Amanda L. Chancey

Effects of Matrix Metalloproteinase Inhibition on Ventricular Remodeling Due to Volume Overload

Background—Left ventricular (LV) hypertrophy and dilatation are important compensatory responses to chronic volume overload. Although LV function is initially preserved by these responses, the continued structural remodeling of the myocardium ultimately becomes maladaptive, leading to the development of heart failure. We have shown previously that increased myocardial matrix metalloproteinase (MMP) activity precedes LV dilatation induced by a chronic volume overload. Accordingly, this study focused on the effects of MMP inhibition therapy (PD 166793, 1 mg · kg−1 · d−1) on LV size and function in a rat model of volume overload–induced heart failure. Methods and Results—Rats were divided into the following groups: treated and untreated infrarenal abdominal aortocaval fistula and treated and untreated sham-operated (control). LV weights of both fistula groups were increased above that of the control group (868±79 mg;P ≤0.001); LV weights in the treated fistula group, however, were lower than in the untreated fistula group at 8 weeks (1447±186 versus 1715±279 mg, respectively;P ≤0.012). The marked ventricular dilatation seen in the untreated fistula group was significantly diminished in the treated fistula group, although the increase in LV compliance was similar in both treated and untreated fistula hearts. Conclusions—MMP inhibition significantly attenuates the myocardial remodeling associated with chronic volume overload, as evidenced by prevention of dilatation, a marked reduction in LV hypertrophy, and preservation of ventricular function.

The Dynamic Interaction Between Matrix Metalloproteinase Activity and Adverse Myocardial Remodeling

The process of cardiac remodeling in response to cardiac injury and/or persistent elevations in wall stress generally relates to the progressive changes that occur in ventricular chamber dimensions and the various components of the myocardium, in particular the cardiomyocytes and the extracellular matrix. Volume overload, pressure overload or myocardial injury produces a sustained abnormal elevation in myocardial wall stress which initiates cardiac remodeling that frequently results in ventricular decompensation and heart failure. Regardless of the inciting cause, there appear to be three distinct phases to this process. In the initial phase, fibrillar collagen is partially degraded secondary to increased matrix metalloproteinase (MMP) activity. Following this, there is a chronic compensatory phase during which MMP activity and collagen concentration return to normal while cardiomyocyte size continues to progressively increase. The final phase is attained once the compensatory hypertrophic mechanisms are exhausted and is characterized by elevated MMP activity, marked ventricular dilatation and prominent fibrosis. Details of this progressive, dynamic remodeling process and its effect on ventricular function during chronic volume overload, chronic pressure overload and following myocardial infarction will be the focus of this article.

The Development of Myocardial Fibrosis in Transgenic Mice With Targeted Overexpression of Tumor Necrosis Factor Requires Mast Cell–Fibroblast Interactions

Background— Transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice) develop progressive myocardial fibrosis, diastolic dysfunction, and adverse cardiac remodeling. Insofar as tumor necrosis factor (TNF) does not directly stimulate fibroblast collagen synthesis, we asked whether TNF-induced fibrosis was mediated indirectly through interactions between mast cells and cardiac fibroblasts. Methods and Results— Cardiac mast cell number increased 2 to 3 fold (P<0.001) in MHCsTNF mice compared with littermate controls. Outcrossing MHCsTNF mice with mast cell–deficient (c-kit−/−) mice showed that the 11-fold increase (P<0.001) in collagen volume fraction in MHCsTNF/c-kit+/− mice was abrogated in MHCsTNF/c-kit−/− mice, and that the leftward shifted left ventricular pressure–volume curve in the MHCsTNF/c-kit+/− mice was normalized in the MHCsTNF/c-kit−/− hearts. Furthermore, the increase in transforming growth factor &bgr;1 and type I transforming growth factor &bgr; receptor messenger RNA levels was significantly (P=0.03, P=0.01, respectively) attenuated in MHCsTNF/c-kit−/− when compared with MHCsTNF/c-kit+/− mice. Coculture of fibroblasts with mast cells resulted in enhanced &agr;-smooth muscle actin expression, increased proliferation and collagen messenger RNA expression, and increased contraction of 3-dimensional collagen gels in MHCsTNF fibroblasts compared with littermate fibroblasts. The effects of mast cells were abrogated by type I transforming growth factor &bgr; receptor antagonist NP-40208. Conclusions— These results suggest that increased mast cell density with resultant mast cell–cardiac fibroblast cross-talk is required for the development of myocardial fibrosis in inflammatory cardiomyopathy. Cardiac fibroblasts exposed to sustained inflammatory signaling exhibit an increased repertoire of profibrotic phenotypic responses in response to mast cell mediators.

Role of Mast Cells in Cardiovascular Disease

Increased numbers of mast cells have been reported in human hearts with end-stage cardiomyopathy and in animal models of myocardial infarction, hypertension, and chronic volume overload secondary to mitral regurgitation and aortocaval fistula. Because of these observations, mast cells have been implicated in the pathophysiology of these cardiovascular disorders. Mast cells are known to store and release a variety of biologically active mediators, including numerous cytokines (e.g.,TNF-α and IL-6) and proteases (e.g., tryptase, chymase, and stromelysin), many of which are potentially involved in activating matrix metalloproteinases (MMPs). Accordingly, in this review, the potential role of cardiac mast cells in MMP activation, thereby causing fibrillar collagen degradation and adverse cardiac remodeling is considered. In particular, the following topics are contemplated: 1) the origin of increased cardiac mast cell density; 2) the functional consequences of cardiac mast cell degranulation; 3) the relationship between mast cell density and MMP activity; 4) the contribution of mast cell derived TNF-α to myocardial remodeling; 5) the effect of pharmacological prevention of mast cell degranulation on myocardial remodeling; 6) the effect of mast cells on fibroblast function; 7) a possible role of atrial natriuretic peptide in initiating the mast cell-MMP activation cascade; and 8) future research questions.

Cardiac Mast Cells as Mediators of Ventricular Remodeling

Mast cells are known to store and release a variety of biologically active mediators including TNF-α, and proteases such as tryptase and chymase. With cardiac chamber distension there is a release of atrial natriuretic peptide, which is known to cause mast cell degranulation (Figure 2). Secreted TNF-α tryptase and chymase are all capable of activating matrix metalloproteinases, which in turn are responsible for fibrillar collagen degradation. Since one of the roles of the extracellular collagen matrix is to maintain ventricular size and shape, its disruption results in adverse remodeling. Also secreted from the mast cell is a yet to be identified substance that stimulates the maturation of resident immature mast cells. Proof of mast cell involvement in these processes is provided by the use of mast cell membrane stabilizing compounds such as cromolyn sodium, which prevent mast cell degranulation. These drugs prevent the activation of MMPs, degradation of collagen, the increase in mast cell density, adverse ventricular remodeling, and the decrease in contractility as well as attenuate the morbidity/mortality associated with chronic volume overload. They are similarly efficacious in preventing the onset of heart failure in hearts subjected to chronic pressure overload. Finally, evidence is rapidly emerging which identifies mast cell-derived TNF-α and/or the downstream cytokine cascade it induces as a major contributor to adverse ventricular remodeling and associated contractile dysfunction.