Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

被引：172

作者：

Brunner, Michael ^{[1
]}

Peng, Xuwen ^{[2
]}

Liu, Gong Xin ^{[3
]}

Ren, Xiao-Qin ^{[3
]}

Ziv, Ohad ^{[3
]}

Choi, Bum-Rak ^{[3
]}

Mathur, Rajesh ^{[1
]}

Hajjiri, Mohammed ^{[3
]}

Odening, Katja E. ^{[3
]}

Steinberg, Eric ^{[2
]}

Folco, Eduardo J. ^{[4
]}

Pringa, Ekatherini ^{[3
]}

Centracchio, Jason ^{[3
]}

Macharzina, Roland R. ^{[1
]}

Donahay, Tammy ^{[3
]}

Schofield, Lorraine ^{[3
]}

Rana, Naveed ^{[3
]}

Kirk, Malcolm ^{[3
]}

Mitchell, Gary F. ^{[5
]}

Poppas, Athena ^{[3
]}

Zehender, Manfred ^{[1
]}

Koren, Gideon ^{[3
]}

机构：

[1] Univ Freiburg Klinikum, Freiburg, Germany

[2] Penn State Univ, Coll Med, Dept Comparat Med, Pennsauken, NJ USA

[3] Brown Univ, Rhode Isl Hosp, Cardiovasc Res Ctr,Dept Med, Warren Alpert Med Sch,Div Cardiol, Providence, RI 02903 USA

[4] Brigham & Womens Hosp, Div Cardiovasc, Harvard Med Sch, Boston, MA 02115 USA

[5] Cardiovasc Engn Inc, Waltham, MA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2008年 / 118卷 / 06期

关键词：

D O I：

10.1172/JCI33578

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of I-Ks, and I-Kr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (> 50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary I-Kr and I-Ks without affecting the steady state levels of the native polypeptides. Thus, the elimination of I repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type a subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

引用

页码：2246 / 2259

页数：14

共 58 条

[11] Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QT syndrome [J].