Cardiotoxicity In Children Research Articles

Italian Society of Pediatric Cardiology (SICP) position paper on the prevention, diagnosis, treatment and follow-up of cardiotoxicity in pediatric patients with cancer

The survival of pediatric cancer patients has significantly increased thanks to the improvement of oncological treatments. Therefore, it is of utmost importance to manage short- and long-term cardiovascular complications. In pediatric cardio-oncology, there are no recognized guidelines as in adults. Several recommendations and many indications have been derived from the data obtained in the adult cancer population, resulting in greater discrepancies in the clinical management of patients. The aim of this position paper of the Italian Society of Pediatric Cardiology (SICP) is to collect the main evidence regarding the diagnosis, prevention, treatment and follow-up of cardiotoxicity in children, to provide useful indications for clinical practice, and to promote a network between pediatric centers.

Risk factors and survival outcomes in children with early cardiotoxicity after allogeneic hematopoietic stem cell transplantation.

Cardiotoxicity in children is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); therefore, early identification of risk factors can improve patient prognosis. However, there are few data on the clinical characteristics of early-stage cardiotoxicity in children after allo-HSCT. We conducted a retrospective single-center study of pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2016 and December 2022 at the Children's Hospital Affiliated with Chongqing Medical University to evaluate the clinical characteristics of early cardiac events (ECEs) after allo-HSCT and their impact on survival outcomes. We enrolled 444 patients who underwent allo-HSCT-304 males (68%) and 140 females (32%)-with a median age of 3.3years (1.8-6.5years) at transplantation. We found that 73 patients (16.4%) had ECEs after allo-HSCT. The ECEs included valvular disease (n = 46), pericardial effusion (n = 38), arrhythmia (n = 9), heart failure (n = 16), and dilated cardiomyopathy (n = 1). Female sex, age ≥ 6years, body mass index (BMI) < 16kg/m2 and HLA-type mismatches were risk factors for ECEs. We designed a stratified cardiac risk score that included these risk factors, and the higher the score was, the greater the cumulative incidence of ECEs. The occurrence of an ECE was closely associated with a lower overall survival (OS) rate and greater nonrelapse mortality (NRM). In addition, stratified analysis based on the number of combined ECEs showed that the greater the number of combined ECEs was, the more significant the negative impact on OS rates.

Circulating Biomarkers for Monitoring Chemotherapy-Induced Cardiotoxicity in Children.

Most commonly diagnosed cancer pathologies in the pediatric population comprise leukemias and cancers of the nervous system. The percentage of cancer survivors increased from approximatively 50% to 80% thanks to improvements in medical treatments and the introduction of new chemotherapies. However, as a consequence, heart disease has become the main cause of death in the children due to the cardiotoxicity induced by chemotherapy treatments. The use of different cardiovascular biomarkers, complementing data obtained from electrocardiogram, echocardiography cardiac imaging, and evaluation of clinical symptoms, is considered a routine in clinical diagnosis, prognosis, risk stratification, and differential diagnosis. Cardiac troponin and natriuretic peptides are the best-validated biomarkers broadly accepted in clinical practice for the diagnosis of acute coronary syndrome and heart failure, although many other biomarkers are used and several potential markers are currently under study and possibly will play a more prominent role in the future. Several studies have shown how the measurement of cardiac troponin (cTn) can be used for the early detection of heart damage in oncological patients treated with potentially cardiotoxic chemotherapeutic drugs. The advent of high sensitive methods (hs-cTnI or hs-cTnT) further improved the effectiveness of risk stratification and monitoring during treatment cycles.

