Ghrelin对慢性充血性心力衰竭家兔三层心肌复极异质性的影响及机制研究

Chronic congestive heart failure (CHF) is the end stage of various heart diseases. Our previous studies showed that the heterogeneity of myocardial cross-sectional distribution of Cx43 is an important cause of dispersion of repolarization. So far, whether transmural heterogeneity of Cx43 is exist in CHF and relation between Cx43 and dispersion of repolarization are unclear. Although recent results show that ghrelin could reduce the occurrence of MVA in structural heart diseases, which was estimated that ghrelin could improve the myocardial expression of Cx43 and directly affected the ion channel activity in cardiac myocytes, specific molecular mechanism of the effects was not entired clear. In this project we will mixed use heart perfusion in vitro and myocardial cell separation technology, Western blot and RT-PCR to observe changes of Cx43 proteins and ionic channels among three myocardial layers, and comprehensive descript physiological mechanisms of MVA in CHF. We will also observe effects of ghrelin perfusion on heterogeneity of Cx43 proteins and ionic channels of three myocardial layers,and explore new methods and theoretical basis for the treatment of MVA in structural heart diseases.

慢性充血性心力衰竭（CHF）是各种心脏病的终末阶段，我们先前的研究发现，左心室三层心肌Cx43的分布异质性是复极不均一的主要原因，但CHF是否存在跨室壁Cx43表达异质性，及其与复极不均一的关系仍是未知的。新近的结果发现，Ghrelin能减少器质性心脏病恶性室性心律失常（MVA）的发生，可能与其改善心肌Cx43表达而直接影响心肌细胞离子通道活性相关，但是具体的分子机制仍不清楚。本项目在前期研究的基础上，将利用离体心脏灌流和心肌细胞分离、Western-bloting和RT-PCR等技术，从体内外多个层面对比CHF三层心肌之间离子通道及Cx43等蛋白分子的差异，观察Ghrelin灌流对这些差异的影响，综合阐述CHF易发MVA 的机制并探讨Ghrelin的影响，为MVA临床防治寻找新的方法和靶点。

本研究本课题研究在前期研究的基础上，利用离体心脏灌流和心肌细胞分离、Western-bloting和RT-PCR等技术，从体内外多个层面对比慢性心力衰竭（CHF）三层心肌之间离子通道及Cx43等蛋白分子的差异，观察Ghrelin灌流对这些差异的影响，综合阐述CHF易发恶性室性心律失常（MVA）的机制并探讨Ghrelin的影响，为MVA临床防治寻找新的方法和靶点。我们的结果显示：与假手术组比较，CHF家兔模型左心室三层心肌间缝隙连接蛋白Cx43表达下降，跨室壁的表达异质性增加，导致CHF中层心肌细胞IK离子通道电流显著减少，跨室壁心电复极离散度增加，这可能是CHF易发MVA的重要生理机制，而给予Cx43促进剂灌流后能改善其跨室壁的表达异质性，降低三层心肌间心电复极离散度。Ghrelin灌流和ERK阻断剂等干预分别改善和增加这种异质性，通过影响IK离子电流，继而改变跨室壁复极离散度，是CHF MVA治疗可能的靶点。根据研究结果，共书写了论文6篇，已经在国内外相关刊物上发表相关论文4篇，录用待发表1篇，培养研究生2名。研究的过程促进了海南地区心电生理基础研究领域的发展，促进了我院心血管内科学科的整体发展。