Clinical impact of novel CMR technology on patients with congenital heart disease. A scientific statement of the Association for European Pediatric and Congenital Cardiology (AEPC) and the European Association of Cardiovascular Imaging (EACVI) of the ESC.

Cardiovascular magnetic resonance (CMR) imaging is recommended in patients with congenital heart disease (CHD) in clinical practice guidelines as the imaging standard for a large variety of diseases. As CMR is evolving, novel techniques are becoming available. Some of them are already used clinically, whereas others still need further evaluation. In this statement the authors give an overview of relevant new CMR techniques for the assessment of CHD. Studies with reference values for these new techniques are listed in the supplement.

Systemic-to-pulmonary collateral flow associations with antegrade pulmonary flow in single ventricle patients: insights from cardiac magnetic resonance imaging.

Purpose: In the palliated single ventricle anomalies, a considerable amount of the aortic flow may be absorbed by the systemic-pulmonary collateral flow (SPCF), which can be noninvasively assessed by cardiac magnetic resonance (CMR). The aims of this study were to (1) identify factors associated with SCPF in pediatric single ventricle patients, and (2) establish a cutoff values indicating an association between SCPF and a reduction in antegrade pulmonary flow. Methods: A retrospective single-tertiary-center cohort study included 158 consecutive CMR studies of patients with a single ventricle. In the uni- and multivariable analysis, SPCF was presented as a percentage of the total pulmonary venous flow (SPCF%PV). The minimal clinically important difference in QP/QS ratios was estimated as ≥0.50, and an optimal cutoff value was defined using the receiver operating characteristic (ROC) curve. Results: SPCF%PV was significantly smaller in the post-total cavopulmonary connection (TCPC) group than in the pre-TCPC patients (p < 0.001). The patient's higher age and a higher antegrade pulmonary flow were associated with a lower SPCF%PV. A negative weak association was observed between the SPCF%PV and systemic saturation (r = -0.39, p < 0.001). SPCF%PV did not associate with ventricular volumes nor ejection fraction. The SPCF%PV was significantly smaller in patients that were palliated primarily with a pulmonary artery banding compared to those palliated with a BT-shunt (p = 0.002) or RV-PA- shunt (p = 0.044). In the ROC analysis, for pre-TCPC patient's, a cutoff of SPCF%PV 42% yielded a sensitivity of 100% and specificity of 80% for significantly reduced antegrade pulmonary flow (AUC 0.97). In the post-TCPC group, the optimal SPCF%PV cutoff was 34% (sensitivity 100%, specificity 98%, AUC 0.99). Conclusion: SPCF results in a considerable left-to-right shunt, which subsequently diminishes spontaneously after TCPC. Our findings indicated that for pre-TCPC patients, an SPCF%PV threshold of 42% (sensitivity 100%, specificity 80%), and for the post-TCPC group, a threshold of 34% (sensitivity 100%, specificity 98%) were effective in identifying reduced antegrade pulmonary flow.

Genome-wide association studies highlight novel risk loci for septal defects and left-sided congenital heart defects.

BACKGROUND: Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database. RESULTS: We discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12-1.23], p = 1.5 × 10-9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80-7.17], p = 7.0 × 10-10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09-1.21], p = 7.1 × 10-9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11-1.20], p = 1.5 × 10-9) which is in significant LD with rs2316327. CONCLUSIONS: Our results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

Cardiomyopathies in children and adolescents: aetiology, management, and outcomes in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Registry.

BACKGROUND AND AIMS: Childhood-onset cardiomyopathies are rare and poorly characterized. This study examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry. METHODS: Prospective data were collected on individuals aged 1-<18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry (June 2014-December 2016). RESULTS: A total of 633 individuals aged ≤18 years with hypertrophic [HCM; n = 388 (61.3%)], dilated [DCM; n = 206 (32.5%)], restrictive [RCM; n = 28 (4.4%)], and arrhythmogenic right ventricular cardiomyopathy [ARVC; n = 11 (1.7%)] were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 [interquartile range (IQR) 0-10] years, and there was a male predominance [n = 372 (58.8%)] across all subtypes, with the exception of DCM diagnosed <10 years of age; 621 (98.1%) patients were receiving cardiac medication and 80 (12.6%) had an implantable cardioverter-defibrillator. A total of 253 patients (253/535, 47.3%) had familial disease. Genetic testing was performed in 414 (67.8%) patients with a pathogenic or likely pathogenic variant reported in 250 (60.4%). Rare disease phenocopies were reported in 177 patients (28.0%) and were most frequent in patients under 10 years [142 (30.9%) vs. 35 (19.6%); P = .003]. Over a median follow-up of 12.5 months (IQR 11.3-15.3 months), 18 patients (3.3%) died [HCM n = 9 (2.6%), DCM n = 5 (3.0%), RCM n = 4 (16.0%)]. Heart failure events were most frequent in RCM patients (36.0%). CONCLUSIONS: The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differed by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment.

Organisation of paediatric echocardiography laboratories and governance of echocardiography services and training in Europe: current status, disparities, and potential solutions. A survey from the Association for European Paediatric and Congenital Cardiology (AEPC) imaging working group.

BACKGROUND: There is limited data on the organisation of paediatric echocardiography laboratories in Europe. METHODS: A structured and approved questionnaire was circulated across all 95 Association for European Paediatric and Congenital Cardiology affiliated centres. The aims were to evaluate: (1) facilities in paediatric echocardiography laboratories across Europe, (2) accredited laboratories, (3) medical/paramedical staff employed, (4) time for echocardiographic studies and reporting, and (5) training, teaching, quality improvement, and research programs. RESULTS: Respondents from forty-three centres (45%) in 22 countries completed the survey. Thirty-six centres (84%) have a dedicated paediatric echocardiography laboratory, only five (12%) of which reported they were European Association of Cardiovascular Imaging accredited. The median number of echocardiography rooms was three (range 1-12), and echocardiography machines was four (range 1-12). Only half of all the centres have dedicated imaging physiologists and/or nursing staff, while the majority (79%) have specialist imaging cardiologist(s). The median (range) duration of time for a new examination was 45 (20-60) minutes, and for repeat examination was 20 (5-30) minutes. More than half of respondents (58%) have dedicated time for reporting. An organised training program was present in most centres (78%), 44% undertake quality assurance, and 79% perform research. Guidelines for performing echocardiography were available in 32 centres (74%). CONCLUSION: Facilities, staffing levels, study times, standards in teaching/training, and quality assurance vary widely across paediatric echocardiography laboratories in Europe. Greater support and investment to facilitate improvements in staffing levels, equipment, and governance would potentially improve European paediatric echocardiography laboratories.

High-sensitive troponinT, interleukin-8, and interleukin-6 link with post-surgery risk in infant heart surgery.

BACKGROUND: This study focuses on biomarkers in infants after open heart surgery, and examines the association of high-sensitive troponin T (hs-cTnT), interleukin-6 (IL-6), and interleukin-8 (IL-8) with postoperative acute kidney injury (AKI), ventilatory support time and need of vasoactive drugs. METHODS: Secondary exploratory study from a double-blinded clinical randomized trial (Mile-1) on 70 infants undergoing open heart surgery with cardiopulmonary bypass (CPB). In this sub-study, the entire study population was examined without considering the study drugs. The biomarkers' peak concentration (highest concentration at 2 or 6 h post-CPB) were used for statistical analyses. RESULTS: Peak IL-8, hs-cTnT, and IL-6 occurred at 2 h post-CPB for 96%, 79%, and 63% of the patients, respectively. The odds ratio of developing AKI2-3 for IL-6 > 293 pg/mL was 23.4 (95% CI 5.3;104.0), for IL-8 > 100 pg/mL it was 11.5 (3.0;44.2), and for hs-cTnT >5597 pg/mL it was 6.1 (1.5; 24.5). In more than two third of the patients with the highest peak concentrations of IL-8, IL-6, and hs-cTnT, there was a need for ventilatory support for >24 h and use of vasoactive drugs at 24 h post-CPB, while in less than one third of the patients with the lowest peak concentrations of IL-8 and hs-cTnT such requirements were observed. CONCLUSIONS: The peak biomarker concentrations and CPB-time strongly predicted AKI2-3, with IL-6 and IL-8 emerging as strongest predictors. Furthermore, our findings suggest that measuring hs-cTnT and IL-8 just 2 h post-CPB-weaning may assist in identifying infants suitable for early extubation and highlight those at risk of prolonged ventilation.

Maternal Diabetes and Overweight and Congenital Heart Defects in Offspring.

Importance: Maternal diabetes and overweight or obesity are known to be associated with increased risk of congenital heart defects (CHDs) in offspring, but there are no large studies analyzing outcomes associated with these factors in 1 model. Objective: To investigate the association of maternal diabetes and overweight or obesity with CHDs among offspring in 1 model. Design, Setting, and Participants: This nationwide, population-based register study was conducted in a birth cohort from Finland consisting of all children born between 2006 and 2016 (620 751 individuals) and their mothers. Data were analyzed from January 2022 until November 2023. Exposures: Maternal prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), categorized as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), and obesity (≥30), was assessed. Maternal diabetes status, classified as no diabetes, type 1 diabetes (T1D), type 2 or other diabetes, and gestational diabetes, was assessed. Main Outcomes and Measures: Odds ratios (ORs) of isolated CHDs in children were found. In addition, 9 anatomical CHD subgroups were studied. Results: Of 620 751 children (316 802 males [51.0%]; 573 259 mothers aged 20-40 years [92.3%]) born in Finland during the study period, 10 254 children (1.7%) had an isolated CHD. Maternal T1D was associated with increased odds of having a child with any CHD (OR, 3.77 [95% CI, 3.26-4.36]) and 6 of 9 CHD subgroups (OR range, 3.28 [95% CI, 1.55-6.95] for other septal defects to 7.39 [95% CI, 3.00-18.21] for transposition of great arteries) compared with no maternal diabetes. Maternal overweight was associated with left ventricular outflow tract obstruction (OR, 1.28 [95% CI, 1.10-1.49]) and ventricular septal defects (OR, 0.92 [95% CI, 0.86-0.98]), and obesity was associated with complex defects (OR, 2.70 [95% CI, 1.14-6.43]) and right outflow tract obstruction (OR, 1.31 [95% CI, 1.09-1.58]) compared with normal maternal BMI. Conclusions and Relevance: This study found that maternal T1D was associated with increased risk for most types of CHD in offspring, while obesity and overweight were associated with increased risk for complex defects and outflow tract obstruction and decreased risk for ventricular septal defects. These different risk profiles of T1D and overweight and obesity may suggest distinct underlying teratogenic mechanisms.

Recessive TMOD1 mutation causes childhood cardiomyopathy.

Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1R189W demonstrated longer thin filaments than GFP-TMOD1wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.

Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.

Risk factors for mortality in patients with hypoplastic left heart syndrome after the Norwood procedure.

OBJECTIVES: Several studies have reported mortality risk factors associated with hypoplastic left heart syndrome (HLHS). However, these data are ambiguous and mainly focused on the independent effects of these factors. We examined both the independent and the cumulative effects of preoperative risk factors for poor outcome in patients undergoing the Norwood procedure. Moreover, we studied the risk factors associated with prolonged initial hospital stays in these patients. METHODS: We performed a retrospective national 18-year observational study of preoperative risk factors for 1 year, as well as total follow-up mortality or need for transplant in patients with HLHS (N = 99) born in Finland between 1 January 2004 and 31 December 2021. RESULTS: Overall, one-year survival was 85.6%. In a multivariable analysis, having a major extracardiac anomaly and being small for gestational age were significant predictors of one-year mortality or the need for a transplant. Aortic atresia was a predictor of total follow-up mortality. An analysis of the cumulative effect indicated that the presence of 2 risk factors was associated with higher mortality. CONCLUSIONS: HLHS remains the defect with the highest procedural risks for mortality in paediatric cardiac surgery. From a prognostic point of view, recognition of independent preoperative risk factors as well as the cumulative effect of risk factors for mortality is essential.The results of this study were presented orally at the 55th Annual Meeting of the Association for European Paediatric and Congenital Cardiology, Geneva, Switzerland, 28 May 2022.

