应用表型组学方法研究Galectin-3致心房纤维化和心房颤动的机制

Atrial fibrosis plays an important role in the natural progression of atrial fibrillation (AF) and the recurrence of AF after radiofrequency catheter ablation in the patients with AF, but the underlying mechanisms are unknown. So far we have established the largest biobank of AF in China and preliminarily have delineated the epidemiological and clinical characteristics of patients with AF in our country. Based on the biobank, we demonstrated that Galectin-3, a biomarker of fibrosis, was associated with the recurrence of AF after radiofrequency catheter ablation in the patients with AF; many studies in other tissues have demonstrated that Galectin-3 play a critical role in the fibrogenesis, thus we propose that Galectin-3 is a key molecular point in the atrial fibrosis. In this project, Aim 1: we plan to establish the atrial fibrillation-atrial fibrosis phenomics with the focusing on the Galectin-3 and its associated biomarks. Aim 2: we plan to investigate the underlying mechanisms for the Galectin-3 associated atrial fibrosis. Aim 3: we plan to explore the inhibition of Galectin-3 to delay or reverse of atrial fibrosis. Taken together, this project is to establish Galectin-3 as a novel target for the prevention and treatment of atrial fibrillation.

心房纤维化在心房颤动（房颤）的自然病程以及房颤患者导管消融术（RFA）后的复发中起关键作用，但具体机制不明。前期工作中我们建立了国内最大样本量的房颤临床资源与样本库，初步勾勒出我国房颤的流行病学和临床特征。我们的前瞻性临床试验首次证实，血浆高Galectin-3（Gal-3）水平与房颤患者RFA术后复发相关，既往研究证明，Gal-3是肝、肺、肾等组织纤维化发生发展的重要分子节点，据此提出“Gal-3是心房纤维化重要分子开关”的核心假说。本项目立足于前期研究基础，以房颤心房纤维化的自然病程和房颤RFA造成的医源性心房纤维化这两个临床问题为切入点，建立以Gal-3为核心的房颤-心房纤维化表型组学，明确Gal-3在房颤临床转归中的作用；在动物模型上研究Gal-3致心房纤维化的机制；探索Gal-3抑制能否延缓甚至逆转心房纤维化。籍此为建立以Gal-3为靶点的房颤防治和术后复发防范策略提供科学依据。

炎症和纤维化在房颤的发生、发展及相关心血管事件中起重要作用，领域内存在如下2个关键科学问题：1.房颤相关事件精准预测模型的建立；炎症和纤维化指标能否提高模型的预测能力；2.炎症致房颤机制尚不明确。本项目在前期国内最大样本量的房颤临床资源与样本库基础上，建立房颤临床表型组学数据库，利用大数据研究手段建立的房颤卒中和栓塞新型预测模型，较传统预测有较高的预测准确性。在此基础上加上包括Galectin-3在内的炎症因子和血清学纤维化标志物，但未明显优化房颤卒中预测模型。基础研究方面，明确Galectin-3作为上游炎症因子，刺激炎症级联扩大反应。炎症因子TNF-α等可通过心房肌细胞线粒体氧自由基-CaMKII-钙紊乱机制致房颤；秋水仙碱显著抑制炎症因子所致心房肌细胞钙紊乱，其治疗机制与其促心肌细胞内微管解聚，减轻炎症因子信号转导相关。建立抗肿瘤药物依鲁替尼致小鼠房颤模型，证实其致房颤机制与依鲁替尼致心房肌细胞钙紊乱与纤维化相关。本研究阐明了炎症因子致房颤的新的发生机制，建立了新的房颤临床事件的预测新模型，但并未发现加入炎症和纤维化血清学指标可进一步优化预测模型。本研究可为进一步探索炎症和房颤发生、发展以及相关临床事件的发生提供理论和数据依据。