Genetic Diseases Affecting the Aorta

Duke Cameron, MD

Division of Cardiac Surgery

There is no disease

more conducive to

clinical humility than

aneurysm of the

aorta.

Sir William Osler

All the science, I don’t understand….

It’s just my job 5 days a week.

Elton John, “Rocket Man”, 1972

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

Aneurysm Morphology

Sinus Ascending Aorta Post-surgical

R Lange, Ann Thor Surg, 2006

Complications of Aortic Aneurysms

Rupture/Dissection Aortic Regurgitation

patient age

heritability

genetic basis

smoothness

calcification

thrombus

debris

risk factors for atherosclerosis

Ascending aortic and descending thoracic/

abdominal aneurysms are two different diseases

The Lamellar Unit

A vascular smooth muscle cell (VSMC) sandwiched between

elastin layers within the extra-cellular matrix (ECM)

■ 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

Syndromic and Non-syndromic Forms of

Familial Forms of Thoracic Aortic Aneurysm

Mutations identified: fibrillin, TGF beta, ACTA2, MYH11, Notch1

Aneurysm size and risk of complications

Elefteriades, Scientific American 2002

“Hinge Points” of Increasing Risk

Elefteriades, JACC, 2010

Genetic Diseases Affecting Aorta

• Bicuspid aortic valve

• Marfan syndrome

• Loeys-Dietz syndrome

• Turners Syndrome

• Ehlers-Danlos

• Familial Thoracic Aortic Aneurysm

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!

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

Marfan Syndrome Shortens Life ExpectancyBy a Third

Normal population

Marfan

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

Caveats for Marfan Aneurysm

Must replace sinuses

Prophylactic arch replacement not necessary

Reimplantation provides better anulus stabilization

Modified Bentall Procedure

Valve Sparing Aortic Root Replacement

Remodeling

(David II, Yacoub)

Reimplantation

(David I)

Loeys-Dietz Syndrome

Hypertelorism Arterial tortuosity and aneurysm

Bifid uvula

Due to mutations in TGFB receptors that led to excess TGFβ signaling

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

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

Matura, Circ 2007

Intervention recommended at >3.5 cm or > 2-2.5 cm/m²

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

Distribution of Vascular Complications in EDS IV

Oderich et al, J Vasc Surg 2005

Often

without

aneurysm!

New Insights into

Pathogenesis

Mutations in the gene

encoding fibrillin-1 (FBN1)

cause Marfan Syndrome

Discovered in 1991

Microfibrils (fibrillin-1)

Elastic fiber

The dogma: Microfibrils are needed for elastic

fiber assembly and therefore Marfan syndrome

manifests failed elastogenesis.

How could structural failure of tissues cause bone overgrowth?

Skeletal and Morphologic Features of the Marfan Mouse

Aortic dissection in a mouse model of Marfan syndrome

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

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

Wild-type C1039G/+ (Propranolol)

C1039G/+ (Losartan)C1039G/+ (Losartan)

C1039G/+ (Placebo)

C1039G/+ (Losartan)

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

• 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

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

Only 25% of thoracic aneurysm patients had mutations!

Did Lincoln

have the

Marfan

syndrome?

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

Thank you

decameron@partners.org

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