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Elastin and collagen are two major components of the arterial wall. Lysyl oxidase (LOX) is one of a family of a copperdependent oxidodeaminases that cross-link lysyl residues on these structural proteins as part of the correct formation of
elastin lamellae and collagen fibers. Using whole-genome sequencing in two members of a family with TAAD, a missense
mutation of the LOX gene that cosegregated with TAAD has been identified. In a murine model with the human mutation
inserted into the orthologous position in the mouse genome, mice bred to homozygosity recapitulated the human phenotype, corroborating a causal role for this mutation in TAAD [42].
Bicuspid Aortic Valve With Thoracic Aortic Aneurysm
Dilatation of the ascending aorta and aortic arch is associated with bicuspid aortic valve (BAV). Although BAV is
present in 1%–2% of the general population, among individuals with aortic dissection at autopsy, 8% have BAV.
Furthermore, echocardiography of young persons with normally functioning BAVs demonstrates aortic root dilatation
in over 50%.
BAVs cluster in families and are found in 9% of first-degree relatives of affected individuals. Family members of probands with BAV and aneurysm can show aneurysm and dissection in the absence of the accompanying valve abnormality,
suggesting that both BAV and aortic aneurysm represent primary manifestations of the underlying gene defect [33].
Genetic Basis and Molecular Mechanisms
Mutations have been identified in NOTCH1, along with KCNJ2, in rare probands with additional congenital cardiac
malformations.
The NOTCH1 gene encodes a member of the Notch family of transmembrane proteins, which share structural characteristics, including an extracellular domain consisting of multiple epidermal growth factor-like repeats, and an intracellular
domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental
processes by controlling cell fate decisions. The Notch-signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells, with an active role in cardiac embryogenesis,
including aortic and pulmonary valve development as well as the development and maintenance of the aorta and other great
vessels [43,44].
KCNJ2: The Kir2.1 inward-rectifier potassium ion channel is encoded by the KCNJ2 potassium voltage-gated channel
subfamily J member 2 gene. Inwardly rectifying potassium channels are important regulators of resting membrane potential
and cell excitability. Mutation carriers exhibit dysmorphic features including hypertelorism along with cardiodysrhythmic
paralysis, known as Andersen–Tawil syndrome.
However, cardiac features noted in a kindred of 41 members with KCNJ2 gene mutation included bicuspid aortic valve,
BAV, and aortic anomalies including coarctation and valvular pulmonary stenosis [45].
Persistent Patent Ductus Arteriosus With Thoracic Aortic Aneurysm
A single large family with 179 members with a high incidence of TAAD in association with patent ductus arteriosus (PDA)
has been extensively studied [46]. With the linkage analysis excluding all known genes implicated in TAAD or autosomal
recessive PDA, the disease was mapped to chromosome 16p12. This gene is MYH11, which encodes myosin heavy chain
protein 11, a contractile protein of smooth muscle cells. The mutation leads to reduced aortic compliance, smooth muscle
cell loss, and elastosis [32].
CONCLUSIONS
Genetic testing is not only essential for the accurate diagnosis of the syndromic and nonsyndromic TAAD, but it is increasingly necessary for the management and surveillance of patients with aortic root and thoracic aortic dilatation (see Table
8.1). Evolving international guidelines for thoracic aortic dilatation are based on the accurate knowledge of the genetic
subtypes of these conditions. The thresholds for prophylactic surgical intervention for aortic root aneurysm are different depending on the specific condition. For example, an aortic root diameter of 4.5 cm prompts surgical intervention for
patients with LDS, whereas intervention is recommended at 5.0 cm for those with MFS. Similarly, the management of
patients with FTAAD will depend on the presence or absence of a mutation of the ACTA2 gene. The presence of this genetic
mutation may prompt earlier prophylactic surgical intervention for thoracic aortic aneurysms.
