Pulmonary hypertension is the chronic, abnormal elevation of pulmonary vascular resistance. Most cases of pulmonary hypertension are associated with underlying conditions that increase, obstruct, or constrict the pulmonary circulation—for example, congenital heart disease (left-to-right shunt), thromboembolism, or hypoxia. In some cases, specific environmental exposures have been implicated, such as the appetite suppressant fenfluramine-phentermine (“fen-phen”). Potential viral causes have been considered at least since 1991, when the incidence of pulmonary hypertension was reported as 0.5% in a cohort of 1200 people with HIV-1 infection (Speich 1991); however, an exhaustive examination failed to localize HIV-1 to the vascular endothelium (Mette 1992) and the underlying pathophysiology remains obscure (Prendergast 2003).
Primary pulmonary hypertension (PPH)—a diagnosis of exclusion—is rare, occurring in 1 per 100,000 to 1,000,000 people. In PPH, increased resistance in the pulmonary circulation is due to lumen-occluding “plexiform” vascular lesions containing endothelial and smooth muscle cells, the result of vascular proliferation and remodeling (Runo 2003). Genetic factors have long been suspected because women are 2-5 times as likely as men to develop PPH, often in their mid-30’s. Although most cases appear to be sporadic, some clustering in families has been observed. In 2000, germline mutations in human BMPR2 (OMIM *600799 BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE II) were identified in several families displaying apparent autosomal dominant inheritance of PPH (Deng, 2000). Subsequently, germline mutations in BMPR2 have been found in about 50% of familial cases and 25% of sporadic cases of PPH
