M, Tranquilli M, Rizzo JA, Johnson M, Elefteriades JA. Concurrent intracranial and thoracic aortic aneurysms. Am J Cardiol 2010;105:417–20.
ICAs [13]. It stands to reason that there are likely to be additional yet undiscovered genes, which contribute to both TAA
and ICA development.
It is noteworthy that there seems to be a stronger association between ICAs and descending TAAs than ICAs and
ascending TAAs [10]. Although the clinical significance of this is unclear, it follows that the understanding of ascending
and descending aneurysms are two different diseases, separated at the ligamentum arteriosum (Fig. 10.3).
Due to the high prevalence of TAAs in patients with ICAs, and vice versa, certain centers have started screening for
concurrent disease. It is now common protocol at many centers in the United States for patients to undergo brain imaging
if a TAA repair is planned.
AORTIC ARCH ANOMALIES
There are a multitude of aortic arch variants, the three most important being the bovine aortic arch, isolated left vertebral,
and aberrant right subclavian (Fig. 10.4). The most common (and most studied) variant is the bovine aortic arch, which
can be subdivided into the true bovine arch and the common origin of brachiocephalic and left common carotid arteries.
Interestingly, the term bovine aortic arch is a misnomer because, in cattle, both carotids and both subclavian arteries share
a common brachiocephalic trunk.
All of these variants were initially believed to be benign; however, this is no longer the case. The presence of aortic arch
abnormalities is more common in patients who have a TAA than in the general population [14–16]. Of the three variants,
the strongest association has been shown with patients who have the bovine arch, with one study suggesting that the bovine
variant is up to three times as common in patients with thoracic aortic disease as in the general population [14]. Those with
an abnormal aortic arch also seem to develop thoracic aortic disease in the absence of any other risk factors and, on average,
present 5 years younger than those with a normally branching aorta [14,15].
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Subclavian
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FIGURE 10.3 Aortic aneurysm is really two diseases: ascending/arch disease differs markedly from descending/abdominal disease. Reprinted
with permission from Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol
2010;55:841–57.
44455
4
233 3
11 1
Normal Arch Bovine Arch Isolated Vertebral
FIGURE 10.4 Aortic arch branching patterns: normal branching variant of the aortic arch, bovine aortic arch variant, isolated left vertebral artery variant, and aberrant right subclavian artery. Numbers correspond to the following arteries: 1, brachiocephalic; 2, left common carotid; 3, left subclavian;
4, right common carotid; 5, left vertebral; 6, aberrant right subclavian. Reprinted with permission from Dumfarth J, Chou AS, Ziganshin BA, et al. Atypical
aortic arch branching variants: a novel marker for thoracic aortic disease. J Thorac Cardiovasc Surg 2015;149:1586–92.
2
Aberrant Right
3
6
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To explain why a bovine aortic arch may predispose to thoracic aortic disease, one must first understand the
embryological origins of the aorta. The descending aorta (distal to the ligamentum arteriosum, see Fig. 10.3) is derived
from mesoderm, whereas the aortic arch is derived from migration of neural crest cells to the pharyngeal arches [17].
Further migration and proliferation of cells lead to the formation of the arch arteries, which then connect to the aortic sac. Normally, the aortic sac should bifurcate, forming the brachiocephalic trunk and left common carotid artery.
Failure of the aortic arch to bifurcate or slow migration of the neural crest cells is thought to result in the bovine
variant. In addition to this, the failure of bifurcation and slow migration may lead to a weakened aortic wall, prone to
aneurysms and dissections [18,19]. Although further histological investigation would be needed to prove this, the fact
that ascending and aortic arch aneurysms are more common in patients with a bovine aortic arch provides supporting
evidence [16].
It is important to note that not only does the presence of a bovine aortic arch predispose to thoracic aortic disease, but
also that the aorta dilates at a faster rate in patients with this abnormality [15]. This observation, combined with the absence
of risk factors and early presentation, should signify that individuals with abnormal arches should be considered at high
risk for thoracic aortic disease.
