Pulmonary Hypertension for Clinicians: Time to Call on Genetics?

Abstract

tery pressure response to exercise and hypoxia, an early indicator of altered pulmonary vascular function [2] . The pathogenesis of PAH is complex and involves a variety of cellular and molecular mechanisms, including the serotoninand nitric oxide system. Therefore, genetic modifiers have been suggested to be involved in the development of PAH [3] . Are genetic changes relevant in our current clinical management of pulmonary hypertension? In the current issue of Respiration , Ulrich et al. [4] describe genetic changes in patients with idiopathic PAH and chronic thromboembolic pulmonary hypertension (CTEPH) who were referred to the pulmonary hypertension centre in Zurich (Switzerland). They performed extensive genetic studies including the analysis of the BMPR2 gene, and polymorphisms in a variety of genes involved in the serotonin and nitric oxide pathway. Additionally, they investigated patients with distinct left heart disease but without pulmonary hypertension. The authors did not find any difference in the genetic analysis between patients with CTEPH, idiopathic PAH or left heart disease. However, they detected a BMPR2 mutation in a patient with coronary artery disease without PAH or a family history of PAH. Furthermore, different polymorphisms of the BMPR2 gene were either present in PAH, or in CTEPH or in both. PAH patients carrying a Over the last decade, pulmonary hypertension has developed from a largely unknown disease to a very well recognised disorder. During this period, three world conferences have been held addressing pathobiology, diagnosis, and treatment of the disease. Currently, we classify approximately 30 different forms of pulmonary hypertension. The early recognition of a hereditary type of pulmonary arterial hypertension (PAH) was suggestive of a genetic cause of the disease. Basic research has revealed genetic alterations in the TGFsystem to be involved in the pathogenesis of PAH. Among the TGFsuperfamily, a mutation in the bone morphogenetic protein receptor 2 (BMPR2) has been linked to PAH, leading to an altered intracellular signalling with subsequent proliferation of smooth muscle cells and increased endothelial cell apoptosis in the pulmonary vasculature. Epidemiological studies have shown a high frequency of BMPR2 mutation in hereditary PAH (70%) and idiopathic PAH (20%), rarely in PAH associated with congenital heart disease and ingestion of appetite suppressants, but so far not in other forms of pulmonary hypertension. Patients carrying a BMPR2 mutation are known to have an earlier onset of the disease and are less likely to show an acute vasodilator response [1] . Furthermore, healthy relatives of PAH patients, who carry the identical BMPR2 mutation, exhibit a higher proportion of hypertensive pulmonary arPublished online: December 7, 2009