Recurrence Post–Atrial Fibrillation Ablation

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 11, No. 4Recurrence Post–Atrial Fibrillation Ablation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBRecurrence Post–Atrial Fibrillation AblationThink Outside the Pulmonary Veins Takanori Yamaguchi, MD and Nassir F. Marrouche, MD Takanori YamaguchiTakanori Yamaguchi Comprehensive Arrhythmia and Research Management (CARMA) Center, Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City. Search for more papers by this author and Nassir F. MarroucheNassir F. Marrouche Comprehensive Arrhythmia and Research Management (CARMA) Center, Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City. Search for more papers by this author Originally published13 Apr 2018https://doi.org/10.1161/CIRCEP.118.006379Circulation: Arrhythmia and Electrophysiology. 2018;11:e006379See Article by Shah et alThe initiation and maintenance of atrial fibrillation (AF) require triggers and a vulnerable atrial substrate. AF often progresses from paroxysmal and trigger-driven arrhythmias to persistent and more substrate-dependent arrhythmias. After the seminal work by Haïssaguerre et al1 who demonstrated that ectopic beats from the pulmonary vein (PV) often trigger AF, catheter ablation of AF has focused on electrical isolation of the PV. PV isolation (PVI) has demonstrated a 60% to 80% success rate of maintaining sinus rhythm in patients with paroxysmal AF.2 Even in nonparoxysmal AF patients, PVI alone conveys a 40% to 50% rate of success.2,3 The current 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement describes permanent electrical isolation of the PVs as a cornerstone of AF ablation.2Despite the advancement of ablation technology such as contact force sensing and cryoballoon technology, PV electrical reconnection is frequently observed. Jiang et al4 studied the incidence of PV reconnection in 32 patients free from AF recurrence at 12 months postradiofrequency ablation: PV reconnection was observed in 29 patients (90.6%). Recently, Nery et al5 analyzed the relationship between PV reconnection and freedom from AF in their meta-analysis including studies using radiofrequency ablation, cryoballoon ablation, and laser balloon ablation. Among patients with and without AF recurrence, 86% and 59% had at least 1 PV reconnection, respectively. The average follow-up periods of the studies included in this meta-analysis were 8±10 months. Durable PVI is associated with a lower risk of AF recurrence; however, the association was modest. Analyses of studies that included exclusively patients with paroxysmal AF in this meta-analysis showed that the association was not statistically significant. Miyazaki et al6 reported that PV reconnection was detected in 65% of patients after second-generation cryoballoon ablation at a median of 6 months postinitial procedure. The incidence of PV reconnection in this study was similar between patients with and without AF recurrence. These studies demonstrate that durable PVI is not always required to maintain sinus rhythm in some patients. There are several possible explanations. First, arrhythmogenic PV(s) has been isolated, and the reconnected PVs were bystanders in patients without clinical recurrences despite PV reconnections. Second, AF drivers and substrates around the PV antrum have been ablated during electrical PVI. Third, antral PVI incidentally ablated ganglionated plexi, which have been implicated in the initiation and maintenance of AF.2 However, the follow-up period of these studies was short, which may underestimate the risk of AF recurrence in patients with PV reconnections.In this issue of Circulation: Arrhythmia and Electrophysiology, Shah et al7 reported the electrophysiological findings and outcomes in 137 patients with AF recurrence after initial long-term success. Long-term success was defined as freedom from recurrent arrhythmia for >36 months off antiarrhythmic drugs. The median arrhythmia-free period was 52 months (41–68 months). The investigator identified electrical reconnection of at least 1 PV in 111 patients (81%), which was isolated during repeat ablation procedures. In addition, anatomic-based non-PV ablation was performed in 127 patients (93%) at the discretion of the operator: posterior wall (46%), septal to right PVs (49%), inferior to right PVs (34%), superior vena cava (35%), coronary sinus (16%), left atrial appendage (15%) and lines at the roof (52%), left inferior PV to mitral annulus (15%), right superior PV to mitral annulus (10%), and cavotricuspid isthmus ablation (33%). After a median follow-up of 17 months, 103 patients (75%) were arrhythmia free. Of the patients who did not have any PV reconnections (n=26), 16 (62%) remained free from any arrhythmia. The investigators provide 2 key findings: (1) PV reconnection is still a common finding in this patient population, and (2) the anatomic-based non-PV (substrate) ablation helps improve long-term AF ablation outcome.The important question that arises from this study is “What is the cause of the very late recurrence in patients with initial long-term freedom from AF?” The hypothesis would include triggers from