Bloedvatmisvorming: van oude moleculen tot nieuwe geneesmiddelen Marfan syndrome and related disorders: a paradigm for thoracic aortic aneurysm Bart LOEYS, MD, PhD Center for Medical Genetics Antwerp University Hospital University of Antwerp
The AORTA ANEURYSM NORMAL ABNORMAL
Aortic aneurysm/dissection Aortic dissection is cause of death in 1-2% of the western population Verstraeten et al, Nat Rev Cardiol, 2017
Abdominal aortic aneurysm 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 Aortic Aneurysms Thoracic aortic aneurysm 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 Verstraeten et al, Nat Rev Cardiol, 2017
Thoracic aortic aneurysm/dissection Vascular smooth muscle cell PRKG1 MLCK NOTCH1 MYH11 FOXE3 ACTA2 TGFBR1 TGFBR2 FBLN4 LOX ELN MFAP5 FLNA FBN2 BGN PLOD1 COL3A1 SKI FBN1 EMELIN1 SMAD2 SMAD3 SMAD4 SMAD6 SLC2A10 Extracellular matrix MAT2A TGFβ signaling Verstraeten et al, Nat Rev Cardiol, 2017
Thoracic aortic aneurysm/dissection Familial cases 20% Non-syndromic 15% FTAAD Syndromic 5% Marfan Loeys-Dietz Ehlers-Danlos Arterial tortuosity Sporadic cases 80% Verstraeten et al, Nat Rev Cardiol, 2017
Aortic aneurysm/dissection: treatment Early and timely recognition saves lifes! Medication - Beta-blocker: slows progression Aortic dissection: 50% mortality in first 24 hours After surgery: Normal lifespan, but recurrence
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? Shortage or poor quality FIBRILLIN-1 (FBN1) FIBRILLIN-1 protein MICROFIBRIL MICROFIBRIL + ELASTIN = ELASTIC FIBER
New insight on pathomechanism: functional role of extra-cellular matrix Study of Marfan mouse models shows that phenotypical manifestations of MFS are the consequence of dysregulated activation of the TGFβ signaling pathway Normal TGFβ complex Marfan Active TGFβ Neptune et al, Nat Genet, 2003
Loeys et al, Nat Genet, 2005 Loeys et al, NEJM, 2006 Lindsay et al, Nat Genet, 2012 Bertoli-Avella, JACC, 2015 New insight: discovery of new disease and new disease genes Loeys-Dietz syndrome TGFbeta signaling genes: TGFBR1/2, TGFB2/3, SMAD2/3
New vision on aneurysm pathogenesis Study Marfan fibrillin-1 mouse models Growth factor: TGFbeta Destruction extracellular matrix Discovery of Loeys-Dietz syndrome and its pathogenesis (TGFbeta related genes)
New therapeutic strategy: blocking TGFbeta in Marfan mouse model PLACEBO Beta-BLOCKER TGFbeta neutralizing antibody Habashi et al, Science, 2006
Losartan (ARB): new use for an old molecule losartan AngII TGF-b losartan TGF-b L T B P Smad2/3 P P P P P Smad2/3 Smad4 Smad2/3 P I-Smads 6 or 7 Rodriguez-Vita et al. Circulation 111:2509, 2005 TF Smad4 Smad2/3 P Habashi et al, Science 2006
Wt New therapeutic strategy: Marfan mouse clinical trial Fbn1 C1039G/+ placebo Propranolol (beta-blocker) Losartan (ATR1-blocker) Follow aortic root diameter by echocardiography Habashi et al, Science 2006
Mouse clinical trial Habashi et al, Science 2006
Mouse clinical trial WT Marfan Fbn1 C1039G/+ placebo Propranolol (beta-blocker) Losartan (AR-blocker) Habashi et al, Science, 2006
Dimension at SOV (mm) Dimension at SOV (mm) Ao Root (cm) 34 30 26 22 18 14 b-blocker ACEi Therapeutic Response to ARBs Surgery 0 10 20 Age (months) 52 47 42 37 b-blocker ACEi in Marfan patients 32 2 4 6 8 Age (years) Surgery 4 3.5 3 2.5 2 1.5 Los Irbesartan (150) 0 2 4 βb Acei Age (years) 32 30 Losartan 38 36 Losartan 28 26 b-blocker 34 32 b-blocker ACE 24 30 22 28 20 0 10 20 30 Age (months) 26 0 20 40 60 Age (months) Brooke et al., New Engl J Med, 2008
Lacro et al, NEJM, 2014
Marfan patient trial results Rate of Change in ARz Atenolol Losartan Rate of Change in Aortic-Root Absolute Diameter P=0.2 P=0.08 Atenolol: -0.139±0.013 SD units/year Losartan: -0.107±0.013 SD units/year Atenolol: 0.069±0.004 cm/year Losartan: 0.075±0.004 cm/year 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. Lacro et al, NEJM, 2014
Marfan patient trial results Lacro et al, NEJM, 2014
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 losartan AT1R Angiotensin II AT2R NAb TGFβ PLC DAG IP3 Hydralazine PKC Enzastaurin RDEA119 perk1/2 (+/- pjnk, pp38) Target Genes
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
ACKNOWLEDGEMENTS Antwerpen: 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 Mortier Baltimore: Gretchen McCarrick, Jennifer Habashi, Alex & Jef Doyle, Elena Gallo, Hal Dietz NIH-trial: Ron Lacro, Lynn Mahony, Pediatric Heart Network investigators Leiden: Boudewijn Kruithof, Marie-José Goumans Osaka/Kobe/Hokkaido: Hiroko & Takayuki Morisaki, Kenji Minatoya, Ritsu Matsukawa, Takuro Tsukube, Noriaki Kubo Nijmegen: Marlies Kempers, Simone Salemink, Janneke Timmermans, Han Brunner Rotterdam: Aida Bertoli-Avelli, Judith Verhaegen, Ingrid van de Laar, Marja Wessels, Jolien Roos-Hesselink Heidelberg: 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!