Treatments affecting splenic function as a risk factor for valvular heart disease in Childhood Cancer Survivors: A DCCSS-LATER study.

PURPOSE: Splenectomy might be a risk factor for valvular heart disease (VHD) in adult Hodgkin lymphoma survivors. As this risk is still unclear for childhood cancer survivors (CCS), the aim of this study is to evaluate the association between treatments affecting splenic function (splenectomy and radiotherapy involving the spleen) and VHD in CCS. METHODS: CCS were enrolled from the DCCSS-LATER cohort, consisting of 6,165 five-year CCS diagnosed between 1963 and 2002. Symptomatic VHD, defined as symptoms combined with a diagnostic test indicating VHD, was assessed from questionnaires and validated using medical records. Differences in the cumulative incidence of VHD between CCS who received treatments affecting splenic function and CCS who did not were assessed using the Gray test. Risk factors were analyzed in a multivariable Cox proportional hazards model. RESULTS: The study population consisted of 5,286 CCS, with a median follow-up of 22 years (5-50 years), of whom 59 (1.1%) had a splenectomy and 489 (9.2%) radiotherapy involving the spleen. VHD was present in 21 CCS (0.4%). The cumulative incidence of VHD at the age of 40 years was significantly higher in CCS who received treatments affecting splenic function (2.7%, 95% confidence interval (CI) 0.4%-4.9%) compared with CCS without (0.4%, 95% CI 0.1%-0.7%) (Gray's test, p = 0.003). Splenectomy was significantly associated with VHD in a multivariable analysis (hazard ratio 8.6, 95% CI 3.1-24.1). CONCLUSIONS AND IMPLICATIONS: Splenectomy was associated with VHD. Future research is needed to determine if CCS who had a splenectomy as part of cancer treatment might benefit from screening for VHD.

A Biomarker-Based Diagnostic Model for Cardiac Dysfunction in Childhood Cancer Survivors.

Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested. Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors. Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics. Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%). Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).

Cardiac screening in pediatric patients with neurofibromatosis type 1: similarities with Noonan syndrome?

Both Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are RASopathies. Characteristic cardiac phenotypes of NS, including specific electrocardiographic changes, pulmonary valve stenosis and hypertrophic cardiomyopathy have not been completely studied in NF1. PURPOSE: The aims of this study were to assess: (1) similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS in asymptomatic patients with NF1, and (2) the presence of discrete myocardial dysfunction in NF1 patients using myocardial strain imaging. METHODS: Fifty-eight patients with NF1 (ages 0-18 years), and thirty-one age-matched healthy controls underwent cardiac assessment including blood pressure measurements, a 12-lead ECG, and detailed echocardiography. Quantification of cardiac chamber size, mass and function were measured using conventional echocardiography. Myocardial strain parameters were assessed using 2-Dimensional (2D) Speckle tracking echocardiography. RESULTS: Asymptomatic patients with NF1 had normal electrocardiograms, none with the typical ECG patterns described in NS. However, patients with NF1 showed significantly decreased calculated Z scores of the left ventricular internal diameter in diastole and systole, reduced left ventricular mass index and a higher incidence of cardiac abnormal findings, mainly of the mitral valve, in contrast to the frequently described types of cardiac abnormalities in NS. Peak and end systolic global circumferential strain were the only significantly reduced speckle tracking derived myocardial strain parameter. CONCLUSIONS: Children with NF1 demonstrated more dissimilarities than similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS. The role of the abnormal myocardial strain parameter needs to be explored.

Cardiovascular health in pediatric patients with X-linked hypophosphatemia under two years of burosumab therapy.

Introduction: X-linked hypophosphatemia (XLH) is caused by an inactivating mutation in the phosphate-regulating endopeptidase X-linked (PHEX) gene whose defective product fails to control phosphatonin fibroblast growth factor 23 (FGF23) serum levels. Although elevated FGF23 levels have been linked with detrimental cardiac effects, the cardiologic outcomes in XLH patients have been subject to debate. Our study aimed to evaluate the prevalence and severity of cardiovascular morbidity in pediatric XLH patients before, during, and after a 2-year treatment period with burosumab, a recombinant anti-FGF23 antibody. Methods: This prospective observational study was conducted in a tertiary medical center, and included 13 individuals with XLH (age range 0.6-16.2 years) who received burosumab every 2 weeks. Clinical assessment at treatment initiation and after .5, 1, and 2 years of uninterrupted treatment included anthropometric measurements and cardiologic evaluations (blood pressure [BP], electrocardiogram, conventional echocardiography, and myocardial strain imaging). Results: The linear growth of all patients improved significantly (mean height z-score: from -1.70 ± 0.80 to -0.96 ± 1.08, P=0.03). Other favorable effects were decline in overweight/obesity rates (from 46.2% to 23.1%) and decreased rates of elevated BP (systolic BP from 38.5% to 15.4%; diastolic BP from 38.5% to 23.1%). Electrocardiograms revealed no significant abnormality throughout the study period. Cardiac dimensions and myocardial strain parameters were within the normative range for age at baseline and remained unchanged during the study period. Conclusion: Cardiologic evaluations provided reassurance that 2 years of burosumab therapy did not cause cardiac morbidity. The beneficial effect of this treatment was a reduction in cardiovascular risk factors, as evidenced by the lower prevalence of both overweight/obesity and elevated BP.

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors.

BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability. RESULTS: 16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well. CONCLUSION: A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study.

Background: Childhood cancer survivors (CCS) are at risk for cardiotoxicity. Objectives: We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors. Methods: This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397 ≥5-year CCS and 277 siblings. Of CCS, n = 1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n = 143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression. Results: CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as <52% in men, <54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunction grade ≥II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors. Conclusions: Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among long-term CCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained risk of cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATER study; NTR7481).

Myocardial Function in Fetuses with Congenital Cytomegalovirus Infection.

INTRODUCTION: The objective of this study was to investigate myocardial deformation of left (LV) and right ventricle (RV) using 2-dimensional speckle-tracking echocardiography (2D-STE) in fetuses with and without congenital cytomegalovirus (CMV) infection. METHODS: This was a prospective single-center study. Vertical transmission was defined by a positive CMV polymerase chain reaction (PCR) test on the amniotic fluid or on the neonate's urine. Fetuses were divided into group 1 and group 2 if CMV-PCR was positive or negative, respectively. LV and RV global longitudinal strain (GLS) values were obtained and adjusted for gestational age by calculating Z-scores. Univariate analysis was carried out to compare cardiac indices between group 1 and group 2. RESULTS: Fetuses from group 1 (n = 11) had a significantly lower LV myocardial shortening than those from group 2 (n = 32). GLS was -20.7 ± 5.2% and -26.3 ± 4.1%, respectively (p = 0.001). Similarly, GLS Z-score was lower (0.02 ± 0.72) in group 1 than in group 2 (-0.80 ± 0.59) (p = 0.001). Similarly, RV GLS Z-score was significantly impaired in group 1 compared to group 2 (-0.44 ± 1.03 vs. -1.04 ± 0.71, p = 0.041). CONCLUSION: Fetuses with congenital CMV showed subclinical biventricular myocardial dysfunction. Further studies are needed to confirm the potential role of 2D-STE in identifying fetuses with congenital CMV at risk of postnatal cardiovascular morbidities.

The prevalence of abnormal right ventricle speckle strain in the setting of acute myocarditis and preserved left ventricle function.

BACKGROUND: Acute myocarditis has a wide spectrum of clinical presentation, from subclinical disease to acute heart failure, and sudden cardiac death. Two-dimensional speckle tracking echocardiography (2D-STE) has been proven effective in early diagnosis of subclinical cardiac injury, however, there is a limited data regarding the right ventricle (RV) involvement among patients with acute myocarditis. PURPOSE: We evaluated the prevalence of early subclinical RV injury assessed by 2D-STE, among patients with acute myocarditis and preserved left ventricle (LV) function. METHODS: We performed a retrospective single-center study at Tel-Aviv Sourasky Medical Center, including all adult patients hospitalized with acute myocarditis, who presented with preserved LV function. 2D-STE analysis of the RV was performed offline, assessing both the RV four-chamber longitudinal strain peak systolic (RV4CLS PK) and the free wall longitudinal strain peak systolic (RVFWLS PK). The myocarditis group was compared to a healthy control group. RESULTS: From 2011 to 2020, a total of 90 patients included in the study and were compared to 70 healthy subjects. RV 2D-STE emerged as significantly lower for both the RV4CLS PK (-21.8 ± 4.2 vs. -24.9 ± 4.8, P < 0.001) and RVFWLS PK (-24.7 ± 4.9 vs. -28.4 ± 5, P < 0.001), and remained significant in a multivariate analysis. CONCLUSION: We presented for the first time the presence of subclinical RV dysfunction, assessed by 2D-STE, in patients diagnosed with acute myocarditis, in the presence of preserved LV function. Further studies are needed to evaluate its' role in the development of LV dysfunction, heart failure and mortality.

High neutrophil-to-lymphocyte ratio as an early sign of cardiotoxicity in breast cancer patients treated with anthracycline.

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. A 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: Evaluating whether elevated NLR, during 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. 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 at T2 was found to be the optimal predictive cutoff for LV GLS deterioration. A relative LV GLS reduction ≥10% was significantly more common among patients with high NLR (50% vs. 20%, p = .009). NLR ≥ 2.58 at T2 increases the risk for LV GLS reduction by fourfold (odds ratio [OR]: 4.63, 95% confidence interval [CI]: 1.29-16.5, p = .02), with each increase of 1-point NLR adding an additional 15% risk (OR: 1.15, 95% CI: 1.01-1.32, p = .046). CONCLUSIONS: Our study provides novel data that high NLR levels, during ANT exposure, have an independent association with the development of LV dysfunction. Routine surveillance of NLR may be an effective means of risk-stratifying.

The prognostic value of right ventricular strain and mechanical dispersion on mortality in patients with normal left ventricle function.

AIMS: We aimed to assess if right ventricular (RV) 4-chamber longitudinal strain (RV4CLS), RV free wall longitudinal strain (RVFWLS) and RV mechanical dispersion index (RVMDI) have prognostic independent value in patients with preserved ejection fraction (pEF), without clearly elevated LV filling pressure. METHODS: Retrospective analysis of Peak RV4CLS, RVFWLS, RVMDI and comprehensive echocardiographic assessment including left ventricle (LV), atrium (LA) strain and RV parameters in patients with pEF (EF ≥ 50%; E/e' < 14). Multivariate Cox regression hazards model were used to determine the independent association between RV strain parameters to all-cause mortality and cardiovascular events. RESULTS: We analyzed 224 consecutive patients with pEF (age 65.2 ± 19.8, 44% female, Charlson Comorbidity Index median = 3.8), with all-cause mortality of 64 patients and 28 cardiovascular events, during a median follow-up of 8.2 years (interquartile range: 6.8 to 8.4 years). The best strain univariate predictors of mortality were RV4CSL [1.16 (1.07-1.26); p = 0.0001] and RVMDI [1.01 (1.001-1.02); p = 0.02] being superior to LV and LA strain, or other RV functional indices. Moreover, after adjustment for clinical (age, gender, Charlson Comorbidity Index), conventional echocardiographic parameters (LA volume, E/e' average, LVEDD, routine RV functional indices), LV and LA STE, RV4CLS and RVFWLS remained statistically significant associates of all-cause mortality and cardiac events. RV4CLS, or RVFWLS remained statistically significant associated for all-cause mortality, after additional adjustment for RVFAC and RVMDI. CONCLUSIONS: RV4CSL and RVMDI provide significant prognostic additive value in patients with preserved ejection fraction with excellent reproducibility, incremental to routine clinical, hemodynamic and LV and LA STE parameters.

Comprehensive Evaluation of Pediatric Patients with Ebstein Anomaly Requires Both Echocardiography and Cardiac Magnetic Resonance Imaging.

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.

Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

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/m2 (moderate recommendation). No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m2, 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.

Cardiac function in childhood cancer survivors treated with vincristine: Echocardiographic results from the DCCSS LATER 2 CARD study.

BACKGROUND: Anthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential cardiotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine-treated >5-year childhood cancer survivors (CCS). METHODS AND RESULTS: We cross-sectionally compared echocardiograms of 101 vincristine-treated CCS (median age 35 years [range: 17-53], median vincristine dose 63 mg/m2) from the national Dutch Childhood Cancer Survivor Study, LATER cohort, to 101 age- and sex-matched controls. CCS treated with anthracyclines, radiotherapy involving the heart region, cyclophosphamide or ifosfamide were excluded. Twelve CCS (14%) versus four controls (4%; p 0.034) had a decreased left ventricular ejection fraction (LVEF; men <52%, women <54%). Mean LVEF was 58.4% versus 59.7% (p 0.050). Global longitudinal strain (GLS) was abnormal in nineteen (24%) CCS versus eight controls (9%; p 0.011). Mean GLS was 19.0% versus 20.1% (p 0.001). No ≥grade 2 diastolic dysfunction was detected. In multivariable logistic regression analysis CCS had higher risk of abnormal GLS (OR 3.55, p 0.012), but not abnormal LVEF (OR 3.07, p 0.065), than controls. Blood pressure and smoking history contributed to variation in LVEF, whereas obesity and diastolic blood pressure contributed to variation in GLS. Cumulative vincristine dose was not associated with either abnormal LVEF or abnormal GLS in multivariable models corrected for age and sex (OR per 50 mg/m2: 0.88, p 0.85 and 1.14, p 0.82, respectively). CONCLUSIONS: Vincristine-treated long-term CCS showed an abnormal GLS more frequently than controls. Their risk for future clinical cardiac events and the role of risk factor modification should be further elucidated.

Candidate Plasma Biomarkers to Detect Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A Case Control Study in the Dutch Childhood Cancer Survivor Study.

Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.

Electrocardiographic abnormalities in childhood cancer survivors treated with cardiotoxic therapy: a systematic review.

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.

Cardiac Events in Childhood Cancer Survivors Treated with Anthracyclines: The Value of Previous Myocardial Strain Measurement.

In echocardiographic surveillance of anthracycline-treated childhood cancer survivors (CCS), left ventricular ejection fraction (LVEF) has insufficient prognostic value for future cardiac events, whereas longitudinal strain may be more sensitive. We describe the long-term incidence of cardiac events in CCS after previous measurement of LVEF and myocardial strain. Echocardiography, including four-chamber view longitudinal strain (4CH-LS), of 116 anthracycline-treated CCS was obtained between 2005−2009 (index echocardiography). Follow-up was obtained at the late-effects clinic. Primary outcome was occurrence of cardiac events, defined as either symptomatic heart failure, life-threatening arrhythmias, LVEF < 40% or cardiac death, in CCS with normal versus abnormal index 4CH-LS. LVEF from subsequent echocardiograms was obtained to evaluate its natural course as a secondary outcome. After index echocardiography (median 13.1 years since childhood cancer diagnosis), our study added a median follow-up of 11.3 years (median last clinical contact 23.6 years since diagnosis). Only three CCS developed a cardiac event (6.2, 6.4 and 6.7 years after index echocardiography), resulting in a ten-year cumulative incidence of 2.7% (95%CI 0.9−8.2). All three CCS had a clearly reduced index 4CH-LS and relevant cardiovascular risk factors, whereas their index LVEFs were around the lower limit of normal. Index LVEF correlated with index 4CH-LS but mean long-term natural course of LVEF was comparable for CCS with abnormal versus normal index 4CH-LS. Absolute 10-year cumulative incidence of cardiac events in anthracycline-treated CCS during long-term follow-up was low. Sensitive echocardiographic measurements, such as 4CH-LS may be useful to tailor surveillance frequency in a selected group of CCS without cardiovascular disease.

Prevalence of Right Ventricle Strain Changes following Anthracycline Therapy.

BACKGROUND: Anthracycline (ANT) is the most recognized therapy known to cause cardiotoxicity, mainly left ventricle (LV) dysfunction. Global Longitudinal Strain (GLS) is the optimal tool for assessment of subclinical LV dysfunction. Right ventricle (RV) function has been recognized as an independent factor for cardiac outcomes; however, data evaluating RV GLS is limited. We aimed to evaluate the change in RV GLS following ANT therapy. METHODS: The study cohort is part of the Israel Cardio-Oncology Registry (ICOR). All patients performed echocardiography before (T1) and at the end (T3) of ANT therapy. A significant reduction was defined as a relative reduction of ≥10% in RV GLS values. RESULTS: The study included 40 female patients with breast cancer treated with ANT. During follow-up, both RV GLS and free wall longitudinal strain systolic peak (RV FWLS PK) decreased significantly (p < 0.001 and p = 0.002). Altogether, 30 (75%) and 23 (58%) patients showed RV GLS and RV FWLS PK ≥ 10% relative reduction. At T3, LV ejection fraction and LV GLS were within normal range. CONCLUSIONS: RV GLS and RV FWLS PK reduction following ANT exposure is extremely frequent, comparing to LV GLS reduction.

Asymptomatic systolic dysfunction on contemporary echocardiography in anthracycline-treated long-term childhood cancer survivors: a systematic review.

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.

Effects of maternal aspirin treatment on hemodynamically significant patent ductus arteriosus in preterm infants - pilot study.

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 <34 weeks whose mothers were treated with aspirin during gestation, and were screened for patent ductus arteriosus due to severe respiratory distress syndrome and the need for positive pressure ventilation. These infants were compared to 42 preterm infants born without exposure to aspirin in utero. RESULTS: We found significantly lower frequency of hs-PDA and higher rate of successful pharmacological PDA closure after single course of ibuprofen treatment along with significantly lower cumulative doses of ibuprofen in the study group. Furthermore, PDA closure was achieved significantly earlier in the study group (day 4 versus 11, p = .02). CONCLUSION: Aspirin treatment during pregnancy seemed to reduce the incidence of hs-PDA in preterm infant and to increase infant responsiveness to postnatal medical treatment of PDA.

Evolution of right and left ventricle routine and speckle-tracking echocardiography in patients recovering from coronavirus disease 2019: a longitudinal study.

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.