Intra-atrial activation pattern is useful to localize the areas of non-pulmonary vein triggers of atrial fibrillation

Kazuo Sakamoto; Yasushi Mukai; Shunsuke Kawai; Kazuhiro Nagaoka; Shujiro Inoue; Susumu Takase; Daisuke Yakabe; Shota Ikeda; Hiroshi Mannoji; Tomomi Nagayama; Akiko Chishaki; Hiroyuki Tsutsui

doi:10.1371/journal.pone.0264894

Peer Review History

Original SubmissionOctober 26, 2021
6 Dec 2021 Decision Letter - Luigi Sciarra, Editor PONE-D-21-34225Intra-atrial activation pattern is useful to localize the areas of non-pulmonary vein triggers of atrial fibrillationPLOS ONE Dear Dr. Mukai, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ACADEMIC EDITOR: Dear Authors, after a careful evaluation of your paper, according to our reviewers' suggestion, our opinion is that your manuscript cannot be accepted as it is, but it needs major revisions. In particular, some methodological issues needs to be better clarified. Please submit your revised manuscript by Jan 20 2022 11:59PM. 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The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The work is very interesting and well written. I would discuss two aspects in depth: 1. Before the analysis of non-PV triggers, the importance of the electrophysiological study, especially in paroxysms without heart disease, should be highlighted in order to find any organized arrhythmias. Please read Sciarra L, Rebecchi M, De Ruvo E, De Luca L, Zuccaro LM, Fagagnini A, Corò L, Allocca G, Lioy E, Delise P, Calò L. How many atrial fibrillation ablation candidates have an underlying supraventricular tachycardia previously unknown? Efficacy of isolated triggering arrhythmia ablation. Europace. 2010 Dec;12(12):1707-12. doi: 10.1093/europace/euq327. Epub 2010 Sep 10. PMID: 20833693. 2. I would also briefly mention the role of the substrate as the islets of fibrosis in the left atrium (Rillo M, Palamà Z, Punzi R, Vitanza S, Aloisio A, Polini S, Tucci A, Pollastrelli A, Zonno F, Anastasia A, Giannattasio CF, My L. A new interpretation of nonpulmonary vein substrates of the left atrium in patients with atrial fibrillation. J Arrhythm. 2021 Feb 22;37(2):338-347. doi: 10.1002/joa3.12521. PMID: 33850575; PMCID: PMC8021999. ) Reviewer #2: Comments to the Author This paper focused on the method to distinguish the areas of non-pulmonary vein triggers of AF with an electrode catheter. I clinically agree with author’s ideas, but there are some major problems. In particular, parts of the Methods section are considerably lacking. Major comments 1. This CS catheter you recommend is generally difficult to use. Aren’t the electrode catheters over-used, such as the PentaRay or BeeAT catheter? Therefore, I think it is difficult to use this method as a standardized algorithm. 2. Although there is a description of 751 sessions, the total number of cases and paroxysmal and non-paroxysmal cases are unknown. This study is a retrospective study and more patient information should be provided. 3. Were the 35 cases in this study completely cured for the entire follow-up period by the focal ablation of the non-pulmonary vein origins? Did you try to re-induce AF after the ablation of the non-pulmonary vein origins? This study found that paroxysmal and non-paroxysmal non-pulmonary vein origins were approximately equal. Moreover, in the intracardiac electrocardiogram shown in Fig. 1B, the onset of the AF is far from the previous QRS. From the above, it is hard to believe that it was the correct site to prove the origin of AF. Finally, I consider it to have an overall low credibility. 4. There were too few cases of non-pulmonary vein origins in this study. The authors wrote that in the Discussion section, but you should strongly state it in the Limitations section. In addition, the number of PV origin cases should also be clearly written in the manuscript. Reviewer #3: Authors presented an interesting paper focused on the research of non PV trigger areas in the setting of atrial fibrillation. PVI was firstly performed and induction of AF was subsequently attempted to observe non PVI foci. Some considerations: - retrospective analysis is not the best way to investigate the issue (this concept has been underlined in limitations) - The possibility to discover extra PV trigger for AF as been previously well described (How many atrial fibrillation ablation candidates have an underlying supraventricular tachycardia previously unknown? Efficacy of isolated triggering arrhythmia ablation. Sciarra L, Rebecchi M, De Ruvo E, De Luca L, Zuccaro LM, Fagagnini A, Corò L, Allocca G, Lioy E, Delise P, Calò L. Europace. 2010 Dec;12(12):1707-12. doi: 10.1093/europace/euq327. Epub 2010 Sep 10). Why has been not a first research of triggers attempted? Please add a comment. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Reviewer #3: Yes:** Antonio Scarà [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. 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Revision 1
