PONE-D-24-46135Study on the efficacy of NetrodTM Six-electrode Radiofrequency Renal Denervation system on renal artery vesselsPLOS ONE

Dear Dr. Nan,

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.

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This is an interesting study that requires work. Though the study is novel, it requires the addressing of all comments raised by both the reviewers.

Additionally, in the first paragraph of Introduction, I would mention the clinical utility of renal denervation currently, beyond hypertension. You could refer to reviews encapsulating these findings, such as: https://doi.org/10.1016/j.cpcardiol.2023.102196

Furthermore, the discussion requires work. An additional paragraph on comparing and contrasting your findings with existing literature, what's novel about your results, and some background with pros and cons on all three types of electrodes used and their comparisons in either the introduction or second paragraph of the discussion is warranted. 

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Please submit your revised manuscript by Jan 10 2025 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Academic Editor

PLOS ONE

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Additional Editor Comments:

This is an interesting study that requires work. Though the study is novel, it requires the addressing of all comments raised by both the reviewers.

Additionally, in the first paragraph of Introduction, I would mention the clinical utility of renal denervation currently, beyond hypertension. You could refer to reviews encapsulating these findings, such as: https://doi.org/10.1016/j.cpcardiol.2023.102196

Furthermore, the discussion requires work. An additional paragraph on comparing and contrasting your findings with existing literature, what's novel about your results, and some background with pros and cons on all three types of electrodes used and their comparisons in either the introduction or second paragraph of the discussion is warranted.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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: No

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

Reviewer #1: N/A

Reviewer #2: N/A

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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: No

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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: No

Reviewer #2: Yes

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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: In this manuscript, the authors examined the depth and circumference of ablation lesions produced by the Netrod and other radiofrequency renal denervation systems through simulation models and phantom experiments. While the information provided has clinical significance, there are several methodological limitations and content inconsistencies that cast doubt on the conclusions.

The title (referring to efficacy and safety, as shown on the first page, which differs from the title on the first page of the text) is inconsistent with the content presented, which only addresses the extent of ablations and does not discuss efficacy or safety.

Major limitations requiring clarification:

Abstract Inconsistency: The abstract on the first page of the PDF file mentions animal studies and histological analysis. However, the main text and its abstract only present data on ablation lesion depth and circumference from different radiofrequency renal denervation systems. Additionally, the titles differ between sections. The content is limited and inconsistent with the title on the first page ("Study on the efficacy and safety of Netrod™ Six-electrode Radiofrequency Renal Denervation system on renal artery vessels"), as no information regarding clinical efficacy and safety is presented.

Unsupported Assumptions in Introduction: The authors assume that "continuous circumferential (ring)" ablation is superior for renal denervation without providing supporting evidence. The Medtronic Symplicity Spyral system deliberately uses a "non-continuous" circumferential ablation pattern to prevent continuous vessel injury, which might lead to renal artery stenosis. The authors should provide histological evidence demonstrating the safety of continuous circumferential ablations achieved by the Netrod before asserting its superiority over non-continuous circumferential ablation in terms of efficacy or safety.

Missing Table: Table 3 is referenced in Results 3.1 but is not present in the manuscript.

Incomplete Information in Figure 9: The vessel diameter in the simulation model should be specified, as this parameter significantly influences the continuity of ablation lesions across different systems.

Inequitable System Comparisons: The default ablation times for different renal denervation systems are either 60 or 120 seconds. Comparing ablation extent at 30 seconds (Figure 8) or 5 seconds (Figure 9) provides an unfair comparison. Results should be shown for at least 60-second ablations across all systems.

Contradictory Results: In Results 3.3, the authors note that phantom experiments allow for optimal manual positioning of the Netrod™ Six-electrode against the vessel wall, while simulation experiments show poorer wall apposition. However, the smaller ablation depth and extent observed in phantom experiments contradict the expected benefits of better contact. This discrepancy requires explanation.

Incomplete Methodology: The ablation settings for other renal denervation systems are not described. These parameters should be clearly detailed to substantiate the fairness of the comparisons.

Reviewer #2: Comments for the Editors

The title of the manuscript does not indicate that this is an experiment and nor a clinical study.

This is not even an animal study, but a mathematical simulation on software and phantoms that limits the overall relevance of the experiments.

This should be specified in the title and the conclusions of the manuscript.

