PONE-D-22-03577Impairment in Quantitative Microvascular Function in Non-Ischemic Cardiomyopathy as Demonstrated Using Cardiovascular Magnetic ResonancePLOS ONE

Dear Dr. Slivnick,

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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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: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: 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 assessed the prevalence of MVD in 41 NICM pts as compared with 58 controls, using stress CMR. MVD was defined visually as the presence of a subendocardial perfusion defect and semiquantitatively by myocardial perfusion reserve index (MPRI<1.51). NICM patients had lower rest slope (3.9 vs 4.9, p=0.05), lower stress perfusion slope (8.8 vs 11.7, p<0.001), and MPRI (1.41 vs 1.74, p=0.02). Visual analysis had a lower sensitivity in detecting MVD. The topic is interesting, but several points should be addressed.

-One of the main limitation is the choice of control subjects, which appears as an heterogeneous group referred to CMR for several different reasons, and found (a posteriori) to have preserved LVEF (but 50-55% LVEF was included!), no LGE, no regional perfusion defects, no history of cardiac diseases. This is not a proper control group.

-In the control cohort, the indication for stress CMR was chest pain in 38 (66%), but it is unclear whether CAD was ruled out in these subjects. They still might suffer from microvascular angina, meaning that their MPRI is low because of an underlying cardiological disease.

-In the control patients, focal perfusion defects on first pass stress perfusion was an exclusion criterion, which is quite unclear. How many patients had an isolated perfusion defects?

-In the control patients, LGE was present in 16% of cases. What was the underlying disease? Might this impact on the microvascular function of these "normal" patients?

-In the methods, it is unclear whether a single short axis or 3 short axis slices were used for qualitative and semiquantitative perfusion analysis.

-A second main limitation is the lack of clinical and prognostic data. Actually, the Authors described MVD in two cohorts of patients with two different methods, without any reference standard, any correlatoion with disease type and severity (biohumoral data? arrhythmic burden?) or prognosis. Please comment/extend your data.

-In the conclusion, the Authors state that "Compared with visual analysis, semiquantitative analysis had a higher sensitivity for detecting impaired stress perfusion with CMR", but these thwo methods were not compared against a reference standard (PET? quantitative perfusion CMR?) to assess their real diagnostic accuracy. The Authors should revise this point, for example: "MVD by visual analysis was present in significantly fewer patients than MVD according to semiquantitative analysis...".

-A possible confounding variable is represented by the relatively thinner ventricles in NICM patients, which might increase the incidence of dark rim artifacts and should be carefully excluded from analysis. Did the Authors check for this point? Was there a relationship between wall thickness and MVD? And between LV volume and MVD?

Reviewer #2: The Authors retrospectively studied patients with non ischemic cardiomyopathy (NICM) and 58 control patients with preserved systolic function who underwent stress cardiac magnetic resonance (CMR) between 2011-2016. Microvascular disfunction (MVD) was defined visually as presence of a subendocardial perfusion defect and semiquantitatively by myocardial perfusion reserve index (MPRI). MPRI was compared between groups using univariate analysis and multivariable linear regression. 41 patients with NICM (mean age 51 ± 14, 59% male) and 58 controls (mean age 51 ± 13, 31% 35 male) were identified. In the NICM group, MVD was present in 23 (56%) and 11 (27%) by semiquantitative and visual evaluation respectively. Compared with controls, NICM patients had lower rest slope (3.9 vs 4.9, p=0.05) and stress perfusion slope (8.8 vs 11.7, p <0.001) and MPRI (1.41 vs 1.74, p=0.02). MPRI remained associated with NICM after controlling for several parameters, such as gender, hypertension, ethnicity, diabetes, and late gadolinium enhancement. The Authors observed that MVD—as assessed using CMR—is highly prevalent in NICM when compared to control patients with preserved systolic function. They concluded that semiquantitative assessment is more sensitive for detecting MVD compared to visual methods alone. The study was well planned and the results are really interesting, The method is suggesting and promising, stimulating further studies for the assessment of MVD.

Minor concerns are related to statistical analysis: please specify pair or unpair Student’s t-test.

Reviewer #3: This study uses CMR to assess coronary microvascular deficiency in NICM patients. It is well done,simple and clear.

