心房肌细胞延迟钠电流增大的促触发活动和致心房颤动作用及其机制

The prevalence of atrial fibrillation (AF) is about 10% in elderly patients. Reentry mechanism is attributed to the genesis of AF. Preliminary research from this group indicated that the increase in late sodium current (late INa) and calmoduline kinase II-mediated positive feedback mechanism were associated with the triggered activities in the atrial cells, which is either independently or dependent to reentry mechanism to initiate the episodes of polymorphic atrial tachycardia and AF. In the isolated heart model of New Zealand white rabbit, the increase in late INa by ATX-II was found to cause triggered activities, and both premature beat triggered (at 3-5 nM range) or spontaneous （at 10-15 nM range）polymorphic atrial tachycardia and AF. A 96 channel atrial mapping recording confirmed that multiple triggered activities and reentry were responsible for the genesis of AF. Later INa inhibitors ranolazine and low dose TTX, and calmoduline kinase II inhibitors KN-93 and AIP were found to be effectively in reducing the inducible window and the burden of the AF. Endogenous late INa and the response to the late INa enhancer were found to be greater in the atrial cells than that in the ventricular cells. The expression of both calmoduline kinase II and phospholamban was increased in atrial tissue after treatment with late INa enhancer ATX-II. This study was built up on the foundation of our previous research to further clarify the possible novel mechanism of the AF and the success of this study may help to develop new treatment options for AF.

心房颤动（房颤）在老年人发病率达10%，一般认为是多发折返机制引起。我们假设心房肌细胞延迟钠电流增大和与钙调蛋白激酶正反馈通路相关的心房肌细胞触发活动可独立的或与折返机制一起作为房颤的发生机制。在新西兰大白兔的离体心脏模型上，使用延迟钠电流增强剂海葵毒素（ATX-II，3-15纳摩尔）可诱发触发激动、及期前刺激诱发的和自发性的多形性房速和房颤。心房标测证明延迟钠电流增强剂可引发多发性触发活动和折返激动。选择性延迟钠电流阻断剂雷诺嗪和TTX或钙调蛋白激酶抑制剂KN-93和AIP可减少触发激动点，降低房颤的诱发窗口和房颤负荷并消除房颤。心房肌细胞内源性延迟钠电流水平高、ATX-II易诱发触发激动、对延迟钠电流抑制剂的反应突出。ATX-II处理过的心房肌存在钙调蛋白激酶和磷蛋白的表达增高。本课题以对延迟钠电流的深入研究为基础，明确其在急性房颤发生机制中的作用，为房颤治疗提供可能的新路径。

项目背景.心房颤动（房颤）是心房电活动的紊乱，合并症严重，发生机制包括心房内折返和异位激动触发。与以往不同，我们发现心房肌细胞晚钠电流增大造成的动作电位时程（APD）和有效不应期（ERP）延长在急性房颤触发中有重要作用，且可增加其他因素的致房颤作用。.研究内容.雌性新西兰兔整体心脏电生理研究结合单细胞和分子生物学技术研究生理性（内源性）和病理性（增强的）延迟钠电流在房颤发生，特别是触发机制致房颤中的作用。药物包括晚钠电流增强剂海葵毒素（ATX-II）及促房颤药物伊伐布雷定，晚钠电流抑制剂雷诺嗪、河豚毒素TTX和GS-615、钙调蛋白激酶抑制剂KN-93。.研究结果.1.ATX-II显著延长心房肌MAPD90和ERP、增大房颤诱发窗口和房颤负荷。在等于或高于3nM时可引起期前刺激诱发性房颤，在5-15nM浓度下引起自发性房颤，其致房颤作用有明确的剂量依赖性特征。.2. TTX、雷诺嗪、GS615及KN-93缩短心房肌MAPD90，改变房颤时心房激动的传导速度及传导类型，降低房颤诱发窗口和房颤负荷，减少或终止房颤发生，且有浓度依赖性量效关系特征。.3.房颤起始阶段，心房激动模式及传导方向紊乱，传导减慢.心房 96 通道标测证明ATX-II诱发房颤的起始阶段，心房肌每搏电位的形态不断变化，激动模式杂乱无章，激动传导减慢，平均激动时间显著延长。.4. 伊伐布雷定可延长心房肌MAPD90，本身具有弱的致房颤作用，在ATX-II处理的心脏，其致房颤作用显著增大。.5.ATX-II增加钙调蛋白激酶II（CaMKII）的表达，晚钠电流抑制剂雷诺嗪、TTX和CaMK-II抑制剂KN-93均可抑制ATX-II引起的CaMKII表达增强。.科学意义.本研究证明心房肌细胞晚钠电流增大造成的APD和有效不应期延长及与钙调蛋白激酶活性正反馈通路相关的心房肌细胞的触发活动是急性房颤发生的重要机制，参与房颤的发生及其调控，且可诱发或增大其他因素的致房颤作用，具有晚钠电流及其相关作用通路具有抑制作用的药物或毒素有抗房颤作用。这种与晚钠电流增大相关的致房颤机理与传统房颤模型不同，结果对了解房颤的发生机制具有重要意义，可能为房颤治疗提供新的靶点。