Matrix metalloproteinases: regulation and dysregulation in the failing heart

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for myocardial extracellular protein degradation. Several MMP species identified within the human myocardium may be dysregulated in congestive heart failure (CHF). For example, MMPs that are expressed at very low levels in normal myocardium, such as collagenase-3 (MMP-13) and the membrane-type-1 MMPs, are substantially upregulated in CHF. However, MMP species are not uniformly increased in patients with end-stage CHF, suggesting that a specific portfolio of MMPs are expressed in the failing myocardium. With the use of animal models of CHF, a mechanistic relationship has been demonstrated with respect to myocardial MMP expression and the left ventricular (LV) remodeling process. The tissue inhibitors of the MMPs (TIMPs) are locally synthesized proteins that bind to active MMPs and thereby regulate net proteolytic activity. However, there does not appear to be a concomitant increase in myocardial TIMPs during the LV remodeling process and progression to CHF. This disparity between MMP and TIMP levels favors a persistent MMP activation state within the myocardium and likely contributes to the LV remodeling process in the setting of developing CHF. The elucidation of upstream signaling mechanisms that contribute to the selective induction of MMP species within the myocardium as well as strategies to normalize the balance between MMPs and TIMPs may yield some therapeutic strategies by which to control myocardial extracellular remodeling and thereby slow the progression of the CHF process.     

Novel approaches to retard ventricular remodeling in heart failure

While the etiologies of congestive heart failure (CHF) are diverse, a common event in the progression of this disease process is LV remodeling, increased wall stress, and subsequent pump dysfunction. Therapeutic approaches for CHF have been focused upon reducing LV afterload through vasodilator therapy, or by blocking/interrupting the effects of neurohormonal stimuli. However, another therapeutic approach would be to directly intervene in the LV remodeling process with CHF. An important determinant in the maintenance of myocyte shape, alignment and transduction of myocyte shortening into an overall ejection is the structural support provided by the fibrillar collagen matrix. As in most tissue remodeling processes, LV myocardial remodeling with CHF is accompanied by changes in the structure and composition of the collagen matrix. Matrix metalloproteinases (MMPs) are an endogenous family of zinc-dependent enzymes which have been identified to be responsible for matrix remodeling and alterations in MMP expression and activity have been identified in clinical and animal models of CHF. Moreover, alterations in the tissue inhibitors of MMPs (TIMPs) have also been identified to occur in the end-stage CHF myocardium. Thus, it is very likely that increased MMP activity and reduced inhibitory control of the TIMPs contribute to the LV remodeling process with CHF. A number of bioactive peptides and cytokines influence MMP and TIMP expression and activity. In addition, pharmacologically active MMP inhibitors have been synthesized and are currently under study. Accordingly, the control of MMP and TIMP expression and activity within the failing myocardium represents a new and potentially significant therapeutic target for CHF.     

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.     

Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective

A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. Recent clinical and experimental studies have noted that increased release of tumor necrosis factor alpha (TNF-alpha) can contribute to LV myocardial remodeling. Experimental studies have noted that the induction of TNF-alpha can result in LV dilation and proceed to LV pump dysfunction. The biological effects of TNF-alpha are mediated through TNF receptors that are present on all nucleated cells in the heart. TNF receptor activation can induce a number of cellular and molecular events which contribute to LV remodeling in CHF, and include changes in myocyte size and viability and alterations in myocardial structure/composition. In vitro studies have demonstrated that TNF receptor activation can cause the induction of a proteolytic system. This proteolytic system, the matrix metalloproteinases (MMPs), is upregulated in models of LV dysfunction and possesses the capacity to degrade a wide variety of extracellular matrix components. Therefore, one pathway by which TNF-alpha can influence LV myocardial remodeling is through the induction of a specific portfolio of MMP species. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling will provide new insight into this disease process and future therapeutic modalities.     

Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target

A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.     

Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure?

Increased activity of matrix metalloproteinases (MMPs) has been implicated in numerous disease processes, including tumor growth and metastasis, arthritis, and periodontal disease. It is now becoming increasingly clear that extracellular matrix degradation by MMPs is also involved in the pathogenesis of cardiovascular disease, including atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction. Administration of synthetic MMP inhibitors in experimental animal models of these cardiovascular diseases significantly inhibits the progression of, respectively, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump dysfunction, and infarct healing. This review focuses on the role of MMPs in cardiovascular disease, in particular myocardial infarction and the subsequent progression to heart failure. MMPs, which are present in the myocardium and capable of degrading all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. The recent finding that acute pharmacological inhibition of MMPs or deficiency in MMP-9 attenuates left ventricular dilatation in the infarcted mouse heart led to the proposal that MMP inhibitors could be used as a potential therapy for patients at risk for the development of heart failure after myocardial infarction. Although these promising results encourage the design of clinical trials with MMP inhibitors, there are still several unresolved issues. This review describes the biology of MMPs and discusses new insights into the role of MMPs in several cardiovascular diseases. Attention will be paid to the central role of the plasminogen system as an important activator of MMPs in the remodeling process after myocardial infarction. Finally, we speculate on the use of MMP inhibitors as potential therapy for heart failure.     

Myocardial Remodeling in Viral Heart Disease: Possible Interactions Between Inflammatory Mediators and MMP-TIMP System

Matrix metalloproteinases (MMP), a family of proteases, are involved in the degradation of extracellular matrix proteins and hence in the determination of interstitial architecture. In the heart, MMPs have been found to play a significant role in the development of myocardial remodeling and congestive heart failure. Tissue inhibitors of matrix metalloproteinases (TIMPs) represent a family of proteins which are known to regulate the expression and activity of MMPs. TIMPs are endogenous physiological inhibitors of MMPs and their concomitant downregulation in heart failure suggests the existence of a critical balance between MMPs and TIMPs in the normal maintenance of myocardial interstitial homeostasis. In addition, cytokines regulate expression of both MMPs and TIMPs besides eliciting a direct effect on myocardial cell function. Therefore, myocardial inflammation may also contribute to the development of cardiac remodeling along with other stimuli like mechanical stress and humoral factors. Viral myocarditis, a predisposing factor for dilated cardiomyopathy, is a condition in which extent of intramyocardial inflammation is thought to determine the progression of disease. Inflammatory events in the heart following viral infection are speculated to be responsible for the transition of myocarditis to dilated cardiomyopathy. In viral myocarditis and other inflammatory heart diseases, the inflammatory cells and their battery of cytokines may also alter the myocardial MMP-TIMP system and eventually lead to dilation of the heart and ventricular dysfunction. The objective of this review is to present an overall picture of the inflammatory phase in viral myocarditis and discuss the possible interactions between inflammation and myocardial MMP profiles which may lead to the evolution of dilated cardiomyopathy.     

Matrix metalloproteinase inhibition and the prevention of heart failure

Matrix metalloproteinases (MMPs) are members of a large family of enzymes that can degrade extracellular matrix as well as other molecules. MMPs participate in a broad variety of normal and pathologic states, and recent evidence implicates the MMP family as potential mediators of cardiac dilation and progression to heart failure. This evidence is based on several lines of investigation. First, members of the MMP family are overexpressed in the myocardium in both experimental and human myocardial injury, infarction, and dilation. Second, overexpression of at least one MMP (MMP-1) in the hearts of transgenic mice can cause cardiac hypertrophy, dilation, and systolic dysfunction. Third, studies from multiple laboratories with different experimental models indicate that inhibition of MMPs through small molecules or gene transfer of endogenous inhibitors favorably affects cardiac remodeling. Fourth, targeted deletion of MMP genes in mice attenuates cardiac remodeling. These compelling results appear to fulfill Koch's Postulates as they may be applied to a non-infectious mediator of a disease, and thus current evidence supports MMP inhibition as a promising strategy for preventing heart failure. However, the crucial question of whether MMP inhibition benefits long-term left ventricular function and survival should be answered.     

