genetic diseases affecting the aorta...genetic diseases affecting the aorta duke cameron, md...
TRANSCRIPT
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Genetic Diseases Affecting the Aorta
Duke Cameron, MD
Division of Cardiac Surgery
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There is no disease
more conducive to
clinical humility than
aneurysm of the
aorta.
Sir William Osler
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All the science, I don’t understand….
It’s just my job 5 days a week.
Elton John, “Rocket Man”, 1972
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Thoracic Aortic Aneurysm
▪ 15th leading cause of death in
patients > 65 years
▪ Often clinically silent until fatal
rupture
▪ Approximately 20% have
affected relatives
▪ Autosomal dominant with
variable penetrance
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Aneurysm Morphology
Sinus Ascending Aorta Post-surgical
R Lange, Ann Thor Surg, 2006
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Complications of Aortic Aneurysms
Rupture/Dissection Aortic Regurgitation
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patient age
heritability
genetic basis
smoothness
calcification
thrombus
debris
risk factors for atherosclerosis
Ascending aortic and descending thoracic/
abdominal aneurysms are two different diseases
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The Lamellar Unit
A vascular smooth muscle cell (VSMC) sandwiched between
elastin layers within the extra-cellular matrix (ECM)
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■ The aortic wall is a dynamic environment composed of cellular and
extracelluar components that have important regulatory functions that maintain
homeostasis
■ Dysfunction of one or more components of the cytoskeleton–receptor–
extracellular matrix complex can lead to structural and functional dysregulation
of aortic wall properties
■The transforming growth factor β1 pathway is important in matrix regulation
in health and disease, and increased activity is a key component of various
forms of thoracic aortic aneurysms (TAAs)
■TAAs are characterized by apoptosis and disarray of vascular smooth muscle
cells, fragmentation of elastin, inflammatory infiltration, and upregulation of
matrix metalloproteinases
Nature Reviews Cardiology, 2009
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Syndromic and Non-syndromic Forms of
Familial Forms of Thoracic Aortic Aneurysm
Mutations identified: fibrillin, TGF beta, ACTA2, MYH11, Notch1
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Aneurysm size and risk of complications
Elefteriades, Scientific American 2002
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“Hinge Points” of Increasing Risk
Elefteriades, JACC, 2010
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Genetic Diseases Affecting Aorta
• Bicuspid aortic valve
• Marfan syndrome
• Loeys-Dietz syndrome
• Turners Syndrome
• Ehlers-Danlos
• Familial Thoracic Aortic Aneurysm
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Bicuspid Aortic Valve
1-2% population
50-60% have ascending aorta dilatation
Faster growth rates than trileaflet Aovalves
Similar risk of rupture, except:➢ Aortic stenosis
➢ Coarctation
Intervention: > 5cm, growth > 0.5 cm/yr, valve pathology
More pts with BAV than all other forms of CHD combined!
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Marfan Syndrome
• Most common inherited
connective tissue disorder
• Cardinal features in skeletal,
ocular and cardiovascular
systems
• Premature mortality due to
aortic catastrophe
• Lifespan shortened by one third
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Marfan Syndrome Shortens Life ExpectancyBy a Third
Normal population
Marfan
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Marfan syndrome aneurysm
Ao dilation present at birth
Principally sinus aneurysm; valve usually competent
Rupture and dissection rare before age 12 but most common cause of death in MFS adults
Indications for surgery:➢ Root > 5cm
➢ Growth > 0.5cm/yr
➢ Progressive AI
➢ dissection
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Caveats for Marfan Aneurysm
Must replace sinuses
Prophylactic arch replacement not necessary
Reimplantation provides better anulus stabilization
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Modified Bentall Procedure
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Valve Sparing Aortic Root Replacement
Remodeling
(David II, Yacoub)
Reimplantation
(David I)
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Loeys-Dietz Syndrome
Hypertelorism Arterial tortuosity and aneurysm
Bifid uvula
Due to mutations in TGFB receptors that led to excess TGFβ signaling
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Natural history in 90 LDS patients
Mean age at death (n = 22): 26.1 yrs (6m - 43 yrs)Mean age at first surgery: 18.7 yrs (14m - 38yrs)Mean age at first dissection: 25.6 yrs (6m - 47yrs)Surgery or death in childhood (< 19yrs) n = 26; 34%Life-threatening events in pregnancy 7/11 pregnant women (64%)
(5 Aortic rupture; 2uterine ruptures
Cause of death:Thoracic aortic dissection n = 13Abdominal aortic dissection n = 6Subclavian artery dissection n = 1 Cerebral bleeding: n = 2
Arterial Aneurysms/dissections n= 129):Ascending aorta n = 68Abdominal aorta n = 9Transverse aorta n = 9 Descending aorta n = 9Thoracic circulation n = 19Cerebral circulation n = 9Abdominal circulation n = 6
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Loeys-Dietz Syndrome (LDS)
Surgical approach similar to Marfan syndromeEarlier intervention➢Children: Ao root > 3cm➢Adults: Ao root > 4cm
Require thorough imaging of entire vascular tree Close follow and surveillance imaging are important
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Matura, Circ 2007
Intervention recommended at >3.5 cm or > 2-2.5 cm/m²
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Ehlers-Danlos Syndrome(Type IV, Vascular)
• Joint hypermobility, skin hyperelasticity, tissue fragility due to abnormal collagen
• 1 in 50,000 births; autosomal dominant; half are new mutations
• Life expectancy 48 years; by 40 years, 80% of pts have major complications (60% vascular)
• Rupture at any diameter; aneurysm frequently absent
• 5-10 % operative mortality; 40% have bleeding or anastamotic complications
• Genes responsible COL5A1/2
• Also collagen testing
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Distribution of Vascular Complications in EDS IV
Oderich et al, J Vasc Surg 2005
Often
without
aneurysm!
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New Insights into
Pathogenesis
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Mutations in the gene
encoding fibrillin-1 (FBN1)
cause Marfan Syndrome
Discovered in 1991
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Microfibrils (fibrillin-1)
Elastic fiber
The dogma: Microfibrils are needed for elastic
fiber assembly and therefore Marfan syndrome
manifests failed elastogenesis.
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How could structural failure of tissues cause bone overgrowth?
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Skeletal and Morphologic Features of the Marfan Mouse
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Aortic dissection in a mouse model of Marfan syndrome
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From Fibrillin Mutation to TGFβ
▪ Using human genome database, a sequence homology was identified between fibrillinand TGFβ binding (Dietz)
▪ High levels of TGF β seen in Marfan mouse tissues
▪ In other models, TGFB mutations known to lead to overproduction of collagen and disarray of elastin
▪ Potent stimulator of collagen-producing fibroblasts
▪ Fibrillin is a regulator of TGFβ; fibrillinmutation leads to excess TGFβ signaling
▪ Anti-TGF β antibody given to Marfanmouse prevented aneurysm
TGFβ
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Gro
wth
(m
m)
Postnatal losartan inhibits aortic growth
in Marfan mice
p = 0.001 p = 0.02
p < 0.0001
p < 0.0001
NS
Wild-type Placebo Propranolol Losartan
n = 11 n = 10 n = 7 n = 5
C1039G/+
mm
/ 6
month
s
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Wild-type C1039G/+ (Propranolol)
C1039G/+ (Losartan)C1039G/+ (Losartan)
C1039G/+ (Placebo)
C1039G/+ (Losartan)
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20
22
24
26
28
30
32
0 10 20 30
26
28
30
32
34
36
38
0 20 40 60
Aortic Growth in 2 MFS Children Treated
with Losartan
Root
Dim
ensio
n(m
m)
Age (months) Age (months)
-blocker
Losartan
-blocker
ACE
Losartan
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• 608 pts with Marfan syndrome
• Mean age 11 yrs (6 mos - 25 yrs)
• Baseline aortic root Z-score >3
• Randomized to Atenolol versus Losartan
• Both drugs reduced Z-score over 3 years
• No significant difference between Atenolol and Losartan
• ?Equivalent dosing
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Genetic Testing and Aortic Disease
▪ Most common genes are FBN1, TGFß 1
and 2, ACTA2, MYH11, and SMAD 3
▪ Array testing usually includes 15-20 genes
▪ May confirm diagnosis and modify
threshold for intervention
▪ Genetic counselling
▪ Cost < $500/panel or $2500-$4500 exome
▪ Insurance coverage is variable
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Only 25% of thoracic aneurysm patients had mutations!
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Did Lincoln
have the
Marfan
syndrome?
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Conclusions
▪ Genetic conditions underlie many aortopathies (particularly Marfan syndrome, Loeys-Dietz syndrome, and probably bicuspid aortic valve)
▪ Specific syndromes or mutations will modify threshold for surgery previously based on aortic diameter alone
▪ TGF β signaling may be a final common pathway for many aneurysm syndromes and disease scenarios
▪ When TAD is no longer viewed as a simple degenerative process, the outlook for prophylactic interventions may be improved
▪ The role of genetic screening and gene therapy remains unclear