Circulation. 2003;108:2066-2069
Published online before print October 20, 2003, doi: 10.1161/01.CIR.0000099502.17776.C2
Published online before print October 20, 2003, doi: 10.1161/01.CIR.0000099502.17776.C2
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(Circulation. 2003;108:2066.)
© 2003 American Heart Association, Inc.
Brief Rapid Communications |
Long-Term Treatment With Oral Sildenafil Is Safe and Improves Functional Capacity and Hemodynamics in Patients With Pulmonary Arterial Hypertension
From the Vascular Biology Group and Pulmonary Hypertension Program, Department of Medicine (E.D.M., W.T., L.W., X.-C.W., S.L.A.), the Department of Diagnostic Imaging (M.N.), Division of Pulmonary Medicine (D.L.), and Department of Surgery (Cardiothoracic) (S.-H.W., D.M.), University of Alberta, Edmonton, Canada.
Correspondence to E.D. Michelakis, MD, University of Alberta, 2C2 Walter C Mackenzie Health Sciences Centre, 8440 112th St, Edmonton, Alberta, Canada, T6G 2B7. E-mail emichela{at}cha.ab.ca
Received April 28, 2003; de novo received September 4, 2003; accepted September 9, 2003.
Background— The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown.
Methods and Results— We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger’s syndrome; New York Heart Association class II to III). Functional class improved by 
1 class in all patients. Pretreatment versus posttreatment values (mean±SEM) were as follows: 6-minute walk, 376±30 versus 504±27 m, P<0.0001; mean PA pressure, 70±3 versus 52±3 mm Hg, P<0.007; pulmonary vascular resistance index 1702±151 versus 996±92 dyne · s · cm-5 · m-2, P<0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels.
Conclusion— This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of $492 Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.
Key Words: hypertension, pulmonary • sildenafil • potassium
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