Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmonary hypertension treated with bosentan

Objectives: To address if baseline endothelin-1 (ET-1) plasma levels might predict clinical worsening (CW) in patients with idiopathic pulmonary hypertension (IPAH) treated with bosentan. Methods: Forty-four consecutive patients with IPAH (WHO classes II-III) were included in this study. After an initial assessment (clinical status, pulmonary hemodynamics, samples for adrenomedullin (ADM), ET-1 and brain natriuretic peptide (BNP) plasma levels), patients were treated with bosentan and followed-up for CW. Results: We observed CW in 24 patients. Actuarial rates of freedom from CW were 74% at 1 year, 56% at 2 years, and 43% at 3 years. Patients with CW had a worse WHO functional class (II/III; no-CW 14/6 vs CW 5/19, p = 0.002), six-minute walk-test distance (no-CW 439 + 94 m vs CW 385 + 82 m, p = 0.04), mean pulmonary artery pressure (no-CW 47.4 + 10.6 mm Hg vs CW 56 + 12.6 mm Hg, p = 0.02) and pulmonary vascular resistance (PVR no-CW 12.5 + 4.8 WU vs CW 16.4 + 6.3 WU, p = 0.03) than the no-CW group. Moreover ET-1 (no-CW 14.1 + 4.2 pg/ml vs CW 21.3 + 6.3 pg/ml, p = 0.0001), ADM (no-CW 14.9 + 7 pg/ml vs CW 21.5 + 10.4 pg/ml p = 0.002) and BNP (no-CW 82.8 + 35.3 pg/ml vs CW 115.4 + 39.6 pg/ml, p = 0.007) plasma levels were significantly higher in the CW group than in the no-CW group. The multivariate Cox proportional hazards model identified WHO class III (RR 4.6, 95%CI 14.6-1.45), ET-1 plasma levels (RR 1.1, 95%CI 2.05-1.01) and PVR (RR 1.2, 95%CI 1.3-1.03) as independent risk factors for CW. Conclusions: These data confirm the high rate of CW in patients with IPAH treated with bosentan and document the impact of the endothelin system on CW of these patients.