Shimizu W, Antzelevitch C
Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan.
J Electrocardiol. 1999;32 Suppl:177-84. doi: 10.1016/s0022-0736(99)90077-8.
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 micromol/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 micromol/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 steeper 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 torsade de pointes (TdP) were observed in all 3 models. Propranolol (1 micromol/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 micromol/L) abbreviated the QT and APD more in the LQT3 model, but decreased TDR and suppressed TdP in the 3 models.
基因研究已确定了四种先天性长QT综合征（LQTS），它们由位于3号染色体（LQT3）、7号染色体（LQT2）、11号染色体（LQT1）和21号染色体（LQT5）上的离子通道基因突变引起。初步临床研究报告了每种基因型不同的表型心电图模式以及对起搏或药物治疗的不同敏感性。从犬左心室的动脉灌注楔形组织中同时记录了跨壁心电图以及心外膜、M细胞和心内膜细胞的跨膜动作电位。在存在I(Ks)阻滞剂色满醇293B（30微摩尔/升）（LQT1模型）的情况下，异丙肾上腺素（100纳摩尔/升）使M细胞动作电位时程（APD）优先延长，导致复极跨壁离散度（TDR）增加以及出现基底部较宽的T波，这在LQT1患者中较为常见。I(Kr)阻滞剂D - 索他洛尔（100微摩尔/升）（LQT2模型）以及增强晚钠电流（I(Na)）的药物ATX-II（20纳摩尔/升）（LQT3模型）也分别使M细胞APD优先延长、TDR增加，并分别出现低振幅且呈分叉状的T波（LQT2）以及延迟出现的T波（LQT3）。LQT3模型中APD、QT和TDR与心率的关系比LQT1或LQT2模型中的关系陡峭得多，而LQT1和LQT2模型中的心率关系均比对照条件下的关系陡峭。在所有3种模型中均观察到了自发和程控电刺激诱发的尖端扭转型室速（TdP）。β受体阻滞剂普萘洛尔（1微摩尔/升）在LQT1和LQT2模型中完全阻止了异丙肾上腺素持续或短暂增加TDR以及诱发TdP的作用，但在LQT3模型中促进了TdP的发生。ⅠB类钠通道阻滞剂美西律在LQT3模型中剂量依赖性地（2 - 20微摩尔/升）缩短QT和APD的程度更大，但在这3种模型中均降低了TDR并抑制了TdP。
