Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3734_Библиотеки_им_академика_М_И_Перельмана
.pdf
Genetically-Triggered Aortic Dissections
https://t.me/med1917
MelissaL.Russo andJiaJenniferDing
Introduction
Aortic aneurysm and aortic dissection are life-threatening events that can greatly
inuence a person’s life. Greater than 20% of all thoracic aortic aneurysms have
been attributed to a genetic etiology [1]. The estimation of the genetic contributions
to aortic dissection may actually be an underestimate secondary to silent thoracic
aneurysms being undiagnosed and an under-utilization of genetic testing in the clinical arena [2]. Therefore, it is imperative for the cardiologist and cardiovascular
surgeon to have an understanding of the genetic conditions associated with an
increased risk for aortic dissection.
The genetic conditions with a predisposition for aortic aneurysm and dissection
can be classied into syndromic conditions versus non-syndromic alterations in
gene expression that predispose to aortic aneurysm and dissection (Table 1). The
syndromic conditions are typically autosomal dominant and have characteristic features on history and physical exam that identify these individuals. The syndromic
conditions include Marfan syndrome, Loeys-Dietz syndrome, vascular EhlersDanlos syndrome, Turner syndrome and bicuspid aortic valve aortopathy. In contrast, non-syndromic genetic conditions do not have any identifying systemic
features. Modern genomic sequencing technology has identied pathogenic variants in genes important for functioning of vascular smooth muscle cells. The nonsyndromic genetic conditions have familial aggregation. The non-syndromic genetic
M. L. Russo (*)
Maternal-Fetal Medicine and Clinical Genetics, Women and Infants Hospital, Warren Alpert
Medical School of Brown University, Providence, RI, USA
e-mail: MLRusso@Wihri.org
J. J. Ding
PGY4 Resident Educational Chief, Obstetrics and Gynecology Residency, Women and
Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
J. S. Coselli et al. (eds.), Aortic Dissection and Acute Aortic Syndromes,
https://doi.org/10.1007/978-3-030-66668-2_4
45© Springer Nature Switzerland AG 2021
46
M. L. Russo and J. J. Ding
https://t.me/med1917
Table 1 Genetic conditions with predisposition for aortic aneurysm and dissection
Genetic condition
Marfan syndrome FBN1 • Aortic root dilation
Loeys-Dietz syndrome TGFBR1
Vascular Ehlers Danlos
syndrome (type IV)
Turner syndrome Karyotype XO• Aortic dilation at root/ascending
Bicuspid Aortic Valve
Aortopathy
Familial thoracic aortic
aneurysm
a
Association only in some cases
Gene
affected Clinical features
• Ectopia lentis
• Skeletal features
• Aortic and arterial aneurysms
TGFBR2
SMAD3
TGFB2
TGFB3
SMAD2
COL3A1 • Arterial, intestinal or uterine rupture
NOTCH1
ACTA2
MYH11
MYLK
PRKG1
LOX
• Arterial tortuosiy
• Craniofacial features-hypertelorism, bid uvula/
cleft, craniosynostosis
• Cutaneous features-translucent skin
• Thin, translucent skin
• Easy bruising
• Characteristic facial appearance-pinched nose,
thin lips, prominent eyes
• Short stature
• Premature ovarian failure
a
None unless with underlying syndrome
None
conditions with increased risk for aortic dissection include pathogenic variants in
ACTA2, MYH11, MYLK, PRKG1 and LOX [3].
This chapter will outline the major features and method of diagnosis for genetic
conditions with a predisposition for aortic dissection. In addition, this chapter will
highlight national and international recommendations on imaging surveillance,
pharmacotherapy, prophylactic surgical guidelines and surgery recommendations in
regards to these conditions.
General Guidelines withGenetic Conditions
withPredisposition forAortic Dissection
Over the few decades, there have been tremendous medical advancements for some
of genetically-triggered aortic dissections conditions with prophylactic aortic surgery, revised methods for diagnosis with clinical criteria and genetic testing, and
medical treatment.
The diameter of the enlarged aortic root is an important risk factor for future
aortic dissection in the setting of monogenetic disorders where increased wall
Genetically-Triggered Aortic Dissections
https://t.me/med1917
tension in the presence of weakened connective tissues causes the aorta to enlarge
slowly before dissection occurs. A majority of aortic aneurysms in these conditions
arise at the aortic root or ascending aorta. The key points of optimal care include
early diagnosis, close surveillance of aneurysms, eliminating modiable risk factors
and appropriate medical and surgical treatment.
