Diagnosis and Treatment of Genetic Aortopathies for the ... · Diagnosis and Treatment of Genetic...

©2018 MFMER | slide-1

Juan Bowen, MD

Diagnosis and Treatment of Genetic Aortopathiesfor the Practicing Cardiologist


Harisios Boudoulas, MDCharles Wooley, MD

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiZtP2_6YjeAhWf8oMKHV3TCBEQjRx6BAgBEAU&url=https://www.auth.gr/council/en/index_en.htm&psig=AOvVaw33gZIVknSa488HqRtDr2NQ&ust=1539705785627970


• Milestones and important discoveries

• Structure and function of the ascending aorta

• Making a specific genetic diagnosis – a guide for clinicians

• Medical management of genetic aortopathies

• Surgical management of genetic aortopathies

Diagnosis and treatment of genetic aortopathies


Marfan Syndrome Milestones

©2012 MFMER | 3209410-5

1896Antoine MarfanClinical description

1952Cooley & DeBakey

Thoracic aneurysm repair

1956Victor McKusick

Heritable Disorders of

Connective Tissue

1968Hugh BentallComposite graft

1991, 2003Hal Dietz

Fibrillin gene

TGFB

2007

Dianna Milewicz

VSMC mutations


Basic and Clinical Research

©2012 MFMER | 3209410-6

1991FBN1

2003TGFB

2014PHN TRIAL

AVR TRIAL

2007ACTA2

GenTAC

2013MAC

Aorta Journal


The elastic fiber network and aortic function


Elastic fiber fragmentation


40x

Verhoeff van Gieson Stain (Elastic Stain)

Normal


Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms

and Dissections Disrupt This Structure

Ashkan Karimi, MD, and Dianna M. Milewicz, MD, PhD

Canadian J of Cardiology 2016

Perrucci, et al.

Cell. Mol. Life Sci.

(2017) 74:267–277

Galllo MacFarlane Cold Spring Harbor Perspectives in Biology 2017


History

Exam

Imaging

Genetics

DIAGNOSIS

Diagnosis: As specific as possible

PLAN

Prognosis

Management

Lifelong Care


Comments on the medical history

• Personal history

• Cardiac

• Noncardiac

• Skin, eye, musculoskeletal

• Family history – Aortic and aortic valve disease, early death

• Symptoms


Comments on the physical examination

• Phenotype can be normal.

• Many features of connective tissue dysplasia are nonspecific.

• “Hard” findings are more meaningful than “soft” findings.

• CV – aortic and mitral valves.

• Non-CV – Skin, eye, musculoskeletal.


Ectopia lentisFBN


Imaging

Diagnosis

Monitoring

Non CV

CV


Comments on imaging

• Echocardiography - aortic root Z score

• CTA and MRA - gated

• First evaluation - chest/abdomen/pelvis

• Follow up imaging - individualized

0

1

23


40 mm 48 mm

Multimodality Imaging

Braaverman JACC VOL. 65, NO. 13, 2015



Marfan syndrome


MFS


MFS facial features

• Dolicocephaly

• Enophthalmos

• Downslanting palpebral

fissures

• Malar hypoplasia

• Retrognathia

Dolci, et al. Clinical Anatomy 31:380–386 (2018)


Aortic root aneurysm



MFS Systemic Score

Maximum score 20

Score ≥ 7 means systemic involvement

FAMILY HX MFS

One of the following

Ectopia lentis

Aortic dilation

Z-score ≥ 2 (age ≥ 20)

Z-score ≥ 3 (age <20)

Systemic score ≥ 7

1NO FAMILY HX MFS

Z-score ≥ 2 or dissection + EL

Z-score ≥ 2 or dissection + FBN1 mutation

Z-score ≥ 2 or dissection + SS ≥7

Aorta + Ectopia lentis + FBN1 mutation


MFS DIAGNOSIS

www.marfan.org

Wrist and thumb sign 3

Wrist OR thumb sign 2

Pectus carinatum 2

Pectus excavatum

or chest asymmetry 1

Hindfoot deformity 2

Pes planus 1

Pneumothorax 2

Dural ectasia 2

Protrusio acetabulae 2

↓ US/LS ratio AND

↑ Arm span/height 1 2

Scoliosis OR

thor-lumb kyphosis 1

↓ Elbow extension 1

3/5 Facial features 1

Skin striae 1

Myopia >3 diopters 1

Mitral valve prolapse 1 1


Risk assessement by genotype

• Truncating/splicing variants associated with aortic events.

• Haploinsufficiency mutations have more risk for aortic eventsthan dominant negative mutations.

Franken R, et al. Heart 2017;103:1795–1799.

FBN Mutation: haploinsufficiency vs. dominant-negative

Aortic root

(mm)

Age

60

50

40

30

5040302010 60 70


Loeys-Dietz syndrome


LDS

LDS


Arterial tortuosity

Multiple aneurysms


Are all TGF beta pathway mutations clinically equivalent?

