PONE-D-22-02168Cardiovascular effects of exercice induced dynamic hyperinflation in COPD patients – dynamically hyperinflated and non-hyperinflated  subgroups.PLOS ONE

Dear Dr. Varga,

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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The authors presented a longitudinal study that investigates how lung mechanical and cardiovascular parameters change in hyperinflated and nonhyperinflated COPD patients during physical exercise. Some significant results are presented related to the impact of dynamic exercise hyperinflation on cardiovascular system. I think this results are important in the field and want to encourage the authors to improve their manuscript according to the reviewers' comments. Please, resolve all the reviewer's considerations and suggestions.

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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: No

Reviewer #2: Yes

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

Reviewer #1: No

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: No

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: PONE-D-22-02168: statistical review

SUMMARY. This is a longitudinal study that investigates how lung mechanical and cardiovascular parameters change in hyperinflated and nonhyperinflated COPD patients during physical exercise. The statistical analysis is essentially based on repeated measures anova and Friedman tests for the analysis of cardiovascular parameters at different load levels. I have several concerns about this paper, (see major issues below). I also append below some specific points that should be addressed.

MAJOR ISSUES

1. As said in the abstract, the goal of this paper is to investigate “how lung mechanical and cardiovascular parameters change in hyperinflated and nonhyperinflated patients”. However ANOVA and Friedmann tests do not give a full answer to this question: they just test whether differences between different load levels are significant or not. A fully specified mixed model with random slopes would provide a more comprehensive analysis.

2. Almost nothing is said about the assumptions made. Results of the Kolmogorov-Smirnov test are not displayed and we don’t know which variables have been analyzed by ANOVA and which ones have been analyzed by a Friedman test. In addition, nothing is said about spericity of the ANOVA methods. This lack of material makes the results not reproducible and difficult to compare.

3. Hyperinflation is treated as a factor on which the statistical analysis is conditioned. However, the presence of dynamic hyperinflation is a response observed during the physical exercise. As a result, the whole statistical analysis doesn’t seem quite appropriate. Under this setting, a more natural strategy would be a battery of mixed models where both hyperinflation and cardiovascular parameters are treated as responses.

4. The available covariates described in Table 1 are ignored. The two samples of hyperinflated and nonhyperinflated COPD patients are treated as two homogeneous samples. I’d welcome a comparison between the two samples: significant associations between some covariates and the occurrence of hyperinflation could invalidate the whole analysis.

5. Results section: “the data set was reduced to 3 load levels in each case by averaging the parameters measured at medium load levels.” This is an unnecessary waste of information: repeated measure methods allow time series of different lengths

SPECIFIC POINTS

1. Although the authors state that the data are available without restrictions, data are not attached as supplementary material. Data should be attached to the submission or made availale in a public repository and metadata provided.

2. There are still English typos across the paper: please correct them.

3. Numbering pages and lines would facilitate the reviewer’s job …

Reviewer #2: The manuscript presents some significant results related to the impact of dynamic hyperinflation on cardiovascular system, a research direction that was recently emphasized by Smith et al. (ref [35] in the manuscript), who showed that COPD patients have lower stroke volume and cardiac output during exercise than controls and that hyperinflation has a major impact on central hemodynamics. Comparing two groups of COPD patients with and without dynamic hyperinflation and using noninvasive methods for measuring cardiovascular parameters, the authors showed that even if the cardiac output, stroke volume and oxygen delivery changes had a lower increase at exercise in the hyperinflated group, the left ventricular function (evaluated by the left ventricular ejection time index LVETi) was in good ranges in the two groups, with no significant differences between the groups; the authors are concluding that these results reflect the central circulatory effect of dynamic hyperinflation at exercise.

The intervention is a mixed combination between standard techniques and an original protocol.

The size of the study group was well established.

Acceptance by Ethical Committee is mentioned.

The methods are generally well described; nevertheless there are important aspects of the methods which are detailed elsewhere in the manuscript (method of defining hyperinflation and to calculate LVETi) and should be better mentioned in the “Methods” section:

- Page 9 paragraph 2 “Discussion” [...] decrease of IC, at least 5% and 100 ml (“DH group”) [...]

- Page 11 paragraph 5 [...] Ejection distance (ED) is the time [...] using ED and the heart rate we calculate LVETi [...] - ED is used instead of LVET which was previously mentioned as one of the parameters being measured.

The data underlying the findings in the manuscript were not fully available neither as part of the manuscript nor deposited in a public repository.

I recommend to include in the Results section a table which describes separately the subjects in the 2 groups: DH and non-DH, similar to table 1. It should also include the mean absolute values of cardiac parameters (SV, CO, CI, DO2, LVET and LVETi) at rest and after exercise for the DH and non-DH groups.

The results support in general the conclusion. However, while the Discussion section presents some previously published results, there is little comparison between these publications and the authors' results.

The authors describe also some limitations of their research.

The manuscript needs a more concise organization and a thorough revision for English and grammar. I strongly recommend language editing, as several misspelling are encountered throughout the paper.

Examples:

1. The second paragraph of the introduction does not contain references, and is repeated entirely in the Discussion section (third paragraph).

2. The last sentence in the conclusion should be rewritten:

[…] We can evaluate the effectiveness of different intervention in a complex way including cardiopulmonary function, which including pharmacotherapeutical and physical treatment, also.

3. Lack of citations:

In “Measurement of cardiovascular parameters”

[…] Previous studies have shown that the “Finometer Pro” measures the absolute values […]. This technique can therefore be used to quantify […]

4. There is no uniform style of citations:

Laveneziana et al. instead of Laveneziana P. et al […]

5. There is no uniform use of notation for gases:

DO2 versus DO2

6. The authors are using abbreviations not explained in the text:

PVR page 10 paragraph 3

PEEPi,Dyn page 11 paragraph 4

7. There are no uniform notation for parameters at rest:

Xspont versus Xrest

8. There are repeated paragraphs:

[…] To compare parameters for different load levels, repeated measures ANOVA or Friedman tests were performed. […]

Next paragraph:

[…] Within both groups, we examined the differences between the parameters at different load levels with repeated measures ANOVA or Friedman tests.

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Reviewer #1: No

Reviewer #2: No

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Cardiovascular effects of exercise induced dynamic hyperinflation in COPD patients – dynamically hyperinflated and non-hyperinflated subgroups

PONE-D-22-02168R1

Dear Dr. Varga,

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,

Nejka Potocnik

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

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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: (No Response)

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

Reviewer #1: (No Response)

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 Response)

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 Response)

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: (No Response)

Reviewer #2: (No Response)

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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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