the dilated aorta - washington university...

The Dilated Aorta: What Disease and How to Evaluate

Alan C. Braverman, MD, FACC

Alumni Endowed Professor in Cardiovascular Diseases Professor of Medicine

Director, Marfan Syndrome Clinic, Barnes-Jewish Hospital Director, Inpatient Cardiology Firm

Washington University School of Medicine, St. Louis, MO Chair, Professional Advisory Board, The Marfan Foundation

Disclosure

§  Nothing relevant to disclose

From: Braverman AC, Thompson R, Sanchez L. Diseases of the Aorta, Chapter 60. In, Bonow RO, Mann DL, Zipes DP, Libby P. Braunwald’s Heart Disease, 9th Edition. pp. 1309-1337 . Elsevier, Philadelphia. 2011

Why do I have a dilated aorta?

Why did I have an aortic dissection?

Am I at risk for an aortic aneurysm or dissection?

Clinicians Concerns in Thoracic Aortic Diseases

1. Accurate diagnosis of the underlying disease

2. Pharmacologic therapy

4. Lifestyle modification

3. Timing of aortic surgery

Thoracic aortic

aneurysm

Genetically triggered syndrome

Degenerative

Inflammatory Mechanical

Infectious

Marfan

Loeys-Dietz

FTAA

BAV aortopathy

vEDS

Turner syndrome

Others…

HTN

atherosclerosis

Giant cell arteritis

Non-specific aortitis

Takayasu’s arteritis

Reiter’s syndrome

Kawasaki disease

Behcet’s syndrome

Aortic dissection

Trauma

Bacterial

Staph, Salmonella

Syphilis

Fungal

Infected TEVAR

•  Marfan syndrome

•  Loeys-Dietz syndrome

•  Familial thoracic aortic aneurysm/dissection

•  Vascular Ehlers-Danlos syndrome •  Bicuspid aortic valve aortopathy

•  Turner Syndrome

Genetically Triggered Thoracic Aortic Disease

•  Marfan syndrome

•  Loeys-Dietz syndrome

•  Familial thoracic aortic aneurysm/dissection

Genetically Triggered Thoracic Aortic Disease

The different disorders leading to thoracic aortic

aneurysm have variable natural histories and different

inherent risks of aortic and branch vessel aneurysm and

dissection.

Importance of a Correct Diagnosis:

What are the Red Flags in Diagnosis of TAA Disease?

1. Family History:

TAA, aortic dissection

Bicuspid aortic valve

Cerebral aneurysm

Features of connective tissue disease

2. History and Physical examination

Marfan syndrome features FBN1

Marfan Syndrome

¨  Autosomal Dominant Connective Tissue Disorder

¨  FBN1 mutation (fibrillin-1) ¨  Incidence: 1:5000 – 1:10,000 ¨  25% Cases: Spontaneous Mutation ¨  Multisystem manifestations

Marfan Syndrome: Importance of Accurate Diagnosis

¨  May be diagnosed at birth or not recognized until late in life

¨  If unrecognized and untreated, the

average age of death in Marfan syndrome is ~45 years old.

¨  Aortic Complications (Aortic Dissection

and Aortic Regurgitation) are responsible for 90% of the Morbidity and Mortality in Marfan syndrome.

¨  Careful assessment and long term follow-

up are critical to the outcome of patients with Marfan syndrome.

¨  Median probability of survival is now into the 70’s.

Molecular Genetics of the Marfan Syndrome

FBN1 •  65 Exons spanning 235 kb of genomic DNA

•  encodes a 350 kDa glycoprotein—fibrillin-1

•  most mutations occur within the 47 tandemly repeated EGF-like domains,

--disrupts cysteine residues or Ca++ binding sites

~3200 mutations reported in FBN1 on Chromosome 15 causing Marfan syndrome.

What Does Marfan Syndrome Look Like?

Marfan Syndrome: Skeletal Features

• Facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)

Highly arched palate with dental crowding

Skeletal System

Sponseller PD, et al. J Bone Joint Surg Am 2010:92:1868-75

Ocular System

Minor Criteria: ¨  Abnormally flat cornea (as

measured by keratometry) ¨  Increased axial length of globe

(as measured by ultrasound)

¨  Hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis

Major Criterion:

•  Ectopia Lentis

Feature Value

Wrist and Thumb sign 3 Wrist or Thumb sign 1 Pectus Carinatum deformity 2 Pectus Excavatum or chest asymmetry 1 Hindfoot deformity 2 Plain flat foot (pes planus) 1 Pneumothorax 2 Dural Ectasia 2 Protrusio acetabulae 2 Reduced US/LS ratio and increased arm span/height 1 Scoliosis or thoracolumbar kyphosis 1 Reduced elbow extension 1 3 or 5 facial features 1 Skin striae 1 Myopia (>3 diopters) 1 Mitral valve prolapse 1

Systemic Features Scoring (> 7 points)

The Revised Ghent Nosology for the Marfan syndrome.

