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As in other cardiomyopathies, extracellular matrix (ECM) remodeling plays an important role in anthracycline-induced cardiomyopathy. To understand the pattern and timing of ECM remodeling pathways, we conducted a systematic review in which we describe protein and mRNA markers for ECM remodeling that are differentially expressed in the hearts of animals with anthracycline-induced cardiomyopathy. We included 68 studies in mice, rats, rabbits, and pigs with follow-up of 0.1–8.2 human equivalent years after anthracycline administration. Using meta-analysis, we found 29 proteins and 11 mRNAs that were differentially expressed in anthracycline-induced cardiomyopathy compared to controls. Collagens, matrix metalloproteinases (MMPs), inflammation markers, transforming growth factor ß signaling markers, and markers for cardiac hypertrophy were upregulated, whereas the protein kinase B (AKT) pro-survival pathway was downregulated. Their expression patterns over time from single time point studies were studied with meta-regression using human equivalent years as the time scale. Connective tissue growth factor showed an early peak in expression but remained upregulated at all studied time points. Brain natriuretic peptide (BNP) and MMP9 protein levels increased in studies with longer follow-up. Significant associations were found for higher atrial natriuretic peptide with interstitial fibrosis and for higher BNP and MMP2 protein levels with left ventricular systolic function. Supplementary Information The online version contains supplementary material available at 10.1007/s00109-021-02098-8.

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.

BACKGROUND: Sudden cardiac death (SCD) is the main preventable cause of death in patients with adult congenital heart disease (ACHD). Since robust risk stratification methods are lacking, we developed a risk score model to predict SCD in patients with ACHD: the PRospEctiVE study on implaNTable cardIOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD) risk score model. OBJECTIVE: The purpose of this study was to prospectively study predicted SCD risk using the PREVENTION-ACHD risk score model and actual SCD and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) rates in patients with ACHD. METHODS: The PREVENTION-ACHD risk score model assigns 1 point each to coronary artery disease, New York Heart Association class II/III heart failure, supraventricular tachycardia, systemic ejection fraction < 40%, subpulmonary ejection fraction < 40%, QRS duration ≥ 120 ms, and QT dispersion ≥ 70 ms. SCD risk was calculated for each patient. An annual predicted risk of ≥3% constituted high risk. The primary outcome was SCD or VT/VF after 2 years. The secondary outcome was SCD. RESULTS: The study included 783 consecutive patients with ACHD (n=239 (31%) left-sided lesions; n=138 (18%) tetralogy of Fallot; n=108 (14%) closed atrial septal defect; median age 36 years; interquartile range 28-47 years; n=401 (51%) men). The PREVENTION-ACHD risk score model identified 58 high-risk patients. Eight patients (4 at high risk) experienced the primary outcome. The Kaplan-Meier estimates were 7% (95% confidence interval [CI] 0.1%-13.3%) in the high-risk group and 0.6% (95% CI 0.0%-1.1%) in the low-risk group (hazard ratio 12.5; 95% CI 3.1-50.9; P < .001). The risk score model's sensitivity was 0.5 and specificity 0.93, resulting in a C-statistic of 0.75 (95% CI 0.57-0.90). The hazard ratio for SCD was 12.4 (95% CI 1.8-88.1) (P = .01); the sensitivity and specificity were 0.5 and 0.92, and the C-statistic was 0.81 (95% CI 0.67-0.95). CONCLUSION: The PREVENTION-ACHD risk score model provides greater accuracy in SCD or VT/VF risk stratification as compared with current guideline indications and identifies patients with ACHD who may benefit from preventive implantable cardioverter-defibrillator implantation. ispartof: HEART RHYTHM vol:18 issue:5 pages:785-792 ispartof: location:United States status: published

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

Cardiac diseases in the growing population of childhood cancer survivors are of major concern. Cardiotoxicity as a consequence of anthracyclines and chest radiotherapy continues to be relevant in the modern treatment era. Mitoxantrone has emerged as an important treatment-related risk factor and evidence on traditional cardiovascular risk factors in childhood cancer survivors is accumulating. International surveillance guidelines have been developed with the aim to detect and manage cardiac diseases early and prevent symptomatic disease. There is growing interest in risk prediction models to individualize prevention and surveillance. This State-of-the-Art Review summarizes literature from a systematic PubMed search focused on cardiac diseases after treatment for childhood cancer. Here, we discuss the prevalence, risk factors, prevention, risk prediction, and surveillance of cardiac diseases in survivors of childhood cancer.

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.

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

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

ObjectiveTo 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.MethodsWe 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 ResultsOf 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.ConclusionsIn 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.

Introduction Plasma biomarkers may aid in the early diagnosis of anthracycline-induced cardiomyopathy in long-term childhood cancer survivors (CCS) and may provide insights into the underlying mechanisms involved. Natriuretic peptides and troponins are of limited value to diagnose left ventricular dysfunction in CCS >1 year after anthracycline treatment. To improve cardiomyopathy surveillance in long-term CCS, we aim to identify new plasma biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy. Methods Five-year CCS treated with anthracyclines and ≥18 years at time of the study were identified from the ongoing Dutch Childhood Oncology Late Effects After Childhood Cancer (DCOG-LATER) study. Genetic cardiomyopathy cases were identified from a dilated cardiomyopathy cohort in the Amsterdam UMC (figure 1). Levels of 184 plasma proteins (from 32 different biological processes) were compared between three groups of 30 patients: anthracycline-induced cardiomyopathy cases (left ventricular ejection fraction (LVEF) Results The results will be available in August 2019 and will be presented during the congress. Conclusion Targeted proteomics in CCS treated with anthracyclines may identify new biomarkers for the early diagnosis of anthracycline-induced cardiomyopathy in CCS and may provide additional insights into the pathophysiology of anthracycline cardiomyopathy.

Introduction Long-term childhood cancer survivors (CCS) treated with cardiotoxic cancer therapies (CTCT) are screened for LV dysfunction (LVD). The intervals of 2 to 5 years in the Dutch Childhood Oncology Group guideline (Annals of Oncology 2012) depend on anthracycline (300 mg/m2) and radiotherapy dose (30 Gy). There is a gap between detection of LVD, defined as an ejection fraction (EF) Methods Patient and treatment characteristics were collected from a CCS cohort diagnosed with cancer between 1966 and 1997 who received anthracyclines and/or chest radiotherapy. Patients with congenital heart disease and heart failure before baseline echocardiogram were excluded. The first available echocardiogram at >5 years since cancer diagnosis was the baseline echocardiogram. All subsequent echocardiograms were collected. FS was measured by M-mode echocardiography. EF was calculated from two apical chamber views by the Simpson formula. If no EF was available, EF was calculated using the Teicholz formula. Patients with an available baseline echocardiogram were stratified into three subgroups: Reduced (EF Results Of 671 CCS eligible, 448 had a baseline echocardiogram at a median of 17years since cancer diagnosis and 381 had at least one follow-up echocardiogram. At baseline, 6, 41, and 334 CCS were in the reduced, grey zone and preserved EF group respectively. CCS in the grey zone received higher anthracycline dose (median 350 mg/m2) compared to the preserved group (median 200 mg/m2), and more CCS with anthracycline dose >300 mg/m2 were present in the grey zone (51.2% vs 26.6%). In the grey zone group 4.9% and 7.3% developed an EF Conclusion Long-term CCS treated with CTCT with an EF in the grey zone are at an increased risk of developing an EF