靶向干预心脏交感通路对心脏重构和心力衰竭的影响及机制研究

在心脏重构和心力衰竭的发生发展过程中，交感神经的过度活化，发挥了举足轻重的作用，通过非药物手段抑制交感神经活性是治疗心脏重构和心力衰竭的重要策略。既往的解剖学证据以及申请人前期的研究结果提示，颈后神经节和Marshall韧带远段作为支配心脏交感神经通路的关键环节，是抑制心脏交感活性的潜在干预靶点。基于以上基础，我们提出靶向消融颈后神经节或Marshall韧带远段能够有效降低交感神经活性，遏制心脏重构和心力衰竭的进展，具有很好临床转化潜能。本项目拟应用大型动物犬，建立心肌梗死，压力超负荷以及快速起搏模型，模拟临床常见疾病所引起的心脏重构和心力衰竭，选择性消融颈后神经节或Marshall韧带远段，明确这些交感神经潜在干预靶点的有效性，安全性和特异性，探讨其对心脏重构和心力衰竭的治疗作用，并深入剖析下游的分子机制，以期为非药物性手段干预交感神经活性，抑制心脏重构，治疗心力衰竭提供新的策略。

Sympathetic overactivation is the predominant factor in the development of heart remodeling and heart failure. Inhibition of sympathetic activity by non-pharmacological interventions is an import therapeutic strategy for the treatment of these diseases. Anatomical evidences and our preliminary data indicate that caudal cervical ganglion and the distal part of the ligament of Marshall (LOMLSPV) are the crucial pathways of cardiac sympathetic innervation, serving as potential intervention targets to suppress cardiac sympathetic activity. On the basis of the above, we propose that targeted ablation of caudal cervical ganglion or LOMLSPV can effectively reduce sympathetic activity, inhibit the progress of cardiac remodeling and heart failure, and have great potential for clinical transformation. In this project, canines will be used to establish large animal models induced by myocardial infarction, pressure overload and rapid pacing to simulate cardiac remodeling and heart failure caused by common cardiovascular diseases. Selective ablation of caudal cervical ganglion or LOMLSPV will be conducted. We aim to investigate the efficacy, safety and specificity of these potential intervention targets for sympathetic suppression, to explore their therapeutic effects on cardiac remodeling and the resultant heart failure, and to clarify the underlying molecular mechanisms. The achievements of this project will pave the way for promising non-pharmacological strategies to inhibit sympathetic activity and treat cardiac remodeling and heart failure.