Objectives To define whether adults with a Fontan circulation, who have life-long venous congestion and limited cardiac output, have impaired glomerular filtration rate (GFR) or elevated urinary biomarkers of kidney injury. Methods We measured circulating cystatin C and creatinine (n=70) and urinary creatinine, albumin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl glucosaminidase (NAG)(n=59) in ambulatory adult Fontan patients and 20 age- and sex- matched controls. Urinary biomarkers were normalized to urine creatinine concentration. Survival free from non-elective cardiovascular hospitalization was compared, by estimated GFR and urinary biomarker levels using survival analysis. Results Cystatin C GFR was lower in the Fontan group compared with controls (114.2±22.8 vs. 136.3±12.8mL/min/1.73m2, p<0.0001); GFR<90mL/min/1.73m2 in 14.3% vs. 0% of controls. Albumin-to-creatinine ratio (ACR), KIM-1 and NAG were elevated compared with controls; ACR=23.2 [7.6–38.3] vs. 3.6 [2.5–5.7]mg/g, p<0.0001; NAG=1.8 [1.1–2.6] vs. 1.1 [0.9–1.6]U/g, p=0.02; KIM-1=0.91 [0.52–1.45] vs. 0.33 [0.24–0.74]ng/mg, p=0.001. Microalbuminuria, ACR>30mg/g, was present in 33.9% of the Fontan patients but in none of the controls. Over median 707 [IQR 371–942] day follow-up, 31.4% of patients had a clinical event. Higher KIM-1 and NAG were associated with higher risk of non-elective hospitalization or death (HR/+1SD=2.1, 95%CI=1.3–3.3, p=0.002; HR/+1SD=1.6, 95%CI=1.05–2.4, p=0.03, respectively); cystatin C GFR was associated with risk of the outcome (HR/+1SD=0.66, 95%CI=0.48–0.90, p=0.009) but creatinine-based GFR was not (HR/+1SD=0.91, 95%CI=0.61–1.38, p=0.66). Neither ACR nor NGAL were associated with events. Conclusions The Fontan circulation is commonly associated with reduced estimated GFR and evidence for glomerular and tubular injury. Those with lower cystatin C GFR and tubular injury are at increased risk of adverse outcomes.

BackgroundGalectin‐3 may play a role in cardiac and noncardiac fibrosis, and elevated circulating levels of this protein predict adverse outcomes in patients with heart failure who do not have congenital heart disease. We investigated galectin‐3 in adults with single‐ventricle Fontan circulation, patients who are prone to premature clinical deterioration in the context of extensive multiorgan fibrosis.Methods and ResultsWe measured plasma galectin‐3 concentrations in 70 ambulatory adult Fontan patients and 21 age‐ and sex‐matched control participants. Galectin‐3 level was significantly higher in the Fontan group (11.85 ng/mL, interquartile range 9.9 to 15.0 ng/mL) versus the control group (9.4 ng/mL, interquartile range 8.2 to 10.8 ng/mL; P<0.001). Among Fontan patients, galectin‐3 was positively correlated with age, uric acid, and high‐sensitivity C‐reactive protein and negatively correlated with estimated glomerular filtration rate. There was no significant relationship between galectin‐3 and oxygen saturation, Fontan type, or ventricular morphology. Over a median follow‐up of 461 days, 15 events occurred among the Fontan patients: 12 nonelective hospitalizations (with 2 subsequent deaths) and 3 deaths without prior hospitalization. Patients with elevated galectin‐3 (n=19, defined as >2 SD above the control group mean value) had a higher risk of nonelective hospitalization or death (hazard ratio 6.0, 95% CI 2.1 to 16.8, P<0.001). This relationship persisted after individual adjustment for covariates including age, New York Heart Association functional class, C‐reactive protein, and estimated glomerular filtration rate and after multivariable adjustment for independently predictive covariates (hazard ratio 9.2, 95% CI 2.4 to 35.2, P=0.001).ConclusionsGalectin‐3 concentrations are elevated among adults with a Fontan circulation, and elevated galectin‐3 is associated with an increased risk of nonelective cardiovascular hospitalization or death.

Background— Exercise oscillatory ventilation (EOV) refers to regular oscillations in minute ventilation (V E ) during exercise. Its presence correlates with heart failure severity and worse prognosis in adults with acquired heart failure. We evaluated the prevalence and predictive value of EOV in patients with single ventricle Fontan physiology. Methods and Results— We performed a cross-sectional analysis and prospective survival analysis of patients who had undergone a Fontan procedure and subsequent cardiopulmonary exercise test. Data were reviewed for baseline characteristics and incident mortality, heart transplant, or nonelective cardiovascular hospitalization. EOV was defined as regular oscillations for >60% of exercise duration with amplitude >15% of average V E . Survival analysis was performed using Cox regression. Among 253 subjects, EOV was present in 37.5%. Patients with EOV were younger (18.8±9.0 versus 21.7±10.1 years; P =0.02). EOV was associated with higher New York Heart Association functional class ( P =0.02) and V E /V CO 2 slope (36.8±6.9 versus 33.7±5.7; P =0.0002), but not with peak V O 2 (59.7±14.3 versus 61.0±16.0% predicted; P =0.52) or noninvasive measures of cardiac function. The presence of EOV was associated with slightly lower mean cardiac index but other invasive hemodynamic variables were similar. During a median follow-up of 5.5 years, 22 patients underwent transplant or died (n=19 primary deaths, 3 transplants with 2 subsequent deaths). EOV was associated with increased risk of death or transplant (hazard ratio, 3.9; 95% confidence interval, 1.5–10.0; P =0.002) and also predicted the combined outcome of death, transplant, or nonelective cardiovascular hospitalization after adjusting for New York Heart Association functional class, peak V O 2 , and other covariates (multivariable hazard ratio, 2.0; 95% confidence interval, 1.2–3.6; P =0.01). Conclusions— EOV is common in the Fontan population and strongly predicts lower transplant-free survival.