title: Rationale and design of a trial on the role of bosentan in Fontan patients: improvement of exercise capacity?
abstract: BACKGROUND
  The Fontan circulation is a palliative procedure performed in patients with complex congenital heart disease (CHD), making transpulmonary blood flow dependent on the systemic venous pressure. In a Fontan circulation a low pulmonary vascular resistance (PVR) is crucial, as is epitomized by the observation that a high PVR is a strong predictor of mortality. Long-term follow-up has shown that PVR may rise many years after the Fontan procedure has been performed, possibly due to micro-emboli from a dilated right atrium or from the venous system. Other mechanisms of increased PVR might be aging, obstructed airways caused by lymphatic dysfunction, lack of pulsatile pulmonary flow causing a release of endothelium-derived vasoactive molecules, and prolonged overexpression of vasoconstrictors such as endothelin-1. Mean plasma level of endothelin-1 has been shown to be significantly higher in Fontan patients compared to healthy controls. In patients with pulmonary arterial hypertension (PAH), therapy with bosentan, an endothelin-1 receptor antagonist, has demonstrated to improve exercise capacity and to reduce the elevated PVR. In addition, reduction of PVR is shown early and late after the Fontan procedure on treatment with exogenous NO, another advanced PAH therapy. However, the long term effect of reducing the PVR by bosentan treatment on exercise capacity in Fontan patients is still unknown.
  
  
  METHODS
  We designed a prospective, multicenter, randomized open label trial to study the effect of bosentan in Fontan patients. The primary endpoint will be the change in maximum exercise capacity (peak V'O2).
  
  
  CONCLUSIONS
  We hypothesize that treatment with bosentan, an endothelin-1 receptor antagonist, improves maximum exercise capacity and functional capacity in adult Fontan patients.
authors.affiliation: Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Schuuring
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Vis
authors.forename: Berto J
authors.initials: BJ
authors.lastname: Bouma
authors.forename: Arie P J
authors.initials: AP
authors.lastname: van Dijk
authors.forename: Joost P
authors.initials: JP
authors.lastname: van Melle
authors.forename: Petronella G
authors.initials: PG
authors.lastname: Pieper
authors.forename: Hubert W
authors.initials: HW
authors.lastname: Vliegen
authors.forename: Gertjan Tj
authors.initials: GT
authors.lastname: Sieswerda
authors.forename: Barbara J M
authors.initials: BJ
authors.lastname: Mulder
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D002985:Clinical Protocols; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects*; D005260:Female; D018729:Fontan Procedure; D006801:Humans; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects*; D018579:Patient Selection; D011446:Prospective Studies; D011897:Random Allocation; D012107:Research Design; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D013449:Sulfonamides; D000077300:Bosentan