Atrial Secondary Mitral Regurgitation: Pathophysiology, Diagnosis, and Surgical Implications

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

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Scientific Review & Critical Appraisal

Title: Atrial Secondary Mitral Regurgitation: Pathophysiology, Diagnosis, and Surgical Implications

Authors: Venturiello et al.

Journal: Medicina (MDPI)

1. General Assessment

The manuscript provides a comprehensive narrative review of Atrial Secondary Mitral Regurgitation (A-SMR), a phenotype increasingly recognized in patients with atrial fibrillation (AF) and Heart Failure with preserved Ejection Fraction (HFpEF). The authors successfully delineate the differences between A-SMR and Ventricular Secondary Mitral Regurgitation (V-SMR), emphasizing the "atrial-centric" nature of the disease. The clinical relevance is high, especially given the recent inclusion of A-SMR in the 2025 ESC/EACTS guidelines.

2. Critical Points and Areas for Improvement

A. Precision in Evidence Citation (Crucial Methodological Flaw)

• Critique: Throughout the text, there is a recurring tendency to use the plural "studies" followed by only a single reference, which is often a narrative review rather than primary data.

• Recommendation: When citing evidence, authors must reference specific primary studies. Furthermore, it is essential to define the study population and report relevant clinical outcomes, including statistical parameters such as p-values, Odds Ratios (OR), and Hazard Ratios (HR). This will transform the manuscript from a general commentary into a rigorous scientific synthesis.

B. Patient Selection and "Dual Phenotype" Complexity

• Critique: The manuscript mentions the "dual functional mitral regurgitation phenotype" (mixed atrial and ventricular mechanisms), which accounts for nearly 60% of patients in some cohorts. However, the management section primarily focuses on "pure" A-SMR.

• Recommendation: The authors should provide a more detailed decision-making algorithm for this dual phenotype. Specifically, how should a clinician weigh the atrial vs. ventricular contribution when deciding between isolated annuloplasty and more complex subvalvular repairs?

C. Long-term Durability of TEER in A-SMR

• Critique: The manuscript briefly mentions concerns regarding the long-term durability of Transcatheter Edge-to-Edge Repair (TEER) in a predominantly annular disease like A-SMR.

• Recommendation: This section needs expansion. Authors should contrast the results of the COAPT and MITRA-FR trials (focused on V-SMR) with more recent, specific registries or subgroup analyses involving A-SMR patients. Adding a dedicated table comparing surgical annuloplasty vs. TEER outcomes specifically for A-SMR would provide significant value.

D. Surgical Technique: Partial vs. Complete Rings

• Critique: The review identifies partial band annuloplasty as an independent predictor of recurrence, yet the discussion on why partial bands are still used—or in which specific cases they might be considered—is insufficient.

• Recommendation: Provide a more rigorous technical discussion on ring sizing and selection. Since functional mitral stenosis is a risk with undersized rings, authors should offer specific guidance on how to balance effective regurgitation reduction with the maintenance of a proper valve area in the A-SMR population.

E. Advanced Atrial Myopathy and "Point of No Return"

• Critique: The authors note that delayed intervention in the presence of severe atrial enlargement and fibrosis leads to poor outcomes.

• Recommendation: The authors should propose concrete imaging "red flags" (e.g., specific cut-offs for Left Atrial Volume Index or strain values) that should prompt surgical referral before the disease reaches an irreversible stage. This would move the review from a descriptive summary to a more practical clinical guide.

F. Visual Aids and Summaries

• Critique: While Figure 1 and Table 1 are helpful, the manuscript is text-heavy for a 30-page document.

• Recommendation: Include a Central Illustration summarizing the "A-SMR Journey"—from AF/HFpEF triggers to diagnostic criteria (TTE/CMR), and finally to stratified treatment (Medical → Rhythm Control → TEER/Surgery).

3. Minor Suggestions and Corrections

• Abstract Formatting: References should not be included in the abstract (e.g., [1] on line 21). Please remove them to comply with standard journal guidelines.

• Terminology: Ensure consistent use of "A-SMR" vs. "AF-MR" throughout the text to avoid confusion.

• Language & Abbreviations:  E.g. On line 85, ensure the Italian term is fully translated into English as "Heart Failure with preserved Ejection Fraction (HFpEF)".

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 the re-submitted files.

