Pulmonary Hypertension Pulmonary Hypertension Understanding Management 2012Understanding Management 2012

Majdy M IdreesSaudi Arabia

www.saph.med.sa

The Egyptian Society of Chest Disease The 53rd International Congress

Cairo, Egypt27-30 March 2012

Circulation in the LungCirculation 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 CirculationHuman Circulation

Lung is only organ to

receive entire cardiac

output.

What is Pulmonary Hypertension?What is Pulmonary Hypertension?

• It is a hemodynamic state defined as mPAP > 25 mmHg, as measured by RHC

Circulation in the LungCirculation in the Lung

Muscular artery lumen

A

M Isensors and effectors

transmit changes in flow and pressure through the release of vasoregulator and growth factors.

sensors and effectors transmit changes in flow and pressure through the release of vasoregulator and growth factors.

Circulation in the LungCirculation in the Lung

Dynamic of PH pathologyDynamic of PH pathology

Pulmonary Vascular Diseases

Pulmonary Vascular Diseases

Pulmonary Vascular Resistance

Pulmonary Vascular Resistance

Pulmonary Hypertension

Pulmonary Hypertension

Remodelling Vascular tone

Progress of the diseasesProgress of the diseases

Endothelial FunctionEndothelial Function

Vasoconstriction

Endothelin-1Angiotensin IISerotonin

NOPGI2ANPAdrenomodullin

Endothelial FunctionEndothelial Function

VasodilatationVasocostriction

Endothelin-1Angiotensin IISerotonin

NOPGI2ANPAdrenomodullin

Pulmonary hypertension

Smooth Muscle Smooth Muscle VASCONSTRICTORY PATHWAY VASCONSTRICTORY PATHWAY

ET-1ANG II

Gq PCR

Phospholipase C

PKC

DAG

IP3

Ca+2

VASOCONSTRICTION

5HT

Gi PCR

ATP

cAMP

Adenyl

cyclase

RemodellingRemodelling

Pathology of PAHPathology of PAH

Plexiform Lesion

Intimal proliferation

Adventitialproliferation

Medialhypertrophy

Resting lumen

ApoptosisProliferation &

generation

Vascular endothelial growth factor Vascular endothelial growth factor (VEGF) (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: Pulmonary Arterial Hypertension: A Disease of Microvascular Insufficiency?A Disease of Microvascular Insufficiency?

Courtesy of Dr. Michelakis, University of Alberta

Tyrosine Kinase (PDGF, VEGF)Tyrosine Kinase (PDGF, VEGF)

ApoptosisApoptosis ProliferationProliferation

Ghofrani et al NEJM 2005

Remodelling ProcessRemodelling Process

Proliferation

Apoptosis

MigrationMigration

Differentiation and

dedifferentiation

Differentiation and

dedifferentiation

DysangiogenesisThrombosisThrombosis

Remodelling

GeneticsGenetics

BM

PR

-ii

BMP

SMAD

BM

PR

-1P

Gene expression

SMAD = Small Mothers Against Decapentaplegic homolog

Genetic predisposition Genetic predisposition

P

TG

F-β

r-I

P

TG

F-β

r-II

BM

PR

-ii

BM

PR

-1

5-HT

Proliferation Inhibition

BMPLEGEND

Genetic predisposition Genetic predisposition

BMPR-2 Mutation

TGF-β

Dynamic process of remodelling Dynamic process of remodelling after BMPR-2 mutationafter BMPR-2 mutation

SummarySummaryRemodelling model of PHTRemodelling model of PHT

Adopted from Michelakis, ED, Circ Res, 98:172-175, 2006

EC ApoptosisEC Apoptosis

Exposure to Growth Factors

Survivin expression

Exposure to Growth Factors

Survivin expression

EC Apoptosis Resistance EC Apoptosis Resistance

Further growth and obliterati0on

Further growth and obliterati0on

Endothelia dysfunctionEndothelia dysfunction

Progress of the diseaseProgress of the disease

VasoconstrictionVasoconstriction

Damage of ECDamage of EC

Geneticssusceptibilitymutation (BMPR2)Tie2 and others

Geneticssusceptibilitymutation (BMPR2)Tie2 and others

Injury

RV function

Time

PAP

PVR

CO

Pre-symptomatic/ Compensated

Symptomatic/ Decompensating

Symptom Threshold

Right Heart Dysfunction

Declining/ Decompensating

PH PH A progressive diseaseA progressive disease

Symptoms

RV function on mortality in patients with PAH

MONTHSMONTHS

Cum

ulat

ive

prop

ortio

n S

urvi

ving

Cum

ulat

ive

prop

ortio

n S

urvi

ving

Group 1 Group 1 Group 1 Group 1

PA RVEF PA RVEF

PA RVRF. PA RVRF.

PA RVEF PA RVEF

PA RVEF PA RVEF

Ghio ET SL J Am Coll Cardiol. 2001; 37: 183. Ghio ET SL J Am Coll Cardiol. 2001; 37: 183.

Management ApproachManagement Approach

Definition of Patient’s status

Initiation of TherapyManagement Approach

Reservoir

NO-Cylinder

NO-measurement

Valves

indwelling Swan-Ganz-Catheter

• A decrease in mean PAP A decrease in mean PAP >1>10 mmHg to 0 mmHg to ≤ ≤ 40 mmHg40 mmHg

• Normal or Normal or ↑ CI↑ CI

Sitbon et al. Circ 2005

Vasoreactivity Testing

Initiation of Therapy

Initiation of Therapy

Calcium Channel Blockers

Sitbon et al. Circ 2005

Initiation of Therapy

Initiation of Therapy: Target Therapy

Sitbon et al. JACC 2002

100100

MonthsMonths

8080

6060

4040

2020

00

IV epoprostenolIV epoprostenol

Historical controlHistorical control

00 1212 2424 3636 4848 6060 7272 8484 9696 108108 120120

Su

rviv

al %

Su

rviv

al %

at 1, 2, 3, 5 years: 85%, 70%, 63%, 55%at 1, 2, 3, 5 years: 85%, 70%, 63%, 55%at 1, 2, 3, 5 years: 58%, 43%, 33%, 28%at 1, 2, 3, 5 years: 58%, 43%, 33%, 28%

IV Epoprostenol: IV Epoprostenol: Long-term Outcome in Idiopathic PAHLong-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

Vascularendothelium

ET-1ET-1

ECE Big-ET-1 ETB

ET-1

ETBETA

NOPGI2

Smooth muscle cell

Vasoconstrictionproliferation

Vasodilationantiproliferation

Endothelin System in Vascular Tissue

Dupuis. Lancet 2001

N Eng J Med (2002): 346 (12)

Bosentan in PAHBreath 1 Study

Decreased [Ca2+]i

GTPGTP cGMPcGMP

NO Soluble guanylate cyclase

Vascular smoothVascular smoothmuscle relaxationmuscle relaxation

Inactive GMP

Cyclic nucleotidePhosphodiesterases

Nitric Oxide: Nitric Oxide: Impact on Vascular ToneImpact on Vascular Tone

Sildenafil--

Riociguat

++

CONCLUSIONS

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

Sildenafil in PAHSUPER Study

Management Algorithm

Take Home MessagesTake Home Messages

The Egyptian Society of Chest Disease The 53rd International Congress

Cairo, Egypt27-30 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 53rd International Congress

Cairo, Egypt27-30 March 2012