Thank you for the possibility of cooperating with the Journal, and kind regards.

PONE D-24-46135

Article type: Research Article

Study on the efficacy and safety of Netrod TM Six-electrode Radiofrequency Renal Denervation system on renal artery vessels

Comments to the authors

General

First of all, this experimental study has not been performed in renal arteries, but in a cylindrical synthetic mold made of Polyacrylamide. Therefore, the title should not mention the words renal artery vessels but rather “polyacrylamide phantom”. Likewise, not been performed in biological tissues of living organisms it cannot refer to “safety”.

Introduction. Authors should remove the comment on Flex and limit to spiral since the flex has no possibilities of spatial orientation of the electrode.

Specific

The following sentenced is not supported by the presented data and should be deleted:

“The NetrodTM Six-electrode device demonstrated effective ablation of renal sympathetic nerves, achieving temperatures of up to 45°C at distances of approximately 5.08 mm (>4 mm) from the electrodes. This confirms the feasibility and efficacy of using the NetrodTM Six-electrode for radiofrequency ablation of the renal sympathetic nerve”.

Indeed, such a sentence cannot be accepted since by no means the authors are testing the effect of the device on renal nerves, but in a phantom. The reader would be mislead with such a sentence that should clearly state that was changes color as an indirect indicator of heat is a synthetic material and not real tissues.

To affirm that the observed changes obtained after heating the RF electrodes are effective in ablating nerves, the experiments should be performed in animal models or in human cadavers.

Similarly, further in the results: “NetrodTM Six-electrode to be positioned optimally against the vessel wall”

Or in the discussion: “Results show that the NetrodTM Six- electrode system provides more comprehensive coverage and better continuity of the ablation zone compared to both the single electrode and the spiral six electrodes under the same setup. Lesion formation is influenced by several factors, including ablation power, ablation time, the number of electrodes, the area in contact with tissue, and blood flow”

Sentences as such cannot be proposed since there is no vessel wall, but a simple synthetic cylinder. Authors should therefore be clear with the reader and avoid any reference to tissues, vessels, blood and nerves.

Comparison of ablation effect of NetrodTM Six-electrode with single electrode and spiral six electrode: the authors do not explain the method used to detect and quantify the dispersion of the heath in figures 7,8 and 9.

What is the model used to test 6 spiral electrodes? The commercially available spiral system (Medtronic) has 4 electrodes and not 6. If the spiral 6 electrodes used in this study was developed by the investigators please provide details of the model used and clarify that is not the one commercially available, and that the effect described for 6 electrodes may not apply to a 4 electrodes spiral catheter.

Figure 10. Please explain how the phantom model was constructed and how was the effect of RF assessed.

The authors affirm that “The electrodes are treated as uniformly heated sources, spreading heat consistently into the bloodstream and surrounding tissue through conduction” how can they say that if their model has no fluid circulation, and therefore, temperature dispersion by blood temperature and flow cannot be calculated?

Authors used 60°C for 120 seconds with their device.

Other commercially available use variable temperature for 60 seconds. The authors should explain on which observations (ideally obtained in animals) they base the selection of temperature and duration of the energy delivery, and demonstrate in biological tissue of animals or cadavers, that such combination of temperature and duration is not creating unintended tissue damage to neighbor structures such as the artery wall, veins, lymphatic or urinary structures.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-46135R1Study on the efficacy of NetrodTM Six-electrode Radiofrequency Renal Denervation system on renal artery vesselsPLOS ONE

Dear Dr. Nan,

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.

Please look below for changes suggested by me, the Editor, and the reviewers at the end of this email.

Please submit your revised manuscript by Mar 19 2025 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,

Aman Goyal

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:

Dear Dr. Nan,

As I mentioned during the round one of revision. Please do add a more complete and expanded discussion. The discussion is too short and does not delve into comparing of your own results, with the results of existing literature on this topic that is published.

Please follow this format:

First paragraph of discussion: Key results

Second paragraph: Importance of your findings, and how it is clinically relevant.

Third paragraph: Comparison of your results with existing literature.

Fourth paragraph: Strengths and Limitations of your study

Followed by conclusion.

Please make sure the discussion has points that bring to light the clinical relevance of your study, how it guides future research that needs to be conducted.

Please address points raised by the reviewers as well.

