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CLINICAL RESEARCH: HEART FAILURE

Transpulmonary B-Type Natriuretic Peptide Uptake and Cyclic Guanosine Monophosphate Release in Heart Failure and Pulmonary Hypertension

The Effects of Sildenafil

Department of Cardiology, Institute of Clinical and Experimental Medicine–IKEM, Prague, Czech Republic

Manuscript received February 9, 2009; revised manuscript received March 30, 2009, accepted May 6, 2009.

^_* Reprint requests and correspondence: Dr. Vojtech Melenovsky, Department of Cardiology, Institute for Clinical and Experimental Medicine–IKEM, Videnska 1958/9, Prague 4, 140 21, Czech Republic (Email: vojtech.melenovsky{at}ikem.cz).

Objectives: 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.

Background: Mechanisms of PVR increase in patients with chronic HF are incompletely understood.

Methods: 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.

Results: 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 E₁.

Conclusions: 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.

Key Words: heart failure • pulmonary vascular resistance • cGMP • sildenafil • pulmonary hypertension

Abbreviations and Acronyms   BNP = B-type natriuretic peptide   CAD = coronary artery disease   cGMP = cyclic guanosine monophosphate   HF = heart failure   H-PVR = high pulmonary vascular resistance   L-PVR = low pulmonary vascular resistance   LV = left ventricular   NP = natriuretic peptide   PA = pulmonary artery   PDE = phosphodiesterase   PGE1 = prostaglandin E1   PH = pulmonary hypertension   PV = pulmonary vein   PVR = pulmonary vascular resistance

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