Renal-hepatic-pancreatic dysplasia type 2: Perinatal lethal condition or a multisystemic disorder with variable expressivity.

BACKGROUND: Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data. METHODS: An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the oldest known living patient, and report the cumulative phenotypes from the existing published patients. RESULTS: With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life. Of the four cases living past the first year of life, one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure. Two are currently alive and well at one year and 13 years. Two cases have had transplantation with one resulting in long-term survival. CONCLUSIONS: These patients serve to expand the existing phenotype of RHPD2 as a perinatal lethal condition into a pediatric disorder with variable expressivity. Additionally, we introduce the consideration of transplantation and outcomes within this cohort and future patients.

Maternal first trimester metabolic profile in pregnancies with transposition of the great arteries.

BACKGROUND: Higher maternal body mass index (BMI) and abnormal glucose metabolism during early pregnancy are associated with congenital heart defects in the offspring, but the exact mechanisms are unknown. METHODS: We evaluated the association between maternal first trimester metabolic profile and transposition of the great arteries (TGA) in the offspring in a matched case-control study with 100 TGA mothers and 200 controls born in Finland during 2004-2014. Cases and controls were matched by birth year, child sex, and maternal age and BMI. Serum samples collected between 10- and 14-weeks of gestation were analyzed for 73 metabolic measures. Conditional logistic regression was used to assess the risk for TGA in the offspring, and a subgroup analysis among mothers with high BMI was conducted. RESULTS: Higher concentrations of four subtypes of extremely large very-low-density lipoprotein (VLDL) particles and one of large VLDL particles were observed in TGA mothers. This finding did not reach statistical significance after multiple testing correction. The pooled odds ratio (OR) of the all metabolic variables was slightly higher in TGA mothers in the subgroup with maternal BMI over 25 (OR 1.25) and significantly higher in the subgroup with maternal BMI over 30 (OR 1.95) compared to the original population (OR 1.18). CONCLUSIONS: Our findings indicate that an abnormal maternal early pregnancy metabolic profile might be associated with TGA in the offspring, especially in obese mothers. A trend indicating altered VLDL subtype composition in TGA pregnancies warrants further research.

Institutional transition from invasive to non-invasive imaging in children with univentricular heart defects: safety and cost savings.

OBJECTIVES: Patients with univentricular heart defects require lifelong imaging surveillance. Recent advances in non-invasive imaging have enabled replacing these patients' routine catheterisation. Our objective was to describe the safety and cost savings of transition of a tertiary care children's hospital from routine invasive to routine non-invasive imaging of low-risk patients with univentricular heart defects. METHODS: This single-centre cohort study consists of 1) a retrospective analysis of the transition from cardiac catheterisation (n = 21) to CT angiography (n = 20) before bidirectional Glenn operation and 2) a prospective study (n = 89) describing cardiac magnetic resonance before and after the total cavopulmonary connection in low-risk patients with univentricular heart defects. RESULTS: Pre-Glenn: The total length of CT angiography was markedly shorter compared to the catheterisation: 30 min (range: 20-60) and 125 min (range: 70-220), respectively (p < 0.001). Catheterisation used more iodine contrast agents than CT angiography, 19 ± 3.9 ml, and 10 ± 2.4 ml, respectively (p < 0.001). Controlled ventilation was used for all catheterised and 3 (15%) CT angiography patients (p < 0.001). No complications occurred during CT angiography, while they emerged in 19% (4/21) catheterisation cases (p < 0.001). CT angiography and catheterisation showed no significant difference in the radiation exposure. Pre-/post-total cavopulmonary connection: All cardiac magnetic resonance studies were successful, and no complications occurred. In 60% of the cardiac magnetic resonance (53/89), no sedation was performed, and peripheral venous pressure was measured in all cases. Cost analysis suggests that moving to non-invasive imaging yielded cost savings of at least €2500-4000 per patient. CONCLUSION: Transition from routine invasive to routine non-invasive pre-and post-operative imaging is safely achievable with cost savings.

