左心房流体力学变化介导的心房结构重构在心房纤颤的发生与发展作用及机制

Atrial fibrillation is one of the most common and debilitating features of cardiovascular disease, accounting for high amounts of mortality and morbidity. Despite its clinical significance, the specific mechanism of atrial fibrillation has not been fully elucidated as of yet. In the left atrium, the hydrokinetic forces are suspected to be pivotal in development of the atrial fibrillation, because of the left atrium’s complex and unique anatomy and physiology. Our previous study has found that left atrial structural fibrosis plays a vital role in the development of atrial fibrillation. In this study, we use 4D flow MRI and DE-MRI technology to analyze this structural change. Using an existing canine model of right atrial chronic atrial fibrillation, including rapid pacing and mitral regurgitation, we apply the 4D flow MRI and DE-MRI technology to elucidate the relationship between the atrial hydrokinetic changes, flow field characteristics and fibrosis in the animal model of chronic atrial fibrillation at different stages of disease progression. Furthermore, by studying patients with rheumatic heart disease and severe atrial fibrillation, we explore the relationship between atrial fibrillation after the intervention of radiofrequency ablation and associated changes in left atrial hydrokinetic forces and atrial fibrosis. Additionally, according to the paradigm of ‘hydrokinetic—myocardial fibrosis factor—atrial structural reengineering—development of atrial fibrillation’, we explore how atrial structural reengineering changes with respect to the differing atrial hydrokinetic changes. Using this afore mentioned proposed technique, we will be able to investigate the development mechanisms of atrial fibrillation in terms of the atrial structural fibrosis and hydrokinetic changes, and radiofrequency ablation on atrial structural reengineering.

房颤是临床最常见的心律失常之一，严重影响患者的生活质量甚至威胁生命。到目前为止，房颤发生发展的具体机制仍未被阐明。左心房在发生房颤与发展阶段均会现出现流体力学特性的显著改变，并且研究发现左心房结构重构即纤维化在房颤的发生与发展中起到了重要作用。本项目拟采用四维流场磁共振（4D flow MRI）和延迟增强磁共振（DE-MRI）技术作为研究手段，利用已有的慢性房颤动物模型，应用4D flow MRI和DE-MRI技术深入研究不同类型房颤动物模型在房颤发生与发展的不同阶段心房流体力学变化及流场特性与纤维化联系。以接受外科手术的风心病合并永久性房颤患者作为研究对象，探索房颤射频消融术后心房易颤性与左心房流体力学变化和心房纤维化之间的关系，以 “流体力学改变 – 心肌纤维化因子 – 心房重构结构重构 - 房颤的发生及发展”思路为主线，从一个崭新的视角探索房颤发生与发展机制。

虽然近些年来对于房颤的治疗无论在药物及手术等方法上均取得了长足的进步，但其发生发展的机制仍未被阐明，对于房颤的机制研究已经成为世界性难题。房颤心肌纤维化形成机制对于提高房颤治疗效果及改善预后非常关键。.本研究（1）构建快速起搏心房诱发房颤动物模型和二尖瓣反流诱发房颤动物模型，应用心外膜与体表电位标测系统同时采集房颤心律时心外膜和体表电位信号。通过信号独立成分分析联合二阶盲辨识分离方法获得除去心房信号和噪声干扰的体表和心外膜电位信号，分别计算其主导频率。实验中的犬成功构建慢性房颤模型，证明了体表采集房颤电位信号的可靠性。（2）运用四维流场磁共振技术（four-dimensional flow MRI，4D flow MRI）动态监测动物模型和临床患者不同阶段心房血流动力学特性改变情况，衡量了房颤病人与正常人，在完整心动周期内涡量的差异。对于血流动力学分析部分，我们利用一个拉格朗日平均涡度偏差（Lagrangian-Averaged Vorticity Deviation，LAVD）算法量化左心房内的漩涡并观察漩涡的发展，在正常和非正常的心腔实现心腔内拉格朗日漩涡的识别。并分析流“流体力学 - 心肌蛋白质组学变化–心房重构（电重构及结构重构）-房颤的发生与发展”四者间的关系。（3） 针对延迟增强磁共振成像（Delayed-Enhancement MRI, DE-MRI）评价动物模型与临床房颤患者左心房心肌纤维化程度。我们提出了一种基于深度学习的DE-MRI图像重构技术，从而提高心肌图像的超分辨率，进行定量分析评价心肌纤维化程度。（4）通过生物信息分析所引用的分子生物学方法（RT-PCR及EMSA法），测定不同实验阶段，心房不同区域心房肌肉组织纤维化蛋白质表达水平与活性（TGF-β1，MMPs，TIMPs），并结合心房不同区域流体力学特性，心房纤维化程度，探索“流体力学改变 - 心肌纤维化蛋白因子–心房结构重构 - 房颤的发生及发展”之间的潜在联系及因果关系。最后成功开发了完整的量化心血管血流参数的系统,在发掘心房颤动机制方面上建立了新的心脏模型。.关键词: 心房颤动机制；四维流场磁共振技术; 延迟增强磁共振成像；心房纤维化；血流动力学