47
Diagnosis
• Early diagnosis is critical in order for individuals to have proper surveillance and
treatment to slow aortic root growth and mitigate risk for aortic dissection.
• A clinical diagnosis is made after a thorough history and detailed physical exam
focused on signs of connective tissue condition.
• Detailed three generation family history is recommended as some of these condi-
tions have reduced penetrance and variable expressivity. It is important to ask
about family history of thoracic aortic aneurysm/dissection, aneurysms in any
location, or sudden cardiac death before age 45 [5].
• Syndromic conditions have clinical criteria that will be reviewed in the individ-
ual sections and genetic testing is recommended to conrm diagnosis in
most cases.
Screening
• Once a diagnosis is made, serial imaging is recommended to assess the aortic
root with transthoracic echocardiograms and assessment of the entire vascular
tree is also recommended.
• Frequency of imaging surveillance will be reviewed in individual sections but
generally is performed on a yearly basis.
• Screening other rst relatives in a family is also recommended as a majority of
these conditions are autosomal dominant in inheritance.
Management
• Pharmacotherapy of beta-blockers, angiotensin receptor blockers or a combina-
tion of the two medications is recommended to slow aortic root growth. However
their role in prevention of aneurysm is equivocal in some of the previous studies.
• Mitigation of risk with smoking cessation, treatment of dyslipidemia and hyper-
tension is a part of the treatment plan to prevent aortic dissection.
• Recommendations for prophylactic aortic root repair in genetic conditions based
on aortic root threshold measurements have been put forth by national and inter-
48
M. L. Russo and J. J. Ding
https://t.me/med1917
national societies (Table2). Prophylactic surgery has been the main driving force
that has increased life expectancy in some of these conditions.
• Individuals with these conditions are advised to avoid high-stress isometric exer-
cises, contact sports and competitive sports. However, there are no evidence-
based guidelines for exercise in this population. Animal models have shown that
some exercise is benecial to prevent aortic root growth [6].
• Pregnancy is higher risk period for aortic dissection secondary to hemodynamic
and hormonal changes of the physiological state of pregnancy. Therefore, it is
important for providers to have a discussion about a person’s reproductive plans
and ensure they understand the risks. It is also advisable to involve maternal-fetal
medicine specialists in these discussions.
• For management of type A dissections in genetic conditions, open thoracic sur-
gery with resection of the affected part of the aorta and replacement with syn-
thetic Darcon vascular prosthesis is performed. If required, reimplantation of the
coronary arteries can also be performed at this time. Secondary to these surgeries
being performed earlier in life aortic root replacement sparing the aortic valve is
preferred if possible.
• With type B dissections that require surgical intervention, thoracic endovascular
aortic repair (TEVAR) is traditional approach in the general population.
However, in individuals with weakened connective tissues, this approach may
be problematic and is not generally recommended except for emergent cases.
Open surgery for repair of type B dissections is preferred for this population
currently.
Table 2 Recommended indications for prophylactic aortic surgery in genetic conditions
Genetic syndrome Indications for surgery (maximal aortic root diameter)
Marfan syndrome • >50mm—No risk factors
Loeys-Dietz
syndrome
Vascular EhlersDanlos syndrome
Bicuspid Aortic
Valve Aortopathy
Turner syndrome • ASI
Familial Thoracic
Aneurysms
a
ASI is Max aortic diameter/body surface area [17, 18]
• >45mm—growth rate>3mm/year, desire for pregnancy, severe valve
regurgitation
• >42mm
• Role of prophylactic surgery has not been established
• Surgery reserved for life-threatening complications
• May be considered for large aneurysm/rapid growth
• >55mm—No risk factors
• >50mm- growth rate>3mm/year, systemic hypertension, desire for
pregnancy
a
> 27mm/m
• No specic recommendations due to heterogeneity and lack of data on
natural history-management individualized with attention to family
history
2
Genetically-Triggered Aortic Dissections
https://t.me/med1917
49
Marfan Syndrome
Marfan syndrome is an autosomal dominant condition with FBN1 as the causative
gene that encodes an extracellular matrix protein, brillin-1. There have been over
1800 different mutations identied in FBN1 that cause Marfan syndrome. This
genetic condition is highly penetrant and with variable expression between individuals and additionally there is variability in family members with the same pathogenic mutation. Marfan syndrome affects 1in 5000 individuals and is implicated as
the cause in 3–5% of all aortic dissections [7, 8]. It mainly affects the cardiovascular, ocular and musculoskeletal systems. The primary cause of death in persons with
Marfan syndrome is progressive aortic root dilatation that leads to subsequent aortic
dissection. Advancements mainly in surgical management of aortic aneurysms coupled with medical management have improved survival. The average life expectancy historically was 45 years however now is 70 years, closer to the general
population’s life expectancy [9, 10].
