Vitamin D in Cardiovascular Medicine: From Molecular Mechanisms to Clinical Translation
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIn the manuscript, entitled » Vitamin D in Cardiovascular Medicine: From Molecular Mechanisms to Clinical Translation« submitted to Nutrients for a potential publication, the authors present the review of the most important studies about the role of vitamin D in cardiovascular medicine. The area of presentation is interesting, anyway, there are plenty review as well as research articles covering this field. In addition, it is quite long and I am of opinion, that in the present form, it is not good enough to be published in your journal and should be revised and shortened, enabling easier reading and understanding. My comments are enclosed.
The comments:
- The article is long and not clear enough. It should be shortened and additionally structured, enabling easier reading and understanding. The presentation of all studies should be short and clear. Biology and metabolism part are quite extensive. Figure 1 is not so important and could be omitted.
- Metodology of article´s acqusition should be presented. Namely, there is plenty of research in this field with some published studies of limited and questionable scientific importance.
- The type of review should be listed.
- In Introduction, vitamin D deficiency and insufficiency shoud be defined, as well as their importance.
- For each molecular and cellular mechanism some clinical studies should be shortly mentioned.
- The importance of obesity in correlation with vitamin D and cardiovascular risk should be clearly presented.
Author Response
The article is long and not clear enough. It should be shortened and additionally structured, enabling easier reading and understanding. The presentation of all studies should be short and clear. Biology and metabolism part are quite extensive. Figure 1 is not so important and could be omitted. Metodology of article´s acqusition should be presented. Namely, there is plenty of research in this field with some published studies of limited and questionable scientific importance. The type of review should be listed. In Introduction, vitamin D deficiency and insufficiency shoud be defined, as well as their importance. For each molecular and cellular mechanism some clinical studies should be shortly mentioned. The importance of obesity in correlation with vitamin D and cardiovascular risk should be clearly presented.
RE: Thank you for your comments and suggestions. Respectfully, we were actually invited to submit a "long" narrative review. Deficiency and insufficiency are now better described. We mention several clinical studies. The importance of obesity is now addressed, as requested.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors have not described all enzymes involved in vitamin D metabolism. In addition, there is no schematic figure to help explain the concepts the authors are attempting to convey in the review.
Each subsection under “Functional Roles of Vitamin D in Cardiovascular Development and Physiology” requires further elaboration, as very limited information is provided regarding the associated pathways. The manuscript contains numerous subheadings; however, these sections lack sufficient detail and depth.
The role of vitamin D as a biomarker in the pathophysiology of cardiovascular diseases is not adequately explained. Moreover, the manuscript does not clearly address whether vitamin D can be used as a biomarker from a clinical perspective in cardiovascular disease.
It is recommended that the authors include and critically discuss all relevant studies in which vitamin D has been evaluated as a biomarker.
Finally, while the authors have mentioned concentration levels related to vitamin D toxicity, similar clarity and detail should be provided regarding safe and optimal levels.
Author Response
The authors have not described all enzymes involved in vitamin D metabolism. In addition, there is no schematic figure to help explain the concepts the authors are attempting to convey in the review.
RE: We have added a paragraph (and a new Figure 1) dedicated to the description of the VitD activation pathway. Thanks.
Each subsection under “Functional Roles of Vitamin D in Cardiovascular Development and Physiology” requires further elaboration, as very limited information is provided regarding the associated pathways. The manuscript contains numerous subheadings; however, these sections lack sufficient detail and depth.
RE: We have expanded all the subsections under “Functional Roles of Vitamin D in Cardiovascular Development and Physiology”, as requested. Thanks.
The role of vitamin D as a biomarker in the pathophysiology of cardiovascular diseases is not adequately explained. Moreover, the manuscript does not clearly address whether vitamin D can be used as a biomarker from a clinical perspective in cardiovascular disease.
It is recommended that the authors include and critically discuss all relevant studies in which vitamin D has been evaluated as a biomarker.
RE: These aspects are now discussed in Section 8.
Finally, while the authors have mentioned concentration levels related to vitamin D toxicity, similar clarity and detail should be provided regarding safe and optimal levels.
RE: These aspects are now discussed.
Reviewer 3 Report
Comments and Suggestions for AuthorsThis narrative review is thorough, well-researched, and relevant, effectively integrating molecular biology, epidemiology, and clinical trial data. The manuscript demonstrates mastery of the literature and appropriately acknowledges the gap between mechanistic plausibility and the outcomes of neutral randomized trials. However, its length, density, and limited integration into practical clinical frameworks reduce accessibility and translational impact.
The sections on VDR signaling, RAAS regulation, inflammation, oxidative stress, mitochondrial function, and epigenetics are comprehensive, precise, and well-referenced. The integration of genetic, non-genomic, and tissue-specific functions is a significant strength.
A detailed summary of clinical trials, including major randomized controlled trials (RCTs) such as VITAL, ViDA, D-Health, FIND, and EVITA, as well as meta-analyses, is provided.
Tables summarizing trials and meta-analyses serve as valuable reference tools.
Definitive Positioning of Vitamin D as a Biomarker
The characterization of vitamin D as a risk integrator rather than a universal treatment is well-supported and evidence-based.
Focus on Precision Medicine and Distinct Populations
The inclusion of genetics, chronic kidney disease, heart failure, ethnicity, and pharmacokinetics enhances clinical relevance.
Major and Issues
1. Prolixity and Redundancy
Mechanistic themes such as inflammation, RAAS, and endothelial function are repeated across sections with little additional insight. Many sections could be condensed without sacrificing scientific rigor.
