Protection from adverse myocardial remodeling secondary to chronic volume overload in mast cell deficient rats

Mast cells have diverse roles throughout the body as evidenced by their heterogeneous nature. In the heart, cardiac mast cells have been implicated in left ventricular (LV) remodeling in response to elevated myocardial stress. Accordingly, the purpose of this study was to use mast cell deficient rats (Ws/Ws) to delineate the interaction between cardiac mast cell activation and LV remodeling. LV matrix metalloproteinase (MMP) activity, fibrillar collagen, TNF-α levels, and LV diameter were compared in Ws/Ws and wild type (WT) rats subjected to 5 d (n = 3/group) and 8 weeks (n = 4/group) of aortocaval fistula-induced volume overload. In contrast to attenuation of myocardial remodeling in the Ws/Ws group: 1) MMP-2 activity was significantly increased in the WT group at 5 days; 2) there was marked degradation of the extracellular collagen matrix in WT at 5 days and 8 weeks; 3) the percent increase in LV diameter from baseline was significantly greater in WT at 2, 4, 6, and 8 weeks post-fistula; and 4) myocardial TNF-α levels were markedly elevated in the WT group at 5 days post-fistula. These results underscore the importance of cardiac mast cells in mediating MMP activation, collagen degradation and LV dilatation and suggest that mast cell-derived TNF-α plays a role in early myocardial remodeling.