Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
J Am Coll Cardiol. 2011 Jan 18;57(3):366-75. doi: 10.1016/j.jacc.2010.07.045.
The purpose of this study was to test the hypothesis that the late Na current blocker ranolazine suppresses re-entrant and multifocal ventricular fibrillation (VF).
VF can be caused by either re-entrant or focal mechanism.
Simultaneous voltage and intracellular Ca(+)² optical mapping of the left ventricular epicardial surface along with microelectrode recordings was performed in 24 isolated-perfused aged rat hearts. Re-entrant VF was induced by rapid pacing and multifocal VF by exposure to oxidative stress with 0.1 mM hydrogen peroxide (H₂O₂).
Rapid pacing induced sustained VF in 7 of 8 aged rat hearts, characterized by 2 to 4 broad propagating wavefronts. Ranolazine significantly (p < 0.05) reduced the maximum slope of action potential duration restitution curve and converted sustained to nonsustained VF lasting 24 ± 8 s in all 7 hearts. Exposure to H₂O₂ initiated early afterdepolarization (EAD)-mediated triggered activity that led to sustained VF in 8 out of 8 aged hearts. VF was characterized by multiple foci, appearing at an average of 6.8 ± 3.2 every 100 ms, which remained confined to a small area averaging 2.8 ± 0.85 mm² and became extinct after a mean of 43 ± 16 ms. Ranolazine prevented (when given before H₂O₂) and suppressed H₂O₂-mediated EADs by reducing the number of foci, causing VF to terminate in 8 out of 8 hearts. Simulations in 2-dimensional tissue with EAD-mediated multifocal VF showed progressive reduction in the number of foci and VF termination by blocking the late Na current.
Late Na current blockade with ranolazine is effective at suppressing both pacing-induced re-entrant VF and EAD-mediated multifocal VF.
本研究旨在验证假设，即晚期钠电流阻滞剂雷诺嗪可抑制折返性和多灶性室颤（VF）。
VF 可由折返或局灶机制引起。
在 24 个离体灌注的老年大鼠心脏中，同时进行左心室心外膜表面的电压和细胞内 Ca(+)²光学映射以及微电极记录。通过快速起搏诱导折返性 VF，通过 0.1 mM 过氧化氢（H₂O₂）暴露诱导多灶性 VF。
快速起搏在 8 个老年大鼠心脏中的 7 个心脏中诱导持续 VF，表现为 2 到 4 个宽的传播波前。雷诺嗪显著（p<0.05）降低动作电位时程恢复曲线的最大斜率，并将持续 VF 转换为持续时间为 24±8s 的非持续 VF，在所有 7 个心脏中均如此。暴露于 H₂O₂ 引发早期后除极（EAD）介导的触发活动，导致 8 个老年心脏中的持续 VF。VF 的特征是多个焦点，平均每 100ms 出现 6.8±3.2 个，这些焦点仍然局限于一个小区域，平均为 2.8±0.85mm²，在平均 43±16ms 后消失。雷诺嗪在 H₂O₂ 介导的 EAD 之前给予，可预防和抑制 H₂O₂ 介导的 EAD，减少焦点数量，导致 8 个心脏中的 VF 终止。在 EAD 介导的多灶性 VF 的 2 维组织模拟中，通过阻断晚期钠电流，焦点数量逐渐减少，VF 终止。
雷诺嗪的晚期钠电流阻断对起搏诱导的折返性 VF 和 EAD 介导的多灶性 VF 均有效。
