Relationship between high shear stress and OCT-verified thin-cap fibroatheroma in patients with coronary artery disease

Naotaka Okamoto; Yuliya Vengrenyuk; Valentin Fuster; Habib Samady; Keisuke Yasumura; Usman Baber; Nitin Barman; Javed Suleman; Joseph Sweeny; Prakash Krishnan; Roxana Mehran; Samin K. Sharma; Jagat Narula; Annapoorna S. Kini

doi:10.1371/journal.pone.0244015

Peer Review History

Original SubmissionJuly 24, 2020
1 Oct 2020 Decision Letter - Xianwu Cheng, Editor PONE-D-20-22797 Relationship between high shear stress and OCT-verified thin-cap fibroatheroma in patients with coronary artery disease PLOS ONE Dear Dr Kini 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. Please submit your revised manuscript by October 16, 2020. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Xianwu Cheng, M.D., Ph.D., FAHA Academic Editor PLOS ONE Additional Editor Comments: Although the topic is interesting, as you will gather from the reviews, the referees identified substantive methodological problems, statistical analysis, and data presentation as well as the recruitment of all subjects.　 The editorial broad member also concurs. You may resubmit a revised version but it will be re-reviewed and there exists no guarantee that even with revision it will necessarily be accepted. 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. Thank you for stating the following in the Competing Interests section: "I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Samady has received research grants from Abbott Vascular, Medtronic, National Institutes of Health, St. Jude Medical, and Gilead. Dr. Baber: speaker honoraria from Boston Scientific and Amgen, speaker honoraria and grants from AstraZeneca; Dr. Mehran: Abbott Vascular consultant and research grant, Boston Scientific consultant. Dr. Sharma: speaker honoraria from Abbott, Boston Scientific, Cardiovascular Systems, Inc. All other authors have no relationships relevant to the contents of this paper. " Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes ****** 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: This manuscript addresses an important question, the relationship between blood shear stress and thin cap fibroatheroma. The results are suggestive but the results are presented in a cursory manner with important details. Additional information is needed about the following: 1. The authors need to verify that they have performed the appropriate analysis to optimize the meshes for the numerical simulation and provide details on the mesh sizes and number of elements used in these validations. Indicate spatial resolution of shear stress. 2. Show representative inlet flow waveforms and explain how they were obtained. 3. Provide details on wall shear stress calculation over the plaque and how averaging over the cardiac cycle was performed. The lengths of lesion used to calculate proximal, middle and distal WSS need to be defined. 4. Since different methods were used to measure the dimensions of the fiberoatheromatous plaque and reconstruct the vessel geometry, describe the agreement in plaque dimensions using angiography and OCT and NIRS/IVUS. 5. Clarify whether the odds ratio means the likelihood of finding a fiberoatheromatous lesion based on a given shear stress or if a lesion is located in a region with a given proximal wall shear stress the odds of it being fiberoatheromatous. A minor point to correct is the following. Figure 2. Panels A, B, and C are not described. Reviewer #2: The study aims to test the hypothesis that invasive coronary angiography-based high WSS is associated with the presence of TCFA detected by OCT in obstructive lesions. This manuscript selected patients who had two angiographic projections to create a 3D reconstruction model to assess WSS. The results demonstrated that high WSS in the proximal segments of obstructive lesions is an independent predictor of OCT-verified TCFA. The paper is well written. Research was carefully designed and performed. This is a very important study and should be published with some minor changes. 1. Introduction. The current manuscript is short of past publications on high WSS research. Some published studies on high WSS should be included and identify the research gaps that current research is trying to address. 2. Method. For the convenience of understanding and reading, the definition of some plaque morphology parameters (such as LCBI etc.) should be expressed by some figures or formulas. 3. Result. The study aims to test the hypothesis that invasive coronary angiography-based high WSS is associated with the presence of TCFA detected by OCT in obstructive lesions. Use of mean WSS is fine, but maximum WSS could also be considered which could be a more sensitive measure? There is a chance that mean WSS could get some important findings “averaged out”. The author needs to consider the maximum WSS to explain whether the mean WSS in the manuscript is a better measure to test the hypothesis? 4. Table3. Please give the explanation of DS (diameter stenosis). 5. “The optimal cutoff value of WSSproximal to predict TCFA was 6.79Pa (AUC: 0.710; sensitivity: 76.9%; specificity: 63.2%, p=0.02).” A figure with the ROC curve is needed to show where the values come from. ****** 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: Yes:** George A. Truskey 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. https://doi.org/10.1371/journal.pone.0244015.r001