 

Point-by-point response to Comments and Suggestions for Authors

2. Critical Points and Areas for Improvement

A. Precision in Evidence Citation (Crucial Methodological Flaw)

 

• Critique: Throughout the text, there is a recurring tendency to use the plural "studies" followed by only a single reference, which is often a narrative review rather than primary data.
• Recommendation: When citing evidence, authors must reference specific primary studies. Furthermore, it is essential to define the study population and report relevant clinical outcomes, including statistical parameters such as p-values, Odds Ratios (OR), and Hazard Ratios (HR). This will transform the manuscript from a general commentary into a rigorous scientific synthesis.

 

Response to comment A: We thank the Reviewer for this methodological remark. We have revised the manuscript to avoid generic statements such as “studies have shown” when supported by a single reference. Whenever possible, we now cite primary cohorts/registries and explicitly report study design, population size, follow-up, and key outcomes (including HR/OR and p-values when available). When evidence derives from narrative reviews or expert statements, we have explicitly labeled these sources accordingly and rephrased the text to maintain accurate attribution.

B. Patient Selection and "Dual Phenotype" Complexity

 

• Critique: The manuscript mentions the "dual functional mitral regurgitation phenotype" (mixed atrial and ventricular mechanisms), which accounts for nearly 60% of patients in some cohorts. However, the management section primarily focuses on "pure" A-SMR.
• Recommendation: The authors should provide a more detailed decision-making algorithm for this dual phenotype. Specifically, how should a clinician weigh the atrial vs. ventricular contribution when deciding between isolated annuloplasty and more complex subvalvular repairs?

 

Response to Comment B: We thank the Reviewer for this insightful comment. We agree that mixed atrial–ventricular mechanisms are frequently encountered in clinical practice and deserve a more structured discussion. Accordingly, we have added a dedicated subsection clarifying the pathophysiological continuum between atrial and ventricular secondary mitral regurgitation and proposing a mechanism-oriented decision framework. In the revised manuscript, we now describe how quantitative imaging parameters—such as left ventricular geometry and function, degree of leaflet tethering, annular dilatation, and left atrial remodeling—can help define the dominant mechanism. We emphasize that: In atrial-dominant phenotypes (preserved LV geometry and function, marked annular dilatation, minimal tethering), annuloplasty-based strategies are generally appropriate. When ventricular remodeling and significant leaflet tethering are present, isolated annuloplasty may be associated with higher recurrence, and treatment should be individualized by the Heart Team, balancing optimized medical therapy, cardiac resynchronization when indicated, and transcatheter or surgical options in accordance with contemporary ESC/EACTS recommendations. This addition aims to provide a practical, imaging-guided algorithm to assist clinicians in managing patients with mixed phenotypes.

C. Long-term Durability of TEER in A-SMR

 

• Critique: The manuscript briefly mentions concerns regarding the long-term durability of Transcatheter Edge-to-Edge Repair (TEER) in a predominantly annular disease like A-SMR.
• Recommendation: This section needs expansion. Authors should contrast the results of the COAPT and MITRA-FR trials (focused on V-SMR) with more recent, specific registries or subgroup analyses involving A-SMR patients. Adding a dedicated table comparing surgical annuloplasty vs. TEER outcomes specifically for A-SMR would provide significant value.

 

Response to Comment C: We thank the Reviewer for this important and constructive suggestion. We have substantially expanded the section addressing transcatheter edge-to-edge repair (TEER) in atrial secondary mitral regurgitation (A-SMR).

In the revised manuscript, we now:

1. Explicitly contrast the COAPT and MITRA-FR trials—both conducted in ventricular secondary MR populations characterized by left ventricular remodeling and leaflet tethering—with the distinct annular-dominant pathophysiology of A-SMR.
2. Provide a mechanism-oriented discussion highlighting the potential implications of treating an annulus-driven disease with a leaflet-based repair strategy, particularly with respect to long-term durability.
3. Include a dedicated comparative table (Table X) summarizing available meta-analytical estimates of surgical annuloplasty versus TEER in atrial functional MR populations. We clearly state that these data derive from observational studies and should be considered hypothesis-generating, given the absence of randomized head-to-head trials and the baseline risk imbalance between treatment groups.

 

We believe that these additions strengthen the manuscript by offering a balanced and evidence-based appraisal of current knowledge while transparently acknowledging existing limitations.

D. Surgical Technique: Partial vs. Complete Rings

 

• Critique: The review identifies partial band annuloplasty as an independent predictor of recurrence, yet the discussion on why partial bands are still used—or in which specific cases they might be considered—is insufficient.
• Recommendation: Provide a more rigorous technical discussion on ring sizing and selection. Since functional mitral stenosis is a risk with undersized rings, authors should offer specific guidance on how to balance effective regurgitation reduction with the maintenance of a proper valve area in the A-SMR population.

