Discussion

The Fontan procedure, while a vital palliative strategy for single-ventricle physiology, is associated with long-term challenges stemming from circulatory inefficiency and multiorgan dysfunction. Exercise intolerance is a recognised characteristic of Fontan physiology and correlates with increased morbidity and mortality. ^{Reference Cordina, O’Meagher and Gould3,Reference Tran, D’Ambrosio and Verrall5} In this study, we evaluated the overall clinical and functional profiles of 30 Fontan patients at our centre and investigated the relationships between body composition, muscle strength, and exercise performance, demonstrating significant correlations between handgrip strength, fat-free mass, and 6MWT distance. These findings highlight the combined role of skeletal muscle mass and limb perfusion in determining exercise capacity in this complex patient population.

Several studies have investigated the haemodynamic outcomes and functional capacity associated with different types of Fontan procedures, including intra-extracardiac total cavopulmonary connection and extracardiac total cavopulmonary connection. ^{Reference Hirose, Ikai and Murata14} De Leval et al. suggest that surgical techniques that better preserve laminar flow contribute to reduced energy dissipation, thereby improving exercise tolerance and overall functional capacity in Fontan patients. ^{Reference de Leval15} The maintenance of laminar flow is essential for optimising haemodynamic efficiency, as it reduces energy loss within the Fontan circulation. This has been associated with enhanced exercise capacity and improved quality of life. Among various Fontan techniques, the intra-extracardiac approach is hypothesised to offer advantages in minimising energy loss and maintaining physiological flow dynamics. ^{Reference Gewillig and Brown1,Reference de Leval15,Reference Ohye, Schranz and D’Udekem16} Although our study did not reveal a significant difference between surgical techniques in terms of functional capacity (Table 4), the importance of preserving laminar flow in Fontan circulation remains a key factor. Theoretically, the intra-extracardiac Fontan method may offer advantages in preventing energy loss within the Fontan circulation, ensuring a more efficient haemodynamic state. This technique facilitates smoother venous return, reduces turbulence-related energy dissipation, and optimises flow distribution across the pulmonary vascular bed. While our findings did not confirm this distinction, previous studies suggest that optimising flow dynamics through minimising energy dissipation could contribute to better long-term outcomes. ^{Reference Gewillig and Brown1,Reference de Leval15,Reference Ohye, Schranz and D’Udekem16}

Red cell distribution width is a quantitative measure of the variation in erythrocyte volume and serves as an indicator of anisocytosis. It is routinely used in the differential diagnosis of microcytic and normocytic anaemias. Although iron deficiency remains one of the most common and clinically relevant causes of elevated red cell distribution width, this parameter may also reflect other underlying pathophysiological processes. ^{Reference Cordina, O’Meagher and Gould3,Reference van den Berg, Pos, Scheffers, van den Berg and Helbing7} An increased red cell distribution width has been associated with a range of cardiovascular diseases, including acute coronary syndromes and heart failure. ^{Reference Felker, Allen and Pocock17}

In our study, red cell distribution width was negatively correlated with both the 6MWT distance (r = −0.631, p < 0.001) and handgrip strength (r = −0.413, p = 0.029), suggesting that higher red cell distribution width values were associated with reduced functional performance. This association might be partially explained by unrecognised iron deficiency or anaemia, both of which are known to impair exercise tolerance and peripheral muscle strength. A recent review by Wittczak et al. emphasised that red cell distribution width can serve as a surrogate marker of iron deficiency and has been associated with reduced exercise capacity in patients with Fontan circulation. ^{Reference Wittczak, Mazurek-Kula, Banach, Piotrowski and Bielecka-Dabrowa18} Iron studies were not available in this cohort, which limits the interpretability of the red cell distribution width findings. Therefore, the observed relationship between elevated red cell distribution width and impaired functional status in our Fontan group may be multifactorial—potentially reflecting the combined effects of unmeasured disturbances in iron metabolism and Fontan-specific haemodynamic and systemic factors. We recommend that future studies incorporate comprehensive iron status assessments (e.g., ferritin, transferrin saturation, haemoglobin) to better understand the respective contributions of iron deficiency and Fontan-related mechanisms to red cell distribution width elevation and functional impairment.