19 Jan 2022 Author Response Reviewer #1: The work is very interesting and well written. Thank you for your general understanding to our work. I would discuss two aspects in depth: 1. Before the analysis of non-PV triggers, the importance of the electrophysiological study, especially in paroxysms without heart disease, should be highlighted in order to find any organized arrhythmias. Please read Sciarra L, Rebecchi M, De Ruvo E, De Luca L, Zuccaro LM, Fagagnini A, Corò L, Allocca G, Lioy E, Delise P, Calò L. How many atrial fibrillation ablation candidates have an underlying supraventricular tachycardia previously unknown? Efficacy of isolated triggering arrhythmia ablation. Europace. 2010 Dec;12(12):1707-12. doi: 10.1093/europace/euq327. Epub 2010 Sep 10. PMID: 20833693. We completely agree with the reviewer. We well consider that SVT can be a trigger of AF in some cases. In the enrolled patients in the present study, no SVTs were induced except 3 cavotricuspid isthmus (CTI)-dependent atrial flutters in EPS. Now this is mentioned in the Result section. We have also added the mentioned study as a reference. The analyzed non-PV triggers in this study were ectopic foci that initiate fibrillatory activities from the beginning. (Results) We considered supraventricular tachycardias (SVT) as possible triggers of AF as well [19]. CTI-dependent atrial flutters were induced during EPS in 3 cases, but no other SVTs were induced in the studied patients. (References) 19. Sciarra L, Rebecchi M, De Ruvo E, De Luca L, Zuccaro LM, Fagagnini A, et al. How many atrial fibrillation ablation candidates have an underlying supraventricular tachycardia previously unknown? Efficacy of isolated triggering arrhythmia ablation. Europace. 2010;12:1707-12. 2. I would also briefly mention the role of the substrate as the islets of fibrosis in the left atrium (Rillo M, Palamà Z, Punzi R, Vitanza S, Aloisio A, Polini S, Tucci A, Pollastrelli A, Zonno F, Anastasia A, Giannattasio CF, My L. A new interpretation of nonpulmonary vein substrates of the left atrium in patients with atrial fibrillation. J Arrhythm. 2021 Feb 22;37(2):338-347. doi: 10.1002/joa3.12521. PMID: 33850575; PMCID: PMC8021999. ) We completely agree with the reviewer and we also strongly recognize the relationship between left atrial degeneration and arrhythmogenic substrate. It is a　great theme whether to go with trigger mapping/ablation or substrate modification. In terms of AF trigger, we previously reported that non-PV AF trigger is likely to arise from degenerated atrial tissue where maintenance substrate of AF may co-exist. (reference #15) Reviewer #2: Comments to the Author This paper focused on the method to distinguish the areas of non-pulmonary vein triggers of AF with an electrode catheter. I clinically agree with author’s ideas, but there are some major problems. In particular, parts of the Methods section are considerably lacking. We appreciate the reviewer’s general comment to our work. We would like to further explain our research design and what we would like to demonstrate. We considered the above-mentioned issues and revised the manuscript as below. Major comments 1. This CS catheter you recommend is generally difficult to use. Aren’t the electrode catheters over-used, such as the PentaRay or BeeAT catheter? Therefore, I think it is difficult to use this method as a standardized algorithm. As reviewer pointed out, the CS catheter (BeeAT) used in this study may not be available worldwide and we know that usable number of electrode is limited in some countries. What we intended to demonstrate in this study was that the basically-positioned catheters in the HRA and CS provide useful information to localize a non-PV trigger of AF and help further detailed mapping. Since we understand that our strategy cannot be universally recommended, we have revised and added sentences in Limitations section as below. (Limitations) From Finally, the assessment of the intra-cardiac electrograms might be difficult soon after a defibrillation because it takes a few seconds for the baseline of electrograms to return to where it was. To Fourth, the assessment of the intra-cardiac electrograms might be difficult soon after a defibrillation because it takes a few seconds for the baseline of electrograms to return to where it was. Finally, the electrode catheter used in this study, which can simultaneously record CS and RA potentials (BeeAT), is not available worldwide and can only be used in limited regions. Therefore, it is necessary to verify whether the same results can be obtained using widely available separate CS and RA catheters. 2. Although there is a description of 751 sessions, the total number of cases and paroxysmal and non-paroxysmal cases are unknown. This study is a retrospective study and more patient information should be provided. As the reviewer mentioned, the type of AF (paroxysmal and persistent) is very important in AF ablation studies. Therefore, the number of patients with paroxysmal and persistent AF and the number of non-PV triggers in all 751 sessions were added to the Methods as follows. (Methods) from We retrospectively analyzed 37 non-PV triggers in 751 ablation sessions for symptomatic AF from January 2017 to December 2020. To We retrospectively analyzed 37 non-PV triggers in 751 ablation sessions for symptomatic AF (including 310 paroxysmal AF) from January 2017 to December 2020. 