Rate of Cardiotoxicity in Childhood Acute Lymphoblastic Leukemia Treated with Daunorubicin Using Echocardiography and Troponin I

Background and Aim: Acute lymphoblastic leukemia (ALL) is the commonest malignancy in childhood. Childhood ALL Survivors have a lifelong increased risk for cardiovascular morbidity and mortality compared to the general population, mainly caused by chemotherapy with daunorubicin. The aim of the study is to detect the rate of daunorubicin induced cardiotoxicity in children with acute lymphoblastic leukemia during induction phase chemotherapy. Meterials &amp; Methods : This prospective observational study was conducted in the department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU) on 40 newly diagnosed patients of ALL aged between 1 to17.9 years who got daunorubicin during induction. Complete blood count and echocardiography were done and troponin I was measured in all patients before and after completion of induction period. Result: Of the 40 patients, 8 patients (20%) had developed cardiotoxicity evidenced by reduction of left ventricular ejection fraction (LVEF) in echocardiography. Baseline LVEF was 68.80±5.98% which was then reduced to 65.32±7.07% after induction phase of chemotherapy (p=0.023). No significant alteration of troponin I was seen (P= 0.581) between baseline and after completion of induction. Total WBC count and hemoglobin had a significant difference (P&lt;0.05) between baseline and after induction period. Male patients had a greater risk of developing cardiotoxicity than females but statistically was not significant (P=0.643). There was no significant association between age of the patients and cardiotoxicity (P=0.112).Cardiotoxicity was seen higher in patient with initial high WBC count (p=0.039). Echocardiography also reveled increased tendency of mitral regurgitation and left ventricular hypertrophy after induction phase chemotherapy. Conclusion: This study showed the rate of cardiotoxicity was 20% in ALL patients treated with daunorubicin. It also found that LVEF was decreased during therapy.Echocardiography can be used to detect early cardiotoxicity induced by daunorubicin. University Heart Journal 2023; 19(1): 20-25

Acute and early-onset cardiotoxicity in children and adolescents with cancer: a systematic review

BackgroundCardiotoxicity is among the most important adverse effects of childhood cancer treatment. Anthracyclines, mitoxantrone and radiotherapy involving the heart are its main causes. Subclinical cardiac dysfunction may over time progress to clinical heart failure. The majority of previous studies have focused on late-onset cardiotoxicity. In this systematic review, we discuss the prevalence and risk factors for acute and early-onset cardiotoxicity in children and adolescents with cancer treated with anthracyclines, mitoxantrone or radiotherapy involving the heart.MethodsA literature search was performed within PubMed and reference lists of relevant studies. Studies were eligible if they reported on cardiotoxicity measured by clinical, echocardiographic and biochemical parameters routinely used in clinical practice during or within one year after the start of cancer treatment in ≥ 25 children and adolescents with cancer. Information about study population, treatment, outcomes of diagnostic tests used for cardiotoxicity assessment and risk factors was extracted and risk of bias was assessed.ResultsOur PubMed search yielded 3649 unique publications, 44 of which fulfilled the inclusion criteria. One additional study was identified by scanning the reference lists of relevant studies. In these 45 studies, acute and early-onset cardiotoxicity was studied in 7797 children and adolescents. Definitions of acute and early-onset cardiotoxicity prove to be highly heterogeneous. Prevalence rates varied for different cardiotoxicity definitions: systolic dysfunction (0.0–56.4%), diastolic dysfunction (30.0–100%), combinations of echocardiography and/or clinical parameters (0.0–38.1%), clinical symptoms (0.0–25.5%) and biomarker levels (0.0–37.5%). Shortening fraction and ejection fraction significantly decreased during treatment. Cumulative anthracycline dose proves to be an important risk factor.ConclusionsVarious definitions have been used to describe acute and early-onset cardiotoxicity due to childhood cancer treatment, complicating the establishment of its exact prevalence. Our findings underscore the importance of uniform international guidelines for the monitoring of cardiac function during and shortly after childhood cancer treatment.

Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Cardiotoxicity in children with cancer treated with anthracyclines: A position statement on dexrazoxane.

Cardiovascular disease is the leading cause of non-malignant morbidity and mortality in childhood cancer survivors (CCSs). Anthracyclines are included in many treatment regimens for paediatric cancer, but unfortunately, these compounds are cardiotoxic. One in 10 CCSs who has received an anthracycline will develop a symptomatic cardiac event over time. Given the crucial need to mitigate anthracycline-related cardiotoxicity (ARC), the authors critically examined published data to identify effective cardioprotective strategies. Based on their expert analysis of contemporary literature data, it was concluded that consideration should be given for routine use of dexrazoxane in children with cancer who are at risk of ARC.

