维拉帕米减少2型长 QT 综合征楔形心肌块模型跨室壁复极离散度并预防尖端扭转型室速

Verapamil reduces transmural dispersion of repolarization and prevents torsade de pointes in myocardial wedge model of type 2 long QT syndrome

目的探讨维拉帕米治疗2型长QT综合征(LQT2)的作用机制。方法制备兔左心室楔形心肌块,稳定1 h后灌注E-4031 0.5μmol·L-1建立LQT2心肌块模型;同时按照分组分别灌注维拉帕米0.5,1.0和2.5μmol·L-1,30 min后开始采集数据,采集时间持续30 min。以2000 ms基础步长连续起搏(S1S1刺激),同步记录心内、外膜下心肌的跨膜动作电位和跨壁心电图,测量动作电位复极达90%的时程(APD90)、跨壁复极离散度(TDR)和心电图QT间期,并观察各组自发和程序刺激(S1S2刺激)诱发的早期后除极(EAD)和尖端扭转型室速(TdP)的发生率。结果灌注E-4031 0.5μmol·L-1后,左心室楔形心肌块心内、外膜下APD90和QT间期均显著延长(P<0.01),TDR显著增加(P<0.01),并观察到自发或程序刺激诱发的EAD及TdP发作。同时灌注维拉帕米0.5,1.0和2.5μmol·L-1,LQT2模型内、外膜下心肌APD90和QT间期呈浓度依赖性地缩短(P<0.01),TDR显著减小(P<0.01),自发或程序刺激诱发的EAD和TdP明显受到抑制。硝苯地平1.0μmol·L-1有类似作用,且强度更大。结论维拉帕米可通过缩小心肌TDR和抑制EAD减少LQT2患者TdP的发生。

OBJECTlVE To investigate the mechanism of verapamil in the treatment of type 2 Iong QT syndrome（LQT2）using a rabbit Ieft ventricuIar myocardial wedge preparation. METHODS E-4031 （0.5 μmol·L-1 ）was used to induce the LQT2 model after rabbit Ieft ventricuIar wedge preparations were equilibrated for 1 h,and verapamil（0.5,1.0 and 2.5 μmol·L-1 ,respectively）was perfused in different groups. Data were colIected for a period of 30 min starting 30 min after adding the respective drug. Transmembrane action potentials of endocardial and epicardial myocardium were recorded simuItaneously at a basic cycIe Iength of 2000 ms（S1S1）together with a transmural ECG. The effect of verapamil （0.5,1.0 and 2.5 μmol·L-1 ）on action potential duration at 90% repolarization（APD90 ）,QT interval, transmural dispersion of repolarization（TDR）and the development of earIy afterdepolarization（EAD） and torsades de pointes（TdP）were evaluated in the LQT2 myocardial wedge model. RESULTS E-4031 （0.5 μmol·L-1 ）markedIy prolonged endocardial and epicardial APD90 and QT interval（ P﹤0.01）,and dramaticalIy increased TDR（P﹤0.01）. Spontaneous or programmed electrical stimuIation-induced EAD and TdP were also observed in the model. Verapamil（0.5,1.0 and 2.5 μmol·L-1 ）dose-dependentIy abbreviated endocardial and epicardial APD90 and QT interval（P﹤0.01）,significantIy decreased TDR（P﹤0.01）,and suppressed EAD and TdP in the LQT2 model. Concordant but stronger effects on the electro-physiological properties of the LQT2 model were noticed when nifedipine was perfused. CONCLUSlON Verapamil inhibits TdP in the LQT2 model by reducing TDR and suppressing EAD.