EDITORIAL COMMENT
The Pulmonary VeinsSpeedy Recoveries and Early Discharges*
Bradley P. Knight, MD, FACC*
Division of Cardiology, Department of Internal Medicine, University of Chicago, Chicago, Illinois.
* Reprint requests and correspondence: Dr. Bradley P. Knight, University of Chicago Hospitals, Center for Advanced Medicine, MC 9024, 5758 South Maryland Avenue, Chicago, Illinois 60637. (Email: bknight{at}medicine.bsd.uchicago.edu).
Atrial fibrillation (AF) often recurs immediately after electrical cardioversion. Figure 1
shows a rhythm strip recorded during an attempt at electrical cardioversion in a patient with persistent AF. A 200-J biphasic external shock restores sinus rhythm, but is followed by frequent atrial premature depolarizations (APDs) and an immediate recurrence of AF. The first APD conducts to the ventricle, the second blocks in the atrioventricular node, and the third reinitiates AF. What is the mechanism of an immediate recurrence of AF?
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Figure 1 A Rhythm Strip Showing an Immediate Recurrence of AF After Electrical Cardioversion
See the text for explanation. AF = atrial fibrillation; APD = atrial premature depolarization; Sinus = sinus rhythm.
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The phrase "AF begets AF" first appeared in the literature in 1995 in the title of an animal study published by Wijffels et al. (1) from Maastricht. In this study, an epicardial atrial pacemaker was permanently implanted in goats to artificially maintain AF by rapid atrial pacing. Induced episodes of AF caused temporary shortening of the atrial effective refractory periods (ERPs), a reversion of physiologic rate adaptation, and a propensity for longer subsequent episodes of AF. The atrial refractory periods eventually normalized, but the shortening persisted for a duration that was directly proportional to the duration of pacing. Similar observations were subsequently made in the electrophysiology laboratory in humans by Daoud et al. (2).
Shortening of atrial refractory periods promotes recurrent and longer episodes of AF ultimately leading to permanent AF. The mechanism underlying reversible shortening of atrial refractoriness after a brief episode of AF is probably related to transient intracellular calcium overload and a reduction of L-type calcium channels caused by rapid atrial rates. Longer episodes of AF may cause more permanent structural remodeling by mechanisms that include apoptosis and fibrosis.
The pulmonary veins (PVs) play a major role in the initiation and maintenance of AF (3). Their role appears to be greatest in patients with paroxysmal AF in the absence of structural heart disease. The importance of the PVs during AF may be explained by their distinctive electrophysiological properties. For example, it has been shown that PV myocytes resemble sinus nodal cells and that the refractoriness of the PVs in patients with AF is significantly shorter compared with that of patients without AF (4).
In this issue of the Journal, Rostock et al. (5) bring the work on short-term electrical remodeling in the atria to the PVs. The authors determined the relative effect of brief episodes of AF on the refractory period of the PVs compared with that of the remaining atria. At baseline, the ERP of the PVs was longer than those of the right and left atria. However, the degree of ERP shortening after a brief episode of pacing-induced AF was more prominent in the PVs compared with ERP shortening in the right and left atria. In addition, after an episode of AF, compared with baseline, conduction velocity was slower in the PVs, but not in the atria. This study has some limitations, including the absence of autonomic blockade and inclusion of patients without a history of AF. However, the data provide evidence that the electrophysiological behavior of the PVs differs from that of the atria and may further explain the dominant role that PVs play in patients with AF.
The authors further show that tachycardia-induced ERP shortening in the PVs may facilitate the initiation of AF. This relationship is consistent with and predicted by the widely accepted AF model of multiple wavelets of re-entry. In the present study of the PVs by Rostock et al. (5) and in previous studies of the atria (1,2), the delivery of an atrial extrastimulus, while attempting to measure the atrial ERP, is more likely to induce AF after an episode of AF compared with baseline. Using the same model of re-entry, shorter recovery times also translate into shorter re-entrant wavelengths, which permit more wavelets of re-entry within a given amount of tissue and make it less likely that the AF will extinguish. As well, nonunifiorm shortening may create an increase in regional variation in refractory periods, further promoting AF.
It is clear that both atrial and PV refractory periods shorten during AF. However, does this refractory period shortening explain why AF begets AF? Is it possible that electrical remodeling is just an epiphenomenon? An additional explanation for why an episode of AF leads to further AF is that the initial episode induces subsequent spontaneous ectopy that increases the likelihood of re-entry. In other words, the critical impact of an episode of AF may be more related to its increase in the number of triggers that induce AF rather than to its modification of the substrate. Calcium overload during atrial tachyarrhythmias not only shortens the refractory periods that foster re-entry, but also leads to spontaneous depolarizations. Honjo et al. (4) showed that PVs have the potential to generate spontaneous activity after an episode of tachycardia. After treatment with ryanodine, which induces calcium-independent calcium release from the sarcoplasmic reticulum, and after rapid atrial pacing, rabbit PVs were shown to develop spontaneous activity. Another line of evidence that suggests triggers may be more important than electrical remodeling comes from heart failure animal models. In these models, AF leads to persistent AF in the absence of significant shortening of atrial refractory periods, possibly due to an increase in triggered activity and delayed afterdepolarizations.
