Matrix metalloproteinase therapy in heart failure

Abstract

Milestones in the progression to heart failure following myocardial infarction (MI) are changes in left ventricular (LV) geometry and function, termed post-MI remodeling. Critical to this adverse remodeling process are changes in the expression, synthesis, and degradation of myocardial extracellular matrix (ECM) proteins. The myocardial ECM is not a passive entity but a complex and dynamic microenvironment that represents an important structural and signaling system within the myocardium. In particular, basic and clinical studies have provided conclusive evidence that abnormal and persistent activation of the ECM degradation pathway, notably through the matrix metalloproteinases (MMPs), contribute to adverse post-MI remodeling. This review examines recent clinical studies that provide further support to the hypothesis that a specific portfolio of MMPs are diagnostic and likely contributory to LV remodeling and the progression to heart failure after MI. Future translational and clinical research focused on the molecular and cellular mechanisms regulating ECM structure and function likely will contribute to an improved understanding of post-MI LV remodeling and yield novel therapeutic targets.

Figure 1

Profiling of matrix metalloproteinases (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been performed in a number of clinical studies in patients following acute coronary syndromes/myocardial infarction (MI). The generalized changes in the predominant types of MMPs in the early (days) and late stages (months) post-MI are shown. The arrows indicate the relative change in terms of a baseline or referent control value. Robust changes in MMP-8 and MMP-9 occur during and following an MI; and these MMP types are prototypically induced in a wound healing/inflammatory cascade. In contrast, other MMP types and TIMP-1 tend to show temporal profiles which likely reflect the dynamic changes occurring during the LV remodeling response following MI.