Clinical Features and Natural History of Preadolescent Nonsyndromic Hypertrophic Cardiomyopathy.

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.

Relationship Between Maximal Left Ventricular Wall Thickness and Sudden Cardiac Death in Childhood Onset Hypertrophic Cardiomyopathy.

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.

External validation of the HCM Risk-Kids model for predicting sudden cardiac death in childhood hypertrophic cardiomyopathy.

AIMS: Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. METHODS AND RESULTS: A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1-16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48-2.78]. Model validation showed a Harrell's C-index of 0.745 (95% CI 0.52-0.97) and Uno's C-index 0.714 (95% 0.58-0.85) with a calibration slope of 1.15 (95% 0.51-1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60-0.81). CONCLUSIONS: This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.

Cardiac Function After Cardiotoxic Treatments for Childhood Cancer-Left Ventricular Longitudinal Strain in Screening.

Background: The majority of childhood cancer survivors (CCSs) have been exposed to cardiotoxic treatments and often present with modifiable cardiovascular risk factors. Our aim was to evaluate the value of left ventricular (LV) longitudinal strain for increasing the sensitivity of cardiac dysfunction detection among CCSs. Methods: We combined two national cohorts: neuroblastoma and other childhood cancer survivors treated with anthracyclines. The final data consisted of 90 long-term CCSs exposed to anthracyclines and/or high-dose chemotherapy with autologous stem cell rescue and followed up for > 5 years and their controls (n = 86). LV longitudinal strain was assessed with speckle tracking (Qlab) and LV ejection fraction (EF) by three-dimensional echocardiography (3DE). Results: Of the CCSs, 11% (10/90) had abnormal LV longitudinal strain (i.e., < -17.5%); of those, 70% (7/10) had normal 3DE LV EF. Multivariable linear model analysis demonstrated that follow-up time (p = 0.027), sex (p = 0.020), and BMI (p = 0.002) were significantly associated with LV longitudinal strain. Conversely, cardiac risk group, hypertension, age, cumulative anthracycline dose or exposure to chest radiation were not. Conclusion: LV longitudinal strain is a more sensitive method than LV EF for the detection of cardiac dysfunction among CCSs. Therefore, LV longitudinal strain should be added to the screening panel, especially for those with modifiable cardiovascular risk factors.

Heart Transplantation for Early-Onset Anthracycline-Induced Cardiomyopathy Within 5 Months of Chemotherapy Completion.

A 9-year-old boy developed progressive anthracycline-induced cardiomyopathy three months after completion of chemotherapy for osteosarcoma. Five months after completion of chemotherapy, at the age of 10 years, heart transplantation was performed. At 29 months since transplantation, the patient remains free of rejection and recurrence of osteosarcoma. (Level of Difficulty: Intermediate.).

Persistent Aortic Stiffness and Left Ventricular Hypertrophy in Children of Diabetic Mothers.

