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Recombinant Tissue Inhibitor Subdues Matrix Metalloproteinases and Produces Novel Images With New Possibilities.

In this issue of the Journal, Thorn et al 1 report a novel, image-based approach that holds promise for guiding future therapeutic strategies in acute myocardial infarction patients. The authors convincingly demonstrate in experimental pigs that a pharmacologically induced suppression of activated MMPs (matrix metalloproteinases) in infarcted myocardium can be assessed noninvasively, both qualitatively and quantitatively. The use of a SPECT/CT system together with 2 radiotracers—one for imaging myocardial perfusion and flow quantification (Tl-201) and a second one, Tc-99m RP805, as an MMP-targeted radioligand for intracoronary delivery of a rTIMP (recombinant tissue inhibitor of MMP) shortly before reperfusion after a 90-minute coronary occlusion—resulted in smaller regions with less intensive Tc-99m RP805 retention in the infarct zone. Activated MMPs play a critical role in inflammatory and reparative processes in infarcted myocardium. Levels of activated MMPs in infarcted myocardium correlate with subsequent adverse ventricular remodeling, left ventricular enlargement, and development of heart failure.2–4 Infarct healing entails a finely tuned temporal sequence of different phases, with an initial inflammatory phase being followed by a reparative and proliferative phase and then by a maturation phase.5,6 Initiated and orchestrated by chemokines and cytokines, the first phase involves the recruitment of monocytes and macrophages and a rise in tissue levels of activated MMPs. It is a phase of predominantly apoptotic, proteolytic, and inflammatory activity combined with MMP cleavage of protein cell debris and extracellular matrix proteins. In a distinctly different second phase, the recruitment of monocytes continues but of a monocyte subtype with properties that attenuate the inflammatory response and promote myofibroblast accumulation, angiogenesis, and collagen deposition. Between the inflammatory and reparative phases there exists a delicate balance that is sensitive to MMP tissue levels. An MMP-dependent shift to the inflammatory phase, for example, may delay the reparative phase and lead to excessive proteolytic loss of structural components without adequate repair and scar formation, with infarct extension, ventricular rupture, or worsened adverse ventricular remodeling as possible consequences. Previous studies in the authors’ laboratory have firmly established and validated the MMP-targeting specificity of Tc-99m RP805.7,8 The radiolabeled macrocyclic compound binds to the exposed catalytic domain shared by MMPs but not by other proteases. In a porcine model of myocardial infarction without reperfusion, Tc-99m RP805 uptake in the infarct region correlated well with active MMP tissue levels in infarcted myocardium.9 Importantly, levels of active MMP in infarcted myocardium correlated in a nonlinear fashion with the degree of adverse ventricular remodeling. In the current study, the ≈50% reduction in Tc-99m RP805 © 2019 American Heart Association, Inc. Circulation: Cardiovascular Imaging