Shimizu W, Antzelevitch C
Masonic Medical Research Laboratory, Utica, NY 13501-1787, USA.
Circulation. 1997 Sep 16;96(6):2038-47. doi: 10.1161/01.cir.96.6.2038.
This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS).
A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 291+/-14 to 354+/-35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51+/-15 to 72+/-17 ms). QT interval increased from 320+/-13 to 385+/-37 ms. ATX-II produced a preferential prolongation of the M cell APD90 (280+/-25 to 609+/-49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40+/-5 to 168+/-40 ms). QT-, APD90-, and dispersion-rate relations were much steeper in the ATX-II than in the d-sotalol model. Mexiletine (2 to 20 micromol/L) dose-dependently abbreviated the QT interval and APD90 of all cell types, more in the ATX-II than in the d-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 micromol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 micromol/L) totally suppressed stimulation-induced TdP.
Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2.
本研究在模拟与先天性长QT综合征（LQTS）相关的HERG和SCN5A缺陷的条件下，探讨跨膜活性的跨壁异质性对T波表型模式的影响以及起搏和钠通道阻滞的作用。
在犬左心室动脉灌注楔形组织中同时记录跨壁心电图和心外膜、M细胞以及心内膜或浦肯野细胞的跨膜动作电位。用d - 索他洛尔模拟LQT2，而用ATX - II模拟LQT3。d - 索他洛尔优先延长M细胞动作电位时程（APD90，从291±14毫秒延长至354±35毫秒），导致T波宽大，有时振幅较低且呈双峰，复极跨壁离散度增加（TDR，从51±15毫秒增加至72±17毫秒）。QT间期从320±13毫秒增加至385±37毫秒。ATX - II优先延长M细胞APD90（从280±25毫秒延长至609±49毫秒），导致T波起始明显延迟且TDR急剧升高（从40±5毫秒升高至168±40毫秒）。在ATX - II模型中，QT、APD90和离散度 - 速率关系比在d - 索他洛尔模型中陡峭得多。美西律（2至20微摩尔/升）剂量依赖性地缩短所有细胞类型的QT间期和APD90，在ATX - II模型中的作用比在d - 索他洛尔模型中更明显，但在两个模型中均同等程度地降低TDR。2至5微摩尔/升的美西律完全抑制了两个模型中的自发性尖端扭转型室速（TdP），并缩小了单个期外刺激可诱发TdP的易损窗口。更高浓度的美西律（10至20微摩尔/升）完全抑制了刺激诱发的TdP。
我们的结果表明，尽管起搏和钠通道阻滞在缩短LQT3的QT间期和TDR方面非常有效，但这些治疗方法在降低LQT2心律失常的发生率方面可能也有价值。
