Assessing emerging causes of mitral regurgitation: atrial functional mitral regurgitation

Abstract

Functional or secondary mitral regurgitation is linked to increased cardiovascular morbidity and mortality. From a mechanical perspective, secondary mitral regurgitation occurs due to an imbalance between the forces that tether the mitral leaflets and those that close them. This results in incomplete coaptation. Most commonly, functional mitral regurgitation, which occurs in both ischaemic and non-ischaemic disease states, is usually caused by dysfunction and changes in the left ventricle. Atrial functional mitral regurgitation (AFMR) is a disease state that has been more recently recognized. It occurs when mitral annular enlargement is associated with left atrial dilatation, preserving left ventricular geometry and function. AFMR is typically seen in patients with chronic atrial fibrillation or heart failure who have a conserved ejection fraction. Published reports and ongoing investigations vary in how they define AFMR. This publication examines the pathophysiology of AFMR and highlights the importance of having a common working standard for the definition of AFMR to ensure consistency in the data reported and to drive forward the much needed research into the outcomes and treatment strategies in this area. Several studies have reported that restrictive annuloplasty and transcatheter edge-to-edge repair can reduce mitral regurgitation and improve symptoms. This narrative review will explore the pathophysiology, echocardiographic diagnosis and treatment of AFMR.

Introduction

Functional or secondary mitral regurgitation (FMR/SMR) is caused by a failure of the mitral valve due to abnormal left-sided heart function, rather than intrinsic structural valve changes. ¹ From a mechanical point of view, this type of mitral regurgitation (MR) is caused by an unbalanced force distribution between leaflet tethering and leaflet closure, resulting in inadequate functional coaptation.^2,3 SMR typically arises from irregularities in the function of the global/regional left ventricle (LV) and LV remodelling, known as ventriculogenic functional mitral regurgitation (VFMR), which leads to the apical tethering of one or both leaflets. This is evident in disorders affecting the LV, whether ischaemic or non-ischaemic. A less frequent and more current scenario is that LV geometry and function are first maintained. The cause of this is mitral annular enlargement linked to left atrial (LA) dilatation. This decreases the mitral leaflet coaptation, creating atrial functional mitral regurgitation (AFMR). This typically happens when dealing with chronic atrial fibrillation (AF) or heart failure (HF) with preserved ejection fraction (HFpEF) of the LV.

Determining the actual frequency of secondary MR is challenging due to variations among studies in patient selection, methodologies, grading of MR severity and the lack of longitudinal data. This is because studies often merge ischaemic and non-ischaemic causes. To improve accuracy, it is important to use consistent grading criteria and to collect longitudinal data.^4–6 The prognosis and treatment implications are best understood for VFMR. Even mild MR has a negative prognostic value, and as the severity of VFMR rises, patient outcomes worsen.^7–10 Medical therapy for HF, including resynchronization therapy in suitable patients, has been found to reduce MR severity.^11–15 However, the reduction in MR through surgical intervention has not yet shown any enhancement in clinical results. On the contrary, the important trial evidence from two randomized clinical trials evaluating transcatheter edge-to-edge repair has produced conflicting results.^7,8 Various factors have been suggested to account for the divergent outcomes, such as differences in study design, extent of mitral regurgitation and left ventricular size. ⁹ It is now acknowledged that there exist distinct subtypes of VFMR that exhibit varying responses to medical treatment. ¹⁰ In comparison with VFMR, the entity of AFMR remains unclear in terms of its prevalence, pathophysiology, prognostic implications and possible therapies. The recent acknowledgement and evaluation of this entity partially contribute to this.^13,14 Restoring sinus rhythm in patients with AF is associated with reduced LA volumes, mitral annular size and MR severity. It is possible that controlling rhythm instead of rate in AF may prevent or alleviate AFMR, but this has not been formally evaluated. Additionally, there is variability in published reports and ongoing investigations regarding the definition of AFMR. This report examines the pathophysiology of AFMR and emphasises the necessity for a standardized definition of AFMR, which may improve the consistency of reported data and improve the understanding of the management and treatment of AFMR (Figure 1).

Figure 1.

Echocardiograms exhibit normal findings along with atrial functional mitral regurgitation (AFMR) and ventriculogenic functional mitral regurgitation (VFMR), both demonstrating mitral valve concavity loss. This is caused by the significant enlargement of both the left atrium and mitral annulus, which flatten the mitral valve leaflets. AFMR and VFMR diagnostic criteria are explained and compared. EF, ejection fraction; AF, atrial fibrillation; LV, left ventricle; LA, left atrium; MR, mitral regurgitation. The colour version of this figure is available at: http://imr.sagepub.com.

