MicroRNA and DNA Methylation Adaptation Mechanism to Endurance Training in Cardiovascular Disease: A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Key Points

Positioning and novelty in the literature

By relating endurance exercise to epigenetic mechanisms (miRNAs and DNA methylation) in patients with cardiovascular diseases, the manuscript tackles a topic that is both current and pertinent.

More clearly outlining the review's differences from earlier systematic or narrative reviews on exercise and epigenetics in healthy populations or animal models, however, would enhance its novelty.

The method and thoroughness of the search

Even though the review was registered in PROSPERO and adhered to PRISMA guidelines, the reported PubMed search string is imprecise, containing redundant information and ambiguous Boolean combinations. This calls into question how thorough the search was.

The included studies' heterogeneity

There was significant variation in the populations (heart failure, coronary artery disease, hypertension) and exercise regimens among the six studies that were included.

This reduces the strength of conclusions and restricts comparability. The impact of this heterogeneity on interpretation should be discussed more critically.

Assessment of the risk of bias

Although the JBI critical appraisal tool was used, the majority of the reporting is descriptive. Methodological flaws in the included studies (such as inadequate control groups, small sample sizes, and concurrent medical treatment) should be critically and thoroughly explained in the narrative.

Combining the results

Though the narrative primarily lists results without a more thorough comparative analysis, the results are presented clearly in tables.

Findings should be weighed according to study quality and design, with consistency and discrepancies highlighted in a more critical synthesis.

To prevent overstating conclusions, these statements should be carefully revised.

Small Details

Figures and tables

Although thorough, the tables' readability is diminished by their density and excessive use of acronyms. Think about making them simpler or reserving more in-depth information for supplemental material.

Writing redundancies

The phrase "This systematic review was conducted according to the PRISMA guidelines" appears twice in the Methods section. Duplications of this kind ought to be eliminated.

Title

The title could be shorter. "Epigenetic mechanisms of cardiac adaptation to endurance exercise: a systematic review in cardiovascular disease" is the suggested revision.

Style and language

Although the manuscript is comprehensible, it would benefit from expert English editing to enhance clarity and flow, especially by cutting out superfluous words and minimizing repetition.

Setting the Scene

Comparing results with those from animal models and healthy populations could enhance the discussion and place the review more firmly in the larger body of literature.

Suggested Choice

Significant Revision.
The manuscript has the potential to contribute significantly and tackles a significant and developing field. However, before the paper can be considered for publication, significant improvements in critical analysis, methodology reporting, and presentation clarity are needed.

Author Response

Manuscript Cardiogenetics-3837278

Response to reviewer

 

Thank you for taking the time to review our manuscript for publication in the Cardiogenetics journal. Through this letter, we will address all comments point by point. These answers shall appear in blue. Every change made to the manuscript was highlighted in yellow. Page and line numbers refer to the revised manuscript.

 

Reviewer’s comments to Authors:

Positioning and novelty in the literature

By relating endurance exercise to epigenetic mechanisms (miRNAs and DNA methylation) in patients with cardiovascular diseases, the manuscript tackles a topic that is both current and pertinent.

More clearly outlining the review's differences from earlier systematic or narrative reviews on exercise and epigenetics in healthy populations or animal models, however, would enhance its novelty.

Authors’ response: Thank you for your suggestion. We have added content in the introduction, lines 73-75, page 2.

 

The method and thoroughness of the search

Even though the review was registered in PROSPERO and adhered to PRISMA guidelines, the reported PubMed search string is imprecise, containing redundant information and ambiguous Boolean combinations. This calls into question how thorough the search was.

Authors’ response: Both researchers knew when implementing this Pubmed search string that it was quite ambiguous and redundant. We actually had a difficult time finding the right search string. We tried many with fewer search terms and less Boolean operators, but every attempt resulted in either too few or too many articles. After trying hundreds of different search strings, we ultimately settled on this one, aware of its flaws but recognising that it provided the best results (in terms of articles retrieved through this search).

 

The included studies' heterogeneity

There was significant variation in the populations (heart failure, coronary artery disease, hypertension) and exercise regimens among the six studies that were included.

