GDF‐15 (Growth Differentiation Factor 15) Is Associated With Hospitalization and Mortality in Patients With a Fontan Circulation

BACKGROUND: We investigated serial serum levels of GDF‐15 (growth differentiation factor 15) in Fontan patients and their relation to outcome. METHODS AND RESULTS: In this single‐center prospective study of consecutive Fontan patients, serial serum GDF‐15 measurement and clinical assessment was done at baseline (n=81) and after 2 years (n=51). The association between GDF‐15 and the combined end point of all‐cause mortality, heart transplant listing, and Fontan‐related hospitalization was investigated. Median age at baseline was 21 years (interquartile range: 15–28 years). Median GDF‐15 serum levels at baseline were 552 pg/mL (interquartile range: 453–729 pg/mL). GDF‐15 serum levels correlated positively with age, age at Fontan initiation, New York Heart Association class, and serum levels of NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and ɣGT (γ‐glutamyltransferase) and negatively with exercise capacity. During a median follow‐up of 4.8 years (interquartile range: 3.3–5.5 years), the combined end point occurred in 30 patients (37%). Multivariate Cox regression showed that patients with the highest baseline GDF‐15 (n=20, defined as the upper quartile) had a higher risk of hospitalization or death than the lowest 3 quartiles (hazard ratio [HR], 2.76; 95% CI, 1.27–6.00; P=0.011). After 2 years of follow‐up, patients in whom serum level of GDF‐15 increased to >70 pg/mL (n=13) had a higher risk of hospitalization or death than the lowest 3 quartiles (HR, 2.69; 95% CI, 1.03–6.99; P=0.043). CONCLUSIONS: In Fontan patients, elevated serum levels of GDF‐15 are associated with worse functional status and predict Fontan‐related events. Furthermore, serial measurements showed that an increase in GDF‐15 serum level was associated with increased risk for adverse outcome.