Prevention of Thoracic Aortic Aneurysm Formation the THORA - study   Prof.dr. BJM Mulder     Prof.dr. MC DeRuiter Cardiolo...
Principal investigators Dr. MJ Goumans, Molecular Cellbiology, LUMC Prof. dr. B Loeys, Clinical Genetics, RUNMC  Prof. dr....
Health Care problem <ul><li>Problem </li></ul><ul><li>Prevalence of Thoracic Aortic Aneurysm (TAA) in NL: 200.000; yearly ...
Research plan THORA
Research questions <ul><li>WP1: Development/pathomorphology </li></ul><ul><li>What is the role of various embryonic cell p...
Translation THORA Development pathomorphology Genetics Disease Modeling Outcome and Prevention Animal Human Mice Models Fi...
Focus areas Dutch Heart Foundation <ul><li>Focus consortium: </li></ul><ul><li>Identify risk factors for aneurysm developm...
Perspective <ul><li>Dutch research </li></ul><ul><li>This project will accelerate basic knowledge in aneurysmal pathology,...
WP 1a: MRM Jongbloed (LUMC), J Lindeman (LUMC), J Essers (EMC) WP 1b: MM Bartelings (LUMC), RJM Klautz (LUMC), BJ Bouma (A...
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Presentatie Prof.dr. BJM Mulder en Prof.dr. MC DeRuiter

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Prevention of Thoracic Aortic Aneurysm Formation. The THORA - study

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Presentatie Prof.dr. BJM Mulder en Prof.dr. MC DeRuiter

