Fontan patients undergo multiple cardiothoracic surgeries in childhood. Following these procedures, ventricular function is temporarily decreased, and recovers over months. This is presumably... Show moreFontan patients undergo multiple cardiothoracic surgeries in childhood. Following these procedures, ventricular function is temporarily decreased, and recovers over months. This is presumably related to cardiopulmonary bypass, but this is incompletely understood. Throughout the Fontan palliation, cardiac function is also affected by volume unloading. We aimed to gain insight into the biological processes related to impaired ventricular function and recovery following Fontan palliations using a panel of biomarkers. Furthermore, we described changes in ventricular function across the Fontan palliation due to volume unloading. We performed a prospective multicenter observational study in patients undergoing partial (PCPC) or total cavo-pulmonary connection (TCPC). Patients underwent assessment—including echocardiography and blood sampling—before surgery (T1), at first follow-up (T2), and 1 year after their procedures (T3). Blood samples were analyzed using a biomarker panel (OLINK CVD-III). Ninety-two biomarkers were expressed as principal components (PC) to limit multiple statistical testing. We included 32 PCPC patients aged 7.2 [5.3–10.3] months, and 28 TCPC patients aged 2.7 [2.2–3.8] years. The single ventricular longitudinal strain (SV GLS) temporarily decreased for PCPC patients at T2 (−15.1 ± 5.6 (T1) to −13.5 ± 5.2 (T2) to −17.3 ± 4.5 (T3), p < 0.047 for all differences), but not following TCPC. The serum biomarkers were expressed as 4 PCs. PC1, including biomarkers of cell–cell adhesion, was not related to any patient characteristic. PC2, including biomarkers of superoxide anion regulation, increased at T2. PC3, including biomarkers of cardiovascular development, related to the stage of Fontan palliation. PC4 was of uncertain biological or clinical significance. No PC was found that related to ventricular performance. The SV GLS was temporarily diminished following PCPC, but not following TCPC. Several biomarkers were related to post-operative stress and adaptation to the PCPC or TCPC circulation, but none were related to the outcome Show less
Ven, J.P.G. van der; Bosch, E. van den; Kamphuis, V.P.; Terol, C.; Gnanam, D.; Bogers, A.J.J.C.; ... ; Helbing, W.A. 2022
BACKGROUND: Ventricular performance is temporarily reduced following surgical atrial septa! defect closure. Cardiopulmonary bypass and changes in loading conditions are considered important factors... Show moreBACKGROUND: Ventricular performance is temporarily reduced following surgical atrial septa! defect closure. Cardiopulmonary bypass and changes in loading conditions are considered important factors, but this phenomenon is incompletely understood. We aim to characterize biventricular performance following surgical and percutaneous atrial septal defect closure and to relate biomarkers to ventricular performance following intervention.METHODS AND RESULTS: In this multicenter prospective study, children scheduled for surgical or percutaneous atrial septal defect closure were included. Subjects were assessed preoperatively, in the second week postintervention (at 2-weeks follow-up), and 1-year postintervention (1-year follow-up). At each time point, an echocardiographic study and a panel of biomarkers were obtained. Sixty-three patients (median age, 4.1 [interquartile range, 3.1-6.1] years) were included. Forty-three patients underwent surgery. At 2-weeks follow-up, right ventricular global longitudinal strain was decreased for the surgical, but not the percutaneous, group (-17.6 +/- 4.1 versus -27.1 +/- 3.4; P<0.001). A smaller decrease was noted for left ventricular global longitudinal strain at 2-weeks follow-up for the surgical group (surgical versus percutaneous, -18.6 +/- 3.2 versus -20.2 +/- 2.4; P=0.040). At 1-year follow-up, left ventricular performance returned to baseline, whereas right ventricular performance improved, but did not reach preintervention levels. Eight biomarkers relating to cardiovascular and immunological processes differed across study time points. Of these biomarkers, only NT-proBNP (N-terminal pro-B-type natriuretic peptide) correlated with less favorable left ventricular global longitudinal strain at 2-weeks follow-up.CONCLUSIONS: Right, and to a lesser degree left, ventricular performance was reduced early after surgical atrial septal defect closure. Right ventricular performance at 1-year follow-up remained below baseline levels. Several biomarkers showed a pattern over time similar to ventricular performance. These biomarkers may provide insight into the processes that affect ventricular function. Show less