3. Were the 35 cases in this study completely cured for the entire follow-up period by the focal ablation of the non-pulmonary vein origins? Did you try to re-induce AF after the ablation of the non-pulmonary vein origins? This study found that paroxysmal and non-paroxysmal non-pulmonary vein origins were approximately equal. Moreover, in the intracardiac electrocardiogram shown in Fig. 1B, the onset of the AF is far from the previous QRS. From the above, it is hard to believe that it was the correct site to prove the origin of AF. Finally, I consider it to have an overall low credibility. We appreciate the reviewer’s insightful comments. As for prognosis, we have previously reported that non-recurrence rate of successfully ablated non-PV trigger cases was comparable to those with no detectable non-PV triggers (reference #15). We would like the reviewer to understand that the present study is not a long-term outcome study but deals with a mapping methodology. Yes. We re-induced AF after ablation to confirm the elimination of targeted non-PV triggers as stated in Methods. In order to certify the methodology, we added a sentence in Methods as follows. (Methods) AF induction test was repeated to see if there were any other non-PV triggers remaining. In appreciation with the reviewer’s suggestion, we also have added sentences regarding the prevalence of non-PV triggers in patients with paroxysmal and non-paroxysmal AF respectively in the Discussion section as follows. (Discussion) The occurrence of non-PV triggers was comparable in paroxysmal (17 in 310, 5.5%) and in non-paroxysmal cases (18 in 441, 4.1%). The Prevalence of non-PV triggers was similar regardless of arrhythmia type, which is consistent to previous reports including ours [15, 23]. Finally, we would like to discuss the credibility of the non-PV mapping in Figure 1B. We would like to the reviewer to understand that Figure 1B is never showing an earliest activation electrogram but the measurement strategy in this study. As a note, coupling interval (CI) between the previous atrial potential and the ectopic beat potential recorded at the RA was 303 msec, which was not that long and the atrial activation showed so-called P on T. More than anything, the ectopic beat actually had initiated AF. We thus would like to ensure that atrial premature beat in Figure 1B is of an exact non-PV trigger. 4. There were too few cases of non-pulmonary vein origins in this study. The authors wrote that in the Discussion section, but you should strongly state it in the Limitations section. In addition, the number of PV origin cases should also be clearly written in the manuscript. Thank you for this insightful comment. The incidence of non-PV triggers may be lower in this study than in some previous studies. However, please ensure that we just focused on atrial AF triggers and thus excluded SVC triggers in this study. Considering this, prevalence of non=PV triggers in this study is not that small. We think that SVC can be treatable in a preventive manner (as the 5th thoracic vein) and a SVC trigger is not difficult to map. What we intended to clarify was how to map an atrial trigger of AF. Prevalence of PV trigger in our EPS strategy is published in-detail in our previous study (refenrence #15). In this study, non-PV triggers were induced after completion of PVI as mentioned in Method. Therefore, non-PV triggers in the near PV antrum might have been eliminated by PVI. We now mentioned this point in Limitations. (Limitations) The low incidence in this study of non-PV triggers may be partly because we excluded SVC triggers in this study. Another reason may be because non-PV triggers were induced after completion of PVI in this study. Thus, non-PV triggers originating from near PV antrum might have been eliminated by PVI. Reviewer #3: Authors presented an interesting paper focused on the research of non PV trigger areas in the setting of atrial fibrillation. PVI was firstly performed and induction of AF was subsequently attempted to observe non PVI foci. Thank you for your general understanding to our work. Some considerations: - retrospective analysis is not the best way to investigate the issue (this concept has been underlined in limitations) As the reviewer mentioned, it is difficult to conclude only with a retrospective study. Therefore, we emphasized this point further in Limitations as below. (Limitations) From First, this study was a retrospective study analyzing a limited sample size, therefore, a prospective study with more data is needed. To First, this study was a retrospective study analyzing a limited sample size, therefore, a prospective study with more data is needed to standardize this analysis method for clinical practice. - The possibility to discover extra PV trigger for AF has been previously well described (How many atrial fibrillation ablation candidates have an underlying supraventricular tachycardia previously unknown? Efficacy of isolated triggering arrhythmia ablation. Sciarra L, Rebecchi M, De Ruvo E, De Luca L, Zuccaro LM, Fagagnini A, Corò L, Allocca G, Lioy E, Delise P, Calò L. Europace. 