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New insights into the pathogenesis and treatment of primary pulmonary hypertension
  1. N Rudarakanchanaa,
  2. R C Trembathb,
  3. N W Morrella
  1. aDepartment of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK, bDivision of Medical Genetics, University of Leicester, Leicester LE1 7RH, UK
  1. Dr N W Morrellnwm23{at}cam.ac.uk

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Clinical presentation of primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is defined clinically by a sustained elevation of pulmonary arterial pressure (>25 mm Hg at rest or >30 mm Hg during exercise) without a demonstrable cause. Symptoms of PPH are largely non-specific but may include worsening shortness of breath, chest pain, syncope, fatigue, and peripheral oedema. It is a rare disorder with an estimated incidence of 2–3 per million per year.1 PPH shows a female bias with a F:M ratio of 2.3:1. The median age at diagnosis is 36 years but it may occur at any age. PPH is a progressive, often fatal, disease with mean survival from diagnosis of 2.8 years.2

The precise molecular mechanisms underlying PPH have hitherto remained elusive. Clues to the aetiology of the disease have been suggested by environmental stimuli associated with the development of severe pulmonary hypertension, pathologically indistinguishable from PPH. The association with appetite suppressants, in particular the fenfluramine/dexfenfluramine group,3 suggested a role of re-uptake inhibition of serotonin.4 Severe PPH may also follow HIV-1 infection, and PPH is associated with autoimmune thyroid disease and the presence of circulating anti-Ku and antinuclear antibodies.1

Cellular pathology of PPH

Pathologically, PPH is characterised by the obliteration of precapillary pulmonary arteries leading to right ventricular failure. Histologically, small pulmonary arteries show increased wall thickness, distal extension of smooth muscle into normally non-muscular vessels, the formation of a neointima, and plexiform lesions. The nature of the cell type responsible for the intimal obliteration of small pulmonary arteries in PPH has been the subject of considerable debate.5-7 The intimal lesions comprise myofibroblast-like cells, and the expression of endothelium specific markers is confined to cells lining the vascular lumen.5 8 Further debate surrounds the composition of the plexiform lesion,9 although substantial evidence exists for regarding this lesion as a proliferation of endothelial cells supported by a …

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