抗AT1受体自身抗体在克山病室性心律失常和猝死发生中的作用及机制

Keshan disease is an unexplained endemic cardiomyopathy with high mortality and high morbidity in our country.The incidence of Keshan disease dropped significantly after active prevention for many years, but still have a high rate of sudden death. Studies have shown that there are close relationship between ventricular arrhythmias (VA) and sudden death in Keshan disease .AngⅡhad been confirmed to participate in the incidence of malignant VA and play action through AT1 receptor.In recent years, the role of immune mechanisms in cardiovascular disease gradually got attention,autoantibodies against AT1 receptor (AT1-AA) were found to have similar biological effects with AngⅡand can be blocked by ARB.However, the relationship between AT1-AA and VA has not been reported.On the basis of full summary of current research and our preliminary findings,this study hypothesize that as a result of long-term physiological disorder caused by changes in hormone levels and myocardial damage, autoimmune response induced and AT1-AA produced in patients with Keshan disease.AT1-AA may cause Cx43 change in ventricular myocytes and the excessive release of Ca2+ stimulate Na+/Ca2+ exchanger and cause delayed after depolarization, and therefore resulting the increased susceptibility for VA. Variety of experiments would be intended to verify the above hypotheses in this study,and the results are expected to provide a scientific basis for reducing the rates of ventricular arrhythmias and sudden death,evaluate prognosis and to choose the best treatment for Keshan disease.

克山病是一种我国所特有的原因不明的病死率高、致残率高的地方性心肌病。经过多年积极防治，克山病发病率明显下降，但患者猝死率仍然很高。研究表明，室性心律失常（VA）与克山病猝死和预后关系密切。血管紧张素Ⅱ（AngⅡ）被证实参与了恶性VA的发生，而其效应主要由AT1受体介导。近年来免疫机制在心血管疾病中的作用倍受关注，抗AT1受体自身抗体（AT1-AA）被发现具有与AngⅡ类似的生物学效应且可被AT1受体拮抗剂（ARB）阻断。本项目在充分总结国内外研究现状及我们已有研究成果的基础上，提出了克山病患者自身免疫应答产生的AT1-AA，通过相应的信号通路引起心室肌细胞膜缝隙连接蛋白Cx43变化，同时细胞内过量Ca2+释放激活NCX引起延迟后除极，导致VA易感性增加的假说，并拟通过多种实验方法进行验证。研究结果有望为降低克山病VA发生率和猝死率、评价预后效果以及选择最优治疗方案提供科学依据。