Caridad de la Uz

Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current.

BACKGROUND Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function. METHODS/RESULTS Two probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS. CONCLUSIONS The CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.

Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture

Background—Cardiac device implantation can be complicated by inability to adequately place leads because of significant lead capture issues. This study sought to determine whether there are genetic bases that underlie poor lead capture. Methods and Results—Retrospective review of all patients with structurally normal hearts who underwent new device implantation at Texas Children’s Hospital between 2009 and 2014 was performed. Patients with inability to capture at 10 V or a final capture threshold ≥3 V at 0.4 ms during implant were analyzed. Among a total of 136 patients (median age, 13 years; range, 3 days to 46 years), 11 patients (8.1%) who underwent dual chamber device implantation had elevated thresholds in the atria (4), ventricle (3), or both chambers (4; atrial-lead threshold, 4.7±4.3 versus 0.7±0.3 V; ventricular-lead, 3.0±3.3 versus 0.7±0.3 V). All 11 patients presented with sinus node dysfunction and 10 had atrial arrhythmias. At implant, inability to find atrial capture was seen in 4 patients. Three demonstrated intermittent complete loss of ventricular capture after implantation: 1 has recurrent syncope, 2 eventually died. Genetic testing performed in 10 demonstrated 7 patients with 6 distinct SCN5A mutations, all predicted to be severe loss-of-function mutations by bioinformatic analyses. In the remaining patients, although putative pathogenic mutations were not found, multiple SCN5A polymorphisms were identified in 2 and a desmin mutation in 1. Conclusions—This study suggests that significant capture issues at implant may be because of loss-of-function SCN5A mutations, providing new insights into SCN5A function. Recognition of this association may be critical for planning device implantation strategies and patient follow-up.

Late outcomes in children with Shone's complex: a single-centre, 20-year experience.

OBJECTIVE Shones syndrome is a complex consisting of mitral valve stenosis in addition to left ventricle outflow obstruction. There are a few studies evaluating the long-term outcomes in this population. We sought to determine the long-term outcomes in our paediatric population with Shones syndrome and the factors associated with left heart growth. METHODS All patients diagnosed with Shones syndrome with biventricular circulation treated between 1978 and 2010 were reviewed. Baseline echocardiograms and data from catheterisations were also reviewed. Number of interventions (surgical+transcatheter), incidence of mitral valve replacement, and incidence of heart transplantation were tracked. Survival of the population and left heart structural growth were also reviewed. RESULTS A total of 121 patients with Shones syndrome presented at a median age of 28 days (0-17.3 years) and were followed-up for 7.2 years (0.01-35.5 years). These patients underwent 258 interventions during the study period, and the presence of coarctation was associated with repeat left heart interventions. The 10-year, transplant-free survival was 86%. Presence of pulmonary hypertension was associated with mortality. Left heart structural growth was seen for mitral and aortic valve annuli and left ventricular end-diastolic dimension over time. CONCLUSIONS Shones syndrome patients undergo a number of left heart interventions. Coarctation of the aorta is associated with an increased likelihood for repeat interventions. Survival appears to be more favourable than expected. Significant left heart growth will occur in the population. Pulmonary hypertension is associated with an increased risk of mortality.

Reassessing Risk Factors in Pediatric Patients With Pacemakers Implanted for Atrioventricular Block: The Impact of Nonsustained Ventricular Tachycardia

In pediatric patients with pacemakers implanted for atrioventricular block (AVB), nonsustained ventricular tachycardia (NSVT) detected during routine surveillance is a finding of unknown significance. We sought to describe the incidence of NSVT and determine if there was an association between NSVT and adverse outcomes in these patients.