Bart Loeys, Harry Dietz, Alan C. Braverman, Bert Callewaert, Julie De Backer, Richard Devereux, Yvonne Hilhorst, Guillaume Jondeau, Laurence Faivre, Diane Milewicz, Reed

Pyeritz, Paul Sponseller, Paul Wordsworth, Anne De Paepe. J Med Genet 2010;47:476-485.

In the absence of family history:* (1) Ao (Z≥2) + EL = MFS (2) Ao (Z≥2) + FBN1 = MFS (3) Ao (Z≥2) + Syst (≥7pts) = MFS (4) EL + FBN1 with known Ao = MFS

In the presence of family history:* EL + FH of MFS (as defined above) = MFS Syst (≥7 pts) + FH of MFS (as defined above) = MFS Ao (Z≥3) + FH of MFS (as defined above) = MFS

absence of features suggesting an alternative disorder—i.e. LDS,SGS,FTAA


1. Family History:



Cerebral aneurysm



Marfan syndrome features

Bifid uvula, cleft palate

Velvety skin, visible veins

Hypertelorism, clubbed feet

Loeys-Dietz

TGFBR1/2

Loeys-Dietz Syndrome: TGFBR1 and TGFBR2 mutations

Hypertelerism Bifid/broad uvula Arterial tortuosity

Aortic aneurysm and dissection Branch vessel aneurysms

Craniosynostosis Club feet

Cutaneous features Blue sclera Scoliosis

Loeys-Dietz Syndrome

Aneurysm Syndromes Caused by Mutations in TGFB Receptors. Loeys et al. NEJM 2006;355:788

Correlation exists between the severity of craniofacial features and severity of cardiovascular phenotype and age of 1st cardiovascular event


Clues from Imaging Studies:

Arterial tortuosity

ectasia of arteries

branch vessel dilatation or dissection

LDS, SMAD3, TGFB2

Skeletal Features in Loeys-Dietz Syndrome

Overlap with Marfan syndrome

joint laxity, pectus deformity, scoliosis, pes planus Distinct from Marfan syndrome

contractures of feet (talipes equinovarus) and fingers (campylodactyly)

Chiari malformations

cervical spine defects or instability/subluxation

Abnormalities of the Uvula in Loeys-Dietz Syndrome

Bifid uvula, trilobed uvula, broad uvula, prominent raphe

Cutaneous Features in Loeys-Dietz Syndrome

Velvety, translucent skin with visible veins

Easy bruising,

Wound healing may be delayed. Some scars dystrophic


1. Family History:



Cerebral aneurysm






Hypertelorism, club feet

Loeys-Dietz

TGFBR1/2


1. Family History:



Cerebral aneurysm






Hypertelorism, clubfeet

Loeys-Dietz

TGFBR1/2

TGFB2, TGFB3

1. Family History:



Cerebral aneurysm







Loeys-Dietz

TGFBR1/2

TGFB2/3 Osteoarthritis SMAD3


1. Family History:



Cerebral aneurysm







Livedo reticularis, PDA, premature CAD, CVD, Moya-Moya

FTAA/D ACTA2

MYH11 PDA


Familial Thoracic Aortic Aneurysm and Dissection FTAA/D

Molecular Genetics in FTAA/D Syndromes: Gene Panels •  ACTA2 SMC α-actin (10-14% of FTTA/D)

Associated with livedo reticularis, PDA, BAV, iris flocculi, cerebral aneurysms, premature CAD

•  MYH11 (myosin heavy chain 11) 16p13.13-p13.12 (1%)

Associated with patent ductus arteriosus, livedo reticularis, BAV

•  MLCK (myosin light chain kinase) (1%)

•  SMAD3 (aneurysms and premature osteoarthritis) 15q22.33 (3%)

•  TGFBR1 (2%);

•  TGFBR2 (4%)

•  TGFB2-ligand loss of function mutations

•  TGFB3

•  COL3A1; COL5A1, SKI, FLNA, SLC2A10

•  More to come….

