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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., (© 2024. The Author(s).)

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%., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Anthracycline-induced cardiotoxicity can lead to clinical and subclinical heart failure. Decrease of global longitudinal strain is a predictor for heart failure. Early detection of subclinical cardiotoxicity is crucial for timely intervention and prevention of further progression. Cardiac function of 41 survivors of childhood acute lymphoblastic leukemia (ALL) was assessed. Values of cardiac troponin T, N-terminal-pro-brain natriuretic peptide, conventional and myocardial 2D strain echocardiography were measured before (T = 0), during (T = 1, cumulative dose of 120 mg/m 2 ), shortly after (T = 2) and long after anthracycline treatment (T = 3, ≥5 years after anthracycline exposure). Cardiac function of survivors at the latest follow up was compared with 70 healthy age-matched controls. None of the survivors showed clinical signs of cardiac failure at T = 3. Strain values decreased during anthracycline treatment and an ongoing reduction was seen at the latest follow-up (T = 3) with preserved cardiac function (normal ejection fraction and shortening fraction). At T = 1, a relative reduction in longitudinal strain (≥10% compared with baseline) was observed in 38% of the survivors, which increased to 54% at T=3. ALL survivors showed significantly lower conventional and myocardial 2D strain values, especially strain rate, compared with healthy age-matched controls. At T = 3, we did not find any abnormal cardiac troponin T levels. Six percent of the survivors showed abnormal N-terminal-pro-brain natriuretic peptide levels. This prospective study showed an ongoing reduction of 2D myocardial strain and strain rate, with preserved left ventricular ejection fraction (≤10% decrease compared with baseline) in asymptomatic ALL survivors at late follow-up., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: ECG and echocardiography are noninvasive screening tools to detect subclinical cardiotoxicity in childhood cancer survivors (CCSs). Our aims were as follows: (1) assess the prevalence of abnormal ECG patterns, (2) determine the agreement between abnormal ECG patterns and echocardiographic abnormalities; and (3) determine whether ECG screening for subclinical cardiotoxicity in CCSs is justified., Procedure: We retrospectively studied ECG and echocardiography in asymptomatic CCSs more than 5 years after anthracycline treatment. Exclusion criteria were abnormal ECG and/or echocardiogram at the start of therapy, incomplete follow-up data, clinical heart failure, cardiac medication, and congenital heart disease. ECG abnormalities were classified using the Minnesota Code. Level of agreement between ECG and echocardiography was calculated with Cohen kappa., Results: We included 340 survivors with a mean follow-up of 14.5 years (range 5-32). ECG was abnormal in 73 survivors (21.5%), with ventricular conduction disorders, sinus bradycardia, and high-amplitude R waves being most common. Prolonged QTc (>0.45 msec) was found in two survivors, both with a cumulative anthracycline dose of 300 mg/m 2 or higher. Echocardiography showed abnormalities in 44 survivors (12.9%), mostly mild valvular abnormalities. The level of agreement between ECG and echocardiography was low (kappa 0.09). Male survivors more often had an abnormal ECG (corrected odds ratio: 3.00, 95% confidence interval: 1.68-5.37)., Conclusions: Abnormal ECG patterns were present in 21% of asymptomatic long-term CCSs. Lack of agreement between abnormal ECG patterns and echocardiographic abnormalities may suggest that ECG is valuable in long-term follow-up of CCSs. However, it is not clear whether these abnormal ECG patterns will be clinically relevant., (© 2016 Wiley Periodicals, Inc.)

Previous studies to determine the sensitivity of the electrocardiogram (ECG) for left ventricular hypertrophy (LVH) in children had their imperfections: they were not done on an unselected hospital population, several criteria used in adults were not applied to children, and obsolete limits of normal for the ECG parameters were used. Furthermore, left ventricular mass (LVM) was taken as the reference standard for LVH, with no regard for other clinical evidence. The study population consisted of 832 children from whom a 12-lead ECG and an M-mode echocardiogram were taken on the same day. The validity of the ECG criteria was judged on the basis of an abnormal LVM index, either alone or in combination with other clinical evidence. The ECG criteria were based on recently established age-dependent normal limits. At 95% specificity, the ECG criteria have low sensitivities (<25%) when an elevated LVM index is taken as the reference for LVH. When clinical evidence is also taken into account, the sensitivity improved considerably (<43%). Sensitivities could be further improved when ECG parameters were combined. The sensitivity of the pediatric ECG in detecting LVH is low but depends strongly on the definition of the reference used for validation.

Noonan syndrome is a developmental disorder with distinctive facial features, short stature and cardiac abnormalities. In this cross-sectional study, we evaluated characteristic electrocardiographic (ECG) findings and cardiac abnormalities in 84 patients with Noonan syndrome, 56 (67%) of who were positive for a PTPN11 mutation. As reported previously, pulmonary stenosis was the most common cardiac abnormality, followed by atrial septal defect and hypertrophic cardiomyopathy. The ECG showed at least one characteristic finding in 50% of cases including left axis deviation in 38 (45%), small R waves in the left precordial leads in 20 (24%) and an abnormal Q wave in 5 (6%) patients with Noonan syndrome. A wide QRS complex was not detected in any of these patients. The characteristic ECG findings of Noonan syndrome patients were not associated with a PTPN11 gene mutation, or with a (specific) cardiac anomaly. We conclude that there are characteristic ECG findings in Noonan syndrome, but the ECG pattern is neither a useful tool for the phenotype characterization of a PTPN11 mutation, nor for the presence or type of cardiac abnormality.

