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Contains fulltext : 291299.pdf (Publisher’s version ) (Open Access) With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8-17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs'), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33-42). TAPSE and fRVs' were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36-58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, p

Aims We aim to assess changes in routine echocardiographic and longitudinal strain parameters in patients recovering from Coronavirus disease 2019 during hospitalization and at 3-month follow-up. Methods and results Routine comprehensive echocardiography and STE of both ventricles were performed during hospitalization for acute coronavirus disease 2019 (COVID-19) infection as part of a prospective pre-designed protocol and compared with echocardiography performed ∼3 months after recovery in 80 patients, using a similar protocol. Significantly improved right ventricle (RV) fractional area change, longer pulmonary acceleration time, lower right atrial pressure, and smaller RV end-diastolic and end-systolic area were observed at the recovery assessment (P < 0.05 for all). RV global longitudinal strain improved at the follow-up evaluation (23.2 ± 5 vs. 21.7 ± 4, P = 0.03), mostly due to improvement in septal segments. Only eight (10%) patients recovering from COVID-19 infection had abnormal ejection fraction (EF) at follow-up. However, LV related routine (E, E/e′, stroke volume, LV size), or STE parameters did not change significantly from the assessment during hospitalization. A significant proportion [36 (45%)] of patients had some deterioration of longitudinal strain at follow-up, and 20 patients (25%) still had abnormal LV STE ∼3 months after COVID-19 acute infection. Conclusion In patients previously discharged from hospitalization due to COVID-19 infection, RV routine echocardiographic and RV STE parameters improve significantly concurrently with improved RV haemodynamics. In contrast, a quarter of patients still have LV systolic dysfunction based on STE cut-offs. Moreover, LV STE does not improve significantly, implying subclinical LV dysfunction may be part and parcel of recovering from COVID-19 infection., Graphical Abstract Graphical Abstract

Contains fulltext : 235000.pdf (Publisher’s version ) (Open Access) 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 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.

Purpose Echocardiographic surveillance for asymptomatic left ventricular systolic dysfunction (ALVSD) is advised in childhood cancer survivors (CCS), because of their risk of heart failure after anthracycline treatment. ALVSD can be assessed with different echocardiographic parameters. We systematically reviewed the prevalence and risk factors of late ALVSD, as defined by contemporary and more traditional echocardiographic parameters. Methods We searched databases from 2001 to 2020 for studies on ≥ 100 asymptomatic 5-year CCS treated with anthracyclines, with or without radiotherapy involving the heart region. Outcomes of interest were prevalence of ALVSD—measured with volumetric methods (ejection fraction; LVEF), myocardial strain, or linear methods (fractional shortening; FS)—and its risk factors from multivariable analyses. Results Eleven included studies represented 3840 CCS. All studies had methodological limitations. An LVEF < 50% was observed in three studies in 1–6% of CCS, and reduced global longitudinal strain (GLS) was reported in three studies in 9–30% of CCS, both after a median follow-up of 9 to 23 years. GLS was abnormal in 20–28% of subjects with normal LVEF. Abnormal FS was reported in six studies in 0.3–30% of CCS, defined with various cut-off values (< 25 to < 30%), at a median follow-up of 10 to 18 years. Across echocardiographic parameters, reported risk factors were cumulative anthracycline dose and radiotherapy involving the heart region, with no ‘safe’ dose for ALVSD. Conclusions GLS identifies higher prevalence of ALVSD in anthracycline-treated CCS, than LVEF. Implications for Cancer Survivors The diagnostic and prognostic value of GLS should be evaluated within large cohorts. Protocol registration PROSPERO CRD42019126588

Item does not contain fulltext BACKGROUND: Diastolic dysfunction is a common finding in patients receiving cancer therapy. This study evaluated the correlation of diastolic strain slope (Dss) with routine echocardiography diastolic parameters and its role in early detection of systolic dysfunction and cardiovascular (CV) mortality within this population. METHODS: Data were collected from the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling adult patient receiving cancer therapy. All patients performed at least three echocardiography exams (T1, T2, T3), including left ventricle Global Longitudinal Strain (LV GLS) and Dss. Systolic dysfunction was determined by either LV GLS relative reduction of ≥ 15% or LV ejection fraction reduction > 10% to

Background: Due to the improved survival rates of children and adolescents with congenital heart disease (CHD), more attention is now being directed towards their health-related quality of life (HRQoL), emotional and behavioral problems. Ebstein anomaly (EA) is a rare CHD with a broad clinical spectrum. The aim of the current study is to evaluate self- and proxy-reported HRQoL and emotional and behavioral problems in children and adolescents with EA. Methods: In this cross-sectional, multicenter study, we included EA patients (aged 8-17 years), who underwent routine clinical assessments in Dutch university hospitals between May 2017 and March 2019. The Generic Pediatric Quality of Life Inventory 4.0 (for ages 8-12/13-17 years) was used to assess HRQoL. The Child Behavior Checklist, Youth Self-Report and Teacher's Report Form were completed to measure emotional and behavioral problems. Results: Questionnaires for thirty-eight patients (median age: 13 years; 48% male) were completed by patients themselves, parents and teachers. Compared to normative data, self-reported HRQoL was not significantly impaired, except for social functioning in children aged 8-12 years. Gender, severity of tricuspid regurgitation or previous surgery did not predict HRQoL. Parents reported significantly more internalizing (anxiety/depression), attention and thought problems in children with EA. These problems, however, were not reported by adolescents themselves. School teachers reported significantly fewer externalizing problems compared to the norm. Conclusions: Overall, despite satisfactory HRQoL, children and adolescents show emotional and behavioral problems. We recommend routine HRQoL and psychological assessment to screen for less apparent internalizing and psychosocial problems.

Immune checkpoint inhibitors (ICI) have transformed the standard care of cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy. To characterize ICI-mediated myocarditis and re-introduction to immunotherapy. During 2019, 849 patients were treated with ICI at Tel Aviv Sourasky Medical Center for the diagnosis of lung adenocarcinoma, gastric adenocarcinoma, urothelial carcinoma, and hepatocellular carcinoma. Overall, seven (0.8%) patients were diagnosed with ICI-mediated myocarditis, according to the European Society of Cardiology guidelines of myocarditis 2013. We retrospectively evaluated their presentation, severity, and clinical outcomes. Among the seven patients, only one had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody. All patients were treated with single-agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical cardiac magnetic resonance; however, only three had reduced ejection fraction. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I and II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden. The one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and, therefore, therapy was interrupted permanently. ICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life-saving cancer therapy. The current data suggest that re-introduction may be considered in low-grade patients; however, a better definition of the diagnosis and grading is needed.

Background: Cardiotoxicity, defined mainly as left ventricle (LV) dysfunction, is a significant side effect of anthracyclines (ANT) therapy. The need for an early simple marker to identify patients at risk is crucial. High Neutrophil-to-Lymphocyte Ratio (NLR) has been associated with poor prognosis in cancer patients, however, its role as a predictor for cardiotoxicity development is unknown. Objective: We aimed to evaluate whether elevated NLR, following ANT exposure, plays a predictive role in the development of cardiotoxicity as defined by LV global longitudinal strain (LV GLS) relative reduction (≥10%).Methods and results: Data were prospectively collected as part of the Israel Cardio-Oncology Registry (ICOR). A total of 74 female patients with breast cancer, scheduled for ANT therapy were included. NLR levels were assessed at baseline (T1) and during ANT therapy (T2). All patients underwent serial echocardiography at baseline (T1) and after the completion of ANT therapy (T3). NLR≥ 2.58 was found to be the optimal predictive cut-off for LV GLS deterioration. A relative LV GLS reduction ≥10% was significantly more common among patients with high NLR (50% vs. 20%, p=0.009). NLR ≥ 2.58 increases the risk for LV GLS reduction by 4-fold (OR 4.63, 95%CI 1.29-16.5, p = 0.02), with each increase of 1-point NLR adding an additional 15% risk (OR 1.15, 95%CI 1.01-1.32, p = 0.046).Conclusions: Our study provides novel data that high NLR levels, following ANT exposure, have an independent association with the development of LV dysfunction. Routine surveillance of NLR may be an effective means of risk-stratifying.

