Bloedvatmisvorming - kennismakersLindsay et al, Nat Genet, 2012 Bertoli-Avella, JACC, 2015 •Study Marfan fibrillin-1 mouse models Growth factor: ... ACE Losartan Brooke et al., New

Bloedvatmisvorming: van oude moleculen tot nieuwe geneesmiddelen

Marfan syndrome and related disorders: a paradigm for thoracic aortic aneurysm

Bart LOEYS, MD, PhDCenter for Medical GeneticsAntwerp University Hospital

University of Antwerp

The AORTA

NORMAL ABNORMAL

ANEURYSM

Aortic aneurysm/dissection

Aortic dissection is cause of death in 1-2% of the western population

Verstraeten et al, Nat Rev Cardiol, 2017

• Older age

• M/F 6:1 ratio

• Occasional family history

• Risk factors: hypertension, smoking, atherosclerosis,…

• Genetic predisposition

• Risk genes identified: DAB2IP (9q33), LRP1 (12q13), ANRIL(9p21), contactin (3p12)

• Other loci: 19q13 and 4q33

• SNPs in several candidate genes

• Young age

• M/F 1.7:1 ratio

• 20% positive family history

• Few or no other risk factors

• Strong genetic influence

• Genes and loci identified:

Syndromic forms:COL3A1, COL1A2, FBN1, TGFBR1/2, GLUT10, FBLN4, FLNA,

SMAD2/3, TGFB2/3, SKI, BGN

Non-syndromic forms: ACTA2, MYH11, MLCK, PRKG1, MFAP5, FOXE3, LOX, MAT2A,

SMAD6, BAV loci

Abdominal aortic aneurysm Thoracic aortic aneurysm

Aortic Aneurysms


TGFβ signaling

Extracellular

matrixFBLN4ELN

TGFBR1TGFBR2

SMAD2SMAD3SMAD4SMAD6

FBN1

SLC2A10

ACTA2

MFAP5

COL3A1

FLNA

LOX

MAT2A

FBN2

SKI

EMELIN1

PLOD1

MYH11

PRKG1MLCK

FOXE3

NOTCH1

Vascular smooth

muscle cell

BGN

Thoracic aortic aneurysm/dissection


Thoracic aortic aneurysm/dissection

Familial cases 20%

Sporadic cases 80%

Non-syndromic 15%

Syndromic 5%FTAAD

Marfan

Loeys-Dietz

Ehlers-Danlos

Arterial tortuosity

…


Aortic aneurysm/dissection: treatment

Early and timely recognition saves lifes !

Aortic dissection:50% mortality in first 24 hours

After surgery:Normal lifespan, but recurrence

Medication -Beta-blocker: slows progression

Study of rare monogenic disease as a paradigm for the study of common disease

Marfan syndrome&

Loeys-Dietz syndrome

Thoracic aortic aneurysm

Marfan syndrome

Autosomal dominant, 30% de novo

Deficiency of FIBRILLIN-1 (FBN1)

Clinical diagnosis based on nosology

Loeys et al, JMG, 2010

Old vision on pathomechanism of aneurysm: structural failure of the extra-cellular matrix

What is the cause of Marfan syndrome ?

FIBRILLIN-1 protein

MICROFIBRIL

MICROFIBRIL + ELASTIN = ELASTIC FIBER

Shortage or poor quality FIBRILLIN-1 (FBN1)

Marfan

TGFβ complexActive TGFβ

Normal

Study of Marfan mouse models shows that phenotypical

manifestations of MFS are the consequence of

dysregulated activation of the TGFβ signaling pathway

Neptune et al, Nat Genet, 2003

New insight on pathomechanism: functional role of extra-cellular matrix

New insight: discovery of new

disease and new disease genes

Loeys-Dietz syndrome TGFbeta signaling genes: TGFBR1/2, TGFB2/3, SMAD2/3

Loeys et al, Nat Genet, 2005Loeys et al, NEJM, 2006

Lindsay et al, Nat Genet, 2012Bertoli-Avella, JACC, 2015

• Study Marfan fibrillin-1 mouse models

Growth factor: TGFbeta ↑

Destruction extracellular matrix

• Discovery of Loeys-Dietz syndrome and its pathogenesis (TGFbeta related genes)

New vision on aneurysm pathogenesis

New therapeutic strategy:

blocking TGFbeta in Marfan mouse model

PLACEBO Beta-BLOCKER TGFbetaneutralizing

antibody

Habashi et al, Science, 2006

P

PPP P

Smad2/3

Smad4

I-Smads

6 or 7

TGF-b

L

T

B

P

TGF-b

P

TF

Smad2/3

Smad4

Smad2/3

losartan

losartan

AngII

P Smad2/3

Rodriguez-Vita et al. Circulation 111:2509, 2005

Losartan (ARB): new use for an old molecule

Habashi et al, Science 2006

New therapeutic strategy:

