Milberg P, Reinsch N, Osada N, Wasmer K, Mönnig G, Stypmann J, Breithardt G, Haverkamp W, Eckardt L
Medizinische Klinik und Poliklinik C, Kardiologie und Angiologie, Universitätsklinikum Münster, Albert-Schweitzer Str. 33 , 48149, Münster, Germany.
Basic Res Cardiol. 2005 Jul;100(4):365-71. doi: 10.1007/s00395-005-0533-8. Epub 2005 Jun 10.
In long QT syndrome (LQTS), prolongation of the QT-interval is associated with sudden cardiac death resulting from potentially life-threatening polymorphic tachycardia of the torsade de pointes (TdP) type. Experimental as well as clinical reports support the hypothesis that calcium channel blockers such as verapamil may be an appropriate therapeutic approach in LQTS. We investigated the electrophysiologic mechanism by which verapamil suppresses TdP, in a recently developed intact heart model of LQT3.
In 8 Langendorff-perfused rabbit hearts, veratridine (0.1 microM), an inhibitor of sodium channel inactivation, led to a marked increase in QT-interval and simultaneously recorded monophasic ventricular action potentials (MAPs) (p < 0.05) thereby mimicking LQT3. In bradycardic (AV-blocked) hearts, simultaneous recording of up to eight epi- and endocardial MAPs demonstrated a significant increase in total dispersion of repolarization (56%, p < 0.05) and reverse frequency-dependence. After lowering potassium concentration, veratridine reproducibly led to early afterdepolarizations (EADs) and TdP in 6 of 8 (75%) hearts. Additional infusion of verapamil (0.75 microM) suppressed EADs and consecutively TdP in all hearts. Verapamil significantly shortened endocardial but not epicardial MAPs which resulted in significant reduction of ventricular transmural dispersion of repolarization.
Verapamil is highly effective in preventing TdP via shortening of endocardial MAPs, reduction of left ventricular transmural dispersion of repolarization and suppression of EADs in an intact heart model of LQT3. These data suggest a possible therapeutic role of verapamil in the treatment of LQT3 patients.
在长QT综合征（LQTS）中，QT间期延长与尖端扭转型室性心动过速（TdP）这种潜在危及生命的多形性心动过速导致的心脏性猝死相关。实验及临床报告均支持如下假说，即钙通道阻滞剂（如维拉帕米）可能是LQTS的一种合适治疗方法。我们在最近建立的LQT3完整心脏模型中研究了维拉帕米抑制TdP的电生理机制。
在8个经Langendorff灌注的兔心脏中，钠通道失活抑制剂藜芦定（0.1微摩尔）导致QT间期显著延长，并同时记录到单相心室动作电位（MAPs）（p<0.05），从而模拟了LQT3。在心动过缓（房室传导阻滞）的心脏中，同时记录多达8个心外膜和心内膜MAPs显示复极总离散度显著增加（56%，p<0.05）以及反向频率依赖性。降低钾浓度后，藜芦定在8个心脏中的6个（75%）可重复性地导致早期后除极（EADs）和TdP。额外输注维拉帕米（0.75微摩尔）可抑制所有心脏中的EADs并继而抑制TdP。维拉帕米显著缩短心内膜而非心外膜的MAPs，这导致心室跨壁复极离散度显著降低。
在LQT3完整心脏模型中，维拉帕米通过缩短心内膜MAPs、降低左心室跨壁复极离散度及抑制EADs，在预防TdP方面非常有效。这些数据提示维拉帕米在治疗LQT3患者中可能具有治疗作用。