Item does not contain fulltext PURPOSE: The purpose of this study is to assess the available literature on the prevalence and risk factors of electrocardiographic (ECG) abnormalities after cardiotoxic treatment in childhood cancer survivors (CCS). METHODS: A literature search was performed within MEDLINE, EMBASE, and CENTRAL (1966-11/2020) and reference lists of relevant studies. Studies were eligible for inclusion if they reported ECG abnormalities ≥2 years after cancer diagnosis in ≥50 CCS treated with anthracyclines, RT involving the heart region and/or mitoxantrone. Information about population, treatment, outcome, and risk factors were extracted and risk of bias was assessed. RESULTS: Of 934 identified publications, 10 studies were included. Outcome definitions, treatment regimens, follow-up period, and risk of bias varied. These ECG abnormalities and prevalences were reported: major (5%-23%) and minor (12%) abnormalities according to the Minnesota Code, rhythm abnormalities (0%-12%), conduction abnormalities (0.3%-7.1%), depolarization abnormalities (0%), and repolarization abnormalities (0%-65%). The reported risk factors of ECG abnormalities (two studies) are male sex, anthracyclines, RT involving the heart region, and hypertension, although results were not univocal between studies and abnormalities. CONCLUSIONS: Multiple ECG abnormalities have been described in CCS ≥2 years from diagnosis, some of which can have important implications. Future research is needed to evaluate the exact long-term incidence and risk factors, and to investigate their clinical relevance and relation with cardiac dysfunction or future cardiac events. This could improve cardiac surveillance for CCS.

With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8-17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs'), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33-42). TAPSE and fRVs' were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36-58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, p 0.001). While echocardiography is a versatile tool in the complex geometry of the Ebstein heart, it has limitations. CMR offers a total overview and has the advantage of reliable volume assessment of both ventricles. Comprehensive evaluation of pediatric patients with EA may therefore require a synergistic implementation of echocardiography and CMR.

Item does not contain fulltext Survivors of childhood cancer are at risk of anthracycline-induced cardiotoxicity, which might be prevented by dexrazoxane. However, concerns exist about the safety of dexrazoxane, and little guidance is available on its use in children. To facilitate global consensus, a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the existing literature and used evidence-based methodology to develop a guideline for dexrazoxane administration in children with cancer who are expected to receive anthracyclines. Recommendations were made in consideration of evidence supporting the balance of potential benefits and harms, and clinical judgement by the expert panel. Given the dose-dependent risk of anthracycline-induced cardiotoxicity, we concluded that the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m(2) (moderate recommendation). No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m(2), due to insufficient evidence to determine whether the risk of cardiotoxicity outweighs the possible risk of subsequent neoplasms. Further research is encouraged to determine the long-term efficacy and safety of dexrazoxane in children with cancer.

Item does not contain fulltext AIM: To assess the burden of hemodynamically significant patent ductus arteriosus (hs-PDA) in preterm infants exposed to aspirin in utero. METHODS: We retrospectively reviewed the medical records of 21 preterm infants

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.

Context Turner syndrome (TS) is a genetic condition that is reported to be associated with a prolonged rate-corrected QT (QTc) interval. Objectives To evaluate the prevalence of QTc prolongation in patients with TS, to compare their QTc intervals with healthy controls, and to investigate whether QTc prolongation is associated with a monosomy 45,X karyotype. Method Girls (n = 101) and women (n = 251) with TS visiting our center from 2004–2018 were included in this cross-sectional study. QT intervals of 12-leaded electrocardiograms were measured manually, using Bazett’s and Hodges formulas to correct for heart rate. A QTc interval of >450 ms for girls and >460 ms for women was considered prolonged. Corrected QT (QTc) intervals of patients with TS were compared to the QTc intervals of healthy girls and women from the same age groups derived from the literature. Results In total, 5% of the population with TS had a prolonged QTc interval using Bazett’s formula and 0% using Hodges formula. Mean QTc intervals of these patients were not prolonged compared with the QTc interval of healthy individuals from the literature. Girls showed shorter mean QTc intervals compared with women. We found no association between monosomy 45,X and prolongation of the QTc interval. Conclusions This study shows that the QTc interval in girls and women with TS is not prolonged compared with the general population derived from the literature, using both Bazett’s and Hodges formulas. Furthermore, girls show shorter QTc intervals compared with women, and a monosomy 45,X karyotype is not associated with QTc prolongation.

