Serum Proteomic Profiling Implicates a Dysregulated Neurohormonal-Inflammatory Axis in Post-Fontan Tachycardia

Abstract Background Post-operative tachycardia is a common and poorly understood complication following the Fontan procedure. Post-operative factors such as surgical scarring and venous hypertension can contribute to tachycardia risk, but the specific molecular signaling cascades triggering acute tachycardia remain uncharacterized, limiting therapeutic innovation and leaving clinicians with only reactive management strategies. Here, we present a retrospective translational study leveraging serum proteomics and machine learning to identify the molecular drivers of post-operative Fontan tachycardia. Methods We integrated a clinically relevant ovine animal model of the Fontan circulation with continuous telemetric heart rate monitoring and human patient data. Serum proteomics coupled with machine learning algorithms (LASSO and Boruta) were employed to identify protein panels predictive of post-operative 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 post-operative day (POD) 1, peaking at POD 3 (159.4 ± 11.7 bpm vs. pre-operative 105.3 ± 10.5 bpm, p