Molecular basis of electrical remodeling in atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is ofte n associated with other cardiovascular disorders and diseases. AF can lead to thromboembolism, reduced left ventricular function and stroke, and, impo rtantly, it is independently associated with increased mortality. AF is a p rogressive disease; numerous lines of evidence suggest that disease progres sion results from cumulative electrophysiological and structural remodeling of the atria. There is considerable interest in delineating the molecular mechanisms involved in the remodeling that occurs in the atria of patients with AF. Cellular electrophysiological studies have revealed marked reducti ons in the densities of the L-type voltage-gated Ca2+ current, I-Ca,I-L, th e transient outward K+ current, I-TO, and the ultrarapid delayed rectifier K+ current, I-Kur, in atrial myocytes from patients in chronic AF. Similar (but not identical) changes in currents are evident in myocytes isolated fr om a canine model of AF and, in this case, the changes in currents are corr elated with reduced expression of the underlying channel forming subunits. In both human and canine AF, the reduction in I-Ca,I-L, appears to be suffi cient to explain the observed decreases in action potential duration and ef fective refractory period that are characteristic features of the remodeled atria. In addition, expression of the sarcoplasmic reticulum Ca2+ ATPase i s reduced, suggesting that calcium cycling is affected in AF. These recent studies suggest that calcium overload and perturbations in calcium handling play prominent roles in AF-induced atrial remodeling. Although considerabl e progress has been made, further studies focused on defining the detailed structural, cellular and molecular changes that accompany the different sta ges of AF in humans, as well as in animal models of AF, are clearly warrant ed. It is anticipated that molecular insights gleaned from these studies wi ll facilitate the development of improved therapeutic approaches to treat A F and to prevent the progression of the arrhythmia. (C) 2000 Academic Press .