Nam Gi-Byoung, Burashnikov Alexander, Antzelevitch Charles
Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501-1787, USA.
Circulation. 2005 May 31;111(21):2727-33. doi: 10.1161/CIRCULATIONAHA.104.479295. Epub 2005 May 23.
Mutations in the ryanodine 2 receptor (RyR2) gene have been identified in patients with catecholaminergic polymorphic ventricular tachycardia. We examined the cellular basis for the ECG features and arrhythmia mechanisms using low-dose caffeine to mimic the defective calcium homeostasis encountered under these conditions.
A transmural ECG and action potentials were recorded simultaneously from epicardial, M, and endocardial cells in arterially perfused canine ventricular wedge preparations. Caffeine alone produced no change (10 to 100 micromol/L) or a slight abbreviation (300 micromol/L) of the QT interval and no change in transmural dispersion of repolarization. Isoproterenol (100 nmol/L) alone induced sustained monomorphic ventricular tachycardia (VT) that originated in the epicardium in 3 of 14 wedge preparations. Isoproterenol in the presence of caffeine (100 to 300 micromol/L) induced epicardial VT in 9 of 16 wedge preparations. Delayed afterdepolarization-induced triggered beats that originated in the epicardium were associated with an increased Tpeak-Tend interval and transmural dispersion of repolarization. Bidirectional VT developed in 11 of 16 wedge preparations as a consequence of alternation in the origin of ectopic activity between endocardial, M, and epicardial regions. Single extrastimuli delivered during sustained epicardial VT induced a rapid polymorphic VT/ventricular fibrillation (VF) in 3 of 9 wedges. Spontaneous polymorphic VT was observed in 3 of 16 preparations. Propranolol (1.0 micromol/L) or verapamil (1.0 micromol/L) completely suppressed ectopic activity that arose from the epicardium and prevented induction of polymorphic VT.
Our data suggest delayed afterdepolarization-induced extrasystolic activity serves to trigger catecholamine-induced VT/VF under conditions of defective calcium handling. Epicardial origin of the ectopic beats increases transmural dispersion of repolarization, thus providing the substrate for the development of reentrant tachyarrhythmias that underlie rapid polymorphic VT/VF.
在儿茶酚胺能多形性室性心动过速患者中已鉴定出兰尼碱2受体（RyR2）基因突变。我们使用低剂量咖啡因来模拟这些情况下存在的钙稳态缺陷，研究心电图特征和心律失常机制的细胞基础。
在动脉灌注的犬心室楔形标本中，同时记录心外膜、M细胞和心内膜细胞的透壁心电图和动作电位。单独使用咖啡因（10至100微摩尔/升）对QT间期无影响或使其轻微缩短（300微摩尔/升），复极的透壁离散度无变化。单独使用异丙肾上腺素（100纳摩尔/升）在14个楔形标本中的3个中诱发了起源于心外膜的持续性单形性室性心动过速（VT）。在咖啡因（100至300微摩尔/升）存在的情况下，异丙肾上腺素在16个楔形标本中的9个中诱发了心外膜VT。起源于心外膜的延迟后除极诱发的触发搏动与T波峰 - T波末间期增加和复极的透壁离散度增加有关。由于心内膜、M细胞和心外膜区域异位活动起源的交替，16个楔形标本中的11个出现了双向VT。在持续性心外膜VT期间给予单个额外刺激，在9个楔形标本中的3个中诱发了快速多形性VT/心室颤动（VF）。在16个标本中的3个中观察到了自发性多形性VT。普萘洛尔（1.0微摩尔/升）或维拉帕米（1.0微摩尔/升）完全抑制了起源于心外膜的异位活动，并防止了多形性VT的诱发。
我们的数据表明，在钙处理缺陷的情况下，延迟后除极诱发的早搏活动有助于触发儿茶酚胺诱发的VT/VF。异位搏动的心外膜起源增加了复极的透壁离散度，从而为折返性快速心律失常的发生提供了基质，而折返性快速心律失常是快速多形性VT/VF的基础。
