Correspondence

Epoprostenol (Prostacyclin) Therapy in Primary Pulmonary Hypertension

N Engl J Med 1998; 338:1773-1774June 11, 1998

Article

To the Editor:

The study by McLaughlin et al. (Jan. 29 issue)1 implies that hypertensive pulmonary arteries develop beneficial structural changes after prolonged treatment with prostacyclin in patients with primary pulmonary hypertension. Since marked remodeling occurs throughout the vascular tree by the time severe pulmonary hypertension develops, structural changes could occur either proximally or distally. One might conjecture that more recent (i.e., less fibrotic and therefore potentially more reversible) remodeling is located proximally rather than in the distal vessels.

One wonders whether the clinical benefits of prostacyclin may be due primarily to altered hemodynamics, with secondary effects on pulmonary-artery structure, rather than to a direct effect of the drug on pulmonary-artery remodeling.

The reductions in pulmonary-artery pressures were significant, but pressures still remained elevated. We have not found a beneficial effect of prostacyclin on pulmonary vascular remodeling itself, in an animal model in which neointimal lesions develop that resemble the lesions seen in primary pulmonary hypertension,2 when prostacyclin or iloprost was continuously infused at doses similar to those given to patients (unpublished data). Several studies have shown that profibrotic factors are present at sites of active remodeling in patients with primary pulmonary hypertension, including transforming growth factor-β,3 angiotensin-converting enzyme,4 and nitric oxide synthase.5 If the implication of this study is borne out — that an antiremodeling approach is clinically beneficial — combination-drug therapies aimed at interfering directly with profibrotic and proliferative processes may be more successful than prostacyclin alone or prostacyclin plus calcium-channel blockers.

Mitchell Botney, M.D.
Washington University School of Medicine, St. Louis, MO 63110

5 References

1. 1

   McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998;338:273-277
   Full Text | Web of Science | Medline

2. 2

   Okada K, Tanaka Y, Bernstein M, Zhang W, Patterson GA, Botney MD. Pulmonary hemodynamics modify the rat pulmonary artery response to injury: a neointimal model of pulmonary hypertension. Am J Pathol 1997;151:1019-1025
   Web of Science | Medline

3. 3

   Botney MD, Bahadori L, Gold LI. Vascular remodeling in primary pulmonary hypertension: potential role for transforming growth factor-β. Am J Pathol 1994;144:286-295
   Web of Science | Medline

4. 4

   Schuster DP, Crouch EC, Parks WC, Johnson T, Botney MD. Angiotensin converting enzyme expression in primary pulmonary hypertension. Am J Respir Crit Care Med 1996;154:1087-1091
   Web of Science | Medline

5. 5

   Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214-221
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Dr. Botney correctly points out that the precise changes that occur in the pulmonary vascular bed in patients with primary pulmonary hypertension treated with prostacyclin were not elucidated in our study. Only serial open-lung biopsies could have revealed those changes. His comments also underscore our limited understanding of the way the pulmonary vascular bed responds to injury as well as to drug therapy.

The majority of patients treated with prostacyclin have a far greater decrease in pulmonary vascular resistance than in pulmonary-artery pressure.1 The determinants of the pressure–flow relation in the pulmonary vascular bed in disease states remain uncertain. Our data, however, do support a direct effect of prostacyclin on the pulmonary vasculature, since patients who had minimal vasodilator responsiveness still had on average a 39 percent decrease in pulmonary vascular resistance after treatment for one year.1 Studies in animals might not show representative remodeling of neointimal lesions unless the animals were also treated for prolonged periods, which is both difficult and expensive.

Finally, we agree wholeheartedly that the future medical therapy of pulmonary hypertension may use new strategies — perhaps induction therapy, followed by maintenance therapy consisting of a combination of drugs targeted at reversing the spectrum of abnormalities that occur in the endothelial and medial layers of the pulmonary vasculature.

Stuart Rich, M.D.
Vallerie V. McLaughlin, M.D.
Rush–Presbyterian–St. Luke's Medical Center, Chicago, IL 60612

1 References

1. 1

   Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301
   Full Text | Web of Science | Medline