Surgery to Prevent Post Infarction Ventricular Remodeling

 描述（由申请人提供）：每年有超过100万美国人遭受心肌梗死（MI），许多人经历MI后左心室（LV）重塑，这表现为LV结构和功能的进行性变化。MI后LV重构是近70%的心力衰竭（HF）病例的原因。HF严重致残500万美国人，每年杀死超过25万人。该拟议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，重点关注新形成的MI，旨在中断LV重塑并预防症状性HF的发展。扩张（拉伸）是MI材料性能逐渐变化的结果，已被确定为启动和维持不良LV重塑的生物力学现象。该项目将建立在我们之前完成的工作的基础上，并将其向前推进，该工作表明，通过手术放置约束装置来防止梗死扩展可显著降低LV重塑。该项目的总体目标是确定新型生物材料的靶向递送，这些生物材料经工程设计诱导应答巨噬细胞从M1（蛋白水解）表型向M2（修复）表型的表型转变，将促进细胞外基质（ECM）稳定性，有利地改变梗死材料特性，限制梗死扩展并改善LV重塑。在特定目标1中，我们将测试以下假设：通过透明质酸（HA）水凝胶载体将单核细胞趋化蛋白-1（MCP-1）靶向递送至梗死区域，使响应性巨噬细胞极化转向有利于M2表型，从而促进ECM稳定性，有利地改变梗死材料性质，限制梗死扩展并改善LV重塑。在具体目标2中，我们将测试以下假设：当与单独的PLGA微球或MCP-1递送相比时，HA-水凝胶载体中的PLGA微球和MCP-1靶向递送至梗死区域将协同增强巨噬细胞极化，有利于M2表型和ECM稳定性，进一步减少梗死扩张并限制LV重塑。通过使用临床相关的大型动物MI模型和在特定目标3中应用微创基于导管的心外膜方法，在最先进的电解剖梗死标测指导下输送生物材料，进一步增强了拟议项目的重要性。这两者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.