Background In childhood cancer survivors (CCS) at risk for heart failure, echocardiographic surveillance recommendations are currently based on anthracyclines and chest-directed radiotherapy dose. Whether the ejection fraction (EF) measured at an initial surveillance echocardiogram can refine these recommendations is unknown. Objectives The purpose of this study was to assess the added predictive value of EF at >5 years after cancer diagnosis to anthracyclines and chest-directed radiotherapy dose in CCS, for the development of left ventricular dysfunction with an ejection fraction, Central Illustration

Contains fulltext : 241413.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 237466.pdf (Publisher’s version ) (Open Access) Turner syndrome (TS) is a chromosomal condition which is associated with an increased prevalence of cardiac morbidity and mortality. In this cross-sectional study, Minnesota-based electrocardiographic (ECG) abnormalities, aortic dimensions, routine- and myocardial strain echocardiographic parameters, and karyotype-cardiac phenotype associations were assessed in girls with TS. In total, 101 girls with TS (0-18 years) were included. The prevalence of major ECG abnormalities was 2% (T-wave abnormalities) and 39% had minor ECG abnormalities. Dilatation of the ascending aorta (z-score > 2) was present in 16%, but the prevalence was much lower when using TS-specific z-scores. No left ventricular hypertrophy was detected and the age-matched global longitudinal strain was reduced in only 6% of the patients. Cardiac abnormalities seemed more common in patients with a non-mosaic 45,X karyotype compared with other karyotypes, although no statistically significant association was found. Lowering the frequency of echocardiography and ECG screening might be considered in girls with TS without cardiovascular malformations and/or risk factors for aortic dissection. Nevertheless, a large prospective study is needed to confirm our results. The appropriate z-score for the assessment of aortic dilatation remains an important knowledge gap. The karyotype was not significantly associated with the presence of cardiac abnormalities, therefore cardiac screening should not depend on karyotype alone.

ObjectiveTo 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.MethodsWe 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 end-point 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.ResultsWe included 57 patients (26 ECC; 31 ILT) aged 12.8 (IQR (10.3–15.5)) years. During dobutamine stress atrial cyclic volume change increased (3.0 (0.4–5.9) mL/m2, p2, p=0.001) and late emptying volume (2.2 (0.2–4.4) mL/m2, pVentricular early filling decreased (−1.6 (−5.7 to 0.7) mL/m2,p=0.046) and ventricular late filling increased (1.0 (−0.4 to 3.4) mL/m2,pOnly for patients with the ECC modification, atrial early emptying volume increase correlated with peak oxygen uptake (ρ=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.ConclusionsDobutamine 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.

Contains fulltext : 241430.pdf (Publisher’s version ) (Open Access) The purpose of this study was to investigate left ventricular contraction patterns in asymptomatic Childhood cancer survivors (CCS) using two-dimensional speckle tracking echocardiography (2DSTE). Left ventricular longitudinal and circumferential myocardial parameters were assessed using 2DSTE, in asymptomatic CCS and age matched healthy controls. Time to peak (T2P) systolic strain was quantified. Dyssynchrony index (DI) was measured by calculating the standard deviation of T2P systolic strain of six segments in each view. Difference between T2P systolic longitudinal strain of septal and lateral wall was also assessed as a parameter for dyssynchrony. We included 115 CCS with a median age of 17.2 years (range 5.6-39.5) and a median follow up of 11.3 years (range 4.9-29.5) and 119 controls. Conventional echocardiographic parameters and global longitudinal strain were significantly decreased in CCS compared to controls (p

Contains fulltext : 231547.pdf (Publisher’s version ) (Open Access) With the improvement in survival rate, cardiotoxicity has emerged as a significant adverse effect of cancer therapy. Early diagnosis of subclinical cardiac injury may allow the initiation of cardioprotective therapy and preventing the interruption of optimal cancer therapy and the development of irreversible cardiac dysfunction. In this article, we review the role of two-dimensional speckle tracking echocardiography (2D-STE), beyond the common left ventricle global longitudinal strain in the diagnosis of early subclinical cardiac injury in patients treated with cancer therapies.

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 young cohort who have undergone the Fontan procedure. Methods and Results In 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 (β=0.33, P =0.003) between DLK‐1 and stress cardiac magnetic resonance imaging functional reserve. Conclusions NT‐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.

