PONE-D-22-29848Catheter Ablation of Atrial Arrhythmias in Cardiac Amyloidosis

Impact on Heart Failure and MortalityPLOS ONE

Dear Dr. Maury,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Daniel A. Morris, M.D

Academic Editor

PLOS ONE

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Additional Editor Comments:

The aim of this study is clinically relevant. However, there are some major limitations in this study that should be addressed.

1) Small sample size: just 22 patients had AF, which is the more important event/variable to analyze. Hence, the authors should increment significant the sample size of the study, including at least 200 patients in order to avoid bias and to increment the clinically relevance of this study.

2) Subgroup analysis: Patients with Al-Amyloidosis and ATTR-Amyloidosis should be analyzed separately, since these subtypes of amyloidosis have significantly different outcomes and treatment.

3) The primary endpoint of this study should be only recurrence of AF at 1 and 2 years of follow-up.

Reviewers' comments:

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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

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

Reviewer #1: N/A

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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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

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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 the current paper, the authors reported their experience about the impact of catheter ablation on outcomes in patients with amyloidosis. The paper was well written in general. Please include more data about the catheter ablation procedure regarding the left atrial scarring in the study group.

Reviewer #2: The authors report on outcome post catheter ablation for atrial arrhytmias (AT, Aflutter or AF) in a patient series comprising 31 patients with cardiac amyloidosi.

Cardiac amyloidosis is an infiltrative disease with poor outcome, bacause of development of advanced heart failure leadingt o death.

Although the presented case series is limited with regard to the number of patients, the study is interesting and one of the rare reports on this topic. The study demonstartes the potential for improved hemodynamics, NAHY class and BNP levels, in those CA-patients in whom sinus rhythm can be maintained by combination of cathetr ablation and antiarrhythmic drug therapy. Notably, betablocker treatment was not beneficial in this patient cohort with restrictive CMP.

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PONE-D-22-29848R1

Catheter Ablation of Atrial Arrhythmias in Cardiac Amyloidosis. Impact on Heart Failure and Mortality

PLOS ONE

Dear Dr. Maury,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

Specifically, as it has been stated in the first revision, this small, descriptive, and retrospective report has serious limitations and major biases such as very small sample size (only 22 patients had AF), lack of subgroup analysis (Al- and ATTR-Amyloidosis), and lack of primary endpoint analysis at 1 and 2 years (i.e., recurrence of AF at 1 and 2 years of follow-up). 

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Kind regards,

Daniel A. Morris, M.D

Academic Editor

PLOS ONE

PONE-D-22-29848R2Catheter Ablation of Atrial Arrhythmias in Cardiac Amyloidosis. Impact on Heart Failure and MortalityPLOS ONE

Dear Dr. Maury,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

 

1. There are minor grammatical errors in the abstract section. In methods section: “ AA were atrial fibrillation..” this statement needs better grammatical construction. Also in this section authors mention “ Atrial common flutter” , do you mean “ Atrial flutter” 

2. Its not clear looking at the abstract about what the main aims of the study are. In the methods section—may be we should explain that we compared outcomes before and after ablation etc? to assess long term efficacy of ablation etc

       Throughout rest of the article, there are statements which need grammatical correction such as

  “AA undergoing ablation were AFib in 22 (71%) (paroxysmal in 10 and persistent in 12), CTI-dependent AF in 17 (55%) and AT in 11 (35%)”---- better statement----   ‘ Among patients undergoing ablation for arrythmia, 71%  had afib, 55% had CTI-dependent afib and 11% had AT” etc

“A previous history of catheter ablation was present in only two cases (for AF)” –  correct grammar “ only 2 cases had a hx of catheter ablation prior to our study.

“When comparing before and after ablation while in SR (median 9 months later, IQR 17), creatinine and natriuretic peptides levels significantly decreased as well as NYHA class, without relevant change in weight, while left atrial dimensions and pulmonary arterial pressures, although decreased, did not significantly change (see table 2)”--   Full stop after “change in weight”. Then last statement should start ( my suggestion)

may be get assistance of professional grammatical correction services

             

3. How do we know that this study shows long term efficacy of ablation in CA patients?

Is ablation in CA patients better or worse than ablation in patients without CA? Whats the control population to compare with?. How do we know that history of amyloidosis interacting/or not interacting with ablation outcomes

If we compared effects of ablation between patients who had cardiac amyloidosis and patients who did not have cardiac amyloidosis: then significance of these results would have been better understood.