Assessment of left heart dysfunction to predict doxorubicin cardiotoxicity in children with lymphoma.

The objectives of this study were to assess the changes in the left myocardial function after chemotherapy for childhood lymphoma and observe the predictive or monitor value for cancer treatment-related cardiac dysfunction (CTRCD) by speckle-tracking echocardiography. A total of 23 children with histopathological diagnoses of lymphoma were included, with age-matched normal controls. Comparative analysis of clinical serological tests and left heart strain parameters in children with lymphoma, including left ventricular global longitudinal strain (LVGLS); global myocardial work (GMW) indices, which include global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency; and the LS of subendocardial, middle, and subepicardial layer myocardium during left ventricular systole were measured: left atrial strain of reservoir phase (LASr), left atrial strain of conduit phase (LAScd), and left atrial strain of contraction phase (LASct). One-way ANOVA showed that GLS, GWI, GCW, LASr, and LAScd were closely associated with CTRCD and multivariate logistic regression analysis showed that GLS was the most sensitive predictor for detecting patients at lofty risk of anthracycline-related cardiotoxicity. Both before and after chemotherapy, GLS in the left ventricle showed a pattern of basal segment < middle segment < apical segment and subepicardial < middle < subendocardial layer (p < 0.05), and the degree of decrease also showed a regular pattern of epicardial layer < middle layer < subendocardial layer while the difference was not significant (p > 0.05). After chemotherapy, maximum flow rate in early mitral relaxation/left atrial systolic maximum flow rate (E/A) and left atrial volume index of each group were in the normal range, and the values of LASr, LAScd, and LASct slightly increased in the second cycle and decreased significantly in the fourth cycle after chemotherapy, reaching the lowest level; LASr and LAScd were positively correlated with GLS. LVGLS is a more sensitive and earlier indicator to predict CTRCD compared with conventional echocardiography-related parameters and serological markers, and GLS of each myocardial layer showed a certain regularity. Left atrial strain can be used for early monitoring of cardiotoxicity in children with lymphoma after chemotherapy.

Cardioprotective effects of deferoxamine in acute and subacute cardiotoxicities of doxorubicin: a randomized clinical trial

BackgroundCardiotoxicity is a major concern following doxorubicin (DOX) use in the treatment of malignancies. We aimed to investigate whether deferoxamine (DFO) can prevent acute cardiotoxicity in children with cancer who were treated with DOX as part of their chemotherapy.ResultsSixty-two newly-diagnosed pediatric cancer patients aged 2–18 years with DOX as part of their treatment regimens were assigned to three groups: group 1 (no intervention, n = 21), group II (Deferoxamine (DFO) 10 times DOX dose, n = 20), and group III (DFO 50 mg/kg, n = 21). Patients in the intervention groups were pretreated with DFO 8-h intravenous infusion in each chemotherapy course during and after completion of DOX infusion. Conventional and tissue Doppler echocardiography, serum concentrations of human brain natriuretic peptide (BNP), and cardiac troponin I (cTnI) were checked after the last course of chemotherapy.Sixty patients were analyzed. The level of cTnI was < 0.01 in all patients. Serum BNP was significantly lower in group 3 compared to control subjects (P = 0.036). No significant differences were observed in the parameters of Doppler echocardiography. Significant lower values of tissue Doppler late diastolic velocity at the lateral annulus of the tricuspid valve were noticed in group 3 in comparison with controls. By using Pearson analysis, tissue Doppler systolic velocity of the septum showed a marginally significant negative correlation with DOX dose (P = 0.05, r = − 0.308). No adverse effect was reported in the intervention groups.ConclusionsHigh-dose DFO (50 mg/kg) may serve as a promising cardioprotective agent at least at the molecular level in cancer patients treated with DOX. Further multicenter trials with longer follow-ups are needed to investigate its protective role in delayed DOX-induced cardiac damage.Trial registration IRCT, IRCT2016080615666N5. Registered 6 September 2016, http://www.irct.ir/IRCT2016080615666N5.

