Nuyens D, Stengl M, Dugarmaa S, Rossenbacker T, Compernolle V, Rudy Y, Smits J F, Flameng W, Clancy C E, Moons L, Vos M A, Dewerchin M, Benndorf K, Collen D, Carmeliet E, Carmeliet P
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.
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.
心脏SCN5A钠通道中氨基酸残基1505 - 1507（KPQ）的缺失会导致常染色体显性遗传的心电图QT间期延长（3型长QT综合征或LQT3）。低心率时动作电位过度延长使LQT3患者易发生致命性心律失常，通常在休息或睡眠期间发作。在此我们报告，敲入型KPQ缺失杂合子小鼠（SCN5A(Δ/+)）表现出LQT3的基本特征，并自发出现危及生命的多形性室性心律失常。出乎意料的是，心率突然加快或早搏会导致Scn5a(Δ/+)小鼠动作电位延长并伴有早期后去极化，进而引发心律失常。肾上腺素能激动剂在体外可使对心率加快的反应恢复正常，并在体内抑制早搏刺激诱发的心律失常。这些结果表明心率突然加快可能存在风险。具有起搏诱导性心律失常倾向的Scn5a(Δ/+)小鼠可能有助于开发针对LQT3综合征的新疗法。