20% of individuals with TAA or Type A aortic dissection have an affected 1st degree relative. Coady et al. Arch Surg 1999; 134:361-7

Familial Thoracic Aortic Aneurysm and Dissection FTAA/D

Molecular Genetics in FTAA/D Syndromes: Gene Panels •  ACTA2 SMC α-actin (10-14% of FTTA/D)

Associated with livedo reticularis, PDA, BAV, iris flocculi, cerebral aneurysms, premature CAD

•  MYH11 (myosin heavy chain 11) 16p13.13-p13.12 (1%)

Associated with patent ductus arteriosus, livedo reticularis, BAV

•  MLCK (myosin light chain kinase) (1%)

•  SMAD3 (aneurysms and premature osteoarthritis) 15q22.33 (3%)

•  TGFBR1 (2%);

•  TGFBR2 (4%)

•  TGFB2-ligand loss of function mutations

•  TGFB3

•  COL3A1; COL5A1, SKI, FLNA, SLC2A10

•  More to come….

20% of individuals with TAA or Type A aortic dissection have an affected 1st degree relative. Coady et al. Arch Surg 1999; 134:361-7

In many families with TAA aneurysm or dissection, a specific mutation in one of these genes will not be present.



56 year old woman with acute type A aortic dissection



Lumbosacral Dural Ectasia

MFS FBN1

LDS TGFBR1/2, TGFB2, SMAD3

vEDS COL 3A1



Pattern of Aortic Dilatation SOV, Aortic Root

MFS, LDS, SMAD3, TGFB2, others



Pattern of Aortic Dilatation Ascending Aorta

BAV disease

ACTA2

MYH11

overlap

“Medical Management” of Thoracic Aortic Aneurysm Disease

Pharmacotherapy Education Advocacy Lifestyle modification Exercise guidelines Pregnancy guidelines

•  Theoretical benefits of pharmacologic therapy.

Lower BP, less aortic stress, anti-inflammatory

•  Animal (mouse) model data.

•  Studies in humans are very limited.

Controlling HTN, smoking cessation, and treating hyperlipidemia is recommended for patients with TAA disease.

Medical Therapy in Thoracic Aortic Aneurysm Disease: Caveats

Progression of Aortic Dilatation and the Benefit of Long-Term Beta-Adrenergic Blockade in Marfan’s Syndrome

Shores et al. New Engl J Med 1994;330:1335-1341.

Beneficial Effects of Beta Blockers:

•  Decreased rate of aortic root enlargement •  Fewer patients developed aortic dissection

TAD guidelines recommend beta blocker therapy in patients with Marfan syndrome to reduce the rate of aortic dilatation.1

1Hiratzka LF, et al. Guidelines for the diagnosis and management of patients with thoracic aortic disease. J Am Coll Cardiol. 2010;55:e27-e129.

TGFβ stimulates both canonical (SMAD) and non-canonical pathways. Perinatal antagonism of TGF-β using neutralizing antibody rescues pathologic phenotype in Marfan mice. AT1-receptor blockade (using angiotensin receptor blocker Losartan) induces a decrease in TGF-β signaling.

Doyle JJ, Gerber EE, Dietz HC. FEBS Letters 2012;586:2003-15

Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome

Habashi JP, Judge DP et al. Science 2006;312:117-121

ARB Therapy in Marfan Syndrome Brooke et al. NEJM 2008;358:2787

17 pts aged 14 months to 16 years who had received ARB therapy for >1 year.

These pts had severe aortic enlargement (mean z-score of 7.2 at time of ARB therapy).

Pts on ARB therapy had significant decrease in the rate of change of aortic root diameter (3.5 mm/yr vs. 0.5 mm/yr).

Change in Aortic-Root Diameter Standardized According to the Time of Initiation of Therapy with an Angiotensin II–Receptor Blocker (ARB).

ARB Trials in Marfan Syndrome

Randomized Trial of Atenolol Versus Losartan in Children and Young Adults

with Marfan Syndrome

Ronald V. Lacro, Harry C. Dietz, Lynn A. Sleeper, Anji T. Yetman, Timothy J. Bradley, Steven D. Colan, Gail D. Pearson, Elif Seda Selamet Tierney, Jami C. Levine, Andrew M. Atz, D. Woodrow Benson, Alan C. Braverman, Shan Chen, Julie De Backer, Bruce D. Gelb, Paul D. Grossfeld, Gloria L.

