Preserving reserve in the Fontan circulation

This perspective is conceptual and not prescriptive, and recommendations are physiologically aligned and evidence-informed.

The Fontan circulation is inherently constrained. Without a sub-pulmonary ventricle, pulmonary blood flow is passive, cardiac output is preload limited, and systemic venous pressure is chronically elevated. The reserve is narrow, and modest increases in pulmonary vascular resistance or declines in ventricular or venous function can sharply reduce forward flow and end organ perfusion. ^{Reference Gewillig and Brown1–Reference Van de Bruaene, Claessen, Salaets and Gewillig3}

Fontan failure usually evolves gradually with rising venous pressures, reduced exercise capacity, renal vulnerability, and progressive hepatic and lymphatic disease. ^{Reference Gewillig and Goldberg2,Reference Elder, McCabe and Hebson4–Reference Becker, Uebing and Hansen6} Early failure primarily reflects an upstream barrier effect with congestion and reduced forward flow. Late failure reflects the same upstream limitation compounded by progressive diastolic dysfunction and in some patients rising pulmonary vascular resistance. By the time failure becomes clinically evident, layered constraints often coexist, many processes are advanced, and reversibility is limited. In a system with narrow reserve and no durable mechanical substitute, intervention at this stage is intrinsically late.

We propose a serial constraints framework and align therapies to the shifting dominant constraint. The goal is not short-term surrogate change but preservation of forward flow capacity and end-organ tolerance over years in a preload-limited system. ^{Reference Gewillig and Brown1}

Serial physiologic constraints in the Fontan circulation

Fontan performance depends on domains operating in series, including the pulmonary vascular bed, pulmonary venous return and ventricular filling, systemic ventricular function, systemic arterial driving pressure, venous and lymphatic integrity, and end organ tolerance (Figure 1). ^{Reference Gewillig and Goldberg2,Reference Van de Bruaene, Claessen, Salaets and Gewillig3}

Figure 1.

Serial physiologic constraints in the Fontan circulation.

Figure 1. Long description

A diagram of the Fontan circulation process. Panel A: The diagram starts with increased pulmonary resistance, indicated by lungs and an arrow pointing to the next stage. Panel B: This stage shows increased venous and lymphatic congestion, represented by water droplets and an arrow pointing to the next stage. Panel C: The next stage depicts decreased ventricular function, shown by a heart with a monitor displaying a heart rate of 70 and an arrow pointing to the next stage. Panel D: The final stage illustrates end-organ compromise, represented by a liver, kidneys, and brain with an arrow indicating progressive injury. The diagram also includes candidate therapies at each stage: PDE-5 inhibitors for pulmonary resistance, prn diuretics and lymphatic interventions for venous and lymphatic congestion, and SGLT-2 inhibitors, MCA’s, and exercise for ventricular function. The overall concept highlights limited forward flow and reserve in the Fontan circulation.

A limitation at any point restricts overall flow only insofar as it constitutes the haemodynamically critical bottleneck at a given time. In a closed hydrodynamic circuit with multiple constraints in series, overall flow is determined by the dominant constraint. When that bottleneck is relieved, forward flow increases only to the extent permitted by the next limiting physiology.

Chronic preload restriction may contribute to impaired ventricular compliance, further amplifying this constraint within the circulatory series. ^{Reference Cools, Van Puyvelde and Rega7}

Reduction in pulmonary vascular resistance may unmask intrinsic ventricular diastolic dysfunction, which is nearly universal and may then emerge as the prevailing limitation to systemic flow. ^{Reference Van de Bruaene, Claessen, Salaets and Gewillig3,Reference Elder, McCabe and Hebson4} Haemodynamic data suggest that ventricular end-diastolic pressure and pulmonary vascular resistance are closely coupled determinants of outcome in the Fontan circulation, with the effect of ventricular diastolic dysfunction in part mediated through pulmonary vascular load. ^{Reference Suthar, Yang and Beshish8} Thus, isolated reduction in pulmonary vascular resistance without addressing elevated ventricular filling pressure may yield limited improvement in forward flow.

As the reserve narrows, the limiting domain often shifts, and therapies aimed at early constraints may yield diminishing returns once diastolic dysfunction, venous hypertension, or organ fibrosis predominate.

Reassessing biventricular heart failure paradigms

This framework does not preclude the use of conventional heart failure agents for clearly defined indications. Chronic loop diuretics may be necessary for symptomatic relief in volume-overloaded patients but are unlikely to modify long-term Fontan reserve and may further narrow preload in marginal circulations. Sustained ventricular volume deprivation may accelerate progressive diastolic stiffening.

