Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

here my comments:

 

Permitting a time frame of up to three months before and after the procedure for transthoracic echocardiography introduces potential variability. Both mitral regurgitation severity and left atrial dimensions may fluctuate within this period, particularly in patients who undergo clinical optimization prior to the intervention. Thus a more detailed discussion is warranted regarding how this variability may influence the study’s findings.

The reported hazard ratio of 0.17 indicating a protective effect appears unusually strong and may reflect residual confounding, such as indication bias or selection effects. Authors should elaborate more this aspect.

The categorization of MR as “mild-moderate” and “moderate” requires clarification as it is unclear whether these represent standard echocardiographic classifications or are specific to institutional reporting practices.Authors should then provide a rationale for the observed effect and adjust for additional relevant confounders, such as underlying structural heart disease.

Further elaboration on potential pathophysiological mechanisms is encouraged. This should include emerging concepts such as the atrial myopathy hypothesis, mitral annular disjunction, and advanced imaging markers of atrial fibrosis. In particular authors are encouraged to include the concept of “atrial cardiomyopathy” (consider using doi: 10.23736/S2724-5683.25.06725-0) to their manuscript which is so relevant for the topic.

Author Response

Reviewer #1

Here are my comments:

1. Permitting a time frame of up to three months before and after the procedure for transthoracic echocardiography introduces potential variability. Both mitral regurgitation severity and left atrial dimensions may fluctuate within this period, particularly in patients who undergo clinical optimization prior to the intervention. Thus a more detailed discussion is warranted regarding how this variability may influence the study’s findings.

Answer: We thank the reviewer for his justified comment. Notably, as written in the 3^rd paragraph  of the Results section, the actual time of pre-procedure TTE was 4 [1-42] days, meaning that most patients had their TTE within a month before the ablation (page 7). Nevertheless, we totally agree with the reviewer’s comment that MR severity is dynamic and highly dependent on volume and blood pressure status. Accordingly, we revised the limitation paragraph to emphasize this issue as written in revised limitation #4 (page 12-13).

 

2. The reported hazard ratio of 0.17 indicating a protective effect appears unusually strong and may reflect residual confounding, such as indication bias or selection effects. Authors should elaborate more this aspect.

Answer: We must admit that we were also surprised by this apparently low HR for anti-arrhythmic Ic medications, suggesting their strong effect protecting from post-ablation AF recurrence. First of all, we checked again the multivariable analysis and this is indeed true. As the reviewer recommended, we extended the revised discussion paragraph elaborating on the clinical characteristics associated with post-ablation AF recurrence (page 10, bottom paragraph) to highlight this issue and suggest that their protective effect may result from a selection bias given the fact that these medications are used by patients with normal LV function and no ischemic background (according to both clinical practice and guidelines), representing structurally normal hearts.  Thus, anti-arrhythmic Ic use may represent a reliable marker for normal hearts. Notably, when adjusting for other parameters associated with LV function as LVEF and LA size (representing systolic and diastolic function, respectively) the protective impact of Ic medications  is lower and not significant any more (HR 0.39; p 0.144 in Table 3), suggesting that Ic use is associated with normal hearts.

 

3. The categorization of MR as “mild-moderate” and “moderate” requires clarification as it is unclear whether these represent standard echocardiographic classifications or are specific to institutional reporting practices. Authors should then provide a rationale for the observed effect and adjust for additional relevant confounders, such as underlying structural heart disease.

Answer: We thank the reviewer for this important comment regarding our use of the term ‘significant’ MR. Notably, the initial motivation for our study was to evaluate whether significant baseline MR is associated with post-ablation AF recurrence and thereafter thinking of a future study to check if MR reduction (for example via trans-catheter edge-to-edge repair (TEER)) may lead to lower AF recurrence and hence to an increased ablation success. Thus, in accordance with many studies regarding TEER, we defined patients with ‘significant’ MR as those with moderate-severe (grade 3) and/or severe (grade 4) MR, which are the common candidates for these procedures. 

 

Supporting Evidence:

A. ESC/EACTS Guidelines 2021 on Valvular Heart Disease. The guidelines refer to patients with moderate-to-severe or severe MR, as potential candidates for intervention, especially when discussing the indications for trans-catheter edge-to-edge repair (TEER). Vahanian A et al. Eur Heart J. 2022;43(7):561-632.

Notably, these are still valid in the updated 2025 ESC guidelines on management of valvular heart disease (ref #16 in our study).

B. COAPT Trial (Stone et al., NEJM 2018). This pivotal study ,evaluating the efficacy of trans-catheter mitral valve repair in heart failure patients, included patients with moderate-to-severe (3+) or severe (4+) secondary MR, labeling them as significant MR for trial inclusion. Reference: Stone GW et al. N Engl J Med. 2018;379(23):2297-2306.

In many major clinical trials (like COAPT and MITRA-FR), both moderate-to-severe (3+) and severe (4+) MR, are joined together, especially with regard to percutaneous mitral valve repair options. Nevertheless, we acknowledge that this is not a standard universal definition and thus, we explicitly defined it in the revised abstract and methods sections (Method’s echocardiography paragraph, page 5 top). Moreover, we added a few sentences regarding the initial motivation for our study at the end of the revised Introduction section (page 4), and at the Methods’ Echocardiography paragraph, explaining the rationale with supporting references for our definition for ‘significant’ MR (page 5, top), so the reader mind would be more focused on mitral valve percutaneous interventions, which usually apply to patients with moderate-severe or severe MR, as shown above.

The reviewer also comments regarding adjustment of MR effect with other confounders. For this purpose a multivariable analysis including main clinical parameters, known to impact post-ablation AF recurrence, were added including LA size, AF type (persistent versus paroxysmal) and EF (Cox multivariable model in Table 3, page 17). Notably, EF is one of the main parameters representing structural disease and EF along with LA size are basically surrogates for systolic and diastolic LV function, respectively. Accordingly, as shown in table 3, baseline MR severity was still significantly and independently associated with post-ablation AF recurrence after adjustment with all above parameters.

 

4. Further elaboration on potential pathophysiological mechanisms is encouraged. This should include emerging concepts such as the atrial myopathy hypothesis, mitral annular disjunction, and advanced imaging markers of atrial fibrosis. In particular authors are encouraged to include the concept of “atrial cardiomyopathy” (consider using doi: 10.23736/S2724-5683.25.06725-0) to their manuscript which is so relevant for the topic.

Answer: We thank the reviewer for this important comment, regarding the need to elaborate on the pathophysiological mechanisms underlying AF with emphasis on atrial cardiomyopathy, which has utmost importance in the understanding that AF is not a “stand-alone” arrhythmia but rather an arrhythmic phenotype of atrial cardiomyopathy, involving structural, function, and electrical remodeling. Furthermore, by this concept of atrial cardiomyopathy one may understand the potential pathophysiological relation between MR (mainly functional, resulting from atrial annular dilatation) and AF which could both result from and lead to atrial cardiomyopathy. Accordingly, we dedicated a new paragraph in the revised manuscript to discuss this topic (second paragraph, page 11), relying on the above recommended reference and other pivotal studies as well.  

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

It is an interesting article on a controversial subject.

Despite its limitations, as you have acknowledged in your analysis, there is an educational value to take into account. If feasible, it will take time to develop a large-scale randomised controlled trial to specifically address your research question. Therefore, what is your proposal? I think this aspect should be further developed in the discussion: should we ablate patients with significant mitral regurgitation? Should we treat mitral regurgitation first? Should we consider a combined treatment? Which treatment: surgical or interventional? Should we define specific group of patients and act accordingly?

Author Response

Reviewer #2

It is an interesting article on a controversial subject.

Despite its limitations, as you have acknowledged in your analysis, there is an educational value to take into account. If feasible, it will take time to develop a large-scale randomized controlled trial to specifically address your research question. Therefore, what is your proposal? I think this aspect should be further developed in the discussion: should we ablate patients with significant mitral regurgitation? Should we treat mitral regurgitation first? Should we consider a combined treatment? Which treatment: surgical or interventional? Should we define specific group of patients and act accordingly?

Answer:

We thank the reviewer for this important comment. We agree that the key clinical question is not only whether AF ablation should be performed in patients with atrial secondary MR, but also how best to sequence or combine AF and MR-directed therapies.

In line with the 2025 ESC/EACTS guidelines, our interpretation is that management should begin with optimal AF treatment—including rhythm or rate control, anticoagulation, and catheter ablation when appropriate—given that restoration of sinus rhythm can improve left atrial size, mitral annular dynamics, and in some cases reduce MR severity. If significant MR persists despite adequate AF management, surgery (Class IIa) or transcatheter edge-to-edge repair (Class IIb) may be considered in selected patients, and concomitant AF ablation should be addressed in surgical candidates.

As the reviewer highlights, these recommendations are largely based on expert consensus rather than randomized data. We therefore expanded our discussion to emphasize the current uncertainty.

Finally, we added the ongoing CAMERA-Pilot randomized trial (NCT05846412), which is designed to compare AF ablation versus TEER in atrial MR, and which may provide the first prospective evidence to guide whether treatment should be sequential, combined, or directed at the MR.

We have revised the Discussion accordingly (page 10, 2^nd paragraph:

“In the 2025 ESC/EACTS guidelines, management of atrial MR should begin with optimal AF treatment, including rhythm or rate control strategies, catheter ablation when appropriate, and anticoagulation [16]. Restoration of sinus rhythm can improve atrial size, mitral annular dynamics, and in some cases reduce the severity of MR, potentially delaying or obviating the need for valve intervention. If significant MR persists despite adequate AF management and the patient remains symptomatic, mitral valve surgery is considered reasonable (Class IIa), while transcatheter edge-to-edge repair may be considered in selected patients (Class IIb). In those undergoing surgery, concomitant AF ablation should also be considered to address the underlying atrial pathology(1). Importantly, these recommendations, particularly regarding the role of TEER in AF patients with functional MR, are not based on randomized controlled trials, and prospective data are needed. The CAMERA-Pilot trial (NCT05846412), a randomized study directly comparing AF ablation per se versus trans-catheter edge-to-edge repair (TEER) in patients with atrial MR, is expected to provide the first controlled evidence to guide therapeutic strategies in this population, helping to refine future guideline recommendations.”

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Congratulations to the authors for their valid answers.

Author Response

Thanks.