Extramiana Fabrice, Antzelevitch Charles
Masonic Medical Research Laboratory, Utica, NY 13501, USA.
Circulation. 2004 Dec 14;110(24):3661-6. doi: 10.1161/01.CIR.0000143078.48699.0C. Epub 2004 Nov 29.
The short-QT syndrome is a new clinical entity characterized by corrected QT intervals <300 ms and a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Gain-of-function mutations in the gene for outward potassium currents have been shown to underlie the congenital syndrome. The present study examined the cellular basis of VT/VF in an experimental model associated with short QT intervals created with a potassium channel activator.
Transmembrane action potentials from epicardial and M regions, 4 transmural unipolar electrograms, and a pseudo-ECG were simultaneously recorded in canine arterially perfused left ventricular wedge preparations. At a basic cycle length of 2000 ms, pinacidil (2 to 3 mumol/L) abbreviated the QT interval from 303.7+/-5.4 to 247.3+/-6.9 ms (mean+/-SEM, P<0.0001). The maximal transmural dispersion of repolarization (TDR(max)) increased from 27.0+/-3.8 to 64.9+/-9.2 ms (P<0.01), and an S2 applied to the endocardium induced a polymorphic VT (pVT) in 9 of 12 wedge preparations (P<0.01). Addition of isoproterenol (100 nmol/L, n=5) led to greater abbreviation of the QT interval, a further increase in TDR(max) (from 55.4+/-13.7 to 69.7+/-8.3 ms), and more enduring pVT. TDR(max) was correlated significantly with the T(peak)-T(end) interval under all conditions. The effects of pinacidil were completely reversed by glybenclamide (10 micromol/L, n=4) and partially reversed by E4031 (5 micromol/L, n=5), which prevented induction of pVT in 3 of 5 preparations.
Our data suggest that heterogeneous abbreviation of the action potential duration among different cell types spanning the ventricular wall creates the substrate for the genesis of VT under conditions associated with short QT intervals.
短QT综合征是一种新的临床病症，其特征为校正QT间期<300毫秒，且室性心动过速（VT）和颤动（VF）的发生率很高。外向钾电流基因的功能获得性突变已被证明是这种先天性综合征的基础。本研究在一个由钾通道激活剂创建的与短QT间期相关的实验模型中，研究了VT/VF的细胞基础。
在犬动脉灌注左心室楔形标本中，同时记录心外膜和M区的跨膜动作电位、4个跨壁单极电图和一个伪心电图。在基本周期长度为2000毫秒时，吡那地尔（2至3微摩尔/升）将QT间期从303.7±5.4毫秒缩短至247.3±6.9毫秒（平均值±标准误，P<0.0001）。最大跨壁复极离散度（TDR(max)）从27.0±3.8毫秒增加至64.9±9.2毫秒（P<0.01），并且施加于心内膜的S2在12个楔形标本中的9个中诱发了多形性VT（pVT）（P<0.01）。添加异丙肾上腺素（100纳摩尔/升，n = 5）导致QT间期进一步缩短，TDR(max)进一步增加（从55.4±13.7毫秒增加至69.7±8.3毫秒），并且pVT持续时间更长。在所有条件下，TDR(max)与T(peak)-T(end)间期显著相关。吡那地尔的作用可被格列本脲（10微摩尔/升，n = 4）完全逆转，并被E4031（5微摩尔/升，n = 5）部分逆转，E4031可防止5个标本中的3个诱发pVT。
我们的数据表明，在与短QT间期相关的条件下，跨心室壁不同细胞类型之间动作电位时程的异质性缩短为VT的发生创造了基质。