This is a narrative review based on the author’s knowledge. The author conducted a search of the PubMed®, MEDLINE® and Embase® databases using the terms ‘Functional Mitral Regurgitation’, ‘Secondary Mitral Regurgitation’ and ‘Atrial Functional Mitral Regurgitation’, as well as in combination with ‘diagnosis’ and ‘treatment’. This review covers full-text articles, reviews and meta-analyses published within the last 10 years until the end of September 2023. However, the inclusion of some older publications, which are commonly referenced and highly regarded, was necessary as they explore major society guidelines and expert consensus documents. The articles were categorized according to echocardiographic assessment, risk factors, classification, clinical diagnosis, management and treatment. It is important to note that effective treatment requires strategies and long-term follow-up. A peculiarity of this disease is the lack of randomized trials on optimal treatment.

Assessment of mechanism of mitral regurgitation related to AF and ventriculogenic functional mitral regurgitation subjacent valve tethering mechanisms

Functional mitral regurgitation defines dysfunction of the LV as an imbalance of forces that causes the mitral valve to close during systole. This is due to increased tethering forces and decreased closing forces produced by the LV.^16–25 Tethering forces occur when the mitral leaflets are anchored through displacement of the papillary muscles, annular dilation, or both. Thus, even in the presence of fairly standard LV geometry and function, the localized annular dilation typical of AFMR may result in increased mitral valve tethering.^26–30

Mitral regurgitation can occur due to an enlarged annulus, which weakens leaflet alignment. This problem is not exclusive to AF and can arise from any related annular expansion. Diminished annular area movement may also lead to heightened tethering.^7,9,11,12,15 The following points demonstrate increased tethering in AFMR.

Systolic mitral regurgitation may display a biphasic pattern in many cases

In VFMR, mitral regurgitation typically shows two peaks during early and late systole, respectively. These peaks represent the interplay between closing forces and tethering. As a result, when the peak LV systolic pressure forces the leaflets to close, the effective regurgitant orifice area (EROA) of the MR is decreased in mid-systole.^16–21 Further studies are required to confirm whether these proposed mechanisms apply to AFMR.

Variable displacement of the point where the leaflets meet should be minimized for optimal cardiac functioning

When tethering occurs, the leaflet coaptation point is displaced towards the apex and away from the annular hinge points in an apical 4-chamber view. This displacement is less significant than in VFMR but varies depending on the degree of annular dilation and leaflet compensation, resulting in varying levels of regurgitation.^25,30,31 Therefore, compared with the loss of leaflet concavity relative to the LV, the apical shift of the coaptation site is less relevant as a mechanism for AFMR. AFMR causes mild tethering of the leaflets due to the need for the leaflets and chordae to bridge the papillary muscle-annular distance, resulting in leaflet tethering despite the absence of papillary muscle displacement due to LV remodelling. Significant tethering is absent in valve adaptation, which will be discussed later. Increased leaflet area counterbalances annular dilation and restores leaflet position to a normal state.

Decrease or leakage of the standard leaflet concavity towards the LV

Normally, during systolic pressure, the LV causes the leaflets to curve inward toward it (as seen in Figure 2).^25,27,30,32 The presence of opposing forces to LV pressure is indicated by the loss of curvature or the curving inward towards the left atrium. These forces are exerted through the chordae and cause the mitral valve to straighten.

Figure 2.

Illustration of the diagnostic criteria for distinguishing isolated atrial functional mitral regurgitation (AFMR) from ventriculogenic functional mitral regurgitation (VFMR). A cardiac schematic rendering of AFMR and VFMR presenting valvular or subvalvular disorder is presented. The cardiac schematic rendering for AFMR and VFMR shows noteworthy distinctions, which are influenced by the systolic phase (early, mid or end-systole) of dimension assessment, especially if not normalized, and also by sex, with significant differences observed between men and women. Since AFMR is linked to annular leaflet imbalance^14,44 rather than annular dilation itself, a suitable alternative might be a relative measure of annular dilation (systolic DAP/diastolic AML length >1.3). In the published data, systolic annular dimension values from the 4-chamber view were not separately reported. 3D, three-dimensional; AA, annular area; AML, anterior mitral leaflet; DAP, anteroposterior diameter; GLS, global longitudinal strain; LA, left atrium; LAVI, left atrial volume index; LV, left ventricle; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; PLAX, parasternal long axis view.^3,25,43–51 The colour version of this figure is available at: http://imr.sagepub.com. Modified with consent from Yap et al. ²⁴

