criteria, listing status, and organ allocation Future Directions Modifications in treatment strategies have resulted in a tremendous improvement in survival for those with a functionally univentricular heart since the first Fontan operation more than 40 years ago These include staged palliation with an intermediate bidirectional Glenn shunt and modifications of the Fontan procedure that result in improvements in efficiency of the circulation and reduce the rate of late arrhythmia Transformational advances in areas such as immunosuppression or targeted stem cell implantation may change the treatment pathway of patients with a functionally univentricular heart in its entirety, by vastly increasing organ availability and longevity, developing destination intravascular pumps (see later), or allowing growth of hypoplastic ventricles In the absence of progress in these areas, incremental improvements in outcome will involve interventions that further optimize the Fontan circulation and improve health and well-being Areas where preliminary information is encouraging and further information is likely to emerge are detailed in the following paragraphs Selective Pulmonary Vasodilators In a two-ventricle circulation, exercise results in a twofold to fourfold increase in cardiac output and an increase in pulmonary vascular resistance Left ventricle preload is maintained through a substantial increase in right ventricle work In the absence of a subpulmonary ventricle, peak exercise capacity is reduced as there is a limited capacity to increase systemic ventricle preload, the latter being dependent on the CVP and pulmonary resistance In the Fontan circulation, pulmonary vascular resistance has been described as a dam holding back systemic venous return.407 “Lowering the dam” would thus provide more pulmonary venous return to the systemic ventricle (preload) at a lower CVP (see Chapter 70) Investigations to date have focused on the safety of pulmonary vasodilators and their potential to increase exercise capacity in this patient population Results of small, well-designed studies in the Fontan population have demonstrated that these agents are safe over the short term.61,62,408 The most common side effects are flushing with the phosphodiesterase 5 inhibitor sildenafil and the endothelin receptor antagonist Bosentan, and a slight reduction in hemoglobin with Bosentan Neither medication is associated with a dramatic improvement in exercise capacity; however, relatively small increases in ventilatory efficiency and maximal and submaximal exercise capacity have been demonstrated in several studies,61,62 and an improvement in functional class and reduction in BNP has also been reported.62 The potential to reduce pulmonary vascular resistance over the long term has implications beyond exercise capacity Much of the late morbidity associated with the Fontan circulation is due to chronically elevated CVP and low cardiac output A slow decline in functional class and liver and renal function is well described, as is a gradual increase in pulmonary vascular resistance Whether the latter is related to endothelial dysfunction, chronic microemboli and thrombosis, or a response to low cardiac output remains a point of conjecture The potential for long-term pulmonary vasodilator treatment to modify the pattern of gradual but relentless end-organ dysfunction is attractive However, there is a concerning growing lack of equipoise because many practitioners are currently using these medications routinely, prior to larger studies determining efficacy It is important to emphasize that safety over the long term must be determined, given the generally abnormal drug clearance seen in many patients with a Fontan circulation It is critically important to emphasize that large long-term, randomized studies will be required to better define the clinical utility of these medications to improve the efficiency of the Fontan circulation, as well as to identify subsets of patients most likely to benefit from treatment Exercise Programs The role of exercise programs in improving health and well-being in the Fontan population is controversial Nevertheless, emerging evidence suggests that specific exercise programs may have a beneficial effect on exercise capacity.336 In addition, the amount of physical activity undertaken by Fontan patients is lower than controls and correlates with perceived health status.331,409 Increasing physical activity may have a positive impact on well-being through improved self-esteem, increased muscle mass, and reduced body mass index.410 In the normal circulation, skeletal muscle augments venous return during exercise This function is particularly important in the Fontan circulation given the absence of a subpulmonary ventricle The relative contribution of peripheral skeletal muscle and chest wall mechanics to stroke volume augmentation during exercise has been elegantly demonstrated (Fig 73.30).334 Stoke volume and