Abstract 9749: Anthracicline-Induced Cardiotoxicity in Children. Pharmacogenetics and Clinical Study at a Tertiary Center

Introduction: Children and adolescents treated with anthracyclines are at increased risk of developing cardiomyopathy. Although several guidelines are available, no consensus exists on an optimal strategy scheme for predict or avoid anthracycline-induced cardiotoxicity. Methods: Cardiotoxicity was defined as a reduction in left ventricle ejection fraction &gt;10% from baseline and &lt;53%, and/or global longitudinal strain drop of &gt;15%.The incidence of cardiotoxicity, its relation with cumulative anthracycline doses, clinical significance and reversibility were retrospectively evaluated in a paediatric population (0-18 years) treated with anthracycline at a tertiary hospital (2010-2020). Analysis of 3 genetic polymorphisms related to cardiotoxicity (RARG (rs2229774), SLC28A3(rs7853758) and UGT1A6(rs17863783)) was performed. Results: A total of 84 patients (45 males) were included. The mean age at diagnosis was 10.7± 3.8 years with average cumulative anthracycline dose 195 mg/m2 (60-460mg/m2). Median follow-up was 5 years. Anthracycline-induced cardiotoxicity occurred in 12 (14,2%) of treated patients, 75% were asymptomatic. 5 patients experimented acute cardiotoxicity during treatment. 8 patients were treated with ACE-inhibitors and/or beta-blockers. 11 patients had full function recovery. Cumulative doxorubicin dose was a risk factor of cardiotoxicity, being affected 9/20 treated with &gt;250 mg/m2; 3/51 treated with 100-250m2; while no patient out of 13 receiving &lt;100 mg/m2 had an abnormal echocardiogram (P &lt;0.01). A higher percentage of patients treated with mediastinum radiation and chemotherapy (3/7:42%) presented cardiotoxicity compared to those with chemotherapy only (9/77:9%) (p0.09). Younger age, female sex or the presence of genetic polymorphisms studied were not statistically significant risk factors. Conclusions: Dose-dependent anthracycline risk for developing cardiomyopathy was confirmed. However, previously identified risk factors including female sex, early age at diagnosis and genetic polymorphism were not replicated in this population, possibly due to the small sample size and the relatively short follow-up period. A tailored monitoring strategy based on cardiac risk stratification is needed.

Cardio-Oncology in Childhood: State of the Art.

Cardio-oncology is an increasingly important field of cardiology that focuses on the detection, monitoring, and treatment of cardiovascular disease (CVD) occurring during and after oncological treatments. The survival rate for childhood cancer patients has dramatically increased thanks to new treatment protocols and cardiovascular (CV) sequelae represent the third most frequent cause of mortality in surviving patients. This study aims to provide a complete and updated review of all the main aspects of cardio-oncology in childhood and to highlight the critical issues. The problem of CV complications in childhood cancer survivors raises the need to make an early diagnosis of cardiotoxicity by the new imaging and laboratory techniques in order to intervene promptly and to implement pharmacological strategies and lifestyle changes to reduce or even to prevent cardiac injury. Furthermore, a stratification of CV risk, also including new predisposing factors such as the presence of some genetic mutations, is of paramount importance before undertaking oncological treatments. Besides, a systematic and personalized planning of long-term follow-up is fundamental to ensure a transition from pediatric to adult hospital and to avoid missed or late diagnosis of cardiomyopathy. We reviewed the main risk factors for cardiotoxicity in children, both traditional and emerging ones: the mechanisms of toxicity of both old and new antineoplastic therapies, the techniques for detecting cardiac damage, and the current evidence regarding pharmacological cardioprotection. At the end, we focused our attention on the existing guidelines and strategies about the long-term follow-up of childhood cancer survivors.

Impact of single-nucleotide variants and nutritional status on population pharmacokinetics of Doxorubicin, and its effect on cardiotoxicity in children with leukemia.