Background Childhood cancer survivors (CCS) treated with anthracyclines and/or chest-directed radiotherapy receive life-long echocardiographic surveillance to detect cardiomyopathy early. Current risk stratification and surveillance frequency recommendations are based on anthracycline- and chest-directed radiotherapy dose. We assessed the added prognostic value of an initial left ventricular ejection fraction (EF) measurement at >5 years after cancer diagnosis. Patients and methods Echocardiographic follow-up was performed in asymptomatic CCS from the Emma Children's Hospital (derivation; n=299; median time after diagnosis, 16.7 years [inter quartile range (IQR) 11.8–23.15]) and from the Radboud University Medical Center (validation; n=218, median time after diagnosis, 17.0 years [IQR 13.0–21.7]) in the Netherlands. CCS with cardiomyopathy at baseline were excluded (n=16). The endpoint was cardiomyopathy, defined as a clinically significant decreased EF (EF5 years after cancer diagnosis was analyzed with multivariable Cox regression models in the derivation cohort and the model was validated in the validation cohort. Results The median follow-up after the initial EF was 10.9 years and 8.9 years in the derivation and validation cohort, respectively, with cardiomyopathy developing in 11/299 (3.7%) and 7/218 (3.2%), respectively. Addition of the initial EF on top of anthracycline and chest radiotherapy dose increased the C-index from 0.75 to 0.85 in the derivation cohort and from 0.71 to 0.92 in the validation cohort (p99% in both cohorts. Conclusion The addition of the initial EF >5 years after cancer diagnosis to anthracycline- and chest-directed radiotherapy dose improves the 10-year cardiomyopathy prediction in CCS. Our validated prediction model identifies low-risk survivors in whom the surveillance frequency may be reduced to every 10 years. Calibration in both cohorts Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Heart Foundation

Introduction Plasma biomarkers may aid in the surveillance for anthracycline-induced cardiomyopathy (ACM) in long-term childhood cancer survivors and provide insight into the pathophysiological mechanisms involved. In this pilot study, we aimed to identify new plasma markers associated with ACM. Methods A case-control study within the Dutch Late Effects After Childhood Cancer Cohort study (Dutch LATER) was conducted. We compared 184 plasma markers (Olink) between ACM cases (LVEF Results In total, 28 ACM cases (median anthracycline dose 351 mg/m2; median age at study 38 years, 29% chest radiotherapy) and 29 controls (median anthracycline dose 300 mg/m2; median age at study 44 years, 7% chest radiotherapy) were included. Eight markers were significantly associated with ACM (Table 1) and were implicated in ventricular wall stress, apoptosis, inflammation and endothelial dysfunction (Figure 1). The AUC of the model including only the clinical variables was 0.73 (95% confidence interval (CI) 0.60–0.86), and improved to 0.82 (95% CI 0.71–0.94) with the addition of NT-proBNP and further to 0.86 (95% CI 0.76–0.97) with the addition of all 8 markers. Conclusion In this biomarker discovery study, 8 markers related to ventricular wall stress, apoptosis, inflammation and endothelial dysfunction were associated with ACM. We intend to validate these markers quantitatively in the Dutch LATER cohort study. Figure 1. Pathway analysis of significant markers Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Heart Foundation Grant; Amsterdam University Funding