Matrix modulation and heart failure: new concepts question old beliefs

PURPOSE OF REVIEW: Myocardial remodeling is a complex process involving several molecular and cellular factors. Extracellular matrix has been implicated in the remodeling process. Historically, the myocardial extracellular matrix was thought to serve solely as a means to align cells and provide structure to the tissue. Although this is one of its important functions, evidence suggests that the extracellular matrix plays a complex and divergent role in influencing cell behavior. This paper characterizes some of the notable studies on this dynamic entity and on adverse myocardial remodeling that have been published over the past year, which further question the belief that the extracellular matrix is a static structure. RECENT FINDINGS: Progress has been made in understanding how the extracellular matrix is operative in the three major conditions (myocardial infarction, left ventricular hypertrophy due to overload, and dilated cardiomyopathy) that involve myocardial remodeling. Several studies have examined plasma profiles of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases following myocardial infarction and during left ventricular hypertrophy as surrogate markers of remodeling/remodeled myocardium. It has been demonstrated that bioactive signaling molecules and growth factors, proteases, and structural proteins influence cell-matrix interactions in the context of left ventricular hypertrophy. Finally, studies that either removed or added tissue inhibitor of metalloproteinases species in the myocardium demonstrated the importance of this regulatory protein in the remodeling process. SUMMARY: Understanding the cellular and molecular triggers that in turn give rise to changes in the extracellular matrix could provide opportunities to modify the remodeling process.     

Mechanisms of extracellular matrix remodeling in dilated cardiomyopathy

BACKGROUND: The mechanisms underlying myocardial remodeling during heart failure have historically been attributed as the consequence of intrinsic changes in cardiac myocytes. Nevertheless, over the last several years, it has become increasingly evident that disruption of extracellular matrix (ECM) homeostasis is also a deciding factor for the progression of myocardial failure. PATHOGENETIC MECHANISMS: Collagens, the chief components of extracellular matrix, are a tightly regulated family of proteins that determine the structural and functional integrity of heart. Synthesis of collagens is regulated at the cellular level while deposition of these proteins depend on a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). Infiltrating inflammatory cells are major producers of MMPs though myocardial cells are also found to synthesize these proteolytic enzymes. However, immune-mediated regulation of myocardial collagen synthesis and deposition during myocardial inflammation remains poorly understood. It seems likely that a paracrine/autorine effect of a repertoire of cytokines on inflammatory cells and myocardial cells may lead to an imbalance in myocardial MMP/TIMP ratio resulting, eventually, in altered myocardial extracellular matrix architecture and contribute significantly to the development of left ventricular remodeling and dysfunction. CONCLUSION: Attempts to delineate the cross-talk between immune cells, myocardial cells and extracellular matrix are important as chronic myocardial inflammation is documented in about 50% of patients with dilated cardiomyopathy.     

Matrix metalloproteinases and coronary artery diseases

Matrix metalloproteinases (MMPs) play an important role in cardiovascular remodeling by degrading the extracellular matrix. Enhanced MMP expression has been detected in the atherosclerotic plaque, and activation of MMPs appears to be involved in the vulnerability of the plaque. Circulating MMP levels are elevated in patients with acute myocardial infarction and unstable angina. Increased MMP expression is also observed after coronary angioplasty, which is related to late loss index after the procedure. These observations suggest that MMP expression may be not only related to instability of the plaque, but also to the formation of restenotic lesions. The development of therapeutic drugs targeted specifically against MMPs may be useful in the prevention of atherosclerotic lesion development, plaque rupture, and restenosis.     

