Acute Cardiovascular Manifestations in 286 Children With Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe.

BACKGROUND: The aim of the study was to document cardiovascular clinical findings, cardiac imaging, and laboratory markers in children presenting with the novel multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) infection. METHODS: This real-time internet-based survey has been endorsed by the Association for European Paediatric and Congenital Cardiologists Working Groups for Cardiac Imaging and Cardiovascular Intensive Care. Children 0 to 18 years of age admitted to a hospital between February 1 and June 6, 2020, with a diagnosis of an inflammatory syndrome and acute cardiovascular complications were included. RESULTS: A total of 286 children from 55 centers in 17 European countries were included. The median age was 8.4 years (interquartile range, 3.8-12.4 years) and 67% were boys. The most common cardiovascular complications were shock, cardiac arrhythmias, pericardial effusion, and coronary artery dilatation. Reduced left ventricular ejection fraction was present in over half of the patients, and a vast majority of children had raised cardiac troponin when checked. The biochemical markers of inflammation were raised in most patients on admission: elevated C-reactive protein, serum ferritin, procalcitonin, N-terminal pro B-type natriuretic peptide, interleukin-6 level, and D-dimers. There was a statistically significant correlation between degree of elevation in cardiac and biochemical parameters and the need for intensive care support (P<0.05). Polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was positive in 33.6%, whereas immunoglobulin M and immunoglobulin G antibodies were positive in 15.7% cases and immunoglobulin G in 43.6% cases, respectively, when checked. One child in the study cohort died. CONCLUSIONS: Cardiac involvement is common in children with multisystem inflammatory syndrome associated with the Covid-19 pandemic. The majority of children have significantly raised levels of N-terminal pro B-type natriuretic peptide, ferritin, D-dimers, and cardiac troponin in addition to high C-reactive protein and procalcitonin levels. In comparison with adults with COVID-19, mortality in children with multisystem inflammatory syndrome associated with COVID-19 is uncommon despite multisystem involvement, very elevated inflammatory markers, and the need for intensive care support.

Chemotherapy-Induced Cardiotoxicity in Adolescent After Heart Transplant: Do Not Forget the Right Ventricle.

The evaluation of oncologic patients at risk of chemotherapy-induced cardiotoxicity usually focuses on left ventricular function. However, recent studies have demonstrated that right ventricle impairment often coexists (and in some cases precedes) left-side affectation. We present the case of a 19-year-old heart transplant recipient who developed severe right ventricular dysfunction secondary to treatment of an abdominal lymphoma.

Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients.

PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial ß-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.

Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.

OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.

Biplane interventional pediatric system with cone-beam CT: dose and image quality characterization for the default protocols.

The aim of this study was to assess image quality and radiation dose of a biplane angiographic system with cone-beam CT (CBCT) capability tuned for pediatric cardiac procedures. The results of this study can be used to explore dose reduction techniques. For pulsed fluoroscopy and cine modes, polymethyl methacrylate phantoms of various thicknesses and a Leeds TOR 18-FG test object were employed. Various fields of view (FOV) were selected. For CBCT, the study employed head and body dose phantoms, Catphan 504, and an anthropomorphic cardiology phantom. The study also compared two 3D rotational angiography protocols. The entrance surface air kerma per frame increases by a factor of 3-12 when comparing cine and fluoroscopy frames. The biggest difference in the signal-to- noise ratio between fluoroscopy and cine modes occurs at FOV 32 cm because fluoroscopy is acquired at a 1440 × 1440 pixel matrix size and in unbinned mode, whereas cine is acquired at 720 × 720 pixels and in binned mode. The high-contrast spatial resolution of cine is better than that of fluoroscopy, except for FOV 32 cm, because fluoroscopy mode with 32 cm FOV is unbinned. Acquiring CBCT series with a 16 cm head phantom using the standard dose protocol results in a threefold dose increase compared with the low-dose protocol. Although the amount of noise present in the images acquired with the low-dose protocol is much higher than that obtained with the standard mode, the images present better spatial resolution. A 1 mm diameter rod with 250 Hounsfield units can be distinguished in reconstructed images with an 8 mm slice width. Pediatric-specific protocols provide lower doses while maintaining sufficient image quality. The system offers a novel 3D imaging mode. The acquisition of CBCT images results in increased doses administered to the patients, but also provides further diagnostic information contained in the volumetric images. The assessed CBCT protocols provide images that are noisy, but with very good spatial resolution.

Safety and efficacy of the Amplatzer™ Trevisio™ intravascular delivery system: Post-approval study results.