Klein, Wyman W. Lai, Aimee Liou, Bart L. Loeys, Larry W. Markham, Aaron K. Olson, Stephen M. Paridon, Victoria L. Pemberton, Mary Ella Pierpont,

Reed E. Pyeritz, Elizabeth Radojewski, Mary J. Roman, Angela M. Sharkey, Mario P. Stylianou, Stephanie Burns Wechsler, Luciana T. Young,

Lynn Mahony for the Pediatric Heart Network Investigators

Losartan reduces aortic dilatation rates in adults with Marfan syndrome: a randomized controlled trial.

Groenink M et al. Eur Heart J 2013:34;3491-50.

Multicenter, open-label, RCT with blinded assessments Losartan added to prior treatment in operated and unoperated Marfan patients (72% on beta blocker therapy) 233 patients (38 + 13 years, 47% females) followed 3.1 + 0.4 years

Aortic root size ~44 mm

116 treated with losartan; 117 treated with no add’l treatment 100 mg in 63 pts (54%) 50 mg in 34 pts (29%) 15% patients stopped losartan due to side effects

Losartan reduces aortic dilatation rates in adults with Marfan syndrome: a randomized controlled trial.

Groenink M et al. Eur Heart J 2013:34;3491-50.

Outcome MRI

(change in mm/3 years)

Control N=105

Losartan N=113 P-value

Aortic root 1.35 + 1.55 0.77 + 1.36 0.014 Ascending

aorta 0.85 + 1.23 0.78 + 1.32 0.726

Aortic arch 0.61 + 1.35 0.52 + 1.37 0.598 Descending aorta (PA) 0.72 + 1.40 0.54 + 1.40 0.366

Outcome TTE

Aortic root 1.93 + 1.39 1.34 + 1.51 0.021

19 pts underwent prophylactic aortic root replacement. No difference between groups.

Ha et al. Radiographics 2007

Prophylactic Aortic Root Surgery in the Marfan Syndrome

When the aortic root reaches 5 cm*

Patients, n Event, n Follow-Up, patient-y Annual Risk, % (95% CI)

Aortic event without surgery

Aortic diameter (mm)

0–39 423 2 2353 0.09 (0.00–0.20)

40–44 219 1 995 0.10 (0.00–0.30)

45–49 157 2 675 0.30 (0.00–0.71)

50–54 54 1 75 1.33 (0.00–3.93)

55–59 14 1 12 8.14 (0.00–24.10)

Aortic event with surgery

Aortic diameter (mm)

0–39 423 7 2353 0.30 (0.08–0.52)

40–44 219 3 995 0.30 (0.00–0.64)

45–49 157 31 675 4.59 (2.98–6.21)

50–54 54 39 75 51.75 (35.51–68.00)

55–59 14 12 12 97.68 (42.41–100.00)

Annual Aortic Risk Depends Upon Aortic Size (732 patients, mean f/u 6.6 years) Jondeau G et al. Circulation 2012;125:226-232

Aortic Root Replacement in Marfan Syndrome

Special Considerations:

1. Family history of aortic dissection

2. Diffuse aortic enlargement

4. Rapid aortic growth rate (>5 mm/year)

5. Body surface area and gender

6. Requirement for mitral valve surgery

7. Aortic valve regurgitation 8. The patient’s desire to go forward now!

3. Prior type B aortic dissection

“Not All Aortic Aneurysms are Equal”

Underlying disease: LDS > MFS > BAV Family history of aortic dissection (size of aorta)

Rapid growth of aorta: 4 4.3 4.6 4.9 cm

4 4.1 4.1 4.2 cm

Body size/: 4.9 cm aorta in 6’5”, 235 lb (2 cm/m2) versus Gender 4.9 cm aorta in 5’9”, 125 lb (2.95 cm/m2)

Other predictors: ?biomarkers (TGF-β, microfibrils, fibrillin); aortic elasticity; wall stress /dynamic flow measurements; arterial tortuosity

18 patients (55%) underwent prophylactic aortic root replacement at a mean age of 25 + 14 yrs. 13 VSRR; 4 CVG; 1 homograft

LDS Adults (n=33)

TGFBR1 (n=16) TGFBR2 (n=17)

Aortic surgery 7 (44%) 16 (94%) Prophylactic aortic root replacement 6 (37.5%) 13 (71%)

Age at time of surgery (years)