[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: All comments have been addressed

Reviewer #2: (No Response)

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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: (No Response)

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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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

Reviewer #2: (No Response)

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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: No

Reviewer #2: (No Response)

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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 revised extensively according to the comments. The revised version is much improved, though there are still some points need to be clarified. There are quite a few grammatical/tense errors, which require detailed English editing to make it friendly to the readers.

1. Title: The title “Study on the efficacy of NetrodTM Six-electrode Radiofrequency Renal Denervation system on renal artery vessels” does not match the findings. The authors provide information includes studies based on mathematical modeling, phantom experiments and animal study. It is not solely based on studies on renal arteries. It would be more rational and informative to revise the title to “The efficacy of NetrodTM Six-electrode Radiofrequency Renal Denervation system: mathematical modeling, phantom experiments and animal studies”.

2. Abstract: The statement “Systematic ablation can reach the target temperature in a shorter period of time, with faster warming, greater peripheral coverage of the lesion, and a more continuous ablation zone.” is not consistent with the findings. Given there is no comparison with other devices, it would not be rational to state that Netrod is “shorter”, “faster”, or “greater”. The authors should revise and describe the findings in a neutral manner.

3. Lesion continuity: Given that the depth of 45 degree boundary at 30 seconds of heating was 2.69 mm (Table 3), the distance between electrodes should be less than 5.4 mm to achieve continuity. The authors should introduce the distance between electrodes in the manuscript to make readers realize how continuity could be established, rather than simply showing a figure with no supportive data. Further, the authors did not provide data regarding the statement in the Abstract “Circumferential coverage was up to 91.99% and the ablation zone was continuously.” The authors should provide relevant data.

4. Lesion depth and width in animal studies: According to Figure 12, the mean ablation depth in animal studies seems to be less than 3 mm, which is less than the distance reported in simulation and phantom studies (5-6 mm). As the authors mentioned in the Discussion “AI Raisi et al. [30] reported a circumferential coverage angle of 54.90° ± 4.36° for a single electrode RF application, encompassing approximately 15% of the arterial wall circumference”, the authors should provide exact numbers of ablation depth and width (or coverage angle) in a Table and a representative H&E figure to show how the lesion depth and width were measured. The authors should discuss why there was such a discrepancy in ablation depth between animal studies and simulation studies and whether it would impact the so-called “continuity” to be established and the corresponding ablation strategy.

5. Confusing terms and grammatical errors: It is confusing what “test article”, “preanatomic” (Figure 7 legend), “blank control” refer to. It might be “treatment group”, “pre-ablation” and “sham-control”, but it is definitely hard for readers. Extensive language editing is required.

Reviewer #2: The authors have aproperly addressed my requests.

I have no other comments

The authors have aproperly addressed my requests.

I have no other comments

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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

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[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.

Attachments

Attachment

Submitted filename: PONE-D-24-46135_R1_reviewer.pdf

The efficacy of NetrodTM Six-electrode Radiofrequency Renal Denervation system: mathematical modeling, phantom experiments and animal studies

PONE-D-24-46135R2

Dear Dr. Nan,

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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Aman Goyal, MD

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

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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

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

Reviewer #1: Yes

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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

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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: In this revised manuscript, the authors adequately responded to the comments I made in the review. There are some minor issues to be solved in this version, which I mention below.

1. Depth of ablation in animal studies: It should be commended that the authors displayed the depth of ablation in detail in Figure 13. Even though the depth is smaller than what had been observed in simulation and phantom studies, the authors should emphasize in the Discussion that the depth measured in animal studies was based on the furthest nerve damaged, rather than soft tissue involved, which would be difficult to judge. Hence, the depth of ablation could be underestimated inherently, if the distribution of nerves surrounding the renal artery segment was scarce beyond 3 mm. The authors should mention this as one of the reasons why there were discrepancies between the depths observed in different settings.

2. Abstract: The timing of assessment (7, 30, and 60 days) in animal studies should be mentioned in the Abstract.

3. Abstract: The statement should be neutral. “Strong” in the last sentence of the Abstract seems not appropriate.

4. “TM” should be typed as superscript throughout the article.

5. Results: The sentence in Animal Study Results, “pre-anatomic diastolic and mean arterial pressures in animals 101 may not be statistically different relative to pre-ablation due to individual differences (P>0.05)”, is confusing. The word “pre-anatomic” should be “post-ablation”.

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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:  Tzung-Dau Wang

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