PONE-D-23-00760Low serum Brain-Derived Neurotrophic Factor may predict poor response to cardiac rehabilitation in patients with cardiovascular diseasePLOS ONE

Dear Dr. Tsukada,

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 submit your revised manuscript by Mar 24 2023 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Rabbanie Tariq Wani

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. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://doi.org/10.1093/eurheartj/ehy565.P2552

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

4.  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:

One of the reviewers have suggested for a minor review, please find there comments attached

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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

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

Reviewer #1: 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

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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

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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: The authors showed that serum BDNF levels can predict the effect of exercise therapy on patients with cardiovascular disease. Furthermore, they showed that serum BDNF levels were associated with patient nutritional status. This reviewer considers this study to be an interesting study. I have some questions.

1. Nakano et al. reported that serum BDNF levels were associated with skeletal muscle strength, but not skeletal muscle mass (Int Heart J 2020;61(1):96-102). Present study also showed no association between BDNF levels and skeletal muscle mass, consistent with previous result. What indicators of skeletal muscle strength are measured in this study?

2. Previous reports have shown that serum BDNF levels are decreased in patients with heart failure and that serum BDNF and peak oxygen uptake are closely related (J Card Fail 2015;21(4):300-306, Int J Cardiol 2013;168:e142-144). In this study, peak oxygen uptake before exercise therapy was not associated with serum BDNF levels. Please discuss these differences.

3. BDNF is believed to be secreted from skeletal muscle during exercise. Did serum BDNF levels change after exercise therapy?

4. FIG. 1 shows the before-and-after changes of an individual patient. Therefore, please show the graph with a line connecting the points before and after so that you can see the change.

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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.

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Reviewer #1: No

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PONE-D-23-00760R1

Low serum brain-derived neurotrophic factor may predict poor response to cardiac rehabilitation in patients with cardiovascular disease

PLOS ONE

Dear Dr. Tsukada,

Thank you for submitting your manuscript to PLOS ONE. One additional expert reviewer carefully evaluated your manuscript. The comments are included below. Although the reviewer and I find merit in your study, I myself found concerns about the statistical analysis that precludes its acceptance for publication in PLOS ONE.

I invite you to respond to the reviewer’s comments and my own, and submit a revision if you believe you can adequately address the concerns. Please note that this request for revision does not imply that the manuscript will ultimately be accepted, but that the manuscript must be meticulously revised before further consideration is provided.

Your revised submission must include an itemized, point-by-point response to the comments of the reviewer and editor.

Please submit your revised manuscript by Aug 19 2023 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,

Yuichiro Nishida

Academic Editor

PLOS ONE

Additional Editor Comments :

Major comments:

The topic of the present study is interesting, and the results are potentially important for the development of tailored, optimized exercise programs for patients with cardiovascular disease. However, I have concerns regarding the statistical analysis. To answer the main research question, you used paired t-tests to assess pre-post changes in AT and Peak VO2 within groups. This is not sufficient to answer the research question. Instead, you should statistically compare pre-post changes in AT and Peak VO2 “between” the three groups (instead of “within” groups). For instance, the changes (increases) in AT and Peak Vo2 in the high BDNF group are significantly greater than the changes (increases) in AT and Peak Vo2 in the low BDNF group? Additionally, to adjust for potential confounding factors, an analysis of covariance (ANCOVA) may be used to calculate the adjusted means (and 95% confidence intervals) of the changes in AT and Peak VO2 in the three groups. Although there were no statistically significant differences among the three groups for age, sex, main disease, comorbidities, medication, ejection fraction, or SMI at baseline, there may be tendencies that the subjects in the low BDNF group are older, have a lower percentage of males, a lower percentage of coronary artery disease, a higher percentage of post-operated, and a higher percentage of β blocker use (as shown in Table 1). These factors are considered potential confounding factors that should be adjusted as covariates in the multivariate analysis. Although you may not be familiar with multivariate analysis, you should use multivariate analysis (e.g., ANCOVA) to adjust for at least age and sex as covariates and statistically compare the adjusted means (and 95% confidence intervals) of the changes in AT and Peak VO2 “between” the three groups. According to the additional results obtained from the new analyses, the whole manuscript (especially, the methods section, the results section, and the discussion and conclusion sections) should be revised adequately.

