Tipping the extracellular matrix balance during heart failure progression: do we always go right?

of MMP-2, 3, and 9 progressively increased with severity of heart failure, while levels of TIMP-1 and full-length fibronectin declined. The change in MMP and TIMP expression levels correlated strongly with the decline in NYHA class. While these results place these analytes at the scene of the crime, several questions remain to be answered before a guilty plea can be entered. For one, there is a need to measure other MMPs and TIMPs that will provide a more complete picture of the ECM turnover status in the failing left ventricle. While the authors state that ‘only the most important myocardial MMPs ... were evaluated’, the conclusion that MMP2, 3, and 9 are most important is derived from the fact that they are the most frequently measured. Whether frequency equals importance has not been established for the MMP family. In particular, information on additional inflammatory-related MMPs (7, 8, 12, 14, 16, 28) would fill in crucial details for the detectives. While the authors demonstrate a decrease in TIMP-1 levels in this study, plasma TIMP-1 increases during different stages of hypertension and myocardial infarction [10, 11] . In fact, increased TIMP-1 has been proposed as Matrix metalloproteinases (MMPs) are highly implicated regulators of cardiac remodeling, and multiple teams have measured MMP and tissue inhibitor of metalloproteinase (TIMP) levels in various cardiac disease models. Animal and human studies have demonstrated that MMPs increase and are positively associated with remodeling parameters [1–3] . Mice with targeted deletion of specific MMPs or the TIMPs have also incriminated particular MMPs and TIMPs, including MMP-2 and 9 and TIMP-1, in adverse remodeling following myocardial infarction [4–7] . However, MMP inhibition strategies have not proven effective in limiting post-myocardial infarction remodeling [8] . At this juncture, a crucial question to ask is: if MMPs and extracellular matrix (ECM) degradation are on the right side of the scale and TIMPs and ECM accumulation are on the left side, is interfering with the right side (using MMP inhibitors) the only viable therapeutic strategy to tip the balance? In this issue of Cardiology , Yang et al. [9] examine levels of MMP-2, MMP-3, and MMP-9, as well as TIMP-1 and fibronectin, in patients with congestive heart failure. Compared to control levels, plasma and ventricular levels Received: May 17, 2010 Accepted: May 18, 2010 Published online: July 2, 2010