Can we talk about this in the discussion? May be cite articles talking about outcomes of catheter ablation in general for atrial arrythmias?

4) Please review reviewer comments below

==============================

Please submit your revised manuscript by Nov 02 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Vikramaditya Samala Venkata

Academic Editor

PLOS ONE

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

Reviewer #6: All comments have been addressed

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2. 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 #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

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

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

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4. 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 #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

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5. 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 #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

Reviewer #6: Yes

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6. 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 #3: 1) NYHA Class 2 was noted in the page 7, Table 1 baseline characteristics. In Page 10, prior to ablation NYHA Class 3 was mentioned. Was baseline NYHA >2?, please clarify.

2) Stage of Cardiac amyloidosis, when cardiac ablation was performed

3) Page 2 -Background: This study sought to investigate the long-term impact of catheter ablation in patients with CA and AA. Page 4 sentence 2,3-The aim of this study was to explore the efficacy and impact of catheter ablation in CA complicated by AA in terms of reversal of congestive heart failure and mortality.

Please clarify in page 2 background section, is the study designed to evaluate impact on cardiological outcomes?

4) Page 9 -Mortality rate 39 % (12 patients)- 3 End stage CHF ,1 Sudden Cardiac Death,1 stroke (total 5). 1 pt passed away from Covid ,1 patient passed away from unknow cause (Total 2). Another 5 patients passed away from later complication of Amyloidosis? Please clarify.

5) Page 8- AV nodal ablation and ICD, have their own impact on CHF and mortality, potential confounding factor

Reviewer #4: Well written paper and good research design. I am pleasantly surprised that the researchers were able to find so many patients with Atrial tachycardia and Cardiac Amyloidosis who underwent ablation. I would have loved to see a discussion about comparing the impacts of catheter ablation in patients with cardiac amyloidosis and patients who do not have amylodosis. This would have put the results in a better perspective. Please consider including this in the discussion portion of the paper.

Reviewer #5: Authors have addressed all the prior comments by reviewers and editors and manuscript can be accepted for publication.

Reviewer #6: Amyloidosis is a rare diagnosis and CA is especially diagnosed very late in the process. The limited study population and late referral to tertiary centers makes this a challenging endeavor. The study is provided with relevant intro, patient characteristics, statistical analyses and references. Additional studies with increased enrollment is needed. In the interim, smaller studies like these with an understanding of its limitations are always helpful to advance the understanding of this rare diagnosis.

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Reviewer #3: Yes: Srikanth Puli

Reviewer #4: No

Reviewer #5: No

Reviewer #6: No

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PONE-D-22-29848R3

Catheter Ablation of Atrial Arrhythmias in Cardiac Amyloidosis. Impact on Heart Failure and Mortality

PLOS ONE

Dear Dr. Maury,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

Specifically:

1. I do not completely agree with conclusions of the results as stated by authors

In the results section

When results are not significant, not sure we can there is a positive trend ( especially when the total N is also very low), So not sure if we can come to this conclusion

-Ex” Lef atrial volume and Sys pulm artery pressure: P is 0.6 and 0.26 with only minimal change in pulm artery pressure?). So not sure if we can come to this conclusion

-There was no significant difference in HF hospitalizations ( p=0.1) and all cause mortality (p=0.2)when comparing with AA recurrence.