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TABLE 8.1 Panel of Relevant Genes for TAAD Patient Diagnostics
Gene Locus OMIM Comment
FBN1
TGFBR1
TBFBR2
TGFB2
TGFB3
SMAD3
SKI
COL3A1
COL5A1
COL1A1
TNXB
COL1A2
PLOD1
SLC2A10
EFEMP2
ELN
PTPN11
ACTA2
MYH11
MYLK
PRKG1
LOX
NOTCH1
KCNJ2
15q21.1 134797 MFS, MASS phenotype
9q22.33 190181 LDS
3p24–25 190182 LDS
FTAAD (TAAD2)
1q41 190220 LDS
14q24.3 190230 LDS-like syndrome
15q22.33 603109 LDS
1p36.33-p3632 182212 Shprintzen–Goldberg Syndrome
2q32.2 120180 EDS vascular type
9q34.3 120215 EDS classic type
17q21.33 120150 EDS classic type
6p21.33-p21.32 600985 EDS, classic type
7q21.3 120160 EDS, valvular type
1p36.22 153454 EDS, kyphoscoliotic
20q13.12 606145 Arterial tortuosity Syndrome
11q13.1 604633 AR cutis laxa
7q11.23 130160 AD cutis laxa
12q24.13 176876 Noonan’s
10q23.31 102620
16p13.11 160745
3q21.1 600922
10q11.23 176894
5q23.1 153455
9q34-q35 190198 BAV/TAAD
17q23.1–q24.2 600681 BAV/Coarctation
AD, autosomal dominant; AR, autosomal recessive; BAV, bicuspid aortic valve; EDS, Ehlers–Danlos syndrome; FTAAD, familial TAAD; LDS, Loeys–Dietz
syndrome; MFS, Marfan syndrome; p, short arm of chromosome; q, long arm of chromosome; TAAD, thoracic aortic aneurysm leading to aortic dissection.
Locus: This is the specific location of a gene or DNA sequence on a chromosome; humans’ estimated “haploid” protein coding genes are numbered up to
25,000, on the 23 different chromosomes. A variant of the similar DNA sequence located at a given locus is called an allele. The ordered list of loci known
for a particular genome is called a genetic map. Gene mapping is the process of determining the locus for a particular biological trait. Gene location on
a typical chromosome: 22q12.3 represents a gene located on the long arm “q” of chromosome 22, at region 1, band 2, sub-band 3; the bands are visible
under a microscope when a chromosome is suitably stained; each band is numbered beginning with 1 for band closest to centromere.
OMIM: Online Mendelian Inheritance in Man. OMIM is a comprehensive anthology of human genes and genetic phenotypes that is constantly updated,
authored, and edited at the McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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[39] Milewicz DM, Regalado ES. J Thorac Cardiovasc Surg 2015;149(2 0):S3–5.
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FURTHER READING
[1] Renard M, Callewaert B, Baetens M, Campens L, MacDermot K, Fryns J, et al. Novel MYH11 and ACTA2 mutations reveal a role for enhanced
TGFβ signaling in FTAAD. Int J Cardiol 2013;165(2):314–21.
Chapter 9
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Congenital Malformations (Bicuspid, Right
Aortic Arch, Coarctation)
Shahzad G. Raja
Harefield Hospital, London, United Kingdom
Chapter Outline
Introduction 101
Bicuspid Aortic Valve and Associated Aortopathy 101
Newer Developments 102
Right Aortic Arch 103
Newer Developments 103
INTRODUCTION
Coarctation 104
Newer Developments 104
Conclusion 104
Acknowledgment 105
References 105
Aortic congenital anomalies are common and comprise a heterogenous group of conditions that may be due to either
embryological or vessel wall architectural defects. Congenital malformations of the aorta may be divided into three main
groups. The most common group includes diseases that obstruct blood flow to the distal circulatory system. The classical
pathology in this category is aortic coarctation. Coarctation is a congenital stenotic anomaly of the aortic lumen, typically
located between the left subclavian artery and aortic isthmus. Infrequently, coarctation may also be detected at the level of
subclavian artery or between the left carotid artery and subclavian artery [1–3]. Coarctation is seen in 8%–10% of all the
patients with congenital cardiac defect and is twice as common as other congenital cardiac defects. Collateral circulation
is provided by internal mammary, costocervical, and intercostal arteries; these enlarged collaterals cause the characteristic
sign of rib notching on chest radiogram. These patients present findings of congestive heart failure, cardiomegaly, hypertension, weak femoral pulse, and differences of blood pressure between upper and lower extremities.
The second category includes those diseases that obstruct either the trachea or the esophagus. Right aortic arch (RAA) is
a representative of this category. In this anomaly, the aortic arch is located on the right main bronchial trunk and on the right
of the trachea. The vessels originating from the arch are a mirror image of normal structures, and the structure completing
the ring is the ductus ligament or the ductus located on the left. It is the second most common cause of vascular ring and
embryologically it is formed due to persistence of the fourth RAA. The symptoms of the RAA are due to the compression
on the trachea and sometimes on the esophagus [4,5].
A third category of congenital diseases of the aorta includes abnormalities of the mechanical composition of the aorta.
Classical entity in this category is Marfan syndrome. However, bicuspid valve and its associated aortopathy also qualify
for this category and will be the focus of this chapter along with aortic coarctation and RAA. This chapter will provide an
overview of these three congenital anomalies of aorta as well as newer developments in the diagnosis and management of
these conditions.
BICUSPID AORTIC VALVE AND ASSOCIATED AORTOPATHY
Biscuspid aortic valve (BAV) is one of the most common congenital heart anomalies and the most common congenital
anomaly in adults, occurring in 0.5%–2% of the population based on echocardiography and autopsy series [6]. It is an
inherited defect that appears to occur in an autosomal dominant pattern. BAV is the cause of aortic stenosis in 70%–85%
of pediatric cases and about 50% of adult cases [6]. BAV is associated with an aortopathy manifested by dilatation of the
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00009-2
Copyright © 2018 Elsevier Inc. All rights reserved.
101
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FIGURE 9.1 (A) Computed tomography (CT) scan showing bicuspid aortic valve. (B) CT scan of the same patient showing ascending aortic aneurysm
(bicuspid valve–associated aortopathy).
ascending thoracic aorta (Fig. 9.1A and B). The ascending aorta behaves differently with a BAV than a tricuspid aortic
valve (TAV). A thoracic aortic aneurysm occurs at a younger age in patients with BAV than with TAV [7]. The clinical consequences of this aortopathy are the need for periodic monitoring of aortic diameters, elective prophylactic surgical aortic
repair, and the occurrence of aortic dissection or rupture [8].
Newer Developments
Recent studies have shed light on BAV-associated aortopathy [9]. Two distinct BAV phenotypes have been identified, which
may have different causes of their associated aortopathy. Increasing evidence suggests that the BAV stenosis phenotype
is predominantly secondary to hemodynamic perturbances in transvalvular flow and is associated with a more benign
long-term prognosis once the stenotic BAV is replaced. In contrast, the root phenotype—which is associated with aortic
insufficiency—appears to have a genetic origin and may be associated with a higher risk of adverse aortic complications,
irrespective of the extent of valvular disease [9].
Guidelines have previously recommended prophylactic aortic surgery at a smaller aortic aneurysm size for patients with
BAV compared with aneurysms in patients with a TAV. Recent guidelines have presented differing indications regarding
the appropriate timing of prophylactic surgery for BAV–associated aneurysms. The 2014 American College of Cardiology
(ACC)/American Heart Association (AHA) Valve Disease guidelines have recommended (class I) prophylactic replacement of the aortic root and/or ascending aorta in adults with BAV disease when the aortic dimension exceeds 5.5 cm [10].
