Pulmonary Hypertension Understanding Management 2012 Majdy M Idrees Saudi Arabia The Egyptian Society of Chest Disease The 53 rd International Congress Cairo, Egypt March 2012

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

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

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

MuscularPartially MuscularNon Muscular Circulation in the Lung

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

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

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

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

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

Remodelling

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

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.

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

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

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

Remodelling Process Proliferation Apoptosis Migration Differentiation and dedifferentiation Dysangiogenesis Thrombosis Remodelling

Genetics

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

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

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

Summary Remodelling model of PHT Adopted from Michelakis, ED, Circ Res, 98: , 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

RV function

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

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.

Management Approach

Definition of Patient’s status

Initiation of Therapy Management Approach

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

Initiation of Therapy

Calcium Channel Blockers Sitbon et al. Circ 2005

Initiation of Therapy

Initiation of Therapy: Target Therapy

Sitbon et al. JACC Months IV epoprostenol Historical control 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

IV Epoprostenol IV Flolan: Mode of delivery

Prostacyclin Analogues Subcutaneous infusion: Treprostinil Inhaled Iloprost Prostacyclin analogues

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

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

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 ++

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

Management Algorithm

Take Home Messages The Egyptian Society of Chest Disease The 53 rd International Congress Cairo, Egypt March 2012

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

The Egyptian Society of Chest Disease The 53 rd International Congress Cairo, Egypt March 2012