miRNA-21表达与超声新指标优化主动脉瓣二瓣化手术指征选择的研究

Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality occurring in of the population. Despite the high prevalence of BAV, its cause and genetic origins remain elusive. BAV is associated with accelerated leaflet calcification and valvular dysfunction progression，as well as the myocardial fibrosis. Aberrant flow pattern and congenital fragility bestows BAV with a propensity toward ascending aorta dilatation, aneurysm, and dissection, independently of the presence of concomitant vulvar dysfunction. The current management of aortic valve replacement (AVR) for BAV in asymptomatic patients remain based on experts’ opinions rather than proofs from prospective trials, and whether isolated valve replacement (AVR) can improve the aberrant flow field and function remodeling, and prevent further aorta dilatation in BAV remain controversial. According to 2012 European Society of Cardiology (ESC) guidelines, advanced echocardiographic techniques combined with cardiac biomarkers has the great value for determining the surgical indications. Advanced three-dimensional speckle tracking Echocardiography (3D-STE)and Vector flow mapping（VFM）provides comprehensive assessment of left ventricular (LV) and aorta geometric，hydromechanics and mechanical deformation, thus is much more sensitive and accurate than conventional two-dimensional echocardiography. Recently, miRNA-21 has been established as an important regulator in the left ventricular myocardial remodeling, while the modulation of miR-21 to TGF-β/Smads signal pathway is still unclear. Our project is aimed to perform a prospective two-year trial in BAV patients undergoing AVR. We wish to detect the remolding changes in LV myocardium and aorta function after AVR using 3D-STE and VFM, and establish the prognostic value on the post-operation LV and aorta function recovery. The project will quantify the expression level of miR-21 from aorta, myocardium and plasma.The prognostic value of TGF-β1, miR-21 and smads3, MMP expression with respect to LV myocardial fibrosis and aorta functional changes will be assessed. We expect to provide more scientific，comprehensive evidences for improving clinical decision making of AVR for BAV in combination with echocardiography and biomarker information.

先天性主动脉瓣二瓣化(BAV)出现左室心肌纤维化与主动脉扩张是患者严重并发症, 恰当干预时机对治疗效果与预后有重要意义。目前BAV狭窄的传统手术指征缺乏客观、敏感的界定指标，寻找有效生物标记物结合超声新指标，有望改进其手术指征选择。近年来miRNA对心血管疾病基因表达的调控作用受到更多关注。研究表明miR-21在血流负荷导致的左室重构及扩张主动脉中均显著表达增加，但miR-21表达是否参与BAV并发症进程的机制研究尚少。本课题假设miRNA-21在诱导组织纤维化与细胞基质重构的TGF-β/Smads信号通路中，通过对TGF-β1、smad3及MMP等靶基因调控，促进BAV心肌纤维化和升主动脉重塑进程。同时课题结合超声新指标描述BAV瓣膜置换前后左室与主动脉力学与血流动力学特征；检测血浆与组织miR-21表达及蛋白水平与超声新指标的相关性，以期优化BAV手术指征选择，预测BAV术后功能转归。

先天性主动脉瓣二瓣化(BAV)出现左室心肌纤维化与主动脉扩张是患者严重并发症, 恰当干预时机对治疗效果与预后有重要意义。目前BAV狭窄的传统手术指征缺乏客观、敏感的界定指标，亟需寻找有效生物标记物及更有价值的无创干预指标，改进其手术指征选择。近年来miRNA对心血管疾病基因表达的调控作用受到更多关注。本项目发现BAV 重度狭窄患者外周血 miR-21-5p、 miR-29a、 miR-133a、miR-19b 可预测患者心肌纤维化，VFM 技术能够实现血流 流场和基于局部流线的层流和涡流等流体状态的可视化观察;对瓣膜功能正常的 BAV 患者，BAV 左房功能与 BAV 主动脉根部早期改变的关联性可能为 BAV 手术时机提供新的参考依据;超声新指标第一阶段左室射血分数(EF1)对主动脉缩窄 大鼠的早期心肌纤维化具有预测价值，可能为超声诊断主动脉疾病带来新的研究方向。

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