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Background: Measurement of ventricular volumes and function using MRI is an important tool in pediatric congenital heart disease. However, normal values for children are sparce and analysis methods are inconsistent. Purpose: To propose biventricular reference values in children for two MRI postprocessing (contouring) techniques. Study Type: Retrospective. Subjects: A total of 154 children from two institutions (13.9 ± 2.8 years; 101 male) that were referred for a clinical MRI study. Field Strength/Sequence: 1.5 T; balanced steady‐state free precession (bSSFP) sequence. Assessment: Left ventricular (LV) and right ventricular (RV) end‐diastolic and end‐systolic volumes (LVEDV, LVESV, RVEDV, RVESV) and end‐diastolic and end‐systolic myocardial mass (LVEDMM, LVESMM, RVEDMM, RVESMM) were measured from short‐axis images using two contouring techniques: 1) papillary muscles, trabeculations and the moderator band were included in the ventricular blood volume and excluded from the myocardial mass, 2) papillary muscles, trabeculations and the moderator band were excluded from the ventricular volume and included in the ventricular mass. Statistical Tests: Univariable and multivariable linear regression models were used to evaluate relationships between sex, weight, height, body surface area (BSA) and age and volumetric results. Reference graphs and tables were created with the LMS‐method. Contouring techniques were compared by intraclass correlation, regression analysis and Bland–Altman plots. A P value < 0.05 was considered statistically significant. Results: Height and BSA were significantly associated with LVESV (method 1) and with LVEDV and RVEDV (method 2). LVESV (method 2), RVESV (both methods), RVEDV (method 1), and LVEDMM and RVEDMM (both methods), showed significant associations with height and weight. LVSV and RVSV (both methods) were significantly associated with BSA and weight. RVESV (method 1) was significantly associated with age. Gender showed significant associations for all parameters. Data Conclusion: The proposed pediatric reference values can be used in the diagnosis and follow‐up of congenital or acquired heart disease and for research purposes. Evidence Level: 3 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background: Measurement of atrial volumes by MRI is becoming increasingly important in pediatric cardiac disorders. However, MRI normal values for atrial volumes in children are lacking. Purpose: To establish pediatric reference values for atrial volumes. Study Type: Retrospective. Subjects: A total of 155 healthy children from two large institutions (103 male, age 13.9 ± 2.8 years, range 4–18 years). Field Strength/Sequence: A 1.5 T; balanced steady‐state free precession (bSSFP) sequence. Assessment: The monoplane and biplane area‐length methods were used to measure minimal and maximal left and right atrial volumes (LAmin, LAmax, RAmin, and RAmax) from four‐chamber (4ch) and two‐chamber (2ch) MR cine images. Centile charts and tables for atrial volumes were created. Statistical Tests: Descriptive statistics, lambda‐mu‐sigma (LMS)‐method of Cole and Green, univariable and multivariable linear regression models. A P value < 0.05 was considered to be statistically significant. Results: In the multivariable linear model, body surface area was significantly associated with all atrial volumes and sex was significantly associated with RA volumes, LA volumes measured in the 2ch‐view as well as biplane LAmax. Average atrial volumes measured: monoplane 4ch: LAmin 13.1 ± 4.8 mL/m2, LAmax 33.4 ± 8.8 mL/m2, RAmin 18.5 ± 6.8 mL/m2, RAmax 33.2 ± 9.6 mL/m2; monoplane 2ch: LAmin 12.7 ± 4.9 mL/m2, LAmax 30.5 ± 9.5 mL/m2; biplane: LAmin 12.3 ± 4.5 mL/m2, LAmax 30.9 ± 8.7 mL/m2. Data Conclusion: Pediatric MRI reference values for atrial volumes have been provided. Technical Efficacy: 2 Evidence Level: 4 [ABSTRACT FROM AUTHOR]

