Exercise Intolerance, Benefits, and Prescription for People Living With a Fontan Circulation: The Fontan Fitness Intervention Trial (F-FIT)—Rationale and Design

Abstract

Background: Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe—and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials.Aims and Methods: The Fontan Fitness Intervention Trial (F-FIT)—a phase III clinical trial—aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (<16 years) will be randomized to either a physical activity and exercise program of moderate-to-vigorous intensity or usual care in a two-arm trial with a 1:1 allocation. The primary outcome is a change in aerobic exercise capacity (peak oxygen uptake) at 4-months. Secondary outcomes include safety, and changes in cardiopulmonary exercise testing measures, peripheral venous pressure, respiratory muscle and lung function, body composition, liver stiffness, neuropsychological and neurocognitive function, physical activity levels, dietary and nutritional status, vascular function, neurohormonal activation, metabolites, cardiac function, quality of life, musculoskeletal fitness, and health care utilization. Outcome measures will be assessed at baseline, 4-months, and 12-months. This manuscript will describe the pathophysiology of exercise intolerance in the Fontan circulation and the rationale and protocol for the F-FIT.

Narrative review of single ventricle: where are we after 40 years?

“…More recently, several programs of cardiopulmonary training, including exercise training, fitness intervention trials, home-based long-term physical endurance and inspiratory muscle trainings, have been instituted in Fontan patients. These programs have been shown to be safe and beneficial, improving exercise capacity, cardiorespiratory performance and cardiac biomarker values, and self-reported quality of life (273)(274)(275)(276)(277).…”

Exercising with a Single Ventricle: Limitations and Therapies

“…There is a high prevalence of skeletal muscle and lean body mass [ 4 , 30 ] deficit in patients with Fontan circulation compared to age and sex-matched controls [ 30 , 31 ]. The causes of this include chronically elevated central venous pressure, physical inactivity, neurohormonal activation, and altered skeletal muscle blood flow [ 30 , 32 ]. Muscle mass deficiency is associated with impaired muscle aerobic capacity, suggesting a functional deficiency of muscle in Fontan patients [ 31 ].…”

“…Prescribed exercise training is an established therapy that is used routinely in individuals with various cardiopulmonary conditions [ 51 ]. Currently, exercise training is the most effective, noninvasive therapy for improving aerobic capacity in patients with Fontan circulation [ 32 ]. The benefits of exercise training include position effects on hemodynamics, both central and peripheral, as well as ventilatory and metabolic parameters.…”

“…Importantly, no serious adverse events were reported during exercise training sessions, such as arrhythmias, syncope, or other symptoms other than fatigue, suggesting that this effective treatment modality is also safe [ 31 , 52 ]. Increased aerobic capacity is also associated with healthier end-organ (e.g., liver) function biomarkers, possibly due to chronically decreased central venous pressure, improved hemodynamics, and reduced hepatic congestion [ 32 ].…”

A diffusion MRI study of brain white matter microstructure in adolescents and adults with a Fontan circulation: Investigating associations with resting and peak exercise oxygen saturations and cognition

“…Fontan physiology is characterized by unique hemodynamics, including prolonged mild cyanosis that often results from a patent fenestration (allowing right to left shunting of deoxygenated blood to the systemic circulation) and development of veno-venous collaterals or pulmonary arteriovenous malformations ( Ohuchi, 2017 ). Reduced exercise tolerance is also a concern and may have important functional implications ( Tran et al, 2022 ). Chronic hypoxemia is associated with long-term morbidity and late mortality, even in cases of mild desaturation ( Schafstedde et al, 2021 , Egbe et al, 2017 , Zentner et al, 2020 ), and may be an important predisposing factor for altered cerebral development, white matter (WM) injury, and subsequent cognitive functioning ( Owen et al, 2011 , Morton et al, 2017 , Limperopoulos et al, 2010 , Sun et al, 2015 , Claessens et al, 2018 , Spaeder et al, 2017 , Claessens et al, 2019 , Rajagopalan et al, 2018 , Lee et al, 2021 , Sadhwani et al, 2022 ).…”