Atrial fibrillation (AF), the most common sustained cardiac arrhythmia in clinical practice, is often associated with progressive dilatation and remodeling of the atria which constitute the substrate of the arrhythmia. This atrial remodeling is characterized by complex structural and function alterations of the atrial myocardium: short action potentials, heterogeneous refractory periods, dystrophic myocytes and interstitial fibrosis which act together to favor local conduction bloc, activation of ectopies and the forma¬tion of microreentries of the electrical excitation. However, the underlying mechanisms of the AF substrate are not yet fully understood. Beside alterations in myocytes excitability, fibrosis, myocytes hypertrophy and endothelial dysfunction are important features of the AF substrate. Atrial hemodynamic overload and local activation of the renin-angiotensin system is one well-established pathogenic factor. Thrombin that accumulates in dilated and fibrillating atria could be another important mediator of the myocardial structural alterations during AF. This peptide, by binding on its receptor PAR1, can modulate several signaling pathways regulating growth and survival of myocardial cells. Accumulation of epicardial adipose tissue too has been associated with the risk of AF while the underlying mechanisms are unknown. During the session, data will presented that could provide new clues to better understand how these pathogenic factors contribute to the formation of the AF substrate.