Inherited aortopathy aortic dissection \marfan

1. Inherited Aortopathy
Dr Ihab Suliman
March 2022

2. Complications
• Aortic dissection.
• Repeated Surgeries
• Concomitant diseases

4. • In patients born with congenital heart disease,
dilatation of the aorta is a frequent feature at
presentation and during follow-up after surgical
intervention.
• This review provides an overview of the
pathologies associated with aortopathy, and
discusses the current knowledge on
pathophysiology, evolution, and treatment
guidelines of the aortic disease associated with
congenital heart defects.

5. • Primary aortic dilatation is mainly associated with
coarctation of the aorta (CoA), bicuspid aortic
valve (BAV), and conotruncal abnormalities such
as tetralogy of Fallot (TOF), pulmonary atresia
with ventricular septal defect (PA/VSD), or
truncus arteriosus. It can be a key feature in
genetic syndromes with connective tissue
disorders, such as Marfan, Loeys-Dietz, vascular
Ehlers-Danlos, aneurysm-osteoarthritis, and
Turner syndrome.

6. • Secondary dilatation of the aortic root and to a
lesser extent of the ascending aorta is seen after
congenital cardiac surgery, when the original
aortic root is replaced by a pulmonary autograft,
as in the Ross operation, or modified as in the
arterial switch operation (ASO) or systemic
outflow tract reconstruction in single ventricle
(SV) patients. In these situations the neo-aortic
root consists mainly of pulmonary arterial root
tissue introduced in the high-pressure left-sided
system, often leading to dilatation in a time-
dependent fashion.

7. MORPHOGENESIS OF THE AORTIC AND
PULMONARY ROOT
• The aortic and pulmonary trunks originate from the
remodeling of the pharyngeal arch arteries during the
early embryonic development. The original six
symmetrical arteries, attached to the dorsal aorta, give
rise to the ascending aorta (partly derived from the left
fourth artery), and pulmonary trunk (derived from the
left sixth artery), with two branch pulmonary arteries
attached. Neural crest cells migrate to the caudal
pharyngeal arches and into the common outflow
truncus of the primitive heart tube, participating in
distal septation of the common outflow tract into two
independent separate extra-pericardial vessels.

9. Syndromic aortopathies
• This term includes discuss
• Marfan syndrome (MFS);
• Turner syndrome (TS);
• Loeys Dietz syndrome (LDS);
• Ehlers-Danlos, particularly type IV (vascular
subtype);
• and arterial tortuosity syndrome (ATS).

11. • Most of these conditions are characterised by
autosomal dominant inheritance. Turner
syndrome is due to sex chromosome
aneuploidy with the loss of one of the X
chromosomes (45,X). ATS is a rare autosomal
recessive condition.

12. Most Serious complication
Aortic dissection
• The most serious complication of an aortopathy
is an aortic dissection. Aortic dissection due to an
underlying heritable disorder (whether syndromic
or non-syndromic) presents in the same way as
aortic dissection in the general community.
Guidelines are available regarding investigation,
diagnosis and treatment of this potentially life-
threatening complication .Consideration of an
underlying heritable disorder should be given
particularly in the setting of occurrence at a
young age .

13. Epidemiology MFS
https://marfan.org/
• First described in 1896; named in 1902.
• Common inherited connective tissue disorder
• Incidence: 1 in 3000-5000; approximately
200,000 Americans affected
• M = F; men with shorter life expectancy
• Races affected equally

14. Aortic Dissection
• Marfan syndrome
(Present in 5-10% of ascending aortic dissections, .02% of adults)
• Aortic dilatation
• Bicuspid aortic valve, coarctation
• Turner, Ehlers-Danlos (type IV), Noonan syndrome
• Family history of…
Marfan syndrome, aortic dissection, aortic disease
• Hypertension
(Present in 70-90% of dissections, but 20-40% of adults)