Minor comments:

How was the sample size (n = 99) determined?

How was the study participants’ adherence to the cardiac rehabilitation program in the three groups?

Page 16, last line: Font size is large.

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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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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

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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

Reviewer #2: 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: (No Response)

Reviewer #2: The paper is very solid and definitely publishable. They could consider including a recent paper of close to 900 followed 7 years showing peak VO2 after CR is the strongest predictor of survival ( Carbone Set al. EHJ-QCCO 2022; 8: 361-367) and a State of the Art discussing how cardiorespiratory fitness predicts survival following CR ( Tutor A et al. Prog Cardiovasc Dis 2022; 70: 2-7.)

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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: Yes: Carl " Chip" Lavie MD

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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-23-00760R2Low serum Brain-Derived Neurotrophic Factor may predict poor response to cardiac rehabilitation in patients with cardiovascular diseasePLOS ONE

Dear Dr. Tsukada,

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 submit your revised manuscript by Nov 30 2023 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,

Yuichiro Nishida

Academic Editor

PLOS ONE

Additional Editor Comments:

You performed additional statistical analyses as requested by me. However, unfortunately, there are still a few severe concerns related to the additional analyses. I feel that your revision is insufficient.

The conclusion (described in the Abstract and the last paragraph of the Discussion section) is still mainly supported by the within-group comparison of AT and peak VO2. As I previously suggested, the conclusion must be based on the between-group comparison of the difference (%change) in the aerobic capacity indices.

In the Methods in the Abstract, there is no explanation of the statistical analysis mainly used. A description of the between-group comparison of the difference (%change) in aerobic capacity indices using ANCOVA is missing.

Please clearly mention which statistical analysis is mainly used to make a conclusion in the Statistical Analysis section. For instance, “Analysis of covariance (ANCOVA) followed by post-hoc analysis using Turkey’s HSD test was conducted to compare age- and gender-adjusted %increase in AT and peak VO2 after 3-week CR, as a main statistical analysis of the present study”.

In the Results section, you mentioned that “However, age- and gender-adjusted %increase in AT did not differ among the three groups”. Please show exact P values for these differences. Did age- and gender-adjusted %increase in AT not show a similar tendency as the peak VO2?

If there is not that tendency, please touch on the potential reason why the significant effect was seen only in the peak VO2 in the Discussion section.

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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.

PONE-D-23-00760R3Low serum Brain-Derived Neurotrophic Factor may predict poor response to cardiac rehabilitation in patients with cardiovascular diseasePLOS ONE

Dear Dr. Tsukada,

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 submit your revised manuscript by Jan 19 2024 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,

Yuichiro Nishida

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:

The description regarding the association analysis (as one of the main statistical analyses in the present study to support the conclusion) is completely missing. Did you analyze the multivariate association of baseline BDNF (as an independent variable) with the % increases in AT or peak VO2 (as dependent variables) with adjustment for age and gender? Is the baseline BDNF (as an independent variable) treated as a continuous (mg/ml) or categorical [low, middle, high] variable? Similarly, is age (as a covariate) treated as a continuous (years) or categorical variable (another covariate gender should be treated as a categorical variable)? This important information should be clearly written in the manuscript (in the Methods in the Abstract and the Statistical Analysis in the Methods section). I have recognized that the description regarding the other main statistical analysis ANCOVA is also missing in the Methods in the Abstract.

The expression regarding the main result “correlation with baseline BDNF levels was found for the CR-induced increases in peak VO2” is somewhat strange. Please change the expression from “correlation with baseline BDNF levels was found for the CR-induced increases in peak VO2” to “ (significant) association between baseline BDNF levels and CR-induced increase in peak VO2 was found (or [significant] association of baseline BDNF levels with CR-induced increase in peak VO2 was found)” throughout the manuscript.

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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.

Low serum Brain-Derived Neurotrophic Factor may predict poor response to cardiac rehabilitation in patients with cardiovascular disease

PONE-D-23-00760R4

Dear Dr. Tsukada,

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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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,

Yuichiro Nishida

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for your revision. Congratulations!

Reviewers' comments: