Thomas Pilcher

Somatic mosaicism contributes to phenotypic variation in Timothy syndrome

Timothy syndrome type 1 (TS‐1) is a rare disorder that affects multiple organ systems and has a high incidence of sudden death due to profound QT prolongation and resultant ventricular arrhythmias. All previously described cases of TS‐1 are the result of a missense mutation in exon 8A (p.G406R), an alternatively spliced variant of the L‐type calcium channel gene (Cav1.2, CACNA1C). Most patients reported in the literature represent highly affected individuals who present early in life with severe cardiac and neurological manifestations. Here, we describe somatic mosaicism in TS‐1 patients with less severe manifestations than the typical TS‐1 patient. These findings suggest that the TS prognosis may not be as dismal as previously reported. Moreover, our findings have implications for genetic counseling in that previously described de novo TS mutations may represent cases of parental mosaicism and warrant careful genotyping of parental tissue other than peripheral blood lymphocytes.

Inappropriate ICD shocks in pediatrics and congenital heart disease patients: Risk factors and programming strategies

BACKGROUND Inappropriate implantable cardioverter-defibrillator (ICD) shocks are a common and significant problem in pediatric patients and patients with congenital heart disease (CHD). OBJECTIVE The purpose of this study was to evaluate the effect of programming high detection rates and long detection duration on inappropriate shocks in this population. METHODS We performed a retrospective review of all patients with ICDs at a single pediatric center. Inappropriate shocks were defined as a shock for any rhythm except ventricular tachycardia or fibrillation. RESULTS A total of 144 patients were included, 63 (44%) with CHD. At implant, mean age and weight were 17 ± 10 years and 57 ± 23 kg. ICDs were single chamber in 35 (24%), dual chamber in 97 (67%), and biventricular in 12 (8%). The mean follow-up duration was 42 ± 39 months. Appropriate shocks occurred in 29 (20.1%) and inappropriate shocks in 14 (9.7%). Causes of inappropriate shocks were supraventricular tachycardia (n = 6), lead malfunction (n = 4), sinus tachycardia (n = 3), and T-wave oversensing (n = 1). The mean ventricular fibrillation detection rate was 222 ± 15 beats/min, and the detection duration was 18 ± 12 beats. Patients with shocks programmed in the ventricular tachycardia zone were more likely to receive an inappropriate shock (P = .03). There were no associations between inappropriate shocks and age or weight at implant, presence of CHD, dual-chamber vs single-chamber device, history of supraventricular tachycardia, or antiarrhythmic use. There were no adverse events as a result of programming. CONCLUSION Programming high detection rates and long detection duration resulted in a low rate of inappropriate shocks without associated adverse events in this large cohort of pediatric and CHD patients with ICDs.

Safety and Results of Cryoablation in Patients <5 Years Old and/or <15 Kilograms

Current recommendations discourage elective radiofrequency ablation in patients <5 years old and/or weighing <15 kg, primarily because of the greater complication rate. To describe the current use, complications, and immediate outcomes of cryoablation in this patient population, a multicenter retrospective review of all patients <5 years old and/or weighing <15 kg who were treated with cryoablation for arrhythmia was performed. Eleven centers contributed data for 68 procedures on 61 patients. Of those, 34% were elective and 24% (n = 16) were both cryoablation and radiofrequency ablation. The median age and weight at ablation was 3.5 years (range 8 days to 9.9 years) and 15.2 kg (range 2.3 to 23), respectively. Congenital heart disease was present in 23% of the patients. The immediate success rate of cryoablation alone was 74%. No major complications occurred with cryoablation only; however, 2 of the 16 patients who underwent cryoablation and radiofrequency ablation had major complications. Of the 50 patients receiving cryoablation, 8 (16%) had variable degrees of transient atrioventricular block. The recurrence rate was 20% after cryoablation and 30% after cryoablation plus radiofrequency ablation. In conclusion, cryoablation appears to have a high safety profile in these patients. Compared to older and larger patients, the efficacy of cryoablation in this small, young population was lower and the recurrence rates were higher. Cryoablations effect on the coronary arteries has not been fully elucidated and requires additional research.

Catheter ablation of supraventricular tachyarrhythmia after extracardiac Fontan surgery

BACKGROUND Extracardiac total cavopulmonary connection (E-TCPC) is widely performed for single ventricle palliation, yet there is little experience with catheter ablation in this population. OBJECTIVES We hypothesized that atrial tachycardia substrates after primary E-TCPC would be similar to those in other forms of congenital heart disease and that catheter ablation could be performed effectively using a primarily transconduit approach. METHODS Catheter ablation characteristics of patients with E-TCPC from 9 centers were collected. Acute procedural success was defined as elimination of all sustained supraventricular tachyarrhythmias. Procedural complications, acute success, and recurrences were assessed. RESULTS Forty-six catheter ablation procedures were performed in 36 patients. Access to the atrium was by transconduit puncture in 29 procedures (63%). The most common supraventricular tachyarrhythmia mechanism was intra-atrial reentrant tachycardia (IART) in 21 patients (58%); and for all patients with primary E-TCPC and IART, an isthmus between the atrioventricular valve annulus and the oversewn inferior vena cava was critical for maintenance of tachycardia. Overall, acute success was achieved in 38 procedures (83%). There were 8 complications, with only 1 requiring intervention (epicardial pacemaker) and none related to conduit puncture. Recurrence after the final procedure occurred in 6 patients (17%) over a median follow-up duration of 0.4 years (interquartile range 0.1-1.5 years). CONCLUSION Catheter ablation could be performed effectively in this group of patients with E-TCPC, and the underlying IART substrate after primary E-TCPC appears to be reproducible. Catheter ablation may be a reasonable alternative to long-term antiarrhythmic therapy in this patient group.

