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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 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, VO 2 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 (β = -0.27, p = 0.010), a correlation between FABP4 and Max VO 2 (β = -0.41, p ≤0.001 and between MMP-2 and tricuspid valve E/A ratio (β = -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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients., Methods and Results: In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress - parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan-Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5-34.0), age at TOF repair 0.9 years (0.6-2.1)]. After a median follow-up of 8.6 years (6.7-14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (-17 ± 15 vs. -26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5-43.7; P = 0.001) as predictor for the composite endpoint., Conclusion: An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To evaluate the additional value of dobutamine stress testing in patients with repaired tetralogy of Fallot (TOF) by relating stress imaging parameters at baseline to relevant parameters of clinical condition and right ventricular (RV) size during a serial follow-up., Methods and Results: We prospectively included 27 patients (14 ± 4 years at baseline), who were studied twice with a 5-year interval. Patients underwent cardiovascular magnetic resonance imaging to assess RV systolic and diastolic function at rest and during dobutamine stress. Normal response to dobutamine was defined as a decrease in RV end-systolic volume, and a increase in RV ejection fraction (EF) during stress. Exercise testing and electrocardiography were performed to determine peak oxygen uptake (peak VO₂), QRS duration, and QT interval corrected for heart rate (QTc) interval. RV volumes, QRS duration, and QTc interval increased significantly from baseline to follow-up; peak VO₂ tended to decrease (95 ± 20-89 ± 14%, P = 0.086). Response to dobutamine was normal in 26 of 27 patients and remained stable during the follow-up [relative increase in RVEF during stress: +25 ± 9% (baseline) vs. +27 ± 10% (follow-up)]. A smaller relative increase in RVEF during stress at baseline related to a larger relative decrease in peak VO₂ during the follow-up (r = 0.59, P = 0.004). No significant associations were found with the relative increase in QRS duration, QTc interval, or RV end-diastolic volume during a 5-year follow-up., Conclusion: In a young TOF population, response to dobutamine stress was normal and remained stable during the 5-year follow-up. A smaller increase in RVEF during stress at baseline was predictive for a larger decrease in peak VO₂ during the 5-year follow-up.

Objective: To study the changes over time in biventricular size and function, and clinical parameters in patients after repair of tetralogy of Fallot (TOF) without subsequent pulmonary valve replacement (PVR)., Methods: We prospectively included 78 non-PVR patients (age 20(6-60)years at baseline), who were studied twice with a 5-year interval. Patients underwent magnetic resonance imaging for assessment of biventricular size and function. Exercise testing and electrocardiography were performed to determine peak oxygen uptake (peak VO2) and QRS duration. N-terminal prohormone brain natriuretic peptide (NT-proBNP) was assessed additionally., Results: Pulmonary regurgitation (PR), right ventricular (RV) volumes and QRS duration increased during 5-year follow-up (RV end-diastolic volume (EDV) 130 ± 30 ml/m(2) to 138 ± 34 ml/m(2); QRS 132 ± 27 msec to 139 ± 27 msec); peak VO2 decreased (96 ± 19% to 91 ± 17%). RV ejection fraction, RV effective stroke volume (eff.SV), and NT-proBNP levels remained unchanged. The slope of RVEDV increase was 1.6 ± 3.0 ml/m(2)/year, and depended on RVeff.SV, not on RVEDV, at baseline. Increase in RVEDV correlated with increase in QRS duration over time (r=0.28, p=0.016), and with decrease in RV mass/EDV ratio over time (r=-0.42, p<0.001), not with decrease in peak VO2. In subgroup analysis, patients with larger RVs at baseline showed larger increase in PR during follow-up and larger decrease in NYHA class over time., Conclusions: In TOF patients with moderate RV dilatation, RVEDV increased by 1.6 ± 3.0 ml/m(2)/year, irrespective of RV size at baseline, but depended on RVeff.SV at baseline. Despite limited progression in RV size, unfavourable changes occurred during 5 years follow-up, which suggests there is a need for close follow-up., (© 2013.)

