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Atrial fibrillation is the most common arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system contributes to the creation of atrial fibrillation substrates. Atrial electrophysiology is influenced differently by sympathetic and parasympathetic activation. Several strategies are available to modulate the complex interaction between the autonomic nervous system and the heart. However, different approaches target the problem differently making the prediction of arrhythmogenic and/or antiarrhythmic effects difficult. We discuss the role of the autonomic nervous system on the development of a substrate for atrial fibrillation and explore the potential antiarrhythmic and/or arrhythmogenic effect of modulation of the autonomic nervous system by renal sympathetic denervation, ganglionated plexi ablation, ganglion stellatum ablation, high thoracic epidural anesthesia, low-level vagal …