Surgery is suggested (class IIa) when the aorta is >5.0 cm, if there are risk factors such as a family history of aortic dissection or rapid growth of the aorta (>0.5 cm/year) [10]. These recommendations are similar to the 2012 European guidelines
[11], but differ from the 2010 Thoracic Aortic Disease (TAD) guidelines, which recommended elective operation at smaller
diameters [12]. For many, the 2010 TAD guidelines translated into recommending aortic surgery once the aorta reached
or exceeded 5.0 cm, the size threshold also recommended in the 2006 ACC/AHA Valve guidelines [13]. The Society of
Thoracic Surgeons Clinical Practice Guidelines recommends surgery when the BAV aorta exceeds 5 cm [14]. The Canadian
Cardiovascular Society provides a range of aortic dimensions (5–5.5 cm) for aortic replacement in the presence of BAV,
with smaller dimensions if certain criteria are met [15].
Finally, the usefulness of medical treatment for BAV-associated aortopathy is an area of ongoing research and controversy.
Slowing the progression of BAV-associated aortopathy by the employment of different pharmacological treatments is advocated. Such treatments are not specific to BAV, but due to histological similarities of medial cystic degeneration exhibited by
both BAV and Marfan syndrome aortas, similar medical regimens have been recommended for the treatment of aortopathy
in both [16]. Therapies include β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.
Few studies have proposed the use of doxycycline as a matrix metalloproteinase inhibitor, but human trials have not yielded
reliable results [17]. Medical therapy to decrease the load on the aortic wall and hence to slow the progression of aortopathy
by using β-adrenergic receptor antagonist has been indicated [18,19]. The most recent guidelines for the management of
aortopathy in non-Marfan patients recommend the use of β-blockers to decrease the blood pressure as low as the patient can
tolerate [19]. Currently, the results of the losartan therapy trial are eagerly awaited [20]. This trial is evaluating the hypothesis
that blockade of the angiotensin II type 1 receptor with losartan decreases aortic damage in Marfan syndrome. The results
of this clinical trial could lead to profound modification of the management of aortic risk and complications in patients with
Marfan syndrome and possibly in patients with thoracic aortic aneurysms of other etiologies including BAV [20].
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FIGURE 9.2 Right aortic arch with aberrant left subclavian artery.
RIGHT AORTIC ARCH
An RAA occurs in 0.1% of the population [21]. It is caused by persistence of the right fourth arch and right dorsal aorta
and involution of the left fourth arch and dorsal aorta. A right arch begins to the right of the midline and begins descending on the right (Fig. 9.2). At the level of the diaphragm, the descending aorta is on the left, regardless of the laterality
of the arch. This transition from right to left is gradual, except for a circumflex aorta. The right main bronchus may be
compressed by a sagittally oriented ascending and descending aorta [22]. The typical pattern consists of a right ductus or
ligamentum between the proximal descending aorta and the right pulmonary artery, and it is not associated with major
intracardiac anomalies. In contrast, the presence of a left ductus or absence of the ductus is associated with major intracardiac anomalies. Tetralogy of Fallot is seen in 30% of patients [23]. The most common branching patterns of the right
arch are the mirror image branching pattern (84% of cases) and the aberrant left subclavian artery (14% of cases) [24].
A mirror image branching pattern is associated with cardiac anomalies in 90% of cases, with tetralogy the commonest
abnormality [23].
Newer Developments
The key development has been in the sonographic evaluation of the fetal aortic arch anatomy. Prenatal evaluation of aortic
arch anatomy and its branching has been classically performed by using the axial three-vessel and trachea view [25,26].
Recently, the addition of the subclavian artery axial view has been proposed as a valuable tool for confirming normal or
abnormal anatomy [27] and to improve the differential diagnosis of aortic arch anomalies, for example, the different types
of RAAs (with a left subclavian artery vs. mirror imaging branching) and differentiation between a double aortic arch and
an RAA with a persistent left-sided ductus arteriosus [28–30]. Assuming that these entities show different ranges of associated conditions (congenital heart disease and 22q11 microdeletion), this view allows physicians to offer additional testing
and a more precise prognosis to parents.
