β-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle
β-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle
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DOI：
10.1038/s41598-017-16218-3
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发表时间：
2017-11-21
影响因子：
4.6
通讯作者：
Efimov, I. R.
中科院分区：
文献类型：
--
作者：
Kang, C.;Badiceanu, A.;Efimov, I. R.
长QT综合征（LQTS）是一种遗传性或药物诱导的疾病，与延迟复极和心源性猝死有关。心脏钾通道I-Kr和肾上腺素敏感性心脏钾电流I-Ks是心脏复极的两个主要贡献者。本研究旨在阐明β-肾上腺素能（β-AR）刺激在介导I-Kr和I-Ks对人左心室复极的贡献中的作用（n = 18）。在存在I-Ks阻断剂JNJ-303和I-Kr阻断剂E-4031的情况下，使用光学标测测量动作电位时程（APD）。我们发现JNJ-303单独给药不会增加APD。然而，在异丙肾上腺素（ISO）下，JNJ-303和额外E-4031的应用均显著增加APD。与心内膜相比，使用JNJ-303时，ISO降低心外膜APD的程度显著更高，后续应用E-4031增加中膜和心内膜APD 80的程度显著高于心外膜。我们发现，β-AR刺激显著增强了IKs阻断剂JNJ-303的作用，而I-Kr阻断剂E-4031的作用降低。我们还观察到ISO和E-4031的组合协同增强跨壁复极梯度。我们的结果表明β-AR介导的跨壁复极离散度增加，这可能对LQTS患者造成致心律失常的风险。
Long QT syndrome (LQTS) is an inherited or drug induced condition associated with delayed repolarization and sudden cardiac death. The cardiac potassium channel, I-Kr, and the adrenergic-sensitive cardiac potassium current, I-Ks, are two primary contributors to cardiac repolarization. This study aimed to elucidate the role of beta-adrenergic (beta-AR) stimulation in mediating the contributions of I-Kr and I-Ks to repolarizing the human left ventricle (n = 18). Optical mapping was used to measure action potential durations (APDs) in the presence of the I-Ks blocker JNJ-303 and the I-Kr blocker E-4031. We found that JNJ-303 alone did not increase APD. However, under isoprenaline (ISO), both the application of JNJ-303 and additional E-4031 significantly increased APD. With JNJ-303, ISO decreased APD significantly more in the epicardium as compared to the endocardium, with subsequent application E-4031 increasing mid-and endocardial APD80 more significantly than in the epicardium. We found that beta-AR stimulation significantly augmented the effect of IKs blocker JNJ-303, in contrast to the reduced effect of I-Kr blocker E-4031. We also observed synergistic augmentation of transmural repolarization gradient by the combination of ISO and E-4031. Our results suggest beta-AR-mediated increase of transmural dispersion of repolarization, which could pose arrhythmogenic risk in LQTS patients.