The pathogenesis of FMR: searching mitral valve leaflet maladaptation

Mechanical displacement of the papillary muscle causes mitral leaflet stretch, which triggers adaptive growth in the surface area of the mitral leaflet.^{17,18,20–23,31} This growth is related to the reactivation of the embryonic growth mechanism (i.e. endothelial-to-mesenchymal transformation). Cellular and fibrotic changes in the valve, following myocardial infarction, counteract adaptive leaflet expansion, resulting in a smaller, stiffer valve that has an impaired ability to coapt.^27,33–40 Annular dilation is also linked to a compensatory rise in leaflet area.^{13,15,25,27,34} However, this growth is not sufficient for larger annular areas, resulting in MR due to leaflet insufficiency.^25,27 It is noteworthy that the adaptation of the valve leaflets fails to correspond with the posterior-predominant dilation of the expanding annulus.^25,27

Maladaptive modifications of the valve in AFMR may also be related to the increased thickness of the leaflets in these patients,^23,25,27,30 which is in keeping with the inflammatory nature of AF and AFMR-related HF;^41,42 as well as the endothelial-to-mesenchymal transformation observed in the atrial wall in AF also induced by contributions from prestrains, hyperelasticity and muscle fibre activation.^27,38,42 These inadequacies in leaflet adaptation are independently connected to significant AFMR development. Whether favourable modification, as seen in post-infarction VFMR, ³⁸ can be achieved is an area for future investigation.

Definition of isolated AFMR

Based on the aforementioned pathogenetic mechanisms, isolated AFMR can be defined and characterized as functional MR with the following primary features, as outlined in Figure 2:^3,25,43–51 (i) the LV cavity and systolic function are within the normal range, both globally and regionally, with no displacement of the papillary muscles, although the LV may dilate in later stages of significant AFMR; (ii) mitral annular dilation and left atrium enlargement are present; (iii) the mitral valve systolic leaflet does not exhibit the characteristic concavity towards the LV. AFMR causes increased leaflet tethering, resulting in the loss of typical systolic leaflet concavity towards the LV.^18,21,25,27 The degree of tethering may cause the leaflet coaptation point to shift apical to the line connecting the annular hinge points in an apical 4-chamber view, but this is not specific and can vary.^18,21,25,27Two features that do not define AFMR are not applicable in this context: (i) increased leaflet thickness; and (ii) MR jet direction (see below).

Increased leaflet thickness

After a heart attack, valve regurgitation can often occur due to thickened leaflets resulting from fibrosis and cellular transformation of the valve.^33–40 The same thickened leaflets have also been observed in patients with AFMR.^18,25,27,52 This aligns with the inflammatory nature of AF and AFMR-associated HF that encourages profibrotic cellular and matrix alterations in the valve.^{20,21,27,28,30} However, greater leaflet thickness is not consistently observed.

MR jet direction

A central jet of MR is characteristic of AF-related MR and common in ventriculogenic functional-related MR. Nevertheless, jets of an eccentric appearance may arise from various mechanisms: (i) changes in the ventricle in VFMR may result in the overshoot of one leaflet, causing an eccentrically directed jet; (ii) alternatively, the valve geometry may be tethered with a shorter posterior leaflet excursion, leading to the jet originating further posteriorly (the Coanda effect). ⁵³ This causes it to adhere to the LA posterior wall, creating an impression of an eccentric jet. However, it is actually a centrally directed jet that is drawn to the adjacent LA wall.^29,54 Several independent studies have reported a link between posterior leaflet tethering angles and AFMR.^55–57 This subtype of AFMR is infrequent but has a tendency to result in worse outcomes. ⁵⁸

Clinical framework and potential coexisting status in AFMR

Atrial functional mitral regurgitation primarily originates from excessive LA and mitral annular dilation that leads to leaflet tethering and malcoaptation.^9,13,26 There are two common clinical scenarios that may result in excessive LA and subsequent mitral annular dilation in the context of preserved LV function: AF and/or HFpEF.^26,27 Both syndromes are linked by LA remodelling and dysfunction. It is well established that AF acts as both cause and consequence of atrial remodelling. ⁵⁹ High pressure levels in the heart may cause harmful changes in the anatomical and functional structure of the LA in individuals with HFpEF. This includes the dilation of the LA, which can lead to reduced compliance and reservoir function. Additionally, the LA booster pump function may become fatigued. Both AF and HFpEF are related due to the shared cardiovascular risk factors and they may exacerbate each other. Significant recent data indicate a prevalent occurrence of hidden HFpEF in patients with AF and breathing difficulties, particularly in those who don’t recover fully after sinus rhythm restoration.^60,61 This led various groups to decipher a subtype that involves AF dominating HFpEF, with more severe LA myopathy that doesn’t correspond to the extent of LV dysfunction.^61–63

