The Key Role of Mast Cells in the Evolution to Congestive Heart Failure

Abstract

Mast cells are multifunctional cells containing various mediators such as cytokines, proteases and histamine. They are found in the human heart, and have been implicated in ventricular hypertrophy and heart failure. However, their roles in pathogenesis of these disorders are unknown. To clarify the roles of mast cells, cultured cardiomyocytes from neonatal rats were incubated with mast cell granules (MCGs) for 24 h. We found that mast cells cause apoptosis of cardiomyocytes and proliferation of other intramyocardial cells. These observations suggest that mast cell chymase plays a role in the progression of heart failure, since loss of cardiomyocytes and proliferation of non-myocardial cells both amplify its pathophysiology. Therefore, we examined the role of mast cells in the progression of heart failure, using mast cell-deficient WBB6F1-W/W^v mice and their congenic contorls (WT mice). Systolic pressure overload was produced by banding of the abdominal aorta, and cardiac function was monitored by serial echocardiography over 15 weeks. Left ventricular performance gradually decreased in WT mice, and pulmonary congestion became apparent at 15 weeks (decompensated hypertrophy). In contrast, decompensation of cardiac function did not occur in W/W^v mice; left ventricular performance was preserved thoughout, and pulmonary congestion was not observed. Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/Wv mice. Treatment with tranilast, a mast cell-stabilizing agent, also prevented the evolution from compensated hypertrophy to heart failure. These observations suggest that mast cells playa critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure.