A Rare Cause of a Continuous Murmur in a Newborn.

We describe what we believe to be the first reported case of a neonate with right coronary ostial atresia with the right coronary artery originating from the left circumflex coronary artery, in conjunction with a right coronary artery to right ventricle fistula in a patient with otherwise normal cardiac anatomy. This was found following an evaluation for a continuous murmur at 2 weeks of life with elevated troponin and abnormal electrocardiogram. Thus far the child has required no intervention and is asymptomatic at 17 months of age, but he will require long-term follow-up to monitor the size of the fistula and potential for myocardial insufficiency.

Increased interstage morbidity and mortality following stage 1 palliation in patients with genetic abnormalities.

BACKGROUND: Hypoplastic left heart syndrome and single ventricle variants with aortic hypoplasia are commonly classified as severe forms of CHD. We hypothesised patients with these severe defects and reported genetic abnormalities have increased morbidity and mortality during the interstage period. METHODS AND RESULTS: This was a retrospective review of the National Pediatric Cardiology Quality Improvement Collaborative Phase I registry. Three patient groups were identified: major syndromes, other genetic abnormalities, and no reported genetic abnormality. Tukey post hoc test was applied for pairwise group comparisons of length of stay, death, and combined outcome of death, not a candidate for stage 2 palliation, and heart transplant. Participating centres received a survey to establish genetic testing and reporting practices. Of the 2182 patients, 110 (5%) had major genetic syndromes, 126 (6%) had other genetic abnormalities, and 1946 (89%) had no genetic abnormality. Those with major genetic syndromes weighed less at birth and stage 1 palliation. Patients with no reported genetic abnormalities reached full oral feeds sooner and discharged earlier. The combined outcome of death, not a candidate for stage 2 palliation, and heart transplant was more common in those with major syndromes. Survey response was low (n = 23, 38%) with only 14 (61%) routinely performing and reporting genetic testing. CONCLUSIONS: Patients with genetic abnormalities experienced greater morbidity and mortality during the interstage period than those with no reported genetic abnormalities. Genetic testing and reporting practices vary significantly between participating centres.

Treatment of attention deficit/hyperactivity disorder in children with CHD.

INTRODUCTION: The prevalence of attention deficit/hyperactivity disorder in the general population is common and is now diagnosed in 4%-12% of children. Children with CHD have been shown to be at increased risk for attention deficit/hyperactivity disorder. Case reports have led to concern regarding the use of attention deficit/hyperactivity disorder medications in children with underlying CHD. We hypothesised that medical therapy for patients with CHD and attention deficit/hyperactivity disorder is safe. METHODS: A single-centre, retrospective chart review was performed evaluating for adverse events in patients aged 4-21 years with CHD who received attention deficit/hyperactivity disorder therapy over a 5-year span. Inclusion criteria were a diagnosis of CHD and concomitant medical therapy with amphetamines, methylphenidate, or atomoxetine. Patients with trivial or spontaneously resolved CHD were excluded from analysis. RESULTS: In 831 patients with CHD who received stimulants with a mean age of 12.9 years, there was only one adverse cardiovascular event identified. Using sensitivity analysis, our median follow-up time was 686 days and a prevalence rate of 0.21% of adverse events. This episode consisted of increased frequency of supraventricular tachycardia in a patient who had this condition prior to initiation of medical therapy; the condition improved with discontinuation of attention deficit/hyperactivity disorder therapy. CONCLUSION: The incidence of significant adverse cardiovascular events in our population was similar to the prevalence of supraventricular tachycardia in the general population. Our single-centre experience demonstrated no increased risk in adverse events related to medical therapy for children with attention deficit/hyperactivity disorder and underlying CHD. Further population-based studies are indicated to validate these findings.

Comparison of growth and feeding method in infants with and without genetic abnormalities after neonatal cardiac surgery.

