Reframing medical therapy in the Fontan circulation: toward preservation of physiologic reserve and durability

The Fontan circulation is defined by unique physiological constraints that limit preload, elevate systemic venous pressure, and reduce the capacity to compensate for stress or injury. Traditional paradigms for managing biventricular heart failure are often misaligned with the pathophysiology of this preload-limited, non-pulsatile system. In this editorial, we propose a conceptual reframing of medical therapy in the Fontan circulation, centred on preserving physiological reserve and long-term durability rather than reversing established failure. We introduce a serial constraints model that emphasises the interconnected roles of the pulmonary vascular bed, ventricular filling, systemic output, venous and lymphatic function, and end-organ tolerance. As limitations shift over time, therapeutic focus must also evolve from pulmonary vasodilation in early stages to addressing ventricular dysfunction, venous congestion, and fibrosis later in the trajectory. We review emerging applications of phosphodiesterase type 5 inhibitors, sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists and exercise within this framework, while cautioning against routine use of conventional renin-angiotensin-aldosterone system inhibition or beta-blockers in the absence of clear comorbid indications. Antithrombotic strategies remain important due to a persistent thrombo-inflammatory milieu. We advocate for a shift from reactive to trajectory-preserving therapy, targeting flow under stress, organ protection, and reserve conservation. This physiology-aligned, evidence-informed approach provides a rationale for earlier intervention and testable hypotheses for future Fontan-specific trials.