Proteases as Potential Targets in Left Ventricular Remodeling After Myocardial Infarction

Abstract

Left ventricular (LV) remodeling plays a key role in the march to heart failure after myocardial infarction (MI). The remodeling process involves a complex series of changes that occur at structural and extracellular as well as cellular, subcellular, and molecular levels. Typically, the changes are time dependent, occur in tandem sequence, and span the healing/repair process after MI and extend well beyond. Proteases play a major role in the remodeling that occurs at the extracellular as well as cellular, subcellular, and molecular levels. Evidence since the mid-1970s has established the critical roles of the extracellular matrix (ECM) for maintaining normal cardiac shape and function and the dramatic adverse remodeling post-MI, with LV shape deformation and dysfunction that results from disruption of the ECM driven primarily by an imbalance between the class of proteases known as matrix metalloproteinases (MMPs) and the endogenous tissue inhibitors of the MMPs or TIMPs. Evidence since the 1990s has implicated several other classes of proteases in adverse LV remodeling and dysfunction after MI and the march to HF, disability, and death. Experimental studies have shown that pharmacologic inhibition or genetic deletion of key MMPs can effectively prevent or limit post-MI LV remodeling, and some clinical studies have tested MMP inhibitors. Proteases are therefore attractive as potential targets to limit, prevent, or reverse remodeling and dysfunction after MI. However, further studies are needed to identify the optimal strategy to maximize the benefits of protease inhibitors after MI.