Role of endo-epicardial dissociation of electrical activity and transmural conduction in the development of persistent atrial fibrillation.

Atrial fibrillation (AF) is an arrhythmia that occurs as a result of numerous pathophysiological processes in the atria. High rate, neurohumoral activation, aging and chronic stretch activate a variety of signaling pathways leading to electrical and structural remodeling. In particular, endomysial fibrosis within the epicardial layer, which also occurs as a result of AF itself, can disrupt electrical connections between muscle bundles. This leads to electrical dissociation not only within the epicardial layer, but also between the epicardial layer and the endocardial bundle network. Although the normal, healthy atrium has a complex 3-dimensional shape, differences in activation time between the epicardial layer and the underlying trabecular network in the atrial free walls are small, and the atrial walls essentially function as a 2-dimensional surface for propagating fibrillation waves. However, progressive structural remodeling leads to increased dissociation of epicardial and endocardial activation patterns. Epi-endocardial dissociation allows fibrillation waves to propagate between epicardium and endocardium, and become visible as 'breakthrough waves' that add to the overall complexity of fibrillatory conduction and thus to AF stability. This process greatly increases the effective surface area available to fibrillation waves and causes the atrial walls to behave as a 3-dimensional substrate. Computer models support that this behavior can increase AF stability. Under these conditions, ectopic activity originating from e.g. the pulmonary veins is likely to trigger longer episodes of AF. Experiments using simultaneous endo-epicardial mapping of AF suggest that disseminated, irregular and non-repetitive ectopic focal discharges might also occur during AF. The increasingly 3-dimensional character of AF as a result of structural remodeling lowers the responsiveness to antiarrhythmic compounds and ablation therapy, thus advocating early rhythm control strategies.