Faculty Bibliography

Infants with single ventricle physiology and congenital anomalies of the airway and/or lung are potentially poor candidates for staged palliation. The prevalence and midterm outcomes for patients with anomalies of the airway or lung with hypoplastic left heart syndrome are unknown. We performed an analysis of data in infants with hypoplastic left heart syndrome from the National Pediatric Cardiology Quality Improvement Collaborative registry. The prevalence of congenital anomalies of the airway or lung in the registry was determined. Clinical characteristics and midterm outcomes were compared between infants with hypoplastic left heart syndrome with and without anomalies of the airway or lung. Fifty-seven (2.3%) of 2467 infants with hypoplastic left heart syndrome enrolled in the registry had congenital airway or lung anomalies. Infants congenital anomalies of the airway or lung had significantly lower transplant-free survival at 1 year (49.5 vs 77.2%, p < 0.001). Infants with airway or lung anomalies had longer combined hospital length of stay for stage 1 and stage 2 palliation (102 vs 65.1 days, p < 0.001) and underwent more major procedures (2.04 vs 0.93 procedures, p < 0.001) than those without. There was no difference in the number of interstage readmissions (1.85 vs 1.89, p = 0.87) or need for non-oral feeding supplementation (71.4 vs 54.5%, p = 0.12) between groups. Infants enrolled in the National Pediatric Cardiology Quality Improvement Collaborative registry with hypoplastic left heart syndrome and anomalies of the airway or lung have increased morbidity and mortality at 1 year compared to those with hypoplastic left heart syndrome alone.

Phenytoin is a versatile drug with utility in neurological, dermatological, and even cardiac disease processes. Though phenytoin is widely available due to its excellent anti-epileptic properties, it is now rarely used as an antiarrhythmic. Phenytoin has well-studied sodium-channel blocking abilities which can be taken advantage of to treat ventricular arrhythmias. Thus, it should remain in the arsenal of antiarrhythmics for any electrophysiologist. We present two cases of intractable ventricular arrhythmia in children that were controlled with phenytoin at supra-therapeutic serum levels, preventing the need for heart transplantation. This article is protected by copyright. All rights reserved.

Background The objective of this international multicenter study was to investigate both early and late outcomes of cardiac resynchronization therapy (CRT) in patients with a systemic right ventricle (SRV) and to identify predictors for congestive heart failure readmissions and mortality. Methods and Results This retrospective international multicenter study included 13 centers. The study population comprised 80 adult patients with SRV (48.9% women) with a mean age of 45±14 (range, 18-77) years at initiation of CRT. Median follow-up time was 4.1 (25th-75th percentile, 1.3-8.3) years. Underlying congenital heart disease consisted of congenitally corrected transposition of the great arteries and dextro-transposition of the great arteries in 63 (78.8%) and 17 (21.3%) patients, respectively. CRT resulted in significant improvement in functional class (before CRT: III, 25th-75th percentile, II-III; after CRT: II, 25th-75th percentile, II-III; P=0.005) and QRS duration (before CRT: 176±27; after CRT: 150±24 milliseconds; P=0.003) in patients with pre-CRT ventricular pacing who underwent an upgrade to a CRT device (n=49). These improvements persisted during long-term follow-up with a marginal but significant increase in SRV function (before CRT; 30%, 25th-75th percentile, 25-35; after CRT: 31%, 25th-75th percentile, 21-38; P=0.049). In contrast, no beneficial change in the above-mentioned variables was observed in patients who underwent de novo CRT (n=31). A quarter of all patients were readmitted for heart failure during follow-up, and mortality at latest follow-up was 21.3%. Conclusions This international experience with CRT in patients with an SRV demonstrated that CRT in selected patients with SRV dysfunction and pacing-induced dyssynchrony yielded consistent improvement in QRS duration and New York Heart Association functional status, with a marginal increase in SRV function.

We conducted a scientific survey of paediatric practitioners who manage heart failure with dilated cardiomyopathy in children. The survey covered management from diagnosis to treatment to monitoring, totalling 63 questions. There were 54 respondents from 40 institutions and 3 countries. There were diverse selections of management options by the respondents in general, but also unanimity in some management options. Variation in practice is likely due to the relative paucity of scientific data in this field and lack of strong evidence-based recommendations from guidelines, which presents an opportunity for future research and quality improvement efforts as the evidence base continues to grow.

BACKGROUND:Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated. METHODS:Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC. RESULTS:We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy. CONCLUSIONS:LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.

BACKGROUND:Moxifloxacin is a priority recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics, QT-interval prolongation and evaluate optimal dosing in children with RR-TB. METHODS:Pharmacokinetic data were pooled from two observational studies in South African children 0-17 years of age with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. RESULTS:Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were <2 years of age, and 8 (9%) were HIV-positive. The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16 kg child. Stunting and HIV infection increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥ 500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (inter-individual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children. CONCLUSIONS:Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when co-administered with other QT-prolonging agents.

Congenital left ventricle to coronary sinus fistula is a rare entity. We report a case of an infant with prenatal finding of left ventricle to right atrial shunt. The anatomy was defined by multi-modality imaging. Baseline electrocardiogram was notable for a Wolff-Parkinson-White pattern. He underwent successful catheter device closure of the left ventricle to coronary sinus fistula. The patient developed supraventricular tachycardia and underwent successful ablation of the accessory pathway.