Volume 346:933-935 March 21, 2002 Number 12

Primary pulmonary hypertension predominantly affects women, frequently in the prime of life, and usually leads to death from right ventricular failure within a few years after diagnosis. It is a vascular disease but is oddly confined to the small pulmonary arterioles, where intimal fibrosis and medial hypertrophy lead sequentially to vascular obstruction, elevated pulmonary vascular resistance, pulmonary hypertension, and right ventricular overload. Coagulation at the endothelial surface contributes to obstruction, and thromboembolism may occur as a secondary event. The right ventricle compensates through hypertrophy, and although it can sustain function at high pressures for months to years, decompensation is ultimately manifested in reduced cardiac output and the development of peripheral edema.1 Many conditions and diseases lead to similar pulmonary vascular lesions and clinical outcomes, including the scleroderma spectrum of diseases, human immunodeficiency virus infection, liver disease, and the use of certain anorectic drugs.2 These illnesses, along with primary pulmonary hypertension, are now classified as types of pulmonary arterial hypertension.

Primary pulmonary hypertension first came under coordinated scientific scrutiny when the National Institutes of Health created the national Primary Pulmonary Hypertension Patient Registry in 1982, at a time when there was increasing optimism about a role for vasodilator therapy.3 Although there had been multiple previous reports of benefit from beta-agonists, alpha-blockers, and hydralazine, these responses were usually not sustained, and the relevant studies were not appropriately powered to detect true effects. The discovery that calcium-channel blockers could cause a sustained reduction in pulmonary vascular resistance in about 20 to 25 percent of previously untreated patients led to aggressive approaches to short-term vasodilator testing and long-term vasodilator therapy. Although not every patient with acute vasodilatation has a durable response to therapy, this feature carries a favorable prognosis, and many such patients are treated with calcium-channel blockers alone.4 It has not been proved that vasoconstriction is a pathogenetic mechanism of primary pulmonary hypertension, but this possibility seems logical and deserves continued study.

What can be done for the 75 percent of patients who do not have a response to short-term vasodilator therapy? The discovery that intravenous epoprostenol (prostacyclin) improved functional capacity, not only in patients with a response to calcium-channel blockers but also in those without a response, was followed by evidence that it also improves survival among both types of patients.5 This finding has led to widespread use of continuous intravenous epoprostenol therapy in all patients without a response to calcium-channel blockers and in most patients with New York Heart Association class IV heart failure. Beyond the activity of epoprostenol as a potent vasodilator, its mechanisms of benefit are unclear, but they may include a positive inotropic effect, a small degree of systemic vasodilatation, and antiplatelet effects, which theoretically could reverse vascular damage.6

Epoprostenol therapy by continuous infusion through a central catheter is expensive — about $60,000 per year — as well as technically demanding, and it has undesirable side effects. It is widely recognized that simpler effective therapies are needed. Prostacyclin analogues given by continuous subcutaneous infusion, orally, or by intermittent aerosol are under development as alternatives to the intravenous route.6 Subcutaneous treprostinil was recently approved by the Food and Drug Administration for further clinical trials. The prostacyclins act through an increase in the level of the second messenger, intracellular cyclic AMP (cAMP). Other vasodilators, including inhaled nitric oxide and oral sildenafil, act by means of cyclic guanosine monophosphate (cGMP). Sildenafil increases the cGMP level by inhibiting phosphodiesterase type 5, an enzyme that hydrolyzes cGMP.7 Clinical studies are needed to test for potential additive effects of simultaneous increases in cGMP and cAMP by combining the two classes of drugs. Safe generation of nitric oxide in vivo might be attained with the use of oral arginine or citrulline, substrates for the generation of nitric oxide, with resultant cGMP levels sustained by concomitant oral sildenafil.

Endothelin-1 is a potent endogenous peptide mediator that has a role in pulmonary arterial hypertension. It is unclear whether it has a primary pathogenetic role or whether it is a secondary mediator that perpetuates disease. Plasma endothelin levels are increased in patients with primary pulmonary hypertension, and endothelin is released in increased amounts in the blood traversing the lung.8 Endothelin is released by endothelial cells as big endothelin, which is cleaved to pro-endothelin, which, in turn, is converted to endothelin-1 (in systemic and lung vessels) or endothelin-2 (in kidney and gut). Endothelin-1 acts on two receptors — endothelin-A receptors and endothelin-B receptors. Activation of endothelin-B receptors causes the production of nitric oxide and vasodilatation, and activation of endothelin-A receptors results in vasoconstriction and smooth-muscle growth. The ideal endothelin-receptor antagonist is likely to be specific for endothelin-A.