A teenage fainter (dizziness, syncope, postural orthostatic tachycardia syndrome).

This article informs the general pediatrician about the diagnosis, evaluation, and treatment of teenage patients with presyncope and loss of consciousness. The focus is on distinguishing noncardiac fainting from life-threatening syncope. Current treatment strategies of vasovagal syncope and postural orthostatic tachycardia syndrome are also outlined.

Measuring defibrillator surface potentials: The validation of a predictive defibrillation computer model

Implantable cardioverter defibrillators (ICDs) are commonly used to reduce the risk in patients with life-threatening arrhythmias, however, clinicians have little systematic guidance to place the device, especially in cases of unusual anatomy. We have previously developed a computational model that evaluates the efficacy of a delivered shock as a clinical and research aid to guide ICD placement on a patient specific basis. We report here on progress to validate this model with measured ICD surface potential maps from patients undergoing ICD implantation and testing for defibrillation threshold (DFT). We obtained body surface potential maps of the defibrillation pulses by adapting a limited lead selection and potential estimation algorithm to deal with the limited space for recording electrodes. Comparison of the simulated and measured potential maps of the defibrillation shock yielded similar patterns, a typical correlation greater than 0.9, and a relative error less than 15%. Comparison of defibrillation thresholds also showed accurate prediction of the simulations. The high agreement of the potential maps and DFTs suggests that the predictive simulation generates realistic potential values and can accurately predict DFTs in patients. These validation results pave the way for use of this model in optimization studies prior to device implantation.

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. Data from the Pediatric Heart Network randomized trial of atenolol versus losartan in MFS were analyzed (6 months to 25 years old, aortic root diameter z-score > 3.0, no previous aortic surgery and/or dissection). Baseline 24-hour ambulatory electrocardiographic monitoring was performed. Significant ventricular ectopy (VE) and supraventricular ectopy (SVE) were defined as ≥10 VE or SVE/hour, or the presence of high-grade ectopy. Three-year composite clinical outcome of death, aortic dissection, or aortic root replacement was analyzed. There were 274 analyzable monitors on unique patients from 11 centers. Twenty subjects (7%) had significant VE, 13 (5%) significant SVE; of these, 2 (1%) had both. None had sustained ventricular or supraventricular tachycardia. VE was independently associated with increasing number of major Ghent criteria (odds ratio [OR] = 2.13/each additional criterion, p = 0.03) and greater left ventricular end-diastolic dimension z-score (OR = 1.47/each 1 unit increase in z-score, p = 0.01). SVE was independently associated with greater aortic sinotubular junction diameter z-score (OR = 1.56/each 1 unit increase in z-score, p = 0.03). The composite clinical outcome (14 events) was not related to VE or SVE (p ≥ 0.3), but was independently related to heart rate variability (higher triangular index). In conclusion, in this cohort, VE and SVE were rare. VE was related to larger BSA-adjusted left ventricular size. Routine ambulatory electrocardiographic monitoring may be useful for risk stratification in select MFS patients.

A Functional Assay for Sick Sinus Syndrome Genetic Variants

Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information.

Congenital long QT syndrome: A difficult journey for one young survivor

Introduction Congenital long QT syndrome (LQTS) is characterized by prolongation of the repolarization phase after cardiac myocyte depolarization. It affects up to 1 in 2000 people and is a leading cause of sudden cardiac death (SCD) in the young. To date, defects in 16 genes that code for transmembrane cardiac ion channels or accessory proteins have been implicated in more than 80% of cases. Patients with LQTS have a long QT interval on surface ECG and are predisposed to torsades de pointes (TdP). Infants with extremely prolonged repolarization may present with bradycardia from functional 2:1 AV block when the QT interval exceeds the P-P interval. We present a difficult case of LQTS in a highly affected child with a rescinded genetic diagnosis and multiple complications from medical therapies.

Measuring defibrillator surface potentials for simulation verification

Though implantable cardioverter defibrillators (ICDs) are increasing in use in both adults and children, little progress has been devoted to optimizing device and electrode placement. To facilitate effective ICD placement, especially in pediatric cases, we have developed a predictive model that evaluates the efficacy of a delivered shock. We have also developed an experimental validation approach based on measurements from clinical cases. The approach involves obtaining body surface potential maps of ICD discharges during implantation surgery using a limited lead selection and body surface estimation algorithm. Comparison of the simulated and measured potentials yielded very similar patterns and a typical correlation greater than 0.93, suggesting that the predictive simulation generates realistic potential values. This validation approach provides confidence in application of the simulation pipeline and offers areas to focus future improvements.