Doxorubicin is an important antineoplastic agent with wide interindividual variability in response to treatment and in its cardiotoxic effects. To determine the effect of genotypic status of three single-nucleotide variants in ABCC1, NCF4, and CBR3 genes and nutritional status assessed by body mass index, on the population pharmacokinetics of Doxorubicin and its cardiotoxic effects in pediatric patients with leukemia. Seventy pediatric patients treated with Doxorubicin were studied, in which 189 biological samples were obtained to determine Doxorubicin concentrations (1 to 3 samples per patient) at different times, for 20 h. Low body mass index and age ≤ 7 years were associated with decreased clearance of Doxorubicin, and female gender was associated with increased clearance of Doxorubicin. Low BMI and low height were associated with a decrease and increase, respectively, in the intercompartmental clearance (Q) of Doxorubicin. TT homozygosity of the single-nucleotide variant rs3743527 of the ABCC1 gene was associated with an increase in clearance and decreased area under the curve, AA homozygosity of the single-nucleotide variant rs1883112 of the NCF4 gene was associated with a decrease in the volume of distribution in the peripheral compartment (V2), and GG homozygosity of CBR3 rs1056892 with increasing area under the curve. Some covariates studied are directly related to the increase or decrease of the pharmacokinetic parameters of Doxorubicin. Decreased clearance, V2, and increased area under the curve were associated with systolic dysfunction, and decreased Q and V2 were associated with diastolic dysfunction. These results may contribute to the effective and safe use of Doxorubicin in pediatric patients with leukemia.

Development and Validation of a Diagnostic Nomogram to Predict the Anthracycline-Induced Early Cardiotoxicity in Children with Hematological Tumors

This study aimed to establish and validate an effective nomogram to predict the risk of cardiotoxicity in children after each anthracycline treatment. According to the inclusion and exclusion criteria, the eligible children were randomly divided into the training cohort (75%) and the validation cohort (25%). Least absolute shrinkage and selection operator (LASSO) regression was used to select the predictors and a nomogram was developed. Then, concordance index (C-index), the area under the curve (AUC), Hosmer–Lemeshow (H–L) test, and decision curve analysis (DCA) were employed to evaluate the performance and clinical utility of nomogram. Internal validation was processed to inspect the stability of the model. A total of 796 eligible children were included in this study and divided into a training set (n = 597) and a validation set (n = 199). LASSO regression analysis revealed that cumulative anthracycline dose, ejection fractions, NT-proBNP, and diastolic dysfunction were effective predictors of cardiotoxicity. The nomogram was established based on these variables. The C-index and the AUC of the predicting nomogram were 0.818 in the training cohort and 0.773 in the validation cohort, suggesting that the nomogram had good discrimination. The calibration curve of the nomogram presented no significant deviation from the reference line, and the P-value of the H–L test was 0.283, implying a preferable degree of calibration. The threshold of DCA also reflects that the nomogram is clinically useful. A nomogram was developed to predict anthracycline chemotherapy-induced cardiotoxicity in children with hematological tumors. The nomogram has a good prediction effect and can provide a reference for clinicians’ diagnosis and treatment.

Myocardial Deformation Imaging by Speckle-Tracking Echocardiography for Assessment of Cardiotoxicity in Children during and after Chemotherapy: A Systematic Review and Meta-Analysis

Children with cancer and childhood cancer survivors (CCS) are at risk for developing chemotherapy-induced cardiomyopathy. Myocardial deformation imaging has shown potential in the early detection of subclinical myocardial damage with implications on therapeutic interventions and improvement of outcomes. The aim of this study was to perform a systemic review and meta-analysis of literature on the assessment of left ventricular and right ventricular myocardial deformation by speckle-tracking echocardiography at rest and during stress in children with cancer during and in survivors after chemotherapy. A systematic review was performed through searching MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials, and Scopus. Search hedges were created to cover the concepts of childhood cancer, chemotherapy, radiotherapy, anthracycline, cardiotoxicity, speckle-tracking, myocardial strain, and myocardial deformation. Two independent investigators reviewed the eligibility of articles for inclusion. The weighted mean difference in ventricular strain between pre- and postchemotherapy treatment and that between long-term CCS and healthy subjects were estimated using random-effect models with 95% CIs. Heterogeneity and publication bias were assessed using I2 statistics and the Egger test, respectively. Of the total of 8,703 records initially identified, 42 studies with a total of 5,430 children with cancer were included. Of these 42 studies that showed heterogeneities, nine assessed early myocardial injury during chemotherapy, 30 assessed late myocardial injury after chemotherapy with no publication bias, and three studied myocardial mechanics during stress. The main findings were as follows: (1) left ventricular systolic deformation is impaired in children with cancer during the initial treatment phase and among long-term CCS, while data on changes in right ventricular deformation are limited and inconclusive; (2) the predictive value of early reduction of myocardial strain imaging in forecasting subsequent development of cardiotoxicity is unknown, as it has not been studied; (3) limited data suggest the possibility of impaired left ventricular contractile mechanics during stress in CCS; and (4) cumulative anthracycline dose and chest-directed radiotherapy are consistently identified as factors associated with impaired myocardial deformation. Myocardial strain imaging by speckle-tracking echocardiography unveils early evidence of myocardial injury in children with cancer and long-term CCS. To support its adoption for clinical use, more data are required for the better understating of myocardial deformation parameters in the risk stratification of children with cancer and prediction of development of cardiomyopathy among CCS.

Omega 3 fatty acids can reduce early doxorubicin‐induced cardiotoxicity in children with acute lymphoblastic leukemia

Omega 3 polyunsaturated fatty acids are dietary factors with several beneficial cardiovascular effects. This study aimed to assess the possible protective effect of omega 3 fatty acids on early doxorubicin-induced cardiac toxicity in children with acute lymphoblastic leukemia (ALL). Sixty children of newly diagnosed ALL were randomized into two groups: group I (n=30) who received omega 3 fatty acids 1000mg/day for 6months in addition to their usual protocol of chemotherapy including doxorubicin; and group II (n=30) who received their usual doxorubicin protocol during the period from February 2020 till August 2021. Echocardiographic examinations were performed before and after the treatment. Glutathione, malondialdehyde (MDA), superoxide dismutase (SOD), troponin I, creatine kinase MB (CK-MB), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured also before and after omega 3 treatment. After 6months of omega 3 administration, group I had a significantly lower MDA level and a significantly higher glutathione and SOD levels than group II. Similarly, the levels of troponin I, CK-MB, and NT-proBNP were significantly high in group II, whereas they were unchanged in group I after treatment. Similarly, systolic function (presented with peak mitral annular systolic velocity and two-dimensional global longitudinal strain) of the heart was preserved in omega 3-treated patients, unlike the control group that showed significant impairment of left ventricular function after 6months. Omega 3 fatty acids may decrease early cardiac injury and doxorubicin-induced cardiotoxicity in children with ALL.

Anthracycline Treatment and Left Atrial Function in Children: A Real-Time 3-Dimensional Echocardiographic Study

Anthracycline (AC) therapy is associated with left ventricular (LV) dysfunction. Left atrial (LA) size and function are used to assess LV diastolic function in heart failure in adults. Data on LA size and function following AC therapy in children is limited. We hypothesized that LA size and function will be abnormal in children following AC chemotherapy. This retrospective review included patients who received AC for pediatric cancers. Controls had normal echocardiograms performed for evaluation of chest pain, murmur, or syncope. Real-time three-dimensional echocardiography was performed to evaluate LA reservoir, conduit, and booster pump function parameters. In addition to LA volume data, LV shortening fraction, spectral and tissue Doppler variables assessing diastolic function as well as myocardial performance index was obtained. Groups with and without AC therapy were compared by student t-test and chi-square test. We evaluated 136 patients, 55 (40.4%) had received AC. There was no significant difference between the groups in LV shortening fraction, diastolic as well as global function indices. LA reservoir and conduit function parameters were significantly lower in AC group compared to controls. The booster function parameters showed variable results. It is intriguing that AC-treated children have smaller LA reservoir and abnormal booster function. We speculate that these findings may reflect early changes in LA compliance associated with AC exposure. Assessment of LA volumes and function as prognostic markers of AC-induced cardiotoxicity in children is warranted.