ABDOMINAL AORTIC ANEURYSM
Akin to TAAs, AAAs are another deadly condition with a high natural mortality rate. Extensive research has been carried
out regarding optimum screening programs and surgical intervention criteria for AAA. It has long been understood that
aneurysms in other locations, such as popliteal and femoral aneurysms, are a marker for AAAs [20]. It seems logical, there-
fore, that there could be a link between AAAs and TAAs.
Originally, work performed in 2006 suggested a link between AAAs and TAAs. Although this study investigated the
familial nature of TAAs, an incidental finding was that nearly a quarter of patients with TAAs also had AAAs [21].
Further investigation showed the converse relationship to be true. Numerous studies have reported a high incidence of
TAAs in AAA patients. Consistently, this figure is around 25% [3,22,23]. The true number, however, is likely to be higher
than this because patients with known thoracic aortic disease were excluded from these studies.
Even if the aneurysms are not concurrent, patients who have had an AAA are more likely to develop a TAA in the years
following diagnosis of an AAA [3]. Further risk factors for developing a TAA in patients who have had an AAA include
age and female gender [22]. Therefore, when following-up patients with any aortic disease, the entirety of the aorta should
be imaged.
The association between AAA and thoracic aortic disease is more specific to the descending aorta [23]. This is unsurprising given the fact that the abdominal aorta is more closely related to the descending thoracic aorta than the ascending
thoracic aorta. As alluded in the previous section, the ascending and descending thoracic aortas have distinct embryological origins, with the abdominal aorta sharing its origin with the descending. In fact, the risk factors for descending TAAs
are the same atherosclerotic risk factors (hyperlipidemia, hypertension, and smoking) as for AAAs. Perhaps this is due to
angiotensin II, a vasoactive peptide that is raised in hypertension and is proatherosclerotic. In hyperlipidemic mice models,
it has been shown that angiotensin II causes both abdominal and TAAs [24]. However, further work in humans is needed
before concrete conclusions on this etiologic mechanism can be drawn.
Patients who have had AAAs suffer an increased likelihood of developing a concurrent TAA, most likely a descending
TAA. Therefore, when a thoracic or AAA is diagnosed, it is recommended that the whole aorta should be imaged. In addition to this, patients with AAAs are likely to develop TAAs in the future. Hence, it is also recommended that patients who
have undergone AAA repair should have regular follow-up imaging of the thoracic aorta.
BICUSPID AORTIC VALVE
The normal aortic valve has three distinct semilunar leaflets contained in the sinuses of Valsava. Two leaflets are associated with the aperture of a coronary artery, after which the leaflet is named left, right, and noncoronary. The commissures
separate the leaflets from each other [25]. As with everything in the human body, there is variation. The commonest variant
of the aortic valve, indeed the most common congenital cardiac defect, is the BAV (Fig. 10.5)—affecting 0.5%–2% of the
population [26,27].
BAV is the term used to describe an aortic valve with only two functioning leaflets, of which there are multiple subtypes.
True BAV, where there are two symmetrical leaflets, is the rarest of these. More commonly, two leaflets are fused to each
other creating two asymmetrical leaflets. These fusions, in order of prevalence, are right and left fusion (RL), right and
noncoronary (RN), and left and noncoronary (LN) [25].
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FIGURE 10.5 (A) Intraoperative image of a heavily calcified bicuspid aortic valve. (B) An accompanying “bicuspid” ascending aortic aneurysm.
(A) Reprinted with permission from Friedman T, Mani A, Elefteriades JA. Bicuspid aortic valve: clinical approach and scientific review of a common
clinical entity. Expert Rev Cardiovasc Ther 2008;6:235–48.
There has been an extraordinary interest surrounding BAVs and their potential to impact aortic pathology. The unequivocal link between BAV and aortic stenosis is well established, with studies showing which variants are most likely to lead
to disease [28]. In addition to this, the presence of a BAV predisposes to the development of ascending TAAs.