Marfan mouse clinical trial


Wt Fbn1 C1039G/+

placebo Propranolol

(beta-blocker)

Losartan

(ATR1-blocker)

Follow aortic root diameter by echocardiography

Mouse clinical trial


Mouse clinical trial

Habashi et al, Science, 2006

WT Marfan Fbn1 C1039G/+

placeboPropranolol

(beta-blocker)

Losartan

(AR-blocker)

Therapeutic Response to ARBs

in Marfan patients

1.5

2

2.5

3

3.5

4

0 2 4

Ao

Roo

t (cm

)

Age (years)

Irbesartan (150)

Los

βB

Acei

Dim

en

sio

n a

t S

OV

(m

m)

14

18

22

26

30

34

0 10 20

Age (months)

b-blocker

ACEi

Surgery

32

37

42

47

52

2 4 6 8

b-blocker

ACEi

Surgery

Age (years)

20

22

24

26

28

30

32

0 10 20 30

26

28

30

32

34

36

38

0 20 40 60

Dim

en

sio

n a

t S

OV

(m

m)

Age (months) Age (months)

b-blocker

Losartan

b-blocker

ACE

Losartan

Brooke et al., New Engl J Med, 2008

Lacro et al, NEJM, 2014

• No significant difference in the rate of aortic-root dilation between the two treatment groups over 3 years.• The used dose of atenolol was higher (2.7 mg/kg/day, up to 4 mg/kg/day) than routinely prescribed now.

P=0.08

P=0.2

Rate of Change in ARzRate of Change in

Aortic-Root Absolute Diameter


AtenololLosartan

Atenolol: 0.069±0.004 cm/yearLosartan: 0.075±0.004 cm/year

Atenolol: -0.139±0.013 SD units/yearLosartan: -0.107±0.013 SD units/year

Marfan patient trial results


Marfan patient trial results

Future questions:

1. Is combined ARB/β-blocker treatment superior ?

2. Is high dose ARBs better than high dose β-blocker ?

3. Are there other treatment options ?

Dose matters in Marfan mouse models !

Marfan mice

New treatment options emerge…

Angiotensin II

AT1R AT2R

TGFβ PLC

DAG IP3

PKC

pERK1/2 (+/- pJNK, pp38)

Target Genes

losartan

NAb

RDEA119

Enzastaurin

Hydralazine

Conclusions

1. Study of mouse models and molecular deciphering of rare monogenic aneurysmal conditions reveal new pathways and novel targets for treatment.

2. Treatments aiming at reduction of TGFbeta activity, such as angiotensin receptor 1 blockers, can be considered for cardiovascular disease prevention; starting earlier is beneficial

3. Each new discovery brings new questions…

NOG

ACKNOWLEDGEMENTSAntwerpen: Elisabeth Gillis, Dorien Schepers, Dorien Proost, Ilse Luyckx, Nikhita Bolar, Jeannette Meester, Elyssa Cannaerts, Aleksandra Nijak, Eline Simons, Gerarda van de Beek, Celine Geryl, Jarl Bastianen, Ajay Kumar, Emeline Van Craenenbroeck, Johan Saenen, Lieven Laga, Inez Rodrigus, Aline Verstraeten, Maaike Alaerts, Lut Van Laer, Geert MortierBaltimore: Gretchen McCarrick, Jennifer Habashi, Alex & Jef Doyle, Elena Gallo, Hal DietzNIH-trial: Ron Lacro, Lynn Mahony, Pediatric Heart Network investigatorsLeiden: Boudewijn Kruithof, Marie-José GoumansOsaka/Kobe/Hokkaido: Hiroko & Takayuki Morisaki, Kenji Minatoya, Ritsu Matsukawa, Takuro Tsukube, NoriakiKuboNijmegen: Marlies Kempers, Simone Salemink, Janneke Timmermans, Han BrunnerRotterdam: Aida Bertoli-Avelli, Judith Verhaegen, Ingrid van de Laar, Marja Wessels, Jolien Roos-HesselinkHeidelberg: Christina Evers; Subiaco: Gareth Bayram; Birmingham: Julie Vogt; Ottawa: Julie Richer, Luc Beauchesne; Lausanne: Andrea Superti-Furga, Sheila Unger; Chicago: Lucianne Young; Nashville: Larry Markham; Leuven/Kortrijk: Koen Devriendt, Michiel Dumoulein

Thank you !

Documents

Bloedvatmisvorming - kennismakersLindsay et al, Nat Genet, 2012 Bertoli-Avella, JACC, 2015 •Study Marfan fibrillin-1 mouse models Growth factor: ... ACE Losartan Brooke et al., New