Yucatan Mini Swine Model of Persistent Atrial Fibrillation: Clinical Relevance

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the protocol been described in sufficient detail??>

To answer this question, please click the link to protocols.io in the Materials and Methods section of the manuscript (if a link has been provided) or consult the step-by-step protocol in the Supporting Information files.

Reviewer #1: Partly

Reviewer #2: Yes

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3. Does the protocol describe a validated method??>

Reviewer #1: Yes

Reviewer #2: Yes

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4. If the manuscript contains new data, have the authors made this data fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the article presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Comments to the authors

This manuscript presents a new Yucatan mini swine model for sustained AFib which overcomes many of the limitations of previous large-animal models by capitalizing on the anatomical and physiological consistency of the Yucatan mini swine with that of humans. The major novelty of the study is that it uses implantable cardiac monitors (Medtronic Reveal LINQ™) and Fitbark 2.0 activity trackers to allow continuous monitoring of both arrhythmia and behavioral changes – a substantial translational value.

The Yucatan swine animal model is well-given, providing several advantages over other domestic breeds in regard to size consistency and potential long-term investigations. Furthermore, the fact that individual surgical approaches and device modifications, made more extensive operations or those with adverse anatomical conditions feasible, is indicative of good technical performance.

Together, the model provides a reliable and clinically applicable system for chronic AFib investigation and therapy assessment, potentially allowing us to better understand the arrhythmia-associated functional impact.

Major Weaknesses

1.The authors should report exact quantitative details and statistical analysis for their main results?

This manuscript does not yet adequately report statistics on the results (time to AFib induction, variability in ventricular rates, extent of activity reduction) and histological changes observed in trial animals (e.g. fibrosis).

I also invite them to add a more complete statistical analysis and the corresponding graphical summaries (e.g., time to AFib induction as well as activity and rate variability, in the form of Kaplan-Meier curves and bar plots with error bars, respectively) to ensure the clarity and strength of your findings.

2.I'd suggest: They could validate their model more thoroughly on the molecular and histopathological level:

The present manuscript yields little evidence for atrial remodeling, fibrosis or gene expression changes which are necessary to support the translational relevance of model to human AFib.

Integration of echocardiographic and histological analysis, and molecular markers of structural and electrophysiological remodeling, will reveal the pathophysiological relationships between the model and clinical AFib.

3.Proper discussion of limitations of the model in the discussion section?

The manuscript is too focused on strengths of the model without enough discussion of limitations such as: variable ventricular rates, n=6, early death of one animal, and its lack of relevance to other types of AF such as paroxysmal AF.

I suggest a fair and honest account on these challenges and their implications on the robustness and clinical relevance of the model. This makes your results more reliable and easier to interpret.

4.Critically compare the model to the more recent literature of large-animal AFib research?

Although major historical models are mentioned, the manuscript does not provide an in-depth comparison with the more recent and emerging, including transgenic or optogenetic AFib models.

Would like to see more of comparative analysis between your model and current large animal models and incorporate knowledge of modern techniques. This should help place your work more effectively in the changing AFib research environment.

Minor Points for Revision

•Grammar and Style: Clarify sentences and eliminate slangy language (e.g., "pigs presumably feel better").

•Figures: 1) Other than captions figure quality and resolution is needed (e.g., Figure 3 needs statistics and clearly labeled axes).

•Data Availability: raw ECG and summary data should be made available to the research community in an appropriate format.

Reviewer #2: This paper compares previous AFib models with swine and focusing on key methodological differences as well as outcomes. The manuscript is organized nicely. Following comment would strengthen manuscript.

Comment 1: In the result section

•It is not clear in terms of clarity and conciseness, e.g. Persistent AFib was induced in ⅚ subjects within 60 days. It should be 5/6 along with %

•In addition, reorganization contents would help.

•It is unclear about cited reference “Pharmacologic intervention with beta-blockers and calcium channel blockers did not control rapid ventricular rates in one subject (Bishop & Akram, 2021; Pratt et al., 1983)”

•A separate Protocol adjustments section is highly recommended along with reason of amendment.

•A tabular comparison which includes animal model, clinical limitation and clinical relevance would add more weightage.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes:  Prakash Sojitra, PhD

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Yucatan Mini Swine Model of Atrial Fibrillation: Clinical Relevance

PONE-D-25-22478R1

Dear Dr. Goldman,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kamal Sharma

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

?>

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the protocol been described in sufficient detail??>

To answer this question, please click the link to protocols.io in the Materials and Methods section of the manuscript (if a link has been provided) or consult the step-by-step protocol in the Supporting Information files.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Does the protocol describe a validated method??>

Reviewer #1: Yes

Reviewer #2: Yes

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4. If the manuscript contains new data, have the authors made this data fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the article presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The manuscript presents a well-designed and clinically relevant large-animal protocol for inducing persistent atrial fibrillation, addressing key limitations of existing AF models. The use of Yucatan miniswine, chronic atrial pacing, continuous rhythm monitoring, and functional activity tracking represents a significant methodological strength with high translational value. The protocol is described in sufficient technical detail to enable reproducibility by other laboratories, which is a major asset for a methods-focused publication. Validation of persistent AF, survival outcomes, and histological confirmation of atrial remodeling adequately support the robustness of the model. Although the sample size is limited, this is acceptable for a protocol development study and is transparently acknowledged. Overall, this work constitutes a valuable methodological contribution to the field and will be of interest to researchers developing and testing therapies for atrial fibrillation.

Reviewer #2: Revised manuscript is now edited appropriately and justifications cited in cover letter are sufficient.

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #2: Yes:  Prakash Sojitra, PhD

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