Cardiac Sodium Channel Gene Variants and Sudden Cardiac Death in Women

Abstract

Background-Several cardiac ion channel genes have been implicated in monogenic traits with a high risk of sudden cardiac death (SCD). Mutations or rare variants in these genes have been proposed as potential contributors to more common forms of SCD, but this hypothesis has not been assessed systematically. Methods and Results-We directly sequenced the entire coding region and splice junctions of 5 cardiac ion channel genes, SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2, in 113 SCD cases from 2 large prospective cohorts of women (Nurses' Health Study) and men (Health Professional Follow-Up Study). Controls from the same population were then screened for the presence of mutations or rare variants identified in cases, and sequence variants without prior functional data were expressed in Xenopus oocytes to assess their biophysical consequences. No mutations or rare variants were identified in any of the 53 subjects who were men. In contrast, in 6 of 60 women (10%), we identified 5 rare missense variants in SCN5A that either had been associated previously with long-QT syndrome (A572D and G615E), had been reported to alter sodium channel function (F2004L), or had not been reported previously in control populations (A572F and W1205C). Of the 4 variants without prior functional data, 3 variants were located in the I-II linker (A572D, A572F, and G615E), and all resulted in significantly shorter recovery times from inactivation. When compared with 733 control samples from the same population, the overall frequency of these rare variants in SCN5A was significantly higher in the SCD cases (6/60, 10.0%) than in controls (12/733, 1.6%; Pϭ0.001). Conclusion-Functionally significant mutations and rare variants in SCN5A may contribute to SCD risk among women.(Circulation. 2008;117:16-23.)

Primary Prevention Implantable Cardioverter Defibrillator (ICD) Therapy in Women—Data From a Multicenter French Registry

“…In our sample, despite having more women with nonischemic cardiomyopathy, the overall reduction in arrhythmic burden was still present even after adjustment for baseline differences. Several mechanisms have been proposed for sex differences regarding the risk of ventricular arrhythmia: higher resting heart rate, different autonomic response to stress, degree of vagal activation, differences in cardiac repolarization, hormonal differences affecting arrhythmic vulnerability, genetic variants influencing QT interval length or adrenergic receptors, and even nutritional factors, adherence to a low‐risk lifestyle, and behavorial and psychological factors 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. Overall, the interplay between vulnerable substrate (underlying structural and electric heart substrate), triggers, and autonomic tone may be slightly different 30…”

Cardiac Sodium Channel ( SCN5A ) Variants Associated with Atrial Fibrillation

“…In familial arrhythmia syndromes, the absence of a nonsynonymous variant in an appropriately matched control population is often considered adequate evidence to label the variant a disease-causing mutation. 8,12,49 The third limitation of this study relates to the paroxysmal nature and variable symptoms in AF, as well as the older age of onset in many individuals, all of which can make assignment of the clinical phenotype challenging.…”

The complexity of genotype-phenotype relations associated with loss-of-function sodium channel mutations and the role of in silico studies

“…Whereas the authors are the first to associate the mutation with Brugada syndrome, F2004L has also been identified in sudden infant death syndrome (3,18) and in adult sudden cardiac death victims (2). As these clinical disease entities have been associated with Brugada syndrome, these data are compatible with an association between F2004L and Brugada syndrome.…”