15. MFS
CARDIOVASCULAR SYSTEM
MAJOR CRITERIA
• dilation of ascending aorta
• aortic dissection
MINOR CRITERIA
• mitral valve prolapse
• dilation of a main pulmonary artery
• premature mitral anular calcification (<40yrs.)
• descending thoracic or abdominal aortic aneurysm
(< 50 yrs.)
Cardiovascular involvement: one minor criterion

16. OCULAR SYSTEM
MAJOR CRITERION
• Ectopia lentis

17. SKELETAL SYSTEM
MAJOR CRITERIA
Presence of at least four of the following:
• pectus carinatum
• pectus excavatum requiring surgery
• reduced upper to lower segment ratio or arm span
to height ratio > 1.05
• wrist and thumb signs
• scoliosis > 20° or spondylolisthesis
• reduced extension at the elbows (<170°)
• medial displacement of the medial malleolus
causing pes planus
• protusio acetabulae of any degree

20. DIAGNOSIS
Clinical Evaluation
1. Complete physical examination, including a careful
musculoskeletal and skin examination
2. Detailed medical and family history
3. Electrocardiogram (EKG) and echocardiogram, looking for
cardiovascualr involvement
4. Eye examination by an ophthalmologist, who dilates the pupil
and uses a slit lamp to assess for lens dislocation
This series of steps is important, not only in determining the
diagnosis, but also in detecting problems that require immediate
attention or long-term management.

21. • The major criteria for diagnosis of Marfan
syndrome are ectopia lentis, aortic root
dilation/dissection, dural ectasia, or a
combination of more than 4 out of 8 major
skeletal features.

22. Genetics
• Autosomal dominant; variable expression
• ~25% spontaneous mutations
• Genes involved in Marfan Syndrome phenotype:
– Fibrillin-1 (MFS)
• Microfibril glycoprotein in both elastic and non elastic
tissues
• > 97 different mutations
– TGFBR (MFS type II or Loeys-Dietz)
• Works through apoptosis and cell cycle regulation;
prevents proper incorporation of fibrillin into tissue
• Also with triad: hypertelorism, bifid uvula or cleft
palate, generalized arterial tortuosity
• Other gene mutations may lead to similar phenotypes

23. Abraham Lincoln

24. Diagnosis
• Clinical diagnosis: the Ghent criteria
– physical exam: 6 organ systems involved
– family history
– genetic testing
• If (+) family history, additionally you need:
– Involvement of 2 organ systems including 1 major
criterion
• If (–) family history, additionally you need:
– Major criterion from 2 systems and involvement of a
3rd system

25. Clinical Features
• HEENT:
– Eye: superior lens dislocation (ectopia
lentis)
– Oropharynx: high palate and crowded
dentition
• Cardiac:
– Mitral valve prolapse
– Aortic root dilation
• Pulmonary: Spontaneous pneumothorax
• Neurologic: Dural ectasia
• Skin: Stretch marks

26. Clinical Features
• Musculoskeletal:
– Tall stature (dolichostenomelia)
– Long digits (arachnodactyly)
– Thumb sign (distal phalanx protrudes
beyond border of clenched fist)
– Wrist sign (thumb and fifth digit overlap
when around the wrist)
– Sternal deformity (prominent pectus)
– Scoliosis > 20 degrees
– Joint hypermobility
– Arm span exceeding height (ratio >1.05)
– Reduced elbow extension (<170 degrees)
– Medial displacement of medial malleolus

27. Jonathan Larson, playwright/composer

28. Cardiovascular Complications
• Most common cause of M&M (~80%)
• Aortic root disease  aneurysms, AR, dissection
– In 50% children
– In up to 80% of adults
– May lead to neurovascular complications
– AR murmur: decrescendo, diastolic
• Mitral valve prolapse (minor criterion)
– In 60-80% patients; most common valve disorder
– Worsens with time, complicated by rupture
– MVP murmur: ejection click, holosystolic
• Arrhythmias

29. Management: screening/counseling
• Annual
echocardiogram
• Annual ophtho exam
and orthopedic
involvement as
needed
• Counseling regarding
physical activities
• Genetic counseling

