We sought to identify factors that discriminate heart failure (HF) patients with normal
and elevated pulmonary vascular resistance (PVR) and to elucidate the role of cyclic
guanosine monophosphate (cGMP)-dependent vasodilation.
Mechanisms of PVR increase in patients with chronic HF are incompletely understood.
Twenty-two HF patients with high pulmonary vascular resistance (H-PVR) (>200 dyn.s.cm(-5))
were compared with 24 matched low pulmonary vascular resistance (L-PVR) patients of
similar age, sex, body size, HF severity, and volume status who were undergoing invasive
hemodynamic study. Pulmonary arterial (PA) and venous blood samples from a wedged
PA catheter were used to calculate transpulmonary B-type natriuretic peptide (BNP)
uptake and cGMP release. The H-PVR patients were re-examined 1 h after a 40-mg oral
dose of sildenafil.
Although transpulmonary BNP uptake was similar (p = 0.2), cGMP release was diminished
in the H-PVR patients (-1.9 vs. 27.8 nmol.min(-1); p = 0.005). Transpulmonary BNP
uptake and cGMP release correlated in the L-PVR patients (R = 0.6, p = 0.004) but
not in the H-PVR. The H-PVR patients also had lower PA compliance, systemic arterial
compliance (by 47% and 20%, p < 0.001 and p < 0.03), and cardiac index. Sildenafil
reduced PVR (-47%), systemic resistance (-24%) and heart rate (-8%), increased cardiac
index (+24%), and PA compliance (+87%, all p < 0.001), with a parallel increase of
cGMP release (from -5.6 to 16.5 nmol.min(-1), p = 0.047), without affecting BNP uptake
or norepinephrine(PA). The PVR response was not dependent on PA wedge pressure or
pulmonary hypertension reversibility with prostaglandin E(1).
The H-PVR patients have stiffening of both pulmonary and systemic arteries, preserved
transpulmonary BNP uptake, but diminished cGMP release, which is reversible by the
administration of sildenafil. This study provides in vivo evidence that phosphodiesterase
5A inhibition restores sensitivity of pulmonary vasculature to endogenous cGMP-dependent
vasodilators.