Intravenous sotalol for the management of postoperative junctional ectopic tachycardia

Junctional ectopic tachycardia (JET) is a common postoperative arrhythmia seen in children undergoing surgery to repair congenital heart defects.1, 2 If conservative interventions such as cooling, sedation, weaning of inotropic therapy, and atrial overdrive pacing3, 4 are not adequate, intravenous (IV) antiarrhythmic drugs are used. The most commonly used antiarrhythmic drugs for the treatment of JET include amiodarone and procainamide.4, 5, 6 Recently IV sotalol has become available, and initial studies and case reports have shown it to be safe and effective in the management of supraventricular and ventricular arrhythmias in children.7, 8, 9 We report the first use of IV sotalol for the treatment of postoperative JET.

Cardiac Arrest in Pediatric Patients Receiving Azithromycin

Objective To compare outcomes of pediatric patients treated with azithromycin compared with penicillin or cephalosporin. We hypothesized that azithromycin use would not be associated with increased cardiac mortality in the pediatric population. Study design Retrospective cohort study from the Pediatric Health Information System database between 2008 and 2012. Patients <19 years of age with a principal diagnosis of community‐acquired pneumonia who received an antibiotic were included. Primary outcomes were cardiopulmonary resuscitation (CPR) and mortality. Secondary outcomes were ventricular arrhythmias incidences and readmission for ventricular arrhythmia. Statistical analysis was performed with the χ2 test. Multivariable analysis was performed to control for potential confounders among patient, event, and treatment characteristics. Results A total of 82 982 patients (54.3% males) met study criteria. Median age was 2.6 years (IQR 1.2‐5.9 years) and median length of stay was 2 days (IQR 2‐4 days). Azithromycin was used in 5039 (6.1%); penicillin or cephalosporin was used in 77 943 (93.9%). Overall prevalence of antibiotic‐associated CPR was 0.14%. Patients receiving a macrolide antibiotic had a lower prevalence of CPR compared with patients receiving a penicillin or cephalosporin (0.04% vs 0.14%, P = .04), and there was no difference in mortality. Multivariable analysis did not find an association between macrolide use and CPR. Conclusions In contrast to recent adult studies, among children hospitalized for community‐acquired pneumonia, azithromycin use was not associated with a greater prevalence of cardiac arrest compared with penicillin or cephalosporin use.

How active are young cardiac device patients? Objective assessment of activity in children with cardiac devices: DE LA UZ et al.

The daily activity of pediatric patients with implantable cardiac devices provides behavioral evidence of functional outcomes. Modern devices provide continuous accelerometer data that are sensitive to movement, but normative values have not been published for pediatric activity rates. This study provides the first normative accelerometer data on activity rates in a large sample of pediatric cardiac device patients.

Analysis of adults with congenital heart disease presenting to pediatric emergency departments with arrhythmias

OBJECTIVE As survivors of congenital heart disease (CHD) continue to age, healthcare utilization by this population has increased. It is unknown how often these patients utilize the emergency department (ED) at childrens hospitals and how arrhythmias play a role in their utilization of care. DESIGN Using a retrospective cohort design, the Pediatric Hospital Information System (PHIS) database was investigated and we studied adults (≥18 years) with CHD (ACHD) who presented to pediatric EDs from 2004 to 2014. SETTING Tertiary care pediatric hospitals. RESULTS Of the 6310 encounters to pediatric EDs, 1594 (25%) were for arrhythmias. The median age was 21 years (IQR 19.1-25.1). The most common tachyarrhythmia diagnoses during the study period were atrial flutter (32%), atrial fibrillation (15%), and paroxysmal VT (10%). Bradyarrhythmias represented a minority of total arrhythmias. Presentation with arrhythmias was associated with an increased risk of admission, ICU care, and death (P < .01). Arrhythmias are also highly associated with CHD severity with twice as many complex CHD having arrhythmias compared to simple CHD (P < .01). CONCLUSIONS Total admissions of adults with CHD from the ED of childrens hospitals have increased over time while the transfers to outside facilities remain consistently low. While the population of ACHD continues to grow, utilization of pediatric EDs for this cohort has increased. Adults with higher CHD complexity are more likely to present with clinical arrhythmias but there is a growing number of ACHD patients with simple complexity presenting with arrhythmias in recent years. ACHD patients that present with arrhythmias are at increased risk of morbidity and mortality.