INTRODUCTION: Congenital heart disease (CHD) is multifactorial in origin, resulting from an interaction between environmental and genetic factors. Multifactorial growth delay is common in infants with CHD. The impact of a genetic abnormality and CHD on the growth of an infant is lacking in the literature. The aim of this study is to compare the growth and method of feeding following neonatal cardiac surgery in infants with normal versus abnormal genetic testing. METHODS: A retrospective chart review of neonates who underwent a Risk Adjustment in Congenital Heart Surgery IV-VI procedure between 1 January, 2006 and 22 September, 2016 was performed at our institution. Weight, length, head circumference measurements, and feeding method were collected at birth, time of neonatal surgery, and monthly up to 6 months of age. RESULTS: A total of 53 infants met inclusion criteria, of which 22 had abnormal genetic testing. Approximately 90% of infants were discharged following neonatal cardiac surgery with supplemental tube feeds. At each monthly follow-up visit, more infants were exclusively fed orally: 80% of infants with normal genetics at 5 months post-operative follow-up versus 60% of infants with abnormal genetic testing, although statistically insignificant. Growth was not different among the two groups. CONCLUSIONS: Infants with critical CHD with or without genetic abnormalities are at risk for growth delays and many need supplemental tube feeds post-operatively and throughout follow-up. Infants with genetic abnormalities are slower to achieve oral feeds and more likely to require tube feedings. It is important to have a systematic protocol for managing these high-risk infants.

A Case of Idiopathic Acquired Neonatal Bell's Palsy.

Neonatal idiopathic Bell's palsy is a very rare diagnosis with only a few previously published case reports of infants responding well to oral corticosteroid use. This trial therapy likely comes from adult data where clinical outcomes are improved following steroid use, although the data in childhood cases are equivocal. In this specific population of infants <28 days of age at presentation, the most common causes of Bell's palsy include congenital, birth trauma, and syndromic (likely with no indication for steroid treatment). In those with noncongenital Bell's palsy, infectious and structural causes should first be ruled out. In this article, we present the third known case report of a 16-day-old presenting with acute Bell's palsy with negative infectious workup and normal brain imaging. He was treated with a 7-day course of oral prednisone and had eventual resolution of symptoms.

Junctional Ectopic Tachycardia Localization and Procedural Approach using Cryoablation.

BACKGROUND: Idiopathic junctional ectopic tachycardia (JET) may still be difficult to control with antiarrhythmic therapy. Transcatheter ablation can be challenging and may be associated with a high risk of unintended atrioventricular block. The objective of this manuscript is to report the procedural technique, the location of the successful ablation, and the procedural characteristics while utilizing 3D mapping for cryoablation of JET. METHODS: A retrospective analysis was performed on all patients who had undergone cryothermal ablation for the treatment of JET at a single center. Patient, arrhythmia, and procedural information and long-term outcomes were evaluated. RESULTS: Thirteen patients with JET were treated by cryothermal ablation. The JET arrhythmia burden varied greatly, generally with inadequate control on medications. Left ventricular dilation was present in three patients, and one patient had dilated cardiomyopathy. The median age at the time of procedure was 13 years, with median weight of 54.1 kg. The ectopic focus was ablated in 11/13 patients within the lower 2/3 of the triangle of Koch (TOK) with cryotherapy. Ablations, which were not successful, low in the TOK were associated with substantially longer procedures, and had a higher risk of recurrence. There was late resolution of the arrhythmia in two of three acutely unsuccessful ablations. There were no complications. CONCLUSION: In the majority of patients JET can be safely ablated with the use of cryotherapy. Foci not identified in the lower 2/3 of the TOK are associated with longer procedures, more lesions, and decreased chance for long-term success.

Aip1p dynamics are altered by the R256H mutation in actin.

