Pathology of Pulmonary Hypertension Wolter J Mooi Department

Pathology of Pulmonary Hypertension Wolter J. Mooi Department of Pathology, VUmc Amsterdam WJ. Mooi@VUmc. nl

Pulmonary arterial hypertension (WHO definition) • Sustained elevation of pulmonary arterial pressure to more than 25 mm Hg at rest, or to more than 30 mm Hg with exercise • Mean pulmonary wedge pressure and left ventricular end-diastolic pressure less than 15 mm Hg

WHO Classification of Pulmonary Hypertension • Group I: Pulmonary arterial hypertension – – Idiopathic (primary) Familial Associated with significant venous or capillary involvement Persistent pulmonary hypertension of the newborn • Group II: Pulmonary venous hypertension – Left-sided artial or ventricular heart disease – Left-sided valvular heart disease • Group III: Pulmonary hypertension associated with hypoxemia • Group IV: Pulmonary hypertension due to chronic thrombotic disease, embolic disease, or both • Group V: Miscellaneous

WHO Classification of Pulmonary Hypertension: criticisms • Pulmonary arterial hypertension is not limited to Group I (this is inappropriately suggested by its designation as ‘pulmonary arterial hypertension’) – It may be associated with pulmonary venous hypertension – It may be posttrombotic (Group IV) or hypoxic (Group III) • The group ‘miscellaneous’ includes: compression of pulmonary veins, which should be in Group II (pulmonary venous hypertension)

Main histological patterns of pulmonary hypertensive vascular disease • Congestive vasculopathy – Backward failure of left side of heart – Obstruction of pulopmary large veins • Hypoxic pulmonary vasculopathy – COPD, high altitude dwellers, alevoar hypoventialtion disorders, &c • Postthrombotic pulmonary vasculopathy – Chronic recurrent thromboembolism, primary thrombosis • Plexogenic pulmonary arteriopathy – Posttricuspid LR shunts; associated with anorexigens, HIV, portal hypertension, idiopathic • Pulmonary vascular occlusive disease • Miscellaneous rare disorders

Congestive pulmonary vasculopathy • Veins: – Intimal fibrosis – Medial hypertrophy, ‘arterialization’ • Interstitial fibrosis • Haemosiderosis • Arteries: – Intimal fibrosis – Medial hypertrophy – Adventitial thickening

Hypoxic pulmonary vasculopathy • Arteries and arterioles: – Medial hypertrophy (accentuated in smaller branches) – Muscularization of arterioles – Longitudinal smooth muscle bundles – Mild intimal thickening • Veins: – Mild thickening of venule walls (mild smooth medial hypertrophy, mild fibrosis)

Postthrombotic pulmonary arteriopathy • Arteries: – – – Eccentric intimal fibrosis Concentric intimal fibrosis (not concentric laminar) Bands and webs Medial atrophy, fibrosis Arterial obliteration; fibroelastic scars NB-1: abnormalities are focal, so that many arteries may appear normal or near normal, even in the presence of severe obstruction NB-2: arterial changes in fibrosing lung disease are very similar if not identical to postthrombotic arteriopathy

Plexogenic pulmonary arteriopathy • Early phase: – Medial thickening of elastic and muscular pulmonary arteries – Muscularization of pulmonary arterioles – Mild intimal fibrosis • Late phase: – – Concentric laminar intimal fibrosis Fibrinoid necrosis, arteritis Dilatation lesions Plexifom lesions

BMPR 2 germline mutations and familial pulmonary plexogenic arteriopathy Deng et al. , Am J Hum Genet 2000; 67: 737 -44; Lane et al. , Nat Genet 2000; 26: 81 -84

BMPR 2 and pulmonary plexogenic arteriopathy

Heath Edwards grading system of hypertensive pulmonary vasular disease in congenital cardiac septal defects (1958) • Grade 1: retention of foetal-type pulmonary arteries • Grade 2: medial hypertrophy with cellular intimal proliferation • Grade 3: progressive fibrous vascular occlusion • Grade 4: progressive generalized arterial dilatation with formation of dilatation lesions • Grade 5: chronic dilatation with numerous dilatation lesions and pulmonary haemosiderosis • Grade 6: necrotizing arteritis

Heath Edwards grading system Grade 1 Intimal reaction None 2 3 4 Fibrous and fibroelastic changes Plexiform lesion hypertrophy Medial changes 6 Cellular proliferation 5 Some generalized dilatation Local dilatation lesions Haemosidereosis Necrotizing arteritis

Miscellaneous pulmonary hypertensive vasculopathies • • Sarcoidosis Langerhans cell histiocytosis Lymphangioleiomyomatosis Pulmonary vascular misalignment Pulmonary capillary hemangiomatosis Developmental abnormalities &c &c