Real-world experience with edoxaban for anticoagulation in children at risk for coronary artery thrombosis.

Background: Direct oral anticoagulants have the potential to improve care in children requiring chronic anticoagulation. Edoxaban has favourable pharmacokinetics that could benefit younger patients but data on long-term safety and efficacy for specific paediatric indications are lacking.

Study Aims: We present a single-centre experience using edoxaban in children who require chronic anticoagulation for large coronary artery aneurysms secondary to Kawasaki disease.

First comprehensive identification of cardiac proteins with putative increased O-GlcNAc levels during pressure overload hypertrophy.

Protein posttranslational modifications (PTMs) by O-GlcNAc globally rise during pressure-overload hypertrophy (POH). However, a major knowledge gap exists on the specific proteins undergoing changes in O-GlcNAc levels during POH primarily because this PTM is low abundance and easily lost during standard mass spectrometry (MS) conditions used for protein identification. Methodologies have emerged to enrich samples for O-GlcNAcylated proteins prior to MS analysis.

Tolerability of COVID-19 Infection and Messenger RNA Vaccination Among Patients With a History of Kawasaki Disease.

Importance: Kawasaki disease (KD) symptoms significantly overlap with multisystem inflammatory syndrome in children due to COVID-19. Patients with KD may be at risk for adverse outcomes from exposure to SARS-CoV-2 infection or vaccination.

Objective: To describe the outcomes of patients with KD to SARS-CoV-2 infection or vaccination.

A unique cardiovascular presentation of Marfan syndrome.

We report a neonate with severe Marfan syndrome (MS), prenatally identified to have persistent atrial tachycardia, biventricular dysfunction, and an unusual structure within the atria. Detailed postnatal echocardiographic evaluation and cross-sectional imaging confirmed congenital pseudoaneurysm of the mitral-aortic intervalvular fibrosa. Emergent testing by next-generation sequencing identified a FBN1 pathological variant, key to establishing goals of care.

Brain capillary obstruction during neurotoxicity in a mouse model of anti-CD19 chimeric antigen receptor T-cell therapy.

Immunotherapy for haematologic malignancies with CD19-directed chimeric antigen receptor T cells has been highly successful at eradicating cancer but is associated with acute neurotoxicity in ∼40% of patients. This neurotoxicity correlates with systemic cytokine release syndrome, endothelial activation and disruption of endothelial integrity, but it remains unclear how these mechanisms interact and how they lead to neurologic dysfunction. We hypothesized that dysfunction of the neurovascular unit is a key step in the development of neurotoxicity.

Triiodothyronine Supplementation in Infants Undergoing Cardiopulmonary Bypass: A Randomized Controlled Trial.

Cardiopulmonary bypass (CPB) profoundly suppresses circulating thyroid hormone levels in infants. We performed a multicenter randomized placebo controlled trial to determine if triiodothyronine (T3) supplementation improves reduces time to extubation (TTE) in infants after CPB. Infants (n = 220) undergoing cardiac surgery with CPB and stratified into 2 age cohorts: ≤30 days and >30 days to <152 days were randomization to receive either intravenous triiodothyronine or placebo bolus followed by study drug infusion until extubated or at 48 hours, whichever preceded.

Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort.

Purpose: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm.

Methods: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed.

Temporal regulation of protein O-GlcNAc levels during pressure-overload cardiac hypertrophy.

Protein posttranslational modifications (PTMs) by O-linked β-N-acetylglucosamine (O-GlcNAc) rise during pressure-overload hypertrophy (POH) to affect hypertrophic growth. The hexosamine biosynthesis pathway (HBP) branches from glycolysis to make the moiety for O-GlcNAcylation. It is speculated that greater glucose utilization during POH augments HBP flux to increase O-GlcNAc levels; however, recent results suggest glucose availability does not primarily regulate cardiac O-GlcNAc levels.

Sex impacts cardiac function and the proteome response to thyroid hormone in aged mice.

Background: Sex and age have substantial influence on thyroid function. Sex influences the risk and clinical expression of thyroid disorders (TDs), with age a proposed trigger for the development of TDs. Cardiac function is affected by thyroid hormone levels with gender differences.

Protein O-GlcNAcylation levels are regulated independently of dietary intake in a tissue and time-specific manner during rat postnatal development.

Aim: Metabolic sources switch from carbohydrates in utero, to fatty acids after birth and then a mix once adults. O-GlcNAcylation (O-GlcNAc) is a post-translational modification considered as a nutrient sensor. The purpose of this work was to assess changes in protein O-GlcNAc levels, regulatory enzymes and metabolites during the first periods of life and decipher the impact of O-GlcNAcylation on cardiac proteins.

Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

Objective: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial.

Study Design: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models.

First characterization of glucose flux through the hexosamine biosynthesis pathway (HBP) in mouse heart.

The hexosamine biosynthesis pathway (HBP) branches from glycolysis and forms UDP-GlcNAc, the moiety for -linked β-GlcNAc (-GlcNAc) post-translational modifications. An inability to directly measure HBP flux has hindered our understanding of the factors regulating protein -GlcNAcylation. Our goals in this study were to (i) validate a LC-MS method that assesses HBP flux as UDP-GlcNAc (C)-molar percent enrichment (MPE) and concentration and (ii) determine whether glucose availability or workload regulate cardiac HBP flux.

O-GlcNAc Transferase Promotes Compensated Cardiac Function and Protein Kinase A O-GlcNAcylation During Early and Established Pathological Hypertrophy From Pressure Overload.

Background Protein posttranslational modifications by O-linked β-N-acetylglucosamine (O-GlcNAc) increase with cardiac hypertrophy, yet the functional effects of these changes are incompletely understood. In other organs, O-GlcNAc promotes adaptation to acute physiological stressors; however, prolonged O-GlcNAc elevations are believed to be detrimental. We hypothesize that early O-GlcNAcylation improves cardiac function during initial response to pressure overload hypertrophy, but that sustained elevations during established pathological hypertrophy negatively impact cardiac function by adversely affecting calcium handling proteins.

Etanercept With IVIg for Acute Kawasaki Disease: A Randomized Controlled Trial.

Objectives: Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis factor α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression.

Methods: In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.

Cardiac Management of the Patient With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) results in a progressive cardiomyopathy that produces significant morbidity and mortality. To improve the quality of life in patients with DMD, cardiac care is focused on surveillance and management, with the goal of slowing the onset and progression of heart failure complications. The current article is intended to be an expanded review on the cardiac management data used to inform the 2018 DMD Care Considerations recommendations as well as be a discussion on clinical controversies and future management directions.

Frequency of Ventricular Arrhythmias and Other Rhythm Abnormalities in Children and Young Adults With the Marfan Syndrome.

Patients with the Marfan syndrome (MFS) are at risk for sudden death. The contribution of arrhythmias is unclear. This study examines the prevalence of arrhythmias in children with the MFS and their relation to clinical and/or echocardiographic factors.

Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome.

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36 months read in the core laboratory of 608 trial subjects, aged 6 months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3.

Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome.

The Pediatric Heart Network randomized trial of atenolol versus losartan in the Marfan syndrome showed no treatment differences in the rates of aortic-root growth or clinical outcomes. In this report we present treatment effects on aortic stiffness and determine whether baseline aortic stiffness predicts aortic-root growth and clinical outcomes. Echocardiograms at 0, 6, 12, 24, and 36 months from 608 subjects (6 months to 25 years) who met original Ghent criteria and had a maximum aortic-root z-score (ARz) >3 were centrally reviewed.

Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management.

A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD.

AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation.

AMP-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy. Here, we show that submaximal AMPK activation blocks cardiomyocyte hypertrophy without affecting downstream targets previously suggested to be involved, such as p70 ribosomal S6 protein kinase, calcineurin/nuclear factor of activated T cells (NFAT) and extracellular signal-regulated kinases. Instead, cardiomyocyte hypertrophy is accompanied by increased protein O-GlcNAcylation, which is reversed by AMPK activation.

PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis.

Unlabelled: Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology.

Selective cerebral perfusion prevents abnormalities in glutamate cycling and neuronal apoptosis in a model of infant deep hypothermic circulatory arrest and reperfusion.

Deep hypothermic circulatory arrest is often required for the repair of complex congenital cardiac defects in infants. However, deep hypothermic circulatory arrest induces neuroapoptosis associated with later development of neurocognitive abnormalities. Selective cerebral perfusion theoretically provides superior neural protection possibly through modifications in cerebral substrate oxidation and closely integrated glutamate cycling.

Comparison of left ventricular function assessment between echocardiography and MRI in Duchenne muscular dystrophy.

Background: Cardiomyopathy in Duchenne muscular dystrophy (DMD) is associated with death in approximately 40% of patients. Echocardiography is routinely used to assess left ventricular (LV) function; however, it has limitations in these patients.

Objective: We compared echocardiographic measures of cardiac function assessment to cardiac MRI.

c-Myc Alters Substrate Utilization and O-GlcNAc Protein Posttranslational Modifications without Altering Cardiac Function during Early Aortic Constriction.

Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy.