There is a progressive decline in measured aerobic exercise capacity during adolescence in survivors of the Fontan operation. Adolescent survivors of the Fontan operation face an anticipated decline of approximately 2.6 % of predicted aerobic capacity per year during the second decade of life. When aerobic exercise capacity falls below a threshold of approximately 45% of predicted for age and gender;the risk of cardiopulmonary failure, death, or need for heart transplantation increases significantly. A therapy which reduces this observed decline in exercise capacity might forestall the onset of heart failure and prolong transplant-free survival. The Fontan aerobic exercise capacity is limited by the inability to maintain adequate preload to the systemic ventricle. The underlying pathophysiologic mechanisms are limited pulmonary vasodilatory reserve and absence of a sub-pulmonary ventricle to generate an adequate trans-pulmonary pressure gradient. No current therapy for the failing Fontan circulation specifically addresses this problem. The primary aim of this study is to determine if long-term treatment with oral sildenafil will prevent or ameliorate this decline in aerobic exercise performance in adolescents following the Fontan operation. Sildenafil is a selective pulmonary vasodilator that in short term studies increases Fontan aerobic capacity. Its long term effects are unknown. This will be a three-year double-blinded, placebo-controlled, intention to treat, phase 3 clinical trial utilizing sildenafil as a pulmonary vasodilator in adolescent survivors of the Fontan operation. Previous research indicates that submaximal aerobic capacity will be most affected by this treatment strategy. Therefore, oxygen consumption at the ventilatory anaerobic threshold (VAT) will serve as the primary measure of aerobic performance. The rate of decline (trajectory) in VAT measured within the sildenafil and control groups will be compared over the 3 year study period as the primary endpoint. It is hypothesized that the short term effects of sidenafil on aerobic capacity will be sustained and result in a 50% decrease in the rate of decline (trajectory) in the aerobic capacity to 1.3% per year in the adolescent Fontan population in the sildenafil treatment group with a greater decline (2.6% per year) in the placebo group.

Public Health Relevance

The Fontan operation results in long term survival of infants with single ventricle hearts, but results in significant symptoms with aging which are reflected in a steadily decreasing exercise tolerance. This study will test if the long term use of sidenafil, which improves exercise in these children with short term use, will result in sustained improvement in exercise and hopefully delay the onset of these symptoms and mortality.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Cooperative Clinical Research--Cooperative Agreements (U10)
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Special Emphasis Panel (ZHL1-CSR-S (M2))
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Pemberton, Victoria
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Children's Hospital of Philadelphia
United States
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Goldberg, David J; Zak, Victor; Goldstein, Bryan H et al. (2018) Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. Am Heart J 201:1-8
Saarel, Elizabeth V; Granger, Suzanne; Kaltman, Jonathan R et al. (2018) Electrocardiograms in Healthy North American Children in the Digital Age. Circ Arrhythm Electrophysiol 11:e005808
Minich, L LuAnn; Pemberton, Victoria L; Shekerdemian, Lara S et al. (2018) The Pediatric Heart Network Scholar Award programme: a unique mentored award embedded within a multicentre network. Cardiol Young 28:854-861
Lopez, Leo; Colan, Steven; Stylianou, Mario et al. (2017) Relationship of Echocardiographic Z Scores Adjusted for Body Surface Area to Age, Sex, Race, and Ethnicity: The Pediatric Heart Network Normal Echocardiogram Database. Circ Cardiovasc Imaging 10:
Atz, Andrew M; Zak, Victor; Mahony, Lynn et al. (2017) Longitudinal Outcomes of Patients With Single Ventricle After the Fontan Procedure. J Am Coll Cardiol 69:2735-2744
Nathan, Meena; Jacobs, Marshall L; Gaynor, J William et al. (2017) Completeness and Accuracy of Local Clinical Registry Data for Children Undergoing Heart Surgery. Ann Thorac Surg 103:629-636
Mahle, William T; Nicolson, Susan C; Hollenbeck-Pringle, Danielle et al. (2016) Utilizing a Collaborative Learning Model to Promote Early Extubation Following Infant Heart Surgery. Pediatr Crit Care Med 17:939-947
Ravishankar, Chitra; Gerstenberger, Eric; Sleeper, Lynn A et al. (2016) Factors affecting Fontan length of stay: Results from the Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg 151:669-675.e1
Hill, Kevin D; Rhodes, John F; Aiyagari, Ranjit et al. (2013) Intervention for recoarctation in the single ventricle reconstruction trial: incidence, risk, and outcomes. Circulation 128:954-61