The usefulness of the subclavian artery view combined with the three-vessel and trachea view for detection of an aberrant right or left subclavian artery is substantiated in the clinical implications of these anomalies. Regardless of the laterality
of the aortic arch, these anomalies are associated with a higher incidence of 22q11 deletion [30,31] even without congenital
heart disease [32]. Both entities have been reported to be associated with congenital heart disease [28–30] and specifically,
an aberrant right subclavian artery has also been studied as an independent marker for Down syndrome, with a wide range
of positive likelihood ratios from 0 to 3.941 [33].
Detection of fetal aortic arch anomalies, including RAA, should be performed by using the three-vessel and trachea
view, which can be improved by the addition of the subclavian artery view, according to the cardiovascular system sonographic evaluation protocol [34], which is essential for establishing the arch branching pattern and can contribute to the
differential diagnosis and prognosis of these entities.
After the diagnosis of these anomalies, detailed echocardiography and fetal scanning are recommended to rule out associated malformations. Karyotyping, including the detection of 22q11 microdeletion, should be offered to parents mainly
when other related conditions are found. The prognosis of aortic arch anomalies, including RAA, will depend on the associated anomalies and the risk of tracheoesophageal compression [30].
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FIGURE 9.3 Computed tomography reconstruction showing coarctation of aorta.
COARCTATION
Coarctation of the aorta is the sixth most common congenital lesion accounting for 4%–6% of live births with congenital heart disease [35,36] (Fig. 9.3). Although most patients have a discrete narrowing of the thoracic aorta at the
insertion of the ductus arteriosus, the anatomical spectrum may vary from this discrete entity to tubular hypoplasia,
with many variations in between these extremes. Despite these anatomical variations, the effect of the narrowing has
the commonly shared features of increased afterload on the left ventricle, exposure of the upper body to hypertension,
flow disturbance in the thoracic aorta, and decreased perfusion to the lower body. Depending on the balance between
the degree of flow disturbance and the compensatory mechanisms available to overcome it, the clinical presentation
may vary from the critically ill neonate in heart failure to the asymptomatic child or adult with hypertension. Untreated
coarctation carries a poor prognosis with average survival age of 35 years of age; with 75% mortality by 46 years of age
[35,36]. Long-term complications are the consequence of long-term hypertension including premature coronary artery
disease, stroke, endocarditis, aortic dissection, and heart failure [36]. Furthermore, recurrent coarctation and future
aneurysm formation can occur following successful surgical and endovascular repair that mandates long-term close
surveillance [36].
Newer Developments
One of the promising recent advances in stent technology is the development of biodegradable stents that may offer a
solution for endovascular therapy for neonatal and infant coarctations. These stents keep the coarcted aortic segment open
and dissolve over a period of months. The scaffolding left over may create a favorable ratio of the normal aortic tissue to
abnormal tissue, which in turn may prevent significant renarrowing [36].
A recently published pilot study confirms the feasibility of delivery and deployment of up to 6-mm-diameter, doubleopposing helical, poly-l-lactic acid, biodegradable stent in rabbit descending aorta [37]. The use of biodegradable metal
stents for the treatment of a long segment recoarctation after a complex surgical repair in a 3-week-old neonate with
severely impaired heart function has also been reported [38]. In neonates and infants with critical aortic coarctation, balloon
angioplasty is considered for the rescue therapy of heart failure. The use of conventional stents is limited because of further
vessel growth, the need of redilation, and later surgical removal. However, a novel bioabsorbable stent might overcome
such restrictions of vessel stenting in newborns. Further clinical trials are needed, however, to validate the indications and
long-term results.
CONCLUSION
Congenital malformations of the aorta carry a significant morbidity and mortality due to delayed diagnosis, missed diagnosis, or inadequate treatment. Newer developments in endovascular technology, improved understanding of the pathobiology, emerging imaging strategies, and evolving indications to treat may potentially reduce the morbidity and mortality
associated with this heterogenous group of conditions.
Congenital Malformations (Bicuspid, Right Aortic Arch, Coarctation) Chapter | 9 105
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ACKNOWLEDGMENT
Images provided by Dr. Tarun Mittal, FRCR, consultant radiologist, Harefield Hospital.
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