Evaluation of Cardiotoxic Effects of Anthracyclines by Tissue Doppler Imaging in Survivors of Childhood Cancer.

Background:Childhood cancer survivors (CCSs) are at risk for anthracycline-induced cardiotoxicity which tends to be more prominent long after completion of the chemotherapy. The aim of this study was to examine echocardiographic parameters of anthracycline-induced subclinical cardiotoxicity in children who had received chemotherapy.Materials and Methods:A cross-sectional single-center study was conducted in a tertiary level university hospital in Eskisehir, Turkey. A total of 50 CCSs and 40 healthy peers were included. The CCSs were divided into 3 subgroups according to cumulative anthracycline dose (100-200 mg/m2, 201-299 mg/m2, and ≥ 300 mg/m2). Biventricular cardiac examination was performed with conventional echocardiography and tissue Doppler echocardiography imaging (TDI).Results:The mean duration from termination of chemotherapy to echocardiographic assessment was 3.9 ± 2.2 years. The mean age of the CCSs was 11.6 ± 3.9 years. TDI-derived mitral annular isovolumetric relaxation time (IVRT) and myocardial performance index (MPI) were higher in the high-dose group of CCSs than in controls (P = .006, P = .007, P < .001, P = .0014, respectively). IVRT was also higher in patients with ≥ 300 mg/m2 cumulative dose than in those with < 200 mg/m2 (P = .007). TDI-derived mitral annular MPI and IVRT were significantly associated with cumulative anthracycline dose (r = 0.288, P = .006, r = 0.340, P = .001).Conclusion:A cumulative anthracycline dose > 300 mg/m2 may lead to subclinical cardiotoxicity, and is therefore a potential risk factor for late onset cardiac failure. TDI-derived MPI can be a sensitive tool to reveal subtle signs of myocardial damage, which may facilitate implementation of preventive therapies for patients suspected to be at risk.

Early-onset Cardiotoxicity assessment related to anthracycline in children with leukemia. A Prospective Study.

Background: Acute leukemias are the most frequent malignancies in children. Advances in treatment have improved the overall survival to 80%. Almost 10% of children with cancer develop clinical cardiac toxicity. Total anthracycline cumulative dose is a risk factor for early-onset cardiotoxicity.Objective: To describe the incidence of early-onset cardiotoxicity in children with acute leukemia treated with chemotherapy.Methods: A prospective descriptive study of patients >1 y and <18 years diagnosed with acute leukemia. Assessed with electrocardiograma, echocardiography, and blood biomarkers at diagnosis and during the follow-up.Results: 94 patients with acute lymphoblastic leukemia and 18 with acute myeloid leukemia were included. 20 patients (17.9%) developed early-onset cardiotoxicity. Statistically significant data was seen after anthracycline dose >150 mg/m2, between the first echocardiographic evaluation and posterior analyses in the left ventricular fraction ejection with Teicholz p 0.05, Simpson p 0.018 and GLS p 0.004. In this study, there was no relation between blood biomarkers and cardiotoxicity.Conclusions: Cancer therapeutic-related cardiac dysfunction is related to anthracycline cumulative dose. In this study, echocardiographic follow-up was useful to predict risk factors for early cardiac dysfunction.