Background: Atrial enlargement may reflect ventricular diastolic dysfunction. Although patients with tetralogy of Fallot (TOF) have been studied extensively, little is known about atrial size and function. We assessed bi-atrial size and function in patients after TOF repair, and related them to biventricular systolic and diastolic function, and clinical parameters., Methods: 51 Patients (21 ± 8 years) and 30 healthy controls (31 ± 7 years) were included and underwent magnetic resonance imaging to assess bi-atrial and biventricular size, systolic and diastolic function. Patients also underwent exercise testing, and N-terminal prohormone brain natriuretic peptide (NT-proBNP) assessment., Results: In patients, right atrial (RA) minimal volume (34 ± 8 ml/m(2) vs. 28 ± 8 ml/m(2), p=0.001) and late emptying fraction were increased; RA early emptying fraction was decreased. Patients had longer right ventricular (RV) deceleration time (0.24 ± 0.10 vs. 0.13 ± 0.04, p<0.001), reflecting impaired RV relaxation, and larger RV volumes. Patients with end-diastolic forward flow (EDFF) had larger RA and RV size, abnormal RA emptying, higher NT-proBNP levels, higher VE/VCO2 slope (ventilatory response to carbon dioxide production), and the most abnormal LV diastolic function (impaired compliance). Patients with abnormal RA emptying (reservoir function <30% and pump function >24%) had higher NT-proBNP levels and worse exercise capacity. RA minimal volume was associated with RV end-diastolic volume (r=0.35, p=0.013)., Conclusions: In TOF patients with moderate RV dilatation, abnormal bi-atrial function and biventricular diastolic dysfunction are common. Abnormal RA emptying was associated with signs of impaired clinical condition, as was the presence of EDFF. These parameters, together with RA enlargement, could serve as useful markers for clinically relevant RV diastolic dysfunction., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: We hypothesized 1) that long-term ventricular outcome and exercise capacity would be better in patients with isolated pulmonary valve stenosis (PS) treated with balloon pulmonary valvuloplasty (BPV) than in patients operated for tetralogy of Fallot (TOF), and 2) that ventricular outcome and exercise capacity would not be different in PS patients and healthy controls., Methods: We included 21 PS patients after BPV (16.2 ± 5.2 years) and 21 patients operated for TOF (16.6 ± 5.6 years), matching them for gender, age at treatment, and age at study. Patients underwent cardiovascular magnetic resonance (CMR) imaging, exercise testing, 12-lead ECG and 24-hour Holter monitoring for assessment of right ventricular (RV) size and function, pulmonary regurgitation (PR), exercise capacity and electrocardiographic status. Healthy controls for CMR imaging and exercise testing were matched for gender and age at study., Results: RV volumes and PR percentage were significantly larger in TOF patients than in PS patients; biventricular ejection fraction (EF) was not different. PR was mild in most PS patients. RV end-systolic volume was significantly larger in PS patients than in healthy controls; RVEF was significantly lower. Both patient groups had similar exercise test results. Peak workload and VO(2) max. were significantly lower in PS patients than in healthy controls., Conclusions: Longstanding mild PR in PS patients can lead to an enlarged RV, reduced RV function and reduced exercise capacity. Despite more PR and larger RV volumes in TOF patients, exercise capacity and biventricular function are similar in both patient groups., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aims The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients. Methods and results In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress − parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan–Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5–34.0), age at TOF repair 0.9 years (0.6–2.1)]. After a median follow-up of 8.6 years (6.7–14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P  = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (−17 ± 15 vs. −26 ± 13 %, P  = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5–43.7; P  = 0.001) as predictor for the composite endpoint. Conclusion An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF. [ABSTRACT FROM AUTHOR]

Aims To evaluate the additional value of dobutamine stress testing in patients with repaired tetralogy of Fallot (TOF) by relating stress imaging parameters at baseline to relevant parameters of clinical condition and right ventricular (RV) size during a serial follow-up. Methods and results We prospectively included 27 patients (14 ± 4 years at baseline), who were studied twice with a 5-year interval. Patients underwent cardiovascular magnetic resonance imaging to assess RV systolic and diastolic function at rest and during dobutamine stress. Normal response to dobutamine was defined as a decrease in RV end-systolic volume, and a increase in RV ejection fraction (EF) during stress. Exercise testing and electrocardiography were performed to determine peak oxygen uptake (peak VO2), QRS duration, and QT interval corrected for heart rate (QTc) interval. RV volumes, QRS duration, and QTc interval increased significantly from baseline to follow-up; peak VO2 tended to decrease (95 ± 20–89 ± 14%, P = 0.086). Response to dobutamine was normal in 26 of 27 patients and remained stable during the follow-up [relative increase in RVEF during stress: +25 ± 9% (baseline) vs. +27 ± 10% (follow-up)]. A smaller relative increase in RVEF during stress at baseline related to a larger relative decrease in peak VO2 during the follow-up (r = 0.59, P = 0.004). No significant associations were found with the relative increase in QRS duration, QTc interval, or RV end-diastolic volume during a 5-year follow-up. Conclusion In a young TOF population, response to dobutamine stress was normal and remained stable during the 5-year follow-up. A smaller increase in RVEF during stress at baseline was predictive for a larger decrease in peak VO2 during the 5-year follow-up. [ABSTRACT FROM PUBLISHER]

Abstract: The population of adult survivors with tetralogy of Fallot (TOF) is growing over the last decades due to improvements in perinatal management, intensive care and surgical techniques. Pulmonary regurgitation (PR) plays a crucial role in the long-term outcome of these patients. Although PR may be tolerated well for many years, eventually it may lead to right ventricular (RV) dilatation, RV dysfunction, exercise intolerance, arrhythmia and sudden cardiac death. Cardiovascular magnetic resonance (CMR) imaging is an important tool in the follow-up of patients after TOF repair, because biventricular volumes and function and PR volume and fraction can be measured with great accuracy and reproducibility. CMR imaging studies have identified risk factors for late adverse outcomes in patients after TOF repair. These include increased RV end-diastolic volume (EDV), reduced left ventricular ejection fraction and abnormal RV outflow tract function. Other applications of CMR include stress imaging, assessment of diastolic function and late gadolinium enhancement, which have provided additional insight in the function of the RV. Timing of pulmonary valve replacement (PVR) is controversial and should balance between the preservation of RV function and the need for subsequent PVR surgery, since the life-span of a homograft is limited. Based on CMR imaging studies, PVR will be considered if the RVEDV reaches a threshold of between 150 and 200ml/m2 in the presence of severe PR. However, timing of PVR should be based on multiple factors, other than RV size and PR fraction alone. [Copyright &y& Elsevier]

An abstract of the conference paper "Bi-atrial function and its relation with biventricular function and clinical parameters in patients operated for tetralogy of fallot," by Saskia E. Luijnenburg and colleagues is presented.