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)可能发生重构过程，表现为LV的结构、几何和功能发生了不利的变化。心肌梗死后的这种重构与心肌细胞外基质(ECM)的重要变化有关，是心肌梗死后发病率和死亡率增加的独立预测因子。细胞外基质的破坏会导致失去正常的结构支持，使心肌处于异常的应力和应变状态，进而导致心肌几何和功能的改变。基质金属蛋白酶(MMPs)是一个蛋白水解酶家族，参与ECM的降解和重塑。通过实验研究，MMPs与LV重构过程之间存在明确的因果关系。然而，在心肌梗死后重塑的演变过程中，一种非侵入性的检测和量化体内基质金属蛋白酶活性的方法还没有开发出来，并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的基质金属蛋白酶靶向分子成像方法和电影磁共振成像方法，以量化局部基质金属蛋白酶的活性以及心肌梗死后左室变形和几何形状的变化。这种分子-力学结合的方法将使我们能够解决这一项目的中心假设：心肌梗死后发生增强的MMP激活，与局部心肌变形相关，有助于加速不利的重构，并且可以通过新颖的多模式无创性成像识别和跟踪基质金属蛋白酶介导的心肌梗死后重构的风险。该项目将开发和验证一种定量的非侵入性方法，用于连续评估心肌梗死后基质金属蛋白酶的激活，并将局部基质金属蛋白酶激活的变化与局部心肌应变和微结构的变化联系起来。这项建议中开发的靶向分子成像方法应该能够提供关于机械力和基质金属蛋白酶激活在参与心室重塑过程中的作用的独特见解，并转化为具有预测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.