Further Advances in Atrial Fibrillation Research: A Metabolomic Perspective

Round 1

Reviewer 1 Report

Overall the study is well written addressing the advances in atrial fibrillation provide the use of metabolomics in this condition. Therefore, I made considerations so that the authors can think about it and seek to improve the review. The article reports a very important topic in the field of scientific research.

1. Patients who have biomarkers for the development of AF, but do not have the disease itself. What would be the prophylactic measures for the patient not to develop AF?

2. Item 2.2 Metabolomic study of atrial fibrillation in an animal model, the fourth line “in dogs” has an extra dot, please remove 

3. Item 3. Discussion, the third line has an extra dot, please remove it.

4. Standardize the references, for example, in reference number 11 the year is not in bold, in the others all years are in bold.

5. Based on the studies shown, what would be the main biomarkers associated with AF in humans?

Author Response

Reviewer 1

 

Overall the study is well written addressing the advances in atrial fibrillation provide the use of metabolomics in this condition. Therefore, I made considerations so that the authors can think about it and seek to improve the review. The article reports a very important topic in the field of scientific research.

1. Patients who have biomarkers for the development of AF, but do not have the disease itself. What would be the prophylactic measures for the patient not to develop AF?

We would like to thank reviewer1 this suggestion that will improve the quality of our review paper. We have included a paragraph in the discussion section about this point. Please see Page 6, paragraph 6:

“In this way, we will be able to continue making progress and achieve a better understanding of the diseases that would be translate in a better quality of life to people who are affected by AF and help people who present abnormal values of these biomarkers although they have not developed the disease yet. The key risk factors are increasing age, miocardial infarction, valvular heart disease and hypertension.  To avoid the development of AF a healthy lifestyle that contributes to normalize biomarkers values should be followed [5]”

2. Item 2.2 Metabolomic study of atrial fibrillation in an animal model, the fourth line “in dogs”has an extra dot, please remove

Removed

3. Item 3. Discussion, the third line has an extra dot, please remove it.

Removed

4. Standardize the references, for example, in reference number 11 the year is not in bold, in the others all years are in bold.

Checked

5. Based on the studies shown, what would be the main biomarkers associated with AF in humans?

We would like to thank again reviewer1 for his thoughts that for sure will improve our manuscript. We have thought carefully about this question, and although several metabolic alterations have been detected in AF patients, we have to recognize that we cannot propose a single metabolic biomarker or a combination of biomarkers for AF. In humans, it is not yet known with certainty which are the most important biomarkers or which of them play a main role in the development of AF. The highlighted plasma biomarkers may not reflect changes in heart tissue with enough confidence to be used in patient stratification yet. As the reviewer studies pointed out, more research in this field is needed to define sensitive predictive or diagnostic biomarkers for AF. We have include this limitation in discussion section. Please see first paragraph on page 6:

 

“However, all the summarized studies present certain limitations. It should be noted the size of the population analyzed as one of the most recurring limitations. In many cases, the patients were volunteers, so there may be a possible selection and observation bias. Further validation of markers in larger independent data sets are needed [13-17]. Specially in human studies, where highlighted plasma biomarkers may not reflect changes in heart tissue with enough confidence to be used in patient stratification yet [13, 15, 16, 18] and further research in this field is needed to define sensitive predictive or diagnostic biomarkers for AF.”

Author Response File: Author Response.docx

Reviewer 2 Report

The authors in this review article “Further advances in Atrial Fibrillation research: A metabolomic perspective” describes the application of metabolomics approach for the study of Atrial Fibrillation. Though the authors pick an interesting topic, there are other serious concerns that warrants this manuscript for not proceeding with the publication in its present form.

• This manuscript requires English editing and through proofreading. There are several instances of inconsistencies and typographical errors.
• The authors should discuss about the limitation of every study that they have described in the manuscript.
• The authors should discuss more about advantage of using metabolomics over other approaches in the Atrial fibrillation research and how metabolomic research have helped in understanding of the mechanism of the disease.  
• Authors should also discuss about the present challenges of Atrial fibrillation research and how metabolomic studies have proven useful in addressing those challenges.

Author Response

Reviewer 2

The authors in this review article “Further advances in Atrial Fibrillation research: A metabolomic perspective” describes the application of metabolomics approach for the study of Atrial Fibrillation. Though the authors pick an interesting topic, there are other serious concerns that warrants this manuscript for not proceeding with the publication in its present form.

• This manuscript requires English editing and through proofreading. There are several instances of inconsistencies and typographical errors.
• The authors should discuss about the limitation of every study that they have described in the manuscript.

This requirement is really appreciated. We have included a paragraph in the discussion section about it. Please see Page 6, first and second paragraphs.

 

“However, all the summarized studies present certain limitations. It should be noted the size of the population analyzed as one of the most recurring limitations. In many cases, the patients were volunteers, so there may be a possible selection and observation bias. Further validation of markers in larger independent data sets are needed [13-17]. Specially in human studies, where highlighted plasma biomarkers may not reflect changes in heart tissue with enough confidence to be used in patient stratification yet [13, 15, 16, 18] and further research in this field is needed to define sensitive predictive or diagnostic biomarkers for AF. Besides that, proposed metabolic biomarkers were analyzed just in certain metabolic pathways, although the participation in more complex processes is well known [13, 14, 16]. The assay technique used in present pilot studies may be limiting if it is not complemented by other techniques that allow the analysis of all biomarkers, as is the case of NMR [14], which presents lower sensitivity and lower analytical resolution than Mass Spectrometry, or undirected metabolomic methods [15] which restrict the accurate valuations. After the bioinformatic analysis, it was observed that some of the molecules found as possible biomarkers have not yet been described, thus their clinical impact is unknown [18]. Likewise, it is possible that there are still undiscovered markers that can be used for patient stratification [6, 13-19].”

 

• The authors should discuss more about advantage of using metabolomics over other approaches in the Atrial fibrillation research and how metabolomic research have helped in understanding of the mechanism of the disease.
• Authors should also discuss about the present challenges of Atrial fibrillation research and how metabolomic studies have proven useful in addressing those challenges.

We have followed the reviewer suggestions to improve our manuscript, thus we have discussed about advantages of metabolomics research in introduction section. Please see Page 2, second paragraph  

“Phenotypic changes in AF seem to point to changes in metabolites induced by environmental factors [6]. Therefore, understanding and defining all the molecules involved in these processes and their interactions is one of the great current challenges. Compared to genomics and proteomics, metabolomics are more closely related to phenotypic expression and influential environmental factors and therefore can better reflect the state of the human body and help to achieve a better understanding of AF.”

Round 2

Reviewer 2 Report

The authors in this revised version of the review manuscript “Further advances in Atrial Fibrillation research: A metabolomic perspective” have addressed all the comments reported in my previous review and the manuscript now looks acceptable.  However, the manuscript requires English editing and thorough proofreading as there are several instances of inconsistencies and typographical errors. For instance, in the discussion section, on page 6 authors have mentioned "miocardial infarction".