Revision 1
5 Nov 2020 Author Response Response to Reviewers Additional Editor Comments: Although the topic is interesting, as you will gather from the reviews, the referees identified substantive methodological problems, statistical analysis, and data presentation as well as the recruitment of all subjects.　 The editorial broad member also concurs. You may resubmit a revised version but it will be re-reviewed and there exists no guarantee that even with revision it will necessarily be accepted. 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 Response: The manuscript was re-formatted according to PLOS ONE’s style requirements and file naming guidelines. 2. Thank you for stating the following in the Competing Interests section: "I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Samady has received research grants from Abbott Vascular, Medtronic, National Institutes of Health, St. Jude Medical, and Gilead. Dr. Baber: speaker honoraria from Boston Scientific and Amgen, speaker honoraria and grants from AstraZeneca; Dr. Mehran: Abbott Vascular consultant and research grant, Boston Scientific consultant. Dr. Sharma: speaker honoraria from Abbott, Boston Scientific, Cardiovascular Systems, Inc. All other authors have no relationships relevant to the contents of this paper. " Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Response: The statement has been added to the cover letter for the revised manuscript Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 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 This manuscript addresses an important question, the relationship between blood shear stress and thin cap fibroatheroma. The results are suggestive but the results are presented in a cursory manner with important details. Additional information is needed about the following: 1. The authors need to verify that they have performed the appropriate analysis to optimize the meshes for the numerical simulation and provide details on the mesh sizes and number of elements used in these validations. Indicate spatial resolution of shear stress. Response: We greatly appreciate the reviewer’s comments and add additional information on mesh and solution convergence analyses, boundary conditions and WSS averaging to the revised manuscript as described below (pages 2-4). The appropriate elements size for the models was determined as a results of a mesh refinement study to ensure that WSS values are size independent. The discrepancy in the mean WSS values for each segment of 3% of less was acceptable. The average length of the study vessels was 22 mm and the largest (proximal) diameter was 3.1 mm. As a result of the mesh convergence analyses, we used the following settings for mesh generating: max face size 0.2 mm, min size 0.02 mm. The average number of elements in the study was 287,265 ± 114,712 (surface area 0.021±0.010 mm2 and min edge length 0.044±0.026 mm). Each simulation was monitored for convergence using absolute criteria with 10-6 as a threshold for the residual error. Several models required local refinement of the mesh at the bifurcation segment in order to achieve convergent solution. We added the following details to the revised manuscript: Methods, page 6: The optimal mesh size was determined based on a mesh refinement study to ensure that the results are not affected by the element size. The average number of finite elements in the study was 287,265, and the mean surface area was 0.021 mm2. 2. Show representative inlet flow waveforms and explain how they were obtained. Response: We calculated velocity of the contrast in angiography images for each vessel using a frame count method with the first frame showing the front of contrast bolus entering analyzed segment and the last frame in which contrast reaches the end of the segment. The velocity was calculated as follows: [segment length assessed by angiography, mm][acquisition speed, frames/sec]/[last frame number – first frame number, frames] as described in the Fame II post-hoc analysis by Kumar and co-authors (Ref #9). Similar to the study, the patient-specific calculated velocity was applied as an inlet boundary condition with a flat profile. We added the following details to the revised manuscript: Materials and Methods (Page 6, new text is underlined): Patient-specific inlet velocities were calculated using flame counts ([segment length assessed by angiography][acquisition speed]/[last frame number – first frame number, frames]) and applied as inlet boundary conditions with a flat profile as previously described (9). 