London Barry, Baker Linda C, Petkova-Kirova Polina, Nerbonne Jeanne M, Choi Bum-Rak, Salama Guy
University of Pittsburgh, Cardiovascular Institute, Pittsburgh, PA 15213, USA.
J Physiol. 2007 Jan 1;578(Pt 1):115-29. doi: 10.1113/jphysiol.2006.122622. Epub 2006 Nov 16.
Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, I(to,f), have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4-/-) that lack the slow component of I(to) (I(to,s)), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DN x Kv1.4-/-) mice that lack both I(to,f) and I(to,s), have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 +/- 2.5 ms, P < 0.01, n = 6), Kv1.4-/- (28.4 +/- 0.4 ms, P < 0.01, n = 5) and Kv4.2DN x Kv1.4-/- (34.3 +/- 2.6 ms, P < 0.01, n = 6) mice than controls (20.3 +/- 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 +/- 0.5 ms, n = 6, P < 0.05) but enhanced in Kv1.4-/- (14.2 +/- 2.0 ms, n = 5, P < 0.05) and Kv4.2DN x Kv1.4(-/-) (15.0 +/- 3 ms, n = 5, P < 0.5) mice compared with controls (10 +/- 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4-/- (n = 4/5) and Kv4.2DN x Kv1.4-/- hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that I(to,f) was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability.
复极离散度（DR）增强和不应期改变可能是长QT（LQT）综合征心律失常发生的核心统一机制。在几种基因工程小鼠品系中研究了DR在促发心律失常中的作用：（a）Kv4.2显性负性转基因小鼠（Kv4.2DN）缺乏瞬时外向电流（I(to,f)）的快速成分，其动作电位（AP）和QT间期延长，但无自发性心律失常；（b）Kv1.4靶向敲除小鼠（Kv1.4-/-）缺乏I(to)的慢速成分（I(to,s)），QT间期无延长且无自发性心律失常；（c）双转基因（Kv4.2DN×Kv1.4-/-）小鼠同时缺乏I(to,f)和I(to,s)，有AP和QT间期延长以及自发性室性快速心律失常。对心脏进行灌注，用di-4-ANEPPS染色并进行光学标测。各品系之间的激动模式和传导速度相似，但Kv4.2DN小鼠（28.0±2.5毫秒，P<0.01，n=6）、Kv1.4-/-小鼠（28.4±0.4毫秒，P<0.01，n=5）和Kv4.2DN×Kv1.4-/-小鼠（34.3±2.6毫秒，P<0.01，n=6）的动作电位复极75%时的时程（APD75）比对照组（20.3±1.0毫秒，n=5）更长。Kv4.2DN小鼠心尖与心底之间的不应期离散度显著降低（0.3±0.5毫秒，n=6，P<0.05），而Kv1.4-/-小鼠（14.2±2.0毫秒，n=5，P<0.05）和Kv4.2DN×Kv1.4(-/-)小鼠（15.0±3毫秒，n=5，P<0.5）的不应期离散度比对照组（10±2毫秒，n=5）增强。过早刺激在Kv1.4-/-小鼠（n=4/5）和Kv4.2DN×Kv1.4-/-小鼠心脏（n=5/5）中诱发室性心动过速（VT），但在Kv4.2DN小鼠心脏中未诱发（n=0/6）。电压钳记录显示，心尖部心肌细胞的I(to,f)比心底部大30%，这可能是Kv4.2DN小鼠不存在DR的原因。因此，复极离散度（DR）似乎是心律失常易感性的重要决定因素。
