Fontan physiology, hypoxia, and exercise: why cytokines matter

The Fontan pathway reroutes systemic venous return to the pulmonary arteries without a subpulmonary ventricle, producing a circulation that relies on passive flow and low impedance within the pulmonary vasculature. This configuration leaves patients sensitive to changes in intrathoracic pressure, preload, and afterload, with consequences for exercise tolerance. Physiologic stressors, including reduced inspired oxygen and sustained activity, can influence ventilation, cardiac output, and tissue oxygenation. Against this backdrop, circulating immune mediators such as cytokines may reflect compensatory or maladaptive responses. Clarifying whether these signals shift during stress could refine surveillance strategies and tailor counseling.

Hemodynamics of the Fontan pathway

In the absence of a subpulmonary pump, the Fontan circulation depends on low pulmonary vascular resistance and adequate systemic venous pressures to propel blood through the lungs. Exercise can accentuate the interplay among venous return, pulmonary blood flow, and arterial oxygen content. Small perturbations in pulmonary impedance or respiratory mechanics may have outsized effects on forward flow, and chronic changes can contribute to endothelial dysfunction or venous congestion. Because cytokines integrate signals from shear stress, hypoxemia, and tissue perfusion, they can serve as sentinels of pathophysiologic strain. Measuring them during stress testing offers a systems-level view that complements cardiopulmonary metrics.

Immune signaling under physiologic stressors

Acute hypoxia and sustained exercise are known to modulate immune pathways in biventricular physiology, often with transient shifts in inflammatory and anti-inflammatory cytokines. In single-ventricle contexts, the direction and magnitude of change could differ due to altered hemodynamics and baseline neurohormonal activation. A priori, one might anticipate rises in markers of inflammation with prolonged exertion or reduced oxygen, alongside changes related to skeletal muscle recruitment. The present report asked whether those expectations hold in Fontan physiology. The answer, summarized below, is that the overall network of cytokine relationships remained stable, even when physiologic load was increased.

What was measured and what remained stable

The investigators examined circulating cytokines at rest and during hypoxia and exercise, analyzing both individual mediator levels and network behavior. The approach emphasizes correlation structure and connectivity among cytokines rather than isolated changes in single markers. This aligns with the concept that immune signaling operates as a coordinated system integrating environmental and hemodynamic cues. In addition, the testing paradigm provides real-world relevance for clinical decision-making about cardiopulmonary exercise testing. The full report can be found on PubMed at https://pubmed.ncbi.nlm.nih.gov/40921273/.

Protocol overview and assay approach

Participants with Fontan circulation underwent controlled physiologic challenges designed to probe oxygen transport and systemic stress responses. Blood sampling was performed around these stimuli to capture dynamic immune signaling during rest and stress. Although assay details vary across platforms, broad biomarker profiling of cytokines typically includes chemokines, interleukins, and growth factors. Pairing this with physiologic monitoring enables cross-sectional and within-individual assessments. The goal was not simply to detect any change but to determine whether system-level coordination of cytokines reorganizes under hypoxia or exercise.

Network-level readouts and individual markers

Network analysis evaluates how cytokines co-vary, using correlation matrices and related network analysis tools to characterize connectivity and modular structure. In this population, the central result was a stable cytokine network across rest, hypoxia, and exercise. That observation implies that the relative relationships among inflammatory and regulatory signals were preserved even as physiologic load changed. Any small fluctuations in single mediators did not translate into a reorganization of the network or widespread immune activation. From a systems perspective, these data suggest homeostatic resilience during short-term, controlled stressors.

Safety signals and physiologic responses

Clinical application hinges on whether testing conditions are tolerated without provoking maladaptive responses. While cytokines provide a biochemical lens, routine parameters such as perceived exertion, oxygen saturation, and heart rate responses guide immediate safety. The immune readouts add confidence that acute stress under controlled conditions does not trigger disproportionate inflammatory responses in Fontan physiology. This finding supports the feasibility of structured assessments and aligns with the principles of exercise physiology in congenital settings. Taken together, the data indicate that the immune milieu remains orderly during the testing window.

Clinical relevance, limitations, and research directions

Translating these findings to practice requires attention to patient selection, comorbidity burden, and the context of exercise or altitude exposure. For clinicians, a stable cytokine network during brief hypoxia and exercise supports ongoing use of standardized testing protocols in appropriately selected patients. For patients and families, it provides additional reassurance that monitored activity is unlikely to provoke acute immune dysregulation. For researchers, the work refines mechanistic hypotheses about immune and vascular coupling in Fontan physiology. It also points to new questions about longer exposures and recovery dynamics.

Implications for exercise prescription

Cardiac rehabilitation and structured activity plans are increasingly considered in this population, with individualized targets informed by symptoms and objective testing. The observation that cytokine coordination remains stable under stress supports appropriately dosed, supervised exercise rehabilitation. It may also influence threshold setting for intensity and duration, with attention to dynamic oxygenation and hemodynamics. Practical strategies include gradual progression, respiratory muscle training where indicated, and interval formats that respect preload dependence. Importantly, immune stability should be viewed as supportive, not definitive; comprehensive clinical assessment remains essential.

Trial design and biomarker strategy

From a research standpoint, these results inform endpoints and sampling strategies for interventional trials. If the cytokine network is robust to brief stressors, future studies might prioritize longer exposures, recovery-phase sampling, or integration with vascular function measures. Incorporating tissue-level or endothelial readouts could clarify links between immune signaling and flow-limited physiology. Trials may also benefit from harmonized panels to facilitate cross-study synthesis and reduce assay variability. A systems approach, integrating physiology and circulating mediators, can sharpen signal detection for meaningful clinical changes.

Caveats and next steps

Several considerations temper broad generalization. Acute hypoxia and short exercise bouts may not reproduce the demands of daily life, altitude travel, or prolonged training. Heterogeneity within the Fontan population, including anatomy, age, ventricular function, liver status, and prior interventions, could modulate responses. Small sample sizes and single-center designs limit precision and external validity. Finally, cytokines are one layer of a complex system that also includes neurohormonal, metabolic, and vascular pathways. Future work should examine longer stress durations, recovery kinetics, and multi-omic integration alongside clinical outcomes.

In synthesis, the new report shows that short-term hypoxia and exercise do not materially reorganize cytokine coordination in Fontan physiology. Network stability across conditions provides reassurance for monitored testing and supports ongoing refinement of training strategies. The findings also sharpen research priorities toward time scales and contexts where stress might be more consequential, integration with vascular and hepatic metrics, and the search for subgroups with distinct patterns. As evidence accumulates, the field can better align physiologic targets with safe, effective activity prescriptions that respect the unique constraints of single-ventricle circulation.