3. Provide details on wall shear stress calculation over the plaque and how averaging over the cardiac cycle was performed. The lengths of lesion used to calculate proximal, middle and distal WSS need to be defined. Response: CFD simulations with the pulsatile flow were not performed in the study, blood flow was assumed to be steady. Each angiography-defined lesion was divided into 3 equal parts: proximal, middle and distal in the same manner as in the FAME II sub study (ref #9), since we wanted to test the hypothesis that the high WSS is associated with vulnerable plaques by OCT to provide an explanation for the association of high WSS in the proximal segment with future MIs reported in the study. In the original version of the manuscript, we calculated mean WSS in the whole lesion and each sub segment. For the revised paper, we performed additional analyses for the maximal WSS per suggestion of the Reviewer #2, but the mean WSS remained the most sensitive predictor of the presence of TCFA lesion. Considering that the average lesion length in our study was 22 mm (Table 3), each lesion sub segment was around 7.3 mm depending on the case. We’ve added the following clarification to the revised manuscript (page 5, new text is underlined): Materials and Methods (Page 6, new text is underlined): No-slip boundary condition was applied at the vessel wall and blood flow was assumed to be steady Each angiography-defined lesion was divided into 3 equal parts: proximal, middle and distal following the segment definitions introduced in the WSS FAME II sub-study (9). 4. Since different methods were used to measure the dimensions of the fiberoatheromatous plaque and reconstruct the vessel geometry, describe the agreement in plaque dimensions using angiography and OCT and NIRS/IVUS. Response: The vessel geometries were reconstructed based on angiography images using two end-diastolic projections more than 25 degrees apart using validated software QAngio XA 3D. Intravascular imaging (OCT and NIRS/IVUS) was used only to characterize plaque morphology for each lesion. Anatomical landmarks (side branches) visible in both angiography and OCT images were used to identify the location of TCFA lesions within the angiography-based models. 5. Clarify whether the odds ratio means the likelihood of finding a fiberoatheromatous lesion based on a given shear stress or if a lesion is located in a region with a given proximal wall shear stress the odds of it being fiberoatheromatous. Response: We apologize for the confusion. Our data showed the association of high WSS with the presence of OCT-defined TCFA rather than the co-localization of the two measures. While we did mention this in the abstract, it was not clearly described throughout the text. We corrected the wording in several places including pages 3, 11, 13, 15 as follows : ”The study evaluated the relationship between angiography-based WSS and the presence of OCT-verified TCFA in angiographically obstructive lesions in patients with stable CAD” A minor point to correct is the following. Figure 2. Panels A, B, and C are not described. Response: We added Figure 2 panels’ description to the revised manuscript and re-arranged Figures 1 and 2 to better describe the study methods and results. Reviewer #2 The study aims to test the hypothesis that invasive coronary angiography-based high WSS is associated with the presence of TCFA detected by OCT in obstructive lesions. This manuscript selected patients who had two angiographic projections to create a 3D reconstruction model to assess WSS. The results demonstrated that high WSS in the proximal segments of obstructive lesions is an independent predictor of OCT-verified TCFA. The paper is well written. Research was carefully designed and performed. This is a very important study and should be published with some minor changes. 1. Introduction. The current manuscript is short of past publications on high WSS research. Some published studies on high WSS should be included and identify the research gaps that current research is trying to address. Response: We greatly appreciate the reviewer’s comments and add some of the most recent reports on the association of high WSS with lesion vulnerability (please see below). While majority of the studies used intravascular imaging or CTA to create 3D CFD models (1-5), 3D-QCA-derived high WSS in combination with lesion morphology was able to identify plaques prone to future MACE in the last month report from Bourantas and co-authors (6). 1. Hartman EMJ, De Nisco G, Kok AM et al. Lipid-rich Plaques Detected by Near-infrared Spectroscopy Are More Frequently Exposed to High Shear Stress. Journal of cardiovascular translational research. 2020. Epub 2020/10/10. 2. Toba T, Otake H, Choi G et al. Wall Shear Stress and Plaque Vulnerability: Computational Fluid Dynamics Analysis Derived from cCTA and OCT. JACC Cardiovascular imaging. 2020. Epub 2020/09/21. 