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

Presented, in part, at the 76th American Heart Association Scientific Sessions, Orlando, Florida, November 9 to 12, 2003.
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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 VO2versus work rate (ΔVO2/ΔWR), changes in ventilation versus CO2production (VE/VCO2) slope, and recovery VO2time 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/VCO2slope (−9.0%) and recovery tau (−25.8%), and increased (p < 0.01) DLco (+11.1%), DM(+9.9%) peak VO2(+19.7%), ΔVO2/ΔWR (+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/VCO2slope (r = −0.71; p = 0.002), and changes in brachial hyperemia correlated with those in ΔVO2/ΔWR (r = 0.80; p = 0.0002).

Conclusions

This study shows that in CHF PDE5inhibition modulates pulmonary pressure and vascular tone, and improves DLco, exercise peak VO2, aerobic (ΔVO2/ΔWR) and ventilatory (VE/VCO2slope) 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/VCO2slope
slope of increase in ventilation versus carbon dioxide output
VO2
oxygen uptake
ΔVO2/ΔWR
rate of oxygen uptake increase per work rate

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Supported, in part, by a grant from the Luigi Berlusconi Foundation, Milano, Italy.