33 + 19

21 + 9

Aortic size at time of prophylactic surgery (mm) 49 + 3 45 + 4

Descending TAA resection (non-dissection) 0 3 (18%)

Aortic dissection 2 (13%) 6 (35%)

Patient Mutation LDS FH Aortic size

Aortic dissection type, year and age Aortic Surgery

*SC TGFBR2 1 Yes (AD 26 yrs) 3.9 cm Type I (1997)

age 23

1997 CVG, hemiarch, ASD closure 1997 TAA graft 2005 brachiocephalic aneurysm section; aorta to RSC and R carotid bypass 2006 debranching and TEVAR of descending aortic patch and visceral pseudoaneurysms Died 2006 complications

*LS TGFBR2 1 No unknown Type 1 (2006) Age 21

2006 CVG 2007 arch/descending TAA resection (6 cm) 2007  Distal descending and abdominal

aortic replacement (5.6 cm)

MS TGFBR2 1 Yes (AD 53 yrs)

4.0 cm (after AD)

Type 1 (2012) (above root graft)

Age 34 [postpartum]

1996 VSRR 2013 replacement of ascending aorta; arch and 2/3 of descending aorta

KK TGFBR2 1 Yes

3.4 cm (3 mo before

AD


Age 22

2006 VSRR (Yacoub) 2012 AVR/Root (bioprosthetic) 2013 Ascending/arch to prox descending for acute rupture.

*CL TGFBR1 2 No 7.0 cm Type II (2011) age 18 2011 CVG

*AR TGFBR2 2 Yes unknown Type 1 (2001) Age 27

2001 supracoronary graft after acute AD 2005 CVG for root dilatation and AR 2009 TAA graft (extent II)

JM TGFBR2 2 No 4.3 cm Arch (2007) Age 33

Died 2007during surgical repair of aortic dissection (Prophylactic VSRR 2001)

JF TGFBR1 2 Yes (AD 42 yrs) 2.8 cm Type III (2010)

Age 39 [postpartum] 2010 Descending aortic graft 2010 TEVAR descending aorta for rupture. 2011 Ascending and arch graft

Aortic Dissection in Loeys-Dietz Syndrome




age 23






4.0 cm (after AD)


Age 34 [postpartum]


KK TGFBR2 1 Yes

3.4 cm (3 mo before

AD

Ascending (2013) (above root graft)

Age 22













age 23






4.0 cm (after AD)


Age 34 [postpartum]


KK TGFBR2 1 Yes

3.4 cm (3 mo before

AD


Age 22










Condition Aortic Size Threshold for Prophylactic Surgery*†

TAA with TAV 5.5 cm

TAA with BAV *5.5 cm (5.0 cm if +FH of AD or rapid growth)

Marfan Syndrome 5.0 cm 4.5 cm (if +FH of AD < 5cm)

Loeys-Dietz syndrome

~4.0 cm 4.2 cm (TEE)

4.4-4.6 cm (CT/MR) Children with severe CF features…

ACTA2/MYH11 ?4.5-5.0 cm SMAD3 Same as for LDS#

TGFB2 ?<5 cm Other FTAA/D ?5 cm (or as dictated by FH)

Turner syndrome ?2.5 cm/m2

*ratio aortic root area (cm2)/height (m) >10; rapid growth; FH; BSA; and gender considerations. #Roos-Hesselink et al. JACC 2012;60:397

†Aortic dissection reported at aortic size smaller than threshold in all conditions.

Thoracic Aortic Aneurysm Disease: What Disease is It? How to Treat?

1. It is important to make an accurate diagnosis of the underlying disease associated with thoracic aortic aneurysm. There is overlap in the phenotypes of genetically triggered aneurysm syndromes. Many cases have subtle features.

2. Multiple genes predispose to thoracic aortic aneurysms. One should screen 1st degree relatives for TAA disease. Mutation analysis may be very helpful in evaluating patients and families.

3. Phenotypic variation is not uncommon, even in families with the same mutation. There are likely multiple mechanisms influencing expression of mutations including modifiers, other genes, environmental and other factors.

Thoracic Aortic Aneurysm Disease: What Disease is it? How to Treat?

4. Education and awareness of thoracic aortic aneurysm syndromes impacts outcomes. Lifestyle modifications related to pregnancy, physical activity, and work are important, and prophylactic aortic surgery is lifesaving.

5. Advances in molecular, genetic, translational, and clinical research as well as in medical and surgical therapy hold great promise for those with TAA disease.

Thank you

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