Pulmonary vascular remodelling: causes, mechanisms and consequences
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1 Pulmonary vascular remodelling: causes, mechanisms and consequences Ralph Schermuly Department of Pulmonary Pharmacotherapy University of Giessen and Marburg Lung Center
2 DECLARATION OF CONFLICT OF INTEREST Research Grant Research Grant Research Grant Research Grant Research Grant Research Grant Research Grant Research Grant Lecture Fee German Research Foundation, Excellence Cluster Cardio Pulmonary System (ECCPS) University of Giessen and Marburg Lung Center (UGMLC) Actelion Bayer-Schering Ergonex Noxxon Pfizer Gilead Bayer-Schering, Novartis, Pfizer
3 Definition Remodeling outward (positive) remodeling inward (negative) remodeling Structural changes of the vascular wall characterized by intimal, medial and adventitial thickening in response to hypoxia, inflammation, hemodynamic changes or vascular diseases
4 Remodeling affects all vascular layers Endothelium Media (smooth muscle cells) Adventitia (connective tissue)
5 UGMLC Tissue bank
6 Pulmonary vascular diseases Manifest PH CTD Severe PH PAP [ mm Hg ] 70 Latent PH: COPD Fibrosis Left heart failure Aging Cardiac Output [l/min]
7 Clinical Classification of Pulmonary Hypertension (Dana Point) 1. PAH Idiopathic PAH Heritable Drug- and toxin-induced Persistent PH of newborn Associated with: CTD HIV infection portal hypertension CHD schistosomiasis chronic hemolytic anemia 1. PVOD and/or PCH 2. PH Owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction Valvular disease 3. PH Owing to Lung Diseases and/or Hypoxia COPD ILD Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities 4. CTEPH 5. PH With Unclear Multifactorial Mechanisms Hematologic disorders Systemic disorders Metabolic disorders Others Simonneau G et al. J Am Coll Cardiol. 2009
8 Causes of pulmonary vascular remodeling Schermuly et al; Nat Rev Cardiol 2011
9 Changes in Paradigm Vasoconstriction Hyperproliferative Disease Fixed Pulmonary Hypertension Reverse Remodeling Healthy Resistance Vessel Remodeling Chronic Remodeling Loss of Patency Reverse Remodeling
10 Remodeling: (pseudo)malignant disease? Proliferation Apoptosis Metabolism Inflammation
![MCT[42d]/](/docs-images/77/76444504/images/11-4.jpg "RTK-I RTK-I")
![MCT[42d]](/docs-images/77/76444504/images/11-5.jpg "Control")
11 MCT[42d]/ RTK-I MCT[42d]/ RTK-I MCT[42d] MCT[42d] Control Control Effects of Imatinib on proliferation and apoptosis - Dapi + Dapi - Dapi + Dapi 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m 100 µ m PCNA-staining in situ TUNEL assay Schermuly et al., J Clin Invest, 2005
12 Level Pulmonary Vascular Remodeling: consequences Adaptive hypertrophy maladaptive hypertrophy I Preclinical/ No symptoms II Symptomatic / Stable III Progression / declining Pulm pressure RV function Cardiac output Therapeutic window Years Months Time
13 Outcome studies of right ventricular function in cardiovascular diseases Heart Failure PE PAH Banerjee et al., Curr Heart Fail Rep 2010
14 Hypothetical molecular and cellular mechanisms involved in the development of right-heart failure in pulmonary hypertension Bogaard et al., CHEST 2009
15 Model of RV Hypertrophy: Pulmonary Artery Banding (PAB)
16 Pulmonary Artery Banding (PAB) Ø ~ 0,4 mm material: titanium
17 MRI-Imaging
18 Short-axis view of a healthy mouse heart and its 3D reconstruction
19 Mouse Heart: Before and 5 Weeks after PAB Before surgery 5 weeks after PAB
20 Summary Pulmonary vascular remodeling involves intima, media and adventitia Causes: PAH (unknown, genetics, drugs, collagen vascular disease, HIV, schistosomiasis), left heart failure, hypoxia, pulmonary thrombosis,... Mechanisms: Vasoconstriction, proliferation/apoptosis, migration, metabolism and inflammation Consequences: right heart failure
21 University of Giessen Lung Center, Giessen Prof. Dr. Hossein Ardeschir Ghofrani Prof. Dr. Norbert Weißmann Prof. Dr. Friedrich Grimminger Prof. Dr. Werner Seeger Department of Lung Development and Remodelling, MPI for Heart and Lung Research Bad Nauheim Dr. Soni Pullamsetti Dr. Rajkumar Savai Supported by: DFG; BMBF; Excellence Cluster Cardio Pulmonary System (ECCPS); LOEWE University of Giessen and Marburg Lung Center (UGMLC); Max-Planck-Society
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