Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction
Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction
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DOI：
10.1152/ajpheart.00074.2010
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发表时间：
2010-09-01
影响因子：
4.8
通讯作者：
Koren, Gideon
中科院分区：
文献类型：
--
作者：
Odening, Katja E.;Kirk, Malcolm;Koren, Gideon
Odening KE、Kirk M、Brunner M、Ziv O、Lorvidhaya P、Liu GX、Schofield L、Chaves L、Peng X、Zehender M、Choi B、Koren G。转基因长 QT 1 型和 2 型兔的电生理学研究揭示了心室不应性和 His 传导的基因型特异性差异。 Am J Physiol Heart Circ Physiol 299：H643-H655，2010。首次发表于 2010 年 6 月 25 日； doi:10.1152/ajpheart.00074.2010.-我们已经培育出缺乏心脏慢延迟整流 K+ 电流 [I-Ks;长 QT 综合征 1 型 (LQT1)] 或快速激活延迟整流 K+ 电流 [I-Kr； 2 型长 QT 综合征 (LQT2)]。具有任一基因型的兔子都有较长的动作电位持续时间和 QT 间期；然而，只有 LQT2 兔子才会出现房室传导阻滞和多形性室性心动过速。因此，我们试图表征 LQT1 和 LQT2 兔子 AV 传导和心室不应性的基因型特异性差异。我们在 LQT1、LQT2 和同窝对照 (LMC) 兔子的基线、异丙肾上腺素输注期间以及多非利特推注后进行体内电生理学研究，并在基线和多非利特灌注期间对 AV 结/His 区域进行离体光学测绘研究。在异氟烷麻醉下，LQT2 兔子出现 His 下阻滞、His 传导减弱以及 Wenckebach 周期长度延长。在 LQT1 兔子中，多非利特改变了 His 形态并减慢了 His 传导，导致 His 内传导阻滞，并另外延长了心室不应期，导致假性房室传导阻滞。 LQT2 兔右心室心尖部和基底部的心室有效不应期 (VERP) 显着长于 LQT1 (P < 0.05) 或 LMC (P < 0.01)，且 LQT2 兔的 VERP 离散度大于 LQT1 兔。异丙肾上腺素通过使基部的 VERP 比顶端的 VERP 缩短更多，从而减少了 LQT2 兔中的 VERP 离散度，但对 LQT1 中的 VERP 没有影响。 EPS 和光学映射实验证明了 AV 传导和心室不应性的基因型特异性差异。 LQT2 兔在异氟烷作用下出现 His 下阻滞，LQT1 兔在多非利特作用后出现 His 内阻滞，表明兔 His-Purkinje 系统对 I-Kr 和 I-Ks 阻滞药物的局部敏感性不同。
Odening KE, Kirk M, Brunner M, Ziv O, Lorvidhaya P, Liu GX, Schofield L, Chaves L, Peng X, Zehender M, Choi B, Koren G. Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction. Am J Physiol Heart Circ Physiol 299: H643-H655, 2010. First published June 25, 2010; doi:10.1152/ajpheart.00074.2010.-We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K+ current [I-Ks; long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K+ current [I-Kr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P < 0.05) or LMC (P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking I-Kr and I-Ks.