MMP Induction and Inhibition in Myocardial Infarction

Short-term survival following a myocardial infarction (MI) has greatly improved, due in part to therapeutic interventions that restore blood flow and limit infarct size. The increased incidence of infarct-stimulated left ventricular (LV) remodeling that advances to congestive heart failure (CHF), however, is a significant long-term complication and a leading cause of mortality. Changes to ECM structure and function are primary components of LV remodeling and are precipitated by the early increase in infarct area collagen levels that replace necrotic myocytes and form a scar. ECM turnover is coordinated through the synthesis and degradation of ECM and non-ECM components, particularly the matrix metalloproteinases (MMP), a family of proteolytic enzymes that cleave ECM. MMPs have multiple roles in remodeling events that lead to LV dilation. The inhibition or targeted deletion of specific MMPs attenuates LV remodeling events post-MI. MMP inhibitors have been used in animal models to delineate LV remodeling mechanisms and to evaluate the pharmacologic potential of targeting the ECM to modify LV remodeling post-MI. This review summarizes the current knowledge and limitations of MMP inhibition in the post-MI myocardium.     

Matrix Metalloproteinases: Pathways of Induction by Bioactive Molecules

Regulation of the extracellular matrix (ECM) is an important therapeutic target that can potentially attenuate the adverse ventricular remodeling seen in the progression of heart failure. Matrix metalloproteinases (MMPs) degrade numerous ECM proteins. Importantly, the activation of MMPs and their endogenous inhibitors (TIMPs) are associated with ventricular remodeling. Bioactive-molecules (vasoactive peptides) become activated in proportion to the magnitude of heart failure and have been demonstrated to affect directly collagen degradation as well as collagen synthesis in the myocardium. Pro-fibrotic factors such as norepinephrine, angiotensin II, and endothelin-1 stimulate fibrosis by modulating collagen synthesis and MMP/TIMP activity. Antagonism of these bioactive-molecules has produced improved hemodynamic performance concomitant with modulation of MMP/TIMP activity and in association with reverse remodeling. The natriuretic peptides and nitric oxide, both of which function via the second messenger cGMP, demonstrate anti-fibrotic actions by inhibiting collagen synthesis and by stimulating MMP activity. Furthermore, bioactive-molecules along with certain cytokines are reported to amplify MMP activity, suggesting that different signaling systems work together to modulate ECM turnover. Taken together, the evidence supports an important functional role for bioactive-molecules in the regulation of ECM turnover and suggests that pharmacological intervention at the level of such bioactive molecules may provide potential therapeutic strategies for attenuation of the adverse ventricular remodeling associated with the progression of heart failure.     

Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats

OBJECTIVES: We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling. BACKGROUND: Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated. METHODS: In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities. RESULTS: No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo. CONCLUSIONS: Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.     

Disruptions and detours in the myocardial matrix highway and heart failure

Myocardial remodeling invariably occurs in congestive heart failure (CHF) and is a response to a prolonged cardiovascular stress, which is characterized by a cascade of compensatory structural events. Remodeling of the myocardial interstitium occurs in CHF and likely contributes to the progression of the remodeling process. The myocardial matrix can be considered a biological highway in which a large amount of signaling proteins and structural proteins are being moved within the interstitium, entering and exiting the interstitial space, and docking to cellular components. The rates at which these events occur can accelerate and decelerate depending on the particular cardiac disease state and thereby can alter the course of myocardial remodeling. Once considered merely a scaffolding to align cells, the matrix plays a complex and divergent role in influencing cell behavior. For example, the matrix has a functional role in cell migration, proliferation, adhesion, and cell-to-cell signaling. In light of this, the myocardial matrix should not be regarded as merely a static structure, but rather, as a complex system of dynamic interactions between matrix molecules, signaling proteins, and transmembrane proteins. Specific strategies that are targeted at modifying activity along this matrix highway will likely alter the course of myocardial remodeling and heart failure.     

