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