2. Limited Integration into Distinct Conceptual Frameworks
Although the evidence is thoroughly reviewed, integration often remains descriptive rather than synthetic. There is no cohesive figure or structure linking deficiency severity, timing of intervention, molecular pathways, and expected clinical outcomes.
How does vitamin D compare with lifestyle therapies (such as physical activity, weight reduction, and sun exposure) that also increase 25(OH)D levels and independently reduce cardiovascular disease risk?
3. Clarify Clinical Key Messages
Include a concise boxed section:
Actions clinicians should take now
What clinicians should not expect
Areas of uncertainty
4. Refine the Conclusion
Reduce redundancy from earlier sections.
Emphasize how vitamin D exemplifies the limitations of nutrient-focused cardiovascular therapies.
Clearly state whether vitamin D should primarily serve as a risk stratification tool rather than a therapeutic target.
Author Response
This narrative review is thorough, well-researched, and relevant, effectively integrating molecular biology, epidemiology, and clinical trial data. The manuscript demonstrates mastery of the literature and appropriately acknowledges the gap between mechanistic plausibility and the outcomes of neutral randomized trials. However, its length, density, and limited integration into practical clinical frameworks reduce accessibility and translational impact.
RE: Thanks.
The sections on VDR signaling, RAAS regulation, inflammation, oxidative stress, mitochondrial function, and epigenetics are comprehensive, precise, and well-referenced. The integration of genetic, non-genomic, and tissue-specific functions is a significant strength.
RE: Thanks.
A detailed summary of clinical trials, including major randomized controlled trials (RCTs) such as VITAL, ViDA, D-Health, FIND, and EVITA, as well as meta-analyses, is provided.
RE: Thanks.
Tables summarizing trials and meta-analyses serve as valuable reference tools.
RE: Thanks.
Definitive Positioning of Vitamin D as a Biomarker
RE: Thanks.
The characterization of vitamin D as a risk integrator rather than a universal treatment is well-supported and evidence-based.
RE: Thanks.
Focus on Precision Medicine and Distinct Populations
RE: Thanks.
The inclusion of genetics, chronic kidney disease, heart failure, ethnicity, and pharmacokinetics enhances clinical relevance.
RE: Thanks.
Major and Issues
- Prolixity and Redundancy
Mechanistic themes such as inflammation, RAAS, and endothelial function are repeated across sections with little additional insight. Many sections could be condensed without sacrificing scientific rigor.
RE: We have edited these sections.
- Limited Integration into Distinct Conceptual Frameworks
Although the evidence is thoroughly reviewed, integration often remains descriptive rather than synthetic. There is no cohesive figure or structure linking deficiency severity, timing of intervention, molecular pathways, and expected clinical outcomes. How does vitamin D compare with lifestyle therapies (such as physical activity, weight reduction, and sun exposure) that also increase 25(OH)D levels and independently reduce cardiovascular disease risk?
RE: We added a section to address these aspects. Thanks.
- Clarify Clinical Key Messages
Include a concise boxed section:
Actions clinicians should take now
What clinicians should not expect
Areas of uncertainty
RE: These aspects have been addressed, as requested.
- Refine the Conclusion
Reduce redundancy from earlier sections.
Emphasize how vitamin D exemplifies the limitations of nutrient-focused cardiovascular therapies.
Clearly state whether vitamin D should primarily serve as a risk stratification tool rather than a therapeutic target.
RE: Conclusions have been modified as requested.
Reviewer 4 Report
Comments and Suggestions for AuthorsIn recent years, interest in vitamin D has increased significantly, also in relation to its role, proven or not, in various areas, particularly in the cardiovascular system. In this review, the authors precisely highlight the physiological/biochemical action and role of Vitamin D. Although the work is very well-researched, it lacks some aspects: 1- Recent consensus reports have been published by various scientific societies, and it would be appropriate to highlight their specificities and any differences, if any (cite and comment on PMID: 39796548, PMID: 41305623, PMID: 38676447). 2- New formulations for the administration of vitamin D for numerous pathologies are recently under study. The authors highlight this aspect by including a relevant table (insert and cite PMID: 40660647, PMID: 36982396, PMID: 38396866, PMID: 41390950, PMID: 39334856). 3- Include at least two figures relating to the activity of Vitamin D and the activated pathway
Author Response
RE: Thanks for the helpful suggestions. PMID: 38676447 was already included in the previous version of our paper; other expert consensus papers have been included. The other suggested papers on new formulations have been integrated. The Vitamin D activation pathway is now thoroughly described and a new Fig 1 has been added.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsI have carefully read the revised version of the manuscript entitled » Vitamin D in Cardiovascular Medicine: From Molecular Mechanisms to Clinical Translation« submitted to Nutrients for a potential publication. The manuscript has been somewhat improved, taking some of my comments into consideration. Anyway, it is still too long and difficult to follow despite the fact that there has been invitation to prepare a long review, and the methodology has not described. In addition, the clinical part should be upgraded before potential publication.
Author Response
We thank all the other three Reviewers for having recommended acceptance of our revised manuscript.
Reviewer 2: We have added a paragraph to describe the methodology, as requested. We respectfully believe that the review is not "difficult to follow"; the clear outline and the subdivision in sections and subsections will help the Readers in finding what they need. Adding more info to the "clinical part" will make the review even longer, contradicting the point raised by this Reviewer (the review is "too long").
Reviewer 2 Report
Comments and Suggestions for AuthorsAccept in current form
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors have done the alterations.
Author Response
Thanks!
Reviewer 4 Report
Comments and Suggestions for AuthorsI agree new verison
