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[sup.+] 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[sup.[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[sup.[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[sup.[DELTA]/+] mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.
Author(s): Dieter Nuyens [1]; Milan Stengl [2]; Saran Dugarmaa [4]; Tom Rossenbacker [1]; Veerle Compernolle [1]; Yoram Rudy [5]; Jos F. Smits [3]; Willem Flameng [6]; Colleen E. Clancy [5]; [...]