PONE-D-21-34553Electrophysiological Characteristics of Non-Pulmonary Vein Triggers Excluding Origins from the Superior Vena Cava and Left Atrial Posterior Wall: Lessons from the Self-reference Mapping TechniquePLOS ONE

Dear Dr. Nishino,

Thank you for submitting your manuscript to PLOS ONE. Before sending to external reviewers, please clarify several points:

1. How did the authors ensure that PVs were not associated with the AF initiations? Did the authors place PV catheters during determination of the AF origin?

2. How could the authors draw 3D-maps during the initiation of AFs? Did the author also use non-contact mapping to identify the origin (i.e., snap shots)? I think it is difficult to draw 3D-maps during initiation (i.e., only one beat). 

3. Did the authors check voltage maps around the origin of AF? In Fig 1, the signal amplitudes at PEN15-16 keep changing. How were the unipolar signals at the origin of AF?

4. If the authors believe these AFs were not associated with PVs, why did the authors isolate PVs?

Please submit your revised manuscript by Dec 19 2021 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,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Thank you for stating the following financial disclosure: 

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

At this time, please address the following queries:

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. 

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c) If any authors received a salary from any of your funders, please state which authors and which funders.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Additional Editor Comments:

Before sending to external reviewers, please clarify several points:

1. How did the authors ensure that PVs were not associated with the AF initiations? Did the authors place PV catheters during determination of the AF origin?

2. How could the authors draw 3D-maps during the initiation of AFs? Did the author also use non-contact mapping to identify the origin (i.e., snap shots)? I think it is difficult to draw 3D-maps during initiation (i.e., only one beat).

3. Did the authors check voltage maps around the origin of AF? In Fig 1, the signal amplitudes at PEN15-16 keep changing. How were the unipolar signals at the origin of AF?

4. If the authors believe these AFs were not associated with PVs, why did the authors isolate PVs?

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

[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.

PONE-D-21-34553R1Electrophysiological Characteristics of Non-Pulmonary Vein Triggers Excluding Origins from the Superior Vena Cava and Left Atrial Posterior Wall: Lessons from the Self-reference Mapping TechniquePLOS ONE

Dear Dr. Nishino,

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.

Your paper was evaluated by three experts in the field. Though the topic is interesting, I think all reviewers are somehow skeptical of the feasibility and accuracy of the mapping method. Further validation is necessary. Please read the comments carefully and address the issues accordingly.      

Please submit your revised manuscript by Feb 19 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,

Tomohiko Ai, M.D., Ph.D.

Academic Editor

PLOS ONE

[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 #2: (No Response)

Reviewer #3: (No Response)

**********

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 #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: I Don't Know

**********

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 #2: 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 #2: 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: The authors examined the coupling interval and the voltage of the non-PV-SVC-LAPW triggers initiating AF and compared the voltage of them with that of the sinus rhythm. I think this study is interesting. However several issues should be clarified.

1. The authors concluded that Non-PV-SVC-LAPW triggers had a short coupling interval (Page2, Line18). Compared with what was the coupling interval of the AF triggers short? Since it is obvious that the coupling interval of the AF trigger is shorter than the cycle length of the sinus rhythm, the coupling interval of the AF trigger should be compared with those of atrial premature beats not initiating AF that were observed in the 21 patients.

2. The authors described the self-reference mapping technique (Page6, Line4). However, I think that the triggers originating from certain locations such as the CS, region near the tricuspid annulus are cumbersome to map using the PEN catheter alone. Were all the non-PV triggers able to be mapped using the PEN catheter alone without ablation catheter?

3. The authors found that the median number of self-reference mapping points to detect the trigger origin was 8 (Page8, Line12). Was external or internal electrical cardioversion used to restore the sinus rhythm during the mapping? What is the median number of the cardioversion needed to detect the non-PV trigger origin in each patient?

4. The authors showed the activation like preferential conduction (Page9, Line 13). Was the PEN catheter located at the right atrial septum (near the fossa ovalis)? It looks like that the earliest small potential was followed by the large sharp potential at Pen 15-16. The earliest small potential may be caused by ectopy from the LA septum. Was the electrogram of the LA septum simultaneously recorded using the ablation catheter during the mapping?

Reviewer #2: This is a sub-study of their previous report that showed clinical outcomes of their unique technique called self-reference mapping. In the present study, the authors evaluated the electrophysiological characteristics of the AF triggers, excluding origins from the PV, SVC, and LA posterior wall (non-PV-SVC-LAPW).

