The Signaling Mechanism of Remote Postconditioning of the Heart: Prospects of the Use of Remote Postconditioning for the Treatment of Acute Myocardial Infarction

Round 1

Reviewer 1 Report

For the improving the outcome of acute myocardial infection, post-conditioning might be important strategy for decreasing reperfusion injury. The review summarized the recent animal and clinical studies for the remote post-conditioning. The summary of animal studies in Fig 1 and clinical studies for Table 1 is useful. The review is relatively too much descriptive for the protocol in each study and it is hard it understand why some studies are effective and the others are not effective. Authors should more focused about the mechanism and how we can improve the methods for clinics.

Major revision 

1) First, authors should discuss the definition and current problem of remote post-conditioning.

2) In animal studies, authors shoes too much detail for the protocol. Authors should discuss more why some protocol was working and others are not working. For example, the portions of IP were quite different which might affect the results.  

3) The effectiveness of pre-conditioning, coronary post-conditioning and remote post-conditioning. For example oxidative stress, PKC activation, mediators, calcium overload etc might be involved and the different. Intracellular acidosis, calcium overload and oxidative stress should be important. Post-conditioning with lactate infusion to improve intracellular acidosis could be very effective in clinic (Koyama t et al.). Authors might be included the references and perspective should be improved.

There are too much descriptive and some parts are hard to be understood. Please check the English sentences.

Author Response

Manuscript ID: cells-2415301

Dear colleague. Thank you very much for your comment that allowed us to improve the quality of the article.

For the improving the outcome of acute myocardial infection, post-conditioning might be important strategy for decreasing reperfusion injury. The review summarized the recent animal and clinical studies for the remote post-conditioning. The summary of animal studies in Fig 1 and clinical studies for Table 1 is useful. The review is relatively too much descriptive for the protocol in each study and it is hard it understand why some studies are effective and the others are not effective. Authors should more focused about the mechanism and how we can improve the methods for clinics.

We discussed the improvement of clinical efficiency of remote postconditioning in conclusion.

Major revision

1) First, authors should discuss the definition and current problem of remote post-conditioning.

We discussed problem in the mini-chapter 7 and conclusion.

2) In animal studies, authors shoes too much detail for the protocol. Authors should discuss more why some protocol was working and others are not working. For example, the portions of IP were quite different which might affect the results.

Reviewers usually require me to set out detailed protocols. I'm afraid that the second reviewer will give negative feedback, if I shorten the description of the protocols. Researchers usually publish data if they are doing well. Two years ago I applied for a grant for remote postconditioning. Two Russian reviewers gave negative reviews. They wrote that they tried to perform remote postconditioning and they didn't succeed, so they believe that remote postconditioning does not exist. They didn't publish articles saying they couldn't carried out remote postconditioning. In May 2023, I sent my colleague to St. Petersburg to carry out experimental studies there and be able to convince Professor M.M. Galagudza in the existence of remote postconditioning. He abandoned these experiments at the last moment. It is difficult for me to judge why some researchers fail to perform remote postconditioning. They do not publish their negative results.

We found that remote postconditioning does not work in old rats with metabolic syndrome. We found that the K_ATP channel blocker glibenclamide used for treatment of diabetes mellitus completely abolished the infarct reducing effect of remote postconditioning in yang rats [unpublished data]. It was not find the cardioprotective effect of remote postconditioning in clinical study PMID: 31500849. In this study it was included all patients, old and yang with metabolic syndrome, without metabolic syndrome, with diabetes and without diabetes, some patients received the K_ATP channel blockers. In addition, investigators induced I/R of arm but not legs. The most investigators used hindlimb I/R. It is possible that the infarct-reducing effect depends on skeletal muscle mass. 

3) The effectiveness of pre-conditioning, coronary post-conditioning and remote post-conditioning. For example oxidative stress, PKC activation, mediators, calcium overload etc might be involved and the different. Intracellular acidosis, calcium overload and oxidative stress should be important. Post-conditioning with lactate infusion to improve intracellular acidosis could be very effective in clinic (Koyama t et al.). Authors might be included the references and perspective should be improved.

We cited Koyama’s articles and Chepelev’s article on lactate. We added new articles and prepared two additional tables. 

There are too much descriptive and some parts are hard to be understood. Please check the English sentences.

OK.

Sincerely yours, Leonid N. Maslov

Reviewer 2 Report

In the paper entitled “The Signaling Mechanism of Remote Postconditioning of the Heart. Prospects of the Use of Remote Postconditioning for Treatment of Acute Myocardial Infarction", the authors discuss the topic of remote postconditioning (Rpost) of the heart as a potential therapeutic approach. 

The review provides a comprehensive overview of the current knowledge of RPost in the context of AMI treatment, emphasizing the necessity for additional research to establish its clinical efficacy and broaden its therapeutic application.

Only minor points need to be improved:

·      I recommend that authors avoid discussing unpublished data. Cut from the manuscripts the lines: 74-82, 138-139, 244-251, 259-260

·      I suggest authors to add a table covering chapters 2 and 3, it could improve the quality and help the reader to follow the manuscript.

·      Increase the number of references in Chapter 3.

·      Improve discussion about metabolic syndrome

·      Line 213: non-formatted reference.

·      Line 255: Ref 39 is incorrect.

In my opinion, the manuscript is written too schematically in Chapters 2 and 3.

Author Response

Manuscript ID: cells-2415301

Dear colleague. Thank you very much for your comment that allowed us to improve the quality of the article.

Reviewer 2

In the paper entitled “The Signaling Mechanism of Remote Postconditioning of the Heart. Prospects of the Use of Remote Postconditioning for Treatment of Acute Myocardial Infarction", the authors discuss the topic of remote postconditioning (Rpost) of the heart as a potential therapeutic approach.

The review provides a comprehensive overview of the current knowledge of RPost in the context of AMI treatment, emphasizing the necessity for additional research to establish its clinical efficacy and broaden its therapeutic application.

Only minor points need to be improved:

• I recommend that authors avoid discussing unpublished data. Cut from the manuscripts the lines: 74-82, 138-139, 244-251, 259-260 We added our article.
• I suggest authors to add a table covering chapters 2 and 3, it could improve the quality and help the reader to follow the manuscript. We prepared two tables.
• Increase the number of references in Chapter 3. We added only three references on kinases and NOS. New articles on kinase and NOS did not published in 2022 and 2023.
• Improve discussion about metabolic syndrome we added articles
• Line 213: non-formatted reference. OK
• Line 255: Ref 39 is incorrect. Ref 39 is correct. I wrote incorrect.

In my opinion, the manuscript is written too schematically in Chapters 2 and 3.

We cited Koyama articles at the request of the first reviewer.

Sincerely yours, Leonid N. Maslov

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Authors improved manuscript following reviewers concerns.