A multicentre study of patients with Timothy syndrome.

Aims: Timothy syndrome (TS) is an extremely rare multisystem disorder characterized by marked QT prolongation, syndactyly, seizures, behavioural abnormalities, immunodeficiency, and hypoglycaemia. The aim of this study was to categorize the phenotypes and examine the outcomes of patients with TS. Methods and results: All patients diagnosed with TS in the United Kingdom over a 24-year period were reviewed. Fifteen centres in the British Congenital Arrhythmia Group network were contacted to partake in the study. Six patients with TS were identified over a 24-year period (4 boys and 2 girls). Five out of the six patients were confirmed to have a CACNA1C mutation (p.Gly406Arg) and the other patient was diagnosed clinically. Early presentation with heart block, due to QT prolongation was frequently seen. Four are still alive, two of these have a pacemaker and two have undergone defibrillator implantation. Five out of six patients have had a documented cardiac arrest with three occurring under general anaesthesia. Two patients suffered a cardiac arrest while in hospital and resuscitation was unsuccessful, despite immediate access to a defibrillator. Surviving patients seem to have mild developmental delay and learning difficulties. Conclusion: Timothy syndrome is a rare disorder with a high attrition rate if undiagnosed. Perioperative cardiac arrests are common and not always amenable to resuscitation. Longer-term survival is possible, however, patients invariably require pacemaker or defibrillator implantation.

Compound Heterozygous Triadin Mutation Causing Cardiac Arrest in Two Siblings.

We present the case of two siblings who both presented with an out-of-hospital cardiac arrest at 2 years of age. Both siblings underwent internal cardiac defibrillator implantation and both had recurrent episodes of ventricular fibrillation (VF). A compound heterozygous mutation in the triadin gene was discovered; one of these mutations has been described previously in the homozygous state, and the other one is unreported. The combination of these mutations has resulted in a particularly arrhythmogenic phenotype, with cardiac arrest occurring at a very young age and recurrent episodes of VF despite ß-blockade. Flecainide seems to have been very effective in preventing clinical arrhythmias for this particular mutation.

Outcomes From Pediatric Ablation: A Review of 20 Years of National Data.

OBJECTIVES: This study set out to examine outcomes from pediatric supraventricular tachycardia ablations over a 20-year period. This study sought to examine success rates and repeat ablations over time and to evaluate whether modalities such as 3-dimensional (3D) mapping, contact force, and cryotherapy have improved outcomes. BACKGROUND: Ablation of supraventricular tachycardia in pediatric patients is commonly performed in most congenital heart centers with excellent long-term results. METHODS: Data were retrieved from the NICOR (National Institute of Clinical Outcomes Research) database in the United Kingdom. Outcomes over time were evaluated, and procedure-related details were compared. RESULTS: There were 7,069 ablations performed from January 1, 1999, to December 31, 2018, at 10 centers. Overall, ablation success rates were 92% for accessory pathways, 97% for atrioventricular node re-entry tachycardia, and 89% for atrial tachycardia. There was an improvement in procedural success rates over time (p < 0.01). The use of 3D mapping did not alter success or need for repeat ablation but was associated with a higher proportion of lower fluoroscopy cases; 55% of 3D mapping cases used <5 min of fluoroscopy (p < 0.01). Patients needing a repeat ablation were 341 (12%) for accessory pathways, 128 (7%) for atrioventricular node re-entry tachycardia, and 35 (7%) for atrial tachycardia. Overall, the risk of complete heart block was low (n = 12, <0.01%). The use of cryotherapy was associated with an increased risk of needing a repeat ablation. CONCLUSIONS: Overall success rates from pediatric ablations are excellent and compare favorably to other registries. Introduction of newer technologies have likely made procedures safer and reduced radiation exposure, but they have not changed success rates or the need for a repeat procedure.

Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome.

The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss- and gain-of-function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (IhERG ) exhibits uniquely fast inactivation involving conformational changes to the channel pore. The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on IhERG profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C. Under conventional voltage clamp, the current-voltage (I-V) relation for IhERG exhibited a marked right-ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented IhERG , which also peaked much earlier during the AP plateau than did wild-type (WT) IhERG . Instantaneous I-V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance-voltage relation showed an earlier and more sustained rise in S631A compared to WT IhERG conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted IhERG in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions. Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 µmol/L) against S631A IhERG . Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.

Ventricular fibromas in children, arrhythmia risk, and outcomes: A multicenter study.

BACKGROUND: Although ventricular fibromas are rare, they are the second most common type of cardiac tumor in children. While histologically benign, they have a propensity to cause malignant arrhythmias, with cardiac arrest often being the first presentation. OBJECTIVE: The purpose of this study was to evaluate the arrhythmia risk and management strategies for pediatric ventricular fibromas. METHODS: Fifteen centers in the British Paediatric Arrhythmia Group network were contacted to partake in the study to contribute cases. A detailed database search was performed at 2 hospitals for cases of ventricular fibromas. RESULTS: A total of 19 patients were included in the study. Arrhythmias were common, with 5 patients presenting with cardiac arrest and 5 others having documented ventricular tachycardia. Nine patients have undergone surgical resection at various hospitals, and all these patients have survived with good long-term outcomes. One patient who did not have any treatment died, presumably of a ventricular arrhythmia; another died of metastatic disease. There were no recurrences of arrhythmia after surgery, and the need for a defibrillator was alleviated in all cases. CONCLUSION: Ventricular fibromas have a high propensity to cause malignant arrhythmias, and if they are not managed appropriately, mortality is high. The outcomes of surgical resection are good, regardless of size, and this represents the best therapeutic option, with most patients being symptom free in the longer term.