Fibrillin-1 is large extracellular matrix protein encoded by FBN1 and brillin-1
microbrils maintain connective tissue structural integrity. The original hypothesis
was that pathogenic variants in FBN1 led to structural weakness of the aortic wall,
however this was not the full story. In addition to its structural role, brillin-1 is an
essential player regulating cell signaling by sequestering transforming growth
factor- beta (TGFβ) in the extracellular matrix. The loss of brillin-1 leads to
increased bioavailable TGFβ and activation of both canonical SMAD-dependent
and non-canonical SMAD-independent TGFβ signaling pathways, which lead to
aneurysmal dilation (Fig. 1) [11]. Increased TGFβ signaling has been shown in
aneurysmal tissue from aortas in individuals with Marfan syndrome [12].
Excessive TGFE Signaling through non-canonical ERK activation
Latex Complex
LAP
TGFE
LAP
L
T
B
P
Normal Fibrillin-1
LAP
L
T
B
P
Marfan Sydrome
Mutated Fiberillin-1
LAP
Excessive
TGFE
Activation
Fig. 1 Mechanism of aortic aneurysm in Marfan syndrome
SMAD2/3
SMAD4
TGFE
P
P
TGFE
Mutation
P
P
TF
ERK
P
cytoplasm
MEK
ERK
nucleus
P
Phenotypic
Consequence
Aortic Aneurysm
P
P
50
M. L. Russo and J. J. Ding
https://t.me/med1917
Diagnosis
• The Ghent nosology is a set of clinical criteria used to diagnose Marfan syndrome [13]. This was revised in 2010 to put more weight on the cardiovascular
manifestations (Tables 3 and 4). With this nosology ectopia lentis and aortic root
aneurysm are cardinal features and family history is taken into account.
• An FBN1 mutation is not necessary, nor sufcient for diagnosis, however is
incorporated into the clinical criteria.
Screening andSurveillance
• In the condition Marfan syndrome, 75% of cases are familial and 25% are sporadic, de novo mutations [4].
Table 3 Revised Ghent criteria for diagnosis of Marfan syndrome
In the absence of family history:
1. Ao (Z≥2) and Ectopia lentis
2. Ao (Z≥2) and FBN1 pathogenic variant
3. Ao (Z≥2) and systemic score (≥7 points)
4. Ectopia lentis and FBN1 with known Ao
In the presence of family history:
5. Ectopia lentis and family history of Marfan syndrome
6. Systemic score of (≥7 points) and family history of Marfan syndrome
7. Ao (Z≥2 above 20years old and Ao Z≥3 below 20years old) and family history of
Marfan syndrome
Loeys etal. 2010
Table 4 Systemic features scoring system from revised Ghent Nosology Score ≥ 7 indicates
systemic involvement
Wrist and thumb sign (3 points vs 1 point for wrist or thumb sign)
Pectus carinatum deformity (2 points)
Hindfoot deformity (2 points, 1 point for pes planus)
Pneumothorax (2 points)
Dural ectasia (2 points)
Protrusio acetabuli (2 points)
Reduced upper/lower segment AND increased arm span/height AND no severe scoliosis (1
point)
Scoliosis or thoracolumbar kyphosis (1 point)
Reduced elbow extension (1 point)
Facial features- 3/5 dolichocephaly, enopthalmos, downslanting palpebral ssures, malar
hypoplasia, retrognathia (1 point)
Skin striae (1 point)
Myopia >3 diopters (1 point)
Mitral valve prolapse (1 point)
Genetically-Triggered Aortic Dissections
https://t.me/med1917
• Since a majority of cases are familial, with a new diagnosis for an individual, it
is important to additionally screen rst and second degree family members for
this condition if they have any clinical signs genetic testing can be sent.
• Aortic root aneurysms should be followed with serial imaging. Annual imaging
of the root and ascending aorta is recommended along with clinical visit with
specialist on a yearly basis.
51
Management
• The goal of beta-blockers and angiotensin-receptor blockers is to slow the growth
of aneurysmal expansion. Beta-blockers have been shown to decrease the rate of
aortic root growth however a meta-analysis has refuted the effect of this medication [14–16].
