Underling mechanisms of atrial fibrillation induced by atrial pressure/ volume overload, and new therapeutic approach for the management of atrial fibrillation

心房颤动（AF）是老年人群中一种常见而又棘手的心律失常。随着房颤发病率和病型的增加，房颤的预防和治疗是最紧迫的世界性任务之一。房颤的发生有几个因素，其中一个众所周知的因素是心房压力和/或容量过载。最近，一种蜘蛛毒衍生物（gsmtx4）通过抑制拉伸激活通道来预防房颤，这在房颤的治疗中引起了人们的关注。本项目旨在阐明拉伸性房颤的潜在机制，并开发一种新的治疗房颤的方法。本项目的研究结果如下：1)房颤模型，在切除的冠状动脉灌注的兔心脏中，心房急性膨胀；是在我们实验室研发的。2)研究了以GsMtx-4为基础构建的短氨基酸肽（TVP 003, 017）对拉伸诱导Al'的作用。但数据显示，起搏突发引起的房颤易感性没有明显降低。3)他汀类药物和TRP通道抑制剂（SKF-96365, BTP-2）作为备选药物，随后在本研究中进行了研究。这些药物可以降低心房颤动的易感性，这种作用至少部分是通过减少拉伸引起的心房有效不应期（AERP）缩短而实现的。4)基于荧光光学成像系统的跨膜电位动态观察表明，心房充气时，心房过早刺激或高频刺激可诱发不均匀的激活模式，导致心房再入活动。应用TRP通道抑制剂可缩短APD（动作电位持续时间），这与心房膨胀引起的AERP变化一致。

Atrial fibrillation (AF) is a common and troublesome arrhythmia among aged population. Prevention and management of AF is one of the most urgent and worldwide task amid increasing morbidity and modality of AF. Several factors underlie the promotion of AF, one of well-known factors is the pressure and/or volume overload in atria. Recently, prevention of Al' by using a spider venom derivative (GsMtx-4), which inhibits stretch activated channels, has been reported and drawing attention in the management of AF. This project was designed to elucidate the underlying mechanisms of the stretch-induced AF and develop a new therapeutic approach to treat AFSeveral findings in this project have been obtained as below :1) AF model, in which atria were acutely inflated in excised coronary-perfused rabbit hearts, was developed in our laboratory.2) Short amino peptides (TVP 003, 017), which was developed based on GsMtx-4, were investigated to assess the efficacy on stretch-induced Al'. But data resulted in no obvious reduction of vulnerability to AF induced by a burst of pacing.3)Statins and TRP channel inhibitors (SKF-96365, BTP-2), which were enrolled as an alternative candidates, were subsequently examined in the present study. These agents were revealed to reduce the vulnerability to AF and this effect was at least, in part, brought by reducing abbreviation of stretch-induced AERP (atrial effective refractory period) shortening.4) Fluorescence-based optical imaging system, which was designed to observe transmembrane potentials dynamics, demonstrated that inhomogeneous activation pattern, leading to reentrant activities was evoked by atrial premature stimulation or high-frequency stimulation during atrial inflation. Abbreviation of APD (action potential duration) was reduced by application of TRP channel inhibitors, this result was in line with the change in AERP due to atrial inflation.