Abstract 9180: HMG-CoA Reductase Inhibitor Stabilizes Mast Cells and Attenuates Atrial Fibrillation in Stressed Hearts

Abstract

Atrial fibrillation (AF) is a common arrhythmia, which increases the risk of stroke and heart failure. We previously reported that mast cells play a pathogenic role in atrial fibrosis and AF inducibility in transverse aortic constriction (TAC)-operated mice. On the other hand, it has been reported that treatment with HMG-CoA reductase inhibitors significantly decreased the incidence of postoperative AF after cardiac surgery. To explore the potential use of HMG-CoA reductase inhibitors in the upstream therapy for AF, we investigated whether pitavastatin could stabilize mast cells and thereby prevent the occurrence of AF in TAC-operated mice. Pressure overload induced interstitial fibrosis in atrium, and electrical stimulation on atrium evoked AF under Langendorff perfusion. However, treatment with pitavastatin (3 mg/kg/day) remarkably attenuated both atrial fibrosis and AF inducibility in pressure-overloaded mice. In addition, pressure overload induced mast cell degranulation and macrophage infilatration in atrium, which was associated with increased mRNA levels of MCP-1, IL-6, IFN-γ, TNF-α and PDGF-A. Notably, activation of mast cells and macrophages, as well as up-regulations of these inflammatory cytokines and growth factors, in atrium of TAC-operated mice was almost completely inhibited by pitavastatin treatment. Endothelin-1, known as potent mast cell activator, is up-regulated in atrium after TAC operation, and ET-1-induced degranulation in mouse peritoneal cavity-derived mast cells was significantly inhibited by treatment with pitavastatin (5 μM). These results suggest that pitavastatin suppresses mast cell activation both in vitro and in vivo, and thereby alleviates atrial fibrosis and AF inducibility through inhibition of cytokine production and macrophage infiltration in atrium of pressure-overloaded mice.