Burashnikov A, Antzelevitch C
Masonic Medical Research Laboratory, Utica, New York 13501, USA.
J Cardiovasc Electrophysiol. 1998 Sep;9(9):934-48. doi: 10.1111/j.1540-8167.1998.tb00134.x.
Precipitation of torsades de pointes (TdP) has been shown to be associated with acceleration of heart rate in both experimental and clinical studies. To gain insight into the cellular mechanism(s) responsible for the initiation of acceleration-induced TdP, we studied the effect of acceleration of pacing rate in canine left ventricular epicardial, M region, endocardial, and Purkinje fiber preparations pretreated with E-4031, an IKr blocker known to induce the long QT syndrome and TdP.
Standard microelectrode techniques were used. E-4031 (1 to 2 microM) induced early after depolarization (EAD) activity in 31 of 36 M cell, 0 of 10 epicardial, 0 of 10 endocardial, and 9 of 12 Purkinje fiber preparations at basic cycle lengths (BCLs) > or = 800 msec. In 30 of 36 M cells, sudden acceleration from a BCL range of 900 to 4,000 msec to a range of 500 to 1,500 msec induced transient EAD activity if none existed before or increased the amplitude of EADs if already present. Acceleration-induced augmentation of EAD activity was far less impressive and less readily demonstrable in Purkinje fibers (4/12). In M cells, appearance of EAD activity during acceleration usually was accompanied by an abbreviation of action potential duration (APD). Within discrete ranges of rates in the physiologic range, acceleration caused a transient prolongation of APD in 38% of M cells, whether or not a distinct EAD was generated. Acceleration produced still more dramatic APD prolongation and EADs in M cells after the BCL was returned to the original slow rate. Epicardium and endocardium APD showed little change immediately after acceleration. A decrease of BCL as small as 10% and, in some cases, a single premature beat could promote EAD activity and APD prolongation in some M cells. Ryanodine (1 microM, 10/10), flunarizine (10 microM, 3/6), and low Na (97 vs 129 mM, 5/5) abolished the acceleration-induced EAD activity and APD prolongation as well as the EAD activity observed at slow rates in M cells pretreated with E-4031.
Our results suggest that acceleration from an initially slow rate or a single premature beat can induce or facilitate transient EAD activity and APD prolongation in canine ventricular M cell preparations pretreated with an IKr blocker via a mechanism linked to intracellular calcium loading. Our data provide evidence in support of an important contribution of electrogenic Na/Ca exchange current to this process. These acceleration-induced changes can result in the development of triggered activity as well as a marked dispersion of repolarization in ventricular myocardium and, thus, may contribute to the precipitation of TdP in patients with the congenital (HERG defect) and acquired (drug-induced) long QT syndrome.
在实验和临床研究中均已表明，尖端扭转型室性心动过速（TdP）的发生与心率加快有关。为深入了解导致心率加快诱发TdP的细胞机制，我们研究了在经E - 4031预处理的犬左心室心外膜、M区、心内膜和浦肯野纤维标本中，起搏频率加快的影响。E - 4031是一种已知可诱发长QT综合征和TdP的IKr阻滞剂。
采用标准微电极技术。在基础周期长度（BCL）≥800毫秒时，E - 4031（1至2微摩尔）在36个M细胞中的31个、10个心外膜细胞中的0个、10个心内膜细胞中的0个以及12个浦肯野纤维标本中的9个诱发了早期后去极化（EAD）活动。在36个M细胞中的30个中，如果之前不存在EAD活动，从900至4000毫秒的BCL范围突然加速至500至1500毫秒范围会诱发短暂的EAD活动，或者如果已经存在EAD，则会增加其幅度。在浦肯野纤维中（4/12），加速诱发的EAD活动增强远不那么明显且难以证实。在M细胞中，加速过程中EAD活动的出现通常伴随着动作电位时程（APD）的缩短。在生理范围内的离散频率范围内，无论是否产生明显的EAD，加速都会使38%的M细胞的APD出现短暂延长。在BCL恢复到原来的慢速后，加速在M细胞中产生了更显著的APD延长和EAD。加速后心外膜和心内膜的APD立即变化不大。BCL降低小至10%，在某些情况下，单个早搏可促进一些M细胞中的EAD活动和APD延长。Ryanodine（1微摩尔，10/10）、氟桂利嗪（10微摩尔，3/6）和低钠（97对129毫摩尔，5/5）消除了加速诱发的EAD活动和APD延长以及在用E - 4031预处理的M细胞中在慢速时观察到的EAD活动。
我们的结果表明，从最初的慢速加速或单个早搏可通过与细胞内钙负荷相关的机制，在经IKr阻滞剂预处理的犬心室M细胞标本中诱发或促进短暂的EAD活动和APD延长。我们的数据为支持电生钠/钙交换电流对这一过程的重要贡献提供了证据。这些加速诱发的变化可导致触发活动的发生以及心室心肌复极化的显著离散，因此可能促成先天性（HERG缺陷）和后天性（药物诱发）长QT综合征患者TdP的发生。
