Cor Pulmonale

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