4246 Hypercoagulability promotes atrial fibrosis and fibrillation

Introduction: Atrial fibrillation (AF) induces a hypercoagulable state. Coagulation factors provoke pro-fibrotic, pro-hypertrophic, and pro-inflammatory responses in a variety of tissues by stimulation of protease-activated receptors. We studied whether hypercoagulability causes atrial fibrosis and promotes AF. Methods and Results: In mice with enhanced thrombin activity (TMpro/pro), inducibility of AF episodes induced by burst pacing was higher and duration of AF episodes was longer compared to wild type (episodes > 2s in 6 out of 10 versus 0 out of 10 in wild type). In isolated rat cardiac fibroblasts, thrombin (0.05units/ ml) enhanced the phosphorylation of the pro-fibrotic signaling molecules Akt and Erk, and increased expression of tumor growth factor β1 (2.7fold) and the pro-inflammatory factor MCP-1 (6.1fold). Thrombin also increased the incorporation of 3H-proline suggesting enhanced collagen synthesis by cardiac fibroblasts (2.5fold). All effects could be prevented by the direct thrombin inhibitor dabigatran. In 6 goats with persistent AF treated with fraxiparine, endomysial fibrosis and the complexity of the AF substrate were less pronounced compared to control animals (maximal conduction time 23.3±3.1ms in control versus 15.7±2.1ms in fraxiparine,