Progress in Disease Modeling for Myocardial Infarction and Coronary Artery Disease: Bridging In Vivo and In Vitro Approaches

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have written a review article entitled Progress in Disease Modeling for Myocardial Infarction and Coronary Artery Disease: Bridging In Vivo and In Vitro Approaches, the selection of topics is rather popular, and in fact, a large number of studies related to disease modeling for myocardial infarction and coronary artery disease have appeared in the last few years, which is a popular direction at the moment.

I think this paper could be considered for acceptance with major revisions.

Revisions are list below:

1.      The content of chapters 2 and 3 appears to be closely related to Introduction.

2.      Recent advances in in vitro models need to be more elaborated (e.g., microfluidic models, organ-on-a-chip models).

3.      It is necessary for authors to update the latest research results to reflect the innovativeness of the article (especially in the section on animal models).

4.      Adding research-related images where appropriate can add readability and vividness to the article (e.g., how the study by Song et al. successfully modeled the in vivo situation caused by myocardial infarction and the related experiments mentioned in Chapter 11).

5.      Chapters 5 and 6 might be better placed in the same chapter. The same applies to chapters 7 and 8.

6.      Chapter 8 describes the limitations of organoid engineering as applied to the heart; more needs to be added, and the latest research can be referenced. (DOI: https://spj.science.org/doi/10.34133/bmr.0016; DOI: https://doi.org/10.1063/5.0216185).

7.      Maybe chapter 4 should be closer to chapter 9? (Both mouse and rat models are animal models) The authors need to clarify the structural relationship of the article.

8.      Whether additional information is needed on the limitations of the two animal models described in chapters 12 and 10, which are not significantly different (on the limitations of the models).

9.      The language needs to be improved.

Comments on the Quality of English Language

the language needs to be improved.

Author Response

We are grateful to the reviewer for giving us the opportunity to revise and improve our manuscript. We believe that our point-by-point response will address the reviewer's concerns. We hope our manuscript has now improved and will b suitable for the journal.

1. The content of chapters 2 and 3 appears to be closely related to Introduction.

Response: Thank you for the comments. To address the reviewer’s concern, we have made the changes. Please see the updated information highlighted.

2. Recent advances in in vitro models need to be more elaborated (e.g., microfluidic models, organ-on-a-chip models).

Response: Thank you for this suggestion. We have now elaborated the invitro models according to your suggestions. This change can be found on pages 5-6, Lines 137 – 164.

3. It is necessary for authors to update the latest research results to reflect the innovativeness of the article (especially in the section on animal models)

Response: Thank you for this suggestion. We have updated the information with the latest research, as per your suggestion. We believe that the manuscript has improved now.

4. Adding research-related images where appropriate can add readability and vividness to the article (e.g., how the study by Song et al. successfully modeled the in vivo situation caused by myocardial infarction and the related experiments mentioned in Chapter 11).

Response: Thank you for the comments. We strongly agree with the reviewers that adding images related to research will add to the readability. At this point, due to limited time, we were unable to procure such images but tried to provide as much as possible information to convey the valuable message.

5. Chapters 5 and 6 might be better placed in the same chapter. The same applies to chapters 7 and 8.

Response: Thank you for this suggestion. We have made the changes as suggested. This change has been highlighted for your kind review.

6. Chapter 8 describes the limitations of organoid engineering as applied to the heart; more needs to be added, and the latest research can be referenced. (DOI: https://spj.science.org/doi/10.34133/bmr.0016; DOI: https://doi.org/10.1063/5.0216185).

Response: Thank you for this suggestion. We have made the changes and added more information as per the reviewer’s suggestions. This change can be found on page 8, lines 213-231.

7. Maybe chapter 4 should be closer to chapter 9? (Both mouse and rat models are animal models) The authors need to clarify the structural relationship of the article.

Response: Thank you for the comments. We have made the changes as per suggestions.

8. Whether additional information is needed on the limitations of the two animal models described in chapters 12 and 10, which are not significantly different (on the limitations of the models).

Response: Thank you for the comments. We have added more information as per suggestions. This change are highlighted and they can be found on page no 10-12.

9. The language needs to be improved.

Response: Thank you for the comments. We have revised our manuscript as suggested. We believe that the manuscript has improved now.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript provides a well-organized and comprehensive review on the current knowledge of cardiovascular disease models, focusing on both advantages and disadvantages of each disease model in vitro as well as in vivo. However, it would be necessary to add the detailed methods of making different disease model. For example, in vivo models use coronary artery ligation for AMI and TAC for heart failure and cardiac remodeling. The authors should detail these methods in tables.

