IMPORTANCE Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk. OBJECTIVE To develop and validate an SCD risk prediction model that provides individualized risk estimates. DESIGN, SETTING, AND PARTICIPANTS A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017. EXPOSURES The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping. MAIN OUTCOMES AND MEASURES A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise). RESULTS Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95% CI, 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years. CONCLUSIONS AND RELEVANCE This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations.

No abstract

Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classically torsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnormal cellular membrane repolarization. Severely affected phenotypes administered current standard of care therapies may not be fully protected from the occurrence of cardiac arrhythmias. There are 17 different subtypes of LQTS associated with monogenic mutations of 15 autosomal dominant genes. It is now possible to model the various LQTS phenotypes through the generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes. RNA interference can silence or suppress the expression of mutant genes. Thus, RNA interference can be a potential therapeutic intervention that may be employed in LQTS to knock out mutant mRNAs which code for the defective proteins. CRISPR/Cas9 is a genome editing technology that offers great potential in elucidating gene function and a potential therapeutic strategy for monogenic disease. Further studies are required to determine whether CRISPR/Cas9 can be employed as an efficacious and safe rescue of the LQTS phenotype. Current progress has raised opportunities to generate in vitro human cardiomyocyte models for drug screening and to explore gene therapy through genome editing.

The purpose of this study was to define a population of visceral heterotaxy and to investigate the incidence of bacterial sepsis in the current era of universal pediatric pneumococcal immunization. Pediatric echocardiography and radiology databases, along with electronic medical records, were searched for patients followed-up since birth between 1999 and 2009 with either asplenia or polysplenia and cardiac anatomy consistent with heterotaxy syndrome. A total of 29 patients were identified. Seven patients (24%) had a total of 8 sepsis events, and 6 patients (86%) developed sepsis while taking appropriately prescribed antibiotic prophylaxis. Of the patients with sepsis, 5 had polysplenia and 2 had asplenia. Sixty-two percent of sepsis events were nosocomially acquired. No cases of pneumococcal sepsis occurred after the introduction of the conjugated pneumococcal vaccination to the pediatric vaccination schedule. Bacterial sepsis was associated with a 44% mortality rate. An unexpected finding in 3 patients with visceral heterotaxy, asplenia, and an interrupted inferior vena cava (IVC) as the only anomaly on echocardiography was associated intestinal malrotation. Children with visceral heterotaxy remain at significant risk of life-threatening bacterial infection. In addition, the finding of interrupted IVC on echocardiography should prompt screening for intestinal malrotation, even in the absence of additional structural heart disease.

GATA4 and GATA6 are central cardiac transcriptional regulators. The postnatal, stage-specific function of the cardiac transcription factors GATA4 and GATA6 have not been evaluated. In part, this is because current Cre-loxP approaches to cardiac gene inactivation require time consuming and costly breeding of Cre-expressing and “floxed” mouse lines, often with limited control of the extent or timing of gene inactivation. We investigated the stage-specific functions of GATA4 and GATA6 in the postnatal heart by using adeno-associated virus serotype 9 to control the timing and extent of gene inactivation by Cre. Systemic delivery of recombinant, adeno-associated virus 9 (AAV9) expressing Cre from the cardiac specific Tnnt2 promoter was well tolerated and selectively and efficiently recombined floxed target genes in cardiomyocytes. AAV9:Tnnt2-Cre efficiently inactivated Gata4 and Gata6. Neonatal Gata4/6 inactivation caused severe, rapidly lethal systolic heart failure. In contrast, Gata4/6 inactivation in adult heart caused only mild systolic dysfunction but severe diastolic dysfunction. Reducing the dose of AAV9:Tnnt2-Cre generated mosaics in which scattered cardiomyocytes lacked Gata4/6. This mosaic knockout revealed that Gata4/6 are required cell autonomously for physiological cardiomyocyte growth. Our results define novel roles of GATA4 and GATA6 in the neonatal and adult heart. Furthermore, our data demonstrate that evaluation of gene function hinges on controlling the timing and extent of gene inactivation. AAV9:Tnnt2-Cre is a powerful tool for controlling these parameters.

In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (EedCKO) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in EedCKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized EedCKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.DOI: http://dx.doi.org/10.7554/eLife.24570.001

No abstract

Objectives We aimed to assess the experience using a percutaneous axillary artery approach for insertion of arterial ductal stents in patients with critical right ventricular outflow tract lesions at two tertiary pediatric cardiology centers. Background Patent ductus arteriosus stenting is an accepted palliative alternative to BT shunts for neonates with critical right heart lesions. Access to tortuous ductus' may be challenging via the femoral artery, whereas the carotid artery presents a low risk of stroke. Recently, the axillary artery has been utilized for access in these patients. Methods We performed a retrospective review of neonates who underwent stent placement or angioplasty using percutaneous axillary artery approach at two tertiary care centers from October 2016 to November 2018. Medical records were reviewed to ascertain demographic, clinical, and outcome data. Results Axillary artery access was performed in 20 patients (16 primary ductal stents and 4 re‐interventions) at a median (IQR) procedural weight of 3.4 (3–3.9) kg. Median (IQR) procedural time was 110 (75–150) min. The median (IQR) ICU stay and intubation times were 14 (0–94) hr and 5 (0–40) hr, respectively. There were three access‐related vascular complications which were managed conservatively with no long‐term effects. Two patients subsequently died due to non‐procedure related causes. Conclusions Ductal stenting via a percutaneous axillary artery approach is a viable option in neonates with critical right ventricular outflow tract lesions. This approach provides an additional access site for PDA stenting which may be utilized in patients with vertical duct morphology.