Bosch, E. van den; Genuchten, W.J. van; Luijnenburg, S.E.; Duppen, N.; Kamphuis, V.P.; Roos-Hesselink, J.W.; ... ; Helbing, W.A. 2022
Background: To determine the potential prognostic value and clinical correlations of blood biomarkers in a cohort of patients with Tetralogy of Fallot (TOF). Methods: In the setting of multicenter... Show moreBackground: To determine the potential prognostic value and clinical correlations of blood biomarkers in a cohort of patients with Tetralogy of Fallot (TOF). Methods: In the setting of multicenter prospective research studies TOF patients underwent blood sampling, cardiopulmonary exercise testing and low-dose dobutamine stress cardiac magnetic resonance (CMR) imaging. In the blood sample NT-proBNP, GDF-15, Galectin-3, ST-2, DLK-1, FABP4, IGFBP-1, IGFBP-7, MMP-2, and vWF were assessed. During subsequent follow-up, patients were evaluated for reaching the study endpoint (cardiac death, arrhythmia-related hospitalization or cardioversion/ablation, VO2 max <= 65% of predicted). Regression analysis was used to explore the correlation between blood biomarkers (corrected for age and gender) and other clinical parameters. The potential predictive value of blood biomarkers and events were assessed with Kaplan-Meier analysis and Cox proportional hazard analysis. Results: We included 137 Fallot patients, median age 19.2 (interquartile range: 14.6-25.7) years, median age at TOF-repair 0.9 (0.5-1.9) years. After a median follow-up of 8.7 (6.3-10.7) years, 20 (14.6%) patients reached the composite endpoint. In a multivariable cox-regression analysis corrected for age at study baseline, elevated IGFBP-7 and MMP-2 levels were associated with the composite endpoint. We also noted a correlation between DLK-1 and relative change in right ventricular end systolic volume during dobutamine stress CMR (beta = 0.27, p = 0.010), a correlation between FABP4 and Max VO2 (beta = 0.41, p <= 0.001 and between MMP-2 and tricuspid valve E/A ratio (beta = 0.15, p = 0.037). Conclusions: IGFBP-7, MMP-2 and DLK-1 levels are related to cardiac function and long-term outcome in TOF patients. Show less
Bosch, E. van den; Bossers, S.S.M.; Kamphuis, V.P.; Boersma, E.; Roos-Hesselink, J.W.; Breur, J.M.P.J.; ... ; Helbing, W.A. 2021
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
Mheen, M. van der; Meulen, M.H. van der; Boer, S.L. den; Schreutelkamp, D.J.; Ende, J. van der; Nijs, P.F.A. de; ... ; Dalinghaus, M. 2019
BackgroundAortic regurgitation (AR) and subclinical left ventricular (LV) dysfunction expressed by myocardial deformation imaging are common in patients with transposition of the great arteries... Show moreBackgroundAortic regurgitation (AR) and subclinical left ventricular (LV) dysfunction expressed by myocardial deformation imaging are common in patients with transposition of the great arteries after the arterial switch operation (ASO). Echocardiographic evaluation is often hampered by reduced acoustic window settings. Cardiovascular magnetic resonance (CMR) imaging provides a robust alternative as it allows for comprehensive assessment of degree of AR and LV function. The purpose of this study is to validate CMR based 4-dimensional flow quantification (4D flow) for degree of AR and feature tracking strain measurements for LV deformation assessment in ASO patients.MethodsA total of 81 ASO patients (median 20.6years, IQR 13.5-28.4) underwent CMR for 4D and 2D flow analysis. CMR global longitudinal strain (GLS) feature tracking was compared to echocardiographic (echo) speckle tracking. Agreements between and within tests were expressed as intra-class correlation coefficients (ICC).ResultsEleven ASO patients (13.6%) showed AR >5% by 4D flow, with good correlation to 2D flow assessment (ICC=0.85). 4D flow stroke volume of the aortic valve demonstrated good agreement to 2D stroke volume over the mitral valve (internal validation, ICC=0.85) and multi-slice planimetric LV stroke volume (external validation, ICC=0.95). 2D flow stroke volume showed slightly less, though still good agreement with 4D flow (ICC=0.78) and planimetric LV stroke volume (ICC=0.87). GLS by CMR was normal (-18.84.4%) and demonstrated good agreement with GLS and segmental analysis by echocardiographic speckle tracking (GLS=-17.3 +/- 3.1%, ICC of 0.80).Conclusions p id=Par4 Aortic 4D flow and CMR feature tracking GLS analysis demonstrate good to excellent agreement with 2D flow assessment and echocardiographic speckle tracking, respectively, and can therefore reliably be used for an integrated and comprehensive CMR analysis of aortic valve competence and LV deformation analysis in ASO patients. Show less
