PONE-D-19-23361

The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome

PLOS ONE

Dear Dr Kunadian,

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The research is supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle-upon-Tyne Hospitals NHS Foundation Trust and Newcastle University. VK has received research funding from the British Heart Foundation (CS/15/7/31679). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Additional Editor Comments:

The Authors performed unadjusted cox regression models due to the lack of statistically significant difference between tertiles of TL. However, the sample size is small and this could led not to identify any statistically significant difference in baseline characteristics. Thus, I suggest a stepwise approach to be able to provide adjusted models, although incl. a limited number of potential confounders.

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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

Reviewer #2: Yes

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

Reviewer #1: Yes

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: Yes

Reviewer #2: 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

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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: 1. Introduction: Previous data is well summarized and the main aim of the study is clearly specified.

2. Methods:

-Patients were selected from ICON1 study. Authors affirmed that patients aged > 65 years old were included. Maybe this cut-off point does not reflect the real “old patients”, in addition mean age of the patients included in this study is around 80 years old. Did you selected very old patients from the whole sample of ICON1 study or you included any patients older than 65 years old?

-You divided the sample in tertiles. This is completely correct but it might be more precise to do it according to the best cut off point calculated by ROC curve. In this way you can provide data of sensitivity and specificity.

-You designed a composite endpoint with thrombotic and bleeding events. In previous studies, telomere length seems to be connected to atherosclerosis and the evidence about its relationship with bleeding is weaker. It could be interesting to calculate a secondary combined endpoint formed only by thrombotic events.

3. Results

-The incidence of adverse events is too low in your patients. Previous studies of very old patients with ACS showed 6 months mortality around 12% (Alegre et al. J Am Med Dir Assoc. 2017 Nov 17).

-Please, comment the percentage of AMI and unstable angina in your sample.

-Could you provide the incidence of mortality caused by cardiovascular causes in your sample?

-Do you have data about the characteristics of the coronary event of your patients (number of affected arteries, Killip class, number of stents used…)? Is the peak value the troponin measurement provided en table 1?

4. Discussion

--In the reference 25 of your manuscript (Epel et al.), telomere attrition but not initial telomere length was associated to cardiovascular mortality. In your study you did not find any relationship between telomerase activity and mortality. Could you explain in detail how your results agree or disagree with this paper?

-Other papers have studied the prognosis effect of telomere length in older patients with ACS (Am J Cardiol 2014;113:418e421). In this paper telomere length showed a prognostic effect in middle aged men with ACS but not in older patients. The group of elderly patients in this study was small (n: 52), presented STEMI and NSTEMI and revascularization was performed only in the 53% of patients so the sample is quite different to yours. Nevertheless, results are similar so it might be interesting to discuss this paper in your manuscript.

Reviewer #2: The Authors presented a substudy of the ICON-1 Biomarker study, aiming to determine the possible Association between telomere length and telomerase activity with the outcome of old patients presenting with NSTEACS.

The manuscript is well written and addresses a clinically relevant issue with potential translational relevance.

However, there are major issues to be resolved before considering the paper subitable for pubblication.

- was this substudy pre-specified in the trial design? If not, this could be a relevant methodological bias.

- are the patients recruited consecutive?

- the reason why almost half of the patients recruited in the general study have been esclude in this substudy is clear and not reported. Please add. It is also relevant to explain Why Only in 67 patients telomerase activity data were available. These may be considered profound bias in the analysis of the data presented.

- The Authors stated that these patients underwent an invasive management of the NSTEACS. How many of these underwent PCI? Procedural data are not reported. Therapy on admission and at discharge was not reported. All these informations might have a profound impact on the data and outcome analysis.

- the division in to tertiles seems to be arbitrary.

- When considering frail vs pre-frail patients, are there any difference in the distribuition of TL and TA and their association with the outcome?

- Recently Werner et al demonstarted that specific modalities of exercise might influence regulators of cellular senescence (i.e TL e TA). Please comment.

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Reviewer #1: Yes: Jose-Angel Perez-Rivera MD,PhD

Reviewer #2: No

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The association of telomere length and telomerase activity with adverse outcomes in older patients with non-ST-elevation acute coronary syndrome

PONE-D-19-23361R1

Dear Dr. Kunadian,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Gianluigi Savarese

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: 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

**********

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: Thank you very much for your response. You have adequately addressed my suggestions. Congratulations for your research.

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: Yes: Jose-Angel Perez-Rivera

Reviewer #2: No