Reading the Signature of Autophagy in the Ischemic and Infarcted Heart: A Systematic Review of Circulating Biomarkers

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

very good and complete analysis. To my mind the Conclusion is to long and should be shortened to the really important key points and to 1 1/2 pages...

Author Response

We thank the reviewer for the positive feedback. We would like to clarify that the Conclusion is already concise, focusing on the main take-home messages of our review. The Discussion section, on the other hand, is designed to clearly summarize and integrate the key findings from the selected studies, providing the necessary synthesis of the literature. This structure allows the Conclusion to remain focused while ensuring that the important ideas from the review are fully conveyed in the Discussion.

Reviewer 2 Report

Comments and Suggestions for Authors

Radaelli D., et al., IJMS – 4122899, Jan. 31.

The authors (Radaelli D., et al., submitted the manuscript entitled “Reading the Signature of Autophagy in the Ischemic and infarcted heart: A systematic Review of Circulating Biomarkers” in the IJMS.The theme of the manuscript is related with myocardial necrosis and cell deaths focusing on autophagy and several biomarkers in ischemic/reperfused hearts and myocardial infarction under experimental and clinical conditions. Autophagy and its mechanisms have been considered as a cell death process in the pathophysiology of myocardial ischemia followed by reperfusion. This manuscript (Radaelli D., et al) aims to summarize and highlight autophagy-related biomarkers with potential benefits for diagnosis, prognosis, and possible pharmacological therapies. As the major goal of the manuscript, totally 14 articles were selected and reviewed with several ‘autophagy-connected’ biomarkers identified during the various stages of cardiac infarction. The authors concluded that the integration of autophagy markers may improve the risk stratification, therapeutic decision, and prognosis in patients suffered from
ischemic heart diseases.

 

The reading of the manuscript is easy to follow, however, the correction of typos and/or grammatical errors are not among the duties of this reviewer. The manuscript is not a new summary of various cell deaths including necrotic/autophagic mechanisms, however, has some scientific value.

 

Comments:

• The criteria for journal selection by the authors (Radaelli D., et al) was based on the best (highest Impact Factor: IF) journals in both the cardiovascular basic and clinical research (see the entire ‘References’ section) originated from the “top” research laboratories in the World. Each of the “top” laboratories published sometimes several papers about 10-20 publications YEARLY in “top cardiovascular journals”. However, this does not mean that the lower IF journals do not have scientific values. Sometimes, publications in lower IF journals have more valuable results and conclusions in comparison with those of high IF journals. Question: Whether among the “Eligibility Criteria” in the manuscript (Radaelli D., et al), the IF of journals was an important point for the selection of the 14 publication? This could be explained in the revised version of the manuscript.

 

• This reviewer recommends an extra paragraph or section (15-20 extra lines and new references), beside the autophagic mechanisms and processes, to discuss an overlapping among the most common cell deaths, including necrosis, apoptosis and autophagy (e.g., necroapoptophagy”), because these three cell death processes have several connections with common biomarkers. The new paragraph and references may not be originated from and connected to the “top laboratories” in the World.

 

• The incorporation of the aforementioned extra section in the revised version of the manuscript (Radaelli D., et al) may substantially increase the interest of general readers, clinicians and experimental researchers.

 

• Is there any relationship between the necrotic/autophagic mechanism and the sudden cardiac death caused by reperfusion-induced ventricular fibrillation under experimental and clinical conditions? This would be also a good point for selection of “TOP publications” in the section of “Eligibility Criteria”. This should be included or at least discussed in the revised version of the manuscript.

 

• No. 25: this reference (Kojima S.) is incomplete in the “References” section, however, this is one out of the selected Top 14 references in the study.

 

• The involvement of a new creative Figure, in the revised manuscript, can further increase the scientific value of this manuscript.

Author Response

1) The criteria for journal selection by the authors (Radaelli D., et al) was based on the best (highest Impact Factor: IF) journals in both the cardiovascular basic and clinical research (see the entire ‘References’ section) originated from the “top” research laboratories in the World. Each of the “top” laboratories published sometimes several papers about 10-20 publications YEARLY in “top cardiovascular journals”. However, this does not mean that the lower IF journals do not have scientific values. Sometimes, publications in lower IF journals have more valuable results and conclusions in comparison with those of high IF journals. Question: Whether among the “Eligibility Criteria” in the manuscript (Radaelli D., et al), the IF of journals was an important point for the selection of the 14 publication? This could be explained in the revised version of the manuscript.

Response: We thank the reviewer for this important observation. Journal Impact Factor was not used as an eligibility or exclusion criterion in the selection of studies. The inclusion was strictly based on predefined scientific criteria, including relevance to myocardial ischemia/infarction, involvement of circulating biomarkers linked to autophagy pathways, and availability of original experimental or clinical data. We acknowledge that high-quality and impactful studies may also be published in journals with lower Impact Factors. To avoid ambiguity, we have now explicitly clarified this point in the Eligibility Criteria section of the revised manuscript.

 

2) This reviewer recommends an extra paragraph or section (15-20 extra lines and new references), beside the autophagic mechanisms and processes, to discuss an overlapping among the most common cell deaths, including necrosis, apoptosis and autophagy (e.g., necroapoptophagy”), because these three cell death processes have several connections with common biomarkers. The new paragraph and references may not be originated from and connected to the “top laboratories” in the World.

3) The incorporation of the aforementioned extra section in the revised version of the manuscript (Radaelli D., et al) may substantially increase the interest of general readers, clinicians and experimental researchers.

Response: We have added a new paragraph addressing the mechanistic overlap among autophagy, apoptosis, and necrosis, highlighting shared regulatory nodes (p53, Bcl-2 family proteins, RIP kinases) and common biomarkers (Beclin-1, ATG5, LC3, p62, caspases). The paragraph also describes how caspase-mediated cleavage of autophagy-related proteins and modulation of RIPK1/RIPK3/MLKL influence the balance between these pathways, illustrating “necroapoptophagy.”

4) Is there any relationship between the necrotic/autophagic mechanism and the sudden cardiac death caused by reperfusion-induced ventricular fibrillation under experimental and clinical conditions? This would be also a good point for selection of “TOP publications” in the section of “Eligibility Criteria”. This should be included or at least discussed in the revised version of the manuscript.

Response: We appreciate this insightful comment. While the primary focus of our review was circulating biomarkers, we agree that the relationship between autophagy, necrosis, and reperfusion-induced ventricular arrhythmias is clinically relevant. We have now included a brief discussion addressing how dysregulated autophagy and cell death signaling may contribute to electrical instability and sudden cardiac death during reperfusion.

5) 25: this reference (Kojima S.) is incomplete in the “References” section, however, this is one out of the selected Top 14 references in the study.

Response: It was corrected

 

6) The involvement of a new creative Figure, in the revised manuscript, can further increase the scientific value of this manuscript.

Response: Thank you for this valuable suggestion. A new figure has been added to the revised manuscript to enhance clarity and improve the scientific presentation of the study.

Reviewer 3 Report

Comments and Suggestions for Authors

I read this manuscript with genuine interest and pleasure. The authors present a professionally prepared and well-structured systematic review addressing an important and timely topic—the role of autophagy-related circulating biomarkers in ischemic and infarcted myocardium.

The review is comprehensive, clearly written, and methodologically sound. It effectively synthesizes current evidence from both clinical and experimental studies, offering a coherent overview of autophagy-related biomarkers and their dynamic behavior across different stages of myocardial ischemia and infarction. Importantly, the manuscript goes beyond a descriptive summary and provides meaningful biological and translational insight into how autophagy-related pathways may complement classical cardiac biomarkers in early diagnosis, risk stratification, and therapeutic decision-making.

I particularly appreciate the clarity with which complex molecular mechanisms are presented, making the review accessible not only to specialists in autophagy research but also to clinicians interested in the molecular underpinnings of ischemic heart disease. From a reviewer’s perspective, the manuscript has also significantly enriched my own understanding of this rapidly evolving field—which, in my opinion, is a key hallmark of a high-quality review article.

The topic, scope, and scientific level of this work make it an excellent fit for the Special Issue “Latest Molecular Advances in Autophagy.” The manuscript meets the expectations of a state-of-the-art review and does not require substantive revisions.

Author Response

We sincerely thank the reviewer for their thoughtful and encouraging evaluation of our manuscript. We are pleased that the review’s scope, clarity, and methodological rigor were well received, and we greatly appreciate the acknowledgment of the biological and translational insights provided. It is especially gratifying to hear that the manuscript enhanced understanding of autophagy-related biomarkers in ischemic and infarcted myocardium and that the content is accessible to both specialists and clinicians. We are grateful for the reviewer’s support of the manuscript’s suitability for the Special Issue “Latest Molecular Advances in Autophagy.”

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I do like the new structure and illustration. Allthough the discussion is even longer ;)

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript should be accepted for publication as is.