Meanwhile, a deeper discussion on the translational challenges of disease models to clinical practice would enhance the manuscript’s impact.

Lastly, ensure that the sections on future challenges and the role of animal models are fully integrated into the overall discussion rather than appearing as stand-alone segments.

Comments on the Quality of English Language

Moderate editing of English language required

Author Response

We are grateful to the reviewer for giving us the opportunity to revise and improve our manuscript. We believe that our point-by-point response will address the reviewer's concerns. We hope our manuscript has now improved and will be suitable for the journal.

1. The manuscript provides a well-organized and comprehensive review on the current knowledge of cardiovascular disease models, focusing on both advantages and disadvantages of each disease model in vitro as well as in vivo.

However, it would be necessary to add the detailed methods of making different disease model. For example, in vivo models use coronary artery ligation for AMI and TAC for heart failure and cardiac remodeling. The authors should detail these methods in tables.

Response: Thank you for these suggestions. We have included a table describing various methods as per the reviewer’s suggestions. These additions can be found on pages 16-17.

2. Meanwhile, a deeper discussion on the translational challenges of disease models to clinical practice would enhance the manuscript’s impact.

Response: Thank you for this suggestion. We have provided additional information as per suggestions.

3. Lastly, ensure that the sections on future challenges and the role of animal models are fully integrated into the overall discussion rather than appearing as stand-alone segments.

Response: Thank you for the comments. We have made the changes as per suggestions. This change can be found on pages 18-19 and lines 455-483.

Reviewer 3 Report

Comments and Suggestions for Authors

 -  line 34 - the values of AMI prevalence (3 million worldwide) and mortality in the US alone (1 million) seem to be incorrect.

- the second paragraph from the introduction is too general.

- in the introduction the authors should clearly specify the aims of the study, and detail why their study is needed;

- headings 2 and 3 seem too general; they are more appropriate for book chapters, not scientific articles

- overall, the article seems to be too general in its statements. It reads like a book chapter. The authors should clarity what they want to present, and to do an article which properly summarizes the most recent information in the field, not present general information.

As it is, I do not think this is publishable as a scientific article, but rather as a book chapter

Comments on the Quality of English Language

Minor corrections should be made

Author Response

We appreciate the reviewer for these comments and valuable suggestions. We have attempted to respond to all the comments and tried to revise our manuscript. We hope that our point-by-point response has now improved the manuscript.

1. line 34 - the values of AMI prevalence (3 million worldwide) and mortality in the US alone (1 million) seem to be incorrect.

Response: Thank you for the comments. We have corrected the information, provided additional information, and added references. Please see the updated section on page 3, Lines 66-76.

2.- the second paragraph from the introduction is too general.

Response: Thank you for the comments. We have made the changes as per suggestions. We believe that these changes will address the reviewer’s concerns.

3- in the introduction, the authors should clearly specify the aims of the study, and detail why their study is needed;

Response: Thank you for this suggestion. We have made the changes as per your suggestion. This change can be found on page 4, lines 96-102.

4- headings 2 and 3 seem too general; they are more appropriate for book chapters, not scientific articles

Response: Thank you for the comments. We have made the changes as per suggestions. We hope these new changes will address the reviewer’s concerns.

5- overall, the article seems to be too general in its statements. It reads like a book chapter. The authors should clarity what they want to present, and to do an article which properly summarizes the most recent information in the field, not present general information. As it is, I do not think this is publishable as a scientific article, but rather as a book chapter.

Response: Thank you for the comments. We have made various changes throughout the manuscript as per the reviewer’s suggestions. We believe that our manuscript has now improved and suitable for the journal.

Reviewer 4 Report

Comments and Suggestions for Authors

Riya Kar et al. report on the progress in disease modeling for myocardial infarction and coronary artery disease, bridging in vivo and in vitro approaches. They discuss the advantages and limitations of in vitro models, describing studies in zebrafish, mice, rats, and even large animals, and compare the benefits and drawbacks of each.

1. The 'Future Challenges' section, lines 70 to 79, needs references.
2. In the 'Role of Animal Models' section, it is noted that rabbit myocardium shares more similarities with human myocardium than small rodent myocardium. Why wasn't the rabbit model discussed?
3. You include pigs, sheep, and dogs in Figure 1, but why are sheep and dogs not mentioned in the main text?
4. You have cited the most recent WD-fed SR-BIΔCT/ΔCT/Ldlr-/- mouse model in line 197. Is that the best one? How does it compare to other mouse models?

