This Article Figures Only Full Text Full Text (PDF) 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 Similar articles in PubMed 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 PubMed Citation Articles by Guazzi, M. Articles by Guazzi, M. D.

CLINICAL RESEARCH: HEART FAILURE

The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure

Marco Guazzi, MD, PhD, FACC^*,*, Gabriele Tumminello, MD^*, Fabio Di Marco, MD, Cesare Fiorentini, MD^* and Maurizio D. Guazzi, MD, PhD

^* Cardiopulmonary Laboratory, Cardiology Division, University of Milano, San Paolo Hospital, Milan, Italy
Respiratory Unit, University of Milano, San Paolo Hospital, Milan, Italy
Institute of Cardiology, University of Milano, Milan, Italy

Manuscript received June 25, 2004; revised manuscript received August 27, 2004, accepted September 6, 2004.

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

Presented, in part, at the 76th American Heart Association Scientific Sessions, Orlando, Florida, November 9 to 12, 2003.

OBJECTIVES: We sought to investigate the effects of sildenafil, a phosphodiesterase-5 (PDE₅) inhibitor, on lung function and exercise performance in chronic heart failure (CHF).

BACKGROUND: In CHF, nitric oxide-mediated regulation of lung vascular tone and alveolar-capillary membrane conductance is impaired and contributes to exercise intolerance. The potential for benefits due to increased nitric-oxide availability is unexplored.

METHODS: In 16 patients with CHF and 8 normal subjects, we measured—before and 60 min after sildenafil (50 mg) or placebo—ejection fraction, pulmonary hemodynamics, carbon monoxide diffusion capacity (DLco), with its membrane (D_M) and capillary blood volume (V_c) subcomponents, endothelial function (brachial reactive hyperemia) at rest, peak oxygen uptake (VO₂), increments in VO₂ versus work rate (VO₂/WR), changes in ventilation versus CO₂ production (VE/VCO₂) slope, and recovery VO₂ time constant (tau) on exertion.

RESULTS: In CHF, sildenafil did not affect cardiac index, wedge pulmonary pressure, or ejection fraction; it significantly (p < 0.01) decreased pulmonary mean artery pressure (–20.4%) and arteriolar resistance (–45.1%), VE/VCO₂ slope (–9.0%) and recovery tau (–25.8%), and increased (p < 0.01) DLco (+11.1%), D_M (+9.9%) peak VO₂ (+19.7%), VO₂/WR (+11.0%), and brachial reactive hyperemia (+33.3%). No variations occurred in normal subjects and after placebo. Changes in DLco were related to those in VE/VCO₂ slope (r = –0.71; p = 0.002), and changes in brachial hyperemia correlated with those in VO₂/WR (r = 0.80; p = 0.0002).

CONCLUSIONS: This study shows that in CHF PDE₅ inhibition modulates pulmonary pressure and vascular tone, and improves DLco, exercise peak VO₂, aerobic (VO₂/WR) and ventilatory (VE/VCO₂ slope) efficiencies, and oxygen debt (recovery tau). Endothelial mechanisms may underlie these effects.

Abbreviations and Acronyms   AT = anaerobic threshold   CHF = chronic heart failure   CPET = cardiopulmonary exercise testing   DLco = lung diffusing capacity for carbon monoxide   DM = alveolar-capillary membrane conductance   PDE5 = phosphodiesterase-5   tau = oxygen uptake time constant   VA = alveolar volume   Vc = pulmonary capillary blood volume   VCO2 = carbon dioxide output   VE/VCO2 slope = slope of increase in ventilation versus carbon dioxide output   VO2 = oxygen uptake   VO2/WR = rate of oxygen uptake increase per work rate

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]

				D. E. Choi, J. Y. Jeong, B. J. Lim, S. Chung, Y. K. Chang, S. J. Lee, K. R. Na, S. Y. Kim, Y. T. Shin, and K. W. Lee Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats Am J Physiol Renal Physiol, August 1, 2009; 297(2): F362 - F370. [Abstract] [Full Text] [PDF]

				V. Faoro, S. Boldingh, M. Moreels, S. Martinez, M. Lamotte, P. Unger, S. Brimioulle, S. Huez, and R. Naeije Bosentan Decreases Pulmonary Vascular Resistance and Improves Exercise Capacity in Acute Hypoxia Chest, May 1, 2009; 135(5): 1215 - 1222. [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]

				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. Giardini, A. Balducci, S. Specchia, G. Gargiulo, M. Bonvicini, and F. M. Picchio Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients Eur. Heart J., July 1, 2008; 29(13): 1681 - 1687. [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]

				F. N. Salloum, A. Abbate, A. Das, J.-E. Houser, C. A. Mudrick, I. Z. Qureshi, N. N. Hoke, S. K. Roy, W. R. Brown, S. Prabhakar, et al. Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1398 - H1406. [Abstract] [Full Text] [PDF]

				L. Ingle Prognostic value and diagnostic potential of cardiopulmonary exercise testing in patients with chronic heart failure Eur J Heart Fail, February 1, 2008; 10(2): 112 - 118. [Abstract] [Full Text] [PDF]

				M. Guazzi, M. Samaja, R. Arena, M. Vicenzi, and M. D. Guazzi Long-Term Use of Sildenafil in the Therapeutic Management of Heart Failure J. Am. Coll. Cardiol., November 27, 2007; 50(22): 2136 - 2144. [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]

				D. A. Kass, H. C. Champion, and J. A. Beavo Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation Circ. Res., November 26, 2007; 101(11): 1084 - 1095. [Abstract] [Full Text] [PDF]

				G. D. Lewis, R. Shah, K. Shahzad, J. M. Camuso, P. P. Pappagianopoulos, J. Hung, A. Tawakol, R. E. Gerszten, D. M. Systrom, K. D. Bloch, et al. Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension Circulation, October 2, 2007; 116(14): 1555 - 1562. [Abstract] [Full Text] [PDF]

				G. Tumminello, M. Guazzi, P. Lancellotti, and L. A. Pierard Exercise ventilation inefficiency in heart failure: pathophysiological and clinical significance Eur. Heart J., March 2, 2007; 28(6): 673 - 678. [Abstract] [Full Text] [PDF]

				G. D. Lewis, J. Lachmann, J. Camuso, J. J. Lepore, J. Shin, M. E. Martinovic, D. M. Systrom, K. D. Bloch, and M. J. Semigran Sildenafil Improves Exercise Hemodynamics and Oxygen Uptake in Patients With Systolic Heart Failure Circulation, January 2, 2007; 115(1): 59 - 66. [Abstract] [Full Text] [PDF]

				P. Agostoni, M. Bussotti, G. Cattadori, E. Margutti, M. Contini, M. Muratori, G. Marenzi, and C. Fiorentini Gas diffusion and alveolar-capillary unit in chronic heart failure Eur. Heart J., November 1, 2006; 27(21): 2538 - 2543. [Abstract] [Full Text] [PDF]

				A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, B. H. Greenberg, J. D. Knoke, K. U. Knowlton, W. Y.W. Lew, J. Narula, D. Sahn, et al. Highlights of the year in JACC 2004 J. Am. Coll. Cardiol., January 4, 2005; 45(1): 137 - 153. [Full Text] [PDF]