Pulmonary Hypertension Understanding Management 2012

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

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. Non Muscular Partially Muscular Muscular Circulation in the Lung

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

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

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

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

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

11. Remodelling

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

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

15. Pulmonary Arterial Hypertension: A Disease of Microvascular Insufficiency? RA PA Courtesy of Dr. Michelakis, University of Alberta

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

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

18. Genetics

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

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

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

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

23. RV function

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

25. RV function on mortality in patients with PAH  PA RVEF Group 1 Group 1 Cumulative proportion Surviving MONTHS PA RVEF PA RVEF PA RVRF. 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. Vasoreactivity Testing • A decrease in mean PAP >10 mmHg to ≤ 40 mmHg • Normal or ↑ CI Valves Reservoir NO-Cylinder indwelling Swan-Ganz-Catheter NO-measurement Sitbon et al. Circ 2005

30. Initiation of Therapy

31. Initiation of Therapy Calcium Channel Blockers Sitbon et al. Circ 2005

32. Initiation of Therapy

33. Initiation of Therapy: Target Therapy

34. IV Epoprostenol: Long-term Outcome in Idiopathic PAH Idiopathic PAH: Effect on Survival 100 80 60 IV epoprostenol Survival % 40 20 Historical control 0 0 12 24 36 48 60 72 84 96 108 120 Months at 1, 2, 3, 5 years: 85%, 70%, 63%, 55% at 1, 2, 3, 5 years: 58%, 43%, 33%, 28% Sitbon et al. JACC 2002

35. IV Epoprostenol IV Flolan: Mode of delivery

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

37. Endothelin System in Vascular Tissue ET-1 ETB ECE Big-ET-1 Vascularendothelium ET-1 NOPGI2 ETA ETB Vasoconstrictionproliferation Vasodilationantiproliferation Smooth muscle cell Dupuis. Lancet 2001

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

39. Nitric Oxide: Impact on Vascular Tone NO Soluble guanylate cyclase Inactive GMP GTP cGMP Vascular smooth muscle relaxation Decreased [Ca2+]i Sildenafil -- Riociguat ++ Cyclic nucleotide Phosphodiesterases

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

41. Management Algorithm

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

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

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