The presence of AFMR in HFpEF serves as an additional indicator of advanced LA myopathy subtype, resulting in poor haemodynamics and exercise capacity. ⁶⁴ A community study of moderate-to-severe isolated MR revealed that only half of patients with AFMR had previous AF history.^65,66 Regardless of the degree of severity, AFMR was associated with worse outcomes, although this association ceased after correction for LA myopathy. While this finding suggests that the degree of LA myopathy is more crucial than AFMR itself, it still supports the idea that managing AFMR in HFpEF may enhance LA myopathy and outcomes. Moreover, recent cross-sectional data were unable to determine the causal sequence among AFMR, LA myopathy and HFpEF. ⁶⁴ Presumably, there is a bidirectional relationship between AFMR and LA myopathy. ⁶⁴ Further prospective research is required to address these questions.

Epidemiology and evolution of AFMR

The incidence and clinical importance of AFMR is increasingly apparent. As much as one-third of the instances of isolated and moderate-to-severe MR in Olmsted County have been ascribed to AFMR.^65,66 The patients were mostly elderly women with a high prevalence of cardiovascular risk factors and AF.^65,66 Despite its seemingly harmless appearance with a small EROA (mean ± SD EROA: 0.20 ± 0.08 cm²), LV diastolic function, systolic pulmonary artery pressures and HF event rates were substantially worse when compared with cases of high-volume degenerative MR.^65,66 Another recent retrospective study that focused exclusively on severe MR confirmed unfavourable outcomes relative to degenerative MR. ⁵⁸ Moreover, AFMR was linked to a higher 5-year mortality rate (up to 50%) than that of age and sex-controlled groups.^65,66 However, the actual prevalence of possible underlying HFpEF was not determined via these epidemiological studies but regarded to be significant. Specifically, in HFpEF, the European Society of Cardiology Heart Failure registry estimated a 20% prevalence of moderate-to-severe functional MR. ⁶⁷ The Acute Decompensated Heart Failure Syndromes (ATTEND) registry revealed a high prevalence of mild or severe FMR at discharge in 1800 individuals with acutely decompensated HF with preserved ejection fraction. ⁶⁸ Even mild MR was linked to adverse outcomes, regardless of cardiovascular risk factors, drug therapy and AF (adjusted hazard ratio: 1.40 for all-cause mortality and HF rehospitalization). At present, there are no data on the interaction between moderate or severe AFMR, LA myopathy and outcomes. The abundance of comorbidities in subjects with AFMR may contribute to an unfavourable overall prognosis. Nevertheless, recent epidemiological studies demonstrate the potentially detrimental effects of even mild or worse AFMR. This suggests that small levels of regurgitant volume may have a significant prognostic impact on a non-dilated, non-compliant LV with restrictive physiology (as seen in the disproportionality concept of VFMR).^5,9,51 Additionally, there are a scarcity of data on the dynamic nature of AFMR. Moreover, it remains uncertain whether impaired haemodynamics and outcomes are attributable to AFMR itself or the underlying LA myopathy in HFpEF. As both conditions are often concomitant, a randomized controlled prospective trial is essential to determine whether reducing moderate or worse AFMR can help improve outcomes. HFpEF is effective, particularly since AFMR can be more easily treated when substantial leaflet tethering is not present.

Proposed approach for assessing the severity and quantification of MR

The American Society of Echocardiography guidelines recommend an integrated approach to assess the severity of AFMR. ⁶⁹ This should entail the use of colour Doppler parameters and precise quantitative measurements of EROA and regurgitant volume, as well as qualitative supportive signs such as density, profile and duration of the MR jet on continuous wave Doppler, pulmonary vein flow pattern and mitral inflow E-wave velocity. It is essential to consider the timing of the echocardiographic assessment. When patients experience the sudden onset of AF and a rapid ventricular response, cardioversion can significantly improve moderate or severe MR. ²⁸ Restoration of sinus rhythm with ablation can significantly improve MR severity in AFMR. However, assessing MR severity is complicated by AF, especially in fast or highly irregular rhythms. It is advisable to measure MR severity, LV and LA volumes, and strain in sinus rhythm or in AF with a well-controlled ventricular rate and minimal variation in R-R intervals. ¹³ It is recommended to use the indexed beat method by selecting a beat for which the MR jet area and LV and LA volumes are measured. The R-R intervals before and after are comparable.^70,71 However, the timing of measurements, the number of beats measured, heart rate and R-R variability in AF remain unreported in most AFMR studies. Such lack of detail makes it difficult to interpret published reports and compare different studies.

