Predictors of Atrial Fibrillation Recurrence After Catheter Ablation: A State-of-the-Art Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

"Predictors of Atrial Fibrillation Recurrence After Catheter Ablation: A State-of-the-Art Review"

This comprehensive review addresses the critical challenge of atrial fibrillation (AF) recurrence post-catheter ablation, synthesizing evidence on modifiable/non-modifiable predictors, diagnostic tools, and procedural factors.

1.The review systematically categorizes predictors (e.g., age, gender, comorbidities, biomarkers, imaging parameters) and procedural factors (e.g., ablation techniques, anesthesia), offering a holistic view of AF recurrence determinants. Inclusion of emerging fields like gut microbiota and pulsed-field ablation (PFA) reflects up-to-date scholarship.

2. Emphasis on modifiable factors (e.g., obesity, OSA, alcohol) underscores actionable targets for improving ablation outcomes. The discussion of SGLT2 inhibitors and GLP-1 agonists aligns with recent therapeutic advances, highlighting their potential beyond glycemic control.

3.Integration of landmark trials (e.g., EAST-AFNET 4, EARLY-AF) and meta-analyses strengthens the review’s credibility. The inclusion of genetic and biomarker data (e.g., galectin-3, miRNAs) bridges basic science and clinical practice.

While the manuscript provides a thorough overview, several areas require refinement to enhance its clinical and academic impact.

For example: 

   - **Genetic Factors**: The section concludes that genetic susceptibility (e.g., 4q25 variants) has a "net neutral effect" but does not explore mechanisms (e.g., fibrosis pathways) or reconcile conflicting studies. 

   - **Biomarkers**: Elevated NLR and hs-CRP are noted as predictors, but their clinical utility versus established metrics (e.g., LA strain) is not compared. A hierarchical analysis of biomarker efficacy would clarify their role. 

   - **Diabetes and Obesity**: Contradictory findings (e.g., T2DM as an independent predictor vs. no association) are presented without discussing confounders (e.g., glycemic control, study design heterogeneity).

- iThenticate report 36%. Add links.                       

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files

   - **Genetic Factors**: The section concludes that genetic susceptibility (e.g., 4q25 variants) has a "net neutral effect" but does not explore mechanisms (e.g., fibrosis pathways) or reconcile conflicting studies. 

Thank you for pointing that out. We truly appreciate the reviewer’s thoughtful comment. We understand that our section on genetic factors mentions the general neutral effect of common variants related to atrial fibrillation (AF), such as those found at the 4q25 location. However, it doesn't go into detail about the biological mechanisms behind these variants or explain the differences seen in various research studies. This oversight was mainly because our review aimed to focus more on clinical predictors rather than the underlying mechanisms. Atrial fibrosis itself has been mentioned in a separate section. We have briefly mentioned a line on how genetic susceptibility may influence atrial remodeling through ion channel dysfunction and fibrotic signaling.

- **Biomarkers**: Elevated NLR and hs-CRP are noted as predictors, but their clinical utility versus established metrics (e.g., LA strain) is not compared. A hierarchical analysis of biomarker efficacy would clarify their role. 

We appreciate the reviewer for highlighting this important point. While we discussed inflammatory biomarkers such as the neutrophil-to-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein (hs-CRP) as independent predictors of atrial fibrillation (AF) recurrence, we did not directly compare their predictive utility with left atrial (LA) strain, an established echocardiographic parameter.

We agree that a comparative or hierarchical analysis would provide valuable insights into the relative strengths and limitations of these measures. However, we are limited to do so as we are only making a review of previously published studies.

We have included a paragraph on the combination model already (NLR, hs-CRP, and left atrial diameter); however, our literature review did not reveal any studies examining NLR, hs-CRP, and LA strain together.

  - **Diabetes and Obesity**: Contradictory findings (e.g., T2DM as an independent predictor vs. no association) are presented without discussing confounders (e.g., glycemic control, study design heterogeneity).

Thank you for your observation. We have added statements emphasizing glycemic control. It appears that glycemic control significantly contributes to the variation in the findings according to the systematic review and meta-analysis [reference 35], than that of study design or heterogeneity.

- iThenticate report 36%. Add links.    

Thank you, we have worked on it now, and uploaded the updated manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The present manuscript “Predictors of Atrial Fibrillation Recurrence After Catheter Ablation: A State-of-the-Art-Review” of Vempati et al. addresses predictors for atrial fibrillation (AF) recurrence after catheter ablation. While the topic is relevant and timely, the manuscript has content and structural weaknesses that need revision. Notably, there is a lack of critical engagement with the cited studies, and certain redundancies require refinement.

