A Noninvasive Arterial Stiffness Index to Estimate the Severity of Coronary Atherosclerosis in Patients Undergoing Coronary Angiography

Round 1

Reviewer 1 Report

The present study shows the results of a retrospective cohort that was very nicely and detailed followed with many clinical, biochemical and imaging parameters. I believe these results are very valuable and relevant for the study of non-invasive predictive parameters in cardiovascular diseases.

In general, I have no major concerns regarding the study, just a few comments:

1) the word complexity in the title is not clearly justified. To my opinion, severity is sufficient as a term to describe the concept.

2) In the introduction I believe the association between the indices and atherosclerosis needs to be explained in more detail. It is mentioned and cited (refs 13 to 17) but it would be nice to have an explanation here.

3)Figure 1 needs to be improved in design quality

4) the work is focused on Japanese population, as well as Japanese antecedents, therefore, I believe this should be pointed out during the introduction and discussion, since some Chinese work are not properly cited.

Author Response

Attached please find our response to your comments. Thank you for your comments. We sincerely appreciate your comments to our manuscript.

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Reviewer 2 Report

Introduction

The introduction provides a good background on the importance of early diagnosis and treatment of atherosclerosis before onset of cardiovascular disease. However, it lacks specifics on the current limitations and knowledge gaps in existing non-invasive techniques for assessing atherosclerosis severity, which would help establish the rationale and significance for studying AVI and API. More background is needed on AVI and API - how they are measured, what they reflect, and the current evidence on their association with atherosclerosis/CVD risk.

Methods

·       More information is needed on the inclusion/exclusion criteria - were healthy subjects included or only those with established CVD? This has implications for generalizability of findings.

·       Details are lacking on how other clinical variables like hypertension, diabetes were defined and diagnosed.

·       How representative was the study population of the overall patients undergoing cardiac cath during the study period? Details on recruitment process and any selection bias would be useful.

·       A flow diagram showing study enrollment, exclusions, follow up and outcomes would help reader understand design and where losses occurred. 

Results

·       Baseline characteristics provide a good summary of the study population but should also include prevalence of established CAD, medications, other standard CVD risk factors.

·       For main results on AVI/API and outcomes, detailed statistical tests are presented but clearer description of actual findings in prose is needed. For example, highlight that API but not AVI was significantly associated with elective PCI.

Discussion

·       The authors thoughtfully consider reasons for discrepant findings compared to some previous studies on AVI and outcomes.

·       Discussion would benefit from putting results in context of other non-invasive markers like CIMT, FMD etc for predicting revascularization needs.

·       Discussion could be enhanced by comparing findings to recent literature in more detail

Minor correction for typo error required

Author Response

Attached please find our response to your comments. Thank you for your comments. We sincerely appreciate your comments to our manuscript.

Author Response File: Author Response.pdf

Reviewer 3 Report

Dear Authors, Dear Editor,

Thank you very much for this fundamentally exciting paper with the question of possible new parameters of arterial vascular stiffness. In this work, the authors have tried to illustrate what clinical benefit may be given. In summary, however, this publication has clear weaknesses and should be carefully revised. The introduction leads the reader to the question, but questions and ambiguities remain regarding the measurement methodology or comparison to the previousestablished parameters, such as PWV and AIx. Likewise, the title cannot be derived from the actual question. The comparison between the existing parameters and the new ones would at least be a priority work. 

In the methods section, it remains very unclear to which measurement point in time the statements refer. The model of retrospective cohort analysis is also not clearly explained. A flowchart would be desirable to understand at what point in time which subjects are included or lost of follow-up, as the standard deviation is extremely large. Statistically, the analyses should be tested again before the calculation with regard to a normal distribution. Since it remains unclear whether a measurement is taken at the beginning and then the groups are divided or measured at the end and looked into the past, a temporal correction should also be made.

Author Response

Attached please find our response to your comments. Thank you for your comments. We sincerely appreciate your comments to our manuscript.

Author Response File: Author Response.pdf

Reviewer 4 Report

The present work presents a non-invasive method to estimate the severity and complexity of coronary atherosclerosis. Although the manuscript is extremely well structured and the topic is very interesting, the following must be taken into account:

1.      The aim is not well defined at the end of the introduction.

2.      Lines 61-64 belong to the material and method section.

3.      Define the columns in table 1 (e.g. parameter, mean/proportion, etc.)

4.      The discussion part is quite brief, please elaborate.

Minor editing of English language required

Author Response

Attached please find our response to your comments. Thank you for your comments. We sincerely appreciate your comments to our manuscript.

Author Response File: Author Response.pdf

Reviewer 5 Report

- the Ebglish should be extensively corrected, as there are many unclear sentences. e.g.  "Atherosclerosis is a common terminal condition of lifestyle-related diseases " - atherosclerosis is not a terminal condition. Or "Even if those patients survive acute treatment" - the main issue is to survive the acute disease, not necessarily the treatment. Or: " Previous studies including ours 55 have reported that these indices are associated with CV risks" - these indices are useful to evaluate CV risks, the association is with the underlying conditions measured by the indices.  And there are many such issues.

- line 57 - the use of the references [13-17] should be avoided. If the authors wish to actually present the previous studies, they should do so, keeping in mind the relevance for this article. As they are presented, they seem to hide selfcitations.

 - this is a prospective study. I do not consider that an opt-out consent is enough, especially as the study used identifiable data about patients, that were obtained specifically for the purpose of this study, and as the patients were followed for a long period of time (more than 5 years as an average).

- the authors should provide more details about the Syntax and Gensini score, and why they used them

- the AVE-1500 should be described in a single place in the manuscript

Extensive language corrections should be made, as there are many concepts that seem to be improperly translated

Author Response

Attached please find our response to your comments. Thank you for your comments. We sincerely appreciate your comments to our manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Dear authors, dear editors,

The revision of Ishigami's original work has gained in quality thanks to the additions. It was not only useful to change the title so that it better reflects the content. The additional paragraphs and information in the introduction help to better address the research question and enhance the work with key aspects. The question becomes more tangible with the new wording. The flowchart makes it clearer which test subjects were examined. However, it remains unclear whether all 113 subjects were actually followed up. The presentation or reformulation of the SYNTAX score contributes to the reproducibility of the results. The additional information allows the test subjects to be better characterized. The publication has also gained from the changes in interpretation. Overall, acceptance would be useful.

Dear authors,

with regard to the quality of the English language, we would recommend that you take another close look at spaces and punctuation. In some places, double spaces or, above all, missing spaces can be identified.

Author Response

Thank you for your comment on our manuscript. Attached please find our response to reviewer's comment. We sincerely appreciate your comments.

Author Response File: Author Response.pdf

Reviewer 5 Report

The article was improved. By my ethical concern still stays. As it is,the article fails to respect at least two articles from the Declaration of Helskini, namely:

26.       In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information.

32.       For medical research using identifiable human material or data, such as research on material or data contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In such situations the research may be done only after consideration and approval of a research ethics committee.

Therefore, I must reject the article on ethical grounds. An opt-out consent is not, by far protective enough for the patient, even if this is a retrospective study. As they subjects had the possibility to opt out (showing therefore proof that they were able to be contacted, the main reason foe the exception of not obtaining informed consent in retrospective studies), why not provide them with a proper informed consent, which would have avoided this issue althogether,

- minor checks should be still done

Author Response

Thank you for your comments on our manuscript. Attached please find our response to your comments. We sincerely appreciate your comments. 

Author Response File: Author Response.pdf