Even under optimal conditions, AF complicates the majority of conventional methods for assessing MR. The volumetric approach becomes unusable when measurement error is compounded by the 16%–28% beat-to-beat variation in stroke volume reported in AF.^72,73 The difficult proximal convergence method is challenged by the variation of the regurgitated orifice area, both intra- and inter-beat. This is worsened by the common elliptical orifice shape in AFMR, which results in underestimation of MR when applying the standard proximal convergence formula. In the future, advances in three-dimensional (3D) colour Doppler may refine this approach. Even some of the indirect indicators of regurgitant severity may be less reliable; for instance, pulmonary venous Doppler may display reduced systolic flow merely due to AF or high LA pressure even when there is no presence of MR.

When quantifying AFMR severity, it is important to consider the normal size and function of the LV. You can find several published studies about AFMR that show that the LV end-diastolic volume falls within the normal range. This means that in cases of significant MR, the regurgitant volume is often lower than the typical 60 ml seen in primary MR and a remodelled enlarged LV. At a typical end-diastolic volume of 100 ml in the LV and a 60% left ventricular ejection fraction (LVEF), the total LV stroke volume would be 60 ml. It is not possible to have a regurgitant volume of 60 ml, which is typically seen as severe MR. In a patient with an EROA of 0.2 cm² and a regurgitant volume of 30 ml, the regurgitant fraction would be 50%. Therefore, it may be crucial to consider lower quantifiable measures of regurgitant volume when assessing the severity of AFMR in normal LV size and function. Large LA volumes are linked to AFMR, and if the LA is compliant, it may tolerate the regurgitant volume. However, after extensive ablation, the LA may become stiff, which could result in elevated LA pressures even with lower regurgitant volumes. ⁷⁴ To demonstrate the prognostic significance of EROA and regurgitant volume in AFMR, large cohort studies will be required. However, such studies will require careful attention to quantitative methodology and timing, as noted previously in this paper.

The lack of long-term studies could affect our comprehension of the disease process and its progression. For instance, enduring significant AFMR could result in LV dilation in addition to mitral annulus and LA enlargement. This is most precisely assessed when the sequence of events is explicitly identified by successive studies. Ensuing longer-term studies are required for this. Further long-term studies are necessary to clarify the natural progression of AFMR and its incidence of progression to VFMR.

Evaluation of AFMR with magnetic resonance and cardiac computed tomography

Two-dimensional (2D) and 3D echocardiographic techniques should be optimized to evaluate LV size, function, mitral apparatus, annular size and LA size for the assessment of the underlying mechanism of MR. Although echocardiography is the primary evaluation method for mitral valve morphology and haemodynamics due to its informative and easily accessible nature, cardiac magnetic resonance (CMR) and computed tomography (CT) can also aid in the assessment of AFMR in cases where echocardiography is inadequate or additional information is required. If echocardiography is suboptimal, CMR and CT can provide a 2D or 3D evaluation of mitral leaflet morphology, mitral annular size and its geometric alterations throughout the cardiac cycle. Also, they can examine tethered leaflet motion and orifice opening. Both CMR and CT are not restricted by inadequate imaging windows or the subject’s body shape. Besides, they can precisely measure the LV and LA size and function dynamically. However, CMR and CT necessitate cardiac gating and could potentially experience a decline in image quality and difficulty in quantifying LVEF when patients with AF have an irregular cardiac rhythm.