A study using bosentan, a nonspecific endothelin-receptor antagonist, to treat pulmonary hypertension is reported in this issue of the Journal.9 Bosentan had small but measurable beneficial effects in a double-blind, placebo-controlled trial involving 213 patients. The duration of this trial was 16 weeks, which is not sufficient to test for a difference in mortality, but its results suggest that endothelin-receptor blockade has a therapeutic role in some patients with pulmonary arterial hypertension. The effect of bosentan appeared to be limited in most patients, and there was an unacceptable incidence of abnormal hepatic function at the higher dose. Because short-term vasodilator testing was not performed as part of the study, it is not known whether the patients with the best response to the drug were the same patients who might have had a response to other vasodilators. One cannot conclude from this study that bosentan should be the primary drug for the treatment of primary pulmonary hypertension or of other causes of pulmonary arterial hypertension. Follow-up studies are needed to determine the durability of the effect, whether there are differences in survival, what types of complications occur, and whether subgroups of patients have different responses to the drug. It would be useful to measure endothelin levels and to determine whether there are correlations between these levels and clinical effects. Studies should be designed to test whether combining endothelin-receptor antagonists with either inhibitors of phosphodiesterase type 5 or inducers of cAMP results in greater functional improvement than does either class of drug alone.

No current therapies appear to affect the pathogenesis of pulmonary vascular obstructive disease directly. In rare cases, patients receiving epoprostenol have had such dramatic responses that the dose has been reduced, and cessation of drug therapy has been attempted in a few patients, although the outcomes have not been published. The recent discovery that the transforming growth factor (TGF-) superfamily of receptors is involved in the pathogenesis of pulmonary hypertension should lead over the course of the next several years to specific therapies aimed at the origin of the disease. The evidence suggesting the involvement of TGF- receptors is compelling. About half of studied patients with familial primary pulmonary hypertension have mutations in exons of the bone morphogenetic protein receptor II gene (BMPR2), and the majority of others have genetic linkage to areas of chromosome 2 near BMPR2, perhaps in a promoter or upstream regulator or perhaps in intronic DNA.10 In addition, about 25 percent of patients with sporadic primary pulmonary hypertension have been found to have mutations in BMPR2.11 Mutations in the gene for activin-receptor–like kinase 1 (ALK1), another receptor in the TGF- family, are responsible for pulmonary hypertension in at least some patients with hereditary hemorrhagic telangiectasia.12 Clusters of endothelial cells carrying somatic TGF-2–receptor mutations are found in plexiform lesions in the pulmonary arterioles of patients with sporadic primary pulmonary hypertension.13 Studies of these receptor abnormalities in transfected cells, cell cultures from patients' tissues, and transgenic mice are under way, and insights into the relevant mechanisms will certainly emerge during the next several years. Other promising areas of research are potassium-channel function14 and drugs that interrupt the cycle of growth and repair in diseased pulmonary vessels.15

Therapy for primary pulmonary hypertension has progressed from calcium-channel blockers to prostacyclin and now includes adjunctive therapy with bosentan and, in some patients, sildenafil. Combination therapies should be tested in the next generation of studies. It now seems conceivable that the continuous intravenous administration of epoprostenol through a central catheter will soon be history. A better understanding of pathogenesis is at hand because the genes associated with many cases of primary pulmonary hypertension have been identified, but the development of therapies based on this knowledge awaits further insights.

John H. Newman, M.D.

Vanderbilt University School of Medicine

Nashville, TN 37232

References

1.Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111-117.[Full Text]

2.Humbert M, Nunes H, Sitbon O, Parent F, Herve P, Simonneau G. Risk factors for pulmonary arterial hypertension. Clin Chest Med 2001;22:459-475.[Medline]

3.Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-223.[Medline]

4.Rich S, Kaufmann E, Levy PS. The effects of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81.[Abstract]

5.Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994;121:409-415.[Medline]

6.Galie N, Manes A, Branzi A. Medical therapy of pulmonary hypertension: the prostacyclins. Clin Chest Med 2001;22:529-537.[Medline]

7.Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000;343:1342-1345.[Full Text]

8.Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with primary pulmonary hypertension. N Engl J Med 1993;328:1732-1739.[Abstract/Full Text]

9.Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.[Abstract/Full Text]

10.Newman JH, Wheeler L, Lane KB, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 2001;345:319-324.[Abstract/Full Text]

11.Thomson JR, Machado RD, Pauciulio MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPRII, a receptor of the TGF-beta family. J Med Genet 2000;37:741-745.[Abstract/Full Text]

12.Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345:325-334.[Abstract/Full Text]

13.Yeager ME, Voelkel NF, Tuder RM, et al. Mutational analysis of endothelial cell TGF-beta receptor type II in plexiform lesions of patients with primary pulmonary hypertension. Circulation 1999;100:I-587.abstract

14.Michelakis E, Weir EK. The pathobiology of pulmonary hypertension: smooth muscle cells and ion channels. Clin Chest Med 2001;22:419-432.[Medline]

15.Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000;6:698-702.[Medline]