Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil
Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil
复制标题
DOI：
10.1016/j.jacc.2004.09.069
复制
发表时间：
2005-01-18
影响因子：
24
通讯作者：
Sunagawa, K
中科院分区：
文献类型：
--
作者：
Aiba, T;Shimizu, W;Sunagawa, K
目的 我们研究了 QT 延长和随后的尖端扭转型室性心动过速 (TdP) 的细胞和离子机制，以及维拉帕米在模拟与获得性长 QT 综合征 (LQTS) 相关的 KCNQ1（I-Ks 基因）缺陷的条件下的作用。 背景 具有 I-Kr 阻断作用的药物通常会在获得性 LQTS 患者中引起明显的 QT 延长。先前的报告证明了心脏 K+ 通道基因的亚临床突变与药物诱导的 TdP 风险之间的关系。方法在动脉灌注猫左心室制剂中，以 2,000 ms 的基本周期长度同时记录心外膜 (EPI)、心肌中层 (M) 和心内膜 (ENDO) 细胞的跨膜动作电位以及透壁心电图。 结果 I-Kr 阻滞(E-4031: 1 mumol/l) 在对照条件下 (n = 5) 延长 QT 间期，但既不增加跨壁复极离散度 (TDR)，也不诱发心律失常。然而，在模拟 KCNQ1 缺陷 (n = 10) 的 chromanol 293B 10 mumol/l 抑制 I-Ks 的条件下，I-Kr 阻滞剂优先延长 EPI 中的动作电位持续时间 (APD)，而不是 M 或 ENDO，从而显着增加 QT 间期和 TDR。在 EPI 中观察到自发或肾上腺素诱导的早期后除极 (EAD)，随后的 TdP 仅在 I-Kr 和 I-Ks 抑制下发生。维拉帕米（0.1 至 5.0 mumol/l）在 EPI 中比在 M 和 ENDO 中剂量依赖性缩短 APD，从而显着缩短 QT 间期、TDR，并抑制 EAD 和 TdP。 结论 亚临床 I-Ks 功能障碍可能是药物诱发 TdP 的风险。维拉帕米可有效缩短 QT 间期和 TDR，并抑制 EAD，从而预防获得性 LQTS 模型中的 TdP。 (C) 2005 年由美国心脏病学会基金会资助。
OBJECTIVES We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1 (I-Ks gene) defect linked to acquired long QT syndrome (LQTS).BACKGROUND Agents with an I-Kr-blocking efFect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+ channel genes and a risk of drug-induced TdP.METHODS Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations.RESULTS The I-Kr block (E-4031: 1 mumol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the I-Kr blocker under conditions with I-Ks suppression by chromanol 293B 10 mumol/l mimicking the KCNQ1 defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both I-Kr and I-Ks suppression. Verapamil (0.1 to 5.0 mumol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP.CONCLUSIONS Subclinical I-Ks dysfunction could be a risk of drug-induced TdP. Verapamil is effiective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS. (C) 2005 by the American College of Cardiology Foundation.