Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction

Heart Rhythm. 2016 Jan;13(1):289-98. doi: 10.1016/j.hrthm.2015.08.021. Epub 2015 Aug 14.


Background: Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQT1, LQT2, and LQT3 are caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep.

Objective: The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels.

Methods: LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system.

Results: We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 ± 17.6 pA/pF; V2016M 97.2 ± 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 ± 0.01%; V2016M 0.17 ± 0.03%; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation.

Conclusion: We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient.

Keywords: Adrenergic stimulation; Epinephrine; Long-QT syndrome; Protein kinase A; Protein kinase C; SCN5A.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epinephrine / pharmacology*
  • Exercise Test / adverse effects
  • Exercise Test / methods
  • Genetic Predisposition to Disease
  • Humans
  • Long QT Syndrome* / complications
  • Long QT Syndrome* / diagnosis
  • Long QT Syndrome* / genetics
  • Long QT Syndrome* / physiopathology
  • Male
  • Mutation, Missense
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • Sick Sinus Syndrome* / diagnosis
  • Sick Sinus Syndrome* / etiology
  • Sympathomimetics / pharmacology
  • Syncope* / diagnosis
  • Syncope* / etiology
  • Young Adult


  • NAV1.5 Voltage-Gated Sodium Channel
  • Sympathomimetics
  • Epinephrine

Supplementary concepts

  • Long Qt Syndrome 3