Serum Proteomic Profiling Implicates a Dysregulated Neurohormonal–Inflammatory Axis in Post‐Fontan Sinus Tachycardia

Background Postoperative sinus tachycardia is a poorly understood complication following the Fontan procedure. The molecular signaling cascades triggering acute tachycardia remain uncharacterized, limiting therapeutic innovation. Here, we present a retrospective study leveraging serum proteomics and machine learning to identify the molecular drivers of postoperative Fontan sinus tachycardia. Methods We integrated a clinically relevant ovine Fontan model with continuous telemetric heart rate monitoring and human patient data. Serum proteomics coupled with least absolute shrinkage and selection operator and Boruta machine learning algorithms were used to identify protein panels predictive of postoperative sinus tachycardia. Cross‐species validation was performed by comparing proteomic signatures from sheep and pediatric patients undergoing Glenn or Fontan surgery. Results Ovine Fontan animals demonstrated significant heart rate elevation beginning on postoperative day 1, peaking at postoperative day 3 (159.4±11.7 bpm versus preoperative, 105.3±10.5 bpm; P =0.0002), before trending toward baseline by postoperative day 10. This pattern was mirrored in human patients with a more modest magnitude. Surgical controls did not exhibit tachycardia. The principal component most correlated with heart rate (principal component 1: r =0.78, P =2.2×10 −4 ) was enriched for inflammatory and neural pathways. The Boruta algorithm identified an 11‐protein panel with strong predictive power (area under the receiver operating characteristic curve, 0.963). Cross‐species comparison demonstrated that angiotensinogen, angiotensin‐converting enzyme, and pentraxin 3 were similarly dysregulated in both species postoperatively. Conclusions This study provides molecular evidence implicating a dysregulated neurohormonal–inflammatory axis in acute postoperative Fontan sinus tachycardia and establishes a foundation for developing targeted diagnostics and therapeutics for this complication.