Cardiac magnetic resonance provides cine imaging of the morphology of the mitral apparatus and accurately assesses relevant haemodynamics by measuring the severity of MR. With the high temporal resolution of cine imaging (typically at 40–45 ms), CMR may outperform CT in capturing annular distortion or abnormal patterns of leaflet motion. CMR phase-contrast imaging offers precise measurement of aortic systolic blood flow, allowing for the derivation of mitral regurgitant volume and regurgitant fraction by subtracting LV stroke volume using cine imaging. The use of CMR for quantifying mitral regurgitant volume and fraction has demonstrated greater reproducibility compared with echocardiography. ⁷⁵ Additionally, CMR provides a thorough evaluation of LV remodelling by measuring chamber size, LV function and tissue fibrosis.^76,77 In patients with normal sinus rhythm, CT angiography accurately assesses annular geometry, as well as ventricular and atrial volumes. However, due to the absence of haemodynamic information, CT angiography is not useful in determining the severity of MR. In patients with FMR undergoing percutaneous mitral intervention, CT angiography anatomical data has demonstrated the ability to forecast procedural success.^78,79

For patients who exhibit several risk factors for HFpEF or have received chest radiation in the past and display indications of impaired diastolic LV filling, characterizing the pattern of myocardial scarring, fibrosis or infiltration using CMR imaging techniques such as late gadolinium enhancement imaging and T1 mapping may offer valuable insights regarding the severity and origin of the underlying cardiomyopathy, which could potentially contribute to AFMR. CT enables identifying and characterizing calcification of the mitral apparatus, which includes mitral annular calcification or caseating mitral calcification leading to MR.

Treatment of AFMR

Medical treatment and rhythm control

The heart valve disease management guidelines established by the Japanese Circulation Society in 2020 propose a Class I recommendation for standard HF therapy for symptomatic patients affected by AFMR. ⁸⁰ The treatment should include diuretics, which could potentially decrease the size of the LA. To reduce AFMR, rhythm control has been suggested by promoting atrial/annular reverse remodelling ¹³ and by re-establishing the atriogenic and ventriculogenic contributions to annular contraction. Some minor studies substantiate this approach. A study demonstrated that 15 patients with persistent AF had a decrease in the mean EROA from 0.27 to 0.15 cm² after undergoing electrical cardioversion. ⁸¹ Evidence of secondary ischaemic mitral regurgitation complicated by AF treated with cardioversion supports these data.^7,9,34,52,82 Another study found that 47 patients with paroxysmal or persistent AF following catheter ablation and/or electrical cardioversion had a mean decrease in vena contracta width from 0.40 to 0.21 cm. ¹⁴ Research found that over three-quarters of patients with moderate AFMR saw improvement of at least one MR grade after catheter ablation. ⁸³ More research is necessary to understand the effects of rhythm control in patients with AFMR. Data on the impact of rhythm control strategies on clinical outcomes in patients with AFMR are currently limited. A clinical study has shown that catheter ablation leads to a significant reduction in hospitalization due to HF and stroke when compared with patients receiving treatment with beta-blockers, calcium-channel blockers, digoxin and/or antiarrhythmic drugs over a 3-year period. ⁸⁴

Besides reducing MR, rhythm control also increases LVEF and reduces circulating brain natriuretic peptide levels.^83,85 Furthermore, rhythm control improves LV function in patients with HFpEF and AF.

Impaired diastolic function is indicated by a decrease in the ratio of transmitral E-wave velocity (E) to mitral annular e0 velocity (E/e0) and strain rate during isovolumic relaxation (E/SRIVR). ⁸⁶ The 2020 Japanese Circulation Society guidelines for heart valve disease management suggest that catheter ablation should be considered a reasonable option (Class IIa recommendation) for symptomatic patients with persistent AF and severe MR, provided that maintaining sinus rhythm is likely. ⁸⁰

Surgery

Based on the 2020 Japanese Circulation Society guidelines for heart valve disease management, it is a Class IIa recommendation that surgical intervention is a reasonable option for symptomatic patients with severe MR who have not responded to standard HF therapy. ⁸⁰ In contrast, the 2020 heart valve disease guidelines from the American College of Cardiology/American Heart Association suggest a Class IIb recommendation for surgery in symptomatic patients with severe MR who do not respond to therapy for HF, AF or other comorbidities. ⁸⁷ Both recommendations are based on consensus (Level of Evidence: C) and further research is necessary to reconcile the discrepancies between them. The 2021 European Society of Cardiology guidelines for managing valvular heart disease do not provide any formal recommendations for treating AFMR. However, they note that surgery and catheter ablation have been effective treatment methods, although there is limited evidence to support this. ⁸⁸ Mitral valve surgery typically entails restricted ring annuloplasty. ⁸⁹ A large annular area may impede coaptation unless the ring is significantly undersized. This, however, raises the likelihood of dehiscence and mitral stenosis. In such scenarios, mitral valve replacement may be a viable alternative. Patch augmentation of the posterior mitral leaflet using autologous pericardium has also been suggested. ⁹⁰ However, the durability of this repair may be limited due to leaflet shrinkage and stiffening. Pseudoprolapse of the anterior mitral leaflet can usually be corrected with restrictive annuloplasty. ⁹¹