Introduction Right Ventricular (RV) dysfunction is highly prevalent and has major prognostic implication in patients with Heart Failure (HF) with Preserved Ejection Fraction (HFpEF). Different functional indices have been proposed to evaluate RV function, most common are TEI-index, TAPSE and RVFAC%. Recent works suggested that 2-dimensional speckle tracking echocardiography (2DSTE) for RV global longitudinal strain (RVGLS) and free wall strain (RVFWS) are more sensitive in evaluating RV (dys)function than other functional and hemodynamic parameters in specific populations, such as HF with reduced EF. Purpose We aimed to assess if endocardial RVGLS, RVFWS, and RV Septal Wall Strain (RVSWS), might have a prognostic and additive value (on top of the conventional measurements) on the outcome of patients with preserved EF. Methods Retrospective analysis of RV parameters including Peak and End Systolic Strain of RVGLS, RVFWS and RVSWS, RV functional indices (RVFAC% and Machine like TAPSE), Systolic Pulmonary Artery Pressure, in 375 consecutive patients with Preserved Ejection Fraction (EF ≥50%; age 69.1±19; 51% female; Co-morbidity Charlson index 1 (3)). Multivariate Cox regression hazards model was used to determine the association between RV strain parameters to all-cause mortality. Results RVFWS, RVSWS and RVFAC% were strong predictors of mortality in univariate analysis (HR 1.07 [1.03–1.1]; p≤0.0001, HR 1.08 [1.05–1.12]; p≤0.0001, HR 0.97 [0.95–0.99]; p≤0.0002, respectively). Moreover, after adjustment for clinical (age, gender, Charlson index) and echocardiographic parameters (LA volume, E/e' average, systolic pulmonary pressure), all three parameters remained statistically significant predictors of all-cause mortality (p=0.004, p=0.024, p=0.026, respectively). The best strain univariate predictor of mortality was RVGLS (HR 1.09 [1.05–1.13]; p≤0.0001), being superior to other RV functional indices and systolic pulmonary pressure. Also, after multivariate analysis it remained a statistically significant predictor of mortality (p=0.007). All measurements had good intra-observer and inter-observer reproducibility (Single Measures ICC = 0.90 and ICC = 0.88, respectively). Conclusions 2DSTE of RVGLS, RVFWS, RVSWS provides significant prognostic value to predict overall mortality in patients with Preserved Ejection Fraction with excellent reproducibility, incremental to routine clinical, hemodynamic and diastolic parameters. Moreover, the strain results of the septal wall showed to be significant, thereover challenging the known hypothesis that the septal wall is mainly influenced by LV function. Figure 1 Funding Acknowledgement Type of funding source: None

Cardiotoxicity has become a significant adverse effect of cancer therapy, with Anthracyclines (ANT) in particular. There is a crucial need for new imaging techniques for the early subclinical detection of cardiotoxic effect. We aimed to evaluate left atrial strain (LAS) changes during ANT therapy and to assess the correlation between LAS and the routine echocardiographic diastolic parameters.Data were prospectively collected as part of the Israel Cardio-Oncology Registry (ICOR). All female patients with breast cancer, planned for ANT therapy were included. All patients underwent serial echocardiography exams including baseline LAS (before chemotherapy, T1) and shortly after the completion of ANT therapy (T3). LAS was assessed in 3 phases: Reservoir (LASr), Conduit (LASc) and Pump (LASp). Significant reduction in LASr was determined by either a relative reduction of10% or an absolute value of35%. From September 2016 to June 2019, 40 patients were evaluated with a mean Doxorubicin (type of ANT) dose of 237±13.24mg/m2. At T3, significant reduction in LASr was observed among 50% of the patients with a mean LASr reduction from 40.15 ± 6.83% to 36.04 ± 7.73% (p0.001). LASc showed significant reduction as well (p0.004) as opposed to LASp (p=0.076). Both LASr and LASc showed significant correlation to the routine diastolic parameters.LASr and LASc reduction are frequent and occur early in the course of ANT therapy, showing significant correlation to the routine echocardiographic diastolic parameters, which may imply a role in the detection of early cardiotoxicity.

Diastolic dysfunction is a common finding in patients receiving cancer therapy. This study evaluated the correlation of diastolic strain slope (Dss) with routine echocardiography diastolic parameters and its role in early detection of systolic dysfunction and cardiovascular (CV) mortality within this population.Data were collected from the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling adult patient receiving cancer therapy. All patients performed at least three echocardiography exams (T1, T2, T3), including left ventricle Global Longitudinal Strain (LV GLS) and Dss. Systolic dysfunction was determined by either LV GLS relative reduction of ≥ 15% or LV ejection fraction reduction 10% to 53%. Dss was assessed as the early lengthening rate, measured by the diastolic slope (delta%/sec).Among 144 patients, 114 (79.2%) were female with a mean age of 57.31 ± 14.3 years. Dss was significantly correlated with e' average. Mid segment Dss change between T1 and T2 showed significant association to systolic dysfunction development (Odds Ratio (OR) = 1.04 [1.01,1.06]. p = 0.036). In multivariate prediction, Dss increase was a significant predictor for the development of systolic dysfunction (OR = 1.06 [1.03,1.1], P 0.001).An 8% increase in Dss between T1 and T2 was associated with a trend in increased CV mortality (HR = 3.4 [0.77,15.4], p = 0.085).This study is the first to use the novel measurement of Dss in patients treated with cancer therapies and to show significant correlation between routine diastolic dysfunction parameters and Dss. Changes in the mid segment were found to have significant independent early predictive value for systolic dysfunction development in univariate and multivariate analyses.