The authors showed that the non-PV-SVC-LAPW triggers had a short coupling interval and the voltage at the onset of AF was low regardless of the voltage during sinus rhythm.

I found the manuscript to be insightful and well-written. The authors adequately responded to the comments of the previous reviewer. Here, I would like to raise just one but critical issue.

The authors speculated two possible explanations regarding the mechanisms of the voltage change of the trigger site in terms of the voltage during sinus rhythm. They speculated that damaged low voltage tissue might be masked by healthy high voltage tissue during the sinus voltage. I think there were no evidence to support this hypothesis because they did not create whole voltage map and compare the voltage between the trigger and the other intact area.

On the other hand, the authors also presented that the voltage at the onset of AF was consistently low regardless of the voltage during sinus rhythm (Table 3, 0.17 vs. 0.13 mV, p=0.137).

The source-sink relationship could also be the reason for the low voltage at the onset of AF. During the sinus rhythm, the trigger myocardium depolarizes simultaneously with the surrounding myocardium by the propagation from the sinus node. Therefore, the total current at the trigger reflects the simultaneous depolarization of both the trigger myocardium and the surrounding myocardium. However, at the onset of AF, the trigger myocardium depolarizes at first and could only depolarize the neighboring cells, then the total current recorded at the origin becomes low.

I would like to recommend the authors to check the review by Dr. Peter Spector (Circ Arrhythm Electrophysiol. 2013;6:655-661) and consider incorporating this possible mechanism into the discussion.

Reviewer #3: Authors described the electrophysiological characteristics of non-PV trigger excluding the triggers from left atrial posterior wall (LAPW) and superior vena cava (SVC) using the self-reference mapping technique. Thirty-two non-PV-SVC-LAPW triggers were documented in 23 out of 446 patients (5%), and 28 triggers were evaluated in this study. Authors found 1) the trigger voltage at the onset of AF was low, and 2) coupling interval from the non-PV-SVC-LAPW was short. Non-PV-SVC-LAPW trigger appeared from not only the low voltage area but also normal voltage area. Non-PV-SVC-LAPW origin trigger are difficult to map the origin accurately and their electrophysiological characteristics are not well understood. Overall, the manuscript was well written and some findings were very informative to the reader. However, reviewer has some questions and comments.

Major comments

1. Authors divided the non-PV-SVC-LAPW triggers into 2 groups according to the voltage during sinus rhythm. The voltage change ratio was lower in the group with normal voltage during sinus rhythm than the group with low voltage during sinus rhythm. This finding is natural because the voltage of trigger was comparable between 2 groups and authors defined the group according to the voltage during sinus rhythm. What is the difference of electrophysiological significance of the voltage change ratio compared to the voltage during sinus rhythm at the part of the triggers?

2. Authors showed the relationship between the voltage change ratio and trigger coupling interval in Figure 3 right panel. Please create and analyze the diagrams of the relationship between the voltage at the trigger part during sinus rhythm and trigger coupling interval, and the relationship between the voltage of trigger and coupling interval.

3. Please show the outcome of the patients in this study after the procedure. If redo-procedures were performed in recurrent cases, please show the electrophysiological finding of redo-procedure.

Minor comments

1. Authors defined the non-PV trigger as AF initiating triggers and mapped average 8 times to detect the origin of the trigger. That’s means authors required the cardioversion at least average 8 times. Please show the number of cardioversion which authors performed.

2. Please mention the potential of AF initiating triggers induced by the mapping catheter.

**********

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: No

Reviewer #2: No

Reviewer #3: No

[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.

Electrophysiological Characteristics of Non-Pulmonary Vein Triggers Excluding Origins from the Superior Vena Cava and Left Atrial Posterior Wall: Lessons from the Self-reference Mapping Technique

PONE-D-21-34553R2

Dear Dr. Nishino,

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,

Tomohiko Ai, M.D., Ph.D.

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

Reviewer #2: All comments have been addressed

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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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 #2: 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 #2: 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: Thank you for the revision. I think the conclusions has been revised to be reasonable. I have no further comment.

Reviewer #2: The authors have adequately responded to the comment and adopted the source-sink mismatch as the first possible mechanism of the voltage change of the trigger site.

Reviewer #3: I appreciate the authors significant efforts to clarify and address this reviewer's questions. Hopefully the revised manuscript has been strengthened as a result. I have no further comments.

**********

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: No

Reviewer #2: Yes: Taku Nishida

Reviewer #3: No