抑制心房颤动进展中电与结构重构的机理与药物分子基础

心房颤动（房颤）是进展性疾病、治疗困难，其发生过程中的心房电与结构重构又反过来促进房颤的进展。在羊不连续心房快速起搏重建的房颤从阵发到持续过程的研究证明：房颤发生后左、右心房面积进行性增大，离子通道及细胞结构相关的蛋白表达及磷酸化水平增高，其机制是细胞内钙离子浓度增高过度激活钙调蛋白激酶II，引发系列的蛋白质磷酸化。钠通道蛋白的磷酸化引起的晚钠电流增大与钙浓度增高之间存在恶性反馈性促房颤作用，其与电和结构重构相关的蛋白磷酸化增高和代谢组学改变是抗房颤药物治疗新的靶标。RAAS阻断剂依普利酮可减少房颤发生后的左心房扩大并降低蛋白磷酸化，对电重构和代谢无作用。晚钠电流抑制剂雷诺嗪可多靶点地抑制心房电和结构重构，抑制电生理异常和房颤、细胞凋亡、自噬及能量代谢过程，在此基础上合成的先导化合物3a和CVT-10449具有更高的选择性，预期抑制房颤时的电与结构重构，治疗房颤有更好的有效性与安全性。

Atrial fibrillation (AF) is a progressive disease with difficulties in treatment. The progression of AF from paroxysmal to persistent and chronic include electrical and structural remodeling, especially the up- or down-regulation of ion channels with the key mechanism of increased intracellular calcium concentration-induced phosphorylation of many proteins in pathways related to ion currents and cell structure, which may be used as a target of new drug development. In a sheep model of non-sustained atrial pacing induced AF, eplerenone, a RAAS antagonist, was found to abbreviate the atrial remodeling and reduce the amplitude of phosphorylation of ion channels and structural proteins but had limited effect in electrical remodeling. Late sodium current inhibitor ranolazine is also anti-ischemic, may reduce the progression of AF in many mechanistic aspects, including the inhibition of late sodium current-related electrical remodeling, reduction of protein phosphorylation and apoptosis, increase in autophagy, and improvement of abnormal energy metabolism, etc. The leading compounds, e.g., compound 3a and CVT10449, developed based on the chemical structure of existed late sodium current inhibitors was presumed to slow or reverse the progression of AF and therefore can be used as new agents with high efficacy and safety in the treatment of AF.