EDITORIAL COMMENT
Pursuing Sinus Rhythm in Patients With Persistent Atrial FibrillationWhen Is It Too Late?*
David J. Wilber, MD*
Cardiovascular Institute, Loyola University Medical Center, Maywood, Illinois
* Reprint requests and correspondence: Dr. David J. Wilber, Room 6232, Building 110, Loyola University Medical Center, 2160 South First Avenue, Maywood, Illinois 60153 (Email: dwilber{at}lumc.edu).
Key Words: atrial fibrillation • catheter ablation • predictor
Atrial fibrillation (AF) is a progressive disease. In patients with paroxysmal AF at initial clinical evaluation, progression to persistent forms is documented in approximately 10% at 1 year, 25% to 30% at 5 years, and >50% beyond 10 years despite pharmacologic therapy (1–6). Once AF becomes persistent, maintenance of sinus rhythm becomes more difficult. In patients with persistent AF of <1 year duration, only 40% to 60% of patients remain in sinus rhythm 1 year after initiation of treatment, despite multiple cardioversions and antiarrhythmic drugs, with additional relapses over the subsequent years (7–11). Duration of persistent AF >3 years is associated with a <15% probability of long-term sinus rhythm (11). Electrical, contractile, and structural remodeling of the atria occur in parallel with the increasing frequency and duration of AF, facilitating AF stability and persistence (12). The latter includes progressive changes in cellular ultrastructure and extracellular matrix volume and composition, mediated by a complex set of signaling mechanisms, and ultimately resulting in myocyte loss and interstitial fibrosis (13,14). The extent to which structural remodeling is reversible, and the optimal timing and tools for clinical intervention, remain poorly defined.
Although therapy for persistent AF is usually undertaken for control of symptoms most immediately related to AF (palpitations, dyspnea, exercise intolerance), the association between AF and other adverse long-term outcomes, including death, stroke, and heart failure, is well established (15–17). Evidence to date from large-scale clinical trials does not support the concept that these latter risks can be ameliorated or reversed by a proactive strategy directed toward sinus rhythm maintenance (7–10,18); these outcomes may reflect the ineffectiveness and toxicity of antiarrhythmic drug therapy rather than a failure of strategy. Retrospective data indicate that when sinus rhythm can be maintained by drugs or catheter ablation, morbidity and mortality related to AF may be significantly reduced (19–21).
Collectively, these considerations have led many clinicians to advocate earlier intervention to reverse or retard atrial remodeling before long-term maintenance of sinus rhythm becomes improbable, either before AF has become persistent or relatively soon thereafter. Catheter ablation provides a promising alternative to antiarrhythmic therapy, and in experienced centers, is reported to result in sinus rhythm maintenance in 60% to 90% of selected patients with persistent AF without antiarrhythmic drugs during follow-up of 1 to 2 years (22–26). Termination of persistent AF during ablation in this population is technically challenging, and multiple procedures may be required to effect durable maintenance of sinus rhythm. More extensive substrate modification in the left or both atria, in addition to the pulmonary vein isolation, seems necessary to optimize long-term success, consistent with progressive structural remodeling (24–27). Critical, but as yet unanswered, questions remain: How do we identify patients in whom structural remodeling has become irreversible? When is it too late to intervene? The study by Matsuo et al. (28), published in this issue of the Journal, provides important, if preliminary, answers.
The investigators examined the predictors of sinus rhythm maintenance in a group of 90 patients undergoing initial ablation of persistent AF (>1 month duration). The mean and median duration of continuous AF before the procedure were 28 and 19 months, respectively, and >3 years in 25% of patients. The study population was young (mean age 57 years), with a lower incidence of structural heart disease (28%) and hypertension (27%) compared with the general population with persistent AF (7–11). Ablation was performed using a stepwise approach involving pulmonary vein isolation followed by ablation at LA sites showing abnormal electrograms (continuous fractionation, rapid and complex fractionated electrograms, or temporal activation gradients), a roof line, and a mitral isthmus line successively if AF had not terminated. Overall, AF was terminated by ablation in 84% of patients. At least 1 repeat procedure was performed in a majority of patients (mean 1.8 procedures/patient, range 1 to 4 procedures/patient). Antiarrhythmic drug therapy was stopped 1 to 3 months after the baseline procedure.
