Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relationship to myocardial dysfunction.

Left ventricular (LV) remodeling following myocardia l infarction (MI) is characterized by infarct expansion, progressive LV dilation, hypertrophy of non-infarct zones, and overall global ventricular remodeling 1-4. Clinical and animal studies have demonstrated an association between the development of adverse LV remodeling after MI and poor outcomes 1, 2, 5, 6. The changes in anatomic structure or function associated with post-MI LV remodeling are routinely evaluated using imaging modalities including echocardiography, magnetic resonance (MR) imaging, cine x-ray computed tomography (CT), or even conventional nuclear based approaches, like single photon emission computed tomography (SPECT). Although changes in LV size and shape appear to be a direct measurement of remodeling, these indices do not provide information on the underlying molecular processes, which may then be used as surrogate markers of LV remodeling 1. A cause-effect relationship has been established between LV remodeling and activation of the matrix metalloproteinases (MMPs) 7-12. However, defining the spatial and temporal variation of MMP activation post MI in relationship to LV remodeling has been difficult because of the lack of a direct in vivo approach to assess MMP activity. Past studies demonstrated the feasibility of targeted non-invasive imaging with a 99mTc-labeled MMP-targeted radiotracer (99mTc-RP805) for the in vivo detection of regional myocardial MMP activation following MI 13, 14. The current study extended these initial findings to a relevant pre-clinical post MI porcine model in order to test the central hypothesis that enhanced MMP activation occurs following MI, and is associated with altered regional myocardial deformation. The rationale for these studies is that defining the relationship between regional MMP activity and LV geometry and mechanics will be critical to better understand the mechanism underlying LV remodeling post-MI. Accordingly, the aims of the current study were two-fold: First, validate an MMP-targeted radiotracer approach for in vivo evaluation of MMP activation post-MI, comparing radiotracer derived indices of regional MMP activation with quantitative MMP zymography, and second, employ hybrid SPECT/CT imaging of MMP activation in combination with MR image derived indices of regional myocardial deformation to relate temporal changes in regional MMP activation with changes in regional myocardial deformation.