  1. 1. Prevention of Thoracic Aortic Aneurysm Formation the THORA - study Prof.dr. BJM Mulder Prof.dr. MC DeRuiter Cardiology A natomy and Embryology AMC LUMC THORA
  2. 2. Principal investigators Dr. MJ Goumans, Molecular Cellbiology, LUMC Prof. dr. B Loeys, Clinical Genetics, RUNMC Prof. dr. CVC Bouten, Biomedical Engineering, TU/e Prof. dr. AH Zwinderman, Clinical Epidemiology, Biostatistics & Bioinformatics, AMC Disciplines: basic science- clinical practice Cardiology, Pathomorphology, Developmental Biology, Genetics, Thoracic Surgery, Biostatistics, Bioengineering, Computational Modelling Participating centers nationwide AMC, LUMC, UMCG, RUNMC, EMC, UMCU, TUE Consortium THORA
  3. 3. Health Care problem <ul><li>Problem </li></ul><ul><li>Prevalence of Thoracic Aortic Aneurysm (TAA) in NL: 200.000; yearly > 2000 new cases. </li></ul><ul><li>TAA may lead to aortic rupture or dissection (mortality rate 97%) </li></ul><ul><li>TAAs are responsible for 1 to 2% of mortality in the Western World ( ~ 2000 † in NL ) </li></ul><ul><li>Aim of the study : Prevention of Thoracic Aortic Aneurysm formation/growth </li></ul><ul><li>Hypothesis </li></ul><ul><li>TAA’s can be classified in subgroups based on their genetic, developmental and environmental background. </li></ul><ul><li>TGF-β pathways play a crucial role in TAA. </li></ul><ul><li>Classification will facilitate risk stratification, prevention of dissection and optimization of personalized clinical management. </li></ul>THORA
  4. 4. Research plan THORA
  5. 5. Research questions <ul><li>WP1: Development/pathomorphology </li></ul><ul><li>What is the role of various embryonic cell populations in normal/abnormal formation of the aortic wall? </li></ul><ul><li>Which subgroups of aortic disease can be distinguished based on their clinical, morphological features? </li></ul><ul><li>WP2: Genetics </li></ul><ul><li>Are the different subtypes of TAA inheritable and which genetic variants are causal? </li></ul><ul><li>Which genetic variants (TGF-β pathway) can be identified for TAA development and validated in humans? </li></ul><ul><li>WP3: Disease modeling </li></ul><ul><li>How do hemodynamic loads affect aneurysm formation in tissue engineered disease models of TAA? </li></ul><ul><li>Can aneurysm formation & growth be predicted using computational and engineered disease modeling? </li></ul><ul><li>WP4: Clinical outcome and prevention </li></ul><ul><li>Will medical treatment or novel surgical approaches reduce aneurysm progression in mice/men? </li></ul><ul><li>Can phenotyping of patients identify patients at risk for progressive aortic aneurysm? </li></ul><ul><li>Unique combination of linking embryonic origin with prediction and prevention of TAA </li></ul>THORA
  6. 6. Translation THORA Development pathomorphology Genetics Disease Modeling Outcome and Prevention Animal Human Mice Models Fibrillin1 -/- Fibulin 4 -/- Enos -/- ENG/ALK5 -/- Confetti lineage tracing crossed with Cre-lines Expression studies Microarray RNA Lineage specific signaling pathways Whole genome sequencing (blood, families) <ul><li>Cell and tissue models of disease development </li></ul><ul><li>- Mechanotransduction </li></ul><ul><li>Endothelial & cilial signaling </li></ul><ul><li>Therapy testing </li></ul>MRI/echo functional studies <ul><li>Pharmaceutical interventions </li></ul><ul><li>in mouse models </li></ul><ul><li>AT2 (losartan) </li></ul><ul><li>Statins </li></ul><ul><li>Doxycyclin </li></ul><ul><li>NSAID </li></ul>Macro/microscopic phenotyping BioBank, Fresh tissues Retrospective study <ul><li>patient cohorts, </li></ul><ul><li>cross sectional studies, </li></ul><ul><li>medical interventions </li></ul><ul><li>Marfan </li></ul><ul><li>BAV </li></ul><ul><li>CoA </li></ul><ul><li>FTAAD </li></ul><ul><li>Turner </li></ul><ul><li>Pregnant women +TAA </li></ul><ul><li>Prospective study </li></ul>Computational models of hemodynamics Prediction of aneurysm formation <ul><li>Expression and epigenetics </li></ul><ul><li>- RNA </li></ul><ul><li>- miRNA expression </li></ul><ul><li>Methylation (tissues) </li></ul>Clinical and surgical risk models for subgroups
  7. 7. Focus areas Dutch Heart Foundation <ul><li>Focus consortium: </li></ul><ul><li>Identify risk factors for aneurysm development. </li></ul><ul><li>Predict the heterogeneous time course of progressive aortic dilatation. </li></ul><ul><li>Study gender differences, influence of pregnancy and aging. </li></ul><ul><li>WP1: Gender differences in phenotypic risk factors </li></ul><ul><li>WP2: Gender differences in genetic markers for aortic aneurysm </li></ul><ul><li>WP3: Gender differences in hemodynamic characteristics </li></ul><ul><li>WP4: Gender differences in aneurysm growth, effect of e.g. Losartan / Statins / NSAID </li></ul>THORA
  8. 8. Perspective <ul><li>Dutch research </li></ul><ul><li>This project will accelerate basic knowledge in aneurysmal pathology, including clinics, surgery, genetics and pathophysiology. </li></ul><ul><li>Individual risk assessment may provide tailored medical and surgical treatment. </li></ul><ul><li>Dissemination will ensure implementation in the Dutch clinics. </li></ul><ul><li>Europe/International research programs </li></ul><ul><li>Collaboration with existing partners in FP7 (Fighting Aneurysm Disease) will probably be extended on the basis of this application. </li></ul><ul><li>Collaboration with other large Marfan consortia (French, Belgian, British, Italian, American) is expected on various aspects, especially the genetic studies (Leducq, EU Framework Programme) </li></ul>THORA
  9. 9. WP 1a: MRM Jongbloed (LUMC), J Lindeman (LUMC), J Essers (EMC) WP 1b: MM Bartelings (LUMC), RJM Klautz (LUMC), BJ Bouma (AMC), AJJC Bogers (EMC) WP 2a: RMW Hofstra (UMCG), AV Postma (AMC) WP 2b: CMA van Ravenswaay (UMCG), WS Kerstjens (UMCG) WP 3a: FPT Baayens (TUE), BP Hierck (LUMC), J Essers (EMC) WP 3b: FN van de Vosse (TUE), PH Schoof (UMCU), J Kluin (UMCU), M Groenink (AMC), AP van Dijk (RUNMC) WP 4a: MJ Goumans (LUMC), AH Zwinderman (AMC) WP 4b: PG Pieper (UMCG), JJM Takkenberg (EMC), MG Hazekamp (LUMC/AMC), J Timmermans (RUNMC), BJ Bouma (AMC), DR Koolbergen (LUMC/AMC) THORA Participants

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