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

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

BMPR2 germline mutations and familial pulmonary plexogenic arteriopathy Deng et al., Am J Hum Genet 2000; 67: ; Lane et al., Nat Genet 2000; 26: 81-84

BMPR2 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

Grade Intimal reaction NoneCellular proliferation Fibrous and fibroelastic changes Plexiform lesion Medial changes hypertrophy Some generalized dilatation Local dilatation lesions Haemosidereosis Necrotizing arteritis Heath Edwards grading system

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