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The natural history of atrial fibrillation (AF) is characterized by a gradual worsening with time. The recent finding that AF itself produces changes in atrial function and structure has provided a possible explanation for the progressive nature of this arrhythmia. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to an increase in stability of AF. However, 'domestication of AF' must also depend on a 'second factor' since the persistence of AF continues to increase after electrical remodeling has been completed. Atrial contractile remodeling (loss of contractility) leads to a reduced atrial transport function after cardioversion of AF. An important clinical consequence is that during several days after restoration of sinus rhythm, the risk of atrial thrombus formation is still high. In addition, the reduction of atrial contractility during AF may enhance atrial dilatation which may add to the persistence of AF. Tachycardia-induced structural remodeling takes place in a different time domain (weeks to months). Myolysis probably contributes to the loss of atrial contractile force. Although it might explain the loss of efficacy of pharmacological cardioversion and the development of permanent AF, the role of structural remodeling in the progression of AF is still unclear. Atrial structural remodeling also occurs as a result of heart failure and other underlying cardiovascular diseases. The associated atrial fibrosis might explain intra-atrial conduction disturbances and the susceptibility for AF. Thus, both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate. New strategies for prevention and termination of AF should be build on our knowledge of the mechanisms and time course of AF-induced atrial remodeling.

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The disclosure forms of the authors and reviewers are available on the ESC website www.escardio.org/guidelines † Representing the European Association for Cardio-Thoracic Surgery (EACTS). Other ESC entities having participated in the development of this document:.

Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological alterations promoting AF have been studied extensively in animal models. Atrial tachycardia or AF itself shortens atrial refractoriness and causes loss of atrial contractility. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate a variety of signaling pathways leading to histological changes in the atria including myocyte hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix including tissue fibrosis. These changes in electrical, contractile, and structural properties of the atria have been called "atrial remodeling." The resulting electrophysiological substrate is characterized by shortening of atrial refractoriness and reentrant wavelength or by local conduction heterogeneities caused by disruption of electrical interconnections between muscle bundles. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF. Many of these alterations also occur in patients with or at risk for AF, although the direct demonstration of these mechanisms is sometimes challenging. The diversity of etiological factors and electrophysiological mechanisms promoting AF in humans hampers the development of more effective therapy of AF. This review aims to give a translational overview on the biological basis of atrial remodeling and the proarrhythmic mechanisms involved in the fibrillation process. We pay attention to translation of pathophysiological insights gained from in vitro experiments and animal models to patients. Also, suggestions for future research objectives and therapeutical implications are discussed.

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