Surgery to Prevent Post Infarction Ventricular Remodeling

 描述(申请人提供)：每年有100多万美国人患有心肌梗塞(MI)，许多人经历MI后左室(LV)重塑，表现为左室结构和功能的渐进性变化。心梗后左室重构是近70%的心力衰竭(HF)病例的原因。心力衰竭使500万美国人严重残疾，每年导致超过25万人死亡。拟议的项目基于一种非常重要的转化研究方法，旨在开发一种临床适用的微创治疗策略，专注于新形成的心肌梗死，旨在中断左室重构并防止症状性心衰的发展。心肌梗死扩大(拉伸)是心肌梗死材料性质进行性改变的结果，已被认为是启动和维持不利的左室重构的生物力学现象。拟议的项目将在我们之前完成的工作的基础上发展，这项工作表明，通过外科手术放置的约束装置防止梗塞扩大显著减少了左室重构。该项目的总体目标是确定靶向输送新型生物材料将促进细胞外基质(ECM)的稳定性，有利地改变梗塞材料的性质，限制梗塞扩大和改善左室重构。在特定的目标1中，我们将测试这样的假设，即通过透明质酸(HA)水凝胶载体将单核细胞趋化蛋白-1(MCP-1)靶向输送到梗死区，改变响应巨噬细胞的极化，有利于M2表型，从而促进ECM的稳定性，有利于改变梗死物质的性质，限制梗死灶的扩大，改善左室重构。在特定的目标2中，我们将测试这样的假设，即与PLGA微球或MCP-1单独递送相比，PLGA微球和MCP-1在HA水凝胶载体中定向递送到梗死区将协同增强巨噬细胞极化，有利于M2表型和ECM稳定性，进一步减少梗塞扩大和限制左室重构。通过使用临床上相关的大动物心肌梗死模型和在特定目标3中应用基于微创导管的心外膜途径在最先进的电解剖梗死标测指导下进行生物材料输送，拟议项目的意义进一步增强。这两个都提高了拟议工作的快速临床翻译的潜力。

 DESCRIPTION (provided by applicant): Over 1 million Americans suffer a myocardial infarction (MI) each year and many experience post-MI left ventricular (LV) remodeling, which is manifest as progressive changes in LV structure and function. Post-MI LV remodeling is responsible for nearly 70% of all heart failure (HF) cases. HF severely disables 5 million Americans and kills more than 250,000 each year. The proposed project is based on a highly significant translational research approach that seeks to develop a clinically applicable, minimally invasive treatment strategy focused on the newly formed MI intended to interrupt LV remodeling and prevent the development of symptomatic HF. Infarct expansion (stretching) results from progressive changes in MI material properties and has been identified as the biomechanical phenomena that initiates and sustains adverse LV remodeling. The proposed project will build on and advance our previously completed work, which demonstrated that preventing infarct expansion by surgically placed restraint devices significantly reduces LV remodeling. The overarching goal of this project is to establish that targeted delivery of novel biomaterials that have been engineered to induce a phenotypic shift in responding macrophages from the M1 (proteolytic) phenotype to the M2 (reparative) phenotype, will promote extracellular matrix (ECM) stability, favorably alter infarct material properties, limit infarct expansion and improve LV remodeling. In Specific Aim 1 we will test the hypothesis that targeted delivery of monocyte chemoattractant protein-1 (MCP-1) into the infarct region by a hyaluronic acid (HA) hydrogel carrier shifts responding macrophage polarization in favor of the M2 phenotype, which promotes ECM stability, favorably alters infarct material properties, limits infarct expansion and improves LV remodeling. In Specific Aim 2 we will test the hypothesis that the targeted delivery to the infarct region of PLGA microspheres and MCP-1 in a HA-hydrogel carrier will synergistically potentiate both macrophage polarization in favor of the M2 phenotype and ECM stability further reducing infarct expansion and limiting LV remodeling when compared to PLGA microspheres or MCP-1 delivery alone. The significance of the proposed project is further enhanced by the use of a clinically relevant large animal MI model and the application in Specific Aim 3 of minimally invasive catheter-based epicardial approaches for biomaterial delivery guided by state-of-the-art electroanatomic infarct mapping. Both of which heighten the potential for rapid clinical translation of the proposed work.