 

Response to Comment D: We thank the Reviewer for this insightful comment. In the revised manuscript, we have expanded the section on surgical technique to clarify the rationale for partial posterior band use and to provide more detailed guidance on ring selection and sizing in A-SMR. We now explicitly distinguish between annular extent (complete ring vs partial band) and mechanical properties, and we discuss the hemodynamic trade-offs associated with each approach. Contemporary data comparing semirigid complete rings and semirigid posterior bands in functional MR show comparable 10-year survival and MR recurrence, but higher transmitral gradients with complete rings. Importantly, mean transmitral gradient has been identified as an independent predictor of long-term mortality, underscoring the clinical relevance of avoiding excessive annular restriction. In A-SMR, where annular dilatation is typically circumferential and leaflet tethering is limited, we emphasize that complete rings may offer more effective annular stabilization. However, aggressive undersizing should be avoided to reduce the risk of functional mitral stenosis. The revised text now recommends careful sizing based on anterior leaflet height and intertrigonal distance, with intraoperative assessment of transmitral gradients under physiologic loading conditions. Overall, the manuscript now provides a more balanced, mechanism-oriented discussion to guide prosthesis selection in this specific population.

 

E. Advanced Atrial Myopathy and "Point of No Return"

• Critique: The authors note that delayed intervention in the presence of severe atrial enlargement and fibrosis leads to poor outcomes.
• Recommendation: The authors should propose concrete imaging "red flags" (e.g., specific cut-offs for Left Atrial Volume Index or strain values) that should prompt surgical referral before the disease reaches an irreversible stage. This would move the review from a descriptive summary to a more practical clinical guide.

 

Response to Comment E: We thank the Reviewer for this valuable suggestion. We agree that translating the concept of advanced atrial myopathy into practical imaging markers enhances the clinical applicability of the manuscript. In the revised version, we have expanded this section to propose specific imaging “red flags” that may indicate progression toward advanced atrial remodeling. These include marked left atrial enlargement (e.g., left atrial volume index ≥60 mL/m²), severely reduced left atrial reservoir strain, and evidence of atrial fibrosis on advanced imaging modalities. These thresholds are supported by observational studies demonstrating the association between atrial enlargement, impaired atrial mechanics, myocardial fibrosis, and adverse outcomes in mitral regurgitation and heart failure populations. Importantly, we explicitly clarify in the manuscript that no rigid, universally validated cut-off values currently exist specifically for A-SMR. The proposed thresholds should therefore be interpreted as pragmatic reference values derived from the broader atrial remodeling literature rather than definitive intervention triggers. Their purpose is to assist clinicians in identifying advanced atrial disease stages in which delayed referral may compromise reverse remodeling potential and long-term durability. We believe that this addition strengthens the manuscript by providing practical guidance while maintaining appropriate methodological caution.

F. Visual Aids and Summaries

 

• Critique: While Figure 1 and Table 1 are helpful, the manuscript is text-heavy for a 30-page document.
• Recommendation: Include a Central Illustration summarizing the "A-SMR Journey"—from AF/HFpEF triggers to diagnostic criteria (TTE/CMR), and finally to stratified treatment (Medical → Rhythm Control → TEER/Surgery).

 

Response to Comment F: We thank the Reviewer for this helpful suggestion. To improve clarity and enhance the visual synthesis of the manuscript, we have added a dedicated schematic summary (Figure 1) illustrating the “A-SMR Journey.”

Figure 1 provides an integrated overview of the pathophysiological cascade—from AF/HFpEF-driven atrial remodeling and annular dilatation—to imaging-based diagnostic phenotyping (TTE/CMR), and finally to a mechanism-oriented, stepwise treatment strategy (medical therapy → rhythm control → surgery or TEER according to patient risk profile).

We believe that this addition improves readability and offers a concise visual framework linking pathophysiology, diagnosis, and therapeutic decision-making.

 

 

3. Minor Suggestions and Corrections

 

• Abstract Formatting: References should not be included in the abstract (e.g., [1] on line 21). Please remove them to comply with standard journal guidelines.
• Terminology: Ensure consistent use of "A-SMR" vs. "AF-MR" throughout the text to avoid confusion.
• Language & Abbreviations:  E.g. On line 85, ensure the Italian term is fully translated into English as "Heart Failure with preserved Ejection Fraction (HFpEF)".

 

Response to point 3: We thank the Reviewer for these helpful observations.