3. Lee JM, Choi G, Koo BK et al. Identification of High-Risk Plaques Destined to Cause Acute Coronary Syndrome Using Coronary Computed Tomographic Angiography and Computational Fluid Dynamics. JACC Cardiovascular imaging. 2019;12(6):1032-43. Epub 2018/03/20. 4. Yamamoto E, Thondapu V, Poon E et al. Endothelial Shear Stress and Plaque Erosion: A Computational Fluid Dynamics and Optical Coherence Tomography Study. JACC Cardiovascular imaging. 2019;12(2):374-5. Epub 2018/10/22. 5. Murata N, Hiro T, Takayama T et al. High shear stress on the coronary arterial wall is related to computed tomography-derived high-risk plaque: a three-dimensional computed tomography and color-coded tissue-characterizing intravascular ultrasonography study. Heart and vessels. 2019;34(9):1429-39. Epub 2019/04/13. 6. Bourantas CV, Zanchin T, Torii R et al. Shear Stress Estimated by Quantitative Coronary Angiography Predicts Plaques Prone to Progress and Cause Events. JACC Cardiovascular imaging. 2020;13(10):2206-19. Epub 2020/05/18. In addition, the following summary was included in the revised Discussion (page 14): “Consistent with our findings, high WSS was strongly associated with TCFA and lipid-rich plaques in an OCT based CFD analysis of intermediate stenoses [24]. Lipid-rich plaques detected by NIRS have been shown to co-localize with high WSS in an IVUS based CFD study in non-culprit lesions of patients presenting with ACs [23]. In a recent 3D QCA based CFD analysis, a combination of high WSS and high-risk plaque morphology provided an accurate identification of non-obstructive lesions responsible for the future events.” 2. Method. For the convenience of understanding and reading, the definition of some plaque morphology parameters (such as LCBI etc.) should be expressed by some figures or formulas. Response: We appreciate the suggestion and provide definitions for the imaging characteristics used in the study in the Methods and a new Supporting Figure 1 (S1 Fig) showing representative images of a lesion acquired with different image modalities. Materials and Methods. Page 4, 5 (new text is underlined): “Lipid core was identified as a signal-poor region with poorly delineated borders, little or no signal backscattering, and an overlying signal-rich layer, the fibrous cap (S1 Fig) … Raw spectroscopic information from NIRS chemograms was transformed into a probability of lipid that was mapped to a red-to-yellow colour scale, with a low probability of lipid shown as red and a high probability of lipid shown as yellow (S1 Fig). Lipid core burden index (LCBI) was calculated by dividing the number of yellow pixels (probability ≥0.6) by the total number of viable pixels within the plaque multiplied by 1000.” S1 Figure. Representative multimodality images of a study lesion: OCT detected TCFA with minimal fibrous cap thickness 50 µm (inset) and a 305° lipid arc (A); large attenuated plaque detected by IVUS with maximal lipid core burden index (LCBI) within a 4 mm segment 465 detected by NIRS (yellow area). 3. Result. The study aims to test the hypothesis that invasive coronary angiography-based high WSS is associated with the presence of TCFA detected by OCT in obstructive lesions. Use of mean WSS is fine, but maximum WSS could also be considered which could be a more sensitive measure? There is a chance that mean WSS could get some important findings “averaged out”. The author needs to consider the maximum WSS to explain whether the mean WSS in the manuscript is a better measure to test the hypothesis? Response: Thank you for the interesting suggestion. We performed additional analyses to test whether the maximal WSS would be a more sensitive predictor of the presence of TCFA compared to the mean WSS. The results are shown in new S1 and S2 Tables and below. While proximal WSS (max) was significantly higher in TCFA lesions compared to non TCFA lesions (S1 Table), it was not an independent predictor of TCFA by univariate logistic regression analysis (S2 Table) with or without adjustment for 3D contrast velocity. Supporting Table 1. Angiographically derived measurements and computational fluid dynamics: maximal WSS TCFA (n=13) No TCFA (n=57) P-value Total lesion WSS (max), Pa 65.8 (31.3, 98.7) 44.2 (23.7, 67.6) 0.04 Upstream WSS (max), Pa 8.5 (6.2, 21.5) 8.7 (4.4, 21.7) 0.63 Proximal WSS (max), Pa 34.6 (14.7, 54.5) 13.6 (8.6, 29.6) 0.04 Middle WSS (max), Pa 60.5 (25.1, 91.3) 34.9 (18.9, 58.8) 0.12 Distal WSS (max), Pa 24.6 (13.3, 48.9) 16.4 (8.8, 34.0) 0.25 Downstream WSS (max), Pa 14.7 (6.0, 42.7) 13.8 (7.0, 30.1) 0.88 Values are mean ± SD or median (interquartile range); TCFA= thin-cap fibroatheroma; DS= diameter stenosis; WSS= wall shear stress. Supporting Table 2. Relationship between TCFA and maximal WSS Odds ratio 95%CI P value Total lesion WSS (max), Pa 1.017 1.001-1.034 0.04 Upstream WSS (max), Pa 0.996 0.958-1.035 0.84 Proximal WSS (max), Pa 1.014 0.993-1.036 0.20 Middle WSS (max), Pa 1.013 0.995-1.032 0.16 Distal WSS (max), Pa 1.010 0.990-1.031 0.32 Downstream WSS (max), Pa 0.903 0.968-1.038 0.90 Total lesion WSS (max), Pa (adjusted for 3D contrast