PONE-D-20-24916

Endovascular baroreflex amplification and the effect on sympathetic nerve activity in patients with resistant hypertension: a proof-of-principle study

PLOS ONE

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Michiel Voskuil, MD, PhD

Academic Editor

PLOS ONE

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[Monique E.A.M. van Kleef was indirectly paid from a research grant by Vascular Dynamics, Inc. Karsten Heusser, P. Liam Oey, Jens Tank, André Diedrich and Peter J. Blankestijn report no conflict of interest. Jens Jordan served as consultant for Novartis, Boehringer-Ingelheim, Sanofi, Orexigen, Riemser, Vivus, and is cofounder of Eternygen GmbH. Bryan Williams has received honoraria for consultancy from Vascular Dynamics Inc. W. Spiering is a consultant for Vascular Dynamics and has received a research grant from Vascular Dynamics.].

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: Yes

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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: Yes

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: A proof-of-principle study (n=14/10 evaluable) was conducted to explore potential mechanisms for lowering blood pressure. The effects of endovascular baroreflex amplification (EVBA) on muscle sympathetic nerve activity (MSNA) and baroreceptor sensitivity (BRS) were investigated. The primary outcome was change in MSNA. Secondary outcomes were change in baroreflex sensitivity (BRS), cardiovascular responses to a sympathetic stimulus, BP, heart rate (HR) and heart rate variability (HRV). The results are primarily descriptive.

Minor revisions:

1- Line 223: Report occurrences of adverse events with both frequencies and percentages. To provide additional clarity, consider providing a table which summarizes the adverse events.

2- Provide percentages which correspond to the number of patients out of the total evaluated. For example, consider Line 257, indicate that 6 of 10 is 60%.

3- Line 262: Explain how the following statement can be justified statistically. “The trend to decrease in MSNA could not be explained by change in quality of the MSNA measurement, since MSNA signal-to-noise ratio at baseline and 3 months post-implantation were similar.”

Reviewer #2: Van Kleef and colleagues investigated the effects of a novel blood pressure lowering device (Mobius HD) on muscle sympathetic nerve activity (MSNA) and baroreceptor sensitivity (BRS). Mobius HD is a self-expanding nitinol implant that is delivered percutaneously to the internal carotid sinus using an intravascular delivery system. The objective of the implant is to amplify the baroreceptor signaling resulting in reduction of blood pressure through vasodilation. The manuscript is well written and easy to follow and provides us with interesting data. The authors should be congratulated on their work. However, I have some concerns regarding several aspects of the paper that require revisions.

1. This is an ancillary investigation of the CALM-DIEM study. The investigators published their data of the first-in-human trial of this implant in patients with resistant hypertension (Spiering et al. Lancet, 2017). This device was associated with a reduction in 24-hour ambulatory systolic blood pressure of 21/12 mmHg at six months after implantation.

2. The number of patients included in the study seems to be insufficient to draw firm conclusions.

3. The authors report that they did not find a correlation between change in MSNA and BP after Mobius HD implantation. Current study needs to be discussed in light of publications such as Hoogerwaard et al (Clin Res Cardiol, 2019). They reported on the effects of high frequency electrical stimulation of renal nerves on heart rate variability, a non-invasive tool for autonomic nervous system function. Before RDN, high frequency electrical stimulation induced changes in heart rate variability suggesting alteration in autonomic balance with an increased sympathetic autonomic balance tone. Whereas, after RDN, the changes in heart rate variability reflected a lower sympathetic tone and greater parasympathetic tone after RDN.

4. Continuation and discontinuation of beta blockers during follow up need to be reported in conjunction with the statement of changes in MSNA and BRS. Hoogerwaard et al. (Clin Res Cardiol, 2019), reported that changes in heart rate variability were 1.5 times greater in patients off-beta-blockade, and no longer significant in patients on-beta-blockade and in a small group of patients with diabetes mellitus. Did you correct for these potential confounders?

5. While the results of this study are intriguing, it is important to underline that this is a sub-study of a previously published study that lacks power with the limited of patients in the current study weakening the findings and conclusions. The data and the findings are interesting and mostly hypothesis generating.

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Reviewer #1: No

Reviewer #2: No

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Endovascular baroreflex amplification and the effect on sympathetic nerve activity in patients with resistant hypertension: a proof-of-principle study

PONE-D-20-24916R1

Dear Dr. Spiering,

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.

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Kind regards,

Michiel Voskuil, MD, PhD

Academic Editor

PLOS ONE

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

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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: (No Response)

Reviewer #2: Yes

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

Reviewer #1: (No Response)

Reviewer #2: 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: (No Response)

Reviewer #2: 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: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: The authors adequately addressed the issues raised by the reviewers. The manuscript improved significantly after the revisions. No further 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