This reduces the strength of conclusions and restricts comparability. The impact of this heterogeneity on interpretation should be discussed more critically.

Authors’ response: We thank you for your comment. Content was added on page 17, lines 515-519.

 

Assessment of the risk of bias

Although the JBI critical appraisal tool was used, the majority of the reporting is descriptive. Methodological flaws in the included studies (such as inadequate control groups, small sample sizes, and concurrent medical treatment) should be critically and thoroughly explained in the narrative.

Authors’ response: Thank you for highlighting this. We have added content to the discussion: page 17, lines 513–515, and page 18, lines 526-531.

 

Combining the results

Though the narrative primarily lists results without a more thorough comparative analysis, the results are presented clearly in tables.

Findings should be weighed according to study quality and design, with consistency and discrepancies highlighted in a more critical synthesis.

To prevent overstating conclusions, these statements should be carefully revised.

Authors’ response: Thank you for your comment. With only six included studies and considering the substantial heterogeneity in populations, interventions, and outcomes, we believed that separating results by study design or quality would not yield meaningful comparisons. Instead, we chose to organise our results around outcomes that would link different studies. In our view, this approach highlights main themes and provides readers with a clearer synthesis by enabling direct recognition of the most relevant findings. Since none of the included studies demonstrated a lower risk of bias, differentiating results solely based on methodological quality was challenging. Therefore, we decided to present all findings under thematic headings and include a separate section dedicated to a critical appraisal of study quality and risk of bias.

 

Small Details

Figures and tables

Although thorough, the tables' readability is diminished by their density and excessive use of acronyms. Think about making them simpler or reserving more in-depth information for supplemental material.

Authors’ response: We thank you for your comment regarding table readability. Given the significant heterogeneity and complexity of data, and the need to include all relevant details, we did our best to ensure clear formatting but faced limitations. All acronyms were used to keep the tables as concise as possible and to prevent expansion across multiple pages. In tables like Table 3, we again encountered difficulties due to the heterogeneity of data concerning molecular outcomes. Since outcomes were not grouped or categorised by importance in the selected papers, we chose to present every result, knowing it would reduce readability. We had already removed some less relevant details during drafting to improve clarity, and the tables now present the most important information. 

 

Writing redundancies

The phrase "This systematic review was conducted according to the PRISMA guidelines" appears twice in the Methods section. Duplications of this kind ought to be eliminated.

Authors’ response: Thanks to your review, this redundancy has been eliminated following further checking.

Title

The title could be shorter. "Epigenetic mechanisms of cardiac adaptation to endurance exercise: a systematic review in cardiovascular disease" is the suggested revision.

Authors’ response: We thank you for your suggestion and agree that it could benefit from being shorter. The modification was made on page 1.

Style and language

Although the manuscript is comprehensible, it would benefit from expert English editing to enhance clarity and flow, especially by cutting out superfluous words and minimizing repetition.

Author’s response: We thank the reviewer for this suggestion. Without changing the writing style, we improved our English writing to the point where our university English professor deemed it necessary.

Setting the Scene

Comparing results with those from animal models and healthy populations could enhance the discussion and place the review more firmly in the larger body of literature.

Authors’ response: This was discussed by different authors; however, it was decided that we will focus only on patients with cardiovascular diseases for now, recognising that healthy populations and animal models have been studied more extensively to date. We have discussed future research possibilities based on these comparisons.  

Suggested Choice

Significant Revision.
The manuscript has the potential to contribute significantly and tackles a significant and developing field. However, before the paper can be considered for publication, significant improvements in critical analysis, methodology reporting, and presentation clarity are needed.

