BACKGROUND Childhood cancer survivors (CCS) are at risk for cardiotoxicity.OBJECTIVES We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by... Show moreBACKGROUND Childhood cancer survivors (CCS) are at risk for cardiotoxicity.OBJECTIVES We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors.METHODS This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397 $5-year CCS and 277 siblings. Of CCS, n = 1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n = 143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression.RESULTS CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as < 52% in men, < 54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunction grade $II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors.CONCLUSIONS Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among longterm CCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained risk of cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATER study; NTR7481) (J Am Coll Cardiol CardioOnc 2023;5:472-485) (c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). Show less
Background: Anthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential car-diotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine... Show moreBackground: Anthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential car-diotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine-treated >5-year child-hood cancer survivors (CCS). Methods and results: We cross-sectionally compared echocardiograms of 101 vincristine-treated CCS (median age 35 years [range: 17-53], median vincristine dose 63 mg/m2) from the national Dutch Childhood Cancer Survivor Study, LATER cohort, to 101 age-and sex-matched controls. CCS treated with anthracyclines, radiotherapy involving the heart region, cyclophosphamide or ifosfamide were excluded. Twelve CCS (14%) versus four controls (4%; p 0.034) had a decreased left ventricular ejection fraction (LVEF; men <52%, women <54%). Mean LVEF was 58.4% versus 59.7% (p 0.050). Global longitudinal strain (GLS) was abnormal in nineteen (24%) CCS versus eight controls (9%; p 0.011). Mean GLS was 19.0% versus 20.1% (p 0.001). No >= grade 2 diastolic dysfunction was detected. In multivariable logistic regression analysis CCS had higher risk of abnormal GLS (OR 3.55, p 0.012), but not abnormal LVEF (OR 3.07, p 0.065), than controls. Blood pressure and smoking history contributed to variation in LVEF, whereas obesity and diastolic blood pressure contributed to variation in GLS. Cumulative vincristine dose was not associated with either abnormal LVEF or abnormal GLS in multivariable models corrected for age and sex (OR per 50 mg/m2: 0.88, p 0.85 and 1.14, p 0.82, respectively). Conclusions: Vincristine-treated long-term CCS showed an abnormal GLS more frequently than controls. Their risk for future clinical cardiac events and the role of risk factor modification should be further elucidated. Show less
Background: Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term... Show moreBackground: Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results: We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction >= 53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions: We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy. Show less
Merkx, R.; Leerink, J.M.; Feijen, E.A.M.; Kremer, L.C.M.; Baat, E.C. de; Bellersen, L.; ... ; Dutch LATER Study Grp 2021
Background Cardiotoxicity is a well-known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation... Show moreBackground Cardiotoxicity is a well-known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation of echocardiographic measurements for early identification of CCS at highest risk of developing heart failure. This paper describes the design, feasibility, and reproducibility of the echocardiography protocol.Methods Echocardiograms from CCS and sibling controls were prospectively obtained at the participating centers and centrally analyzed. We describe the image acquisition, measurement protocol, and software-specific considerations for myocardial strain analyses. We report the feasibility of the primary outcomes of systolic and diastolic function, as well as reproducibility analyses in 30 subjects.Results We obtained 1,679 echocardiograms. Biplane ejection fraction (LVEF) measurement was feasible in 91% and 96% of CCS and siblings, respectively, global longitudinal strain (GLS) in 80% and 91%, global circumferential strain (GCS) in 86% and 89%, and >= 2 diastolic function parameters in 99% and 100%, right ventricle free wall strain (RVFWS) in 57% and 65%, and left atrial reservoir strain (LASr) in 72% and 79%. Intra-class correlation coefficients for inter-observer variability were 0.85 for LVEF, 0.76 for GLS, 0.70 for GCS, 0.89 for RVFWS and 0.89 for LASr. Intra-class correlation coefficients for intra-observer variability were 0.87 for LVEF, 0.82 for GLS, 0.82 for GCS, 0.85 for RVFWS and 0.79 for LASr.Conclusion The DCCSS LATER 2 CARD study includes a protocolized echocardiogram, with feasible and reproducible primary outcome measurements. This ensures high-quality outcome data for prevalence estimates and for reliable comparison of cardiac function parameters. 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
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
Bosch, E. van den; Cuypers, J.A.A.E.; Luijnenburg, S.E.; Duppen, N.; Boersma, E.; Budde, R.P.J.; ... ; Helbing, W.A. 2020
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... Show moreAims 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 mu g/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= [(parameter(stress) - parameterrest)/parameter(rest)] * 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. 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
Leerink, J.M.; Feijen, E.L.A.M.; Pal, H.J.H. van der; Kok, W.E.M.; Mavinkurve-Groothuis, A.M.C.; Kapusta, L.; ... ; LATER Study Grp 2020
Background Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and... Show moreBackground Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure.Objective To describe the methodology of the Dutch LATER cardiology study (LATER CARD).Methods The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings.Conclusions The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure. 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
Objective To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS)... Show moreObjective To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines. Methods We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, Results Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63-125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions. Conclusions In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted. Show less
Geerdink, L.M.; Delhaas, T.; Helbing, W.A.; Sarvaas, G.J.D.; Heide, H. ter; Rozendaal, L.; ... ; Kapusta, L. 2018
