Background Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a... Show moreBackground Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a young cohort who have undergone the Fontan procedure.Methods and ResultsIn multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT-proBNP (N-terminal pro-B-type natriuretic peptide), GDF-15 (growth differentiation factor 15), Gal-3 (galectin-3), ST2 (suppression of tumorigenicity 2), DLK-1 (protein delta homolog 1), FABP-4 (fatty acid-binding protein 4), IGFBP-1 (insulin-like growth factor-binding protein 1), IGFBP-7, MMP-2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1-12.1) years after Fontan completion. After this baseline study measurement, follow-up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4-15.9) years, median age at Fontan 3.2 (2.5-3.9) years. After a median follow-up of 6.2 (4.9-6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT-proBNP was associated with (all) events during follow-up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32-2.68). The severe event-free survival was better in patients with low levels of GDF-15 (P=0.005) and vWF (P=0.008) and high levels of DLK-1 (P=0.041). There was a positive correlation (beta=0.33, P=0.003) between DLK-1 and stress cardiac magnetic resonance imaging functional reserve.ConclusionsNT-proBNP, GDF-15, vWF, DLK-1, ST-2 FABP-4, and IGFBP-7 levels relate to long-term outcome in young patients who have undergone the Fontan procedure. Show less
Ven, J.P.G. van der; Bossers, S.S.M.; Bosch, E. van den; Dam, N.; Kuipers, I.M.; Iperen, G.G. van; ... ; Helbing, W.A. 2021
Objective To assess the atrial and ventricular diastolic function response to dobutamine stress in Fontan patients, and to relate these measurements to exercise capacity and events during the... Show moreObjective To assess the atrial and ventricular diastolic function response to dobutamine stress in Fontan patients, and to relate these measurements to exercise capacity and events during the follow-up.Methods We performed a secondary analysis of a cross-sectional multicentre study of Fontan patients with intra-atrial lateral tunnel (ILT) or extracardiac conduit (ECC) modification. Subjects underwent cardiac MRI during rest and low-dose dobutamine stress, and cardiopulmonary exercise testing. Atrial and diastolic ventricular function parameters were derived from volume-time curves. Medical records were abstracted for a composite endpoint of death, listing for transplant, arrhythmia and reintervention. Spearman's r correlation tests and Cox proportional hazards models were used to assess the relation between the dobutamine response for atrial and diastolic ventricular function and outcomes, including exercise capacity.Results We included 57 patients (26 ECC; 31 ILT) aged 12.8 (IOR (10.3-15.5)) years. During dobutamine stress atrial cyclic volume change increased (3.0 (0.4-5.9) mL/m(2), p<0.001), as did early (1.9 (-1.6 to 3.6) mL/m(2), p=0.001) and late emptying volume (2.2 (0.2-4.4) mL/m(2), p<0.001).Ventricular early filling decreased (-1.6 (-5.7 to 0.7) mL/m(2),p=0.046) and ventricular late filling increased (1.0 (-0.4 to 3.4) mL/m(2),p<0.001) while stroke volume remained similar.Only for patients with the ECC modification, atrial early emptying volume increase correlated with peak oxygen uptake (p=0.66,p=0.002). No other parameter related to exercise capacity.During a median 7.1-year follow-up, 22 patients reached the composite endpoint. No parameter predicted events during the follow-up.Conclusions Dobutamine stress augmented atrial reservoir and pump function for Fontan patients. Atrial early emptying reserve related to exercise capacity in ECC patients. No other atrial or diastolic ventricular function parameter related to outcomes. Show less
Ven, J.P.G. van der; Alsaied, T.; Juggan, S.; Bossers, S.S.M.; Bosch, E. van den; Kapusta, L.; ... ; Helbing, W.A. 2020
Objective: To assess the role of atrial function on exercise capacity and clinical events in Fontan patients.Design: We included 96 Fontan patients from6 tertiary centers, aged 12.8 (IQR 10.1-15.6)... Show moreObjective: To assess the role of atrial function on exercise capacity and clinical events in Fontan patients.Design: We included 96 Fontan patients from6 tertiary centers, aged 12.8 (IQR 10.1-15.6) years, who underwent cardiacmagnetic resonance imaging and cardiopulmonary exercise testing within 12 months of each other from 2004 to 2017. Intra-atrial lateral tunnel (ILT) and extracardiac conduit (ECC) patients were matched 1:1 with regard to age, gender and dominant ventricle. The pulmonary venous atrium was manually segmented in all phases and slices. Atrial function was assessed by volume-time curves. Furthermore, atrial longitudinal and circumferential feature tracking strain was assessed. We determined the relation between atrial function and exercise capacity, assessed by peak oxygen uptake and VE/VCO2 slope, and events (mortality, listing for transplant, re-intervention, arrhythmia) during follow-up.Results: Atrial maximal and minimal volumes did not differ between ILT and ECC patients. ECC patients had higher reservoir function (21.1 [16.4-28.0]% vs 18.2 [10.9-22.2]%, p =.03), lower conduit function and lower total circumferential strain (13.8 +/- 5.1% vs 18.0 +/- 8.7%, p =.01), compared to ILT patients. Only for ECC patients, a better late peak circumferential strain rate predicted better VE/VCO2 slope. No other parameter of atrial function predicted peak oxygen uptake or VE/VCO2 slope. During a median follow-up of 6.2 years, 42 patients reached the composite end-point. No atrial function parameters predicted events during follow-up.Conclusions: ECC patients have higher atrial reservoir function and lower conduit function. Atrial function did not predict exercise capacity or events during follow-up. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Bosch, E. van den; Bossers, S.S.M.; Robbers-Visser, D.; Boersma, E.; Roos-Hesselink, J.W.; Breur, H.M.P.J.; ... ; Helbing, W.A. 2019