velocity) 1.012 0.988-1.035 0.33 Proximal WSS (max), Pa (adjusted for 3D contrast velocity) 1.015 0.992-1.037 0.83 4. Table3. Please give the explanation of DS (diameter stenosis). Response: Percent diameter stenosis or diameter stenosis is defined as the difference between the reference vessel diameter and minimal luminal diameter, divided by the reference and multiplied by 100. All the measurements were performed automatically by QAngio XA 3D RE software in the study. We added the following clarification to the revised manuscript: Page 5 (new text is underlined): “Three-dimensional quantitative coronary angiography (3D-QCA) and vessel reconstructions were performed using two end-diastolic projections at least 25° apart with commercially available software QAngio XA 3D RE (Medis, Leiden, The Netherlands) followed by automatic quantification of 3D lesion length, minimal and reference diameters, and percent diameter stenosis (DS) (Figure 1A) (14)”. 5. “The optimal cutoff value of WSSproximal to predict TCFA was 6.79Pa (AUC: 0.710; sensitivity: 76.9%; specificity: 63.2%, p=0.02).” A figure with the ROC curve is needed to show where the values come from. Response: We apologize for the oversight, the ROC figure below was added to the revised manuscript ________________________________________ 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: Yes: George A. Truskey 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. ________________________________________ In compliance with data protection regulations, you may request that we remove your personal registration details at any time. (Remove my information/details). Please contact the publication office if you have any questions. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0244015.r002
23 Nov 2020 Decision Letter - Xianwu Cheng, Editor PONE-D-20-22797R1 Relationship between high shear stress and OCT-verified thin-cap fibroatheroma in patients with coronary artery disease PLOS ONE Dear Dr Kini 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. Please submit your revised manuscript by December 31, 2020. 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Xianwu Cheng, M.D., Ph.D., FAHA Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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 issues raised in the review of the original manuscript were addressed. There are a few minor details to address. Specific Comments p. 6, line 7, “flame counts”. Should be “frame counts” p. 6, lines 4-15 “Mean and maximal WSS was calculated …” should be “Mean and maximal WSS were calculated …”. Table 2. Explain why the lipid arc maximum is presented rather than the average lipid arc. Reviewer #2: (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: Yes:** George A Truskey 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. https://doi.org/10.1371/journal.pone.0244015.r003
Revision 2
23 Nov 2020 Author Response Reviewer #1: The issues raised in the review of the original manuscript were addressed. There are a few minor details to address. Specific Comments p. 6, line 7, “flame counts”. Should be “frame counts” p. 6, lines 4-15 “Mean and maximal WSS was calculated …” should be “Mean and maximal WSS were calculated …”. Response: We corrected both typos in the revised manuscript, thank you. Table 2. Explain why the lipid arc maximum is presented rather than the average lipid arc. Response: We apologize for the oversight; the average lipid arc has been added to the Table 2 of the revised manuscript Reviewer #2: (No Response) Attachments Attachment Submitted filename: Response to Reviewers R2.docx https://doi.org/10.1371/journal.pone.0244015.r004
2 Dec 2020 Decision Letter - Xianwu Cheng, Editor Relationship between high shear stress and OCT-verified thin-cap fibroatheroma in patients with coronary artery disease PONE-D-20-22797R2 Dear Dr. Kini 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, Xianwu Cheng, M.D., Ph.D., FAHA Academic Editor PLOS ONE Additional Editor Comments (optional): None. 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 ******** 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) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) Reviewer #2: (No Response) ****** 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) ****** 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) ****** 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) ****** 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:** George A. Truskey Reviewer #2: No https://doi.org/10.1371/journal.pone.0244015.r005
Formally Accepted
9 Dec 2020 Acceptance Letter - Xianwu Cheng, Editor PONE-D-20-22797R2 Relationship between high shear stress and OCT-verified thin-cap fibroatheroma in patients with coronary artery disease Dear Dr. Kini: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Associate Prof. Xianwu Cheng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0244015.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

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