OBJECTIVESOur goals were to compare the outcome of the intra-atrial lateral tunnel (ILT) and the extracardiac conduit (ECC) techniques for staged total cavopulmonary connection (TCPC) and to compare the current modifications of the TCPC technique, i.e. the prosthetic ILT technique with the current ECC technique with a ≥18-mm conduit.METHODSWe included patients who had undergone a staged TCPC between 1988 and 2008. Records were reviewed for patient demographics, operative details and events during follow-up (death, surgical and catheter-based reinterventions and arrhythmias).RESULTSOf the 208 patients included, 103 had the ILT (51 baffle, 52 prosthetic) technique and 105 had the ECC technique. Median follow-up duration was 13.2 years (interquartile range 9.5–16.3). At 15 years after the TCPC, the overall survival rate was comparable (81% ILT vs 89% ECC; P = 0.12). Freedom from late surgical and catheter-based reintervention was higher for patients who had ILT than for those who had ECC (63% vs 44%; P = 0.016). However, freedom from late arrhythmia was lower for patients who had ILT than for those who had ECC (71% vs 85%, P = 0.034). In a subgroup of patients who had the current TCPC technique, when we compared the use of a prosthetic ILT with ≥18-mm ECC, we found no differences in freedom from late arrhythmias (82% vs 86%, P = 0.64) or in freedom from late reinterventions (70% vs 52%, P = 0.14).CONCLUSIONSA comparison between the updated prosthetic ILT and current ≥18-mm ECC techniques revealed no differences in late arrhythmia-free survival or late reintervention-free survival. Overall, outcomes after the staged TCPC were relatively good and reinterventions occurred more frequently in the ECC group, whereas late arrhythmias were more common in the ILT group.

Item does not contain fulltext BACKGROUND: Current methods do not allow a thorough assessment of causes associated with limited exercise capacity in patients with chronic obstructive pulmonary disease (COPD). METHODS: Twenty patients with COPD and 20 matched control subjects were assessed using combined cardiopulmonary and stress echocardiographic testing. Various echocardiographic parameters (left ventricular [LV] volumes, right ventricular [RV] area, ejection fraction, stroke volume, S', and E/e' ratio) and ventilatory parameters (peak oxygen consumption [Vo(2)] and A-Vo(2) difference) were measured to evaluate LV and RV function, hemodynamics, and peripheral oxygen extraction (A-VO(2) difference). RESULTS: Significant differences (both between groups and for group-by-time interaction) were seen in exercise responses (LV volume, RV area, LV volume/RV area ratio, S', E/e' ratio, tricuspid regurgitation grade, heart rate, stroke volume, and Vo(2)). The major mechanisms of reduced exercise tolerance in patients with COPD were bowing of the septum to the left in 12 (60%), abnormal increases in E/e' ratio in 12 (60%), abnormal stroke volume reserve in 16 (80%), low peak A-Vo(2) difference in 10 (50%), chronotropic incompetence in 13 (65%), or a combination of several mechanisms. Patients with COPD and poor exercise tolerance showed attenuated increases in stroke volume, heart rate, and A-Vo(2) difference and exaggerated changes in LV/RV ratio and LV compliance (ratio of LV volume to E/e' ratio) compared with patients with COPD with good exercise tolerance. CONCLUSIONS: Combined cardiopulmonary and stress echocardiographic testing can be helpful in determining individual mechanisms of exercise intolerance in patients with COPD. In patients with COPD, exercise intolerance is predominantly the result of chronotropic incompetence, limited stroke volume reserve, exercise-induced elevation in left filling pressure, and peripheral factors and not simply obstructive lung function. Limited stroke volume is related to abnormal RV contractile reserve and reduced LV compliance introduced through septal flattening and direct ventricular interaction.