BACKGROUND: Fetuses of diabetic mothers develop left ventricular (LV) hypertrophy and are at increased long-term risk of cardiovascular disease. In our previous longitudinal study from midgestation to late infancy we showed persistence of LV hypertrophy and increased aortic stiffness compared with infants of healthy mothers, the latter of which correlated with third trimester maternal hemoglobin A1c. In the present study, we reexamined the same cohort in early childhood to determine if these cardiovascular abnormalities persisted. METHODS: Height, weight, and right arm blood pressure were recorded. A full functional and structural echocardiogram was performed with offline analysis of LV posterior wall and interventricular septal diastolic thickness (IVSd), systolic and diastolic function, and aortic pulse wave velocity. Vascular reactivity was assessed using digital thermal monitoring. Participants also completed a physical activity questionnaire. RESULTS: Twenty-five children of diabetic mothers (CDMs) and 20 children from healthy pregnancies (mean age, 5.6 ± 1.7 and 5.3 ± 1.3 years, respectively; P = not significant) were assessed. Compared with controls, IVSd z score was increased in CDMs (1.2 ± 0.6 vs 0.5 ± 0.3, respectively; P = 0.006), with one-fifth having a z score of more than +2.0. Aortic pulse wave velocity was increased in CDMs (3.2 ± 0.6 m/s vs 2.2 ± 0.4 m/s; P = 0.001), and correlated with IVSd z score (R 2 = 0.81; P = 0.001) and third trimester maternal A1c (R 2 = 0.65; P < 0.0001). Body surface area, height, weight, blood pressure, vascular reactivity, and physical activity scores did not differ between groups. Our longitudinal analysis showed that individuals with greater IVSd, and aortic stiffness in utero, early and late infancy also tended to have greater measures in early childhood (P < 0.001 and P < 0.0001, respectively). CONCLUSIONS: CDMs show persistently increased interventricular septal thickness and aortic stiffness in early childhood.

INTRODUCTION: Les fœtus des mères diabétiques présentent une hypertrophie du ventricule gauche (VG) et sont exposés à un risque accru à long terme de souffrir d'une maladie cardiovasculaire. Dans notre étude longitudinale précédente qui portait sur la période mi-gestationnelle à la fin de la première enfance, nous avons montré la persistance de l'hypertrophie du VG et l'augmentation de la rigidité aortique par rapport aux bébés des mères bien portantes, qui sont en corrélation avec le troisième trimestre de l'hémoglobine A1c maternelle. Dans la présente étude, nous avons réexaminé la même cohorte au début de la seconde enfance pour déterminer si ces anomalies cardiovasculaires persistaient. MÉTHODES: Nous avons enregistré la taille, le poids et la pression artérielle au bras droit. Nous avons réalisé une échocardiographie complète pour évaluer l'état fonctionnel et structurel par analyse hors ligne de la paroi postérieure du VG et de l'épaisseur du septum interventriculaire en diastole (SIVd), la fonction systolique et diastolique, et la vitesse de l'onde de pouls aortique. Nous avons évalué la réactivité vasculaire à l'aide de la surveillance thermique numérique. Les participants ont également rempli un questionnaire sur l'activité physique. RÉSULTATS: Vingt-cinq enfants issus de mères diabétiques (EMD) et 20 enfants de mères bien portantes (âge moyen, 5,6 ± 1,7 et 5,3 ± 1,3 ans, respectivement ; P = non significatif) ont fait l'objet d'une évaluation. Comparativement aux témoins, les EMD avaient un score z du SIVd plus élevé (1,2 ± 0,6 vs 0,5 ± 0,3, respectivement ; P = 0,006), et un cinquième de ces enfants avaient un score z de plus de +2,0. La vitesse de l'onde de pouls aortique était plus élevée chez les EMD (3,2 ± 0,6 m/s vs 2,2 ± 0,4 m/s ; P = 0,001), et était en corrélation avec le score z du SIVd (R 2 = 0,81 ; P = 0,001) et le troisième trimestre de l'A1c maternelle (R 2 = 0,65 ; P < 0,0001). Les scores de la surface corporelle, la taille, le poids, la pression artérielle, la réactivité vasculaire et l'activité physique ne différaient pas entre les groupes. Notre étude longitudinale a montré que les individus qui avaient une plus grande SIVd et une rigidité aortique in utero, au début et à la fin de la première enfance, avaient également tendance à avoir des mesures plus grandes au début de la seconde enfance (P < 0,001 et P < 0,0001, respectivement). CONCLUSIONS: Les EMD montrent une persistance de l'augmentation de l'épaisseur du septum interventriculaire et de l'augmentation de la rigidité aortique au début de la seconde enfance.