Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome -: Effects of β-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes
Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome -: Effects of β-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes
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DOI：
10.1161/01.cir.98.21.2314
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发表时间：
1998-11-24
期刊：
影响因子：
37.8
通讯作者：
Antzelevitch, C
中科院分区：
文献类型：
--
作者：
Shimizu, W;Antzelevitch, C
背景-本研究检测了在模拟先天性长QT综合征LQT 1形式的条件下，β-肾上腺素能激动剂诱导的宽基底T波、跨壁复极离散度（TDR）增加和尖端扭转型室性心动过速（TdP）的表型外观的细胞基础。同时记录犬左心室动脉灌注楔块的内皮细胞。特异性I-Ks阻断剂Chromanol 293 B呈剂量依赖性（1 ~ 100 μ mol/L）延长3种细胞的QT间期和动作电位时程（APD（90）），但不增宽T波、增加TDR或诱导TdP。异丙肾上腺素10 ~ 100 nmol/L与色原烷醇293 B 30 μ mol/L合用，可缩短心外膜和心内膜细胞的APD（90），但M细胞的APD（90）不缩短，导致T波增宽，TDR显著加重。自发以及程序性电刺激（PES）诱导的TdP仅在暴露于I-Ks阻滞剂和异丙肾上腺素后观察到。普萘洛尔的治疗浓度（0.5至1 μ mol/L）阻止异丙肾上腺素增加TDR和诱导TdP的作用。美西律2 ~ 20 μ mol/L缩短M细胞APD（90）的作用大于心外膜和内膜细胞，结论-LQT 1的实验模型表明，单独缺乏I-Ks并不能诱导TdP，但加入β-KKs可以诱导TdP。肾上腺素能影响通过增加跨壁复极离散度使心肌易于发生TdP，最有可能是由于心外膜和内膜细胞中残留I-Ks大量增加，而不是在I-Ks本质上较弱的M细胞中。我们的数据提供了β-肾上腺素能阻滞剂在LQT 1中治疗作用的细胞基础的机制理解，并表明IB类抗心律失常药物的钠通道阻滞可能有效抑制LQT 1中的TdP，就像它们在LQT 2和LQT 3中一样，以及在获得性（药物诱导的）长QT综合征中一样。
Background-This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by beta-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome.Methods and Results-A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific I-Ks blocker, dose-dependently (1 to 100 mu mol/L) prolonged the QT interval and action potential duration (APD(90)) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 mu mol/L abbreviated the APD(90) of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the I-Ks blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 mu mol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 mu mol/L abbreviated the APD(90) of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP.Conclusions-This experimental model of LQT1 indicates that a deficiency of I-Ks alone does not induce TdP but that the addition of beta-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual I-Ks in epicardial and endocardial cells but not in M cells, in which I-Ks is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of beta-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome.