Linking Epicardial Adipose Tissue to Atrial Remodeling: Clinical Implications of Strain Imaging

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

First, the focus on strain imaging and its clinical utility, though detailed, does not sufficiently address the technical challenges and limitations of this modality, such as inter-operator variability, dependency on image quality, and lack of standardization in parameter measurement. Additionally, the therapeutic strategies discussed, including GLP-1 receptor agonists and weight management, are promising but remain limited in scope, neglecting other emerging interventions, such as novel anti-inflammatory therapies. The review also heavily emphasizes correlations between EAT and atrial remodeling without exploring causative mechanisms in depth or addressing potential confounding factors, such as comorbidities or genetic predispositions. Furthermore, while the article briefly touches upon advanced imaging techniques like cardiac MRI and PET scans, it does not critically evaluate their accessibility, cost-effectiveness, or clinical feasibility in routine practice, particularly in resource-limited settings. 

Author Response

Comment 1: First, the focus on strain imaging and its clinical utility, though detailed, does not sufficiently address the technical challenges and limitations of this modality, such as inter-operator variability, dependency on image quality, and lack of standardization in parameter measurement.

Response: We have expanded the discussion on the technical challenges associated with strain imaging. The revised section now addresses inter-operator variability, the dependency on image quality, and the lack of standardization in parameter measurement.

Comment 2: Additionally, the therapeutic strategies discussed, including GLP-1 receptor agonists and weight management, are promising but remain limited in scope, neglecting other emerging interventions, such as novel anti-inflammatory therapies.

Response: We agree that other emerging interventions warrant inclusion. The manuscript has been updated to incorporate a discussion on novel anti-inflammatory therapies, such as IL-6 and TNF-α inhibitors, as well as adiponectin modulators and statins, which have shown promise in reducing EAT-driven inflammation and atrial remodeling. These additions provide a more comprehensive view of therapeutic strategies.

Comment 3: The review also heavily emphasizes correlations between EAT and atrial remodeling without exploring causative mechanisms in depth or addressing potential confounding factors, such as comorbidities or genetic predispositions.

Response: The emphasis on correlations between EAT and atrial remodeling has been balanced with a deeper exploration of causative mechanisms. We have included a discussion on how EAT induces atrial fibrosis, inflammation, and electrical remodeling, supported by specific molecular pathways. Additionally, we address potential confounding factors, including comorbidities such as hypertension, obesity, and diabetes, as well as genetic predispositions, to provide a broader understanding of the factors influencing atrial remodeling.

Comment 4: Furthermore, while the article briefly touches upon advanced imaging techniques like cardiac MRI and PET scans, it does not critically evaluate their accessibility, cost-effectiveness, or clinical feasibility in routine practice, particularly in resource-limited settings. 

Response: We have expanded the section on cardiac MRI and PET scans to critically evaluate their accessibility and cost-effectiveness, particularly in resource-limited settings. Acknowledging these limitations, we emphasize the continued importance of echocardiography as a practical and widely available cornerstone for atrial assessment.

Reviewer 2 Report

Comments and Suggestions for Authors

This article is very well written and elaborated review on the subject, and it is of clinical value for cardiologists. The relationship  between LA-EAT and AFib is well documented . The atrial strain and volumetric assessment as markers of atrial remodelling well described. 

Some points should be clearly improved:

1. Concerning the effect of ablation on atrial remodelling: this paragraph should be improved in order to have more information on LA-EAT and the performance of ablation in experimental studies (how the ablation is impeded by EAD) and how these pathophysiological mechanisms may affect clinical results in persistent AFib ablation....

2. Concerning CMR and EAT what we would expect is more details on the % of adiposity in normal heart, in patients with AFib, in patients with AFib and fibrosis: qualitative and quantitative results are expected

3. Concerning measurable parameters of LA strain: as clinicians we are expecting more details on the reproducibility of the parameters studied as well as more details on the relationship of altered parameters and other conditions than AFib; concerning these parameters are there only available in sinus rhythm ?? etc...     

 

 

 

 

Author Response

Comment 1: Concerning the effect of ablation on atrial remodelling: this paragraph should be improved in order to have more information on LA-EAT and the performance of ablation in experimental studies (how the ablation is impeded by EAD) and how these pathophysiological mechanisms may affect clinical results in persistent AFib ablation....

