Referenced in: none

Automatically associated channels: Kv7.1 , Nav1.5

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

Authors: D Nuyens, M Stengl, S Dugarmaa, T Rossenbacker, V Compernolle, Y Rudy, J F Smits, W Flameng, C E Clancy, L Moons, M A Vos, M Dewerchin, K Benndorf, D Collen, E Carmeliet, P Carmeliet

Journal, date & volume: Nat. Med., 2001 Sep , 7, 1021-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/11533705

Abstract
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.