Atrial remodeling, fibrosis, and atrial fibrillation

Abstract

The fundamental mechanisms governing the perpetuation of atrial fibrillation (AF), the most common arrhythmia seen in clinical practice, are poorly understood, which explains in part why AF prevention and treatment remain suboptimal. Although some clinical parameters have been identified as predicting a transition from paroxysmal to persistent AF in some patients, the molecular, electrophysiological, and inflammation changes leading to such a progression have not been described in detail. Oxidative stress, atrial dilatation, calcium overload, inflammation, microRNAs, and myofibroblast activation are all thought to be involved in AF-induced atrial remodeling. However, it is unknown to what extent and at which time points such alterations influence the remodeling process that perpetuates AF. Here we postulate a working model that might open new pathways for future investigation into mechanisms of AF perpetuation. We start from the premise that the progression to AF perpetuation is the result of interplay among manifold signaling pathways with differing kinetics. Some such pathways have relatively fast kinetics (e.g., oxidative stress-mediated shortening of refractory period); others likely depend on molecular processes with slower kinetics (e.g., transcriptional changes in myocyte ion channel protein expression mediated through inflammation and fibroblast activation). We stress the need to fully understand the relationships among such pathways should one hope to identify novel, truly effective targets for AF therapy and prevention.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Working model for AF-induced remodeling and the substrate for AF perpetuation. Sustained high frequency excitation of the atria results in a complex series of pathophysiological events involving a large number of significant players. These include oxidative stress, calcium overload, atrial dilatation, inflammation and myofibroblast activation (Figure 1), all of which are likely to be involved in AF-induced atrial extracellular matrix (ECM) and electrical remodeling through transcriptionally mediated changes in both cardiac myocytes and fibroblasts.

Figure 2

ROS is elevated in the atria of sheep with PAF. A. ROS fluorescence in freshly dissociated sheep myocytes from left atrial appendage (LAA) and right atrial appendage (RAA), (40×). B. Relative ROS levels in sheep atrial myocytes from sham and PAF sheep (**p

Figure 3

Myofibroblasts induce structural remodeling of cardiomyocytes. Fluorescence microscopy by confocal laser scanning. Protein organization at the myofibroblast (MF)–cardiomyocyte (CM). CM contact sites of vinculin. In the CM, vinculin is reorganized in strands parallel to the direction of the strain imposed by the MF. Modified by permission from Driesen RB, Verheyen FK, Dispersyn GD, Thone F, Lenders MH, Ramaekers FC, Borgers M. Structural adaptation in adult rabbit ventricular myocytes: Influence of dynamic physical interaction with fibroblasts. Cell Biochem Biophys. 2006;44:119–128.