30. Management: medications
 Beta blockade
Standard of care for adult patients (no data on children)
Based on studies of propranolol versus placebo
Slower rate of aortic dilatation with beta blockade
Survival at 10 yrs not significantly improved
 Calcium channel blockers?
 ARBs
Recent animal study models of FBN1 mutants demonstrated
decreased rate of aortic dilatation
Mechanism is via TGFBR
One randomized trial of 17 patients is complete: larger study is
now ongoing

31. Management: surgical intervention
• Better survival with elective repair
• Variable recommendations for aortic root
diameter at which intervention warranted
– ACC/AHA: diameter > 5.0 cm
– ESC: diameter > 4.5 cm
– Rate of increase > 0.5 cm/year
• Earlier intervention indicated in women desiring
pregnancy
• Annual imaging post-op still necessary

32. Similar phenotypes
• Congenital contractual arachnodactyly: FBN2
• MASS (Mitral valve prolapse, aortic dilation, skin
and skeletal abnormalities): FBN1
• Joint hypermobility syndrome
• Ehlers-Danlos: mutation of type V collagen
• Stickler syndrome: mutation of type II and XI
collagen

33. INTRODUCTION
 Marfan syndrome is a multisystemic connective tissue
disorder that affects both sexes equally and is
characterized by skeletal, cardiovascular, and ocular
abnormalities.
 Its prevalence has been estimated at two to three persons
per 10,000
.

34. Case 1
 28years old woman.
 Admitted for acute-onset tearing
central chest pain that radiates to the
back .
 CT angiography showed:
 Stanford type A dissection involving
the ascending thoracic and the
descending aorta
 Brachiocephalic artery dissection
 Right renal artery supplied by the false
lumen with acute renal infarction

35. a dissection flap in the right brachiocephalic artery
Descending
aorta
dissection

36.  Ct also revealed
• A severe
scoliosis .
• A chest wall
deformity

37. Case 2
 A 32 years old man
 Complaining of central chest pain and intermittent episodes
of excruciating back pain confined to the sacral area .
 CT showed an annulo aortic ectasia with aortic aneurysms.

38.  It also showed
 a dural ectasia
 scoliosis

39. Cardiovascular Manifestations
3
. Pulmonary Artery Dilatation
• Dilatation of the main pulmonary artery is one of the
established criteria for the diagnosis of Marfan syndrome.
Like dilatation of the ascending aorta, it occurs
predominantly in the root.
• The upper limits of a normal main pulmonary artery
diameter at the root and at the level of bifurcation, were
34.8 mm and 28.0 mm, respectively

40. Musculoskeletal Manifestations
1. Scoliosis
• Scoliosis is a frequent and potentially severe manifestation
of Marfan syndrome. It occurs in approximately 62% of
patients.
• Scoliosis in Marfan syndrome is more severe, rigid, and
progressive, requiring surgical correction.
• When it occurs in combination with straight back syndrome,
kyphosis, or a chest wall deformity, it may contribute to
cardiopulmonary compromise and restriction of lung volume

41. Musculoskeletal Manifestations
• Measurement of the severity of a scoliotic curve has
practical applications and the Lippman-Cobb method is
widely used to measure the degree of scoliotic curvature.
• CT and MR imaging are helpful to evaluate the bone
structure, associated abnormalities of the spinal cord, and
the nerve roots before treatment planning.

42. Musculoskeletal Manifestations
2
. Chest Wall Deformity
• Approximately 66% of patients with
Marfan syndrome have either pectus
excavatum or pectus carinatum
produced by longitudinal overgrowth
of the ribs.
• The severity of pectus excavatum is
determined according to the pectus
index calculated on the basis of
measurements on CT images.

43. Musculoskeletal Manifestations
3
. Acetabular Protrusion
• Acetabular protrusion is a deformity of the hip joint and
is distinguished by the invasion of the acetabulum and
femoral head into the pelvic cavity.
• Radiographic findings, including an increased center-
edge angle of Wiberg and an obscured teardrop sign,
allow the diagnosis.

