Introduction: The Challenge of the Aging Fontan Population
The Fontan procedure has revolutionized the management of children born with single-ventricle physiology, allowing survival into adulthood for a population once faced with a terminal prognosis. However, the Fontan circulation is inherently non-physiological. By bypassing the subpulmonary ventricle, the system relies on passive venous return to drive pulmonary blood flow. Over time, this results in a state of chronic venous hypertension and low cardiac output, commonly referred to as the Fontan paradox.
As this population ages, clinicians are increasingly encountering ‘Fontan failure,’ characterized by exercise intolerance, protein-losing enteropathy, liver cirrhosis, and premature death. Traditional hemodynamic markers measured at rest have often failed to accurately predict which patients are at the highest risk of clinical decline. Two recent landmark studies, published in the European Heart Journal and the Journal of the American Heart Association, provide a paradigm shift in how we assess and risk-stratify these complex patients, emphasizing the critical role of exercise hemodynamics and novel non-invasive surrogates.
Highlights of the Research
1. In adults with Fontan circulation, the Pulmonary Vascular Resistance Index (PVRI) during exercise is a robust predictor of death or heart transplantation, whereas resting PVRI shows no significant prognostic value.
2. Patients unable to reduce their PVRI during exercise face a significantly higher risk of adverse outcomes, with a two-year event-free survival of only 67% compared to 95% in those with a normal response.
3. A new non-invasive diagnostic algorithm utilizing peripheral venous pressure (PVP) and echocardiographic S/D ratios can accurately identify diastolic dysfunction and impaired pulmonary reserve.
4. These findings advocate for the routine inclusion of exercise provocation during cardiac catheterization to capture the true physiological reserve of the Fontan circuit.
The Prognostic Value of Exercise PVRI
Study Design and Population
The first study, a retrospective cohort analysis led by Cao et al. (2025), included 88 adults with Fontan circulation (mean age 32.2 years). These patients underwent invasive exercise cardiac catheterization using supine cycling. The researchers focused on the PVRI response—specifically whether patients could decrease their resistance as blood flow increased during physical exertion. The primary clinical endpoint was a composite of death or heart transplantation.
Key Findings: The Superiority of Exercise Metrics
The results were striking. While resting PVRI was 1.9 ± 0.9 WU·m2, it fell to an average of 1.2 WU·m2 during exercise. Crucially, resting PVRI was not associated with the clinical endpoint (Hazard Ratio [HR] 0.95; P = 0.86). In contrast, exercise PVRI was a potent predictor of poor outcomes (HR 2.15 per WU·m2; P = 0.007).
Even after adjusting for exercise pulmonary artery wedge pressure (PAWP) and other individual clinical risk factors, exercise PVRI remained an independent predictor of survival. The study categorized patients into those who showed a reduction in PVRI during exercise (n=65) and those who did not (n=23). The ‘no reduction’ group had a dramatically lower two-year event-free survival rate (67% vs. 95%).
Noninvasive Evaluation of Ventricular Filling and Pulmonary Reserve
While exercise catheterization is the gold standard, its invasive nature and requirement for specialized centers limit its routine use. The second study by Cao et al. sought to validate non-invasive surrogates that could reflect these critical hemodynamic shifts.
Predicting Diastolic Dysfunction
The research team evaluated 29 patients using simultaneous exercise hemodynamics and peripheral venous pressure (PVP) measurement. They found that the atrioventricular valve systole-to-diastole duration ratio (S/D ratio) and resting PVP were significant predictors of resting PAWP. Specifically, resting PVP was a strong predictor of diastolic dysfunction (defined as resting PAWP ≥12 mm Hg or exercise PAWP >20 mm Hg).
The 2-Tier Assessment Algorithm
Based on these findings, the authors proposed a simplified 2-tier algorithm for clinical use:
1. Tier 1: Evaluate resting PVP and S/D ratio. If resting PVP is ≤15 mm Hg and S/D ratio is ≤1.1, the likelihood of significant dysfunction is low.
2. Tier 2: For patients with at least one elevated resting parameter, exercise PVP is measured. A threshold of ≤25 mm Hg during exercise indicates preserved function.
This algorithm demonstrated a high negative predictive value (90%) and specificity (95%), making it an excellent tool for screening and monitoring patients in the outpatient setting. Furthermore, exercise PVP indexed to peak oxygen consumption was found to predict the invasively measured exercise PVRI, bridging the gap between non-invasive bedside tests and complex invasive data.
Expert Commentary: Mechanistic Insights
The lack of prognostic value in resting PVRI highlights a fundamental truth about Fontan physiology: at rest, the system may appear compensated despite significant underlying pathology. Exercise acts as a ‘stress test’ for the pulmonary vasculature. In a healthy Fontan circuit, the pulmonary vessels should recruit and dilate to accommodate increased flow. Failure to do so—evidenced by a static or rising PVRI during exercise—indicates pulmonary vascular remodeling or dysfunction that is invisible at rest.
This ‘unmasking’ of pathology is essential for clinical decision-making. If a patient’s exercise PVRI is elevated, it may signal the need for more aggressive pulmonary vasodilator therapy or earlier consideration for transplant, even if their resting numbers look acceptable. However, it is important to note the study’s limitations, including its retrospective nature and the relatively short follow-up period (median 2.2 years). Larger, prospective trials will be needed to determine if interventions targeting exercise PVRI can actually improve long-term survival.
Conclusion: A New Era of Hemodynamic Monitoring
The management of the adult Fontan patient is shifting toward a dynamic assessment model. We can no longer rely solely on resting hemodynamics to guide prognosis. The evidence clearly indicates that exercise PVRI is a superior predictor of clinical outcomes, providing additive value to traditional risk factors.
Furthermore, the introduction of non-invasive algorithms using PVP and S/D ratios provides clinicians with a practical way to monitor these patients more frequently. By integrating invasive exercise testing for high-risk stratification and non-invasive algorithms for routine surveillance, we can move toward a more proactive, evidence-based approach to preserving the health of the Fontan generation.
References
1. Cao JY, Egbe AC, Olsen N, et al. Adults with Fontan circulation: prognostic value of exercise pulmonary vascular resistance index. Eur Heart J. 2025;ehaf941. doi:10.1093/eurheartj/ehaf941.
2. Cao JY, Jain CC, Egbe AC, et al. Noninvasive Evaluation of Ventricular Filling Pressure and Pulmonary Vascular Reserve in Adults With Fontan Circulation. J Am Heart Assoc. 2025;14(22):e043110. doi:10.1161/JAHA.125.043110.
