Regional matrix metalloproteinase activation correlates with microstructure diffusion tensor indices post myocardial infarction

Introduction

Post myocardial infarction (MI) activated matrix metalloproteinases (MMPs) degrade the extracellular matrix (ECM) and alter the tissue microstructure (TMS). Diffusion Tensor MRI (DT-MRI) yields diffusivity and anisotropy indices that characterize the TMS. Our previous studies in pigs post-MI have showed that gross spatial and temporal changes in mean diffusivity () and fractional anisotropy (FA) correlate with MMP activation assessed with a 99 mTc-labeled radiotracer (RP805) targeted at activated MMPs.

Purpose

To determine the correlation between regional MMP activation defined by RP805 with alterations in, FA and a new coefficient of anisotropy, the toroidal curvature (TC).

Methods

Correlation between regional MMP activation using RP805 and DT-MRI was assessed in 3 infarcted porcine hearts at 2- and 4-week post-MI. Two hours prior to euthanasia, RP805 (28 ± 3 mCi) was injected. Each heart was then excised and placed in a container and filled with Fomblin. DT-MRI was performed on a 3.0 T scanner (Siemens, Erlangen, Germany) using a segmented EPI sequence, 6 gradient directions; b-values = 0 (T2-weighted) and 600 s/mm2; voxel-size = 2 × 2 × 2 mm3; slices = 50; TR/TE = 5400/84 ms; 40 averages (EPI-factor = 7). Following MR imaging hearts were sliced (5 mm), cut in 8 radial pies and divided into endocardial and epicardial segments for gamma-well-counting for determination of RP805 activity, expressed as percent of injected dose/gram of tissue (%ID/g). Similarly, T2-weighted images were segmented using the same anatomical landmarks and used to classify tissue as infarcted (I) or non-infarcted (NI). TC is defined as the maximum Gaussian curvature of the toroid-based representation of the DT. Figure 1 displays an example of the, FA and TC maps used in quantification compared with RP805 and morphology.

Figure 1

Mid-ventricular cross-section of MD (A), FA (B), TC (C), and RP805 (D) maps, as well as the relative post mortem slice (E) for a 2-week post-MI porcine heart. Figure shows the spatial correlation between the infacted area (red arrow) and the increse in MD and RP805 and the decrease in FA and TC.

Results

Figure 2 illustrates the positive correlation between regional RP805 activity and for both I (r = 0.563, p < 0.001) and NI (r = 0.628, p < 0.001). There was an inverse correlation between RP805 activity and FA (r = -0.426, p < 0.001) within NI regions, although no correlation within I regions (r = -0.096, p = 0.3). There were inverse correlations between RP805 activity and TC for both NI (r = -0.532, p < 0.001) and I (r = -0.329, p < 0.05) regions. The average (I = 0.52 ± 0.10 mm2/s; NI = 0.43 ± 0.06 mm2/s), FA (I = 0.44 ± 0.06; NI = 0.47 ± 0.06), TC (I = 113.55 ± 39.64, NI = 152.44 ± 45.98) and RP805 activity (I = 0.75 ± 0.34; NI = 0.46 ± 0.19) were all significantly (p < 0.001) different between I and NI regions.

Figure 2

Scatter diagrams showing the correlation between RP805 and MD (A), FA (B), and TC (C) respectively with I (red dots) and NI (black dots) for all animales. The correlation coefficient r and the relative p values are indicated in the upper right corner of each panel.

Conclusion

Therefore, MMP-mediated degradation of the ECM post-MI was associated with increased water diffusivity as reflected by and reduced anisotropy by a decrease in FA and TC. Hence, evaluation of regional DT-MRI indices of microstructure in combination with evaluation of MMP activation may provide new insight in the remodeling process post-MI.