Imaging of MMP activation and myocardial strains

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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.