44. Dural Ectasia and Associated Central Nervous System
Manifestations
• Dural ectasia, which has been observed in 56%
–
65% of
patients with Marfan syndrome, is a ballooning or
significant widening of the dural sac or neural root
sleeves.
• It is sometimes accompanied by bone erosion,
meningoceles, and arachnoid cysts.

45. • Most occurrences of dural ectasia in Marfan syndrome
affect the lumbosacral spine.
• Dural ectasia is depicted on radiographs as a widening of
the interpediculate distance.
• Vertebral body scalloping occurs with a high prevalence
in transition vertebrae.

46. Take home points
• Marfan Syndrome is relatively common
• If you have a patient < 40 with evidence of
aortic root changes, think MFS
• No cure, so cardiovascular management is key
– Annual echo
– Beta blockade
– Counseling on physical activity

47. Coarctation of the aorta
• CoA accounts for 5-8% of CHD.Isolated forms
occur in less than half of the patients, CoA is
often found in combination with BAV and
mitral valve anomalies. It is usually sporadic,
but genetic influences can play a role: There is
a male predominance of 1,5-1,7/1, and 10-
15% of Turner syndrome patients have aortic
CoA.

48. Bicuspid aortic valve
• The BAV is the most frequent congenital cardiac
malformation, with a prevalence of 1-2% in the general
population. Concomitant aortic dilatation is seen in 80% of
patients.
• Three valve morphologies have been identified:
• Type I (the most prevalent, 69-85%) has a fusion of right
and left coronary cusps,
• type II is fusion of right and non-coronary cusps, and
• type III (the least prevalent) shows fusion of the left and
non-coronary cusp. The concomitant aortic dilatation can
be confined to the ascending aorta, the aortic root, or
extend from the aortic annulus up to the proximal aortic
arch.

49. • The lifetime risk of aortic dissection in patients
with BAV has been reported to be 9 times
higher than that of the general population.

50. • The BAV inheritance pattern is autosomal
dominant with incomplete penetrance of 9 to
30%. The male predominance of 3/1 and the
association with Turner syndrome suggest an
X-linked etiology. Mutations in the ACTA2 and
NOTCH1 genes have been found in some BAV
patients, but not the FBN1 gene associated
with Marfan syndrome.

51. • The strong association of BAV with CoA may
indicate that BAV disease involves the ascending
aorta and aortic arch extending to the
ligamentum arteriosum The fact that the
pulmonary trunk in BAV patients shows
histological changes similar to those seen in the
ascending aorta, points to a development
spectrum involving that part of the great vessels
that is derived from neural crest cells.
•

52. Schematic diagram of the anatomic boundaries of BAV disease. The
structures involved in BAV disease (in pink) include the aortic valve, aortic
annulus, sinuses of Valsalva, sinotubular junction, ascending aorta,
pulmonary trunk and coronary ostia. Adapted from Tadros et al. (ref. )

53. • Conotruncal anomalies: Tetralogy of Fallot and
pulmonary atresia/ventricular septal defect

54. TOF
• TOF is the most common form of cyanotic
CHD and accounts for 10% of all congenital
heart defects. Dilatation of the proximal aorta
is a common feature in patients with
unrepaired TOF and PA/VSD, which can
already be observed at fetal
echocardiography. The aorta in TOF is dilated
mainly at the root, tapering down towards the
ascending aorta; the aortic arch is usually of
normal size.

55. • Corrective surgery has dramatically improved
long-term prognosis, with nearly 90% of patients
now surviving well into adulthood.However,
persistent aortic root dilatation is increasingly
reported in adult patients, years after corrective
surgery. Single case reports of progressive aortic
dilatation long after repair of TOF began
appearing in the early 1970s.
• .

