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CLINICAL RESEARCH: HEART FAILURE

Long-Term Use of Sildenafil in the Therapeutic Management of Heart Failure

Marco Guazzi, MD, PhD, FACC^_*,_*, Michele Samaja, PhD, Ross Arena, PhD, Marco Vicenzi, MD^_* and Maurizio D. Guazzi, MD, PhD, FESC

^_* Cardiopulmonary Unit, Cardiology Division, University of Milan, San Paolo Hospital, Milan, Italy
Biochemistry Department, University of Milan, San Paolo Hospital, Milan, Italy
Virginia Commonwealth University, Richmond, Virginia
Institute of Cardiology, University of Milan, Milan, Italy.

Manuscript received April 16, 2007; revised manuscript received July 6, 2007, accepted July 23, 2007.

^_* Reprint requests and correspondence: Dr. Marco Guazzi, Cardiopulmonary Unit, Cardiology Division, University of Milano, San Paolo Hospital, Via A. di Rudinì 8, 20142 Milan, Italy. (Email: marco.guazzi{at}unimi.it).

Presented in part at the 79th American Heart Association Scientific Session, Chicago, Illinois, November 12–15, 2006.

Objectives: This study sought to test the functional exercise capacity and endothelial function in a cohort of chronic heart failure (CHF) patients treated with chronic type 5 phosphodiesterase (PDE₅) inhibitor.

Background: In CHF, endothelial dysfunction is involved in muscle underperfusion, ergoreflex oversignaling, and exercise ventilation inefficiency. Inhibition of PDE₅ by improving endothelial dysfunction might be beneficial.

Methods: Stable CHF patients were randomly assigned to placebo (23 patients) or sildenafil at the dose of 50 mg twice per day (23 patients) in addition to their current drug treatment for 6 months, with assessments (at 3 and 6 months) of endothelial function by brachial artery flow-mediated dilatation (FMD), cardiopulmonary exercise testing, and ergoreflex response.

Results: In the sildenafil group only, at 3 and 6 months we observed reduction of systolic pulmonary artery pressure (from 33.7 to 25.2 mm Hg and 23.9 mm Hg), ergoreflex effect on ventilation (from 6.9 to 2.3 l·min^–1 and 1.9 l·min^–1), ventilation to CO₂ production slope (V_E/VCO ₂, from 35.5 to 32.1 and 29.8), and breathlessness (score) (from 23.6 to 16.6 and 17.2), and an increase of FMD (from 8.5% to 13.4% and 14.2%), peak VO ₂ (from 14.8 to 18.5 ml·min^–1·kg^–1 and 18.7 ml·min^–1·kg^–1), and ratio of VO ₂ to work rate changes (from 7.7 to 9.3 and 10.1). All changes were significant at p < 0.01. In the sildenafil group, a significant correlation was found at 3 and 6 months between changes in FMD and those in ergoreflex. Changes in ergoreflex correlated with those in peak VO ₂ and V_E/VCO ₂ slope. No adverse effects were noted except for flushing in 3 patients.

Conclusions: In CHF, improvement in exercise ventilation and aerobic efficiency with sildenafil is sustained and is significantly related with an endothelium-mediated attenuation of exercising muscle oversignaling. Chronic sildenafil seems to be a remedy based on CHF pathophysiology and devoid of remarkable adverse effects.

Abbreviations and Acronyms   CHF = chronic heart failure   CPET = cardiopulmonary exercise testing   FMD = flow-mediated dilation   PDE5 = type 5 phosphodiesterase   VCO 2 = carbon dioxide production   VD/VT = dead space/tidal volume ratio   VE = ventilation   VO 2 = oxygen uptake   WR = work rate

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