Exercise capacity is a well-established determinant of morbidity and mortality in patients with Fontan physiology. ^{Reference Ohuchi, Negishi and Noritake19} Our findings align with previous studies highlighting myopenia and skeletal muscle dysfunction as key contributors to exercise limitation in Fontan patients. ^{Reference Cordina, O’Meagher and Gould3–Reference Tran, D’Ambrosio and Verrall5} Cordina et al. demonstrated that Fontan adults exhibit significant skeletal muscle atrophy, with lean mass deficits correlating with reduced peak oxygen consumption. ^{Reference Cordina, O’Meagher and Gould3} Similarly, Tran et al. identified a “myopenic profile” in Fontan patients, characterised by lower appendicular lean mass and impaired muscle metabolism, which strongly predicted exercise intolerance. ^{Reference Tran, D’Ambrosio and Verrall5} Powell et al. further supported these findings, reporting that skeletal muscle mass was positively associated with peak oxygen uptake and oxygen pulse, underscoring the importance of preserving muscle integrity to optimise cardiovascular performance. ^{Reference Powell, Wittekind and Alsaied4} Similarly, in our previous case–control study evaluating Fontan patients, quadriceps isometric muscle strength was significantly lower in Fontan patients than in controls (25.53 ± 8.12 kg vs. 33.04 ± 12.04 kg, p = 0.043), despite comparable body composition. Furthermore, both submaximal (6MWT: 583.95 ± 99.18 m vs. 692.79 ± 94.87 m, p = 0.001) and maximal (ISWT: 622.00 ± 192.15 m vs. 838.57 ± 200.13 m, p = 0.001) exercise capacities were markedly reduced in the Fontan group. ^{Reference Tekerlek, Saglam and Kucukdagli20} These findings highlight the importance of peripheral muscle function in exercise performance and support the role of targeted interventions aiming to preserve or improve skeletal muscle strength in Fontan patients. Consistent with these reports, our finding of a positive correlation between handgrip strength and 6MWT distance suggests that greater muscle strength is associated with better physical performance in our study. Given the reliance of Fontan physiology on peripheral muscle function to augment venous return, skeletal muscle health emerges as a critical determinant of overall functional capacity.

Alterations in body composition, including reduced lean mass, have been documented in Fontan patients and may further compromise exercise performance. ^{Reference Tran, D’Ambrosio and Verrall5,Reference van den Berg, Pos, Scheffers, van den Berg and Helbing7} A systematic review by van den Berg et al. found that Fontan patients often exhibit higher fat mass and lower skeletal muscle mass compared to healthy controls, despite a normal body mass index. ^{Reference van den Berg, Pos, Scheffers, van den Berg and Helbing7} This paradox suggests that body mass index alone is insufficient for assessing functional status in this population. Our findings are consistent with previously published studies, demonstrating that fat-free mass positively correlates with exercise capacity and handgrip strength, whereas reduced fat-free mass may exacerbate exercise limitation. These findings support the notion that preserving muscle integrity can enhance exercise tolerance in Fontan patients. In clinical practice, exercise prescription for Fontan patients is often based on laboratory tests such as cardiopulmonary exercise testing. However, the positive association between handgrip strength and 6MWT distance in our study suggests that simple field tests may also have clinical value for monitoring and guiding rehabilitation. The 6MWT, which we have previously shown to be a practical tool in this population, ^{Reference Tekerlek, Saglam and Kucukdagli20} may serve as a useful complement to handgrip strength in identifying patients with reduced peripheral muscle function who could benefit from targeted resistance or combined training programmes.

In a previous longitudinal study, we observed that exercise capacity and muscle strength remained stable over a 20-month follow-up period, whereas body mass index and fat weight increased during somatic growth. ^{Reference Tekerlek, Sağlam and Selçuk21} These findings indicate that even without measurable declines in muscle strength, changes in body composition may still influence functional performance. The current correlation between 6MWT distance and fat-free mass further supports the potential role of 6MWT as a clinically relevant indicator for designing and adjusting individualised exercise programmes in Fontan patients. Overall, these observations underscore the need to preserve skeletal muscle integrity through structured, resistance-based, and personalised rehabilitation to enhance venous return, maintain functional capacity, and support long-term cardiovascular health. ^{Reference Cordina, O’Meagher and Gould3}

Oxygen desaturation following exertion is a key indicator of circulatory efficiency in Fontan patients, reflecting their limited ability to meet increased metabolic demands during exercise. In our study, greater post-exercise desaturation was associated with a shorter 6MWT distance (r = −0.531, p = 0.008) and lower handgrip strength (r = −0.472, p = 0.017). A significant negative correlation was observed between ΔSpO₂ and both 6MWT distance and handgrip strength, suggesting that greater post-exercise desaturation is associated with reduced endurance and muscle strength. These findings are consistent with prior research indicating that oxygen delivery limitations in Fontan physiology contribute to exercise intolerance and increased cardiovascular morbidity. ^{Reference Russell, Moldenhauer and Rychik22} In our study, while Fontan type and fenestration status were not significantly associated with 6MWT distance, patients with intra-extracardiac Fontan and fenestration exhibited higher oxygen desaturation. This may be explained by the fact that our clinic recently preferred the intra-extracardiac Fontan modification and routinely performed fenestration in this modification, in contrast to previous techniques. Therefore, the finding of higher oxygen desaturation in patients with surgical fenestration can be interpreted as an expected situation. Exercise-induced desaturation can be explained by two distinct mechanisms other than ventricular dysfunction. One factor is the presence of fenestration, which, as expected, was associated with significantly greater desaturation compared to patients without fenestration. In addition to fenestration, the development of veno-venous collaterals may indicate a compensatory response to increased central venous pressure and serve as an indicator of adverse Fontan haemodynamics. ^{Reference Sugiyama, Yoo, Williams and Benson23} Their presence may reflect inefficient circulation and systemic venous congestion, which could contribute to reduced exercise capacity and progressive cardiovascular dysfunction. Over time, this may further impair circulatory efficiency and potentially represent an early marker of clinical deterioration.