Matrix Metalloproteinases in Atherothrombosis

The metalloproteinases (MMPs, matrixins) are zinc-containing endopeptidases involved in the metabolism of extracellular matrix as well as in the cleavage of other proteins. The MMP family currently consists of 28 enzymes with somewhat different activities. The members are in part categorized into groups according to either structure or preferred substrates and referred to as collagenases, gelatinases, stromelysins, matrilysins, and membrane-bound MMPs. The proteinase activities exerted by 11 of the 28 MMPs have been implicated in some of the biologic processes associated with atherosclerosis and its ischemic clinical manifestations such as myocardial infarction and stroke. For example, several of the MMPs are locally expressed within human atherosclerotic lesions. However, association studies of subclinical atherosclerosis have generated contradictory results in the role of MMP activities. In addition, circulating MMP levels as well as genetic variations within the genes encoding the different enzymes have been associated with both an increased and decreased cardiovascular risk. Finally, experimental studies of hyperlipemic mice and vascular injury have suggested some of the MMPs function as modulators of atherogenesis, vascular remodeling, and plaque rupture.     

Matrix metalloproteinase inhibition during the development of congestive heart failure : effects on left ventricular dimensions and function.

The development of congestive heart failure (CHF) is associated with left ventricle (LV) dilation and myocardial remodeling. The matrix metalloproteinases (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. Whether increased MMP activity directly contributes to the LV remodeling with CHF remains unknown. Accordingly, this study examined the effects of chronic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi, rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CHF, LV fractional shortening was reduced (19+/-1 versus 45+/-1%), and end-diastolic dimension increased (5.67+/-0.11 versus 3.55+/-0.05 cm), compared with baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shortening increased (25+/-2%) and the end-diastolic dimension was reduced (4.92+/-0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and was significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte length was increased with pacing CHF compared with controls (180+/-3 versus 125+/-4 microm, P<0.05) and was reduced in the CHF/MMPi group (169+/-4 microm, P<0.05). Basal-state myocyte shortening velocity was reduced with pacing CHF compared with controls (33+/-2 versus 66+/-1 microm/s, P<0.05) and was unchanged in the CHF/MMPi group (31+/-2 microm/s). Using an ex vivo assay system, myocardial MMP activity was increased with pacing CHF and was reduced with chronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dilation and reduced wall stress. These results suggest that increased myocardial MMP activity contributes to LV myocardial remodeling in developing CHF.     

Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy

Myocardial fibrosis caused by maladaptive extracellular matrix (ECM) remodeling is implicated in the dysfunction of the failing heart. Matrix metalloproteinases (MMPs) regulate ECM remodeling, and are regulated by cytokines. Transgenic mice with cardiac-specific overexpression of tumor necrosis factor alpha (TNF-alpha) (TNF1.6) develop heart failure. We hypothesized that modulation of TNF-alpha and/or MMP activity might alter the myocardial ECM remodeling process and the development of heart failure. To test this hypothesis, we took advantage of the TNF1.6 mice and studied soluble and total collagens and collagen type profiling by using hydroxyproline quantification, Sircol collagen assay, Northern blot analysis, and immunohistochemistry and studied myocardial function by using echocardiography. Progressive ventricular hypertrophy and dilation in the TNF1.6 mice were accompanied by a significant increase in MMP-2 and MMP-9 activity, an increase in collagen synthesis, deposition, and denaturation, and a decrease in undenatured collagens. In young TNF1.6 mice, these changes in the ECM were associated with marked diastolic dysfunction as demonstrated by significantly reduced transmitral Doppler echocardiographic E/A wave ratio. Anti-TNF-alpha treatment with adenoviral vector expressing soluble TNF-alpha receptor type I attenuated both MMP-2 and MMP-9 activity, prevented further collagen synthesis, deposition and denaturation, and preserved myocardial diastolic function in young, but not old, TNF1.6 mice. The results suggest a critical role of TNF-alpha and MMPs in myocardial matrix remodeling and functional regulation and support the hypothesis that both TNF-alpha and MMPs may serve as potential therapeutic targets in the treatment of heart failure.     

Matrix metalloproteinase therapy in heart failure

Opinion statement  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.