HomeCirculation: Arrhythmia and ElectrophysiologyVol. 14, No. 1Left Atrial Appendage Electrical Isolation Reduces Atrial Fibrillation Recurrences Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBLeft Atrial Appendage Electrical Isolation Reduces Atrial Fibrillation RecurrencesA Simulation Study Ali Gharaviri, PhD Simone Pezzuto, PhD Mark Potse, PhD Sander Verheule, PhD Giulio Conte, MD, PhD Rolf Krause, PhD Ulrich Schotten, MD, PhD Angelo AuricchioMD, PhD Ali GharaviriAli Gharaviri https://orcid.org/0000-0003-1803-8237 Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland (A.G., S.P., G.C., R.K., A.A.). Search for more papers by this author , Simone PezzutoSimone Pezzuto https://orcid.org/0000-0002-7432-0424 Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland (A.G., S.P., G.C., R.K., A.A.). Search for more papers by this author , Mark PotseMark Potse https://orcid.org/0000-0003-4166-2687 Carmen team, Inria Bordeaux Sud-Ouest, Talence, France (M.P.). Université de Bordeaux, IMB, UMR 5251, France (M.P.). Search for more papers by this author , Sander VerheuleSander Verheule https://orcid.org/0000-0001-5196-5425 Department of Physiology, Maastricht University, the Netherlands (S.V., U.S.). Search for more papers by this author , Giulio ConteGiulio Conte https://orcid.org/0000-0003-2248-3456 Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland (A.G., S.P., G.C., R.K., A.A.). Fondazione Cardiocentro Ticino, Lugano, Switzerland (G.C., A.A.). Search for more papers by this author , Rolf KrauseRolf Krause https://orcid.org/0000-0001-5408-5271 Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland (A.G., S.P., G.C., R.K., A.A.). Search for more papers by this author , Ulrich SchottenUlrich Schotten Correspondence to: Ulrich Schotten, MD, PhD, Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. Email E-mail Address: [email protected] https://orcid.org/0000-0003-1532-3315 Department of Physiology, Maastricht University, the Netherlands (S.V., U.S.). Search for more papers by this author , Angelo AuricchioAngelo Auricchio https://orcid.org/0000-0003-2116-6993 Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland (A.G., S.P., G.C., R.K., A.A.). Fondazione Cardiocentro Ticino, Lugano, Switzerland (G.C., A.A.). Search for more papers by this author Originally published24 Dec 2020https://doi.org/10.1161/CIRCEP.120.009230Circulation: Arrhythmia and Electrophysiology. 2021;14:e009230Pulmonary vein (PV) isolation (PVI) improves freedom from atrial tachyarrhythmia recurrences in patients with paroxysmal and persistent atrial fibrillation (AF).1 However, PVI has a limited success rate in persistent AF patients and ablation techniques adjunctive to PVI isolating non-PV triggers remain an area of debate in these patients.1 Recently, there has been a growing interest in the electrical and anatomical role of the left atrial appendage (LAA) in triggering and sustaining AF, particularly in persistent AF patients or after repeated AF ablation procedures.2 Whether isolation of triggers originating from the LAA or substrate modification caused by LAA isolation (LAAI) is the underlying mechanism for AF recurrence prevention is still unknown.The data that support the findings of this study are available from the corresponding author upon reasonable request. We investigated the effect of LAAI in a structurally detailed model of the human atria, extensively described previously3 (material in the Data Supplement). The model entails wall thickness heterogeneities, endocardial trabeculated network, and a subepicardial layer with realistic fiber orientations. The material properties for the atria were set to produce an approximately normal P-wave during sinus rhythm (Table I in the Data Supplement).In total, 20 different pacing locations were selected in both atria based on reported possible sources of extra-PV ectopic focal activity in patients with AF4 (Figure).Download figureDownload PowerPointFigure. Atrial tachyarrhythmia initiation rates and dynamics.A, Catheter ablation patterns and pacing points (pacing locations located outside of ablated areas were indicated by black stars and the pacing location within the ablated area was indicated by yellow). B, Atrial fibrillation and atrial flutter initiation likelihood in control and catheter ablation simulations with different degrees of fibrosis. C, Number of waves per cycle. Wave life span and wave generation rate (the slope of fitted line) in (D) control (E) pulmonary vein isolation (PVI), and (F) PVI+left atrial appendage isolation (LAAI) simulations with sever fibrosis. BOX indicates left atrial posterior wall.In each simulation, AF was initiated by applying incremental pacing with the duration of 2 seconds at a selected pacing site. The pacing cycle length started with 280 ms and gradually reduced to 124 ms. AF initiation likelihood was compared between control (no ablation) and catheter ablation (CA) simulations with different degrees of fibrosis. CA simulations included 4 groups: PVI, PVI plus linear lesions encircling the left atrial posterior wall (BOX), PVI plus LAA circumferential isolation (PVI+LAAI), and BOX+LAAI. Virtual ablation lesions consisted of tissue volumes modeled by nonconductive elements. The outcome of the stimulation protocol was analyzed in terms of the type of self-sustained rhythm after 2 seconds of stimulations. If no activity was observed, the initiation was considered unsuccessful. Otherwise, a distinction between AF and atrial flutter was made (material in the Data Supplement), with the latter being considered unsuccessful.The spatial distribution of fibrosis was uneven, with patches or islands presenting higher degree of fibrosis (Figure I in the Data Supplement).3 Simulations were performed without fibrosis, with moderate fibrosis, and severe fibrosis, in which 0%, 50%, and 70% of elements were fibrotic.3In total, 300 simulations were performed. Each simulation group entails 60 simulations (20 simulations for each fibrosis degree).In control simulations, an increase in the fibrosis degree led to a significant increase in AF initiation likelihood. In simulations without fibrosis or with moderate fibrosis (which may represent patients with paroxysmal AF), PVI, and BOX caused a significant reduction in AF initiation likelihood, either by preventing initiation of fibrillation or by converting AF into atrial flutter (Figure). In contrast, in PVI and BOX simulations with severe fibrosis (which may represent persistent AF patients), we observed no significant reduction in AF initiation likelihood. In simulations with LAAI on top of PVI or BOX, we observed a comparable reduction in AF initiation likelihood as in PVI only or BOX simulations in the absence of fibrosis or in the presence of moderate fibrosis. In severe fibrosis, adding LAAI to PVI or BOX further reduced AF initiation likelihood by at least one-third.An increase in fibrosis degree in control simulations led to a significant increase fibrillation wave generation rate and, therefore, a significant increase in AF conduction pattern complexity, quantified as number of waves per cycle (Figure). In simulations without fibrosis or with moderate fibrosis, CAs caused a significant reduction in fibrillation wave generation rate and AF conduction pattern complexity. In contrast, in severe fibrosis simulations, a significant reduction in wave generation rate and AF pattern complexity was only observed in simulations with LAAI plus PVI or BOX.In our control group, the averaged AF cycle length was 149 ms, value previously reported in patients with AF. In simulations without fibrosis or with moderate fibrosis, CAs caused a significant AF cycle length prolongation (Table II in the Data Supplement). In severe fibrosis simulations only the presence of LAAI concomitant with CAs could significantly increase AF cycle length.The simulations were performed on a single atrial geometry and intersubject variability could have effects on simulations results. However, the in-depth study of the atrial anatomy effect on AF initiation is beyond the scope of this study.We modeled LAAI and investigated its effect on AF recurrences in the presence of different degrees of fibrosis. As presented, adding LAAI to either PVI or BOX significantly lowered AF recurrence rate in severe fibrosis simulations, which is consistent with clinical studies mentioning the significant effect of LAAI in lowering AF recurrence rates in persistent AF patients.2 Finally, we could demonstrate that the mechanisms underlying AF initiation prevention in the presence of LAAI is not due to isolating triggers in LAA, but rather related to the reduction of AF conduction pattern complexity as a result of substrate modification due to LAAI.Nonstandard Abbreviations and AcronymsAFatrial fibrillationBOXleft atrial posterior wallCAcatheter ablationLAAleft atrial appendageLAAIleft atrial appendage isolationPVpulmonary veinPVIpulmonary vein isolationSources of FundingThis work was supported by the Swiss National Supercomputing Centre (CSCS project ID s778), by grants to Dr Schotten from the Netherlands Heart Foundation (CVON2014-09, RACE V), and the EU (ERACoSysMED H2020 ERA-NET). Dr Conte is supported by the Swiss National Foundation (SNF; Ambizione grant no PZ00P3_180055/1).Disclosures Dr Auricchio is a consultant to Boston Scientific, Backbeat, Biosense Webster, Cairdac, Corvia, Microport CRM, Philips, Radcliffe Publisher. He received speaker fee from Boston Scientific, Medtronic, and Microport. He participates in clinical trials sponsored by Boston Scientific, Medtronic, Philips. He has intellectual properties with Boston Scientific, Biosense Webster, and Microport CRM. Dr Schotten received consultancy fees or honoraria from Johnson & Johnson, Roche Diagnostics, and Bayer Healthcare. Dr Schotten is co-founder and shareholder of YourRhythmics BV. He holds intellectual property with Roche and YourRhythmics BV. The other authors report no conflicts.FootnotesThe Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCEP.120.009230.For Sources of Funding and Disclosures, see page 106.Correspondence to: Ulrich Schotten, MD, PhD, Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. Email [email protected]nlReference1. Verma A, Jiang CY, Betts TR, Chen J, Deisenhofer I, Mantovan R, Macle L, Morillo CA, Haverkamp W, Weerasooriya R, et al.; STAR AF II Investigators. Approaches to catheter ablation for persistent atrial fibrillation.N Engl J Med. 2015; 372:1812–1822. doi: 10.1056/NEJMoa1408288CrossrefMedlineGoogle Scholar2. Di Biase L, Burkhardt JD, Mohanty P, Mohanty S, Sanchez JE, Trivedi C, Güneş M, Gökoğlan Y, Gianni C, Horton RP, et al.. Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.J Am Coll Cardiol. 2016; 68:1929–1940. doi: 10.1016/j.jacc.2016.07.770CrossrefMedlineGoogle Scholar3. Gharaviri A, Bidar E, Potse M, Zeemering S, Verheule S, Pezzuto S, Krause R, Maessen JG, Auricchio A, Schotten U. Epicardial fibrosis explains increased endo-epicardial dissociation and epicardial breakthroughs in human atrial fibrillation.Front Physiol. 2020; 11:68. doi: 10.3389/fphys.2020.00068CrossrefMedlineGoogle Scholar4. Chang HY, Lo LW, Lin YJ, Chang SL, Hu YF, Li CH, Chao TF, Chung FP, Ha TL, Singhal R, et al.. Long-term outcome of catheter ablation in patients with atrial fibrillation originating from nonpulmonary vein ectopy.J Cardiovasc Electrophysiol. 2013; 24:250–258. doi: 10.1111/jce.12036CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 2021Vol 14, Issue 1Article InformationMetrics Download: 189 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.120.009230PMID: 33356357 Originally publishedDecember 24, 2020 Keywordsleft atrial appendagefibrosispulmonary vein isolationcatheter ablationatrial fibrillationPDF download SubjectsBasic Science ResearchElectrophysiologyAtrial FibrillationComputational Biology