钙稳态失衡致心房颤动的新机制：钙释放单位重构和紊乱性钙波

Calcium handling disorders in atrial myocytes play a critical role in the development of atrial fibrillation (AF). Accumulating evidences have been demenstrated that Ca2+ leak from dysfunctional RyR2 is a key factor for the initiation of AF,while there is no evidence that dysfunction of RyR2 contributes the maintenance of AF. Recently we observed that catecholamine injection peritoneally induces long term AF in CPVT CASQ2R33Q transgenic mouse model and isolated R33Q atrial myocytes exhibit dyssynchronized spontaneous Ca2+ waves which is a novel pattern of calcium handling disorders, our data support that dysfunction of RyR2 contributes the maintenance of AF. Previously we have demenstrated that dyssynchronized spontaneous Ca2+ waves in R33Q ventricular myocytes are assocaited with the remodeling of calcium release units(CRUs) which would impair the propagation of spontaneous Ca2+ waves. Based on the novel observations in R33Q ventricular myocytes, we propose that 1) there is CRUs remodeling in R33Q atrial myocytes which impairs propagation of spontaneous Ca2+ waves and contributes dyssynchronized spontaneous Ca2+ waves; 2) dyssynchronized spontaneous Ca2+ waves cause heterogeneous electrophysiology in R33Q atrial myocytes which provides a substrate for the maintenance of AF. This project has 2 aims. Aim 1 will verify our hypothesis by multipe state-of-the-art techniques including patch clamp, calcium imaging, electron microscope at different levels spanning from in vivo whole-animals to cell ultrastructure. Aim 2 will test whether the promising therepeutic strategies in CPVT would prevent the AF in CASQ2R33Q transgenic mouse model. The proposed work will elucidate a novel mechanism for the maintenance of AF induced by Ca2+ handling disorder and identify a potential new therapeutic target for AF.

心房细胞钙调节紊乱在心房颤动（AF）发生中起重要作用，多认为兰尼丁受体（RyR2）功能失调所致的钙漏是诱发AF的始动因素，但对其是否参与AF维持尚无依据。最近我们发现儿茶酚胺敏感性室速（CPVT）转基因小鼠（CASQ2 R33Q）可诱发长时程AF；R33Q心房细胞钙漏呈现全新的模式：紊乱性钙波。既往我们研究显示R33Q心室细胞上紊乱性钙波与其钙释放单位（CRUs）重构阻碍钙波传递有关，因此我们推测R33Q心房肌细胞也存在CRUs重构并认为紊乱性钙波可导致心房细胞电生理异质性，构成房颤的维持基质。本课题首先拟在R33Q小鼠，采用钙显像、膜片钳和电镜检测等技术，从整体-细胞-超微结构三个层次，证实上述假说。第二部分为转化医学，验证治疗CPVT有效的措施能否控制R33Q小鼠AF。本课题将阐明一种全新的钙稳态失衡致AF机制，为AF的早期防治提供新的思路。

心房细胞钙调节紊乱在心房颤动（AF）发生中起重要作用，多认为兰尼丁受体（RyR2）功能失调所致的钙漏是诱发 AF 的始动因素，但对其是否参与 AF 维持尚无依据。本课题以CPVT转基因CASQ2 R33Q小鼠为模型，从整体方面，对野生型和CPVT转基因CASQ2 R33Q小鼠在生理条件以及麻醉状态下进行心电记录，并使用CAMKII阻滞剂及其他药物研究对小鼠心电活动的影响；从离体细胞方面，分离小鼠心房肌细胞，研究小鼠心肌细胞钙活动和电生理活动以及钙相关通道定位，并使用药物进行干预研究，明确雷诺嗪以及肿瘤坏死因子-α对房颤的影响及机制探。在整体和离体细胞水平，明确 R33Q 心房肌细胞自发性钙漏和 CRUs 重构之间的关系，及其相互作用导致心房肌细胞紊乱碎裂的钙波和电生理异质性。并以房颤为切入点向临床转化，分别回顾性分析房颤合并心肌肥厚，高血压以及糖尿病患者导管消融术后复发与QTc间期长短的关系，研究QTc延长对房颤治疗预后的影响。本课题阐明了一种全新的钙稳态失衡致房颤的机制，为房颤的早期防治提供新的思路。