Weissenburger J, Davy J M, Chézalviel F
Laboratoire de Pharmacologie, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, Paris, France.
Fundam Clin Pharmacol. 1993;7(1):29-38. doi: 10.1111/j.1472-8206.1993.tb00215.x.
Torsades de pointes is the most typical ventricular tachycardia involving QT-interval prolongation. It is a rather unusual but potentially lethal ventricular tachycardia with a distinctive morphology favored by bradycardia, antiarrhythmic drugs and hypokalemia and requires specific treatment. Torsades de pointes has been shown to be related to bradycardia-dependent early afterdepolarizations (EAD) and/or increased dispersion of repolarization. However, although EAD can be obtained relatively easily in vitro with quinidine or sotalol, torsades de pointes are very difficult to reproduce in animal models. The models of torsades de pointes which have been proposed can be categorized as morphological, EAD-related or pharmacological models. The purpose of the 'morphological' models was to reproduce the twisting of QRS axis typical of torsades de pointes, with no consideration of other aspects such as long QT or bradycardia. These models were produced by epicardial electrical or chemical (aconitine) stimulation at two distant ventricular sites or by overdosing of quinidine in dogs with acute myocardial infarction. The second type of model focused on the conditions producing EAD in vitro. Ventricular tachycardias were obtained in anesthetized dogs using toxics such as cesium or anthopleurine, both producing EAD in vitro. These ventricular tachycardias were shown to be sensitive to magnesium, heart rate and autonomic tone, but torsades de pointes remained rare, at least after cesium injections. The pharmacological models that could be used to study the QT-dependent proarrhythmic effects of drugs are the anesthetized rabbit with alpha-adrenergic stimulation, and the conscious dog model with chronic AV-block and diuretic-induced hypokalemia. Methoxamine-treated anesthetized rabbits develop ventricular tachycardias during clofilium infusions. These ventricular tachycardias, although appearing at very high heart rates, have typical torsades de pointes aspects and are often associated with giant QT waves. The specificity of the model remains to be tested. In our conscious bradycardic and hypokalemic dogs, quinidine and sotalol but not flecainide, propranolol or lidocaine induced QT-dependent arrhythmogenic effects and torsades de pointes. Efficacy of high rate stimulations and magnesium were repeatedly observed. This demanding model, especially designed for qualitative drug comparisons, is also well suited to studies on the mechanisms of initiation of torsades de pointes. The pertinence of these models for estimating the risk of QT-dependent proarrhythmias associated with non-antiarrhythmic agents remains to be tested.
尖端扭转型室速是最典型的与QT间期延长相关的室性心动过速。它是一种相当罕见但可能致命的室性心动过速，具有独特的形态，心动过缓、抗心律失常药物和低钾血症易诱发这种形态，且需要特殊治疗。已证明尖端扭转型室速与心动过缓依赖性早期后除极（EAD）和/或复极离散度增加有关。然而，尽管在体外使用奎尼丁或索他洛尔相对容易诱发EAD，但在动物模型中很难重现尖端扭转型室速。已提出的尖端扭转型室速模型可分为形态学模型、EAD相关模型或药理学模型。“形态学”模型的目的是重现尖端扭转型室速典型的QRS轴扭转，而不考虑其他方面，如长QT或心动过缓。这些模型是通过在两个相距较远的心室部位进行心外膜电刺激或化学（乌头碱）刺激，或在急性心肌梗死的犬中过量使用奎尼丁产生的。第二类模型关注体外产生EAD的条件。使用铯或海葵毒素等毒物在麻醉犬中诱发室性心动过速，这两种毒物在体外均可产生EAD。这些室性心动过速对镁、心率和自主神经张力敏感，但至少在注射铯后，尖端扭转型室速仍然很少见。可用于研究药物QT依赖性促心律失常作用的药理学模型是α-肾上腺素能刺激的麻醉兔，以及慢性房室传导阻滞和利尿剂诱发低钾血症的清醒犬模型。甲氧明处理的麻醉兔在输注氯非铵期间会发生室性心动过速。这些室性心动过速虽然出现在非常高的心率时，但具有典型的尖端扭转型室速特征，且常伴有巨大QT波。该模型的特异性仍有待测试。在我们的清醒心动过缓和低钾血症犬中，奎尼丁和索他洛尔可诱发QT依赖性致心律失常作用和尖端扭转型室速，而氟卡尼、普萘洛尔或利多卡因则不能。反复观察到高频率刺激和镁的有效性。这个要求较高的模型特别设计用于定性药物比较，也非常适合研究尖端扭转型室速的起始机制。这些模型用于评估与非抗心律失常药物相关的QT依赖性促心律失常风险的相关性仍有待测试。