I have serveral  comments:

• Blanking Period: The current recommendation for the blanking period is no longer three months but two months (based on the CIRCA-DOSE study, Steinberg et al., Heart Rhythm 2021). This has also been incorporated into current guidelines (Tzeis et al., Europace 2024). The authors should correct this.
• Early and Late Recurrence: The claim that early recurrence is due to pulmonary vein (PV) reconnection and late recurrence is due to extra-pulmonary triggers is not universally correct and should be nuanced accordingly.
• The logical flow of the introduction is not easy to follow for the reader.
• Figure 1: The graphic is not self-explanatory, particularly the category "IMAGING, TECHNIQUE AND BIOMARKERS," which lacks specificity. A more detailed legend or revision of the figure would be beneficial.

• "Genetics" Section: Please do only citate relevant sources concerning AF recurrence after ablation.
• "Epicardial Adipose Tissue" Section: This section merely summarizes a study without critical reflection. Statements such as "No differences were found between radiofrequency and cryoenergy ablation, and no publication bias was detected" should be critically assessed.
• Sections on OSA, Physical Activity, Alcohol, Chronic Kidney Disease, Mood Disorder, Gut Microbiota, Biomarkers, Echocardiographic Parameters: These sections mostly consist of a collection of study summaries without sufficient contextualization and critical discussion.
• Echocardiographic Parameters: MRI and 3D mapping studies are mixed with echocardiographic parameters. These should be treated separately and supplemented with the latest studies, such as (Teumer et al. JCDD 2024).
• Ablation techniques should be categorized into thermal (e.g., RF, cryo) and non-thermal (e.g., Pulsed Field Ablation, PFA) techniques.
• The EFFICAS II trial on contact force in RF-PVI should be incorporated into the discussion on ablation lesions.
• The ADVENT trial (Reddy et al., NEJM 2023) should be mentioned as a key study in PFA technology.
• The Tailored AF Trial (Deisenhofer et al., Nature Medicine 2025) should be cited regarding artificial intelligence and PVI.
• Some sections (e.g., "Type of Atrial Fibrillation") cite only a single study despite extensive available literature. This is non sufficient.

• Redundancies: The sections "Type of AF" and "Duration of AF" as well as "Early Catheter Ablation Strategy" and "Early Recurrence" (e.g., Lines 428-431 and 444-446) are highly similar and should be consolidated.
• Pharmacological Therapies (SGLT2, RAAS, Statins, GLP-1 Agonists): It is unclear whether the patients had heart failure or diabetes mellitus.
• The manuscript does not clearly indicate or reflect which patients were treated with the respective medications. For example, was the SGLT2 inhibitor studied in non-diabetic patients or diabetics? This differentiation is essential, as it allows the reader to understand whether the medication reduces AF recurrence by treating an underlying risk factor, such as type 2 diabetes mellitus, or if it independently lowers the risk of AF recurrence even in non-diabetic patients.
• The sections "Other Pharmacological Strategies" and "Ablation Techniques" switch from numerical to alphabetical numbering. This should be standardized.
• The statement in the conclusion "Pulsed-field ablation offers the potential for more precise lesion creation" must either be removed or supported by a reference. Current PFA catheters tend to create large, less precise lesions compared to point-by-point RF ablation.
• The conclusion is too lengthy and should be condensed.

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files 

Blanking Period: The current recommendation for the blanking period is no longer three months but two months (based on the CIRCA-DOSE study, Steinberg et al., Heart Rhythm 2021). This has also been incorporated into current guidelines (Tzeis et al., Europace 2024). The authors should correct this.

Thank you for the suggestion, these references has been added to the manuscript now. However, we have decided to include the 2-month blanking period mentioned in the 2024 consensus, which itself assimilated and mentioned CIRCA-DOSE and various other trials/studies before concluding 2 months as a blanking period.

Early and Late Recurrence: The claim that early recurrence is due to pulmonary vein (PV) reconnection and late recurrence is due to extra-pulmonary triggers is not universally correct and should be nuanced accordingly.

Thank you for the suggestion, we have elaborated it appropriately. (See line number 64)

The logical flow of the introduction is not easy for the reader to follow.

Thank you for the suggestion, we have tried to shift/rewrite/edited the sentences to create a flow

Figure 1: The graphic is not self-explanatory, particularly the category "IMAGING, TECHNIQUE AND BIOMARKERS," which lacks specificity. A more detailed legend or revision of the figure would be beneficial.

 Thank you for the suggestion, we have edited our figure 1

"Genetics" Section: Please only cite relevant sources concerning AF recurrence after ablation.