2010 Dec;12(12):1707-12. doi: 10.1093/europace/euq327. Epub 2010 Sep 10). Why has been not a first research of triggers attempted? Please add a comment. Thank you for this valuable comment. As the reviewer stated, SVT can be a cause of AF.　If a SVT could be induced during AF ablation procedure and EPS, we would definitely map and ablate it, whereas there were no cases in which SVT (AVNRT, AVRT, FAT) was induced after PVI in the present study. As in previous studies, there is a strategy to perform EPS eliciting the cause of AF before PVI, however, in order to reduce the recurrence of AF as much as possible, EPS was performed after PVI, which is a standard treatment for AF in practice. We now added the following sentences to the Result section. We have also added the mentioned study as a reference. (Results) We considered supraventricular tachycardias (SVT) as possible triggers of AF as well [19]. Cavotricuspid isthmus-dependent atrial flutters were induced during EPS in 3 cases, but no other SVTs were induced in the studied patients. (References) 19. Sciarra L, Rebecchi M, De Ruvo E, De Luca L, Zuccaro LM, Fagagnini A, et al. How many atrial fibrillation ablation candidates have an underlying supraventricular tachycardia previously unknown? Efficacy of isolated triggering arrhythmia ablation. Europace. 2010;12:1707-12. Attachments Attachment Submitted filename: renamed_75041.docx https://doi.org/10.1371/journal.pone.0264894.r002
9 Feb 2022 Decision Letter - Luigi Sciarra, Editor PONE-D-21-34225R1Intra-atrial activation pattern is useful to localize the areas of non-pulmonary vein triggers of atrial fibrillationPLOS ONE Dear Dr. Mukai, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== ACADEMIC EDITOR: Dear Authors, after a careful evaluation of your paper, our opinion is that the quality of your manuscript significantly improved. However one of our reviewers is still suggesting some revisions. Best regardsLuigi Sciarra============================== Please submit your revised manuscript by Mar 26 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Luigi Sciarra Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments (if provided): Dear Authors, after a careful evaluation of your paper, our opinion is that the quality of your manuscript significantly improved. However one of our reviewers is still suggesting some revisions. Best regards Luigi Sciarra [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Point two on the role of extrapulmonary substrates has not been adequately investigated. I believe it is not possible to treat intra-atrial delays without talking about fibrosis! Reviewer #3: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Zefferino Palamà Reviewer #3: Yes:** Antonio Scarà [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0264894.r003
Revision 2
17 Feb 2022 Author Response Reviewer #1: Point two on the role of extrapulmonary substrates has not been adequately investigated. I believe it is not possible to treat intra-atrial delays without talking about fibrosis! Thank you for your excellent comment again about the atrial fibrosis.　To address the importance of the relationship between left atrial degeneration and arrhythmogenic substrate in AF ablation, the following sentence and the reference below were added in Discussion and Reference. (Discussion) For detailed mapping, it is also important to evaluate the substrate such as fibrosis by using multipolar electrodes [22]. (Reference) 22. Rillo M, Palamà Z, Punzi R, Vitanza S, Aloisio A, Polini S, et al. A new interpretation of nonpulmonary vein substrates of the left atrium in patients with atrial fibrillation. J Arrhythm. 2021;37:338-47. Attachments Attachment Submitted filename: renamed_2ca88.docx https://doi.org/10.1371/journal.pone.0264894.r004
21 Feb 2022 Decision Letter - Luigi Sciarra, Editor Intra-atrial activation pattern is useful to localize the areas of non-pulmonary vein triggers of atrial fibrillation PONE-D-21-34225R2 Dear Dr. Mukai, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Luigi Sciarra Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: (No Response) ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: All queries have been properly addressed. The role of fibrosis in the genesis and maintenance of atrial fibrillation cannot be ignored ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes:** Zefferino Palamà https://doi.org/10.1371/journal.pone.0264894.r005
Formally Accepted
13 Apr 2022 Acceptance Letter - Luigi Sciarra, Editor PONE-D-21-34225R2 Intra-atrial activation pattern is useful to localize the areas of non-pulmonary vein triggers of atrial fibrillation Dear Dr. Mukai: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Luigi Sciarra Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0264894.r006

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