These opposite findings could be explained by the different timing of the drug administration in relation to the onset of the arrhythmia. It could be that verapamil may prevent the electrical remodeling when given before or shortly after the onset of high atrial rates (rapid pacing or AF), but it is totally ineffective or even has a paradoxic worsening effect when given after high atrial rates have already been established and electrical (and possibly structural) remodeling is already present. In support of this hypothesis, Ramanna et al. (10) observed that in patients with chronic AF, early infusion of verapamil determined a shortening of the mean fibrillatory interval, an index of the local refractory period, whereas Duytschaever et al. (11), in a goat model of paroxysmal AF, observed that verapamil infusion shortened the AF cycle length and changed paroxysmal into chronic AF when given intravenously after 24 h of electrically maintained AF. Recently, Sato et al. (29), when administering oral verapamil to patients with chronic AF, found no difference in their atrial refractory periods after cardioversion, as compared with patients in washout. The recovery from electrical remodeling was indeed delayed in patients taking verapamil. On the basis of these results, it is conceivable that verapamil could have different biochemical effects on high rate–activated atrial cells in relation to the timing of its administration. When administered before high rate cell stimulation, the drug could prevent calcium overload and the consequent reduction of ICa. This effect probably outweighs the ICa reduction because of the direct effect of the drug on sarcolemmal L-type calcium channels (30), and thus prevents ERP shortening. In contrast, when electrical remodeling has already occurred, verapamil could not totally reverse the calcium overload, and the prevalent effect of the drug could be a further reduction of ICa, owing to the direct action of verapamil on the L-type calcium channels. This leads to a further shortening of the plateau phase of the monophasic action potential duration and, hence, of refractoriness. Moreover, it is known that although short-lasting high rate depolarization shortens ERPs by direct Ca2+-induced ICa inhibition (31), in patients with long-lasting AF, a further contribution to persistent ERP shortening is also caused by a decrease in messenger ribonucleic acid levels of the L-type calcium channels, leading to downregulation of the channels’ density (32). In this case, a more marked effect on repolarization could be expected, because there is a direct drug-mediated effect of ICa on a reduced number of L-type channels.