Abstract
BackgroundPalliative treatment with the Fontan procedure has greatly improved survival for children with functionally univentricular heart. Since Fontan performed the first successful operation, the procedure has evolved and is now performed as Total Cavo-Pulmonary Connection (TCPC).An increasing prevalence and longer life expectancy of TCPC patients have raised new challenges. The survivors are often suffering complications such as arrhythmias, myocardial dysfunction, thromboembolic events, neuropsychological deficit, protein-losing enteropathy and reduced exercise capacity. Several causes for the reduced exercise capacity may be present e.g. impaired function of the single ventricle, valve dysfunction and chronotropic impairment, and perhaps also increased pulmonary vascular resistance. Thus, plasma endothelin-1 has been shown to correlate with increased pulmonary vascular resistance and the risk of failing Fontan circulation. This has raised the question of the role for pulmonary vasodilation therapy, especially endothelin receptor antagonist in the management of TCPC patients.Methods/DesignThe TEMPO trial aims to investigate whether Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. The trial design is randomized, double-blind and placebo-controlled. Bosentan/placebo is administered for 14 weeks with control visits every four weeks. The primary endpoint is change in maximal oxygen consumption as assessed on bicycle ergometer test. Secondary endpoints include changes in pulmonary blood flow during exercise test, pro brain natriuretic peptide and quality of life.DiscussionWe hypothesize that treatment with Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients.Trial registrationclinicaltrials.gov NCT01292551
Highlights
Palliative treatment with the Fontan procedure has greatly improved survival for children with functionally univentricular heart
We hypothesize that treatment with Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in Total Cavo-Pulmonary Connection (TCPC) patients
The non-pulsatile pulmonary blood-flow following the TCPC procedure may increase pulmonary vascular resistance (PVR) through remodeling, as shown in an animal model [15]. This is supported by the fact that raised levels of the potent vasoconstrictor endothelin-1 correlate with increased PVR and failure of the Fontan circulation [11,16]
Summary
Surgical and medical advances in recent decades have improved the survival of children born with UVH; we can expect a higher prevalence and an increasing age of patients palliated with TCPC in the. In the healthy biventricular individual, the CO is readily increased with a reduction in afterload, augmentation of ventricular contractility or increase in heart rate The effect of these factors is dependent on an abundant preload reserve, in the absence of which CO increase would suffer. In a ramp exercise test, an increase in heart rate will reflect positively on CO as long as the preload is kept intact Since this may not be the fact in a TCPC circulation, any further increase in heart rate will more likely decrease the stroke volume. The Swedish Ethics Committee are informed about the study, and agree with the Danish Committee without making a separate approval, as all the endpoint tests are done in Denmark and the medicine is delivered to the patients in Denmark.
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