1. Pathology of pulmonary hypertension Dr.Ashraf Abdelfatah Deyab Assisstant Professor of Pathology Faculty of Medicine Almajma’ah University

2. Pathology of pulmonary vascular disease ► Damage to the vessels wall: ► - Arteritis with ischaemia and local necrosis (Wegener's granulomatosis, Churg-Strauss syndrome) ► - Good pasture's syndrome (with circulating anti- glomerular basement membrane antibody). ► Obstruction: Thrombo-embolism. ► Variation in intra-vsacular pressure: Arterial or venous hypertension.

3. Goals Pathology of Pulmonary hypertension Goals Pathology of Pulmonary hypertension ► Pathogenesis. ► Morphology ► Clinical features

4. Pulmonary hypertension - PH Introduction ► The pulmonary circulation is normally one of low resistance. ► Pulmonary BP is normally only about one eighth = (1\8) of systemic BP. ► Pulmonary hypertension (PH) defined when mean pulmonary artery pressure reaches one fourth= (1\4) of systemic levels or greater than BP> 25 mm Hg at rest & greater > 30 mm Hg during exercise.

5. Pulmonary hypertension – PH how common? Pulmonary hypertension – PH how common? - 500 to 600 cases diagnosed annually. - 500 to 600 cases diagnosed annually. - Occur in men, women and children of all ages, However most common in women (20-40ys). - Occur in men, women and children of all ages, However most common in women (20-40ys). - Rare in children but sometimes seen in - Rare in children but sometimes seen in infants born with heart defect infants born with heart defect

6. What’s the main causes of increase pulmonary vascular pressure? The pressure within the pulmonary arterial system may be increased for two reasons: ► 1) Increased blood flow ► 2) Increased resistance within the pulmonary circulation.

7. Pulmonary hypertension – PH (Etiology) ► Can be classified into three main causes: ► 1- Secondary pulmonary hypertension. ► 2- Primary pulmonary hypertension. ► 3- Idiopathic.

8. Pulmonary hypertension – PH (Etiology) I) Secondary pulmonary hypertension: Secondary to another medical problem e.g: Secondary to another medical problem e.g: Diseases that impedes flow of blood through Lungs or Diseases that impedes flow of blood through Lungs or Diseases that affect the oxygen levels (periods of low oxygen) in blood. Diseases that affect the oxygen levels (periods of low oxygen) in blood. Examples: COPD, Scleroderma, pulmonary fibrosis, lung diseases such as asbestosis Examples: COPD, Scleroderma, pulmonary fibrosis, lung diseases such as asbestosis

9. Pulmonary hypertension – PH (Etiology) ► Secondary pulmonary hypertension main causes: 1) Cardiac diseases\causes. 2) Recurrent thrombo-embolism. 3) Inflammatory vascular disease. 4) Connective tissue disease 5) Lung diseases

10. Pulmonary hypertension – PH (Etiology) ► Secondary pulmonary hypertension: 1) Cardiac diseases: Congenital or acquired heart disease: - MI- increase left atrial pressure. - MI- increase left atrial pressure. - Left to right shunts e.g. septal defects. - Left to right shunts e.g. septal defects. - Mechanical obstruction e.g. atrial myxoma and mitral stenosis. - Mechanical obstruction e.g. atrial myxoma and mitral stenosis.

11. Pulmonary hypertension – PH (Etiology) 2) Recurrent thromboemboli: reduced vascular bed- increase vascular resistant. 3) Inflammatory vascular diseases: - scleroderma,other CT diseases & vasculitis. - scleroderma,other CT diseases & vasculitis. 4) Lung & Connective tissue diseases: COBD or interstitial, restrictive lung: hypoxia, alveolar and vascular bed damage- increase resistance- increase PH. COBD or interstitial, restrictive lung: hypoxia, alveolar and vascular bed damage- increase resistance- increase PH. - Pneumoconiosis e.g. asbestosis & silicosis. - Pneumoconiosis e.g. asbestosis & silicosis.

12. Pulmonary hypertension – PH (Etiology) 2- Primary pulmonary hypertension (Familial) - Rare, autosomal dominant. - Mutations in signaling pathway (BMPR2). - Mutations in signaling pathway (BMPR2). - No underlying cause for the high BP in lungs - No underlying cause for the high BP in lungs - Due to spasm of the muscle layer in pulmonary arteries, patients are sensitive to vasoconstrictors elements. - Due to spasm of the muscle layer in pulmonary arteries, patients are sensitive to vasoconstrictors elements. ► 3) Idiopathic PH: Sporadic, requires exclusion of other known causes. ► Usually women 20-40 years old, some children.

