November 18, 2003 Access past issues

Reviewed by: Marta Gwinn Office of Genomics and Disease Prevention, CDC

The Health Outcome

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.

The Finding

Cool, et al. (2003) hypothesized that human herpesvirus 8 (HHV-8) infection might be related to pulmonary hypertension: both conditions occur more often in people with HIV-1 infection, and HHV-8 is the causative agent of Kaposi’s sarcoma, which shares some histologic features with the “plexiform” vascular lesions of PPH. They studied lung tissue samples that had been stored for up to 20 years at the Pulmonary Hypertension Center of the University of Colorado. Samples were from 16 patients with PPH; 14 patients with pulmonary hypertension related to underlying causes (5 cardiac defects, 4 autoimmune diseases, 3 HIV-1 infection, 1 sarcoidosis, and 1 fenfluramine use); and 4 “controls” without pulmonary hypertension (3 with other lung diseases, 1 “normal”). All samples were tested for HHV-8 infection by immunohistochemical and PCR assays; those from patients with PPH were also screened for at least 7 variants of the human BMPR2 gene that have been reported in familial clusters of primary pulmonary hypertension (only 3 of these mutations have been reported by more than one group).

Fisher Exact test for associations of HHV-8 infection with primary vs. other pulmonary hypertension: p=0.0024.

Public Health Implications

This clinicopathologic investigation provides the first implication of HHV-8 in pulmonary hypertension: 10/16 PPH cases had evidence of HHV-8 infection, compared with only 1/14 cases attributed to other underlying causes. HHV-8 infection is not rare; seroepidemiologic studies in the U.S. have reported prevalence of 8 percent in HIV-negative people attending STD clinics and up to 3 percent of HIV-negative blood donors.

The prevalence of BMPR2 variants in these non-familial PPH cases (4/16) was similar to that reported in previous studies. The relative prevalence of BMPR2 variants in PPH cases with or without evidence of HHV-8 infection (2/6 vs. 2/8) provides little basis for inference, given the small numbers studied. The prevalence of BMPR2 variants has not been studied among cases of pulmonary hypertension with identifiable causes or in unselected populations, and it was not examined in this study. However, it seems likely that several different combinations of environmental, genetic, and biologic factors can produce the clinical state called pulmonary hypertension.

Another recent study (Du 2003) suggests that different forms of pulmonary hypertension (familial and sporadic, “primary” and acquired) may be united by a common causal pathway, a signaling cascade that regulates the expression of multiple genes, including angiopoietin-1 (ANGPT1), TIE2, BMPR1A, and BMPR2. Systematic evaluation of genetic and environmental factors across the clinical spectrum of pulmonary hypertension, and comparison with unaffected populations, may reveal a “molecular fingerprint” that suggests new avenues for preventing and treating this devastating condition.

References

1. Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest. 1991;100:1268-71.
2. Mette SA, Palevsky HI, Pietra GG, et al. Primary pulmonary hypertension in association with human immunodeficiency virus infection. A possible viral etiology for some forms of hypertensive pulmonary arteriopathy. Am Rev Respir Dis 1992;145:1196-200.
3. Prendergast BD. HIV and cardiovascular medicine. Heart 2003;89:793-800.
4. Runo JR, Lloyd JE. Primary pulmonary hypertension. Lancet 2003;361:1533-44.
5. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene.
   Am J Hum Genet  2000;67:737-44.
6. Cool CD, Rai PR, Yeager ME, et al. Expression of herpesvirus 8 in primary pulmonary hypertension  New Engl J Med 2003;349:1113-22.
7. Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. New Engl J Med 2003;348:500-9.