Thank you so much for the suggestion. Genetics and susceptibility to atrial fibrillation recurrence were widely studied in the literature, and condensing them to a single paragraph, and that too with the limited number of citations, was difficult for us. So, we strongly believe our included citations will be a positive addition to our paper.

"Epicardial Adipose Tissue" Section: This section merely summarizes a study without critical reflection. Statements such as "No differences were found between radiofrequency and cryo energy ablation, and no publication bias was detected" should be critically assessed.

Thank you for the suggestion, we have made appropriate changes to the section

Sections on OSA, Physical Activity, Alcohol, Chronic Kidney Disease, Mood Disorder, Gut Microbiota, Biomarkers, and Echocardiographic Parameters: These sections mostly consist of a collection of study summaries without sufficient contextualization and critical discussion.

Thank you for the suggestion, we have made significant changes to these sections.

Echocardiographic Parameters: MRI and 3D mapping studies are mixed with echocardiographic parameters. These should be treated separately and supplemented with the latest studies, such as (Teumer et al. JCDD 2024).

Thank you so much for the suggestion, we have added 2 sections separately and elaborated with suggested citations.

Ablation techniques should be categorized into thermal (e.g., RF, cryo) and non-thermal (e.g., Pulsed Field Ablation, PFA) techniques.

Thank you for the suggestion, we have made changes

The EFFICAS II trial on contact force in RF-PVI should be incorporated into the discussion on ablation lesions.

Thank you for the suggestion, we have made changes by incorporating EFFICAS I and II.

The ADVENT trial (Reddy et al., NEJM 2023) should be mentioned as a key study in PFA technology.

Thank you for the suggestion, we have made changes by incorporating this trial

The Tailored AF Trial (Deisenhofer et al., Nature Medicine 2025) should be cited regarding artificial intelligence and PVI.

Thank you for the suggestion, we have made changes by incorporating this trial.

Some sections (e.g., "Type of Atrial Fibrillation") cite only a single study despite extensive available literature. This is non sufficient.

Thank you for the suggestion, we have edited to include 2 robust studies.

Redundancies: The sections "Type of AF" and "Duration of AF" as well as "Early Catheter Ablation Strategy" and "Early Recurrence" (e.g., Lines 428-431 and 444-446) are highly similar and should be consolidated.

Thank you for the suggestion, we have tried to consolidate and shift sentences, as well so each paragraph represents what they are supposed to represent.

Pharmacological Therapies (SGLT2, RAAS, Statins, GLP-1 Agonists): It is unclear whether the patients had heart failure or diabetes mellitus.

Thank you for pointing out, studies on SGLT2i and GLP1 agonists have clearly mentioned it, and we have reflected it in the edits.

The manuscript does not clearly indicate or reflect which patients were treated with the respective medications. For example, was the SGLT2 inhibitor studied in non-diabetic patients or diabetics? This differentiation is essential, as it allows the reader to understand whether the medication reduces AF recurrence by treating an underlying risk factor, such as type 2 diabetes mellitus, or if it independently lowers the risk of AF recurrence even in non-diabetic patients.

Thank you for this mention, we have made the edits by carefully reading the parent articles.

The sections "Other Pharmacological Strategies" and "Ablation Techniques" switch from numerical to alphabetical numbering. This should be standardized.

Thank you for the suggestion, we have standardized the division now.

The statement in the conclusion "Pulsed-field ablation offers the potential for more precise lesion creation" must either be removed or supported by a reference. Current PFA catheters tend to create large, less precise lesions compared to point-by-point RF ablation.

Thank you for this suggestion, the wording has been changed to convey the right information as mentioned in the literature.

The conclusion is too lengthy and should be condensed.

Thank you for the suggestion, we have condensed the conclusion

Reviewer 3 Report

Comments and Suggestions for Authors

The paper by Vempati and Coll summarizes the factors related to the recurrence of atrial fibrillation after catheter ablation. However, the authors should consider addressing a few points.

• The sequence of the paragraphs is somewhat difficult to follow. To improve readability, the section regarding predictors should be clearly delineated by separating the different subsections, for example: 2.0 Non-Modifiable Clinical Factors; 3.0 Diagnostic Tests, etc.
• Additionally, the relationship between heart failure and the recurrence of atrial fibrillation after ablation warrants discussion.
• Furthermore, a paragraph addressing essential hypertension is notably absent and should be included.

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files

The sequence of the paragraphs is somewhat difficult to follow. To improve readability, the section regarding predictors should be clearly delineated by separating the different subsections, for example, 2.0 Non-Modifiable Clinical Factors; 3.0 Diagnostic Tests, etc

We acknowledge that the readability may be challenging, but we have followed the journal’s template as required. Therefore, we cannot modify the outline's presentation. Thank you for your understanding.