• Abstract formatting: All references have been removed from the abstract to comply with the journal’s formatting requirements.
• Terminology: The terminology has been revised throughout the manuscript to ensure consistent use of “A-SMR” (atrial secondary mitral regurgitation). Any inconsistent use of “AF-MR” has been corrected to avoid ambiguity.
• Language and abbreviations: All abbreviations have been carefully reviewed for consistency and clarity. Specifically, the term “Heart Failure with preserved Ejection Fraction (HFpEF)” has been fully standardized at first mention, and any residual non-English expressions have been corrected.

Reviewer 2 Report

Comments and Suggestions for Authors

Mitral regurgitation is extremely common in clinical cardiology practice and has various causes: primary, associated with valve damage, and secondary, associated with dilation of the heart chambers, leading to distension of the fibrous ring of the valve while the mitral valve leaflets remain intact.  The authors describe A-SMR as a special form of functional mitral regurgitation in which mitral regurgitation develops not due to left ventricular damage, but due to enlargement of the left atrium and mitral annulus with preserved left ventricular geometry and contractility. This contradicts the classical ‘ventricular’ concept of functional mitral insufficiency and requires a different approach to classification and treatment (both conservative and surgical), which the authors describe well in this review.

There are a number of clarifying questions that need to be addressed.

1. The methodology used to conduct this narrative review is well described: the databases, search depth, and search query structure are specified. However, it would be helpful to know how many articles of each type were included in this review (how many original studies, clinical cases, etc.).
2. One of the leading causes of A-SMR is atrial fibrillation. Are there any specific approaches to treating A-SMR depending on the aetiology of atrial fibrillation? For example, administering immunosuppressive therapy to a patient with myocarditis will in many cases lead to a reduction in the size of the heart chambers and more successful rhythm control, thereby significantly reducing mitral valve insufficiency. I would be grate to see a little more data on the aetiology.

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 the re-submitted files.

 

Comments and Suggestions for Authors

Mitral regurgitation is extremely common in clinical cardiology practice and has various causes: primary, associated with valve damage, and secondary, associated with dilation of the heart chambers, leading to distension of the fibrous ring of the valve while the mitral valve leaflets remain intact.  The authors describe A-SMR as a special form of functional mitral regurgitation in which mitral regurgitation develops not due to left ventricular damage, but due to enlargement of the left atrium and mitral annulus with preserved left ventricular geometry and contractility. This contradicts the classical ‘ventricular’ concept of functional mitral insufficiency and requires a different approach to classification and treatment (both conservative and surgical), which the authors describe well in this review.

 

There are a number of clarifying questions that need to be addressed.

1. The methodology used to conduct this narrative review is well described: the databases, search depth, and search query structure are specified. However, it would be helpful to know how many articles of each type were included in this review (how many original studies, clinical cases, etc.).
2. One of the leading causes of A-SMR is atrial fibrillation. Are there any specific approaches to treating A-SMR depending on the aetiology of atrial fibrillation? For example, administering immunosuppressive therapy to a patient with myocarditis will in many cases lead to a reduction in the size of the heart chambers and more successful rhythm control, thereby significantly reducing mitral valve insufficiency. I would be grate to see a little more data on the aetiology.

 

Response to Reviewer – Comment 1

We thank the Reviewer for this constructive observation. To improve transparency, we have now specified the distribution of study types included in this narrative review. A sentence has been added to the Methods section detailing the number and categories of included studies (observational cohorts, registry analyses, surgical series, interventional studies, meta-analyses, and contemporary reviews), thereby providing a clearer overview of the evidence base informing this manuscript.

 

Response to Reviewer – Comment 2

We thank the Reviewer for this insightful comment. We agree that the aetiology of atrial fibrillation may influence the degree and potential reversibility of atrial remodeling, and consequently the severity of A-SMR.

In the revised manuscript, we have expanded the discussion to clarify that potentially reversible causes of atrial fibrillation—such as inflammatory cardiomyopathies, myocarditis, endocrine disorders, or tachycardia-induced cardiomyopathy—may respond to targeted therapy, potentially leading to partial reverse remodeling and reduction of mitral regurgitation severity. However, in the majority of patients with established A-SMR, atrial fibrillation is long-standing and associated with structural atrial fibrosis and annular dilatation, in which case etiologic treatment alone is unlikely to restore valve competence.

We have therefore emphasized that while etiologic treatment should always be pursued when appropriate, most cases of A-SMR represent a structural atrial cardiomyopathy requiring mechanism-oriented management strategies.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is improved