There are some issues

1) Control group: it is not clear the control group population. It is very likely control group subjects were not healthy because, for example, in these patients LGE has been detected. The authors should select healthy subjects, almost without previous cardiovascular events, in the control group. Moreover, as the author stated, with regard the control group (line 91-92): Additionally, patients with infarct scar by LGE or focal perfusion defects on first pass stress perfusion were excluded from the control group. If we look at table, there are 9 subjects of the control group with LGE……….

2) In the multivariate analysis, the authors did not include any kind of functional and morphological cardiac parameter. It is important to know the relationship between MPRI and EF, MPRI and LV volumes. Also, it could be interesting to know the relationship between regional wall motion analysis (WMSI) and MPRI. This is because WMSI is one of the main cardiac variables with prognostic relevance. The authors stated that low MORI is not related to other clinical variables, but it is very likely they are related to morphological and functional cardiac variables.

3) In the discussion, the second main result, that is the higher diagnostic performance to detect MPR deficiency with semiquantitative method in respect to qualitative method is well known and cannot be a salient result of the study. The authors can mention this result but without highlighting it.

4) In the table 1, please report the value range of the indexed LVEDV. It is very likely that all NICM were not dilated.

5) Table 2: in this table the data are referred to all population and not to NICM patients with and without MPRI <> 1,51. In the text the authors wrote that in the table 2 are reported data of NICM patients only. Please, clear this point. However, it is more important to know the difference among NICM patient with and without MPRI < 1,51.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Alessandro Pingitore

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PONE-D-22-03577R1Impairment in Quantitative Microvascular Function in Non-Ischemic Cardiomyopathy as Demonstrated Using Cardiovascular Magnetic ResonancePLOS ONE

Dear Dr. Slivnick,

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.

==============================

ACADEMIC EDITOR: All issues raised by reviewer are required.

==============================

Please submit your revised manuscript by Nov 06 2022 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,

Vincenzo Lionetti, M.D., PhD

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.

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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: (No Response)

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

********** 

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

********** 

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

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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 performed a qualitative and a semiquantitative analysis of myocardial perfusion in 41 DCM patients compared with 58 patients with preserved EF. The manuscript is interesting and overall well written, even though there are some points to address:

-In patients with preserved EF (16% of which presented LGE), the final diagnosis was not reported; please include in the text or in a table (how many normal scans? how many prior myocarditis? other diseases?)

-Was severe valvular heart disease an exclusion criterion? What about mitral valve prolapse? Please specify in the methods, or comment in the results if any of the patients had similar diseases (which might impact on myocardial perfusion).

-There are no data about medical therapy, both in DCM and in patients with preserved EF; please include in a (supplemental?) table and comment in the text

-There is no mention of some recent studies on quantitative myocardial perfusion in DCM patients (See for example Gulati et al, DOI 10.1016/j.jcmg.2018.10.032), which should be mentioned and briefly discussed in the manuscript.

Reviewer #2: The paper has been revised and improved. It can be accepted for publication. The Authors discussed all the points of comments with success and accuracy.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-22-03577R2Impairment in Quantitative Microvascular Function in Non-Ischemic Cardiomyopathy as Demonstrated Using Cardiovascular Magnetic ResonancePLOS ONE

Dear Dr. Slivnick,

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.

==============================

ACADEMIC EDITOR: Relevant issues addressed by one reviewer require a careful revision.

==============================

Please submit your revised manuscript by Dec 09 2022 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,

Vincenzo Lionetti, M.D., PhD

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.

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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: (No Response)

Reviewer #2: All comments have been addressed

**********

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

**********

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

**********

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

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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 addressed the comments and improved the manuscript; as highlighted in a previous comment, I would suggest the Authors to better specify the final diagnosis not only of the 41 NICM patients (which has now been provided), but also of the 58 control patients (16% of which presented LGE: how many normal scans? how many prior myocarditis? other diseases in the control patients?).

Reviewer #2: The manuscript has been improved. The Authors did reply to the observations raised by referees, The manuscript can be accepted.

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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.

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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.

Impairment in Quantitative Microvascular Function in Non-Ischemic Cardiomyopathy as Demonstrated Using Cardiovascular Magnetic Resonance

PONE-D-22-03577R3

Dear Dr. Slivnick,

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,

Vincenzo Lionetti, M.D., PhD

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

**********

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

**********

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

Reviewer #1: 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

**********

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: (No Response)

**********

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

**********