With regards to TAAs, it has been found that ascending aortic aneurysms dilate at a faster rate in patients who have a
BAV compared to those with a normal valve [29]. A 2016 systematic review found similar results: aortic diameter increased
at a faster rate in patients with BAVs compared to those without (although not reaching statistical significance) [30].
There have also been reports that patients with a BAV are more likely to suffer an aortic dissection, particularly at a
younger age [31,32].
The pathophysiology behind the link between BAVs and TAAs is thought to be multifactorial. Genetics, MMP alterations, and altered hemodynamics are thought to contribute to aneurysm formation. It has been shown that there is a familial
link regarding both BAV and dilatation of the aortic root: both cluster in families [33]. Histologically, high levels of the
proteolytic MMPs have been found in aortic walls of patients with ascending TAAs in the presence of a BAV [34]. As
mentioned earlier in this chapter, high levels of MMPs induce a proteolytic state, weakening the aortic wall. Finally, there
is altered blood flow across BAVs compared to that across normal tricuspid aortic valves. The true BAV seems to result in
the least stress on the aortic wall. However, the RL configuration results in increased stress on the right anterior aortic wall
[35,36]. This increased turbulence could weaken the aortic wall further, resulting in aneurysm formation.
Despite all these negative associations of BAV, the presumed serious impact on aortic safety of patients with BAV has
been elusive to demonstrate. It has been shown that there is no difference in long-term morbidity and mortality between
TAA patients with and without a BAV [29,37]. However, patients with BAVs do present with their ascending aneurysms
earlier than the general population. Bicuspid aneurysm patients are less likely to have serious cardiac comorbidities (due to
their youth) and, thus, tend to demonstrate better medical and surgical outcomes. Regardless of this, if a patient has been
shown to have a BAV, not only is there a tendency to develop aortic stenosis or regurgitation, but an ascending TAA is also
likely. So, investigation and monitoring of the ascending aorta is essential.
A POSITIVE THUMB–PALM SIGN
Connective tissue disorders have long been associated with aortic aneurysm. A connection between Marfan syndrome and
aortic dissection was established as early as the 1940s [38]. Since then, other connective tissue disorders have been linked to
aortic disease, including Ehlers–Danlos Syndrome and Loeys–Dietz Syndrome. Not only are people with these conditions
more likely be affected by aortic aneurysm, but they are especially prone to aortic dissection as well. Management is more
aggressive and suggested aortic diameter criteria for surgery are lower, reflecting the increased risk of dissection [39]. Early
identification of these patients is advantageous.
A positive thumb–palm sign is present when, during adduction of the thumb (active or passive), the distal phalanx of
the thumb extends beyond the ulnar border of the palm, as shown in Fig. 10.6. This is made possible through a combination of long hand bones (arachnodactyly) and excessively lax joints, features suggestive of connective tissue disorders [40].
Indeed, the sign itself forms part of the Ghent nosology for Marfan syndrome [41,42]. We find that not only does the thumb
extend beyond the edge of the palm, but the thumb is able to make a right angle with each edge of the palm.
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FIGURE 10.6 Patient with a positive “thumb–palm” sign for connective tissue disease. Being able to cross the thumb beyond the edge of the palm
indicates that the long bones are excessive and the joints are lax. Reprinted with permission from Elefteriades JA. Thoracic aortic aneurysm: reading the
enemy’s playbook. Curr Probl Cardiol 2008;33:203–77.
In reality, this is a clinical observation rather than a validated sign with statistical empirical evidence to support it.
However, the simplicity of the sign and the ability to perform this test at the bedside make it a useful tool for the clinician.
A negative thumb–palm sign should not rule out the possibility of a TAA but a positive finding should provoke clinical
suspicion.
FAMILY HISTORY OF AORTIC DISEASE
As alluded in the previous section, the link between Marfan syndrome and TAA has long been appreciated; yet Marfan
syndrome accounts for just 5% of all TAA cases. Even including all currently known syndromic connective tissue disorders
into analysis, (such as Ehlers-Danlos syndrome, Loeys-Dietz syndrome and Turner syndrome) this collectively leaves the
vast majority of TAAs unexplained. However, mapping of family trees of those affected by aortic disease shows a strong
preponderance of this disease to run in families—early studies put the figure at 21% of cases (Fig. 10.7) [43,44].
