2P-S4-1

PULMONARY HYPERTENSION IN CHILDHOOD:

CURRENT CONCEPTS OF PATHOGENESIS AND MANAGEMENT

Prof. S.G. Haworth, Institute of Child Health, London, UK

Pulmonary Hypertension (PH) is a common cause of morbidity and mortality in childhood. The principle forms include Persistent PH of the newborn (PPH), primary and secondary, Congenital Heart Disease, Cor Pulmonale and Primary PH. PPH is failure of the pulmonary circulation to extra adapt normally to ex-uterine life, structurally and functionally, informing us about the onset and evolution of pulmonary vascular disease. It entails abnormal postnatal remodeling of the pulmonary arterial smooth muscle cell actin cytoskeleton, produces temporal and spatial changes in smooth muscle cell replication, in gene expression of vasoactive mediators, receptors and matrix components, in the maturation of the NO and Cox pathways, and vaso constrictor mechanisms are enhanced. Management of PPH includes optimizing oxygenation and achieving vasodilatation usually with inhaled NO. PH Congenital Heart Disease demonstrates the response to excessive blood flow and hence to endothelial dysfunction. In vitro, an increase in sheer stress alters gene transcription within one hour and the type of flow, laminar or turbulent, selects for gene expression. In children, correlations made between hemodynamic findings and pulmonary vascular structure emphasize the necessity of operating in early infancy and the need to anticipate pulmonary hypertensive crises postoperatively. We now have the opportunity to improve the management of irreversible pulmonary vascular disease, to delay transplantation. In Primary PH, familial and 20% of sporadic cases are now known to have a mutation in the gene encoding bone morphogenetic protein receptor-2 (International PH Consortium 2000), implicating the TGFb superfamily. This informs us that pulmonary vascular disease can originate as a primary structural abnormality, rather than inevitably starting with endothelial dysfunction. Future management of severe PH will include selection of genetically high risk individuals, conventional and genetic therapy appropriate to patient age and stage of disease, which will include supplementing endogenous vasodilators, preventing the structural and functional sequelae of PH and remodeling the vessel wall.