Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, which invariably occur following a myocardial infarction (MI), and is an important predictor of clinical outcomes. Increased induction of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs) occur in the early and late phases of post-MI remodeling and a loss of endogenous inhibitory control by the tissue inhibitors of MMPs (TIMPs) has been identified as a biological milestone in this process. While MMP inhibition remains an important therapeutic target in the context of post-MI remodeling, systemic delivery of broad spectrum pharmacologic MMP inhibitors can be associated with adverse events, and these concerns coupled with difficulties in dosing regimens, have hindered clinical progress. One potential therapeutic avenue which has yet to be developed in a translational research context is the localized delivery of TIMPs directly within the remodeling MI. While there are 4 known TIMPs, TIMP-3 has been uniformly identified to be reduced in the context of post-MI remodeling. This study will test the central hypothesis that targeted placement of a polymer-hydrogel which provides continuous, localized release of recombinant TIMP-3 protein (rTIMP-3) within the MI region will reduce overall MMP proteolytic activity, stabilize the ECM, reduce MI expansion and favorably affect LV geometry and function. Moreover, using an MMP responsive polymer-hydrogel construct which will release rTIMP-3 in relation to net localized MMP proteolytic activity, will provide a novel and specific approach to interrupt ECM proteolysis and attenuate post-MI remodeling. These translational research studies will provide pivotal functional and mechanistic results regarding efficacy of localized MMP inhibition on directly relevant determinants of post-MI remodeling. These studies will provide the essential pre-clinical information necessary to further advance the therapeutic avenue of localized MMP inhibitory control in order to interrupt the inexorable progression of adverse LV remodeling post-MI and subsequent development of heart failure. One of the most common causes of death and disability in this country is from a heart attack and the subsequent development of heart failure. Following a heart attack, it is now clear that chronic activation of MMPs continue to chew away at the heart ECM and eventually cause the heart to change shape, inducing dilation and the transition to failure. This study will validate a novel therapeuti intervention to control MMPs following a heart attack and thereby develop innovative treatments to prevent progressive myocardial remodeling in patients after a heart attack.

R01HL111090

2012-08-01

2017-05-31