Montalcino Aortic Consortium data

• TGFBR1 and TGFBR2 (n=441) - aggressive aneurysmal disease, hyertelorism, bifid uvula

• TGFB2 and TGFB3 – usually not as severe

• SMAD 3 (n=210) – later onset aortic events, osteoarthritis


Vascular Ehlers-Danlos syndrome


Age 33 renal artery dissection

Age 46 carotid-cavernous sinus fistula

Age 41 ruptured hepatic artery aneurysm



Aneurysms are often minimal


COL3A1 haploinsufficiency results in a variety of

Ehlers-Danlos syndrome type IV with delayed onset of

complications and longer life expectancy

Dru F. Leistritz, MS1, Melanie G. Pepin, MS1, Ulrike Schwarze, MD1, and Peter

H. Byers, MD1,2

Molecular diagnosis in vascular Ehlers-Danlos

syndrome predicts pattern of arterial involvement

and outcomes

Sherene Shalhub, MD, MPH,James H. Black III, MD, et al.


BAV Aortopathy


Ascending aorta

©2018 MFMER | slide-44©2012 MFMER | 3209410-44

BAV Aneurysm and Dissection Risk

0

10

20

30

0 5 10 15 20 25

Michelena et al: JAMA, 2011

%

Years after diagnosisNo. at Risk

Ao dissection 416 387 348 209 110 53

Ao Aneurysm 384 352 309 186 88 39

TAA

Dissection


BAV etiology and genetics

• Etiology of aneurysm is both developmental and hemodynamic.

• No single genetic/developmental cause

• The genetic component of bicuspid aortic valve. An exome-wide association study. Gago-Diaz et al. Journal of Molecular and Cellular Cardiology 2017.


Normal Aortic Flow BAV Aortic Flow

Intrinsic weakness + hemodynamic stress

Galian-Gay L, et al. Heart 2018;0:1–6.


Non-syndromic familial TAA genetic testingMutations found in 15-20%

Gene FTAAD (%)

ACTA2 10-14

TGFBR2 4

SMAD3 2

TGFBR1 1

MYH11 1

MYLK1 1

TGFB2 1


Familial TAA8%

Marfan56%

LDS3%

EDS9%

GCA2%

Arrteritis1%

BAV11%

MYLK1%

ACTA21%

MYH112%

SMAD31% TGFBR1

1%

TGFBR221%

COL3A12%

COL5A11%


Management


Protection of the aorta

• Physical activity recommendations

• Medication

www.marfan.org


Mild aerobic exercise blocks elastic fiber fragmentation and aortic dilatation

in a mouse model of Marfan syndrome associated aortic aneurysm

Gibson, et al. J Appl Physiol 123: 147-160 2017


MFS


Can the disease be modified?

Beta blockade - Grade B evidence

AT1R blockade - Mouse model followed by clinical trials

©2018 MFMER | slide-55©2012 MFMER | 3209410-55

Losartan prevents MFS complications in the mouse model

Habashi, Dietz et al: Science 2006


3,3

3,4

3,5

3,6

3,7

0 1 2 3

PHN Trial 2014: Changes in Aortic-Root Z Score and Aortic-Root Diameter, According to Treatment Group

3,6

3,8

4,0

4,2

4,4

0 1 2 3

Lacro et al: N Engl J Med 2014

Years since randomization Years since randomization

P=0.08 P=0.20

No. at risk

Atenolol 303 286 282 268

Losartan 303 293 279 267

No. at risk

Atenolol 303 287 282 268

Losartan 304 293 279 267

Ao

rtic

-ro

ot

z s

co

re

Maxim

um

ao

rtic

-ro

ot

dia

mete

r (c

m)

MFS Clinical trials

Franken et al> Nature Reviews Cardiology 2015


Timely preventive aortic repair is the primary treatment!


3 4 5 6

Timing of preventive aortic repair

cm


3 4 5 6

Timing of preventive aortic repair

Marfan

≥5.0 cm

Loeys-Dietz

>4.0 cm

cm

BAV

≥5.5 cm

High-risk features: FH or personal history of aortic dissection, rapid enlargement, or planned pregnancy


Selected issues relevant to practice in 2018

• The problem of the distal aorta.

• Clinically relevant biomarkers and tests of aortic function.

• The natural history of many genetic aortopathies is still being discovered.

• Quality of life problems – many are noncardiac.

Den Hertog, et al.

JACC VOL. 65, NO. 3, 2015

Percent free

from type B

dissection

Follow up years

100

80

90

70

60

50

40

5 10 15

Risk of type B dissection in MFS


Summary

• Genetic aortopathies are caused by mutations that affect aortic structureand function.

• The differential diagnosis includes syndromic disorders, vascular EDS, BAV aortopathy, and nonsyndromic familial TAA.

• In some genetic aortopathies the natural history is not fully known.

• Medical therapies are evolving.

• The primary treatment is preventive aortic repair.

• Care is individualized, interdisciplinary, and lifelong.


Thank you

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