BackgroundForecasting the prognosis of a child when diagnosed with Ebstein’s anomaly is difficult. We, therefore, studied which factors at the time of diagnosis are associated with death during childhood.MethodsAll consecutive patients (0–18 years) diagnosed with Ebstein’s anomaly in the Netherlands between 1980 and 2014 were included. Survival curves were obtained using the Kaplan-Meier method. By using the Cox proportional hazard model, we analysed the factors (at diagnosis) that were associated with death.ResultsWe included 176 patients. Thirty-one patients (18%) died before the age of 18 years. The 1-year survival was 84% and remained stable at 82% from 35 months after diagnosis and onwards. Modified Ross Heart Failure Class 4 at the time of diagnosis was the most important risk factor for death during childhood (HR 12.5, 95% CI 4.4 to 35.9). Furthermore, diagnosis in the neonatal period (HR 4.2, 95% CI 1.5 to 12.0), severe tricuspid valve regurgitation (HR 2.4, 95% CI 1.2 to 5.0), severe right ventricular outflow tract obstruction (HR 3.7, 95% CI 1.8 to 7.7) and a patent ductus arteriosus (HR 2.8, 95% CI 1.3 to 6.0) at the time of diagnosis were univariately associated with death. Multivariable analysis showed that presentation with Heart Failure Class 4 and a ventricular septal defect is the strongest predictor of death in childhood and adolescence.ConclusionPatients with Ebstein’s anomaly presenting with Heart Failure Class 4 and a ventricular septal defect have a high risk of death during childhood.

Survival of children with single ventricle heart defects after the total cavopulmonary connection (TCPC) has improved, but impaired cardiac function remains a major cause of morbidity and mortality. Cardiac magnetic resonance imaging (cMRI) is the gold standard in assessing single ventricle volume and function, but high costs and limited availability hamper its routine use. A cheaper and more available alternative is echocardiography. Myocardial function can be studied in more detail using speckle tracking echocardiography (STE). The purpose of the study was to describe the association between myocardial deformation assessed by speckle tracking echocardiography (STE) and single ventricle function assessed by cMRI and to evaluate differences in myocardial deformation in children with single left and single right ventricular morphology. Cross-sectional, multicenter study in 77 children after TCPC was conducted. STE segmental and global longitudinal peak strain and systolic strain rate (SR) of the dominant ventricle were measured. Impaired SV function by cMRI was defined as ejection fraction (EF)

Contains fulltext : 178023.pdf (Publisher’s version ) (Closed access) Accurate 3-D surface segmentation is a challenging task in echocardiography because of the relatively low image quality. We introduce a new method for 3-D segmentation of the endocardium involving temporal decorrelation of echo signals originating from tissue and blood using radiofrequency (RF) signals acquired in 3-D Doppler mode. Temporal features were extracted in 3-D Doppler mode, where a sequence of RF lines is recorded for each image line. Each set of RF lines is highly correlated because of the high pulse repetition frequency. However, for high blood flow, the RF signals will decorrelate over time in contrast to the endocardium, which will remain relatively highly correlated over time. These decorrelation features permit differentiation between myocardial tissue and blood flow. We describe an implementation of a 3-D segmentation model in which temporal information is used as external constraint. The model was validated in a phantom and in vivo in healthy volunteers (n = 5). The phantom study revealed that the model successfully segmented the artificial blood lumen even for low flow velocity and illustrated the sensitivity of the segmentations to flow rate. In healthy volunteers, high Dice similarity indices indicate that 3-D segmentation of the endocardial border in vivo is feasible.

The Fontan operation is used to treat patients with a functional univentricular heart [(1)][1]. Long-term complications include circulatory failure, thromboembolic events, arrhythmias, and death [(1,2)][1]. Cardiovascular magnetic resonance (CMR) using exercise or pharmacological stress might

Immune checkpoint inhibitors (ICI) have transformed the standard care of cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy.To characterize ICI-mediated myocarditis and re-introduction to immunotherapy.During 2019, 849 patients were treated with ICI at Tel Aviv Sourasky Medical Center for the diagnosis of lung adenocarcinoma, gastric adenocarcinoma, urothelial carcinoma, and hepatocellular carcinoma. Overall, seven (0.8%) patients were diagnosed with ICI-mediated myocarditis, according to the European Society of Cardiology guidelines of myocarditis 2013. We retrospectively evaluated their presentation, severity, and clinical outcomes.Among the seven patients, only one had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody. All patients were treated with single-agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical cardiac magnetic resonance; however, only three had reduced ejection fraction. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I and II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden. The one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and, therefore, therapy was interrupted permanently.ICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life-saving cancer therapy. The current data suggest that re-introduction may be considered in low-grade patients; however, a better definition of the diagnosis and grading is needed.

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) 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/).