Prevention of Thoracic Aortic Aneurysm Formation

the THORA - study

Prof.dr. BJM Mulder Prof.dr. MC DeRuiter

Cardiology Anatomy and Embryology

AMC LUMC

Principal investigatorsDr. MJ Goumans, Molecular Cellbiology, LUMCProf. dr. B Loeys, Clinical Genetics, RUNMC Prof. dr. CVC Bouten, Biomedical Engineering, TU/eProf. dr. AH Zwinderman, Clinical Epidemiology, Biostatistics & Bioinformatics, AMC

Disciplines: basic science- clinical practiceCardiology, Pathomorphology, Developmental Biology, Genetics, Thoracic Surgery, Biostatistics, Bioengineering, Computational Modelling

Participating centers nationwide AMC, LUMC, UMCG, RUNMC, EMC, UMCU, TUE

Consortium

Health Care problemProblem• Prevalence of Thoracic Aortic Aneurysm (TAA) in NL: 200.000; yearly > 2000 new cases.

• TAA may lead to aortic rupture or dissection (mortality rate 97%) • TAAs are responsible for 1 to 2% of mortality in the Western World ( ~ 2000 † in NL)

Aim of the study: Prevention of Thoracic Aortic Aneurysm formation/growth

Hypothesis• TAA’s can be classified in subgroups based on their genetic, developmental and

environmental background.

• TGF-β pathways play a crucial role in TAA.

• Classification will facilitate risk stratification, prevention of dissection and optimization of personalized clinical management.

Research plan

Research questions

WP1: Development/pathomorphology• What is the role of various embryonic cell populations in normal/abnormal formation of the aortic wall?• Which subgroups of aortic disease can be distinguished based on their clinical, morphological features?

WP2: Genetics • Are the different subtypes of TAA inheritable and which genetic variants are causal?• Which genetic variants (TGF-β pathway) can be identified for TAA development and validated in humans?

WP3: Disease modeling• How do hemodynamic loads affect aneurysm formation in tissue engineered disease models of TAA?• Can aneurysm formation & growth be predicted using computational and engineered disease modeling?

WP4: Clinical outcome and prevention • Will medical treatment or novel surgical approaches reduce aneurysm progression in mice/men?• Can phenotyping of patients identify patients at risk for progressive aortic aneurysm?

Unique combination of linking embryonic origin with prediction and prevention of TAA

TranslationDevelopmentpathomorphology

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)

Cell and tissue models of disease development

- Mechanotransduction

- Endothelial & cilial signaling

- Therapy testing

MRI/echo functional studies

Pharmaceutical interventionsin mouse models

- AT2 (losartan)- Statins- Doxycyclin- NSAID

Macro/microscopic phenotyping

BioBank, Fresh tissues

Retrospective study

patient cohorts, cross sectional studies,

medical interventions4. Marfan5. BAV6. CoA7. FTAAD8. Turner9. Pregnant women +TAA Prospective study

Computational models of hemodynamics

Prediction of aneurysm formation

Expression and epigenetics- RNA- miRNA expression- Methylation (tissues)

Clinical and surgical risk models for subgroups

Focus areas Dutch Heart Foundation

Focus consortium:• Identify risk factors for aneurysm development.

• Predict the heterogeneous time course of progressive aortic dilatation.

• Study gender differences, influence of pregnancy and aging.

WP1: Gender differences in phenotypic risk factors WP2: Gender differences in genetic markers for aortic aneurysm WP3: Gender differences in hemodynamic characteristics WP4: Gender differences in aneurysm growth, effect of e.g. Losartan / Statins / NSAID

Perspective

Dutch research• This project will accelerate basic knowledge in aneurysmal pathology, including

clinics, surgery, genetics and pathophysiology.

• Individual risk assessment may provide tailored medical and surgical treatment.

• Dissemination will ensure implementation in the Dutch clinics.

Europe/International research programs• Collaboration with existing partners in FP7 (Fighting Aneurysm Disease) will

probably be extended on the basis of this application.

• Collaboration with other large Marfan consortia (French, Belgian, British, Italian, American) is expected on various aspects, especially the genetic studies (Leducq, EU Framework Programme)

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)

Participants