Fontan circulation: the search for targeted therapy.

T he Fontan operation has been the final palliation for children born with congenital heart defects with a functional single ventricle for >4 decades. In the early days of the Fontan operation, focus was rightly on technical modifications and alterations in strategy in an attempt to decrease morbidity and mortality related to the operation itself. 3 In recent years, that focus has shifted toward the long-term implications of a total cavopulmonary connection. 4 It is clear that although the Fontan operation can create a stable circulation through early adulthood, there are inherent limitations to this physiology that affect other organ systems, leading to diminished functional capacity over time. 5 This has led to an intensified search for therapies that specifically and effectively target the deficiencies in the Fontan physiology. In this issue of Circulation, Hebert and colleagues present results of the Treatment with Endothelin receptor antagonist in Fontan patients, a randoMized, Placebo-controlled, double-blind study measuring peak Oxygen consumption (TEMPO) trial. In this study, the authors evaluate the effect of bosentan, an endothelin-1 receptor antagonist , on exercise performance in adolescents and young adults with Fontan physiology. 6 The authors demonstrate a small but statistically significant improvement in oxygen consumption during peak exercise after 14 weeks of treatment compared with placebo. The TEMPO trial is well designed and well executed and adds significantly to the growing literature evaluating the potential role of modula-tors of pulmonary vascular resistance (PVR) in those who have undergone the Fontan operation. Although this study is small relative to many adult heart failure studies, it is the largest placebo-controlled study to date of a pulmonary vasodilator in the Fontan population. The findings from the TEMPO study are encouraging and highlight the need for continued clinical research in larger cohorts of patients with Fontan physiology over a longer period of time. The Fontan circulation, like other forms of heart failure, is characterized by low cardiac output and elevated central venous pressure (CVP). However, unlike other forms of heart failure, the primary limitation of the Fontan circulation is not " pump failure " but rather the absence of a subpulmonary ventricle. 7 Usual heart failure therapies directed at improving pump function or decreasing afterload may not be as relevant in a circulation in which the primary problem is filling as opposed to emptying the ventricle. Instead, therapies targeted at the mediators of ventricular filling in the Fontan circulation are …