Low ventricular chamber stiffness identifies a high-risk eccentric remodeling phenotype in the Fontan circulation: a A FORCE Registry analysis

Background Rising end-diastolic pressure in patients with a Fontan circulation has led to the hypothesis that progressive ventricular stiffening drives circulatory failure. However, end-diastolic pressure is influenced by loading conditions and extracardiac constraint, and may not accurately reflect chamber stiffness. Purpose To characterize ventricular chamber stiffness using the end-diastolic pressure-volume relationship (EDPVR) and examine its clinical and prognostic significance in Fontan patients. Methods In the FORCE registry, chamber stiffness was quantified using the exponential coefficient β derived from single-beat EDPVR reconstruction using paired catheterization and cardiovascular magnetic resonance data. β values were standardized as age- and sex- Z-scores and related to ventricular morphology, clinical characteristics, and a composite adverse outcome (death, transplant listing, sustained atrial or ventricular arrhythmias, protein-losing enteropathy, or plastic bronchitis). Results Among 814 patients (median age 14.7 years; 41.2% female; 46.2% dominant right ventricle), median β was 0.034 (IQR 0.025-0.046) mL-1 and decreased with age and in dominant right or mixed ventricular morphology (Figure 1). Compared with patients with high β Z-score (>+1, n=119), those with low β Z-score (<-1, n=109) had markedly larger ventricular volumes (EDV; 254 vs 73 mL), lower ejection fraction (EF; 37.9% vs 54.8%), higher systemic-to-pulmonary collateral flow (SPC; 1.16 vs 0.68 L/min), and higher intracardiac recirculation (2.92 vs 0.39 L/min, largely reflecting atrioventricular valve [AVV] regurgitation), despite similar Fontan pressures (15 vs 14 mmHg) (Figure 2). Low β Z-score was also associated with higher NYHA III/IV prevalence (24.2% vs 9.3%) and arrhythmia burden (30.7% vs 16.1%). Over a median follow-up of 2.7 years, the composite adverse outcome occurred in 14.5%. In adjusted Cox models (age, sex, BSA, dominant right ventricle, Fontan pressure, and SPC flow), lower β Z-score remained associated with higher risk of adverse outcomes (HR 0.74 per 1-SD increase, 95% CI 0.59-0.93). A β Z-score <-0.33, β <0.025 mL⁻¹, or EDVi >128 mL/m² showed comparable discriminatory performance, particularly in dominant right ventricles. Conclusions Contrary to prevailing assumptions, lower – rather than higher – chamber stiffness was associated with adverse Fontan outcomes, suggesting that Fontan failure more often reflects maladaptive ventricular dilation and excessive compliance than progressive stiffening.