Cardiac Sodium Channel Mutations Link Lone Atrial Fibrillation to the Long QT Syndrome

Editor's Note: This Article of the Month is based on Olesen MS, Yuan L, Liang B, et al. High Prevalence of Long QT Syndrome Associated SCN5A Variants in Patients With Early-Onset Lone Atrial Fibrillation. Circ Cardiovasc Genet 2012;5:450-9.

On occasion, a clinician may encounter an otherwise healthy, relatively young patient who presents to clinic with the chief complaints of intermittent sudden-onset palpitations, rapid and irregular heart rates, and perhaps even fatigue. Further investigation may reveal that the patient is suffering from transient episodes of atrial fibrillation (AF). Although AF is the most common cardiac arrhythmia in adults,1 AF has been considered a “chronic disease of aging” given that advanced age is the most significant risk factor associated with AF,2 and thus, the aforementioned patient encounter would be uncommon. Patients with new-onset lone AF who are otherwise young and free of the commonly known comorbidities associated with AF may comprise 2-16% of all cases.3 In search for an answer, clinicians typically may review for triggers of lone atrial fibrillation including thyroid dysfunction, caffeine and/or alcohol consumption. However, with mounting evidence that also supports a genetic predisposition for AF, thorough review of family history may be more revealing when interviewing a patient with lone AF; given that 30% of patients with lone AF may have a first degree relative with a history of AF.4

The pathophysiology that underlies the development of AF has continued to challenge researchers and clinicians for over a hundred years. In the modern era of genomics and molecular biology, AF research including genome-wide association studies (GWAS) is providing convincing data that there is also a heritable genetic component that is associated with the development of AF.5, 6 Although genetic factors have been known to be strongly linked to the development of lone or familial AF, even the more common presentations of AF afflicting the general patient population may also have a significant genetic basis. Indeed, recent studies have shown that the heritability of AF in the general population approaches that of diabetes mellitus when a first-degree relative developed AF before the age of 60.6 Similar to diabetes mellitus, the genetic contribution to the development of AF is also thought to be polygenic in nature.2

Thus far, GWAS research efforts have identified several susceptibility loci associated with an increased risk of developing common AF and lone AF. Some of the candidate genes code for cardiac ion channels. The cardiac sodium channel gene (SCN5A) has been associated with ventricular arrhythmias such as long QT syndrome (LQTS), Brugada syndrome (BS), dilated cardiomyopathies, and more recently, atrial fibrillation.7 In a recent issue of Circulation Cardiovascular Genetics, Olesen et al. have presented further genomic and electrophysiologic evidence that implicates a role for SCN5A in the pathophysiology of some variants of lone AF in humans.8

In brief, Olesen et al. studied a group of 192 Caucasian patients in Denmark who were diagnosed with at least one episode of AF prior to forty years of age, but were otherwise free of concomitant structural heart disease, hypertension, metabolic or pulmonary disease.8 The SCN5A gene was sequenced in all these patients with lone AF as well as a cohort of 216 control patients with no known history of AF. Eleven patients were found to have rare SCN5A mutations, including 6 patients (3.2% of the lone AF population) with variants of SCN5A that have been associated with LQTS type 3 (LQTS3). All patients with SCN5A variants were further screened at several other loci with known associations with AF but no mutations were found. While the prevalence of SCN5A variants association with LQTS3 is several fold higher than would be expected in the general patient population, only a small percentage of patients with lone AF carried such a mutation. Only two patients with LQTS3-associated mutations had borderline prolonged QTc intervals.

The electrophysiologic effects of LQTS3-associated mutations were studied in-vitro with cell lines in which these mutations were introduced. Whole-cell patch clamp experiments observed altered transient peak sodium currents. Mechanistically, the altered sodium currents may favor the genesis of AF, but further research using whole animal models are needed to validate such findings in-vivo.

The findings by Olesen et al8 contribute to the corpus of studies regarding the genetic basis of AF as well previously described associations of AF with the long QT syndromes. Certainly, the study suggests an increased prevalence of LQTS3-variant mutations in patients with lone AF. Recent research has shown that patients with LQTS3-mutations with even normal QTc intervals are at increased risk for adverse cardiac events.9 However, it is not yet practical to order comprehensive genomic studies on all patients with lone AF, and furthermore, it is not clear as to how the results of such genomic studies would alter clinical decision-making.

Prior studies have also shown an increased prevalence of SCN5A mutations in patients with common AF.7 Olesen et al. chose to focus on patients with lone AF and a narrower age distribution confined to patients less than forty years of age.8 However, the age cut-off is rather arbitrary. Thus, in addition to traditional risk factors such as age and previously well-established clinical risk factors, SCN5A mutations may contribute to a complex process that gives rise to AF as disease modifiers along a broad continuum in patients with lone AF and common AF.

The heritability of lone and common AF is still largely uncharacterized. The factors that contribute to the genesis of AF may include heretofore unknown genetic factors responsible for altering atrial electrical properties as well as complex processes such as fibrosis. As next-generation DNA sequencing technologies improve with respect to accuracy and costs, large-scale genomic testing may shed additional light on the genetics and pathophysiology of AF.


  1. Rienstra M, McManus DD, Benjamin EJ. Novel risk factors for atrial fibrillation: Useful for risk prediction and clinical decision making? Circulation 2012;125:e941-946.
  2. Magnani JW, Rienstra M, Lin H, et al. Atrial fibrillation: Current knowledge and future directions in epidemiology and genomics. Circulation 2011;124:1982-1993.
  3. Campuzano O, Brugada R. Genetics of familial atrial fibrillation. Europace 2009;11:1267-1271.
  4. Ellinor PT, Lunetta KL, Glazer NL, et al. Common variants in kcnn3 are associated with lone atrial fibrillation. Nat Genet 2010;42:240-244.
  5. Kaab S, Darbar D, van Noord C, et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur Heart J 2009;30:813-819.
  6. Sinner MF, Ellinor PT, Meitinger T, Benjamin EJ, Kaab S. Genome-wide association studies of atrial fibrillation: Past, present, and future. Cardiovasc Res 2011;89:701-709.
  7. Darbar D, Kannankeril PJ, Donahue BS, et al. Cardiac sodium channel (scn5a) variants associated with atrial fibrillation. Circulation 2008;117:1927-1935.
  8. Olesen MS, Yuan L, Liang B, et al. High prevalence of long qt syndrome associated scn5a variants in patients with early-onset lone atrial fibrillation. Circ Cardiovasc Genet 2012;5:450-9.
  9. Goldenberg I, Horr S, Moss AJ, et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-qt syndrome and normal-range corrected qt intervals. J Am Coll Cardiol 2011;57:51-59.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Clinical Topic Collection: Dyslipidemia, Prevention, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD & Pediatrics and Arrhythmias, CHD & Pediatrics and Prevention, Lipid Metabolism, Hypertension

Keywords: Atrial Fibrillation, Brugada Syndrome, Caffeine, Chronic Disease, Denmark, Heart Rate, Hypertension, Ion Channels, Long QT Syndrome

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