Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the α subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel

Impact of Obesity on Left Ventricular Thickness in Children with Hypertrophic Cardiomyopathy

Obesity is associated with additional left ventricular hypertrophy (LVH) in adults with hypertrophic cardiomyopathy (HCM). It is not known whether obesity can lead to further LVH in children with HCM. Echocardiographic LV dimensions were determined in 504 children with HCM. Measurements of interventricular septal thickness (IVST) and posterior wall thickness (PWT), and patients' weight and height were recorded. Obesity was defined as a body mass index (BMI) >= 99th percentile for age and sex. IVST data was available for 498 and PWT data for 484 patients. Patient age ranged from 2 to 20 years (mean +/- SD, 12.5 +/- 3.9) and 340 (68%) were males. Overall, patient BMI ranged from 7 to 50 (22.7 +/- 6.1). Obesity (BMI 18-50, mean 29.1) was present in 140 children aged 2-19.6 (11.3 +/- 4.1). The overall mean IVST was 20.5 +/- 9.6 mm and the overall mean PWT was 11.0 +/- 8.4 mm. The mean IVST in the obese patients was 21.6 +/- 10.0 mm and mean PWT was 13.3 +/- 14.7 mm. The mean IVST in the non-obese patients was 20.1 +/- 9.5 mm and mean PWT was 10.4 +/- 4.3 mm. Obesity was not significantly associated with IVST (p = 0.12), but was associated with increased PWT (0.0011). Obesity is associated with increased PWT but not IVST in children with HCM. Whether obesity and its impact on LVH influences clinical outcomes in children with HCM needs to be studied

Risk factors for lethal arrhythmic events in children and adolescents with hypertrophic cardiomyopathy and an implantable defibrillator: An international multicenter study

BACKGROUND Predictors of risk of lethal arrhythmic events (LAE) is poorly understood and may differ from adults in children with hypertrophic cardiomyopathy (HCM). OBJECTIVE The purpose of this study was to determine predictors of LAE in children with HCM. METHODS A retrospective data collection was performed on 446 children and teenagers 20 years and younger (290 [65%] male; mean age 10.1 +/- 5.7 years) with idiopathic HCM from 35 centers. Patients were classified as group 1 (HCM with LAE) if having a secondary prevention implantable cardioverter-defibrillator (ICD) or primary prevention ICD with appropriate interventions or group 2 (HCM without LAE) if having a primary prevention ICD without appropriate interventions. RESULTS There were 152 children (34%) in group 1 and 294 (66%) in group 2. Risk factors for group 1 by univariate analysis were septal thickness, posterior left ventricular (LV) wall thickness, lower LV outflow gradient, and Q wave > 3 mm in inferior electrocardiographic leads. Factors not associated with LAE were family history of SCD, abnormal blood pressure response to exercise, and ventricular tachycardia on ambulatory electrocardiographic monitoring. Risk factors for SCD by multivariate analysis were age at ICD placement (hazard ratio [HR] 0.9; P = .0025), LV posterior wall thickness z score (HR 1.02; P = 5 was associated with LAE. CONCLUSION Risk factors for LAE appear different in children compared to adults. Conventional adult risk factors were not significant in children. Further prospective studies are needed to improve risk stratification for LAE in children with HCM