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(Circulation. 2007;115:59-66.)
© 2007 American Heart Association, Inc.

Heart Failure

Sildenafil Improves Exercise Hemodynamics and Oxygen Uptake in Patients With Systolic Heart Failure

Gregory D. Lewis, MD; Justine Lachmann, MD; Janice Camuso, RN; John J. Lepore, MD; Jordan Shin, MD, PhD; Maryann E. Martinovic, BS; David M. Systrom, MD; Kenneth D. Bloch, MD; Marc J. Semigran, MD

From the Cardiology Division (G.D.L., J.L., J.C., J.J.L., J.S., M.E.M., K.D.B., M.J.S.) and the Pulmonary and Critical Care Unit (D.M.S.) of the Department of Medicine, and the Department of Anesthesia and Critical Care (K.D.B.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Dr Lepore is currently an employee of GlaxoSmithKline.

Correspondence to Marc J. Semigran, MD, Heart Failure and Cardiac Transplantation Unit, Massachusetts General Hospital, Bigelow 800, Fruit St, Boston, MA 02114. E-mail msemigran{at}partners.org

Received April 3, 2006; accepted October 5, 2006.

Background— Heart failure (HF) is frequently associated with dysregulation of nitric oxide–mediated pulmonary vascular tone. Sildenafil, a type 5 phosphodiesterase inhibitor, lowers pulmonary vascular resistance in pulmonary hypertension by augmenting intracellular levels of the nitric oxide second messenger, cyclic GMP. We tested the hypothesis that a single oral dose of sildenafil (50 mg) would improve exercise capacity and exercise hemodynamics in patients with chronic systolic HF through pulmonary vasodilation.

Methods and Results— Thirteen patients with New York Heart Association class III HF underwent assessment of right heart hemodynamics, gas exchange, and first-pass radionuclide ventriculography at rest and with cycle ergometry before and 60 minutes after administration of 50 mg of oral sildenafil. Sildenafil reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased resting and exercise cardiac index (P<0.05 for all) without altering mean arterial pressure, heart rate, or pulmonary capillary wedge pressure. Sildenafil reduced exercise pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular resistance/systemic vascular resistance ratio, which indicates a selective pulmonary vasodilator effect with exercise. Peak O₂ increased (15±9%) and ventilatory response to CO₂ output (E/CO₂ slope) decreased (16±5%) after sildenafil treatment. Improvements in right heart hemodynamics and exercise capacity were confined to patients with secondary pulmonary hypertension (rest pulmonary arterial pressure >25 mm Hg).

Conclusions— The present study shows that in patients with systolic HF, type 5 phosphodiesterase inhibition with sildenafil improves peak O₂, reduces E/CO₂ slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with HF and pulmonary hypertension.

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