Perhaps an episode of AF increases the probability of subsequent episodes of AF neither by its effect on the atrial refractory period nor by its effect on the density of single atrial ectopic beats. Instead, AF may trigger bursts of PV tachycardia. The frequent ectopy seen on the rhythm strip shown in Figure 1 is commonly seen after cardioversion in patients who develop recurrent AF. An important question that remains inadequately explored is whether an APD at the onset of a recurrent episode of AF (Fig. 1) is initiating re-entry, much like an atrial extrastimulus in the electrophysiology laboratory, or whether the APD is just the first beat of a sustained rapid focal discharge. Clinically, when a patient with a history of idiopathic paroxysmal AF is undergoing an electrophysiology procedure, but has no spontaneous ectopy or AF during the procedure itself, a pacing-induced, self-terminating episode of AF is often followed not just by frequent atrial ectopy, but by repeated bursts of PV tachycardia. Therefore, although AF may beget AF in the PVs, the subsequent rhythm may be quite different than the initial rhythm: it may be a focal tachycardia rather than a re-entrant rhythm. In this case the term "beget," meaning creation in one's own likeness, may not accurately apply.
Despite a substantial collection of data, it is difficult to determine the relative importance of the various mechanisms by which an episode of AF might promote recurrent AF. A variety of drugs have been shown to prevent an early recurrence of AF. Intravenous verapamil has been shown to attenuate the effect of a brief episode of pacing-induced AF on electrical remodeling and atrial vulnerability (6). However, vulnerability was based on the ease with which an atrial extrastimulus could induce secondary episodes of AF, not on the frequency of atrial ectopy or spontaneous episodes of AF. Sticherling et al. (7) randomized patients who experienced an immediate recurrence of AF at the time of electrical cardioversion to verapamil and ibutilide. Eight patients (73%) had another episode of immediate recurrence of AF after verapamil, compared with 2 patients (22%) after ibutilide (p < 0.05). However, verapamil may have been ineffective because it was administered after patients had been in AF for a substantial amount of time. Amiodarone has also been shown to prevent recurrent AF. It has been shown to be as effective as ibutilide in preventing an immediate recurrence of AF in patients undergoing PV electrical isolation (8). Although these studies provide practical information, the drugs that were used have multiple electrophysiological effects. None of these studies helps discern the relative importance of substrate versus triggers, or helps determine if immediate recurrences of AF are due to re-entry or repetitive focal discharges. Further studies are needed to determine the relative clinical importance of the different mechanisms by which AF encourages more AF.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954-1968.[Abstract/Free Full Text]2. Daoud EG, Bogun F, Goyal R, et al. Effect of atrial fibrillation on atrial refractoriness in humans Circulation 1996;94:1600-1606.[Abstract/Free Full Text] 3. Jais P, Hocini M, Macle L, et al. Distinctive electrophysiological properties of pulmonary veins in patients with atrial fibrillation Circulation 2003;106:2476-2485. 4. Honjo H, Boyett MR, Niwa R, et al. Pacing-induced spontaneous activity in myocardial sleeves of pulmonary veins after treatment with ryanodine Circulation 2003;107:1937-1943.[Abstract/Free Full Text] 5. Rostock T, Steven D, Lutomsky B, et al. Atrial fibrillation begets atrial fibrillation in the pulmonary veins. on the impact of atrial fibrillation on the electrophysiological properties of the pulmonary veins in humans. J Am Coll Cardiol 2008;51:2153-2160.[Abstract/Free Full Text] 6. Daoud EG, Knight BP, Weiss R, et al. Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans Circulation 1997;96:1542-1550.[Abstract/Free Full Text] 7. Sticherling C, Ozaydin M, Tada H, et al. Comparison of verapamil and ibutilide for the suppression of immediate recurrences of atrial fibrillation after transthoracic cardioversion J Cardiovasc Pharmacol Ther 2002;7:155-160.[Abstract/Free Full Text] 8. Oral H, Ozaydin M, Tada H, et al. Comparison of amiodarone versus ibutilide for the prevention of immediate recurrences of atrial fibrillation during pulmonary vein isolation Am J Cardiol 2002;90:492-495.[CrossRef][Web of Science][Medline]
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