Response: A new paragraph on the effects of AF ablation in patients with LA-EAT has been added. Specifically, the advantages of electroporation are discussed.

 

Comment 2: Concerning CMR and EAT what we would expect is more details on the % of adiposity in normal heart, in patients with AFib, in patients with AFib and fibrosis: qualitative and quantitative results are expected

Response: Data on the percentage of epicardial fat in healthy and AF patients with and without fibrosis have been added. Moreover, CMR characteristics have been discussed.

 

Comment 3: Concerning measurable parameters of LA strain: as clinicians we are expecting more details on the reproducibility of the parameters studied as well as more details on the relationship of altered parameters and other conditions than AFib; concerning these parameters are there only available in sinus rhythm ?? etc...    

Response: Has been explained that LA strain analysis is only available when sinus rhythm has been restored. Challenges in reservoir measurement in AF have been described.

Reviewer 3 Report

Comments and Suggestions for Authors

In this manuscript Cacciapuoti et al present a narrative review on the topic of epicardial adipose tissue to atrial remodeling and use of imaging technologies.  Overall pretty well done and would benefit the readership.  Below are my comments meant for constructive purposes.

Major and minor comments:

1.  Introduction:  Would reference recent expert consensus document for treatment of AF to emphasize the emergingclinical importance of this topic (PMID: 38609733)

2.  Section 3 -  Can authors expand on which inflammatory cytokines are increased?

2. Section 3 - Also would be more specific about how LA-EAT affects electrical remodeling. Study by Mahajan et al which examined chronic obesity model demonstrated correlation between increased epicardial fat and features of electrical remodeling increasing risk for AF (PMID: 26139051)

3.  Section 3 - Authors mention ganglionated plexi and modulation of autonomic activity.  Do the authors have supporting references for their statements that autonomic dysfunction can alter endocrine function of EAT?  Also are their studies authors can reference for reduction of epicardial adipose through wait loss and targeting autonomic neurotransmitter secretion after AF ablation or surgery?  Reviewer assumes in the latter that the authors are referring to GP ablation or surgical (PMID: 34915187, PMID: 37561246)

4.  Section 4 - Can the authors briefly discuss using cardiac MRI to evaluate atrial strain and LAVI, possibly include a figure

 5.  Section 6 - Regarding LA strain - several recently published studies have examined prognostic value of LA strain in pts undergoing catheter ablation and effect of ablation on LA strain itself  (PMID: 37414922, PMID: 36804765, PMID: 38587576, PMID: 35469934).  Please add a brief paragraph discussing these studies at the end of section 6 or do so in paragraph 2 of Section 9.

6.  Section 7 is very well written and informative - no changes recommended

7.  Section 8; line 198-200:  See studies mentioned in comment 5.  Use of LA strain may be useful in stratifying risk for recurrence and selecting patients for RF ablation.

8.  Section 9; paragraph 2 - Again, studies mentioned in comment 5 would be useful to discuss or cite here to back up authors statements

9.  Section 10 - Peak longitudinal atrial strain has been studied using CMR in AF patients.  See earlier paper by dong et al.   CT has also been utilized to view and quantify epicardial fat.  Although there's a figure, some discussion on CT should be added.  For example  this is a method of targeting GP when performing endocardial AF ablation (PMID: 35907756, PMID: 39671156)

10.  Conclusion is a little bit long.  The first 3 paragraphs are restating things mentioned earlier in the manuscript and could be shortened.  The last paragraph is good.  Rather than have a very long conclusion section, I suggest instead the authors create a summary figure, perhaps a flow diagram, of the suggested diagnostic and potential therapeutic management and possible future directions.

Author Response

Comment 1: Introduction:  Would reference recent expert consensus document for treatment of AF to emphasize the emergingclinical importance of this topic (PMID: 38609733)

Response: In the revised introduction, we have incorporated this reference to underscore the significance of updated guidelines in AF management.

 

Comment 2: Section 3 -  Can authors expand on which inflammatory cytokines are increased?

Response: A table of increased cytokines has been added (Table I).

