Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome

Nat Med. 2001 Sep;7(9):1021-7. doi: 10.1038/nm0901-1021.


Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Arrhythmias, Cardiac / drug therapy
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / physiopathology*
  • Cardiac Pacing, Artificial
  • Electrocardiography
  • Humans
  • Isoproterenol / pharmacology
  • Long QT Syndrome / genetics
  • Membrane Potentials
  • Mice
  • Mice, Mutant Strains
  • Myocardium / cytology
  • Myocardium / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel
  • Sequence Deletion
  • Sodium / metabolism
  • Sodium Channels / genetics*


  • Adrenergic beta-Agonists
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Scn5a protein, mouse
  • Sodium Channels
  • Sodium
  • Isoproterenol