• Anders Hebert, Ulla R Mikkelsen, Ulf Thilen, Lars Idorn, Annette S Jensen, Edit Nagy, Katarina Hanseus, Keld E Sørensen, and Lars Søndergaard.
• From the Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (A.H., L.I., A.S.J., L.S.); Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital and Center for Healthy Ageing, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (U.R.M.); Departments of Cardiology (U.T.) and Pediatric Cardiology (K.H.), Lund University Hospital, Lund, Sweden; Department of Cardiology/Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (S.N.); and Department of Cardiology, Skejby, Aarhus University Hospital, Aarhus, Denmark (K.E.S.). andershebert@gmail.com.
• Circulation. 2014 Dec 2; 130 (23): 2021-30.

BackgroundThe Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients.Methods And ResultsSeventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL·kg(-1)·min(-1) (from 28.7 to 30.7 mL·kg(-1)·min(-1)) in the bosentan group compared with 0.6 mL·kg(-1)·min(-1) (from 28.4 to 29.0 mL·kg(-1)·min(-1)) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (P=0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit.ConclusionsBosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity.Clinical Trial Registration Urlhttp://www.clinicaltrials.gov. Unique identifier: NCT01292551.© 2014 American Heart Association, Inc.

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