Atrial fibrillation (AF) is associated with alteration of atrial fiber orientation due to structural remodelling (1). An altered fiber orientation may lead to re-entry, a hallmark of AF.We show that a loss of the physiological fiber orientation can initiate re-entry.A 20 µm resolution rabbit atrial anatomical model was constructed based on contrast enhanced micro-CT imaging (2). The myofiber orientation was reconstructed and visualized using a novel fibre tracking approach (3). A computationally efficient Fenton-Karma excitation model for the rabbit atrial cell type was implemented. 1D strand models were used to estimate inter-cellular diffusion based on experimental longitudinal and transverse conduction velocities (CV) of 50 cm/s and 13 cm/s respectively (4, 5). The estimated diffusion constants were used in the 3D anisotropic model which was simulated using the mono-domain reaction diffusion equations. The SAN location was paced at a physiological pacing rate (2.8 Hz) for 10 beats using a stimulus of 10 pA/pF amplitude for 5 ms. BeatBox, a novel cardiac simulation environment, was used in all simulations.To elicit the effects of fiber orientation, computer simulations were conducted with a reducing amount of fiber orientation heterogeneity. This was accomplished by reducing the ratio of parallel and perpendicular diffusivities. Further simulations were conducted where a premature stimulus was applied at the SAN. The propensity to arrhythmia was evaluated by the formation of re-entrant scroll waves. As the Figure illustrates, under physiological anisotropy conditions, a rapid left atrial activation was followed by the right atrial activation. Excitation waves reached the AV border where they terminated. Upon reduction of heterogeneity, macro re-entry was seen to form. The activation of both atrial chambers was almost simultaneous.Fiber orientation is a mechanism for regulating atrial activation and its attenuation is proarrhythmic.