Persistent Vascular Complications in Long COVID: The Role of ACE2 Deactivation, Microclots, and Uniform Fibrosis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper "Persistent Vascular Complications in Long COVID: The Role of ACE2 Deactivation, Microclots, and Uniform Fibrosis", submitted under the section "Hypotheses", aims to address the potential biological mechanisms underlying long COVID. The content and list of references provide a comprehensive review of the ACE2 mechanisms and are adequate. However, to enhance the paper's readability and value as an educational resource, the following structural reorganisation is proposed to enhance readability.

It is recommended that the paper be restructured by moving Section 3 ("Vascular complications in long COVID-19") before Section 2 ("The role of ACE2 in COVID-19 and long COVID"). This reorganisation will maintain a logical flow, leading the reader from the discussion of vascular complications in long COVID to the role of ACE2 and subsequently to the hypothesis presented in Section 4 ("Hypothesis: ACE2 deactivation or shedding leads to cardiovascular complications"). This change will make the paper more reader-friendly and easier to follow.

Section 5 ("Implementations and suggestions") appears generic in its current form. The authors should expand this section by mentioning specific studies, methods, and parameters to be assessed to enhance its value. Including specific biomarkers to be measured would be particularly beneficial, as this is often expected in papers covering hypothesis topics. These details will provide a more comprehensive understanding of the proposed implementations and suggestions.

 

The paper is well written, and the recommendations aim to improve its readability and value as an educational resource. By implementing the proposed structural reorganisation and expanding Section 5 with specific details, the paper will enhance its accessibility and usefulness for those seeking to use it as an educational resource and for further investigation. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

I highly appreciate the opportunity of reviewing this interesting manuscript. Prognostic and diagnostic biomarkers of long COVID sequelae may increase the level of clinical care provided for patients e. g. with vascular complications.

Here are my minor comments:

1. Figure 1 is not enough clear and lucid. I suggest replacing organ pictograms with more schematic form. Furthermore, 1B contains to much text. The objective of this Figure is to ease future readers understand the pathomechanism of ACE2-related extended symptoms (please illustrate steps described in lines 101-104 as well). Try to follow the direction presented by Bohmwald et al. (2024), doi: 10.3389/fimmu.2024.1341600.

2. There are a few unnecessary shortcuts, e. g. line 96. Please at least list the affected immune mediators or add a table here. Similarly in lines 118-119.

3. Table 1 would benefit from expanding with geographic distribution of the studies. Were there any studies that the authors excluded from the analysis? Please consider including PRISMA flowchart here.

4. I would like the authors to elaborate the issue of post-vaccine vascular complications as this topic turns out to be of utter importance for many unconvinced patients.

5. Can ACE2 be affected by regular COVID treatment? Please discuss.

6. I find the hypotheses of the authors (lines 230-256) the most novel part of the manuscript. In my view this part deserves more specific linkage with the next paragraph. Maybe a table would be a better form of presenting these ideas?

7. There is one important statement that is missing here. SARS-CoV-2 is not over and patients may still produce long COVID complications ever after a recent mild infection.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This review explains the pathophysiology of long-COVID with elevated AT-II, tissue damage, and hypercytokinemia resulting from ACE2 inactivation by SARS-CoV2. The explanation is obvious and convincing. The literature is appropriately cited. We do not recognize any particular points that need to be corrected.

Author Response

Thank you for your positive feedback on our manuscript. We appreciate your recognition of the clarity and comprehensiveness of our explanation regarding the pathophysiology of long COVID, including the roles of elevated AT-II, tissue damage, and hypercytokinemia resulting from ACE2 inactivation by SARS-CoV-2. We are pleased that you found the explanation convincing and that the literature was appropriately cited. We are also grateful for your confirmation that there are no particular points that need correction.

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript is well written and interesting.

I propose to verify these points:

At page 1 on line 34: “from asymptomatic cases to mild symptoms;” I suggest to modify it.

At page 1 on line 36: “nasal congestion[3].” I suggest: “nasal congestion [3].” Please, verify also in other cases in the manuscript.

At page 1 on line 34: “ACE2, is” I think ““ACE2 is”

At page 5 on lines 182-183: “and hypofibrinolytic state [40]. In addition to microvascular” I suggest

“and hypofibrinolytic state [40].

In addition to microvascular”

At page 5 on line 202: “These risks  were most acute” Why do you use “acute”?

At page 7 on line 297: “these microclots persist” I suggest “these microclots could persist”

Author Response

Please see the attachment.

Author Response File: Author Response.pdf