ROLE OF PROLONGED REPOLARIZATION IN CARDIAC ARRHYTHMIAS

心脏复极延长（QT间期延长）与 在某些情况下会引发严重的室性心律失常，但 心律失常抑制。 高达11%的患者开始 奎尼丁出现QT显著增加和潜在致命的多态性 室性心动过速（尖端扭转型室性心动过速）。 另一方面， QT间期延长是心律失常抑制的不变伴随物， 胺碘酮，很少引起尖端扭转型室性心动过速。 的 这项研究将测试一个假设，即一个特定的体外 电生理异常，心动过缓依赖性早期 后除极（埃兹）在体内触发尖端扭转型室性心动过速。 这 这一假说有其基础，在一系列的临床和实验室 我们已经对奎尼丁诱导的延长的复极化进行了研究。 在患者中，我们发现尖端扭转型室性心动过速的发生率 与低钾血症的高发病率相关， 在周期长度突然增加之后。 在狗的浦肯野纤维中 灌流低浓度奎尼丁，降低钾， 缓慢刺激持续触发埃兹。 此外，干预措施 取消埃兹（增加钾或刺激率）与 对尖端扭转型室性心动过速最有效的药物 假设的 埃兹在触发尖端扭转型室性心动过速中的作用将在 这三个方面的建议。 首先，被认为是导致室性心动过速的药物 将检测Pointes（丙吡胺、普鲁卡因胺、奎尼丁代谢物） 犬浦肯野纤维诱导埃兹的能力;干预 延长动作电位但不引起心律失常 （胺碘酮、低钙血症）将进行类似评价。 第二、 将在动物中记录心室单相动作电位 尖端扭转型室性心动过速模型，低钾血症犬伴缓慢心率（AV 阻断）治疗的奎尼丁或其他药物，据报道， 体外（N-乙酰普鲁卡因酰胺，铯）。 我们观察到 我们认为这些动物的单相动作电位代表了 埃兹。 这种异常与先前周期长度的关系， 尖端扭转型室性心动过速发作，预防尖端扭转型室性心动过速的药物将 评估以确认这一发现，从而加强联系 在体外和体内异常之间。 第三，阶段性行动 将在接受动作电位的患者中记录电位 延长药物和既往尖端扭转型室性心动过速患者。 在 这样，识别尖端扭转型室性心动过速风险患者的方法将 完善 这项研究将确定在何种情况下， 心脏复极化延长会诱发心律失常，从而 为改善抗肿瘤药物治疗提供了基础。

Prolongation of cardiac repolarization (increased QT duration) is linked to provocation of serious ventricular arrhythmias in some settings, but to arrhythmia suppression in others. Up to 11% of patients started on quinidine develop marked increases in QT and potentially fatal polymorphic ventricular tachycardia ("Torsades de Pointes"). On the other hand, marked QT increases are an invariable accompaniment of arrhythmia suppression by amiodarone, which only very rarely causes Torsades de Pointes. The research proposed will test the hypothesis that a specific in vitro electrophysiologic abnormality, bradycardia-dependent early afterdepolarization (EADs), triggers Torsades de Pointes in vivo. This hypothesis has its foundation in a series of clinical and laboratory studies we have conducted on quinidine-induced prolonged repolarization. In patients, we found that the occurrence of Torsades de Pointes was associated with a high incidence of hypokalemia and invariably started after an abrupt increase in cycle length. In canine Purkinje fibers superfused with low concentrations of quinidine, lowering potassium during slow stimulation consistently triggered EADs. Furthermore, interventions abolishing EADs (increasing potassium or stimulation rate) were the same as those which are most effective in Torsades de Pointes. The hypothesized role of EADs in triggering Torsades de Pointes will be further explored in three ways in this proposal. First, agents thought to cause Torsades de Pointes (disopyramide, procainamide, quinidine metabolites) will be tested in canine Purkinje fibers for their ability to induce EADs; interventions which prolong action potential but do not induce this arrhythmia (amiodarone, hypocalcemia) will be similarly evaluated. Second, ventricular monophasic action potentials will be recorded in an animal model of Torsades de Pointes, hypokalemic dogs with slow heart rates (AV block) treated with quinidine or other agents reported to induce EADs in vitro (N-acetylprocainamide, cesium). We have observed abnormalities in monophasic action potentials in such animals which we believe to represent EADs. The relationship of such abnormalities to previous cycle length, Torsades de Pointes onset, and drugs which prevent Torsades de Pointes will be evaluated to confirm this finding, thereby strengthening the link between the in vitro and in vivo abnormalities. Third, monophasic action potential will be recorded in patients receiving action potential prolonging drugs and in patients with previous Torsades de Pointes. In this way, methods to identify patients at risk for Torsades de Pointes will be improved. This research will identify circumstances under which prolongation of cardiac repolarization induces arrhythmias, thereby providing the basis for improved antiarrhythmic drug therapy.