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J Am Coll Cardiol, 2004; 44:2339-2348, doi:10.1016/j.jacc.2004.09.041
© 2004 by the American College of Cardiology Foundation
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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{dagger}, Cesare Fiorentini, MD* and Maurizio D. Guazzi, MD, PhD{ddagger}

* Cardiopulmonary Laboratory, Cardiology Division, University of Milano, San Paolo Hospital, Milan, Italy
{dagger} Respiratory Unit, University of Milano, San Paolo Hospital, Milan, Italy
{ddagger} 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 (DM) and capillary blood volume (Vc) subcomponents, endothelial function (brachial reactive hyperemia) at rest, peak oxygen uptake (VO2), increments in VO2 versus work rate ({Delta}VO2/{Delta}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%), DM (+9.9%) peak VO2 (+19.7%), {Delta}VO2/{Delta}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 {Delta}VO2/{Delta}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 ({Delta}VO2/{Delta}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
  {Delta}VO2/{Delta}WR = rate of oxygen uptake increase per work rate




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