• Prophylactic aortic root surgery is recommended at >5cm and lower diameter
for additional risk factors of rapid growth, fam history of dissection, desired
pregnancy, severe aortic or mitral regurgitation (Table2) [17, 18].
Loeys-Dietz Syndrome
Loeys-Dietz syndrome (LDS) is an autosomal dominant condition with variable
expression. There can be variability among family members with the same gene
mutation and there is wide clinical spectrum of disease [19]. The genes associated
with Loeys-Dietz syndrome encode receptors, ligands and downstream signals in
the TGFβ signaling pathway. Pathogenic variation in these genes lead to dysregulation and increased signaling in the TGFβ pathway.
When this condition was rst described, Loeys-Dietz syndrome was classied
into two types with pathogenic genetic changes in the receptors TGFBR1 and
TGFBR2. These individuals had manifestations of disease in the cardiovascular,
craniofacial, neurocognitive and skeletal systems with features of arterial aneurysms, congenital heart disease, craniosynostosis, cleft palate, and mental retardation. The tissues from these persons showed perturbation of TGFβ signaling [20].
One of the largest series of individuals with TGFBR1 and TGFBR2 mutations
showed 80% survive until 60years of age. In this cohort, 23% of individuals with
TGFBR1 and TGFBR2 mutations had aortic dissections and of these cases 18% had
prophylactic aortic surgery prior to rupture. Extra-aortic features in this population
were hypertelorism (29%), cervical arterial tortuosity (53%), widened scars (27%).
Aortic root diameter at dissection was smaller <4.5cm and congenital heart defects
(bicuspid aortic valve, atrial septal defect, patent ductus arteriosus) were also more
common in TGFBR2 patients. The rate of aortic dissection in this cohort was
1.7% [21].
52
https://t.me/med1917
M. L. Russo and J. J. Ding
There are now six different sub-types of Loeys-Dietz syndrome (LDS I-VI) that
have been described with pathogenic variants in six different genes (Table5) [22,
23]. Individuals with LDS type I (TGFBR1) have prominent craniofacial features
including cleft palate, craniosynostosis, micrognathia and bid or broad uvula [24].
Type II LDS has pathogenic variants in TGFBR2 and these individuals have less
prominent craniofacial features, easy bruising, atrophic scars, thin translucent skin
and visceral rupture events, similar to vascular Ehlers-Danlos syndrome. Type III
LDS, also known as aneurysm-osteoarthritis syndrome, with pathogenic variants in
SMAD3 typically have early onset joint abnormalities, arterial tortuosity, aneurysm
and aortic dissections. LDS types IV, V and VI are less common and typically have
milder phenotypic features and less severe clinical course [22].
Diagnosis
• There are no formal criteria for clinical diagnosis, however MacCarrick etal. has
suggested revised nosology of arterial aneurysm or dissection in combination
with pathogenic variant in one of the Loeys-Dietz genes or family member with
known diagnosis of Loeys-Dietz syndrome is sufcient for diagnosis [25]. This
nosology reduces the emphasis on dysmorphic features and focuses on cardiovascular manifestations in conjunction with genetic information.
• Data has suggested that those with more prominent craniofacial features have
more severe disease with cardiovascular complications at younger ages than
those with less prominent facial features [24]. Similar observations about specic features being associated with worse cardiovascular outcomes were noted in
another cohort with hypertelorism, translucent skin and arterial tortuosity being
associated with higher odds ratio of prophylactic surgical aortic repair and aortic
dissection [21].
• Another cardinal feature that should prompt consideration of Loeys-Dietz as a
diagnosis is tortuous cerebrovascular vessels especially those of the head and
neck seen on imaging [26].
• One third of individuals with Loeys-Dietz syndrome have skeletal features
including joint contractures, talipes equinovarus (clubbed foot), camptodactyly,
pectus deformity, arachnodactyly, joint hypermobility or scoliosis [19].
Table 5 Different types of Loeys-Dietz syndrome
Type Gene mutation
Type I TGFBR1
Type II TGFBR2
Type III SMAD3
Type IV TGFB2
Type V TGFB3
Type VI SMAD2
Genetically-Triggered Aortic Dissections
https://t.me/med1917
53
Screening andSurveillance
• With a new diagnosis of Loeys-Dietz, 25% of cases are familial thus rst degree
family members should also be screened for aneurysms and potential diagnosis
of Loeys-Dietz syndrome [27].
• Baseline imaging of the aortic root and entire vascular tree is recommended as
50% of individuals with have aneurysm distant from aortic root [23, 27]. The size
of the aortic root can be monitored with transthoracic echocardiograms however
the rest of the vascular tree is examined with CT or MRA.This cardiovascular
surveillance is preliminarily every 6months and once determined to be stable,
imaging surveillance is recommended at 1–2year intervals. MRA scans are used
alternatively to CT scans to avoid long-term exposure to radiation [25].
• Individuals with Loeys-Dietz may have cervical spine abnormalities including
cervical spine subluxation, instability, scoliosis or kyphosis. In order to assess
the cervical spine, exion/extension X-rays are recommended, especially prior
to any planned procedure or surgery [28, 29].
Management
• Pharmacotherapy with beta-blockers or angiotensin-receptor blockers is recommended to avoid hypertension and also decrease shear forces on blood vessels
[21, 25].
• Patients should be given exercise recommendations that include avoidance of
contact and competitive sports, intense isometric exercise and exercise to the
point of exhaustion [21, 25].
• The decision to proceed with prophylactic aortic surgery is based on the absolute
dimension of the aortic root, rate of progression, valve function, severity of noncardiac features, family history of dissection [25]. There are specic guidelines
set forth by national and international organizations about guidelines for prophylactic surgery (Table2) [17, 18].
• Vascular surgery is generally well tolerated by individuals with Loeys-Dietz syndrome. One study stated survival after vascular surgery of 94% [30]. Another
study showed fatal complications during vascular surgery or immediately after
surgery were 1.7–4.8% in types I and II LDS [24].
• With aortic surgery, there is a long-term risk for need for a subsequent operation
and this risk is higher if the original procedure was performed for a type A dissection and not prophylactic aortic surgery [31, 32].
• With type B dissections that require surgery, open repair is generally preferred in
these patients over endovascular repair. Thoracic endovascular repair of aortic
root (TEVAR) is relatively contraindicated secondary to progressive aortic dilatation and dissection at the landing zones of these devices. Nevertheless, TEVAR
can be considered in an emergency situation as a bridge to later open surgical
repair [25, 27, 31, 32].
54
https://t.me/med1917
M. L. Russo and J. J. Ding
Vascular Ehlers-Danlos Syndrome
Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant condition with
features of thin, translucent skin, easy bruising and risk for rupture of arteries and
hollow organs such as bowel, spleen or uterus. vEDS has been classied as type IV
Ehlers-Danlos syndrome and there are currently 13 sub-types with vEDS subtype
comprising 5–10% of the total Ehlers-Danlos population [33]. The prevalence of
this condition is 1in 10,000 to 25,000 [33]. Pathogenic variants in type III procollagen (COL3A1) affect the amount and/or properties of normal type III collagen.
This results in a loss of tensile strength of arteries, vascular fragility and affects
walls strength of hollow organs.
With vEDS, the type III collagen produced is either defective from substitutions
of glycine residues, exon skip or splice site mutations or, there is less type III collagen produced with null/haploinsufciency mutations. Substitution of glycine residues in Gly-X-Y repeats of a triple helical domain disturbs the type III collagen
folding process, weakening the collagen, and these alterations account for a majority of identied pathogenic variants in COL3A1. There are also variants in splice
acceptor or donor site which lead to exon skipping or frameshift mutations and
results in defective type III collagen. Complications are rare in childhood with
vEDS however about one fourth of individuals have their rst major adverse event
by age 29 and greater than 80% have had a major adverse event by age 40. The
median survival is 51years old and most deaths result from arterial rupture [34–36].
Bowel rupture ultimately affects 20–30% of individuals but rarely leads to death.
There is a milder form of vEDS in individuals with null mutations where a premature stop codon leads to nonsense-mediated decay and there is half of the normal
type III collagen. These nonsense mutations result in a milder phenotype and individuals have a longer life span with the age of rst vascular event delayed about
15years and complications are limited to vascular events [37, 38]. In this group, the
median survival is 51years and in those taken to surgery 70% survive.
Diagnosis
• Traditionally, diagnosis has been based on clinical signs, non-invasive imaging
of vascular system and identication of pathogenic variants in type III collagen
(COL3A1) [33].
• The phenotypical features of vEDS include thin skin with visible veins, easy
bruising, thin pinched nose, thin lips, prominent ears, hollow cheeks and tight
facial skin [34].
• There has been revised nosology [39] suggested that clinical diagnosis should be
considered with two of the following features:
– Thin, translucent skin
– Arterial, intestinal or uterine rupture
Соседние файлы в папке Библиотека им академика М.И. Перельмана