靶向纳米载药系统降低心脏射频消融术后房颤复发率的研究

Atrial fibrillation（AF）is one of the most common arrhythmia and associated with high morbidity and mortality. Radiofrequency ablation（RFA） is an effective treatment for atrial fibrillation, and pulmonary vein isolation is the representative approach. However, there are insufficient and unavailable methods to prevent long-term recurrence of AF due to the recovered pulmonary vein conduction and residual conduction gaps. In patients with a history of AF, antiarrhythmic drugs reduced the rate of early recurrence of arrhythmia but had no effect on the long-term recurrence rate. Currently, doxorubicin loaded liposome which has a special inflammatory targeting effect and cytotoxicity, can be used to reduce the recurrence of atrial fibrillation combined with RFA. The purpose of this study was to establish a novel rabbit model to simulate the recovered electrical conduction and residual conduction gaps by means of ablation and electrophysiological pacing and mapping technology. Otherwise, doxorubicin loaded liposome can be used to further inhibit the activity of residual myocardial cell, reduce residual conduction gaps and hinder recovery of electrical conduction, thereby reducing the recurrence of AF after ablation. This study was carried out to demonstrate the mechanism of RFA combined with targeted nano particle delivery system (NPDS) to prevent the recurrence of AF and provide experimental data and scientific basis for the clinical application of RFA combined with NPDS.

房颤是一种常见的心律失常疾病，发病率高，危害大，临床上药物治疗主要以预防并发症为主，并无根治药物，而以肺静脉电隔离消融为代表的房颤根治手术，仍面临房颤术后远期复发的难题，其原因主要在于消融区域残存电传导和电传导恢复相关，而抗心律失常药物不能预防房颤术后的远期复发。目前，脂质体药物具有独特的炎症靶向效应，可用于心脏消融术后联用，为减少术后房颤复发带来新途径。对此，本课题拟通过兔左心耳根部消融损伤和起博电生理标测等技术，构建心脏消融术后残存、复发电传导动物模型，通过静脉给药，利用阿霉素脂质体的炎症靶向作用和细胞毒性作用，进一步抑制消融区域残存的心肌细胞活性，减少消融术后残存、恢复电传导，从而降低消融术后房颤复发率。通过临床前研究，阐明心脏消融术后联合使用靶向纳米药物减少残存、恢复电传导的相关作用机制，为“射频消融术联合靶向纳米脂质体给药系统”应用于减少房颤术后复发的治疗提供实验数据和科学依据。

目的：验证射频消融（RFCA）联合静脉内注射阿霉素脂质体（L-DOX）是否能有效减少心脏消融术后电传导复发。.方法和结果：在兔子左心耳（LAA）根部进行环状消融，然后给予静脉注射阿霉素脂质体（L-DOX）。在消融术后一周和一月后，通过电生理检查发现在RFCA+L-DOX组左心耳消融环内无法成功起博。同时也采用荧光分光光度法测定了药动学和体内药物组织分布：当DOX包载入脂质体后，药物表现为稳定和持续的缓释效应，并在RFCA术后的第二天开始靶向到LAA消融损伤区域。我们还通过Western blot和免疫组化技术对bcl-2、Bax和cleave--caspase-3进行了检测，以分析LAA消融区域细胞凋亡的情况。结果显示单纯RFCA组损伤区域周围细胞凋亡不明显；然而，L-DOX组明显增加了消融损伤区域心肌细胞凋亡。虽然DOX影响了兔子的肝脏、肾脏和心脏功能，但既往研究表明，这些损害是可逆的，不会影响生存率。.结论：本研究结果证实L-DOX可明显增加LAA消融损伤区域及周边区域的细胞凋亡效应，并因此减少了左心耳消融术后电传导恢复。