Early surveillance of anthracycline induced cardiotoxicity in children using echocardiography and biomarkers: A prospective study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CIHR Background Anthracyclines, which are commonly used in cancer treatment can induce myocardial damage, result in heart failure during treatment and have cardiac effects even decades after treatment. Monitoring of cardiotoxicity during treatment is largely based on the use of echocardiographic functional markers like ejection fraction and more recently myocardial strain imaging. Some studies have also looked at the utility of biomarkers like troponin and BNP. The utility of this surveillance strategy remains controversial as larger prospective studies are lacking. Purpose The aim of this study was to prospectively describe the impact of anthracycline treatment on echocardiographic functional parameters and cardiac biomarkers (high sensitivity troponin T and NT-Pro BNP) during the treatment period and twelve months after completion of treatment. In the current study we wanted to look at whether monitoring parameters during treatment were predictive of left ventricular function 12 months after treatment. Methods This was a prospective multi-centre nested case-control study of 256 children diagnosed with cancer requiring anthracycline therapy. Baseline functional echocardiographic parameters and cardiac biomarkers were obtained prior to starting anthracycline therapy, during the treatment protocol, and 12 months after treatment completion. Patients were assigned to one of two comparison groups based on the fractional shortening at the12-month echocardiogram: patients in group 1 had normal fractional shortening, (FS ³ 28%) while patients in group 2 had reduced fractional shortening (FS &amp;lt; 28%). Results A total of 917 echoes were performed, 376 of these occurred during the treatment period. FS was reduced in 27 (7%) of echoes obtained during the treatment period with 22 patients developing new onset dysfunction. Twelve months after treatment completion 232 patients had normal FS (Group 1), while 24 patients showed reduced FS (Group 2). Both groups had normal systolic function and cardiac biomarkers at baseline, however patients in group 2 were older at diagnosis (13.2 years (11.8-16) vs 6.5 years (3.4-13.2), p = 0.003) and received a higher cumulative anthracycline dose (200 mg/m2 (143-318) vs 125 mg/m2 (75-200), p= 0.005). One third (8/24) of patients in group 2 had at least 1 abnormal echo during the treatment period compared to 7% (16/232) in the normal group P &amp;lt; 0.001. The proportion of patients with at least one abnormal biomarker during this period however, was similar between groups. Conclusion(s) Patients receiving higher accumulative anthracycline doses and those with abnormal FS during the treatment period are at higher risk of having reduced cardiac function 12 months after treatment. High sensitivity troponin and NT-Pro BNP levels during the treatment period fail to discriminate patients at risk of developing early reduced systolic function. The relationship of these early results to long term cardiac function remains to be demonstrated.

Cardiac biomarkers for the detection of cardiotoxicity in childhood cancer-a meta-analysis.

AimsChildhood cancer therapy is associated with a significant risk of therapy‐related cardiotoxicity. This meta‐analysis aims to evaluate cardiac biomarkers for the detection of cancer therapy‐related left ventricular (LV) dysfunction in childhood cancer patients.Methods and resultsPubMed, Cochrane Library, Wiley Library, and Web of Science were screened for studies investigating brain natriuretic peptide (BNP)/N‐terminal proBNP (NT‐proBNP) or cardiac troponin in childhood cancer patients. The odds ratios (OR) for elevation of cardiac biomarkers and association with LV dysfunction were calculated using a random‐effects model. Data from 27 studies with 1651 subjects were included. BNP/NT‐proBNP levels were higher post‐treatment compared with controls or pre‐treatment values [standardized mean difference = 1.0; 95% confidence interval (CI) = 0.6–1.4; n = 320; P < 0.001]. LV dysfunction was present in 11.76% of included patients, and risk for LV dysfunction was increased in patients with elevated BNP/NT‐proBNP (OR = 7.1; 95% CI = 2.0–25.5; n = 350; P = 0.003). The sensitivity of BNP/NT‐proBNP for the detection of LV dysfunction was 33.3%, and the specificity was 91.5%. Sensitivity increased when selecting for studies that assessed patients < 5 years after anthracycline exposure and for studies including high cumulative anthracycline doses. Anthracycline chemotherapy was associated with an increased frequency of elevated troponin (OR = 3.7; 95% CI = 2.1–6.5; n = 348; P < 0.001). The available evidence on the association between elevated troponin and LV dysfunction was insufficient for an adequate analysis. In five included studies, the frequency of LV dysfunction was not increased in patients with elevated troponin (OR = 2.5; 95% CI = 0.5–13.2; n = 179; P = 0.53).ConclusionsBNP/NT‐proBNP is associated with cardiotoxicity in paediatric cancer patients receiving anthracycline therapy, but owing to low sensitivity, BNP/NT‐proBNP has to be evaluated in the context of further parameters including clinical assessment and echocardiography. Future studies are needed to determine whether troponin serves as a marker for cardiotoxicity in children. Standardized recommendations for the application of cardiac biomarkers in children undergoing cardiotoxic cancer therapy may benefit management and clinical outcome.