56. • In 1982 Capelli and Somerville mentioned
persistence of a large aortic root, but
considered it an acquired feature due to long-
standing volume overload by years of
aortopulmonary shunts before complete
repair, and suggested that earlier repair in the
first decade of life might prevent this
complication

57. Secondary aortic dilatation after repair
of CHD
• In this section we will consider the occurrence of
dilatation of the aortic root, and to a lesser extent
of the ascending aorta, after congenital cardiac
surgery, by which the original aortic root is
replaced by a pulmonary autograft, as in the Ross
operation, or modified as in the ASO or systemic
outflow tract reconstruction in SV patients. In
these situations the neo-aortic root consists
mainly of pulmonary arterial root tissue
introduced in the high-pressure left-sided
system,

58. After Ross procedure
• Since the introduction by Sir Donald Ross in 1967 of
the Ross procedure, comprising aortic replacement by
the pulmonary autograft, this operation has gained
widespread applicability both in children and adults
with congenital aortic valve disease.Technically, the
pulmonary autograft can be implanted as a full root
replacement, or as a subcoronary replacement,
inserting the pulmonary autograft as an inclusion
cylinder in the existing aortic root. The right ventricular
outflow tract reconstruction is mostly performed with
a pulmonary homograft or biological xenograft root.

59. After arterial switch operation
ASO
• Over the past two decades, the ASO has
become the procedure of choice for repair of
transposition of the great arteries in neonates
and young infants.The ASO leads to anatomic
correction, in contrast to atrial switch
operation, and thus avoids the long-term
complications of systemic atrioventricular
valve regurgitation and ventricular failure.

60. Single ventricle situations
• Since the introduction of staged procedures for patients
with SV physiology two decades ago, an increasing number
of survivors with a Fontan circulation grow into
adolescence and adulthood.
• When the native aortic valve functions as the only outlet
valve, and no surgery to the original aortic root has been
performed during staging, the chances of this valve
deteriorating over time are small, as the architecture and
wall characteristics are apt to sustain systemic pressures.
However, when volume loading persists during a
considerable period of time, and the Fontan completion is
postponed at an older age, or when the aortic valve is
bicuspid, the aortic root and ascending aorta may dilate
over time and become aneurismal.

61. Surgery to the ascending aorta in BAV patients is
mandated (Class IIa, level C):
• for an ascending aorta of >50 mm, when the
patient has a family history of dissection, or
the size progression is >5 mm/year
• for an ascending aorta of >55 mm, when there
are no risk factors
• for an ascending aorta of >45 mm, when
surgery for the valve is obligatory;
replacement of the aortic sinuses needs to be
individualized

62. Guidelines for follow-up and
treatment
• Guidelines for the follow-up and surgical treatment of
adult patients with valvular heart and thoracic aortic
disease are well established, and regularly updated.[In
these guidelines, only BAV with thoracic aorta
dilatation receives special attention. All guidelines are
based on diameters; aortic size index is never used up
to now.
• Regarding follow-up, all patients with an aortic
diameter of >40 mm should be follow-up regularly.
When the diameter is >45 mm, and patients have a
family history of dissection or show rapid progression,
yearly imaging is mandated.

63. In contrast, nearly no guidelines exist for aortopathy in
CHD.In the ESC guidelines for grown-up CHD, only the
following are mentioned
• surgical treatment for ascending aortic
dilatation in CoA may be considered when the
diameter is >55 mm (>27.5 mm/m2) or if rapid
progression
• aortic surgery should be considered after ASO
when the neo-aortic root is >55 mm providing
adult stature (Class IIa/level C)

65. • In the absence of guidelines for the other pathologies
previously discussed, a pragmatic attitude is probably
appropriate: As no case reports have appeared about
ruptured aortas <55 mm in adult sized patients, this
diameter should be used as a cut-off. A diameter of >60
mm is considered the hinge point for the ascending aorta,
above which the chance for rupture increases
exponentially.In small children, rapid progression in size
may urge faster intervention.
• Medical therapy
• Co-existent arterial hypertension in patients with CHD must
be effectively treated, as hypertension has been shown to
accelerate the aortic dilatation.

66. All are chest x ray findings in thoracic aortic
aneurysm except
• A. Widening of the mediastinal shadow
• B. Displacement or compression of the
trachea
• C. Displacement or compression of left main
stem bronchus
• D. Displacement or compression of right main
stem bronchus

67. • D. Displacement or compression of right main
stem bronchus

70. • C

72. • A

73. • Thank you