We appreciate the reviewer’s encouragement. We worked hard to improve the manuscript to meet the reviewer’s quality expectations. 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This systematic review provides up-to-date information about the linkage between exercise training and epigenetic markers, with the focus on the DNA methylation and miRNA expression, as well as cardiac function especially in individuals with certain types of CVDs. I have no specific complains about the content and structure of this review considering that the direct physiological link from the altered pattern of gene expression due to various factors, such as exercise training is often hard to reveal. So, more experimental studies and reviews summarising the available knowledge are necessary to draw firm conclusions that could be translated into clinical practice

Author Response

Manuscript Cardiogenetics-3837278

Response to reviewer

 

Dear Reviewer,

 

We sincerely thank you for your positive and encouraging feedback.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors, I was reviewing with high interest the manuscript entitled "Epigenetic mechanisms of cardiac adaptation to endurance exercise: A systematic review of microRNA and DNA methylation in cardio-vascular disease". The review handles with a highly interesting topic with lots of confusing and divergent results in the literature. You manage to give a good and clear review over the results of six relevant publications. The relevant data about DNA methylation and miRNA expression is clearly laid out. The presented literature is actual and relevant and the discussion highlights the all aspects. In my opinion the manuscript meets the requirements and criteria for being published in Cardiogenetics.

Author Response

Manuscript Cardiogenetics-3837278

Response to reviewer

 

Dear Reviewer,

 

We sincerely thank you for your positive and encouraging feedback.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I would like to thank the authors for the revisions and improvements made to the new version of the manuscript entitled “MicroRNA and DNA methylation adaptation mechanism to endurance training in cardiovascular disease: a systematic review”. The effort to refine the writing, expand the discussion, and clarify methodological aspects is evident.

Strengths of the revised version:

• The introduction is better structured and provides a clearer context for the relevance of epigenetics in endurance training.

• The methodology section is more detailed, now including the PROSPERO registration and well-defined inclusion/exclusion criteria.

• Results are presented in a more organized way through tables and sub-sections, which improves readability and comprehension.

• The discussion more explicitly integrates molecular findings with clinical outcomes.

Points that still require attention:

1. Causal interpretation: While associations between epigenetic changes and cardiovascular parameters are recognized, the manuscript still tends to infer causality without sufficient evidence. The language should be adjusted to emphasize association rather than causation and highlight limitations more clearly.

2. Study heterogeneity: Although mentioned, the impact of heterogeneity across study designs, populations, interventions, and outcomes on result interpretation should be stressed more strongly.

3. References: Some important statements are supported by limited citations. I recommend adding or updating key references, especially recent work on molecular mechanisms.

4. Writing style: Although improved, certain sections remain redundant or overly long. Further editing would enhance clarity and fluency.

5. Figures/visual summary: Consider including a schematic diagram summarizing the main molecular mechanisms and clinical outcomes to provide a more integrative perspective.

Final recommendation:
I recommend acceptance with minor revisions, mainly focused on writing style adjustments, conceptual precision, and strengthening the discussion of limitations. The manuscript makes a valuable contribution to understanding the relationship between endurance training, epigenetic modifications, and cardiovascular adaptation in patients with cardiovascular disease.

Sincerely,
Samir José Bolívar González
Reviewer

Author Response

Dear Reviewer,

 

Thank you for your comments and your encouragement to keep improving our manuscript. Below you will find the answers to your questions. You can find the relevant modifications in green.

 

1. Causal interpretation: While associations between epigenetic changes and cardiovascular parameters are recognised, the manuscript still tends to infer causality without sufficient evidence. The language should be adjusted to emphasise association rather than causation and highlight limitations more clearly.

 

The needed adjustments were performed accordingly, where it was possible, without changing the manuscript content.

 

 

1. Study heterogeneity: Although mentioned, the impact of heterogeneity across study designs, populations, interventions, and outcomes on result interpretation should be stressed more strongly.

 

The comments regarding heterogeneity were added to reinforce this description.

 

1. References: Some important statements are supported by limited citations. I recommend adding or updating key references, especially recent work on molecular mechanisms.

 

Regarding this issue, four new references were added in the introduction section (2, 4, 9, 15) with more up-to-date resources from 2023 to 2025 to support our various statements.

 

1. Writing style: Although improved, certain sections remain redundant or overly long. Further editing would enhance clarity and fluency.

 

Redundancies were refined where identified.

 

1. Figures/visual summary: Consider including a schematic diagram summarizing the main molecular mechanisms and clinical outcomes to provide a more integrative perspective.

 

We created an image that consistently summarises the article; thank you for the suggestion. 

 

Author Response File: Author Response.docx