פרופ ' נוויל ברקמן מכון הריאה ביה " ח האוניברסיטאי הדסה עין - כרם 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. 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 Pulmonary hypertension: mean pressure >25mm Hg at rest (no values on exercise).

Pulmonary Hypertension Pressure = Cardiac Out put  Resistance

1. PULMONARY ARTERIAL HYPERTENSION Idiopathic (IPAH) Familial (FPAH) Associated with (APAH): connective tissue disorders congenital systemic-pulmonary shunts Portal hypertension HIV Drugs and toxins Other (thyroid disorders, Gaucher’s, glycogen storage dis, HHT, hemoglobinopathies, myeloproliferative disorders, splenectomy) PAH with significant venous and/or capillary involvement pulmonary veno-occlusive disease (PVOD) pulmonary capillary hemangiomatosis (PCH) Persistent PHN Updated clinical classification Dana Point 2009

2. PULMONARY HYPERTENSION WITH LEFT HEART DISEASE Atrial or ventricular heart disease Valvular heart disease 3. PULMONARY HYPERTENSION WITH LUNG DISEASE AND/OR HYPOXEMIA Chronic obstructive pulmonary disease Interstitial lung disease Sleep disorders; Alveolar hypoventilation ; Chronic exposure to high altitude Developmental Abnormalities Updated clinical classification - cont

Updated clinical classification –cont. 4. PH DUE TO CHRONIC THROMBOTIC AND/OR EMBOLIC DISEASE Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries Pulmonary embolism (tumor, parasites, foreign material) 5. MISCELLANEOUS Sarcoidosis, 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 pulmonary Vascular resistance PULMONARY HYPERTENSION

Idiopathic PAH- Clinical Young females 1-2/ million/ yr. Familial in 6-10% (chromosome 2q ) 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 ± O 2 ) 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), or Epoprostenol (A) Class III Oral CCBs (C) Continue CCB (< 10%) Sustained Response Yes No Atrioseptostomy (C) and/or Lung Transplant (C) Vasoreactivity Yes No PDE5 inhibitors Sildenafil (C) No improvement or deterioration (Combination Therapy?) ?

BMPR-II signaling Humbert et al. Eur Respir J 2002;20:741-9 PROLIFERATION