Strategies that lower myocardial oxygen demand with beta-blockade or reduce afterload with renin-angiotensin-aldosterone system inhibition have limited physiological fit in a preload-limited Fontan circulation. Lowering systemic pressure does not reliably increase output and may reduce the driving pressure needed for venous return. ^{Reference Van de Bruaene, Claessen, Salaets and Gewillig3,Reference Rychik, Atz and Celermajer5}

Additionally, randomised controlled trials and observational studies have not shown consistent gains in exercise capacity, ventricular performance or outcomes. ^{Reference Van de Bruaene, Claessen, Salaets and Gewillig3,Reference Elder, McCabe and Hebson4–Reference Becker, Uebing and Hansen6} Accordingly, these agents are not foundational in Fontan care and are best reserved for defined comorbid indications, including systemic hypertension, significant atrioventricular or semilunar valve regurgitation with remodelling, or arrhythmia rate control with careful monitoring for reduced driving pressure or worsened exercise tolerance. ^{Reference Kouatli, Garcia, Zellers, Weinstein and Mahony9,Reference Harteveld, Blom and Espinosa10}

Pulmonary pathway limitation, functional obstruction, and phosphodiesterase type 5 inhibition

Before considering pharmacologic pulmonary vasodilation, mechanical and/or functional obstruction within the Fontan pathway, including stenosis of the central pulmonary arteries, ventricular outflow obstruction, residual coarctation of the aorta and significant regurgitation of the atrioventricular and/or semilunar “exit” valve(s) must be addressed. Even modest obstruction may represent the dominant constraint and negate medical benefit.

Because pulmonary blood flow is passive, modest increases in pulmonary vascular resistance restrict preload delivery, especially with exertion. ^{Reference Van de Bruaene, Claessen, Salaets and Gewillig3,Reference Rychik, Atz and Celermajer5}

In the Fontan Udenafil Exercise Longitudinal trial chronic phosphodiesterase type 5 inhibition did not improve peak oxygen consumption but improved prespecified secondary exercise measures. ^{Reference Kouatli, Garcia, Zellers, Weinstein and Mahony9–Reference Goldberg, Zak and Goldstein11} However, participants with subnormal baseline peak oxygen consumption demonstrated statistically significant benefit in informing ongoing trial design.

Congestion and fibrosis biology, sodium glucose cotransporter 2 inhibition, and nonsteroidal mineralocorticoid receptor antagonism

Fontan decline reflects progressive diastolic and later systolic dysfunction, elevated filling pressures, venous congestion, and reduced preload reserve. ^{Reference Gewillig and Goldberg2,Reference Rychik, Atz and Celermajer5,Reference Goldberg, Zak and Hu12}

Sodium glucose cotransporter 2 inhibitors reduce heart failure events across systolic and preserved ejection fraction phenotypes. ^{Reference Goldberg, Zak and Hu12,Reference Solomon, McMurray and Vaduganathan14} These effects align with Fontan physiology through decongestion, improved myocardial energetics, and renal protection.

Fontan-specific outcome data remain limited. Use should be individualised with attention to volume status and renal function, and these agents are generally avoided when estimated glomerular filtration rate is below 30 mL per minute per 1.73 m².

Mineralocorticoid receptor signalling promotes sodium retention, inflammation, and fibrosis across cardiovascular, hepatic, and renal systems. Chronic venous hypertension and lymphatic congestion are central to Fontan-associated end-organ injury and may also contribute to myocardial stiffening, further limiting ventricular compliance and forward flow. ^{Reference Gewillig and Goldberg2,Reference Becker, Uebing and Hansen6,Reference Solomon, McMurray and Claggett15}

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces cardiovascular events and fibrosis in related disease states. ^{Reference Gaydos, McHugh and Woodard13,Reference Pitt, Filippatos and Agarwal16,Reference Filippatos, Anker and Agarwal17} In contrast to spironolactone, finerenone demonstrates greater receptor selectivity with a lower incidence of gynaecomastia and a reduced risk of hyperkalaemia and exhibits more potent anti-inflammatory and antifibrotic effects, which may be advantageous in the Fontan circulation. Finerenone is not currently approved for paediatric use and has not been studied in the Fontan population.

Thrombo-inflammatory milieu: antithrombotic therapy

The Fontan circulation features low-flow endothelial dysfunction and a persistent prothrombotic state. ^{Reference Firdouse, Agarwal, Chan and Mondal18} Microthrombi and endothelial injury may compound venous and lymphatic vulnerability, making thrombo-prophylaxis relevant to trajectory even when overt events are infrequent. The drainage of the thoracic duct in the lymphovenous junction represents a particularly vulnerable site where a thrombus may have a disproportionate adverse physiologic impact. ^{Reference Kochilas, Shepard, Berry and Chin19} In adults and mixed cohorts, a network meta-analysis suggests reduced thrombo-embolic risk across anti-thrombotic strategies with uncertainty regarding optimal selection. ^{Reference McCrindle, Michelson and Van Bergen20,Reference Van den Eynde, Possner and Alahdab21} Choices should weigh bleeding risk, prior events, and anatomic or procedural factors.

Exercise and physiologic reserve

Exercise is a key determinant of functional capacity and may influence long-term trajectory. Beyond conditioning, exercise promotes ventricular filling and may help maintain lower ventricular end-diastolic pressure through periodic stretching. In addition, exercise improves ventilatory efficiency, which is a critical determinant of effective pulmonary blood flow in the Fontan circulation, and enhances pulmonary mechanics and gas exchange. Improvements in ventilatory efficiency may reduce the work of breathing and augment preload delivery during exertion, thereby supporting forward flow. Evidence suggests no intervention has demonstrated greater improvement in exercise capacity in Fontan patients than exercise itself. ^{Reference La Gerche and Gewillig22,Reference Cordina and d’Udekem23}