1. Pulmonary Hypertension Understanding Management 2012 Majdy M Idrees Saudi Arabia www.saph.med.sa The Egyptian Society of Chest Disease The 53 rd International Congress Cairo, Egypt 27-30 March 2012

2. Circulation in the Lung Pulmonary circulation is a low- pressure system that supplies nutrients for the alveolar ducts and alveoli. Bronchial vessels from the systemic circulation <3% cardiac output for supply nutrition to the rest of the lung

3. Human Circulation Lung is only organ to receive entire cardiac output.

4. What is Pulmonary Hypertension? It is a hemodynamic state defined as mPAP > 25 mmHg, as measured by RHC

5. MuscularPartially MuscularNon Muscular Circulation in the Lung

6. Muscular artery lumen A M I sensors and effectors transmit changes in flow and pressure through the release of vasoregulator and growth factors. Circulation in the Lung

7. Dynamic of PH pathology Pulmonary Vascular Diseases Pulmonary Vascular Resistance Pulmonary Hypertension Remodelling Vascular tone Progress of the diseases

8. Endothelial Function Vasoconstriction Endothelin-1 Angiotensin II Serotonin NO PGI2 ANP Adrenomodullin

9. Endothelial Function Vasodilatation Vasocostriction Endothelin-1 Angiotensin II Serotonin NO PGI2 ANP Adrenomodullin Pulmonary hypertension

10. Smooth Muscle VASCONSTRICTORY PATHWAY ET-1 ANG II Gq PCR Phospholipase C PKC DAG IP3 Ca +2 VASOCONSTRICTION 5HT Gi PCR ATP cAMP Adenyl cyclase

11. Remodelling

12. Pathology of PAH Plexiform Lesion Intimal proliferation Adventitial proliferation Medial hypertrophy Resting lumen Apoptosis Proliferation & generation

13. Vascular endothelial growth factor (VEGF)  VEGF a sub-family of growth factors, of PDGF (platelet-derived growth factor) family   They are important signalling proteins involved in both vasculogenesis and angiogenesis   VEGF-A has been shown to stimulate endothelial cell mitogenesis and cell migration.  Lymphocyt, Mast cells & megakaryocytes secrete VEGF  VEGF & VEGFR2 are expressed in the plexiform lesions.

14. Plexiform lesion Courtesy of Norbert Voelkel (VEGF) immuno-staining of a plexiform lesion

15.   Pulmonary Arterial Hypertension: A Disease of Microvascular Insufficiency? Courtesy of Dr. Michelakis, University of Alberta

16. Tyrosine Kinase (PDGF, VEGF) ApoptosisProliferation Ghofrani et al NEJM 2005

17. Remodelling Process Proliferation Apoptosis Migration Differentiation and dedifferentiation Dysangiogenesis Thrombosis Remodelling

18. Genetics

19. BMPR-ii BMP SMAD BMPR-1 P Gene expression SMAD = Small Mothers Against Decapentaplegic homolog Genetic predisposition

20. P TGF-β r-I P TGF-β r-II BMPR-ii BMPR-1 5-HT Proliferation Inhibition BMP LEGEND Genetic predisposition

21. BMPR-2 Mutation TGF-β Dynamic process of remodelling after BMPR-2 mutation

22. Summary Remodelling model of PHT Adopted from Michelakis, ED, Circ Res, 98:172-175, 2006 EC Apoptosis Exposure to Growth Factors  Survivin expression EC Apoptosis Resistance Further growth and obliterati0on Endothelia dysfunction Progress of the disease Vasoconstriction Damage of EC Genetics susceptibility mutation (BMPR2) Tie2 and others Injury

23. RV function

24. Time PAP PVR CO Pre-symptomatic/ Compensated Symptomatic/ Decompensating Symptom Threshold Right Heart Dysfunction Declining/ Decompensating PH A progressive disease Symptoms

25. RV function on mortality in patients with PAH MONTHS Cumulative proportion Surviving Group 1  PA  RVEF  PA  RVRF.  PA  RVEF  PA  RVEF Ghio ET SL J Am Coll Cardiol. 2001; 37: 183.

26. Management Approach

27. Definition of Patient’s status

28. Initiation of Therapy Management Approach

29. Reservoir NO-Cylinder NO-measurement Valves indwelling Swan- Ganz-Catheter A decrease in mean PAP >10 mmHg to ≤ 40 mmHgA decrease in mean PAP >10 mmHg to ≤ 40 mmHg Normal or ↑ CINormal or ↑ CI Sitbon et al. Circ 2005 Vasoreactivity Testing

30. Initiation of Therapy

31. Calcium Channel Blockers Sitbon et al. Circ 2005

32. Initiation of Therapy

33. Initiation of Therapy: Target Therapy

34. Sitbon et al. JACC 2002 100 Months 80 60 40 20 0 IV epoprostenol Historical control 01224364860728496108120 Survival % at 1, 2, 3, 5 years: 85%, 70%, 63%, 55% at 1, 2, 3, 5 years: 58%, 43%, 33%, 28% IV Epoprostenol: Long-term Outcome in Idiopathic PAH Idiopathic PAH: Effect on Survival

35. IV Epoprostenol IV Flolan: Mode of delivery

36. Prostacyclin Analogues Subcutaneous infusion: Treprostinil Inhaled Iloprost Prostacyclin analogues

37. Vascular endothelium ET-1 ECEBig-ET-1 ET B ET-1 ET B ET A NO PGI 2 Smooth muscle cell Vasoconstriction proliferation Vasodilation antiproliferation Endothelin System in Vascular Tissue Dupuis. Lancet 2001

38. N Eng J Med (2002): 346 (12) Bosentan in PAH Breath 1 Study

39. Decreased [Ca 2+ ] i GTPcGMP NO Soluble guanylate cyclase Vascular smooth muscle relaxation Inactive GMP Cyclic nucleotide Phosphodiesterases Nitric Oxide: Impact on Vascular Tone Sildenafil -- Riociguat ++

40. CONCLUSIONS Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. Sildenafil in PAH SUPER Study

41. Management Algorithm

42. Take Home Messages The Egyptian Society of Chest Disease The 53 rd International Congress Cairo, Egypt 27-30 March 2012

43. Panoramic Picture and therapeutic modalities Understanding Pathophysiology PG PDE5 ERA TKI Cell therapy Biomarkers RHC Remodelling Vasomotor control Imaging Genetic counselling CCB Treatment Diagnosis and follow up Still more and more to learn New drugs Macitentan Selexipag Newer PG Newer TKI Determination of patient status

44. The Egyptian Society of Chest Disease The 53 rd International Congress Cairo, Egypt 27-30 March 2012