Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal

Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal. Physiol Rev 91: 265-325, 2011; doi: 10.1152/physrev.00031.2009.-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.