This review ambitiously discusses all kinds of models but lacks depth and insight. It selects several examples without explaining why these particular examples were chosen. This section should be improved

Comments on the Quality of English Language

Clear.

Author Response

Riya Kar et al. report on the progress in disease modeling for myocardial infarction and coronary artery disease, bridging in vivo and in vitro approaches. They discuss the advantages and limitations of in vitro models, describing studies in zebrafish, mice, rats, and even large animals, and compare the benefits and drawbacks of each.

Response: We are grateful to the reviewer for their kind comments and suggestions. We have now revised our manuscript as per the reviewer's suggestions. We hope that our point-by-point response will address the reviewer's concerns and find our paper suitable for the journal.

1. The 'Future Challenges' section, lines 70 to 79, needs references.

Response: Thank you for the comments. We have made the changes per your suggestions. This change can be found on page 20, lines 455- 483.

2. In the 'Role of Animal Models' section, it is noted that rabbit myocardium shares more similarities with human myocardium than small rodent myocardium. Why wasn't the rabbit model discussed?

Response: Thank you for the comments. We have made the changes as per suggestions. This change can be found on page no 9, Lines 238-240 and 307-325.

3. You include pigs, sheep, and dogs in Figure 1, but why are sheep and dogs not mentioned in the main text?

Response: Thank you for the comments. We have made the changes per your suggestions. This change can be found on pages 16, 17, and 18.

4. You have cited the most recent WD-fed SR-BIΔCT/ΔCT/Ldlr-/- mouse model in line 197. Is that the best one? How does it compare to other mouse models?

Response: Thank you for the comments. We have made the changes per your suggestions. This change can be found on pages 10-11, lines 278-280.

 5. This review ambitiously discusses all kinds of models but lacks depth and insight. It selects several examples without explaining why these particular examples were chosen. This section should be improved

Response: Thank you for these suggestions. We have made the changes as requested. We believe that our revisions have improved the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

accept

Author Response

We thank the reviewer for their valuable suggestions, which have improved our manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

- the article still reads like a book chapter. There is a lot of filler information. The authors did not clearly showed in the revised manuscript their changes, which makes impossible a proper evaluation of what they changed (unless somebody takes each paragraph by hand). There are also some issues with the images - which contain many references. Why? Is the information taken from there? The image? It is unclear.

Comments on the Quality of English Language

Moderate English corrections are needed.

Author Response

Reviewer#2

The article still reads like a book chapter. There is a lot of filler information. The authors did not clearly showed in the revised manuscript their changes, which makes impossible a proper evaluation of what they changed (unless somebody takes each paragraph by hand). There are also some issues with the images - which contain many references. Why? Is the information taken from there? The image? It is unclear.

Author's Response: We appreciate the reviewer's critical review and valuable comments. We have made the changes and highlighted them throughout the manuscript, as suggested by the reviewer. Further, to address the reviewer’s concern, we have removed the references from the figures and inserted them in appropriate positions in the text, as suggested. We hope our manuscript has improved and will suit the journal.

Reviewer 4 Report

Comments and Suggestions for Authors

Cardiovascular diseases (CVD) are the leading cause of death, and animal models are designed to study them. This paper ambitiously discusses models ranging from cellular to various animal models but still lacks deeper insights.

Author Response

Reviewer#3

Cardiovascular diseases (CVD) are the leading cause of death, and animal models are designed to study them. This paper ambitiously discusses models ranging from cellular to various animal models but still lacks deeper insights.

Author's Response: Thank you for these comments. We have revised our manuscript extensively and added more information to address the reviewer’s concern. Please see the highlighted regions throughout the manuscript. We sincerely hope our manuscript has improved and will suit the journal.

Round 3

Reviewer 3 Report

Comments and Suggestions for Authors

The observation about the articles seeming to be a book chapter still remains. The authors should focus their attention to a specific topic, and analyse it depth.

I recommend the authors to read and develop their ideas based on a specific methodology for a narrative review (which they intended to do here). See e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380636/ for details about types of narrative reviews and main ideas about how to conduct it.

Comments on the Quality of English Language

English is readable

Author Response

Response: We appreciate the reviewer’s comments and valuable feedback. We understand the concern regarding the article appearing as a book chapter and appreciate the suggestion to narrow our focus. In response, we have restructured the article by refining our scope and attempted to provide a focused exploration that better aligns with the article's goals. We hope this revision addresses the concern and improves the clarity and coherence of our argument.

1. We carefully read the suggested article and made substantial changes in the manuscript per the reviewer’s suggestions. The changes have been highlighted for clarity. Our review article’s main focus was to “explore the use of in vivo and in vitro models in MI research, highlighting their advantages and limitations. In vivo models provide insights into the systemic effects of MI, while in vitro models offer detailed views of cellular mechanisms. By comparing these approaches, we aim to identify the most appropriate model for different facets of myocardial infarction research.” Please see manuscript page 2, lines 91-95.

2. We also hope that “By bridging these in vivo and in vitro approaches, researchers can gain a more comprehensive understanding of disease mechanisms, validate experimental findings, and accelerate the development of effective therapies. This review highlights recent progress, identifies current limitations, and proposes strategies for future research to enhance the translation of model-based discoveries into clinical practice for MI and CAD. Please kindly see Page 1, Lines 35-39.

3. Further, to address the reviewer’s concern, We have provided more information in the Zebrafish model section, highlighting it as a suitable model over other models. Please see page 10, Lines 395-411 and 423-439.

5.3. Zebrafish as an Alternate Model bridging the gaps in MI and CAD research.

When it comes to cardiovascular disease (CVD) research, zebrafish (Danio rerio) have become a helpful model organism. They have various benefits over other vertebrate systems, such as mice and rats, which are more traditional. Because of their distinct genetic, physiological, and developmental traits, zebrafish offer novel insights into the development of the cardiovascular system, disease processes, and medication screening. Humans and zebrafish have a lot of genetic similarities. Zebrafish conserves over 84% of the genes linked to human disease, including several related in cardiovascular disorders. Over 70% of human genes are also found in zebrafish [110]. Because of this, they serve as a great model for researching the molecular causes of various cardiovascular diseases, including cardiomyopathies and congenital heart abnormalities.  Because zebrafish embryos and larvae are optically transparent, intrusive methods are not required for real-time cardio-vascular system observation [111]. This benefit makes it easier to perform live imaging, in vivo investigations: Non-invasive monitoring of angiogenesis, blood flow, and heart re-generation is possible [112]. Within 48 hours of fertilization, a functioning heart forms in zebrafish embryos, which develop quickly on the outside [111]. Further, zebrafish are perfect for high-throughput genetic screening and chemical testing because of their quick development and high fecundity (hundreds of eggs per week) [110].5.4. Advantages of Zebrafish over other models.

5.4. Advantages of Zebrafish over other models

Compared to the mouse models, mice are genetically closer to humans but lack zebrafish's transparency and regenerative abilities. The longer reproductive cycle and higher maintenance costs also make zebrafish a more efficient choice for rapid genetic screening [108]. Similarly, the rats offer excellent cardiovascular physiology data but share similar limitations with mice regarding regeneration and cost [112]. Further, in vitro Systems such as human stem cells allow for human-specific studies, and zebrafish offer a whole-organism context that in vitro systems lack. This allows for a complete understanding of cardiovascular disease mechanisms [110].

4. Please see the publications below that helped develop the structure of the review article.:

• Catherine T. Nguyen, Qing Lu, Yibin Wang, Jau-Nian Chen, Zebrafish as a model for cardiovascular development and disease, Drug Discovery Today: Disease Models, Volume 5, Issue 3, 2008, Pages 135-140, ISSN 1740-6757, https://doi.org/10.1016/j.ddmod.2009.02.003.
• Bakkers J. Zebrafish as a model to study cardiac development and human cardiac disease. Cardiovasc Res. 2011 Jul 15;91(2):279-88. doi: 10.1093/cvr/cvr098. Epub 2011 May 19. PMID: 21602174; PMCID: PMC3125074.
• Francoeur N, Sen R. Advances in Cardiac Development and Regeneration Using Zebrafish as a Model System for High-Throughput Research. J Dev Biol. 2021 Sep 25;9(4):40. doi: 10.3390/jdb9040040. PMID: 34698193; PMCID: PMC8544412.
• M. González-Rosa. Zebrafish Models of Cardiac Disease: From Fortuitous Mutants to Precision Medicine. Circulation Research 2022 Vol. 130 Issue 12 Pages 1803-1826. DOI: doi:10.1161/CIRCRESAHA.122.320396

We hope that our response will address the reviewer's concerns.

Reviewer 4 Report

Comments and Suggestions for Authors

The author addresses most of my concerns. I agree to publish. in vitro and in vivo would better be italicized because they are Latin terms

Author Response

Response: Thank you very much for this suggestion. We have corrected them and italicized them throughout the manuscript, as suggested.