Maladaptive Remodeling in Aging Myocardium

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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 inductions of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), occur in the early and late phases of post-MI remodeling. 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. During our past performance period, we have successfully moved the field forward in terms of demonstrating that localized delivery of a hyaluronic acid based hydrogel (HA-gel) and release of an MMP inhibitory peptide could effectively attenuate adverse post-MI remodeling. We now propose to further advance the translational and clinical relevance of these proof of concept studies and “repurpose” MMP inhibitors that were advanced clinically by overcoming past obstacles regarding systemic delivery and specificity. Our guiding hypothesis is that using a novel self-assembling HA-gel, which will release a pharmacological MMP inhibitor selectively into the MI region, will effectively and favorably alter the course of adverse post-MI remodeling. We will first establish that localized injection of an HA- gel/MMP inhibitor construct will reduce regional local MMP activity, attenuate post-MI regional remodeling and fibroblast transdifferentiation, and thereby prevent the progression of LV pump failure. Next, we will demonstrate that targeted injection of an HA-gel/MMP inhibitor construct will cause favorable effects on the natural history of post-MI remodeling, whether injected early or late post-MI. Finally, we will advance the translational relevance of these studies by demonstrating the beneficial effects of the HA-gel/MMP inhibitor construct using novel delivery methods. These studies will provide the pivotal pre-clinical information in order 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 heart failure.