PONE-D-22-08288ACUTE CORONARY SYNDROME VERSUS ACUTE MYOCARDITIS IN YOUNG ADULTS – VALUE OF SPECKLE TRACKING ECHOCARDIOGRAPHYPLOS ONE

Dear Dr. Wieczorkiewicz,

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. Specifically, the statistics should be implemented before consideration of further revisions. 

Please submit your revised manuscript by Jun 15 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,

Antonio Cannatà

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. Please provide additional details regarding participant consent. 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

Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 

Additional Editor Comments:

In addition to reviewers' comments, the authors should provide statistical correction for potential confounders especially when validating the role of GLS. Although may suffer collinearity, the variable might be tested against LVEF to highlight its predictive role.

[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. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

**********

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

Reviewer #1: No

Reviewer #2: I Don't Know

**********

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

**********

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

**********

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: In this small retrospective study, authors aim at investigating the value of speckle tracking echocardiography in the differential diagnosis between acute coronary syndrome and acute myocarditis. Due to the possible clinical overlap between these two conditions the differential diagnosis is challenging, sometimes impossible in the acute phase, therefore coronary angiography is still largely performed in the emergency setting to exclude SCA. For this reason, the topic of the paper is very actual, however there are several points pf the work which should be addressed.

Major comments:

- From my point of view, the main limitation of the paper is the lack of clinical implications of the study. Authors conclude that patients with AMI have a significant reduction of global and three layers strains as compared to those with myocarditis. However, it seems difficult to consider using echocardiography strain analysis to discriminate between patients who should undergo coronary angiography and those who should not in the setting of acute chest pain and ST segment elevation ant EKG.

- In the paragraph “conclusion” authors state that “specific strain impairment might provide valuable information to complement the diagnosis of acute myocarditis when CMR is not easily available”. I would rather say that “specific strain impairment might provide valuable information to complement the diagnosis of acute myocarditis when CMR is not easily available in patients without coronary artery disease”.

- Due to the retrospective nature of the study a multivariate analysis should be performs in order to correct the results for confounders especially considering that patients with myocardial infarction were older, had higher Tn levels and more cardiovascular risk factors.

Minor comments:

- Page 3 authors say: “EMB is still the diagnostic gold standard but extremely limited in the clinical practice. Please consider citing the recently published Position Statement by Seferovic et al (DOI: 10.1016/j.cardfail.2021.04.010);

- Please check minor English typos.

Reviewer #2: In the present paper the authors investigate the diagnostic value of clinical and instrumental tools, focusing in particular on speckle tracking echocardiography, in patients with acute coronary syndrome-like myocarditis and acute myocardial infarction. They found that patients with AMI have a significant reduction of global strains and a different layer involvement compared to patients with myocarditis. Thus, they suggest that speckle tracking analysis may become a valuable tool to differentiate these two entities.

The topic is very actual and interesting, however some issues should be addressed:

- As the authors have mentioned, the paper presents some limitations like the small sample size or the absence of a histological confirmation of the myocarditis diagnosis. Furthermore, for patients with AMI diagnosis some information is lacking like the STEMI localization and if there is a different a bigger strain impairment in patients with a more estensive infarction. Also, it is not specify if all AMI patients have undergone PCI.

- There are conflicting data about the differences in layer-specific strain impairment. The major finding of the present study is that the presence of a mainly epicardial strain impairment with preserved endocardial strain can suggest a diagnosis of myocarditis and exclude ACS, in which the three layers are involved. Conversely, the value of endocardial strain, which should be the most compromised, has the higher value (-21) and there was not a significant difference in endo/epi ratio between the two groups.

- The fact that the absolute GLS value was significantly lower in patients diagnosed as AMI compared to the myocarditis group does not provide a relevant additional information given that also the LVEF is lower in the AMI group.

- It is curious that PWd and IVSd were significantly higher in myocardial infarction group because, despite the higher prevalence of hypertension in this group, in the myocarditis group it is expected a ventricular pseudohypertrophy due to myocardial edema.

- It could be interesting to complete the speckle tracking analysis with also the right ventricolare values (in particular for inferior STEMI).

**********

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.

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

[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.

ACUTE CORONARY SYNDROME VERSUS ACUTE MYOCARDITIS IN YOUNG ADULTS - VALUE OF SPECKLE TRACKING ECHOCARDIOGRAPHY

PONE-D-22-08288R1

Dear Dr. Wieczorkiewicz,

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,

Antonio Cannatà

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 #3: 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 #3: Yes

**********

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

Reviewer #3: 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 #3: 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 #3: 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 #3: no additive comment

the manuscript is OK

the results and the discussions are OK

the figure are OK as well as the references

**********

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 #3: No

**********