Aims: Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort.Methods and Results: Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children (<16 years) with HCM from the UK. Seventy-six (84%) had an endovascular system [14 (18%) dual coil], 3 (3%) epicardial, and 11 (12%) subcutaneous system. Defibrillation threshold (DFT) testing was performed at implant in 68 (76%). Inadequate DFT in four led to implant adjustment in three patients. Over a median follow-up of 54 months (interquartile range 28-111), 25 (28%) patients had 53 appropriate therapies [ICD shock n = 45, anti-tachycardia pacing (ATP) n = 8], incidence rate 4.7 per 100 patient years (95% CI 2.9-7.6). Eight inappropriate therapies occurred in 7 (8%) patients (ICD shock n = 4, ATP n = 4), incidence rate 1.1/100 patient years (95% CI 0.4-2.5). Three patients (3%) died following arrhythmic events, despite a functioning device. Other device complications were seen in 28 patients (31%), including lead-related complications (n = 15) and infection (n = 10). No clinical, device, or programming characteristics predicted time to inappropriate therapy or lead complication.Conclusion: In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications. [ABSTRACT FROM AUTHOR]

Aims Understanding the spectrum of disease, symptom burden and natural history are essential for the management of children with hypertrophic cardiomyopathy (HCM). The effect of changing screening practices over time has not previously been studied. This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort. Methods and results Six hundred and eighty-seven patients with HCM presented at a median age of 5.2 years (range 0–16). Aetiology was: non-syndromic (n  = 433, 63%), RASopathy (n  = 126, 18.3%), Friedreich's ataxia (n  = 59, 8.6%) or inborn errors of metabolism (IEM) (n  = 64, 9%). In infants (n  = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P  < 0.0001) or IEM (18.9% vs. 6.4% P  < 0.0001). In those with familial disease, median age of presentation was higher (11 years vs. 6 years, P  < 0.0001), 141 (58%) presented <12 years. Freedom from death or transplantation was 90.6% (87.9–92.7%) at 5 years (1.5 per 100 patient years) with no era effect. Mortality was most frequently sudden cardiac death (SCD) (n  = 20, 2.9%). Children diagnosed during infancy or with an IEM had a worse prognosis (5-year survival 80.5% or 66.4%). Arrhythmic events occurred at a rate of 1.2 per 100 patient years and were more likely in non-syndromic patients (n  = 51, 88%). Conclusion This national study describes a heterogeneous disease whose outcomes depend on the age of presentation and aetiology. Overall mortality and SCD rates have not changed over time, but they remain higher than in adults with HCM, with events occurring in syndromic and non-syndromic patients. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

Congenital Heart Defects (CHD) have a neonatal incidence of 0.8-1%1,2. Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%)3, suggesting a considerable role for de novo mutations (DNM), and/or incomplete penetrance4,5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of ‘syndromic’ patients with extra-cardiac manifestations6,7. We exome sequenced 1,891 probands, including both syndromic (S-CHD, n=610) and non-syndromic cases (NS-CHD, n=1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs, but not inherited PTVs, in known CHD-associated genes, consistent with recent findings8. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three novel genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study reveals distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

BACKGROUND: Existing studies of childhood dilated cardiomyopathy deal mainly with early survival. This population-based study examines long-term outcomes for children with dilated cardiomyopathy. METHODS AND RESULTS: The diagnosis of dilated cardiomyopathy was based on clinical, echocardiographic, and pathological findings. The primary study end point included time to the combined outcome of death or cardiac transplantation. There were 175 patients 0 to <10 years of age at the time of diagnosis. Survival free from death or transplantation was 74% (95% confidence interval, 67-80) 1 year after diagnosis, 62% (95% confidence interval, 55-69) at 10 years, and 56% (95% confidence interval, 46-65) at 20 years. In multivariable analysis, age at diagnosis <4 weeks or >5 years, familial cardiomyopathy, and lower baseline left ventricular fractional shortening Z score were associated with increased risk of death or transplantation, as was lower left ventricular fractional shortening Z score during follow-up. At 15 years after diagnosis, echocardiographic normalization had occurred in 69% of surviving study subjects. Normalization was related to higher baseline left ventricular fractional shortening Z score, higher left ventricular fractional shortening Z score during follow-up, and greater improvement in left ventricular fractional shortening Z score. Children with lymphocytic myocarditis had better survival and a higher rate of echocardiographic normalization. At the latest follow-up, 100 of 104 of survivors (96%) were free of cardiac symptoms, and 83 (80%) were no longer receiving pharmacotherapy. CONCLUSIONS: Death or transplantation occurred in 26% of patients with childhood dilated cardiomyopathy within 1 year of diagnosis and 1% per year thereafter. Risk factors for death or transplantation include age at diagnosis, familial cardiomyopathy, and severity of left ventricular dysfunction. The majority of surviving subjects are well and free of cardiac medication. [ABSTRACT FROM AUTHOR]

The Scimitar syndrome is a complex association of cardiovascular and bronchopulmonary abnormalities, with the main feature a partial or total anomalous right pulmonary venous drainage to the inferior vena cava. A number of cases that lack of all the features of the typical syndrome have been described as Scimitar variant, but the incidence is rare. Familial occurrence is exceptional and limited to few cases in literature. We report two sibling diagnosed with an uncommon variant of the Scimitar syndrome. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular magnetic resonance (CMR) derived global function index (GFI) and myocardial contraction fraction (MCF) were identified as useful imaging markers to assess left ventricular (LV) cardiac performance and can provide prognostic information for several cardiac diseases. As pediatric reference values are lacking, the aim of this retrospective study was to establish these values., Methods: 154 CMR examinations of healthy children and adolescents (4-18 years) were included. LV end-diastolic, end-systolic and stroke volumes, ejection fraction (LVEF) and myocardial mass were measured using short axis stacks. Results were used to calculate LVGFI and LVMCF. Statistically, the Lambda-Mu-Sigma (LMS)-method was applied to create percentile curves and tables., Results: The mean age (standard deviation) of the subjects was 13.8 (2.8) years, 102 were male (66%). Mean LVGFI was 46.3 (6.0)% and mean LVMCF was 110.6 (19.9) %. Both, LVGFI and LVMCF decreased significantly with age (LVGFI: r = -0.30, p < 0.001; LVMCF: -0.30, p < 0.001). There was no statistical difference between girls and boys (p all >0.05). Strong correlations between LVGFI and LVMCF (r = 0.78, p < 0.001) as well as between LVGFI and LVEF (r = 0.80, p < 0.001) were documented whereas the correlation of LVMCF and LVEF was weaker (r = 0.32, p < 0.001). Univariable and multivariable regression analysis demonstrated that LVGFI was strongly associated with age whereas LVMCF was associated with weight. Percentile curves and tables were created accordingly., Conclusion: We provide pediatric CMR reference values for the new cardiac functional markers LVGFI and LVMCF. These may improve the interpretation of clinical CMR studies and can be used for future research studies., (Copyright © 2024. Published by Elsevier B.V.)

Background: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated., Aim: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population., Methods: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters., Results: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7-28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43-1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49-169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58-19.03, p < 0.007) were predictors of SCD on univariate analysis., Conclusion: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further., Competing Interests: Declaration of Competing Interest Wolf CM: consultancy with Day One Biopharmaceuticals, Inc., BioMarin Pharmaceuticals, Adrenomed AG, and Pliant Therapeutics; ownership interest: Preventage Therapeutics. Zenker M: consultancy with Day One Biopharmaceuticals, Inc. and Novo Nordisk., (Copyright © 2023. Published by Elsevier B.V.)

