This Article Figures Only Full Text Full Text (PDF) View Cardiosource Slide Set All Versions of this Article: j.jacc.2007.07.078v1 50/22/2136    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Guazzi, M. Articles by Guazzi, M. D. Search for Related Content PubMed Articles by Guazzi, M. Articles by Guazzi, M. D. Related Collections Related Article

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
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

Related Article

Type 5 Phosphodiesterase Inhibition in Heart Failure: The Next Step

Steven R. Goldsmith
J. Am. Coll. Cardiol. 2007 50: 2145-2147. [Full Text] [PDF]

This article has been cited by other articles:

				V. Melenovsky, H. Al-Hiti, L. Kazdova, A. Jabor, P. Syrovatka, I. Malek, J. Kettner, and J. Kautzner Transpulmonary B-type natriuretic peptide uptake and cyclic guanosine monophosphate release in heart failure and pulmonary hypertension: the effects of sildenafil. J. Am. Coll. Cardiol., August 11, 2009; 54(7): 595 - 600. [Abstract] [Full Text] [PDF]

				M. M. Hoeper, J. A. Barbera, R. N. Channick, P. M. Hassoun, I. M. Lang, A. Manes, F. J. Martinez, R. Naeije, H. Olschewski, J. Pepke-Zaba, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S85 - S96. [Abstract] [Full Text] [PDF]

				J. W. M. Cheng and S. R. Berhane Managing Erectile Dysfunction in Patients With Cardiovascular Diseases: The Efficacy and Safety of Phosphodiesterase-5 Inhibitors American Journal of Lifestyle Medicine, May 1, 2009; 3(3): 201 - 211. [Abstract] [PDF]

				C. S.P. Lam, V. L. Roger, R. J. Rodeheffer, B. A. Borlaug, F. T. Enders, and M. M. Redfield Pulmonary hypertension in heart failure with preserved ejection fraction a community-based study. J. Am. Coll. Cardiol., March 31, 2009; 53(13): 1119 - 1126. [Abstract] [Full Text] [PDF]

				G. D. Lewis The role of the pulmonary vasculature in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol., March 31, 2009; 53(13): 1127 - 1129. [Full Text] [PDF]

				S. Rich The Effects of Vasodilators in Pulmonary Hypertension: Pulmonary Vascular or Peripheral Vascular? Circ Heart Fail, March 1, 2009; 2(2): 145 - 150. [Full Text] [PDF]

				T. Nagayama, S. Hsu, M. Zhang, N. Koitabashi, D. Bedja, K. L. Gabrielson, E. Takimoto, and D. A. Kass Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J. Am. Coll. Cardiol., January 13, 2009; 53(2): 207 - 215. [Abstract] [Full Text] [PDF]

				S. Rich and M. Rabinovitch Diagnosis and Treatment of Secondary (Non-Category 1) Pulmonary Hypertension Circulation, November 18, 2008; 118(21): 2190 - 2199. [Full Text] [PDF]

				W.H. W. Tang and G. S. Francis The Year in Heart Failure J. Am. Coll. Cardiol., November 11, 2008; 52(20): 1671 - 1678. [Full Text] [PDF]

				G. D. Lewis, R. V. Shah, P. P. Pappagianopolas, D. M. Systrom, and M. J. Semigran Determinants of Ventilatory Efficiency in Heart Failure: The Role of Right Ventricular Performance and Pulmonary Vascular Tone Circ Heart Fail, November 1, 2008; 1(4): 227 - 233. [Abstract] [Full Text] [PDF]

				M. Guazzi Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure Circ Heart Fail, November 1, 2008; 1(4): 272 - 280. [Full Text] [PDF]

				A. Caretti, P. Bianciardi, R. Ronchi, M. Fantacci, M. Guazzi, and M. Samaja Phosphodiesterase-5 Inhibition Abolishes Neuron Apoptosis Induced by Chronic Hypoxia Independently of Hypoxia-Inducible Factor-1{alpha} Signaling Experimental Biology and Medicine, October 1, 2008; 233(10): 1222 - 1230. [Abstract] [Full Text] [PDF]

				T. Nagayama, M. Zhang, S. Hsu, E. Takimoto, and D. A. Kass Sustained Soluble Guanylate Cyclase Stimulation Offsets Nitric-Oxide Synthase Inhibition to Restore Acute Cardiac Modulation by Sildenafil J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 380 - 387. [Abstract] [Full Text] [PDF]

				M. Guazzi, R. Arena, and M. D. Guazzi Evolving changes in lung interstitial fluid content after acute myocardial infarction: mechanisms and pathophysiological correlates Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1357 - H1364. [Abstract] [Full Text] [PDF]

				S. R. Goldsmith Type 5 Phosphodiesterase Inhibition in Heart Failure: The Next Step J. Am. Coll. Cardiol., November 27, 2007; 50(22): 2145 - 2147. [Full Text] [PDF]