PONE-D-23-07892How intramyocardial fat can alter the electric field distribution during Pulsed Field Ablation (PFA): Qualitative findings from computer modelingPLOS ONE

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Additional Editor Comments:

Dear Dr. Ana González-Suárez,

I am pleased to inform you that the above-referenced manuscript is of interest and potentially acceptable for publication, but a minor revision is required to meet the concerns of the reviewers. The reviewers' comments are provided below.

Reviewer-1:

In this original article, Pérez and González-Suárez aimed to evaluate the effect of electrical impact of the

fat deposited in the ventricular scar during PFA by means of computer modeling. Computer

models were built considering a PFA 3.5-mm blunt-tip catheter in contact with a 7-mm

ventricular wall (with and without a scar) and a 2-mm epicardial fat layer. The authors should be congratulated on conducting such an important study. The design is fascinating and very inclusive with 6 different scenarios. They have found that intramyocardial fat can alter the electric field distribution positively resulting in deeper lesion size during PFA when compared with tissue without fat. This may be explained by its much lower electrical conductivity than myocardium and fibrotic tissue.

The paper is well written, very relevant to the field of electrophysiology, and very novel. Here are some minor comments:

1. Abbreviations: words should be abbreviated on their first mention and then the abbreviation should be used throughout the entire manuscript. For example in line 6 you say radiofrequency ablation without abbreviation, and then at the end of the introduction (I wished the lines were numbered, would have been easier) you use it abbreviated. But then again in the methods you use full wording; radiofrequency ablation. Please review the manuscript and try to be consistent while using all abbreviations.

2. In your conclusion you state that fat can alter the size. Alter can mean a negative impact (smaller size) and positive impact (bigger lesions). I would revise it to highlight that fat alters the lesions size "positively" resulting in deeper and wider lesions.

3. Fat is not only in the ventricle! The discussion and introduction somehow focus on VT, but that's a small portion of our patients. The majority of our patients are atrial fibrillation patients. Several studies have demonstrated the presence of endocardial and epicardial fat depositions within the atria of patients with atrial fibrillation. I would comment on that and make the paper less oriented to VT only.

Reviwer-2:

This article explores the potential influence of intramyocardial fat on the effects of PFA ablation; the work is based entirely on in silico data. The key finding of this study is that intramyocardial fat alters the distribution of the electric field in multiple ways – including a “shielding” effect of deeper structures as well as the creation of various “hot” and “cold” spots that effectively receive more and less ablative energy. Also notable is the finding that the shielding effect may persist despite current dose escalation.

The authors could significantly boost the relevance of this work by expanding the repertoire of myocardial models in addition to model “D.” In particular, it would be interesting to see how PFA performs in the context of various non-ischemic cardiomyopathies, some of which exhibit particularly strong propensity toward fibrofatty replacement (e.g. ARVC). At the very least, it would be helpful to explore other scenarios where the fatty layer is not essentially compact (as seen in model “D”) but more scattered. Would the same findings be encountered?

It is also important to note that this manuscript’s findings are generally NOT in line with the currently published data. This includes Younis at al. 2022 (PMID 36194542) which the authors cite and Higuchi et al. 2022 (PMID 36779624). While that does not mean that the findings of this work are incorrect, the authors should try to find a way to reconcile this difference. The authors do state that variations in PFA technology make comparisons difficult (p16), the basic “fat shielding” concept should presumably hold regardless of the pulse waveform, frequency and polarity (monopolar vs bipolar) used.

Reviewer-3:

The present study is based on a computer model built from realistic images of histological samples of the cardiac wall, which include intact myocardial tissue, infiltrated fat, and fibrotic tissue derived from a previous myocardial infarction. Despite the limitations inherent to any computer modeling study, the authors present interesting results that are difficult to obtain through in vivo or clinical experimentation. Although the conclusions regarding the impact of fibrosis have already been previously suggested in other studies, the conclusions regarding the impact of fat are novel but also controversial, since there are clinical studies that suggest that PFA would be capable of creating lesions through intramyocardial fat. While this may be true in some circumstances, the fact is that clinical and experimental studies inherently lack control over the real spatial distribution of fat, making it impossible to draw generic or biophysically based conclusions. In contrast, computer modeling based on physical laws of bioelectricity shows that fat has an important impact on the distribution of the electric field. For this reason I consider that the results of this study are novel, relevant and with a clinical impact because they encourage that more experimental studies should be carried out in order to determine the real potential of PFA on cardiac substrates that contain fat.

I have some comments about the manuscript which should be considered:

1) At present, there are different equipments to carry out electropolation of biological tissue, and each manufacturer has its own waveform protocol with its specific characteristics. The authors could suggest what impact the different protocols would have on their results and conclusions. For example, the use of bipolar versus monopolar protocols, or short (2 microseconds) versus long (100 microseconds) pulse widths.

2) There is also a current controversy in relation to how electroporation pulses could affect the electrical conduction system of the heart. Could the authors expand their discussion to include the possible impact of PFA on these types of tissues and its relation with the fat presence?

3) The authors solved a static electrical problem by ignoring the current transient that is generated when the pulses are applied. I suggest including an additional comment about how this could affect the conclusions of the study.

4) Although the authors justify that the spatial distributions of tissues shown in Fig. 2 are sufficiently representative of the clinical cases that can be found in PFA ablation, I wonder if there could be any case in which the electrode is situated almost directly on adipose tissue, and what would be the impact of this in the light of the results of the modeling study.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: N/A

Reviewer #3: N/A

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this original article, Pérez and González-Suárez aimed to evaluate the effect of electrical impact of the

fat deposited in the ventricular scar during PFA by means of computer modeling. Computer

models were built considering a PFA 3.5-mm blunt-tip catheter in contact with a 7-mm

ventricular wall (with and without a scar) and a 2-mm epicardial fat layer. The authors should be congratulated on conducting such an important study. The design is fascinating and very inclusive with 6 different scenarios. They have found that intramyocardial fat can alter the electric field distribution positively resulting in deeper lesion size during PFA when compared with tissue without fat. This may be explained by its much lower electrical conductivity than myocardium and fibrotic tissue.

The paper is well written, very relevant to the field of electrophysiology, and very novel. Here are some minor comments:

1. Abbreviations: words should be abbreviated on their first mention and then the abbreviation should be used throughout the entire manuscript. For example in line 6 you say radiofrequency ablation without abbreviation, and then at the end of the introduction (I wished the lines were numbered, would have been easier) you use it abbreviated. But then again in the methods you use full wording; radiofrequency ablation. Please review the manuscript and try to be consistent while using all abbreviations.

2. In your conclusion you state that fat can alter the size. Alter can mean a negative impact (smaller size) and positive impact (bigger lesions). I would revise it to highlight that fat alters the lesions size "positively" resulting in deeper and wider lesions.

3. Fat is not only in the ventricle! The discussion and introduction somehow focus on VT, but that's a small portion of our patients. The majority of our patients are atrial fibrillation patients. Several studies have demonstrated the presence of endocardial and epicardial fat depositions within the atria of patients with atrial fibrillation. I would comment on that and make the paper less oriented to VT only.

4.

Reviewer #2: This article explores the potential influence of intramyocardial fat on the effects of PFA ablation; the work is based entirely on in silico data. The key finding of this study is that intramyocardial fat alters the distribution of the electric field in multiple ways – including a “shielding” effect of deeper structures as well as the creation of various “hot” and “cold” spots that effectively receive more and less ablative energy. Also notable is the finding that the shielding effect may persist despite current dose escalation.

The authors could significantly boost the relevance of this work by expanding the repertoire of myocardial models in addition to model “D.” In particular, it would be interesting to see how PFA performs in the context of various non-ischemic cardiomyopathies, some of which exhibit particularly strong propensity toward fibrofatty replacement (e.g. ARVC). At the very least, it would be helpful to explore other scenarios where the fatty layer is not essentially compact (as seen in model “D”) but more scattered. Would the same findings be encountered?

It is also important to note that this manuscript’s findings are generally NOT in line with the currently published data. This includes Younis at al. 2022 (PMID 36194542) which the authors cite and Higuchi et al. 2022 (PMID 36779624). While that does not mean that the findings of this work are incorrect, the authors should try to find a way to reconcile this difference. The authors do state that variations in PFA technology make comparisons difficult (p16), the basic “fat shielding” concept should presumably hold regardless of the pulse waveform, frequency and polarity (monopolar vs bipolar) used.

Reviewer #3: The present study is based on a computer model built from realistic images of histological samples of the cardiac wall, which include intact myocardial tissue, infiltrated fat, and fibrotic tissue derived from a previous myocardial infarction. Despite the limitations inherent to any computer modeling study, the authors present interesting results that are difficult to obtain through in vivo or clinical experimentation. Although the conclusions regarding the impact of fibrosis have already been previously suggested in other studies, the conclusions regarding the impact of fat are novel but also controversial, since there are clinical studies that suggest that PFA would be capable of creating lesions through intramyocardial fat. While this may be true in some circumstances, the fact is that clinical and experimental studies inherently lack control over the real spatial distribution of fat, making it impossible to draw generic or biophysically based conclusions. In contrast, computer modeling based on physical laws of bioelectricity shows that fat has an important impact on the distribution of the electric field. For this reason I consider that the results of this study are novel, relevant and with a clinical impact because they encourage that more experimental studies should be carried out in order to determine the real potential of PFA on cardiac substrates that contain fat.

I have some comments about the manuscript which should be considered:

1) At present, there are different equipments to carry out electropolation of biological tissue, and each manufacturer has its own waveform protocol with its specific characteristics. The authors could suggest what impact the different protocols would have on their results and conclusions. For example, the use of bipolar versus monopolar protocols, or short (2 microseconds) versus long (100 microseconds) pulse widths.

2) There is also a current controversy in relation to how electroporation pulses could affect the electrical conduction system of the heart. Could the authors expand their discussion to include the possible impact of PFA on these types of tissues and its relation with the fat presence?

3) The authors solved a static electrical problem by ignoring the current transient that is generated when the pulses are applied. I suggest including an additional comment about how this could affect the conclusions of the study.

4) Although the authors justify that the spatial distributions of tissues shown in Fig. 2 are sufficiently representative of the clinical cases that can be found in PFA ablation, I wonder if there could be any case in which the electrode is situated almost directly on adipose tissue, and what would be the impact of this in the light of the results of the modeling study.

**********

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Reviewer #1: Yes: Arwa Younis

Reviewer #2: No

Reviewer #3: No

**********

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How intramyocardial fat can alter the electric field distribution during Pulsed Field Ablation (PFA): Qualitative findings from computer modeling

PONE-D-23-07892R1

Dear Dr.Ana González-Suárez,

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.

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Kind regards,

Kadiam Venkata Subbaiah, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: