Targeted Imaging of the Spatial and Temporal Variation of Matrix Metalloproteinase Activity in a Porcine Model of Postinfarct Remodeling

Abstract

Background— Matrix metalloproteinases (MMPs) are known to modulate left ventricular (LV) remodeling after a myocardial infarction (MI). However, the temporal and spatial variation of MMP activation and their relationship to mechanical dysfunction after MI remain undefined. Methods and Results— MI was surgically induced in pigs (n=23) and cine magnetic resonance (MR) and dual-isotope hybrid single-photon emission CT (SPECT)/CT imaging obtained using thallium-201 and a technetium-99m-labeled MMP targeted tracer ( 99m Tc-RP805) at 1, 2, and 4 weeks post-MI along with controls (n=5). Regional myocardial strain was computed from MR images and related to MMP zymography and ex vivo myocardial 99m Tc-RP805 retention. MMP activation as assessed by in vivo and ex vivo 99m Tc-RP805 imaging and retention studies was increased nearly 4-fold within the infarct region at 1 week post-MI and remained elevated up to 1 month post-MI. The post-MI change in LV end-diastolic volumes was correlated with MMP activity (y=31.34e 0.48x , P =0.04). MMP activity was increased within the border and remote regions early post-MI, but declined over 1 month. There was a high concordance between regional 99m Tc-RP805 uptake and ex vivo MMP-2 activity. Conclusions— A novel, multimodality, noninvasive hybrid SPECT/CT imaging approach was validated and applied for in vivo evaluation of MMP activation in combination with cine MR analysis of LV deformation. Increased 99m Tc-RP805 retention was seen throughout the heart early post-MI and was not purely a reciprocal of thallium-201 perfusion. The 99m Tc-RP805 SPECT/CT imaging may provide unique information regarding regional myocardial MMP activation and predict late post-MI LV remodeling.