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

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na+ ch annel 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 fa tal arrhythmias, typically at rest or during sleep. Here we report that mic e heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essent ial LQT3 features and spontaneously develop life-threatening polymorphous v entricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afte rdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergi c agonists normalized the response to rate acceleration in vitro and suppre ssed 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.