Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmonary hypertension treated with bosentan Carmine Dario Vizza a, ⁎ , 1 , Claudio Letizia b, 1 , Roberto Badagliacca a , Roberto Poscia a , Beatrice Pezzuto a , Cristina Gambardella a , Alfred Nona a , Silvia Papa a , Serena Marcon a , Massimo Mancone a , Carlo Iacoboni a , Valeria Riccieri c , Maurzio Volterrani d , Francesco Fedele a a Dept. Cardiovascular and Respiratory Science, University of Rome, “La Sapienza”, Italy b Dept. Clinical Sciences, University of Rome, “La Sapienza”, Italy c Dept. of Reumathology, University of Rome, “La Sapienza”, Italy d Dept. of Cardiologic Rehabilitation, IRCCS San Raffaele Pisana, Rome, Italy abstract article info Article history: Received 11 August 2011 Received in revised form 15 December 2011 Accepted 20 December 2011 Available online xxxx Keywords: Endothelin-1 Pulmonary arterial hypertension Clinical worsening 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 indepen- dent 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. © 2011 Published by Elsevier Ireland Ltd. 1. Introduction Pulmonary arterial hypertension (PAH) is a severe disease with pro- gressive elevation of pulmonary vascular resistance (PVR) and pulmo- nary artery pressure (Pap), ultimately producing right heart failure and death [1]. The dual endothelin receptor antagonist bosentan is the first oral therapy approved for the treatment of PAH.[2] In patients with idiopathic PAH (IPAH) or PAH related to connective tissue diseases, randomized, double-blind, placebo controlled studies have demon- strated that bosentan improves hemodynamics, exercise capacity, and functional class [3,4]. In addition, a long-term study [5] showed that first-line bosentan therapy improves survival in patients with IPAH compared with their predicted survival, as determined by the formula based on the National Institute of Health (NIH) registry data [6]. However, it is a common clinical experience that some pa- tients on bosentan therapy have clinical deterioration during long- term therapy. Despite the wide spread use of bosentan as a treatment of PAH, few studies explore the impact of baseline ET-1 plasma levels on the clinical effect of this drug. We recently observed no difference in clin- ical efficacy (functional class, exercise capacity) in two subgroups of PAH patients stratified on the basis of ET-1 plasma levels [7], but the influence on clinical worsening has never been addressed. The purpose of this study is to ascertain if ET-1 plasma levels have an impact on the long-term outcome of patients with IPAH treated International Journal of Cardiology xxx (2012) xxx–xxx Abbreviations: PH, Pulmonary hypertension; PAH, Pulmonary arterial hyperten- sion; Pap, Pulmonary artery pressure; PVR, Pulmonary vascular resistance; ET-1, Endothelin-1; BNP, Brain natriuretic peptide; ADM, Adrenomedullin; NIH, National In- stitute of Health; 6MWT, 6-minute walking-test; ANOVA, Analysis of variance; WHO, World Health Organization; CW, Clinical worsening. ⁎ Corresponding author at: Department of Cardiovascular and Respiratory Disease, I School of Medicine, University of Rome La Sapienza, Policlinico Umberto I, Viale del Policlinico 155-00161 Rome, Italy. Tel.: + 39 06 49979051; fax: + 39 06 49979060. E-mail address: dario.vizza@uniroma1.it (C.D. Vizza). 1 C.Letizia shares the first authorship with CD Vizza. IJCA-14351; No of Pages 5 0167-5273/$ – see front matter © 2011 Published by Elsevier Ireland Ltd. doi:10.1016/j.ijcard.2011.12.104 Contents lists available at SciVerse ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard Please cite this article as: Vizza CD, et al, Relationship between baseline ET-1 plasma levels and outcome in patients with idiopathic pulmo- nary hypertension treated with bosentan, Int J Cardiol (2012), doi:10.1016/j.ijcard.2011.12.104