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. [ABSTRACT FROM AUTHOR]

Objective: This study assessed clinical condition at midterm follow-up after total cavopulmonary connection for a functionally univentricular heart performed on children younger than 5 years. Methods: Thirty-four Fontan patients (median age 10.4 years, range 6.8–20.7 years, 22 boys, median follow-up 7.8 years, 5.0–17.8 years) underwent electrocardiography, Holter monitoring, bicycle exercise testing, cardiac magnetic resonance imaging, and N-terminal prohormone brain natriuretic peptide (NT-pro-BNP) analysis. Results: Twenty-three patients (68%) were in sinus rhythm. Holter monitoring demonstrated normal mean heart rate, low maximal heart rate, and no clinically significant arrhythmias or sinus node dysfunction. With maximal bicycle ergometry (n = 19), maximum workload (60% of normal), maximum heart rate (90% of normal), and maximal oxygen uptake (69% of normal) were all significantly lower in the Fontan group than in a control group (P < .001). Variables of submaximal exercise indicated less efficient oxygen uptake during exercise in all Fontan patients. Ejection fraction was lower than in control subjects (59% ± 13% vs 69% ± 5%, P < .001). Mean end-diastolic and end-systolic volumes and ventricular mass were higher than in control subjects (P < .001). Mean NT-pro-BNP levels were increased relative to reference values, but only 8 patients had levels above the upper reference limit. Conclusion: At midterm follow-up, Fontan patients were in acceptable clinical condition, with preserved global ventricular function, moderately decreased exercise capacity, and NT-pro-BNP levels within reference range. Systemic ventricular mass was elevated, however, suggesting contractility–afterload mismatch. Long-term consequences for ventricular function merit further investigation. [Copyright &y& Elsevier]

Summary: Background: Chemotherapy for the treatment of maternal cancers during pregnancy has become more acceptable in the past decade; however, the effect of prenatal exposure to chemotherapy on cardiac and neurodevelopmental outcomes of the offspring is still uncertain. We aimed to record the general health, cardiac function, and neurodevelopmental outcomes of children who were prenatally exposed to chemotherapy. Methods: We did an interim analysis of a multicentre observational cohort study assessing children who were prenatally exposed to maternal cancer staging and treatment, including chemotherapy. We assessed children at birth, at age 18 months, and at age 5–6, 8–9, 11–12, 14–15, or 18 years. We did clinical neurological examinations, tests of the general level of cognitive functioning (Bayley or intelligence quotient [IQ] test), electrocardiography and echocardiography, and administered a questionnaire on general health and development. From age 5 years, we also did audiometry, the Auditory Verbal Learning Test, and subtasks of the Children''s Memory Scale, and the Test of Everyday Attention for Children, and we also completed the Child Behavior Checklist. This study is registered with ClinicalTrials.gov, number NCT00330447. Findings: 236 cycles of chemotherapy were administered in 68 pregnancies. We assessed 70 children, born at a median gestational age of 35·7 weeks (range 28·3–41·0; IQR 3·3; 47 women at <37 weeks), with a median follow-up period of 22·3 months (range 16·8–211·6; IQR 54·9). Although neurocognitive outcomes were within normal ranges, cognitive development scores were lower for children who were born preterm than for those born at full term. When controlling for age, sex, and country, the score for IQ increased by an average 11·6 points (95% CI 6·0–17·1) for each additional month of gestation (p<0·0001). Our measurements of the children''s behaviour, general health, hearing, and growth corresponded with those of the general population. Cardiac dimensions and functions were within normal ranges. We identified a severe neurodevelopmental delay in both members of one twin pregnancy. Interpretation: Fetal exposure to chemotherapy was not associated with increased CNS, cardiac or auditory morbidity, or with impairments to general health and growth compared with the general population. However, subtle changes in cardiac and neurocognitive measurements emphasise the need for longer follow-up. Prematurity was common and was associated with impaired cognitive development. Therefore, iatrogenic preterm delivery should be avoided when possible. Funding: Research Foundation-Flanders; Research Fund-K U Leuven; Agency for Innovation by Science and Technology; Stichting tegen Kanker; Clinical Research Fund-University Hospitals Leuven; and Belgian Cancer Plan, Ministery of Health. [Copyright &y& Elsevier]

Abstract: We studied the role of global myocardial strain and strain rate in monitoring subclinical heart failure in a large group of asymptomatic long-term survivors of childhood cancer. Global strain (rate) parameters of survivors were compared with those in healthy controls and were related to conventional echocardiographic parameters, N-terminal-pro-natriuretic peptide (NT-pro-BNP) levels and clinical parameters. Two-dimensional (2-D) echocardiography was performed in 111 survivors and 107 healthy controls. Blood samples were taken from survivors to determine NT-pro-BNP levels. We showed that global myocardial strain, strain rate and time to peak systolic strain in asymptomatic survivors of childhood cancer were significantly lower compared with healthy controls (p values <0.0001) and were significantly related to several systolic and diastolic left ventricular parameters. Whether myocardial strain and strain rate are superior to conventional echocardiography in the early detection of subclinical heart failure needs to be explored in further longitudinal prospective studies. (E-mail: A.Mavinkurve@cukz.umcn.nl) [Copyright &y& Elsevier]