• Carmine Dario Vizza, Claudio Letizia, Luigi Petramala, Roberto Badagliacca, Roberto Poscia, Enrico Zepponi, Eleonora Crescenzi, Alfred Nona, Giulia Benedetti, Fabio Ferrante, Susanna Sciomer, and Francesco Fedele.
• Dept. Cardiovascular and Respiratory Science, Italy.
• Regul. Pept. 2008 Nov 29; 151 (1-3): 48-53.

ObjectiveBosentan, an endothelin (ET) ETA-ETB receptors antagonist, is an effective therapy for idiopathic pulmonary arterial hypertension (PAH) and for PAH related to connective tissue disease (CTD). The aim of this study was to evaluate the behaviour of ET-1 and brain natriuretic peptide (BNP) venous plasma levels during a 6-month dual ET-1 receptor blockade and the potential influence of baseline ET-1 venous plasma levels on the clinical efficacy of bosentan.Setting And PatientsTwenty-five patients with PAH (idiopathic n=16, CTD n=9) in WHO functional class II-III were included in this study. After initial evaluation, patients' WHO class, 6-minute walking-test (6MWT), ET-1 and BNP venous plasma levels were assessed at baseline and after 6-month bosentan therapy. To evaluate whether the ET-1 levels could influence the clinical response to bosentan, data were analyzed for the whole population which was stratified according to high and low ET-1 plasma levels (on the basis of the baseline median value of ET-1 plasma: Gr.1<18.7 pg/ml, Gr.2>18.7 pg/ml).ResultsStudy population included patients with moderate-severe PAH. After 6-month of treatment we observed a significant increase in 6MWT distance (from 435+/-85) m to 467+/-77 m, p>0.001) and an improvement in WHO class (from 2.4+/-0.5 to 2+/-0.6 p>0.01), with a significant decrease in BNP (from 87+/-33 pg/ml to 67+/-41 pg/ml, p=0.006) and a trend towards lower ET-1 plasma levels (from 17.7+/-5 pg/ml to 16+/-6 pg/ml, p=ns). Improvement in effort tolerance (Delta distance) was not correlated to modification in ET-1 (DeltaET-1) and BNP (DeltaBNP) plasma levels, while we found a significant correlation between DeltaET-1 and DeltaBNP (r=0.63, p=0.0006). Analyzing the subpopulation, Gr.2 patients were older (Gr.1: 41+/-10 years vs Gr.2: 50+/-9 years, p=0.04), had less effort capacity (6MWT distance, Gr.1: 469+/-76 m, vs Gr.2: 398+/-82 m, p=0.03), and showed a trend towards higher BNP values (Gr.1: 82+/-41 pg/ml vs Gr.2: 92+/-23 pg/ml, p=0.051), but no significant differences in pulmonary hemodynamics. After the 6-month treatment both groups showed a significant improvement in 6MWT (Gr.1: +32+/-24 m, Gr.2: +32+/-21 m p=0.05) without differences between groups. WHO class had a trend towards lower class (Gr.1: -0.5+/-0.5, Gr.2: -0.3+/-0.4 p=0.15) in both groups. BNP plasma levels showed a significant decrease only in Gr.2 (Gr.1: -6+/-41 pg/ml, Gr.2: -34+/-19 pg/ml p=0.02); similarly ET-1 plasma levels showed a trend towards a decrease only in Gr.2 (Gr.1: 0.2+/-4.6 pg/ml, Gr.2: -3.8+/-6.6 pg/ml p=0.09).ConclusionsOur data confirm that bosentan is an effective therapy for patients with PAH. Its clinical efficacy (effort tolerance and NYHA) seems to be independent from baseline venous ET1 plasma levels. Bosentan therapy seems to elicit different patterns in ET-1 and BNP plasma levels, with decrease of the peptides only in patients with higher activation of the systemic endothelin system. Further studies are warranted to explore the potential impact of baseline ET-1 levels on the long-term effects (clinical worsening) of bosentan therapy.

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