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Bloedvatmisvorming - kennismakersLindsay et al, Nat Genet, 2012 Bertoli-Avella, JACC, 2015 •Study...
Transcript of Bloedvatmisvorming - kennismakersLindsay et al, Nat Genet, 2012 Bertoli-Avella, JACC, 2015 •Study...
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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
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The AORTA
NORMAL ABNORMAL
ANEURYSM
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Aortic aneurysm/dissection
Aortic dissection is cause of death in 1-2% of the western population
Verstraeten et al, Nat Rev Cardiol, 2017
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• 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
Verstraeten et al, Nat Rev Cardiol, 2017
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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
Verstraeten et al, Nat Rev Cardiol, 2017
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Thoracic aortic aneurysm/dissection
Familial cases 20%
Sporadic cases 80%
Non-syndromic 15%
Syndromic 5%FTAAD
Marfan
Loeys-Dietz
Ehlers-Danlos
Arterial tortuosity
…
Verstraeten et al, Nat Rev Cardiol, 2017
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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
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Study of rare monogenic disease as a paradigm for the study of common disease
Marfan syndrome&
Loeys-Dietz syndrome
Thoracic aortic aneurysm
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Marfan syndrome
Autosomal dominant, 30% de novo
Deficiency of FIBRILLIN-1 (FBN1)
Clinical diagnosis based on nosology
Loeys et al, JMG, 2010
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Old vision on pathomechanism of aneurysm: structural failure of the extra-cellular matrix
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What is the cause of Marfan syndrome ?
FIBRILLIN-1 protein
MICROFIBRIL
MICROFIBRIL + ELASTIN = ELASTIC FIBER
Shortage or poor quality FIBRILLIN-1 (FBN1)
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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
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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
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• 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
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New therapeutic strategy:
blocking TGFbeta in Marfan mouse model
PLACEBO Beta-BLOCKER TGFbetaneutralizing
antibody
Habashi et al, Science, 2006
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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
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New therapeutic strategy:
Marfan mouse clinical trial
Habashi et al, Science 2006
Wt Fbn1 C1039G/+
placebo Propranolol
(beta-blocker)
Losartan
(ATR1-blocker)
Follow aortic root diameter by echocardiography
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Mouse clinical trial
Habashi et al, Science 2006
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Mouse clinical trial
Habashi et al, Science, 2006
WT Marfan Fbn1 C1039G/+
placeboPropranolol
(beta-blocker)
Losartan
(AR-blocker)
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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
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Lacro et al, NEJM, 2014
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• 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
Lacro et al, NEJM, 2014
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
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Lacro et al, NEJM, 2014
Marfan patient trial results
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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 ?
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Dose matters in Marfan mouse models !
Marfan mice
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New treatment options emerge…
Angiotensin II
AT1R AT2R
TGFβ PLC
DAG IP3
PKC
pERK1/2 (+/- pJNK, pp38)
Target Genes
losartan
NAb
RDEA119
Enzastaurin
Hydralazine
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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…
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NOG
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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
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Thank you !