Background: Myocardial deformation can be assessed from routine cardiac magnetic resonance (MR) images using two-dimensional feature tracking (2D-FT). Although reference values are essential for implementation of strain imaging in clinical practice, data for the healthy pediatric age group are limited., Purpose: To provide pediatric MR reference values for strain and strain rate for all four heart chambers., Study Type: Retrospective., Subjects: One hundred and fifty-seven healthy children from two institutions (102 male, age 4.7-18 years)., Field Strength/sequence: 1.5 T; balanced steady-state free precession sequence., Assessment: Left ventricular (LV) global and regional longitudinal, circumferential, and radial strain and strain rate as well as right ventricular (RV) and atrial global and regional longitudinal strain and strain rate were measured in two-, three-, and four-chamber views and the short axis stack. The relationships between strain parameters and age, height, weight, and gender were investigated. Age- and height-specific centile curves and tables were created for LV strain and strain rate. For all other global strain parameters, the mean was calculated as a reference., Statistical Tests: Lambda-mu-sigma (LMS)-method of Cole and Green, univariable, and multivariable linear regression models. A P value <0.05 was considered to be statistically significant., Results: Age, height and weight had a significant influence on LV global strain values. These parameters also showed an influence on RV strain but only in boys (girls P = 0.12) and none of the variables had a significant influence on atrial strain (P = 0.19-0.49). Gender differences were only found for RV strain values., Data Conclusion: Pediatric potential reference values for myocardial deformation parameters of both ventricles and atria are provided. The values may serve as a reference in future studies and clinical practice., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 5., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized., Objectives: The aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years., Methods: Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years., Results: At baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age., Conclusions: Early-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages., Competing Interests: Funding Support and Author Disclosures This work was supported by the British Heart Foundation (grant FS/16/72/32270) to Drs Norrish and Kaski. This work is (partly) funded by the National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre. Dr Norrish is supported by Great Ormond Street Hospital Children’s Charity. Drs Field and Kaski are supported by Max’s Foundation and Great Ormond Street Hospital Children’s Charity. Dr Kaski is supported by a Medical Research Council–National Institute for Health Research Clinical Academic Research Partnership award. This work was financially supported by the Foundation for Paediatric Research of Finland (Dr Ojala). Dr Fernandez has received speaker fees from Sanofi-Genzyme. Dr Kubus is supported by MH CZ – DRO, Motol University Hospital (00064203). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort., Methods: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids)., Results: MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk., Conclusions: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.

Aims: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort., Methods and Results: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n = 187 (62.1%)], underlying aetiology was non-syndromic (n = 138, 45.6%), RASopathy (n = 101, 33.6%), or inborn error of metabolism (IEM) (n = 49, 16.3%). The most common reasons for presentation were symptoms (n = 77, 29.3%), which were more prevalent in those with syndromic disease (n = 62, 61.4%, P < 0.001), and an isolated murmur (n = 75, 28.5%). One hundred and sixty-one (53.5%) had one or more co-morbidities. Genetic testing was performed in 163 (54.2%) patients, with a disease-causing variant identified in 115 (70.6%). Over median follow-up of 4.1 years, 50 (16.6%) underwent one or more surgical interventions; 15 (5.0%) had an arrhythmic event (6 in the first year of life); and 48 (15.9%) died, with an overall 5 year survival of 85%. Predictors of all-cause mortality were an underlying diagnosis of IEM [hazard ratio (HR) 4.4, P = 0.070], cardiac symptoms (HR 3.2, P = 0.005), and impaired left ventricular systolic function (HR 3.0, P = 0.028)., Conclusions: This large, multicentre study of infantile HCM describes a complex cohort of patients with a diverse phenotypic spectrum and clinical course. Although overall outcomes were poor, this was largely related to underlying aetiology emphasizing the importance of comprehensive aetiological investigations, including genetic testing, in infantile HCM., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort., Methods and Results: Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children (<16 years) with HCM from the UK. Seventy-six (84%) had an endovascular system [14 (18%) dual coil], 3 (3%) epicardial, and 11 (12%) subcutaneous system. Defibrillation threshold (DFT) testing was performed at implant in 68 (76%). Inadequate DFT in four led to implant adjustment in three patients. Over a median follow-up of 54 months (interquartile range 28-111), 25 (28%) patients had 53 appropriate therapies [ICD shock n = 45, anti-tachycardia pacing (ATP) n = 8], incidence rate 4.7 per 100 patient years (95% CI 2.9-7.6). Eight inappropriate therapies occurred in 7 (8%) patients (ICD shock n = 4, ATP n = 4), incidence rate 1.1/100 patient years (95% CI 0.4-2.5). Three patients (3%) died following arrhythmic events, despite a functioning device. Other device complications were seen in 28 patients (31%), including lead-related complications (n = 15) and infection (n = 10). No clinical, device, or programming characteristics predicted time to inappropriate therapy or lead complication., Conclusion: In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)