What is the clinical evidence from this study?

Study design: RCT. Population: Adolescents and adults with Fontan physiology (n=211). Intervention: Macitentan vs. Placebo. Primary outcome: Peak oxygen consumption (peak VO2) (Neutral effect on peak VO2).

What does this research mean for the field?

Endothelin-1 upregulation in failed Fontan physiology contributes to pulmonary vascular resistance, liver injury, and arrhythmias, and targeting this pathway with endothelin-receptor antagonists may improve clinical outcomes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research examines the role of endothelin-1 in complications arising from the Fontan circulation and outlines strategies for more targeted clinical trials.

February 8, 2026Open Access

Endothelin-1 in the failing Fontan: pathobiology, precision therapeutics, and future trial design

Key Result

Macitentan did not significantly improve peak oxygen consumption compared to placebo in adolescents and adults with Fontan physiology over 52 weeks.

Key Points

This research examines the role of endothelin-1 in complications arising from the Fontan circulation and outlines strategies for more targeted clinical trials.
Examined hemodynamic impacts in the Fontan circulation
Analyzed mechanisms of endothelin-1 activation
Reviewed clinical cohorts correlating endothelin-1 with outcomes
Proposed a framework for phenotyping Fontan patients
Endothelin-1 upregulation linked to pulmonary complications
Elevated endothelin-1 correlates with hospitalization and exercise intolerance
Trials of endothelin-receptor antagonists indicate potential benefits on specific outcomes
Proposed stratification approach may lead to improved treatment efficacy

Study Design

Type

RCT (n=211)

Blinding

Double-blind in some trials, crossover in others

Randomization

Randomized

Multicenter

Yes

Structured PICO

Do endothelin-receptor antagonists improve functional capacity and stabilize circulation in patients with failing Fontan physiology?

Population

Patients with Fontan circulation (single-ventricle congenital heart disease) experiencing late morbidities such as elevated pulmonary vascular resistance, Fontan-associated liver disease, protein-losing enteropathy, and arrhythmias.

Intervention

Endothelin-receptor antagonists (bosentan, ambrisentan, macitentan)

Endothelin-1 plays a key role in the pathophysiology of the failing Fontan circulation, and targeted therapies may improve outcomes if future trials utilize physiologically aligned endpoints like ventilatory efficiency rather than peak oxygen consumption.

Main Result

Effect estimate: Neutral effect on peak VO2

Limitations

Modest sample sizes in Fontan trials limit definitive conclusions
Heterogeneity in patient phenotypes may affect treatment response
Peak VO2 as a primary endpoint may be physiologically misaligned with Fontan pathophysiology
Need for phenotype-enriched studies with appropriate endpoints

Abstract

The Fontan circulation, devised as definitive palliation for single-ventricle congenital heart disease, imposes systemic venous hypertension, loss of pulmonary arterial pulsatility, and restricted preload reserve. These hemodynamic trade-offs progressively injure the pulmonary vasculature, liver, and lymphatic system, producing late morbidities including elevated pulmonary vascular resistance, Fontan-associated liver disease (FALD), protein-losing enteropathy, and arrhythmias. Endothelin-1 (ET-1), a potent vasoconstrictor and profibrotic mediator, plausibly unifies these complications. Mechanistic studies demonstrate ET-1 upregulation in failed Fontan lungs, activating PLC–Ca 2+ , RhoA/ROCK, and MAPK/ERK cascades to drive vasoconstriction and remodeling. In cirrhotic livers, ET-1 localizes to stellate cells, promoting contraction and fibrogenesis, mechanisms biologically relevant to congestive FALD. Clinical cohorts consistently show elevated ET-1 correlating with hospitalization, exercise intolerance, and arrhythmias. Trials of endothelin-receptor antagonists (bosentan, ambrisentan, macitentan) demonstrate reassuring safety and suggest benefit when outcomes emphasize ventilatory efficiency or hepatic endpoints rather than peak oxygen consumption, which is physiologically constrained in Fontan physiology. Given the mixed results of existing trials, a framework is outlined that stratifies Fontan patients into pulmonary-inefficiency, congestive-hepatic, lymphatic, and arrhythmia-dominant phenotypes, using co-primary endpoints such as VE/VCO 2 slope, elastography, and biomarker panels. By linking ET-1 biology to pragmatic trial design, this approach emphasizes targeted strategies that may stabilize the circulation, extend transplant candidacy, and improve long-term outcomes.

Bookmark

View Full Paper