The role of restoring sinus rhythm during surgery for mitral valve repair in patients with AFMR has not been clearly defined. One retrospective study found that patients who underwent concurrent Cox maze IV procedures experienced 94% freedom from recurrent MR after 3 years compared with only 44% among those who did not. ⁹² While the data presented may appear convincing, an analysis of 11 AFMR surgical series concluded that Cox maze or CryoMAZE procedures are only carried out on half of patients who undergo mitral valve repair. ⁸⁹ When considering surgical options for AF, it is crucial to take into account both its duration and the size of the LA. ⁹³ In relation to the latter, restoring sinus rhythm becomes improbable when the LA diameter exceeds 6.0 cm. ⁹⁴ Tricuspid regurgitation (TR) caused by enlargement of the tricuspid annulus often occurs with coexistent MR and AF. ⁹⁵ According to the Japanese guidelines for AF and MR published in 2020, surgical repair of the tricuspid valve should be considered for patients with combined AF and MR with TR, although the specific criteria for tricuspid valve intervention with regards to annular size, severity of TR and right ventricular function remain unclear (Class IIa recommendation). ⁸⁰

It is currently uncertain whether addressing AF during tricuspid valve repair surgery can further reduce TR burden, as there has been no systematic examination of this topic. However, one study of patients who underwent mitral valve surgery for MR and/or mitral stenosis along with tricuspid valve repair for mild-to-moderate TR found that failure to address AF during surgery was linked to a greater risk of a composite endpoint that included tricuspid valve reoperation, heart failure and death.^95–97 Some small series have shown a reduction in MR severity and symptoms after receiving mitral valve surgery.^96–101

A previous study presented findings on the surgical outcomes of 97 patients experiencing moderate-to-severe MR. ⁸¹ Of these patients, around half underwent adjunctive tricuspid annuloplasty, with 30% receiving Cox maze IV procedures. The 5-year all-cause mortality rate stood at 15%, while the HF hospitalization rate was 13%. 16% of patients displayed moderate or severe MR recurrence after a period of 5 years. The most extensive surgical series of AFMR patients that has been reported to date involved 123 patients and all of these underwent mitral annuloplasty. ¹⁰² Additional procedures comprised tricuspid annuloplasty (50%) and the maze procedure with LA appendage removal (60%). In this cohort, the 5-year survival rate was approximately 75% and late follow-up revealed recurrent moderate-to-severe mitral regurgitation (defined as >2+) in 5% of cases. Almost three-quarters of patients maintained sinus rhythm after a median follow-up period of close to 3 years.

Percutaneous coronary intervention

Procedures available for minimally invasive mitral valve intervention in patients with AFMR consist of edge-to-edge repair (MitraClip, Abbott Vascular; PASCAL Mitral Valve Repair System, Edwards Lifesciences), direct annuloplasty (Cardioband Mitral System, Edwards Lifesciences; Millipede IRIS Ring, Boston Scientific) and indirect annuloplasty (Carillon Mitral Contour System, Cardiac Dimensions). Transcatheter heart valves designed for use in the mitral position have not undergone studies in patients with AFMR. Several retrospective studies have investigated the effectiveness of using transcatheter edge-to-edge repair in patients with AFMR.^103–106 The Spanish MitraClip registry conducted a multicentre study revealing that MR was acutely reduced from 3 to 4+ down to ≤2+ in 94% of patients. ¹⁰⁵ Prior to the procedure, 90% of patients were classified as New York Heart Association (NYHA) functional class III to IV; after 12 months, only 20% remained in class III, while none were in class IV. However, 20% of patients experienced recurrent MR of >2+ within the first 12 months. By contrast, the Italian MITRA-TUNE registry showed a midterm MR recurrence rate of 11%. ¹⁰⁵ Furthermore, during a median follow-up period of 1 year, the MITRA-TUNE registry, a multi-centred Italian registry for transcatheter treatment of AFMR, substantiated a consistent reduction in anteroposterior and intercommissural annular dimensions. ¹⁰⁵ It is noteworthy that a decrease in the anteroposterior dimension following transcatheter edge-to-edge repair is linked to fibrosis provoked by the MitraClip. This brings about the creation of a tissue bridge between the anterior and posterior segments of the annulus. However, the lasting impact of this structural modification on the severity of MR is yet to be determined.