This group, designated “familial thoracic aortic aneurysm and dissection” (FTAAD), most probably comprises of a collection of related conditions, as yet unnamed. As these conditions have varying underlying genetic causes, the phenotype
seen in this population is quite varied. Some patients will have concomitant congenital cardiac deformities such as BAVs
or aortic arch abnormalities [39].
More comprehensive studies involving a large number of patients have demonstrated that autosomal dominant inheritance predominates, although X-linked and autosomal recessive inheritance patterns are also observed. Another interesting
observation discloses a tendency for the disease to cluster, so that patients with ascending aneurysms are more likely to have
relatives with ascending disease and those with descending aneurysms are more likely to have relatives with descending or
abdominal disease (Fig. 10.8) [21]. This further supports the theory that there are two distinct aortic diseases separated at
the ligamentum arteriosum.
Of clinical importance are the observations that patients with FTAAD present at a younger age than sporadic disease
(58 vs. 66 years) and manifest more rapid aortic enlargement (0.21 cm/yr vs. 0.16) [21].
The importance of family history in aortic disease is reflected in current recommendations from both the American and
European guidelines on management of aortic disease. Both sets of guidelines recommend imaging of first-degree relatives
of those affected and second-degree relatives in families containing two known patients [45,46]. It has been suggested that
relatives of patients who have dissected at an aortic diameter <5.0 cm have surgical repair at an earlier stage than usual, at
a size comparable to the dissection diameter of their relative [39,42].
The familial link in aortic disease has prompted investigation into genetic causes of these conditions. Modern genetic
testing techniques such as whole exome sequencing have enabled faster and cheaper analysis of DNA, permitting researchers to identify specific genes causing familial aortic disease. At the time of writing, 31 genes have been identified, with
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FIGURE 10.7 Among the authors’ first 100 constructed pedigrees, 21 were positive for a family pattern. These 21 positive pedigrees are displayed here.
Reprinted with permission from Coady MA, Davies RR, Roberts M, et al. Familial patterns of thoracic aortic aneurysms. Arch Surg 1999;134:361–67.
FIGURE 10.8 Distribution of sites of arterial aneurysms and dissections in kindred of familial probands. Reproduced with permission from Albornoz G,
Coady MA, Roberts M, et al. Familial thoracic aortic aneurysms and dissections–incidence, modes of inheritance, and phenotypic patterns. Ann Thorac
Surg 2006;82:1400–05.
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FIGURE 10.9 A graphic illustration of simple renal cysts.
more being discovered on a regular basis [47]. The tally of specific genes discovered to cause TAA is tallied and reported
in a special section of the journal AORTA. In turn, these genetic discoveries allow family members to be tested for variants
discovered in aneurysmal probands, enhancing care and safety of relatives of affected individuals. Whole exome sequencing
technology is likely to play a progressively more important role in the management of thoracic aortic disease in the future.
SIMPLE RENAL CYSTS
Simple renal cysts (Fig. 10.9) are discrete lesions of the kidney, commonly detected as incidental findings during abdominal
imaging. Reports of prevalence vary widely between studies, ranging from 5% to 41%, with a weighted average of 12.6% [48].
In 2006, a retrospective cohort study reported increased simple renal cyst incidence in patients with AAA compared to
age- and sex-matched controls [49]. In 2010, Ito et al. added further evidence, including the observation that the association is stronger in elderly patients. The authors remarked that this was an indication that the two diseases “share a similar
pathogenesis” [50].
Although the pathogenesis of simple renal cysts is not entirely known, there are suggestions that MMPs are involved.
Haruda et al. demonstrated increased expression of MMP-2 and MMP-9 in fluid aspirated from renal cysts, noting that
higher levels of MMP were associated with a more aggressive cyst [51]. Liu et al. observed similar findings and, furthermore, were able to slow cyst growth by the administration of doxycycline—an MMP inhibitor [52].
These findings dovetail nicely with the previous work. Chow et al. demonstrated that patients with Marfan syndrome
develop renal cysts more frequently than controls (59.4% vs. 30.4%), in a larger number and at an earlier age [53]. Marfan
syndrome has long been thought to have a pathogenesis involving disruption of MMP balance [54].
More recent evidence has added to the case of associated conditions. Large retrospective studies in different centers have
shown increased prevalence of renal cysts in CT scans of patients treated for aortic disease when compared to controls [48,55].
To conclude, there is strong evidence of an association between renal cysts and aortic disease. However, the high prevalence of renal cysts within the population makes screening those with cysts both resource intensive and, with regards to
radiation exposure, potentially dangerous. It is sensible to practice heightened vigilance in patients with known renal cysts,
however, it is too early to recommend routine aortic imagining for these patients.
GIANT CELL ARTERITIS (AND OTHER AUTOIMMUNE DISORDERS)
GCA is the most common type of primary vasculitis in adults, causing a wide variety of complications. This disease is seen
primarily in older people and women. Although the arteritis largely affects the superficial temporal arteries (Fig. 10.10),
it commonly involves other vessels as well, including the aorta or its branches in 10%–18% of cases. When the aorta is
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FIGURE 10.10 A graphic illustration of temporal arteritis.
involved, the result may be a TAA [45]. Positron emission tomography may “light up” the ascending aorta (personal observations, JAE).
It has been postulated that MMPs play a role in the pathogenesis of this disease, with studies finding increased MMP9/
TIMP1 and MMP2/TIMP2 ratios in GCA compared to healthy controls. This increased proteolytic balance may contribute
to vessel wall disruption and has the potential to produce harmful complications such as aneurysm formation [56–58].
A similar change in MMP9/TIMP1 ratio has been observed in TAA, so it is not surprising that a significant association
has been demonstrated between the two conditions [5].
A systematic review and metaanalysis in 2014 suggested that there is an association between the two diseases; those
with GCA have a threefold higher risk of developing thoracic aortic disease compared to controls. However, the authors
conceded that the true risk is difficult to estimate. Interestingly, they observed that patients taking a lower dose of steroids
are more likely to develop an enlarged aorta later in the course of the disease. The authors proposed that on average, 5–10
patients with GCA would need to be screened to detect one previously unknown TAA [59].
A paper published in 2014 documented the long-term follow-up of a cohort of a patients with GCA screened for aortic
structural damage (ASD). Of 54 patients screened, a significant increase in aortic diameter (ascending and descending) was
found in 16. Surgery was advised in eight of the patients, although it was only feasible in three [60]. This study suggested
that the development of ASD was more frequent in GCA than had been demonstrated in previous retrospective studies and
presented a strong case for screening of these patients.
Other autoimmune disorders have also been linked with aortic disease. For instance, although there is no strong evidence available, scattered case reports suggest an association between aneurysms and rheumatoid arthritis [61,62].
Other Conditions—Ongoing Research
Pregnancy is strongly associated with aortic dissection; up to half of all aortic dissections and ruptures in women younger
than 40 years are associated with pregnancy [63]. Pregnancy can increase the risk of aortic disease through two primary
mechanisms. The first of these is an extensive physiological change of hemodynamics; blood volume, stroke volume, and
heart rate increase, which can boost cardiac output by 50% by mid-third trimester. There is an increase in end-diastolic
volume and remodeling of the heart itself, which demonstrates increased ventricular wall mass [64].
The second mechanism is a histological reorganization of the vessel wall, mediated by estrogen and progesterone. This
remodeling of the tunica intima and media can cause dissection through disruption of the normal mechanics of the ECM
[65,66]. This effect is most pronounced in the third trimester and peripartum period, which correlates with the time of
maximum risk of dissection in pregnancy [63].
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