Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome
Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome
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DOI：
10.1172/jci33578
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Koren, Gideon
中科院分区：
文献类型：
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作者：
Brunner, Michael;Peng, Xuwen;Koren, Gideon
长QT综合征（LQTS）是一种遗传性疾病，在年轻患者中与ECG QT间期延长、室性心动过速和心源性猝死相关。在基因分型的个体中，约90%的受影响个体中存在编码复极化K+通道（LQT 1：KCNQ 1; LQT 2：KCNH 2）的基因突变。在兔心脏中表达人基因KCNQ 1（KvLQT 1-Y315 S）和KCNH 2（HERG-G628 S）的孔突变体产生具有长QT表型的转基因兔。QT间期和动作电位时程的延长是由于心肌细胞中I-Ks和I-Kr电流的消除。LQT 2家兔表现出高的自发性心脏性猝死发生率（1年时> 50%），原因是多形性室性心动过速。光学标测显示心律失常的复极化空间离散度增加。两种转基因引起剩余互补I-Kr和I-Ks的下调，而不影响天然多肽的稳态水平。因此，I复极化电流的消除与可逆复极化电流的下调有关，而不是与先前在LQTS小鼠模型中观察到的代偿性上调有关。这表明突变体KvLQT 1和HERG分别与兔ERG和KvLQT 1的相互野生型a亚基相互作用。这些结果对理解心律失常和心源性猝死的本质和异质性具有重要意义。
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.