 

Comment 3: Section 3 - Also would be more specific about how LA-EAT affects electrical remodeling. Study by Mahajan et al which examined chronic obesity model demonstrated correlation between increased epicardial fat and features of electrical remodeling increasing risk for AF (PMID: 26139051)

Response: The reference to the study by Mahajan et al. (PMID: 26139051) has been added to Section 3 to specifically highlight the correlation between increased epicardial fat and features of electrical remodeling that elevate the risk for AF.

 

Comment 4: Authors mention ganglionated plexi and modulation of autonomic activity.  Do the authors have supporting references for their statements that autonomic dysfunction can alter endocrine function of EAT?  Also are their studies authors can reference for reduction of epicardial adipose through wait loss and targeting autonomic neurotransmitter secretion after AF ablation or surgery?  Reviewer assumes in the latter that the authors are referring to GP ablation or surgical (PMID: 34915187, PMID: 37561246)

Response: We have reviewed the suggested references (PMID: 34915187 and PMID: 37561246) and incorporated them to support the statements regarding the impact of autonomic dysfunction on the endocrine function of EAT.

 

Comment 5: Section 4 - Can the authors briefly discuss using cardiac MRI to evaluate atrial strain and LAVI, possibly include a figure

Response: we have included a brief discussion on the utility of cardiac MRI for evaluating atrial strain and left atrial volume index. We were unable to provide an original figure for this section due to the lack of suitable materials in our database.

 

Comment 6: Section 6 - Regarding LA strain - several recently published studies have examined prognostic value of LA strain in pts undergoing catheter ablation and effect of ablation on LA strain itself  (PMID: 37414922, PMID: 36804765, PMID: 38587576, PMID: 35469934).  Please add a brief paragraph discussing these studies at the end of section 6

Response: We have reviewed the suggested studies (PMID: 37414922, PMID: 36804765, PMID: 38587576, and PMID: 35469934) and added a brief paragraph at the end of Section 6 discussing their findings.

 

Comment 7: Section 7 is very well written and informative - no changes recommended

Response: Thank you for your kind comment.

 

Comment 8: Section 8; line 198-200:  See studies mentioned in comment 5.  Use of LA strain may be useful in stratifying risk for recurrence and selecting patients for RF ablation.

Response: We have incorporated the studies mentioned in comment 5. A brief discussion has been added to highlight the utility of LA strain in stratifying risk for AF recurrence and selecting appropriate patients for RF ablation.

 

Comment 9: Section 9; paragraph 2 - Again, studies mentioned in comment 5 would be useful to discuss or cite here to back up authors statements

Response: We have incorporated the studies mentioned in comment 5.

 

Comment 10: Section 10 - Peak longitudinal atrial strain has been studied using CMR in AF patients.  See earlier paper by dong et al.   CT has also been utilized to view and quantify epicardial fat.  Although there's a figure, some discussion on CT should be added.  For example  this is a method of targeting GP when performing endocardial AF ablation (PMID: 35907756, PMID: 39671156)

Response: We have added a discussion on the use of CT to view and quantify epicardial fat. The references you suggested (PMID: 35907756, PMID: 39671156) have been incorporated to emphasize how CT enhances the precision of GP localization and contributes to procedural success. Additionally, we have included a brief mention of peak longitudinal atrial strain studied using CMR, as highlighted in Dong et al.'s earlier work.

 

Comment 11: Conclusion is a little bit long.  The first 3 paragraphs are restating things mentioned earlier in the manuscript and could be shortened.  The last paragraph is good.  Rather than have a very long conclusion section, I suggest instead the authors create a summary figure, perhaps a flow diagram, of the suggested diagnostic and potential therapeutic management and possible future directions.

Response: We have revised the conclusion section by condensing the first three paragraphs to avoid repetition and retain only the key points. Additionally, we have created a summary flow diagram to illustrate the suggested diagnostic approaches, potential therapeutic management strategies, and future directions.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors addressed all my comments

Reviewer 2 Report

Comments and Suggestions for Authors

I have no further comments. The article has been significantly improved and appears of high quality. The authors have correctly answered the queries.

Reviewer 3 Report

Comments and Suggestions for Authors

I think the authors for the work put in and response to this reviewer's comments.  The manuscript is acceptable in its current form.  Congrats to the authors on this unique review paper.