Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome
Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome
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DOI：
10.1016/s0022-0736(99)90077-8
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发表时间：
1999-01-01
影响因子：
1.3
通讯作者：
Antzelevitch, C
中科院分区：
文献类型：
--
作者：
Shimizu, W;Antzelevitch, C
遗传学研究已经确定了四种形式的先天性长QT综合征（LQTS），由位于染色体3（LQT 3），7（LQT 2），11（LQT 1）和21（LQT 5）上的离子通道基因突变引起。初步的临床研究报告了不同的表型心电图模式和不同的敏感性起搏或药物治疗的每一个基因型。在犬左心室动脉灌注楔块上同时记录了跨壁心电图和心外膜细胞、M细胞和内膜细胞的跨膜动作电位。异丙肾上腺素（100 nmol/L）与色满醇293 B（30 μ mol/L）（一种I-Ks阻断剂（LQT 1模型））联合使用时，可优先延长M细胞动作电位时程（APD），导致跨壁复极离散度（TDR）增加和宽基底T波，与LQT 1患者中常见的情况相同。D-Sotalol（100 μ mol/L），一种I-Kr阻断剂（LQT 2模型），和ATX-II（20 nmol/L），一种增强晚期I-Na的药物（LQT 3模型），也分别产生了M细胞APD的优先延长，TDR的增加，以及具有分叉外观的低振幅T波（LQT 2）和迟发性T波（LQT 3）。LQT 3模型中APD、QT和TDR与心率的关系比LQT 1或LQT 2模型中的睡眠者多，而LQT 1和LQT 2模型中的心率关系均比对照条件下的更陡。在所有3种模型中均观察到自发性和程序性电刺激诱导的尖端收缩（TdP）。普萘洛尔（1 μ mol/L），一种β受体阻滞剂，完全阻止了异丙肾上腺素持续或短暂增加TDR和诱导LQT 1和LQT 2模型中的TdP的作用，但促进了LQT 3模型中的TdP。IB类Na+通道阻滞剂美西律（2-20 μ mol/L）可剂量依赖性地缩短LQT 3模型的QT和APD，但降低3种模型的TDR和抑制TdP。
Genetic studies have identified four forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes located on chromosomes 3 (LQT3), 7 (LQT2), 11 (LQT1), and 21 (LQT5). Preliminary clinical studies have reported different phenotypic electrocardiographic patterns and different sensitivity to pacing or pharmacological therapy for each genotype. A transmural electrocardiogram and transmembrane action potentials from epicardial, M, and endocardial cells were simultaneously recorded from an arterially perfused wedge of canine left ventricle. Isoproterenol (100 nmol/L) in the presence of chromanol 293B (30 mu mol/L), an I-Ks blocker (LQT1 model), produced a preferential prolongation of M-cell action potential duration (APD), resulting in an increase in transmural dispersion of repolarization (TDR) and a broad-based T wave, as commonly seen in LQT1 patients. D-Sotalol (100 mu mol/L), an I-Kr blocker (LQT2 model), and ATX-II (20 nmol/L), an agent that augments late I-Na (LQT3 model), also produced a preferential prolongation of M-cell APD, an increase in TDR, and low-amplitude T wave with a bifurcated appearance (LQT2), and late-appearing T wave (LQT3), respectively. APD-, QT-, and TDR-rate relations were much sleeper in the LQT3 model than in either the LQT1 or LQT2 model, whereas the rate relations in the LQT1 and LQT2 models were both steeper than those under control conditions. Spontaneous and programmed electrical stimulation-induced tor sade de pointes (TdP) were observed in all 3 models. Propranolol (1 mu mol/L), a beta blocker, completely prevented the effect of isoproterenol to persistently or transiently increase TDR and to induce TdP in the LQT1 and LQT2 models, but facilitated TdP in the LQT3 model. Mexiletine, a class IB Na+ channel blocker, dose-dependently (2-20 mu mol/L) abbreviated the QT and APD more in the LQT3 model, but decreased TDR and suppressed TdP in the 3 models.