Mutations in actin cause a range of human diseases due to specific molecular changes that often alter cytoskeletal function. In this study, imaging of fluorescently tagged proteins using total internal fluorescence (TIRF) microscopy is used to visualize and quantify changes in cytoskeletal dynamics. TIRF microscopy and the use of fluorescent tags also allows for quantification of the changes in cytoskeletal dynamics caused by mutations in actin. Using this technique, quantification of cytoskeletal function in live cells valuably complements in vitro studies of protein function. As an example, missense mutations affecting the actin residue R256 have been identified in three human actin isoforms suggesting this amino acid plays an important role in regulatory interactions. The effects of the actin mutation R256H on cytoskeletal movements were studied using the yeast model. The protein, Aip1, which is known to assist cofilin in actin depolymerization, was tagged with green fluorescent protein (GFP) at the N-terminus and tracked in vivo using TIRF microscopy. The rate of Aip1p movement in both wild type and mutant strains was quantified. In cells expressing R256H mutant actin, Aip1p motion is restricted and the rate of movement is nearly half the speed measured in wild type cells (0.88 ± 0.30 µm/sec in R256H cells compared to 1.60 ± 0.42 µm/sec in wild type cells, p < 0.005).

Thoracic aortic aneurysm (TAAD)-causing mutation in actin affects formin regulation of polymerization.

More than 30 mutations in ACTA2, which encodes α-smooth muscle actin, have been identified to cause autosomal dominant thoracic aortic aneurysm and dissection. The mutation R256H is of particular interest because it also causes patent ductus arteriosus and moyamoya disease. R256H is one of the more prevalent mutations and, based on its molecular location near the strand-strand interface in the actin filament, may affect F-actin stability. To understand the molecular ramifications of the R256H mutation, we generated Saccharomyces cerevisiae yeast cells expressing only R256H yeast actin as a model system. These cells displayed abnormal cytoskeletal morphology and increased sensitivity to latrunculin A. After cable disassembly induced by transient exposure to latrunculin A, mutant cells were delayed in reestablishing the actin cytoskeleton. In vitro, mutant actin exhibited a higher than normal critical concentration and a delayed nucleation. Consequently, we investigated regulation of mutant actin by formin, a potent facilitator of nucleation and a protein needed for normal vascular smooth muscle cell development. Mutant actin polymerization was inhibited by the FH1-FH2 fragment of the yeast formin, Bni1. This fragment strongly capped the filament rather than facilitating polymerization. Interestingly, phalloidin or the presence of wild type actin reversed the strong capping behavior of Bni1. Together, the data suggest that the R256H actin mutation alters filament conformation resulting in filament instability and misregulation by formin. These biochemical effects may contribute to abnormal histology identified in diseased arterial samples from affected patients.

Allele-specific effects of thoracic aortic aneurysm and dissection alpha-smooth muscle actin mutations on actin function.

Twenty-two missense mutations in ACTA2, which encodes α-smooth muscle actin, have been identified to cause thoracic aortic aneurysm and dissection. Limited access to diseased tissue, the presence of multiple unresolvable actin isoforms in the cell, and lack of an animal model have prevented analysis of the biochemical mechanisms underlying this pathology. We have utilized actin from the yeast Saccharomyces cerevisiae, 86% identical to human α-smooth muscle actin, as a model. Two of the known human mutations, N115T and R116Q, were engineered into yeast actin, and their effect on actin function in vivo and in vitro was investigated. Both mutants exhibited reduced ability to grow under a variety of stress conditions, which hampered N115T cells more than R116Q cells. Both strains exhibited abnormal mitochondrial morphology indicative of a faulty actin cytoskeleton. In vitro, the mutant actins exhibited altered thermostability and nucleotide exchange rates, indicating effects of the mutations on monomer conformation, with R116Q the most severely affected. N115T demonstrated a biphasic elongation phase during polymerization, whereas R116Q demonstrated a markedly extended nucleation phase. Allele-specific effects were also seen on critical concentration, rate of depolymerization, and filament treadmilling. R116Q filaments were hypersensitive to severing by the actin-binding protein cofilin. In contrast, N115T filaments were hyposensitive to cofilin despite nearly normal binding affinities of actin for cofilin. The mutant-specific effects on actin behavior suggest that individual mechanisms may contribute to thoracic aortic aneurysm and dissection.