Increased flow & pressure are the essential triggers Loss of - PowerPoint PPT Presentation

4/21/2018 Increased flow & pressure are the essential triggers Loss of reversibility in flow-induced pulmonary arterial hypertension is associated with a senescent vascular phenotype Diederik van der Feen, MD Dickinson, AJP 2013; Network van der Feen, Eur Heart J 2017 Pediatric Pulmonary Hypertension University Medical Center Groningen -Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Clinical Problems and Opportunities It has been difficult to ascertain: When PAH-CHD becomes irreversible • How can we recognize reversibility? Why PAH-CHD becomes irreversible Normalisation of Flow ( H aemodynamic U nloading) reverses PAH-CHD… • Why does the one patient with PAH-CHD reverse after HU and the other not? …but not after a certain point of no return. • Study the mechanisms that orchestrate the transition to irreversible PAH. van der Feen, Eur Heart J 2017 University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 1

4/21/2018 MCT+Shunt induces progressive PAH Haemodynamic Unloading by lung transplantation X MCT Sham 14 days 21 days 28 days University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases A Reversible and Irreversible vascular phenotype 21 days of HU Con X T14 T21 21 days T28 University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 2

4/21/2018 A signature of reversibility In PAH induced by MCt+Shunt: Reversal of vascular remodeling depends on the time point of haemodynamic unloading. Reversible (11) Similar to PAH in CHD RNA-Seq Control (5) Irreversible (8) irreversible reversible University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases A shifting balance of apoptosis & apoptosis resistance A phenotypical switch University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 3

4/21/2018 Proliferation is a feature of Reversible PAH only A mechanism that shuts down proliferation But is also related to progression University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases DNA Damage & DNA damage ... and its intricate relation with BMPR2 Irreversible growth arrest / Cellular Senescence Protects from cancer by Degenerative diseases inhibiting hyperproliferation Pathologic features: • Loss of function • Incapable of regeneration • Accumulate in tissue • Develop a senescence-associated secretory phenotype (SASP) • Pro-inflammatory • Promotes fibrosis Adopted from Li, AJRCM 2014 University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 4

4/21/2018 Senescence in PAH When DNA repair fails and damage accumulates... University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Development of a senescent vascular phenotype University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases 5

4/21/2018 Conclusions Further research Healthy DNA damage-induced Proliferating Senescence Identification of a point of no return in PAH induced by MCT+Shunt. Characterization of a vascular phenotype related to reversibility Reversible stage: Apoptosis, DNA repair and Proliferation Irreversible stage: Growth arrest, Apoptosis-Resistance, Inflammation Reversibility Switch: Premature Senescence University Medical Center Groningen Center for Congenital Heart diseases University Medical Center Groningen Center for Congenital Heart diseases Thank you! Vera Moulton Wall Center for Center for Congenital Experimental Cardiology Medical Genetics Pulmonary Vascular Disease Heart diseases Prof. Dr. Rudolf de Boer Dr. Klaas Kok Prof. Dr. Marlene Rabinovitch Prof. Dr. Rolf Berger Dr. Herman Silljé Dr. Jan Reinier Moonen Dr. Beatrijs Bartelds Dr. James Chappell Guido Bossers Medical Biology Lysanne Jorna Prof. Marco Harmsen Stanford Center of Biomedical Informatics Research Quint Hagdorn Ing. Arjen Petersen Prof. Purvesh Khatri Anne-Marie Koop Michel Weij Dr. Francesco Vallania Marlies Haarman Dr. Annemiek van Oosten Dr. Michele Donato Floris-Jan Ridderbos European Institute for Johan Vos the Biology of Aging Marco Demaria Sanna Arjaans Jaskaren Kohli Tom van Leusden University Medical Center Groningen Center for Congenital Heart diseases 6