In addition to well-known predictors of sinus rhythm maintenance from previous long-term outcome studies (age, duration of AF, left atrial size, presence of structural heart disease), the investigators examined the predictive value of global AF cycle length (CL) as determined from short segments of surface electrocardiogram (ECG) lead V1 by time-frequency analysis. The utility of this and related approaches in characterizing AF organization, and the potential extent of structural remodeling, has become increasingly apparent over the past decade (29,30). The investigators provide new evidence that a relatively simple manual measurement of AFCL from the surface ECG could be obtained in the vast majority of patients, and that this measure was highly correlated with more sophisticated determinations of CL by computerized algorithm.
Long-term success was defined as absence of a recurrent atrial tachyarrhythmia >3 min in duration without concomitant antiarrhythmic drugs during the 18 ± 6-month follow-up after the final ablation procedure. This end point was achieved in 84% of patients. Using receiver-operator characteristic curves to identify optimal cut points, the investigators found that both AFCL and AF duration were powerful and independent predictors of both AF termination during the index procedure and long-term maintenance of sinus rhythm after the final procedure. At 1 year, sinus rhythm was maintained in approximately 93% of patients with AFCL >142 ms compared with only approximately 68% in patients with an AFCL <142 ms. In patients with >21 months of continuous AF before the index ablation, sinus rhythm was maintained in only approximately 72% of patients, compared with approximately 95% in patients with a duration <21 months. Of interest, the majority of recurrent arrhythmias after the baseline procedure were atrial tachycardias, which were successfully ablated during repeat procedures. Recurrence of AF after the baseline procedure was associated with a low probability of sinus rhythm maintenance during follow-up (3 of 16 patients), despite repeat ablation.
How should these data impact the referral of patients with persistent AF for catheter ablation? The investigators conclude that ablation of persistent AF <2 years in duration is associated with a high rate of sinus rhythm maintenance, and patients should be referred within this time frame for optimal results. For patients with longer or unknown duration of AF, additional evaluation of the surface ECG AFCL can guide selection of those most likely to benefit. These guidelines are attractive in their simplicity, in that the necessary data can be readily obtained from an initial outpatient visit without extensive additional testing.
However, there are several reasons to consider these guidelines as tentative and preliminary. Notably, in this study, other previously identified predictors of sinus rhythm maintenance had minimal or no impact on the long-term outcome of ablation. This finding may reflect a trend toward selecting a more homogenous population of younger patients with less extensive comorbidity for ablation; some caution is warranted in generalizing these results to the general population with persistent AF. There are few data from this or previous studies regarding the risk of recurrences after the initial 1 or 2 years in sinus rhythm. Maintenance of sinus rhythm after ablation may also differ by procedural technique, particularly with less extensive ablation than that used by Matsuo et al. (28). The investigators do not provide data on the use of concurrent drugs that target potential mediators of structural remodeling (angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, aldosterone antagonists, and statins), and may favorably influence rhythm control (31,32). Finally, use of alternative surface ECG indexes of AF organization and complexity (30), biomarkers of ongoing structural remodeling (33), or direct imaging of the extent and distribution of atrial fibrosis (34) may further refine our predictions of successful outcomes.
Accumulating data support the concept of intervention relatively early in the course of persistent AF to ensure a reasonable probability of maintaining sinus rhythm over subsequent years. Whether catheter ablation will provide a more effective approach than antiarrhythmic therapy to accomplish this task, and reduce attendant morbidity and mortality, is the subject of a recently initiated 3,000-patient multicenter trial, CABANA (Catheter ABlation versus ANtiarhythmic Drug Therapy for Atrial Fibrillation). However, clinicians considering ablation therapy for persistent AF need to be mindful of the potential limitations in overcoming or reversing structural remodeling. The data of Matsuo et al. (28) provide a useful and practical first step in these deliberations.
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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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