reconnected PV, development of non-PV triggers, and progression of the atrial substrate. It is challenging to define 1 certain factor as a cause for late recurrence in this study. First, the investigators performed reisolation of the PVs in all patients who had reconnections (81%) and also performed non-PV (substrate) ablations in 97% of patients at the discretion of the operator, which makes it difficult to prove cause-and-effect relationship in the mechanism of recurrent arrhythmia. Second, they did not differentiate non-PV trigger ablation and non-PV substrate ablation. Non-PV triggers are important mechanism of recurrence in patients with very late recurrence.8 Third, they did not evaluate the progression of structural remodeling, including atrial enlargement and new tissue fibrosis. The latter can be evaluated using electroanatomical voltage mapping or advanced imaging such as cardiac magnetic resonance imaging (MRI). Finally, their methodology of substrate ablation is at operator’s discretion. It is anatomic based but seems to be heterogeneous, which makes it difficult to conclude that which substrate modification is effective in this setting.The previous studies show none or only modest relationship between PV reconnection and AF recurrence during a follow-up period of 6 to 12 months.4–6 However, there is no evidence available on association between PV reconnection and very late recurrence defined as freedom from recurrent arrhythmia for >36 months. In the study by Shah et al,7 the reconnected PV may provide triggers for AF initiation; however, it is more likely that the matured atrial substrate plays a more important role in AF recurrence after initial long-term success.The substrate for AF consists of 2 components: electrical remodeling and structural remodeling of the atria. A significant amount of knowledge has accumulated showing that numerous cardiovascular risk factors such as heart failure, hypertension, diabetes mellitus, obesity, sleep apnea, and aging are all associated with electrical and structural remodeling of the atria.2,9 Experimental models of AF have demonstrated early reversal of electrical remodeling after restoration of sinus rhythm10; however, structural remodeling has been suggested to persist in the long term.11 Teh et al12 reported that abnormal substrate in the right atrium does not reverse, but in some patients, it progresses even after successful catheter ablation. Catheter ablation targets a patient’s AF at its current pathological and structural state. Even if cardiovascular risk factors facilitating atrial remodeling can be treated, structural remodeling associated with aging and comorbidities will continue to progress. Therefore, it is reasonable to speculate that AF-independent structural remodeling would progress even after successful ablation, thus placing the patient at risk for very late AF recurrence.Development and progression of atrial fibrosis is the hallmark of structural remodeling in AF. Fibrosis promotes AF by interrupting fiber bundle continuity and causing local conduction disturbance.8 In addition, myofibroblasts, which present in fibrotic remodeling myocardium, are known to elicit ectopic activity,13 suggesting that the fibrotic tissue may be a source of non-PV triggers. Atrial fibrosis can be detected, localized, and quantified by a modern imaging method based on delayed-enhancement MRI (DE-MRI).14 The DECAAF (Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation) multicenter and prospective study demonstrated that among patients with AF undergoing AF ablation, atrial fibrosis estimated by DE-MRI was independently associated with the likelihood of AF recurrence.14 Furthermore, Akoum et al15 reported that residual fibrosis uncovered by ablation scar is associated with AF recurrence. Another method to estimate fibrotic tissue is the electroanatomical voltage mapping, which is usually performed during ablation procedures. An increased amount of fibrotic tissue expressed as electrical scar defined as bipolar voltage amplitude of <0.05 mV and low-voltage area defined as <0.5 mV during sinus rhythm are strongly related to AF recurrence after PVI.16,17 The STAR-AF II trial (Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II) demonstrated no reduction in the rate of AF recurrence when either empirical linear ablation or ablation of complex fractionated electrograms was performed in addition to PVI.3 This study suggests that more selective targets are needed to better characterize patient’s arrhythmic substrate. Improved AF outcomes may be possible with patient-specific substrate modification based on targeted ablation of atrial fibrosis. Recently, there is increasing evidence that ablation targeting individual low-voltage area in addition to PVI improves ablation outcomes.18,19 A large, multicenter randomized trial, DECAAF II (Efficacy of DE-MRI-Guided Ablation vs Conventional Catheter Ablation of Atrial Fibrillation) designed to assess the efficacy of a DE-MRI–guided AF ablation strategy, is ongoing (URL: https://www.clinicaltrials.gov. Unique identifier: NCT02529319), and the results of this trial will provide further insights into the role of substrate ablation targeting atrial fibrosis in AF ablation. The study reported by Shah et al7 demonstrated that their anatomic-based non-PV substrate ablation conveyed excellent outcomes in the patient population with AF recurrence after initial long-term success (75% of arrhythmia free after a median follow-up of 17 months). Further investigation on patient-specific substrate ablation based on fibrotic tissue versus anatomic-based substrate ablation is needed for this patient population.Progression of atrial fibrosis likely plays an important role in the development of AF and recurrence after AF ablation. Recently, Mahnkopf et al20 reported their preliminary results of atrial fibrosis progression. The investigators analyzed a total of 42 patients without history of AF, who underwent DE-MRI at 2 different time points (average interval: 766±564). The degree of fibrosis at the second MRI was significantly higher in all patients compared with the first MRI. New-onset AF was detected in 7 patients, and the degree of fibrosis at the second MRI was significantly higher in the patients with new-onset AF compared with patients without AF. This study suggests the progressive nature of atrial fibrosis and a relationship between fibrosis progression and new-onset AF. Teh et al12 demonstrated progression of abnormal atrial substrate in some patients in the right atrium after successful AF ablation. However, to the best of our knowledge, the fibrosis progression in patients with AF recurrence has not been clarified. The noninvasive nature of DE-MRI may provide more detailed information on fibrosis progression.As the number of AF ablation procedures increases and the incidence of PV reconnections decreases because of technological advancement, electrophysiologists will more frequently encounter patients with AF recurrence after initial long-term success. The study by Shah et al7 motivates further investigation into characterizing the AF substrate in this patient population and improving ablation strategies.DisclosuresDr Marrouche receives consulting/royalties from Abbott, Biotronik, Wavelet Health, Cardiac Design, Medtronic, Preventice, Vytronus, Biosense Webster, Marrek Inc, and Boston Scientific. He received research grants from Abbott, Boston Scientific, GE Healthcare, Siemens, Biotronik, Vytronus, and Biosense Webster. He also has company interest/ownership in Marrek Inc, Cardiac Design. The other author reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circep.ahajournals.orgNassir F. Marrouche, MD, CARMA Center, University of Utah, 30 N 1900 E, RM 4A 100, Salt Lake City, UT 84132. E-mail [email protected]References1. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.N Engl J Med. 1998; 339:659–666. doi: 10.1056/NEJM199809033391003.CrossrefMedlineGoogle Scholar2. 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Atrial fibrosis detected using LGE-MRI is a progression phenomenon accelerated by atrial fibrillation: comparison between patients without and with atrial fibrillation.In: Abstract EuroCMR/SCMR Meeting; February 2, 2018; Barcelona, Spain.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByMohanty S, Trivedi C, Horton P, Della Rocca D, Gianni C, MacDonald B, Mayedo A, Sanchez J, Gallinghouse G, Al‐Ahmad A, Horton R, Burkhardt J, Dello Russo A, Casella M, Tondo C, Themistoclakis S, Forleo G, Di Biase L and Natale A (2021) Natural History of Arrhythmia After Successful Isolation of Pulmonary Veins, Left Atrial Posterior Wall, and Superior Vena Cava in Patients With Paroxysmal Atrial Fibrillation: A Multi‐Center Experience, Journal of the American Heart Association, 10:11, Online publication date: 1-Jun-2021. Miyauchi S, Tokuyama T, Shintani T, Nishi H, Hamamoto Y, Ouhara K, Furusho H, Miyauchi M, Komatsuzawa H and Nakano Y (2021) Periodontitis and the outcome of atrial fibrillation ablation: Porphyromonas gingivalis is related to atrial fibrillation recurrence , Journal of Cardiovascular Electrophysiology, 10.1111/jce.14952, 32:5, (1240-1250), Online publication date: 1-May-2021. Nagel C, Luongo G, Azzolin L, Schuler S, Dössel O and Loewe A (2021) Non-Invasive and Quantitative Estimation of Left Atrial Fibrosis Based on P Waves of the 12-Lead ECG—A Large-Scale Computational Study Covering Anatomical Variability, Journal of Clinical Medicine, 10.3390/jcm10081797, 10:8, (1797) Royster R, Fernando R and Beaty E (2020) Research Needs and Priorities for Catheter Ablation of Atrial Fibrillation, Journal of Cardiothoracic and Vascular Anesthesia, 10.1053/j.jvca.2020.03.002, 34:7, (1723-1726), Online publication date: 1-Jul-2020. Pranata R, Yonas E, Chintya V, Tondas A and Raharjo S (2020) Serum Galectin-3 level and recurrence of atrial fibrillation post-ablation – Systematic review and meta-analysis, Indian Pacing and Electrophysiology Journal, 10.1016/j.ipej.2020.02.002, 20:2, (64-69), Online publication date: 1-Mar-2020. April 2018Vol 11, Issue 4 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.118.006379PMID: 29654136 Originally publishedApril 13, 2018 Keywordsrecurrencecatheter ablationfibrosisEditorialsatrial fibrillationPDF download Advertisement SubjectsAtrial FibrillationElectrophysiology