BACKGROUND: The Amplatzer™ Trevisio™ Intravascular Delivery System (Trevisio DS; Abbott Laboratories, Chicago, IL, USA) facilitates the delivery of Amplatzer™ Occluders and features an ultraflexible tip, which improves assessment of occluder position before release. AIMS: To assess the safety and efficacy of the Trevisio DS for transcatheter closure of patent foramen ovale and atrial septal defect. METHODS: The Amplatzer™ Trevisio™ Intravascular Delivery System Post-Approval Study was a prospective, postmarket, single-arm, multicentre, observational study of the Trevisio DS. Enrolled patients were indicated for transcatheter closure of patent foramen ovale or atrial septal defect. In all procedures, the Trevisio DS was used to deliver Amplatzer™ Occluders. Technical success was defined as successful deployment and release of at least one occluder. Device- or procedure-related serious adverse events were tracked until discharge or day 7, whichever occurred earlier. RESULTS: The study enrolled 144 patients with patent foramen ovale and 107 patients with atrial septal defect at 22 European sites; 53 patients with atrial septal defect (49.6%) were aged<18years. The rate of technical success was 98.4% (97.2% for atrial septal defect, 99.3% for patent foramen ovale). There was one serious adverse event (0.4%), an acute periprocedural device embolization that occurred after occluder release in a patient with atrial septal defect; the device was retrieved percutaneously. This was determined by the implanter to be unrelated to the performance of the Trevisio DS. CONCLUSIONS: The Trevisio DS exhibited a high rate of technical success and an excellent safety profile during transcatheter closure of patent foramen ovale and atrial septal defect.

Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

Characteristics and outcomes of the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB).

INTRODUCTION AND OBJECTIVES: Bicuspid aortic valve (BAV) disorder is the most common congenital heart disease. The aim of this study was to describe the characteristics of 0- to 18-year olds with BAV in a population-based registry. METHODS: Data from all pediatric patients were obtained from the Spanish registry for pediatric patients with bicuspid aortic valve (REVAB) (< 18 years). For data analysis, patients with BAV were divided into 2 groups by their features: isolated BAV and BAV with associated congenital heart disease. RESULTS: We included 1681 patients from 33 hospitals. Males accounted for 69.6% (n = 1158). Valve morphology was horizontal in 63.4% (n = 1012) and pure (Sievers type 0) in 28.4% (n=469). Isolated BAV was present in 63.7% (n=1060), and concomitant left-sided obstructive lesions in 23.4% (n=390). Interventions were required in 8.6% (n=145). CONCLUSION: These data represent the first large, population-based description of the clinical presentations and outcomes of patients enrolled in the Spanish registry for pediatric patients with bicuspid aortic valve.

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Cardiac resynchronization therapy in an infant with double outlet right ventricle and mechanical dyssynchrony.

Cardiac resynchronization therapy (CRT) is commonly used in adults with heart failure, poor left ventricular ejection fraction (LVEF), and wide QRS complex. CRT has rarely been applied in young patients. We report the case of a 10-month-old infant with congenital heart disease, postsurgical complete atrioventricular block, and severe refractory heart failure. The patient showed a significant clinical improvement and was withdrawn from the heart transplant list 2 months after epicardially established CRT.

Pediatrics Spanish Registry of Percutaneous Melody Pulmonary Valve Implantation in Patients Younger Than 18 Years.

INTRODUCTION AND OBJECTIVES: A decade has passed since the first Spanish percutaneous pulmonary Melody valve implant (PPVI) in March 2007. Our objective was to analyze its results in terms of valvular function and possible mid-term follow-up complications. METHODS: Spanish retrospective descriptive multicenter analysis of Melody PPVI in patients < 18 years from the first implant in March 2007 until January 1, 2016. RESULTS: Nine centers were recruited with a total of 81 PPVI in 77 pediatric patients, whose median age and weight were 13.3 years (interquartile range [IQR], 9.9-15.4) and 46kg (IQR, 27-63). The predominant cardiac malformation was tetralogy of Fallot (n = 27). Most of the valves were implanted on conduits, especially bovine xenografts (n = 31). The incidence of intraprocedure and acute complications was 6% and 8%, respectively (there were no periprocedural deaths). The median follow-up time was 2.4 years (IQR, 1.1-4.9). Infective endocarditis (IE) was diagnosed in 4 patients (5.6%), of which 3 required surgical valve explant. During follow-up, the EI-related mortality rate was 1.3%. At 5 years of follow-up, 80% ± 6.9% and 83% ± 6.1% of the patients were free from reintervention and pulmonary valve replacement. CONCLUSIONS: Melody PPVI was safe and effective in pediatric patients with good short- and mid-term follow-up hemodynamic results. The incidence of IE during follow-up was relatively low but was still the main complication.

Usefulness of 64-detector computed tomography in the diagnosis and management of patients with congenital heart disease.

INTRODUCTION AND OBJECTIVES: Although congenital heart defects are the most common major congenital abnormalities, the associated mortality has been decreasing due to improvements in their diagnosis and treatment. We assessed the usefulness of 64-multidetector computed tomography in the diagnosis and management of these patients. METHODS: This 5-year observational, analytical, retrospective, cohort study included a total of 222 tomographic studies of patients with congenital heart disease. Computed tomography scans were read twice and medical records were reviewed. We assessed the complexity of the disease, patient, and radiological technique, and evaluated the contribution of new data in relation to clinical suspicion and diagnostic change. A confidence interval was set at 95% and a P value of<.05 was used as the cutoff for statistical significance. RESULTS: In 35.1% of patients, the treatment procedure was performed after computed tomography without other tests. Additional diagnostic catheterization was performed in 12.5% of patients. There were new findings in 77% of patients (82.9% with complex disease), which prompted a change in patient management in 35.6%. All unexpected reports described new findings. No significant differences were found by age, sex, study period, urgency of the test order, patient complexity, or difficulty of the technique. CONCLUSIONS: Use of 64-detector computed tomography yields good diagnostic performance in congenital heart disease, prompts changes in management in more than one-third of patients, and reveals new findings in relation to the presumed diagnosis in 77% of patients.

Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes.

OBJECTIVE: Pulmonary hypertension (PH) worsens the prognosis of bronchopulmonary dysplasia (BPD). The following items have not been fully established for PH in BPD: clinical characterization, incidence of cardiovascular anomalies (CVAs), response to PH treatment, and outcome. STUDY DESIGN: A review of clinical records, computed tomography (CT) images and catheterization data of 36 patients with PH-BPD referred to our PH Unit (March 2006 to December 2011) was performed. Twenty-nine patients without major congenital heart defects and with complete follow-up data were included. RESULTS: The diagnosis of PH was made at a median age of 4.5 months (IQR 2.4-7.8), with an echocardiography estimated median right ventricular pressure/systemic pressure ratio of 70% (IQR 60-80%). CT scanning was performed in 21 patients and catheterization in 14 patients. CVAs were found in 19 patients (65.5%): aortopulmonary collaterals (n = 9), pulmonary vein stenosis (n = 7), ASD (n = 4), and PDA (n = 9). Hemodynamic data: PVRI 4.3 UW m(2) (2.7-7); PVRI/SVRI 0.44 (0.32-0.8); and transpulmonary gradient 28 mmHg (19-40). At a median follow-up of 35 months (IQR 21-91), 6 patients had undergone shunts closure, 22 received specific PH drugs, 3 spontaneously improved of their PH, and 8 (26%) had died. CONCLUSION: PH in BPD is not always a transient condition; it can be diagnosed at later stages and can have a protracted course. The incidence of associated CVAs is high. Prompt diagnosis, detection, and treatment of CVAs, and specific drug therapy can improve the outcome in these patients, although the mortality rate remains high.

Comparison of outcomes in adults with congenitally corrected transposition with situs inversus versus situs solitus.

The long-term outcome of patients with congenitally corrected transposition of the great arteries is mainly determined by progressive morphologically tricuspid valve regurgitation, heart block, atrial arrhythmias, and/or systemic ventricular dysfunction. Situs abnormalities have been reported in ≤34% of cases, but whether clinical differences exist between a situs inversus and situs solitus arrangement has not yet been studied. The clinical records of 38 adults with congenitally corrected transposition of the great arteries (mean age 40 ± 15 years) followed for a mean period of 7.4 years were reviewed. Of these 38 patients, 8 presented with situs inversus and 30 with situs solitus. No significant differences were found between the 2 groups in age, gender, ventricular septal defect, pulmonary tract stenosis, previous surgical repair, or duration of follow-up. However, none of the patients with situs inversus presented with an Ebstein-like anomaly of the morphologically tricuspid valve and none developed nonoperative-related complete atrioventricular block compared to 15 (50%; p = 0.013) and 11 (42%; p = 0.032) of the patients with situs solitus, respectively. At follow-up, 2 patients with situs inversus (25%) presented with sustained atrial arrhythmia, severe tricuspid regurgitation, or severe systemic right ventricular systolic dysfunction compared to 22 (73%) of 30 those with situs solitus (p = 0.034). No patient with situs inversus presented with cardiac death or severe heart failure compared to 12 (40%) of 30 with situs solitus (p = 0.038). In conclusion, Ebstein-like anomaly or spontaneous complete atrioventricular block are rare in patients with congenitally corrected transposition of the great arteries with situs inversus, and late complications are uncommon. The long-term outcome of patients with situs inversus was significantly better than that for patients with situs solitus.