Failing Fontan Following Total Cavopulmonary Connection: Extracardiac Biomarkers Reveal 2 Distinct Phenotypes With Divergent Clinical Courses.

OBJECTIVES

Failing Fontan is an increasingly recognized complication after total cavopulmonary connection (TCPC), yet longitudinal biomarker data remain scarce. We aimed to characterize the incidence, biomarker trajectories, and prognostic determinants of failing Fontan.

METHODS

All patients who underwent primary TCPC (n = 650) or conversion to TCPC (n = 19) at our centre between 1994 and 2022 were reviewed. Lymphocyte count, N-terminal pro-brain natriuretic peptide (NT-proBNP) and its zlog value, and Fibrosis-4 index were assessed at 1 year before, 6 months before, at onset, and at last follow-up. Patients were classified into protein-losing enteropathy (PLE)/plastic bronchitis (PB) and heart failure phenotypes.

RESULTS

Failing Fontan developed in 78 primary TCPC patients (12.0%) and 12 conversion patients (63.2%). Conversion patients developed failing Fontan earlier (P < .001), but survival after onset was comparable. Lymphocyte counts declined before onset (2.49 to 0.89 × 10³/µL, P < .001) and the Fibrosis-4 index increased (0.060 to 0.330, P < .001). Phenotypes showed divergent profiles: zlog-NT-proBNP at onset was 0.71 in PLE/PB versus 5.34 in heart failure (P < .001). Lymphocytopenia (LP) predicted mortality early (hazard ratio 6.77, P = .013) but appeared protective at last follow-up (hazard ratio 0.18, P = .049), reflecting a phenotypic shift. On multivariable analysis, lower lymphocyte count independently predicted mortality (hazard ratio 2.44, P = .041), while stent implantation was independently associated with lower mortality (hazard ratio 0.32, P = .040).

CONCLUSIONS

Lymphocyte counts and the Fibrosis-4 index change progressively before clinical onset and may serve as early warning biomarkers. The prognostic interpretation of LP depends on the underlying phenotype, underscoring the need for phenotype-aware monitoring.