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PULMONARY HYPERTENSION AND COR PULMONALE פרופ' נוויל ברקמן מכון הריאה ביה"ח האוניברסיטאי הדסה עין-כרם. Cor Pulmonale. Hypertrophy and/ or dilatation of the right ventricle secondary to respiratory disease. Invariably associated with pulmonary hypertension. - PowerPoint PPT Presentation
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PULMONARY HYPERTENSION AND
COR PULMONALE
פרופ' נוויל ברקמןפרופ' נוויל ברקמן מכון הריאהמכון הריאה
ביה"ח האוניברסיטאי הדסה עין-כרםביה"ח האוניברסיטאי הדסה עין-כרם
Cor Pulmonale
• Hypertrophy and/ or dilatation of the right ventricle secondary to respiratory disease.
• Invariably associated with pulmonary hypertension.
• Right ventricular failure is a late consequence of chronic pulmonary hypertension.
Pulmonary Vascular Bed
NORMAL
• Large cross-sectional area
• low resistance• Low pressure
PULMONARY HYPERTENSION
• Reduced cross-sectional area
• high resistance• high pressure
Pulmonary Hypertension
• Normal pulmonary pressures:15-30/4-12; mean 9-18.
• Pulmonary hypertension:mean pressure >25mm Hg at rest (no values on exercise).
Pulmonary Hypertension
Pressure = Cardiac Output Resistance
1. PULMONARY ARTERIAL HYPERTENSIONIdiopathic (IPAH)Familial (FPAH)Associated with (APAH):
connective tissue disorderscongenital systemic-pulmonary shuntsPortal hypertensionHIVDrugs and toxinsOther (thyroid disorders, Gaucher’s, glycogen storage dis, HHT, hemoglobinopathies, myeloproliferative disorders, splenectomy)
PAH with significant venous and/or capillary involvementpulmonary veno-occlusive disease (PVOD)pulmonary capillary hemangiomatosis (PCH)
Persistent PHN
Updated clinical classification Dana Point 2009
2. PULMONARY HYPERTENSION WITH LEFT HEART DISEASEAtrial or ventricular heart diseaseValvular heart disease
3. PULMONARY HYPERTENSION WITH LUNG DISEASE AND/OR HYPOXEMIAChronic obstructive pulmonary diseaseInterstitial lung diseaseSleep disorders; Alveolar hypoventilation ; Chronic exposure
to high altitudeDevelopmental Abnormalities
Updated clinical classification - cont
Updated clinical classification –cont.
4. PH DUE TO CHRONIC THROMBOTIC AND/OR EMBOLIC DISEASEThromboembolic obstruction of proximal pulmonary
arteriesThromboembolic obstruction of distal pulmonary arteriesPulmonary embolism (tumor, parasites, foreign material)
5. MISCELLANEOUSSarcoidosis, histiocytosis X, lymphangiomatosis,
compression of pulmonary vessels (adenopathies and tumors, fibrosing mediastinitis)
Pulmonary Arterial Hypertension- Pathology
• Vasocostriction• In-situ thrombosis.• Intimal and medial thickening with
obliteration.• Plexiform lesions
Pulmonary Hypertension
Pathophysiology• Increased vasoconstriction
– Thromboxane A2– Fibrinopeptide– endothelin-1– Serotonin
• Reduced vasodilatation– Decreased prostacyclin– Decreased Nitric Oxide– Impaired K+- ion channel
• Enhanced proliferation – Endothelium– smooth muscle
The PAH gene!
• 6% of IPAH are familial• Linkage analysis
localised the PAH gene to chromosome 2q33.
• Autosomal dominant; low penetrance.
The PAH gene!
• Gene identified as the
“ Bone Morphogenetic Protein Receptor II gene (BMPRII)”
Deng, Am J Hum Genet, 2000
BMPR-II
• 72% of PAH families have an identified BMPR2 mutation or show linkage to this locus.
• Mutations of the BMPR2 gene are present in at least 26% of patient with sporadic PAH.
Mechanism of Idiopathic PAH
• Member of the TGF- receptor family.
• Important in the regulation of cell growth, differentiation and apoptosis.
• Other factors; genetic or enviromental are required for the disease to develop.
Enhanced proliferation of smooth muscle cells
Increased pulmonaryVascular resistance
PULMONARYHYPERTENSION
Idiopathic PAH- Clinical
• Young females• 1-2/ million/ yr.• Familial in 6-10% (chromosome 2q
31-32)• Immune features (ANF+ in 20-30%)
• DELAYED DIAGNOSIS
Pulmonary Arterial Hypertension- symptoms
• Dyspnea on exertion• Chest pain• Syncope • Right heart failure• hemoptysis, palpitations.
Pulmonary Arterial Hypertension - signs
• Loud pulmonary second heart sound (P2), often with fixed splitting.
• Right ventricular heave• Tricuspid insufficiency• Third or fourth heart sound.• Right sided cardiac failure: elevated JVP,
hepatomegally, peripheral edema.• Clear lungs• Seldom clubbing
Pulmonary Arterial Hypertension- diagnosis
• ECG:- right ventricular hypertrophy, strain, RBBB, right axis deviation.
• X-ray:- enlarged pulmonary arteries. • Low diffusion capacity, normal lung
volumes• Echocardiography.• Right heart catheterisation.• Exclude other causes: vasculitis,
pulmonary emboli, cardiac shunt, pulmonary parenchymal disease.
Pulmonary Arterial Hypertension- Treatment
• Oxygen• Anticoagulants• Diuretics• Ca-channel blockers (nifedipine, diltiazem)• Prostacyclins (epoprostenol, treprostinil,
iloprost)• Endothelin receptor antagonists (bosentan,
ambrisentan)• Phosphodiesterase -5 inhibitors (sildenafil) • Transplantation, atrial septostomy
Treatment
Humbert et al; N Engl J Med 2004
PPH- Prognosis
• Poor : 50% 3 year survival.• Poor predictors of survival: high
mean PAP, high RAP, low CO, low diffusion capacity.
• Responders to vasodilators do well!• Continuous intravenous
epoprostanol prolongs survival.
PAH, Class III/IV
Conventional therapy (C)(oral anticoagulants ± diuretics ± O2)
Class IV
Epoprostenol (A)Bosentan (A)
Treprostinil (B) Iloprost iv (C)
Endothelin R Antagonists Bosentan (A)
or
Prostanoid Analogues Iloprost inh (B), Treprostinil (B), Beraprost (B),
orEpoprostenol (A)
Class IIIOral CCBs (C)
Continue CCB
(< 10%)
Sustained Response
Yes No
Atrioseptostomy (C)and/or
Lung Transplant (C)
Vasoreactivity
Yes No
PDE5 inhibitorsSildenafil (C)
No improvementor deterioration(Combination
Therapy?)
?
P
P
T arget gene
PP
Co-Sm adSm ad
BM P2
P-38 pathway
ALP-induction
BMPR-II signalingBMPR-II signaling
Humbert et al. Eur Respir J 2002;20:741-9
PROLIFERATION PROLIFERATION