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

被引:196
作者
Nuyens, D
Stengl, M
Dugarmaa, S
Rossenbacker, T
Compernolle, V
Rudy, Y
Smits, JF
Flameng, W
Clancy, CE
Moons, L
Vos, MA
Dewerchin, M
Benndorf, K
Collen, D
Carmeliet, E
Carmeliet, P [1 ]
机构
[1] Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, Louvain, Belgium
[2] Univ Maastricht, Cardiovasc Res Inst Maastricht, Maastricht, Netherlands
[3] Klinikum Friederich Schiller Univ Jena, Inst Physiol, Jena, Germany
[4] Case Western Reserve Univ, Cardiac Bioelect Res & Training Ctr, Cleveland, OH USA
[5] Katholieke Univ Leuven, Lab Expt Cardiac Surg, Louvain, Belgium
关键词
D O I
10.1038/nm0901-1021
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1021 / 1027
页数:7
相关论文
共 40 条
[1]   Lidocaine block of LQT-3 mutant human Na+ channels [J].
An, RH ;
Bangalore, R ;
Rosero, SZ ;
Kass, RS .
CIRCULATION RESEARCH, 1996, 79 (01) :103-108
[2]   Transmural dispersion of repolarization and arrhythmogenicity - The Brugada syndrome versus the long QT syndrome [J].
Antzelevitch, C ;
Yan, GX ;
Shimizu, W .
JOURNAL OF ELECTROCARDIOLOGY, 1999, 32 :158-165
[3]   MOLECULAR MECHANISM FOR AN INHERITED CARDIAC-ARRHYTHMIA [J].
BENNETT, PB ;
YAZAWA, K ;
MAKITA, N ;
GEORGE, AL .
NATURE, 1995, 376 (6542) :683-685
[4]   Cardiac sodium channel and inherited arrhythmia syndromes [J].
Bezzina, CR ;
Rook, MB ;
Wilde, AAM .
CARDIOVASCULAR RESEARCH, 2001, 49 (02) :257-271
[5]  
BOYETT MR, 1980, PROG BIOPHYS MOL BIO, V36, P1
[6]   Acceleration-induced action potential prolongation and early afterdepolarizations [J].
Burashnikov, A ;
Antzelevitch, C .
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, 1998, 9 (09) :934-948
[7]   Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188 [J].
Carmeliet, P ;
Ng, YS ;
Nuyens, D ;
Theilmeier, G ;
Brusselmans, K ;
Cornelissen, I ;
Ehler, E ;
Kakkar, VV ;
Stalmans, I ;
Mattot, V ;
Perriard, JC ;
Dewerchin, M ;
Flameng, W ;
Nagy, A ;
Lupu, F ;
Moons, L ;
Collen, D ;
D'Amore, PA ;
Shima, DT .
NATURE MEDICINE, 1999, 5 (05) :495-502
[8]   Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome [J].
Casimiro, MC ;
Knollmann, BC ;
Ebert, SN ;
Vary, JC ;
Greene, AE ;
Franz, MR ;
Grinberg, A ;
Huang, SP ;
Pfeifer, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (05) :2526-2531
[9]   Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells [J].
Chandra, R ;
Starmer, CF ;
Grant, AO .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 1998, 274 (05) :H1643-H1654
[10]   Genetic basis and molecular mechanism for idiopathic: ventricular fibrillation [J].
Chen, QY ;
Kirsch, GE ;
Zhang, DM ;
Brugada, R ;
Brugada, J ;
Brugada, P ;
Potenza, D ;
Moya, A ;
Borggrefe, M ;
Breithardt, G ;
Ortiz-Lopez, R ;
Wang, Z ;
Antzelevitch, C ;
O'Brien, RE ;
Schulze-Bahr, E ;
Keating, MT ;
Towbin, JA ;
Wang, Q .
NATURE, 1998, 392 (6673) :293-296