Additionally, the relationship between heart failure and the recurrence of atrial fibrillation after ablation warrants discussion.

Thank you for the suggestion, The heart failure section has been added now

Furthermore, a paragraph addressing essential hypertension is notably absent and should be included.

Thank you for the suggestion, The hypertension section has been added now

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript has significantly improved compared to its previous version, showing a clearer structure and better argumentation. However, several aspects should be revised to further enhance readability and scientific value:

1) Some sections contain an extensive amount of detail that is not strictly necessary for evaluating the respective risk factors. Condensing these parts would improve the readability and focus of the manuscript.

- The statins section should be condensed, focusing on the highest quality studies that assess the role of statins in preventing AF recurrence after ablation

- The alcohol section contains too much detailed information, which is difficult to follow. A more concise and focused presentation would improve clarity.

3) Please place Figure 1 earlier in the manuscript—preferably before the discussion of individual risk factors. This would help readers quickly gain an overview of the factors discussed.

4) Unclear Sentences:

Lines 690–692: The phrase “100% paroxysmal AF” is unclear and does not reflect standard terminology. Please clarify what is meant by this expression.

Line 1327: The sentence is difficult to understand and should be rewritten for clarity.

Line 1919: Do you mean after 3 months? The word "after" seems to be missing.

Lines 1920–1923: This section is hard to follow. I assume that the results of the RCA and the cohort study were contradictory—is that correct? Please clarify the meaning.

5) There are some typos that should be corrected (e.g. “by” too much in the Hypertension section, “didn’t” too much in the Epicardial adipose tissue section). Please check the manuscript for these issues.

Author Response

Thank you for the feedback on the manuscript. We are glad to hear that the improvements in structure and argumentation are noticeable. We appreciate your suggestions regarding the aspects that need revision. I reviewed points carefully and worked on enhancing the overall readability and scientific value. Your insights are invaluable in refining the work further.

1) Some sections contain an extensive amount of detail that is not strictly necessary for evaluating the respective risk factors. Condensing these parts would improve the readability and focus of the manuscript.

- The statins section should be condensed, focusing on the highest quality studies that assess the role of statins in preventing AF recurrence after ablation

Thank you for pointing it out. However, we believe it is a condensation of “two” high-quality/robust evidence studies - that is, meta-analysis, representing the pooled outcomes of the studies that they included. Additionally, it is important to mention the contrasting findings from a subgroup analysis of RCTs and retrospective studies to provide a clearer picture through a nuanced explanation.

- The alcohol section contains too much detailed information, which is difficult to follow. A more concise and focused presentation would improve clarity.

Thank you for bringing this to our attention. We recognize that there are many details involved, but we believe it's essential to provide numbers and elaborate on the topic since alcohol is a widely recognized modifiable risk factor that requires a nuanced explanation. We have also made an effort to reduce some redundant sentences. Thank you once again!

3) Please place Figure 1 earlier in the manuscript—preferably before the discussion of individual risk factors. This would help readers quickly gain an overview of the factors discussed.

Done, thank you

4) Unclear Sentences:

Lines 690–692: The phrase “100% paroxysmal AF” is unclear and does not reflect standard terminology. Please clarify what is meant by this expression.

Thank you for asking to clarify. The sentence is edited now.

Line 1327: The sentence is difficult to understand and should be rewritten for clarity.
Thank you for the comment. I have edited the sentence now.

Line 1919: Do you mean after 3 months? The word "after" seems to be missing.

The sentence is appropriate as below, thank you

“In a meta-analysis conducted by Lei et al., the primary focus was on the early recurrence of AF after a single ablation procedure, with or without the use of corticosteroids after a short- and long-term follow-up. Notably, 992 patients with AF were included in this study, and they concluded that corticosteroids reduced the AF recurrence risk 3 months (OR = 0.53, p = 0.02) and 12–14 months (OR = 0.67, p = 0.02) after RFA [113]. “

Lines 1920–1923: This section is hard to follow. I assume that the results of the RCA and the cohort study were contradictory—is that correct? Please clarify the meaning.

Yes, thank you for the comment. The sentence is edited now for clarity. 

5) There are some typos that should be corrected (e.g. “by” too much in the Hypertension section, “didn’t” too much in the Epicardial adipose tissue section). Please check the manuscript for these issues.

Thank you for pointing this out; we have edited for all possible typos now

Reviewer 3 Report

Comments and Suggestions for Authors

No further comment.

Author Response

Thank you