Atrial septal defects (ASDs) are the most common form of congenital heart disease. There are 4 embryologic types of ASDs, and rhythm considerations vary based on type. ASDs have left-to-right shunt and primarily right-sided volume overload. This leads to electrical remodeling that may predispose patients to atrial tachyarrhythmias and conduction disorders. Risk for arrhythmias is increased with late age of ASD repair, shunt size, other factors such as pulmonary hypertension and comorbid conditions. Arrhythmia incidence is decreased after ASD closure, but remains elevated compared to general population. Medical and procedural therapy for arrhythmias should consider type and timing of ASD repair. Conduction disorders are rare. Sinus node dysfunction may be seen with late age of repair and large shunt size. Sinus venosus ASD exhibits a higher rate of sinus node dysfunction, especially with older surgical techniques. Ostium primum ASD has higher risk of spontaneous or post-operative AV block, though this is rare with current surgical techniques. Risk of AV block with surgical repair or device closure of secundum ASD is rare. Familial ASDs and other forms of congenital heart disease may be seen with mutations in associated myocardial transcription factors NKX2.5, GATA4, TBX6, along with conduction disorders such as AV block.

To assess the eruption and emplacement of volumetrically diverse rhyolite lavas, we measured microlite number densities and orientations from samples collected from nine lavas in Yellowstone Caldera and two from Mono Craters, USA. Microlite populations are composed of Fe-Ti oxides ± alkali feldspar ± clinopyroxene. Number densities range from 10^{8.11 ± 0.03} to 10^{9.45 ± 0.15} cm⁻³ and do not correlate with distance from the vent across individual flows and are remarkably similar between large- and small-volume lavas. Together, those observations suggest that number densities are unmodified during emplacement and that ascent rates in the conduit are similar between small domes and large lava flows. Microtextures produced by continuous decompression experiments best replicate natural textures at decompression rates of 1–2 MPa hr⁻¹. Acicular microlites have a preferred orientation in all natural samples. Because the standard deviation of microlite orientation does not become better aligned with distance travelled, we conclude that microlites exit the conduit aligned and that strain during subaerial flow was insufficient to further align microlites. The orientations of microlite trend and plunge in near-vent samples indicate that pure shear was the dominant style of deformation in the conduit. We speculate that collapsing permeable foam(s) provides a mechanism to concurrently allow microlite formation and alignment in response to the combination of degassing and flattening by pure shear.

Transcatheter aortic valve replacement has emerged as a safe and effective alternative to surgical aortic valve replacement for patients with severe symptomatic aortic stenosis across the spectrum of surgical risks based on a series of foundational randomized clinical trials. Of note, patients with bicuspid aortic valve (BAV) disease were excluded from all these pivotal randomized trials, leaving a significant knowledge gap because BAVs are commonly encountered in patients referred for aortic valve surgery or intervention. In this comprehensive review, we aim to provide heart teams with a detailed insight into how to approach patients with BAV disease, focusing on imaging and characterization of bicuspid valves, an overview of surgical approaches, and an understanding of the current data behind the role of transcatheter aortic valve replacement for patients with BAV disease.

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory.

Objective:To survey an international sample of providers to determine their current practices for the prevention, screening, and treatment of congenital heart block (CHB) due to maternal Ro/SSA antibodies. Methods:A survey was designed by the organizing committee of the 9th International Conference of Reproduction, Pregnancy and Rheumatic Diseases. It was sent to attendants of the conference and authors of recent publications or abstracts at ACR 2012, 2013 or 2014 on rheumatic diseases and pregnancy. Results:In anti-Ro/SSA positive women, 80% of 49 respondents recommended screening by serial fetal echocardiogram (ECHO), with most starting at week 16 (59%) and stopping at week 28 (25%), although the time to stop varied widely. For women without a prior infant with neonatal lupus, respondents recommend every other week (44%) or weekly (28%) fetal ECHOs. For women with a prior infant with neonatal lupus, 80% recommend weekly fetal ECHOs. To prevent CHB, HCQ was recommended by 67% of respondents and most would start pre-pregnancy (62%). Respondents were asked about medications to treat varying degrees of CHB in a 20-week pregnant, anti-Ro and La positive SLE patient. For first degree, respondents recommended starting dexamethasone (53%) or HCQ (43%). For second degree, respondents recommended starting dexamethasone (88%). For third degree, respondents recommended starting dexamethasone (55%) or IVIg (33%), although 27% would not start treatment. Conclusion:Despite the absence of official guidelines, many physicians with a focus on pregnancy and rheumatic disease have developed similar patterns in the screening, prevention and treatment of CHB.

Background

We previously described the association of genetic variants in calcium channel genes and susceptibility to Kawasaki disease (KD), an acute, self-limited vasculitis, and the most common cause of acquired cardiac disease in children. Abnormal repolarization of cardiomyocytes and changes in T wave morphology have been reported in KD but have not been studied systematically.

Methods

We analyzed acute and convalescent ECG T wave morphology in two independent cohorts of KD subjects and studied the association between bifid T waves and genetic variants in previously reported genes with SNVs associated with cardiac repolarization.

Results

Bifid T waves in limb leads were identified in 24% and 27% of two independent cohorts of acute KD subjects. Calcium channel voltage-dependent beta 2 subunit gene (CACNB2) (rs1409207) showed association with bifid T waves in both cohorts (nominal P = .04 and P = .0003, respectively). This CACNB2 polymorphism also showed association with KD susceptibility in a previously published KD genome wide association study data (nominal P = .009).

Conclusion

This genotype/phenotype association study uncovered a variant in CACNB2 that may be associated with both KD susceptibility and bifid T waves, a novel signature of altered myocardial repolarization. The present study combined with published reports suggests that genetic variants in calcium channels and intracellular calcium signaling play a prominent role in shaping susceptibility to KD.

Chronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a(-/-) mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155(fl/fl) mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation.

OBJECTIVES:Genetic disorders are a leading contributor to mortality in the neonatal ICU and PICU in the United States. Although individually rare, there are over 6,200 single-gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however, its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care. DESIGN:Retrospective cohort study. SETTING:Single-center PICU in a tertiary children's hospital. PATIENTS:Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018. INTERVENTIONS:Rapid whole genome sequencing with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available. MEASUREMENTS AND MAIN RESULTS:A molecular diagnosis was made by rapid whole genome sequencing in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae. CONCLUSIONS:This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rapid whole genome sequencing in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rapid whole genome sequencing early in PICU admission when the underlying etiology is unclear.

Objectives

This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).

Background

LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.

Methods

A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.

Results

A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).

Conclusions

In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.