13. Abnormally high BP in pulmonary vessels arteries Increased pressure damages large and small pulmonary arteries Blood vessel walls thicken Cannot transfer oxygen and carbon dioxide normally Levels of oxygen in blood fall Constriction of pulmonary arteries Further increase in pressure in pulmonary circulation

14. Pulmonary Hypertension right side of heart must work harderpush blood through pulmonary arteries to lungs right ventricle thickens and enlarges cor pulmonale Heart Failure In some people, the bone marrow will produce more red blood cells to compensate for less of oxygen in blood leading Polycythemia Extra RBCs cause the blood to become thicker and stickier, further increasing the load on the heart Pulmonary Embolism

15. PH- Pathogenesis ► I. Molecular basis (Mutation). (Primary PH). (Primary PH). ► II. Shear and mechanical injury (Secondary PH) (Secondary PH) ► III. Pulmonary vasoconstriction (Secondary PH) (Secondary PH) ► IV. Idiopathic

16. PH pathogenesis- Primary PH ► I. Molecular basis (Mutation): (Familial or primary PH) is caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) signaling (with existence and support of modifier genes and/or environmental triggers), lead to: (Familial or primary PH) is caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) signaling (with existence and support of modifier genes and/or environmental triggers), lead to: Pulmonary vascular thickening& occlusion : proliferation of endothelial, smooth muscle, and intimal cells accompanied by concentric laminar intimal fibrosis. Pulmonary vascular thickening& occlusion : proliferation of endothelial, smooth muscle, and intimal cells accompanied by concentric laminar intimal fibrosis.

17. PH& BMPR2 mutation ► BMPR2 is a cell surface protein belonging to the TGF-β receptor ► BMPR2 specific effects in vascular smooth muscle cells causes inhibition of proliferation & favors apoptosis. ► BMPR2 Mutation lead to increased smooth muscle survival and proliferation may be expected. ► BMPR2 plays it’s effect by support of gene modifier& environmental trigger.

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19. PH pathogenesis- Secondary PH (II) Increased shear and mechanical injury (Secondary PH) produced endothelial cell dysfunction e.g.:: - Left to-right shunts (Mechanical). - Left to-right shunts (Mechanical). - Thromboembolism, injury mediated by biochemical injury produced by fibrin. - Thromboembolism, injury mediated by biochemical injury produced by fibrin.

20. Pulmonary Hypertension 1. Pulmonary Arterial Hypertension 2. Left Heart Disease 3. Chronic Hypoxemia 4. 4.Thromboembolic 5. Miscelaneous -Sarcoid, fibrosing mediastinitis

21. PH pathogenesis-Secondary PH III) Pulmonary vasoconstriction: III) Pulmonary vasoconstriction: Decreased elaboration of prostacyclin& nitric oxide-and increased release of endothelin- this lead to activate platelet Aggregation& adhesion. Decreased elaboration of prostacyclin& nitric oxide-and increased release of endothelin- this lead to activate platelet Aggregation& adhesion. * Endothelial activation, makes endothelial cells thrombogenic and promotes the persistence of fibrin.

22. PH pathogenesis-Secondary PH 3) Production and release of growth factors and cytokines induce the migration and replication of vascular smooth muscle cells and elaboration of extracellular matrix. 4) Vasospastic component, after ingestion of certain plants or medicines.

23. PH morphology ► Atheromas, Atheromatous deposits of pulmonary artery, branches. ► Medial hypertrophy =muscular thickness of muscular and elastic arteries. ► Initimal fibrosis= narrowing of the lumen, ► Organizing or recanalized thrombi, with coexistence of diffuse pulmonary fibrosis this favors recurrence.

24. Morphology of PH-Gross changes Pulmonary hypertension, reveal atheroma formation, usually limited to large vessels

25. Small peripheral pulmonary artery thromboembolus &their direct role in PH

26. Vascular changes in pulmonary hypertension ► Marked medial hyperatrophy ► Alveolar haemorrhages

27. (PH) morphology - Plexiform lesion caused by: - Plexiform lesion caused by: - Longstanding severe primary PH and idiopathic& CHD with left-to-right shift. - Longstanding severe primary PH and idiopathic& CHD with left-to-right shift. - Characterized by multi-channeled out- pouching of the arterial wall due to reparative lesions in areas of fibrinoid necrosis. - Characterized by multi-channeled out- pouching of the arterial wall due to reparative lesions in areas of fibrinoid necrosis.

28. Plexiform lesion- Pulmonary hypertension

29. PH morphology Coexistence morphological features: ► Diffuse pulmonary fibrosis, or severe emphysema and chronic bronchitis. ► Dilated vessels and arteritis may also be present. ► Extensive occlusion of the veins by fibrous tissue.

30. PH Clinical features Signs & symptoms ► Like other forms of HTN are subtle in the early stages. ► Sign& symptoms are hidden by underlying diseases, and varying from pt. to pt.  Initial Symptoms: dyspnea, fatigue, chest angina-like pain, cough, fail to put on wei ght like a normal child with slowed growth (in child) ► Overtime Severe respiratory distress, cyanosis, and right ventricular hypertrophy.

31. PH outcome ► Diagnosis: ► Proper medical work-up& correlation, rule- out others, Echo, lung FT, Lung scan, ect.. ► PH outcome: Death from decompensated cor pulmonale, often with superimposed thromboembolism and pneumonia, usually ensues within 2 to 5 years in 80% of patients. Death from decompensated cor pulmonale, often with superimposed thromboembolism and pneumonia, usually ensues within 2 to 5 years in 80% of patients.

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