Factors mediating the pressor response to isometric muscle contraction: An experimental study in healthy volunteers during lower body negative pressure

Niels A. Stens; Jonny Hisdal; Espen F. Bakke; Narinder Kaur; Archana Sharma; Einar Stranden; Dick H. J. Thijssen; Lars Øivind Høiseth

doi:10.1371/journal.pone.0243627

Peer Review History

Original SubmissionAugust 20, 2020
15 Oct 2020 Decision Letter - Gerson Cipriano Jr., Editor PONE-D-20-26181 The relative importance of central versus peripheral factors in mediating the pressor response to isometric muscle contraction in healthy volunteers PLOS ONE Dear Dr. Lars Øivind Høiseth 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. The manuscript has been assessed by one reviewer; their comments are available below. The reviewer have raised some concerns that need attention in a revision. The reviewer note that Title, introduction and discussion rational sections needs review and they raise questions regarding the conclusion employed. Please submit your revised manuscript by November, 15th, 2020. 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Kind regards, Gerson Cipriano Jr., PT, MsC, Ph.D. Academic Editor PLOS ONE Additional Editor Comments: Dear Dr Lars Øivind Høiseth I want to ask you also to incorporate some additional information, including: - Clinical Trial Registration Number; - Study design description; - Comprehensive statistical analysis description including normality test, - within- and between difference and sample size calculation; - Review of the table's legends, including p-value, units of measure, the measure of central tendency, and dispersion. - Limitation section including the topics presented by the reviewer. 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. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [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. 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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 ****** 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: This study examined the potential interaction between the effects of lower-body negative pressure (LBNP), which unloads the low-pressure baroreceptors and causes a sustained increase in muscle sympathetic nerve activity (MSNA), and the effects of isometric handgrip exercise (IHG), which causes a progressive increase in MSNA. The authors have used a good design, applying two different levels of LBNP - either in isolation or during IHG. While the results are clear, I do not agree with the authors use of the term "central" to refer to events in the heart. As such, the title is very misleading. There is strong evidence that increases in MSNA during IHG are due to increases in sympathetic outflow to muscle vascular bed, leading to an increase in total peripheral resistance (TPR), with peripheral feedback from metaboreceptors coming in later in the contraction as metabolites accumulate. Most investigators consider "central" to mean "central command," which originates in the brain and is responsible for the increase in sympathetic outflow to the blood vessels and the heart, and withdrawal of parasympathetic outflow to the heart, that parallels the increase in skeletomotor and fusimotor activity to the contracting muscles. Indeed, the increase in heart rate is considered to be exclusively due to the increase in central command. Peripheral feedback includes the metaboreceptors and mechanoreceptors in the contracting muscle. Moreover, recent evidence has shown that the increase in MSNA is directed to contracting as well as non-contracting muscle. The authors' conclusions that an increase in TPR is responsible for the increase in MAP during IHG is not particularly novel: this has been known for a long time. The authors need to state what their observations contribute to the literature, particularly given that they did not record MSNA or central venous pressure. ****** 6. 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Revision 1
20 Nov 2020 Author Response Lars Øivind Høiseth Dept. of Anesthesiology Oslo University Hospital Oslo Norway Gerson Cipriano Jr., PT, MsC, Ph.D. Academic Editor PLOS ONE Oslo 15th November 2020 Response to editor and reviewer, PONE-D-20-26181 In behalf of the authors, I would like to thank the editor and reviewer for the thorough review of our manuscript and for the opportunity to submit a revised version. Below, we have gone through the changes made during the revision. Academic editor: - Clinical Trial Registration Number Due to the experimental nature of this study, it was not registered in a clinical trial registry. - Study design description The study design has been added to the title, now reading: “Factors mediating the pressor response to isometric muscle contraction: An experimental study in healthy volunteers during lower body negative pressure” - Comprehensive statistical analysis description including normality test, - within- and between difference and sample size calculation; We have added a sentence regarding normality assumptions (lines 187-189). Within- and between group differences are presented in Tables 1 and 2. When planning the study, we were unfortunately not able to find data allowing for a meaningful sample size analysis. We therefore performed the study with a convenience sample, including a number of subjects within the range which is usual for this kind of experimental study (lines 361-365). - Review of the table's legends, including p-value, units of measure, the measure of central tendency, and dispersion. We have reviewed the tables´ legends and performed minor revisions. - Limitation section including the topics presented by the reviewer. We have added a section “Methodological considerations”, addressing the above limitations and those presented by the reviewer. Reviewer Reviewer #1: This study examined the potential interaction between the effects of lower-body negative pressure (LBNP), which unloads the low-pressure baroreceptors and causes a sustained increase in muscle sympathetic nerve activity (MSNA), and the effects of isometric handgrip exercise (IHG), which causes a progressive increase in MSNA. The authors have used a good design, applying two different levels of LBNP - either in isolation or during IHG. While the result are clear, I do not agree with the authors use of the term "central" to refer to events in the heart. As such, the title is very misleading. There is strong evidence that increases in MSNA during IHG are due to increases in sympathetic outflow to muscle vascular bed, leading to an increase in total peripheral resistance (TPR), with peripheral feedback from metaboreceptors coming in later in the contraction as metabolites accumulate. Most investigators consider "central" to mean "central command," which originates in the brain and is responsible for the increase in sympathetic outflow to the blood vessels and the heart, and withdrawal of parasympathetic outflow to the heart, that parallels the increase in skeletomotor and fusimotor activity to the contracting muscles. Indeed, the increase in heart rate is considered to be exclusively due to the increase in central command. Peripheral feedback includes the metaboreceptors and mechanoreceptors in the contracting muscle. Moreover, recent evidence has shown that the increase in MSNA is directed to contracting as well as non-contracting muscle. The authors' conclusions that an increase in TPR is responsible for the increase in MAP during IHG is not particularly novel: this has been known for a long time. The authors need to state what their observations contribute to the literature, particularly given that they did not record MSNA or central venous pressure. We used the terms “central” as opposed to “peripheral” out of our focus on circulation (e.g. total peripheral resistance). We do acknowledge that this is misleading in the context of the present manuscript, and have changed this throughout the manuscript. We now simply refer to the respective variables by their names. We also agree with the reviewer regarding the current understanding of the mechanisms behind the nervous responses to IHG. Although it is indeed a limitation to our manuscript that we did not measure MSNA, we believe it is a strength that we measured local blood flow and thereby derived resistance to the non-contracting arm which represents a more downstream mediator of the pressor response. The fact that we did not find increased local resistance in the resting arm during IHG is somewhat surprising, regarding the current understanding as stated by the reviewer, and we have emphasized this finding by adding this variable to Table 1. Yours sincerely Lars Øivind Høiseth, MD, PhD https://doi.org/10.1371/journal.pone.0243627.r002
25 Nov 2020 Decision Letter - Gerson Cipriano Jr., Editor Factors mediating the pressor response to isometric muscle contraction: An experimental study in healthy volunteers during lower body negative pressure PONE-D-20-26181R1 Dear Dr. Høiseth, 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, Gerson Cipriano Jr., PT, MsC, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0243627.r003
Formally Accepted
1 Dec 2020 Acceptance Letter - Gerson Cipriano Jr., Editor PONE-D-20-26181R1 Factors mediating the pressor response to isometric muscle contraction: An experimental study in healthy volunteers during lower body negative pressure Dear Dr. Høiseth: 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 Professor Gerson Cipriano Jr. Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0243627.r004

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