AF mechanisms

Overview of mechanisms of AF. Four different positive-feedback loops are proposed as the main driving forces for the atrial remodeling process. Enhanced Ca²+ loading during AF is believed to underlie most of the cellular proarrhythmic mechanisms (trigger loop). The main process in the electrical loop is an altered contribution of ion channels to the action potential configuration that protects atrial myocytes against excessive Ca²+ loading. Abbreviation of the action potential facilitates re-entry and thereby promotes AF. In the structural loop, chronic atrial stretch activates numerous signaling cascades that produce alterations of the extracellular matrix and conduction disturbances, also facilitating re-entrant mechanisms. The main changes of the contractile properties of the heart are loss of atrial contractility which increases atrial compliance and the development of a ventricular tachycardiomyopathy, both of which increase stretch in the atrial wall. The circular positive-feedback enhancement of these pathophysiological changes explains the general tendency of AF to become more stable with time. It should be noted that the different loops are interconnected by mechanisms that are part of more than one loop. For example, increased Ca²+ loading enhances trigger activity (trigger loop) and also results in a change in the ion channel population and activity (electrical loop). Re-entrant mechanisms are promoted by both shortening of refractoriness (electrical loop) as well as by conduction disturbances resulting from tissue fibrosis (structural loop). Like in a system of meshing gear wheels, one loop will drive the other, leading to progression of the arrhythmia. However, the proposed system of gear wheels does not start to move spontaneously. Structural heart diseases, arrhythmias, aging, or inherited diseases are required to initiate movement of one or more of these wheels. When the pathophysiological alterations eventually reach a certain threshold, AF will ensue.