Over the last decade, remarkable progress has been made in the field of atrial fibrillation (AF) pathophysiology and management. There is no doubt that radiofrequency catheter ablation therapy improves the quality of life and left ventricular function in patients with symptomatic AF by improving the maintenance of sinus rhythm. 1 A new antiarrhythmic agent, dronedarone, was recently shown to reduce the composite outcome of cardiovascular hospitalization and death in patients with AF. 2 Moreover, novel approaches such as the dominant frequency (DF) analysis of atrial electrograms have offered clinicians a better insight into the pathogenesis of AF. 3 Despite these advancements, longterm maintenance of sinus rhythm is challenging, and persistent or permanent AF still develops in many patients. In these cases, control of the ventricular rate has an essential role in alleviating the symptoms and preventing the development of tachycardia-induced cardiomyopathy. Spectral analysis of atrial recordings increasingly has been used to detect areas with high atrial activation rate during AF. The main benefit of frequency domain analysis is that it can be applied to the complex electrograms of AF more easily than time domain measurements. 3 Experimental and clinical studies indicate that the DF sites within the pulmonary veins (PV) have an important role in the initiation and maintenance of paroxysmal AF. 4,5 Furthermore, it has been postulated that DF mapping can be used to guide rapid identification of extrapulmonary sites that drive AF. 6 In this issue, Kushiyama et al 7 report the results of a study that evaluated the effects of verapamil on regional distribution of DFs in the PVs and atria in 43 patients undergoing catheter ablation of paroxysmal AF. They found that the highest DF was localized in the PVs and showed that there was a substantial PV-to-atria DF gradient at baseline. These findings are in agreement with previous studies indicating that the PVs are the main drivers of paroxysmal AF. 4,5 It is well established that beta-blockers, calcium channel antagonists, and digitalis slow ventricular rate, but much fewer data are available on their effect on atrial arrhythmogenesis. Verapamil is a nondihydropyridine calcium channel antagonist with potent negative chronodropic and dromodropic effects. Due to its use-dependent dromodropic action, verapamil is highly effective in controlling rapid ventricular rate in AF, but has less effect on atrioventricular (AV) nodal conduction at a normal rate. Kushiyama et al 7 showed that verapamil caused variable changes in the PV excitation. The maximum PV DF increased in 65% of the patients and decreased in the remaining 35%. In contrast, verapamil consistently increased the DFs in all of the atrial recording sites. As a result of these tissue-specific effects, verapamil eliminated the PV-to-atria DF gradient. According to the investigators, this is attributable to regional heterogeneities of action potential morphology and ionic currents responsible for the repolarization (e.g., I CaL ) in the PV myocardial muscle sleeves and atria rather than to a reflex increase in sympathetic tone in response to a reduction in blood pressure. Prior studies indicate that the extrapulmonary DF areas and the absence of the PV-to-atria frequency gradient can be used to identify additional ablation targets. For example, Lin et al 6 have shown that the DF shifts to the right atrium when AF is initiated in the superior vena cava. Sanders et al 5 reported that termination of permanent AF requires ablation of extrapulmonary high-frequency sites in addition to PV isolation. Hence, it is tempting to speculate that ablation of the verapamil-induced atrial high-frequency areas may improve the long-term efficacy of catheter ablation of paroxysmal AF. The results of Kushiyama et al 7 are also important with regard to rate control of AF because they raise the possibility that verapamil may provoke paroxysmal AF by creating new high-frequency sources in the atria. In keeping with this, verapamil facilitated the induction of sustained AF. That is, in all of the 6 patients with no inducible AF at baseline, sustained AF was easily induced after verapamil by burst pacing from the coronary sinus. These findings are consistent with experimental data indicating that verapamil promotes maintenance of AF by shortening the atrial refractory period and AF cycle length and enhancing reentrant activity in the atria. 8 In lieu of these data, the usefulness of verapamil for ventricular rate control in patients with paroxysmal AF may be limited by its profibrillatory effect in
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