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.

Keywords: aerobic exercise; cardiac rehabilitation; congenital heart disease; exercise intolerance; hypoplastic left heart syndrome; single ventricle; telehealth; tricuspid atresia.

Figure 1

Distribution of % predicted peak oxygen uptake (consumption) in patients after Fontan operation and its distribution in patients with different types of Fontan surgery. ec, extracardiac; lat, lateral; TCPC, total cavopulmonary connection. Reproduced from (12).

Figure 2

Various techniques of the Fontan procedure. (A) Atriopulmonary connection. (B) Lateral tunnel total cavopulmonary connection (TCPC). (C) Extracardiac conduit TCPC. IVC, inferior vena cava; RA, right atrium; RPA, right pulmonary artery; and SVC, superior vena cava. Reproduced from (32).

Figure 3

Quadratic regression analysis of mean stroke volume and cardiac output vs. average heart rate values. In people with a Fontan circulation, an additional increase in heart rate beyond peak exercise values would result in (A) a disproportionate fall in stroke volume such that (B) cardiac output cannot increase further. Modified from (56).

Figure 4

Schematic showing the relationship between pulmonary vascular reserve (VR) and end-organ function. Pressure-flow relationship showing change in mean pulmonary artery pressure (mPAP) (Fontan pressure) per unit change in cardiac output (CO), or mPAP/CO slope, during exercise. Abnormal pulmonary VR defined as mPAP/CO slope > 3 (red) is associated with worse endothelial dysfunction and end-organ dysfunction (more liver stiffness, renal dysfunction, volume overload, and exercise intolerance) as compared to normal pulmonary VR defined as mPAP/CO slope ≤ 3 (blue). Reproduced from (61).

Figure 5

Controlled trials of non-invasive therapy to improve aerobic exercise capacity in the Fontan circulation. The percentage change in peak oxygen uptake following non-invasive therapies or placebo in Fontan cohorts are shown. The most effective non-invasive therapy is exercise training. n, non-significant; *, statistically significant; ^†, percentage difference between groups. Kouatli et al. (120); Goldberg et al. (63); Goldberg et al. (62); Hebert et al. (64); Cordina et al. [high intensity resistance training] (108); Turquetto et al. [combined aerobic exercise and light resistance training] (104).

Figure 6

Factors contributing to exercise intolerance in the Fontan circulation. Factors in red may be improved with exercise training.

Figure 7

The Fontan Fitness Intervention Trial (F-FIT) study design flow diagram.

Figure 8

Comparison between the percentage of peak heart rate (HR; [%HRpeak]) and percentage of HR reserve (%HRR) methods to the average reference HR recorded at the corresponding percentage of peak VO₂ (%VO₂) exercise intensity domain. The %HRpeak method significantly underestimates the reference exercise HR. The %HRR method results in clinically insignificant differences to the corresponding reference HR recorded in all exercise intensity domains based on %VO₂ and reflects metabolic load more accurately than the %HRpeak method. Data from 287 congenital heart disease patients at Royal Prince Alfred Hospital.