-Even in patients with permanent AA, p is not significant ( so not sure we can say trend towards higher mortality)

So in conclusion, I agree we can say may be NYHA class and BNP numbers are improving, but rest of the parameters are not showing a significant difference, so not sure we can say positive trend repeatedly despite P value not being significant

1. Paper still has some grammatical errors which need to be corrected ( please see attached file with comments)
2. In the introduction: authors mention that rate control is challenging due to negative inotropic and chronotropic effects of drugs ( can we explain more about this ?) and can we explain why only amio is the drug used
3. Discussion section needs to report results of the paper more in comparison with other ( please see attached paper with comments)

Kind regards,

Vikramaditya Samala Venkata

Academic Editor

PLOS ONE

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For journal use only: PONEDEC3

Attachments

Attachment

Submitted filename: Ca paper- editor comments.docx

Catheter Ablation of Atrial Arrhythmias in Cardiac Amyloidosis. Impact on Heart Failure and Mortality

PONE-D-22-29848R4

Dear Dr. Maury,

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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Kind regards,

Neil

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #7: All comments have been addressed

Reviewer #8: All comments have been addressed

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2. 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 #7: Yes

Reviewer #8: Yes

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

Reviewer #7: I Don't Know

Reviewer #8: Yes

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4. 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 #7: Yes

Reviewer #8: Yes

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5. 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 #7: Yes

Reviewer #8: Yes

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6. 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 #7: The population is extremely low and needs to be increased. It is mentioned that the facility is a tertiary facility which impacts the pool of available patients.However, this may be a good start for following studies. The P values were also addressed.

Reviewer #8: Catheter Ablation of Atrial Arrhythmia's in Cardiac Amyloid. Impact on HF and Mortality.

It's a wonderful hypothesis generating paper. The authors have tackled a difficult question in a population with multiple variables and with high short-term mortality. Any effort to improve symptoms, reduce hospitalizations and improve long term survival is commendable. It is also clear that these are relatively sicker patients referred to tertiary care facilities and therefore at high risk of morbidity and mortality despite advanced therapies.

Since the patient numbers in any of the previous and current studies is small, where AA ablation is deployed as a strategy to reduce HF hospitalization and improve symptoms, there is a clear need to establish a registry to understand such outcomes.

Behavior and natural history of AL and ATTR CA is different. AL tends to behave as an acute myocarditis, with early symptoms and rapid progression to end stage heart failure while ATTR behaves in slower amyloid deposits in atria and ventricle and conduction system (1). NSR is maintained longer in AL and Afib tends to be more common in ATTR. Once Afib is established in AL, it suggests poor prognosis (2). Onset of CHF in CA is a harbinger of poor prognosis and may not only reflect stage of the disease, but it has worse outcomes in patients with AL (3).

It is worth mentioning the pathophysiology of the disease and stage of the disease. Low EDV, reduced SV, atrial electromechanical dissociation (patient has NSR while atria show impaired contractility), increase HR and autoimmune dysfunction may all impact symptoms and progression to HF and impact survival. Risk stratification of CA and clinical management hence becomes challenging (4). Higher stage of ATTR and higher NYHA class and maintenance of NSR impacts survival (5).

Hence, variables of symptoms, hospitalization and survival include Type of CA (ATTR more prone to Afib), thromboembolism risk, stage of CA, NYHA class. Prevalence of HF in ATTR is 6.3% (1-21%) and relatively less common in AL (1.2/100thousand cases). ATTR is also associated more commonly with paradoxical low flow, low gradient AS with a prevalence of 4-29% (6).

The next step should be setting up a registry of CA patients separately for AL and ATTR types. Further stratifying them to stage of the disease and NYHA class, finding patients with AA (predominantly afib), ablating afib early before disease reaches advanced stage and looking at its impact on HF onset, recurrent hospitalization for HF and survival in a prospective fashion. This would also address the power (n) of analysis to get meaningful data. This may also lead to development of longer lasting post ablative strategies (antiarrhythmics) to maintain patients in sinus rhythm. This should go hand in hand with newer disease modifying strategies that reduce amyloid deposits in heart and elsewhere.

1. Capelli F, Cir Heart Failure 2020;13:e 006619

2. Ng PLF, Ann. Non invasive Electrophysiology 2022;27:e1267

3. Thakker, Am J Cardiol 2021;143:125-130

4. Laptsera N, J. Clinical Med, 2023;12:2581

5. JACC Clin Electrophysiology 2020;6:1118-1127

6. Ternacle J, JACC 2019;74(21):2638-2651

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Reviewer #7: Yes: Maha Ahmed

Reviewer #8: Yes: Nadeem Afridi

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