Imaging of MMP activation and myocardial strains

描述（由申请人提供）： 心肌梗死（MI）后，左心室（LV）可能会经历重构过程，这代表了LV结构、几何形状和功能的不利变化。这种心肌梗死后重构与心肌细胞外基质（ECM）的重要变化相关，是心肌梗死后发病率和死亡率增加的独立预测因子。ECM的破坏导致正常结构支持的丧失，使心肌处于异常应力和应变下，这反过来又导致心肌几何形状和功能的变化。基质金属蛋白酶（matrix metalloproteinases，MMPs）是一个负责ECM降解和重塑的蛋白水解酶大家族。MMPs和LV重构过程之间的明确因果关系已通过使用实验研究得到证实。然而，在MI后重塑的演变过程中，用于检测和定量体内MMP活性的非侵入性方法尚未开发，并且形成了将这些基本观察转化为临床应用的关键组成部分。我们一直在开发高灵敏度MMP靶向分子成像方法和电影磁共振（MR）成像方法，以量化局部MMP活性和MI后LV变形和几何形状的变化。这种结合的分子力学方法将使我们能够解决这个项目的中心假设，即增强MMP激活发生在MI后，与局部心肌变形的改变有关，有助于加速不良重塑，MMP介导的MI后重塑的风险可以通过MMP激活和LV变形的新型多模态非侵入性成像来识别和跟踪。该项目将开发和验证一种定量的非侵入性方法，用于心肌梗死后MMP激活的系列评价，并将MMP激活的区域变化与区域心肌应变和微观结构的变化联系起来。本提案中开发的靶向分子成像方法应提供对心室重塑过程中机械力和MMP激活作用的独特见解，并转化为具有预后和诊断潜力的直接临床应用。

DESCRIPTION (provided by applicant): Following myocardial infarction (MI) the left ventricle (LV) may undergo the process of remodeling, which represents the adverse changes in the structure, geometry and function of the LV. This post-MI remodeling is associated with important changes within the myocardial extracellular matrix (ECM) and is an independent predictor of increased morbidity and mortality following MI. Disruption of the ECM results in a loss of normal structural support, placing the myocardium under abnormal stress and strain, which in turn causes changes in myocardial geometry and function. The matrix metalloproteinases (MMPs) constitute a large family of proteolytic enzymes responsible for ECM degradation and remodeling. A clear cause/effect relationship between MMPs and the LV remodeling process has been demonstrated through the use of experimental studies. However, a non-invasive method for detecting and quantifying MMP activity in-vivo during the evolution of post-MI remodeling has yet to be developed and forms a critical component for translating these basic observations to clinical applicability. We have been developing high sensitivity MMP targeted molecular imaging approaches and cine magnetic resonance (MR) imaging methods in order to quantify regional MMP activity and changes in LV deformation and geometry post-MI. This combined molecular-mechanical approach will allow us to address the central hypothesis of this project; that enhanced MMP activation occurs following MI, is associated with altered regional myocardial deformation, contributes to an acceleration of adverse remodeling, and that the risk for MMP mediated post-MI remodeling can be identified and tracked through novel multimodality non-invasive imaging of MMP activation and LV deformation. This project will develop and validate a quantitative non-invasive approach for serial evaluation of MMP activation following myocardial infarction and relate regional changes in MMP activation to change in regional myocardial strain and microstructure. The targeted molecular imaging approach developed in this proposal should provide unique insights into the role of mechanical forces and MMP activation in the processes involved in ventricular remodeling, and translate to direct clinical applications that hold both prognostic and diagnostic potential.