From Iron Deficiency to Overload: A Missing Link in the Mechanisms of Cardiac Autonomic Nervous System Dysfunction
, Klaudia Rybka 1, Jacek Wolf 2 and Ludmiła Daniłowicz-Szymanowicz 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript is well written.
Authors analyze the causes and signs of autonomic nervous system dysfunction among patients with iron metabolism disorders.
In the introduction section, authors should add an other important cause of autonomic dysfunction such as amyloidosis.
In addition, authors should better describe the impact of iron deficiency and disorder in patients with heart failure.
Author Response
Please see the attachment
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis manuscript addresses an important and relatively underexplored topic: the relationship between iron metabolism disorders (iron deficiency and iron overload) and cardiac autonomic nervous system dysfunction. The subject is clinically relevant, timely, and of potential interest to cardiologists, neurologists, and clinicians involved in iron-related disorders.
The review is extensive, mechanistically oriented, and supported by a large body of literature. However, although the authors state adherence to PRISMA guidelines, the manuscript presents substantial methodological, reporting, and structural weaknesses that currently limit its suitability for publication as a systematic review in an MDPI journal.
Major revisions are required, particularly regarding methodological transparency, classification of study types, risk of bias assessment, internal consistency, and scientific rigor in synthesis and conclusions. I listed below my considerations
-Misclassification as a Systematic Review
Although the authors claim adherence to PRISMA, the manuscript does not meet core criteria for a systematic review, for the following reasons. Inclusion of Review articles, Narrative reviews, Brief communications, Animal studies, Heterogeneous clinical designs within the same synthesis.
No:
Explicit PICO framework, predefined primary and secondary outcomes, risk of bias assessment (e.g., ROBINS-I, RoB 2) and GRADE certainty evaluation.
This work is closer to a narrative or scoping review rather than a true systematic review.
Recommendation:
Either reclassify the manuscript as a Narrative Review, State-of-the-Art Review, or Scoping Review or substantially revise the Methods to meet PRISMA standards (clear eligibility criteria, study design restrictions, bias assessment, structured synthesis).
-Search Strategy and Study Selection
The search strategy lacks: full reproducibility (exact search strings not provided), justification for database choice (omission of Embase, Web of Science) and explanation for inclusion of publications dating back to 1983.
Internal inconsistency: the abstract reports 101 included studies while the Methods section reports 103 included papers
Recommendation:
Provide full search strings in Supplementary Materials.
Resolve numerical inconsistencies.
Clarify whether the unit of analysis is studies, papers, or records.
-Statistical and Analytical Issues
No quantitative synthesis was performed.
No meta-analysis, despite repeated claims of “statistically significant results”.
The criteria for labeling results as “significant” across heterogeneous studies are unclear.
Recommendation:
Avoid language implying pooled statistical inference.
Clearly distinguish within-study findings from between-study synthesis.
Consider structured qualitative synthesis tables or thematic analysis.
-Results Section
The Results section is overly descriptive, with excessive mechanistic repetition.
Tables 1 and 2 mix pediatric and adult populations animal and human studies and clinical outcomes and surrogate markers, without hierarchical synthesis.
No assessment of Study quality, Sample size adequacy and Confounding control.
Recommendation:
Separate human vs animal evidence clearly.
Stratify results by iron deficiency vs iron overload, age group and Outcome type (HRV, BRS, ECG markers).
Explicitly acknowledge weak or inconsistent evidence.
-Discussion
Overinterpretation of small, observational, and cross-sectional studies.
Insufficient emphasis on Confounding (anemia severity, comorbidities, medications), Reverse causality and lack of longitudinal data.
Recommendation:
Tone down causal language and clearly label findings as associative rather than mechanistically proven in humans.
-Conclusions
Claims regarding reversibility and cardiovascular risk reduction are not supported by high-certainty evidence.
Clinical recommendations are premature.
Recommendation:
Reframe conclusions to emphasize a hypothesis-generating nature of the evidence, need for prospective, controlled studies with standardized autonomic testing.
-Minor Issues
Multiple typographical errors and encoding issues (e.g., missing characters, formatting artifacts).
Inconsistent terminology (“IO”, “I”, “ID”) across sections.
Figures are not always clearly referenced or integrated.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors have implemented all requested changes.