The most extensive group of symptomatic AFMR patients documented to date holds 126 cases from the European Registry of Transcatheter Repair for Secondary Mitral Regurgitation. ¹⁰⁷ The registry data provides real-world insights. 87% of registrants achieved procedural success, which is defined as MR of ≤2+. The 2-year survival rate was 70%. Prior to repair, approximately 90% of patients were classified under the NYHA functional class III/IV, compared with approximately 40% post-repair. In addition, in patients with pre-procedure NYHA functional class IV, right ventricular dysfunction, which was defined as reduced right ventricular-pulmonary artery coupling ([tricuspid annular plane systolic excursion] divided by [pulmonary artery systolic pressure] <0.34 mm/mmHg), was a significant independent predictor of 2-year survival. ¹⁰⁷

A recent sub-study of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial compared echocardiographic features of patients with and without AF. ⁵⁴ Notably, patients with AF exhibited less reduction in LVEF and fewer LV enlargements, but more LA and mitral annular enlargements. The COAPT investigators determined that these changes demonstrate a unique functional MR phenotype, displaying characteristics of both AFMR and VFMR. Atrial and annular enlargement are largely attributed to the effects of AF, whilst LV abnormalities primarily result from severe MR-related volume overload. Albeit not extensively studied, adverse outcomes such as recurrent MR following transcatheter edge-to-edge repair may be predicted by a wide posterior leaflet angle, shortened residual posterior mitral leaflet, significant annular enlargement, pseudoprolapse and jet eccentricity. According to the Italian MITRA-TUNE registry, worse outcomes (including all-cause mortality and HF hospitalization) were observed when the pre-procedural inter-commissural annular diameter exceeded 34 mm. ¹⁰⁵

Further research is required, but it appears sensible to conduct regular echocardiographic monitoring for recurrent MR after transcatheter edge-to-edge repair, particularly in patients with high-risk mitral valve geometry and/or jet eccentricity. Although transcatheter edge-to-edge repair can alleviate MR and enhance symptoms, it tackles an annular issue through a valvular approach. It remains unclear whether restoring sinus rhythm to address annular enlargement further reduces MR. Randomized trials are necessary to determine the efficacy of this combined approach. Transcatheter annuloplasty devices may offer an alternative for patients with AFMR who are at increased surgical risk or who have anatomy that is not conducive to transcatheter edge-to-edge repair.^{106,108–110}

Transcatheter annuloplasty devices could serve as an alternative for patients with AFMR, who face elevated surgical risks or unfavourable anatomy for transcatheter edge-to-edge repair.^{106,108–110} In a study conducted on 15 patients with moderate-to-severe AFMR, the deployment of the Carillon device resulted in a notable decrease in the annular anteroposterior diameter (4.3 versus 3.8 cm; P < 0.05) and EROA (0.28 versus 0.20 cm²; P < 0.05) within 3 months. ¹¹¹ Another study that included a small sample size compared the efficacy of the Carillon device to the MitraClip in managing HFpEF patients with AFMR and found no significant difference in functional status after 12 months. ¹⁰⁶

Future direction

Further investigations should determine cut-off values for LA and LV size and function to differentiate between AFMR and mixed AFMR/VFMR. Possible research areas could include clinical trials that compare the efficacy, longevity and safety of surgical and transcatheter mitral interventions in patients with AFMR and AFTR. Additionally, it is crucial to establish if combining these approaches with the restoration of sinus rhythm can lead to enhanced results. Specialized transcatheter heart valves demonstrate potential for use in the mitral position and further studies should investigate their effectiveness in treating patients with AFMR. Additional research into the molecular basis of the endothelial-to-mesenchymal transition may lead to the development of new treatments for people who do not have adequate growth of their valve leaflets. Lastly, a randomized trial comparing medical therapy to early surgery for AFMR patients would be very useful (Figure 3).

Figure 3.

Clinical evaluation and diagnostic flowchart for atrial fibrillation mitral regurgitation (AFMR). For a detailed explanation and references see text. AHA/ACC, American Heart association/American College of Cardiology; AF, atrial fibrillation; ESC, European Society of Cardiologists; ETT, echocardiography transthoracic; FU, follow-up; GDMT, goal directed medial therapy; HFpEF, heart failure with preserved ejection fraction; LA, left atrium; LV, left ventricle; MR, mitral regurgitation; PML, posterior mitral leaflet; TEE, transoesophageal echocardiography. The colour version of this figure is available at: http://imr.sagepub.com.