Influence of Rhythm Control on Functional Mitral and Tricuspid Regurgitation Severity and Clinical Outcome in Patients With Atrial Fibrillation: A Propensity-Matched Cohort Study

Author's summary

In this study, we investigated the impact of atrial fibrillation rhythm control therapy on functional mitral regurgitation (MR) and tricuspid regurgitation (TR), cardiac remodeling, and clinical outcomes. Rhythm control therapy—including antiarrhythmic drugs, catheter ablation, and electrical cardioversion—was associated with significant improvement in functional MR and attenuation of TR progression. Patients undergoing rhythm control were more likely to achieve sinus rhythm, which was associated with a greater degree of improvement in functional regurgitation. Improvement in functional regurgitation and restoration of sinus rhythm associated with rhythm control therapy were also linked to favorable clinical outcomes.

Abstract

Background and Objectives

This study evaluated the efficacy of atrial fibrillation (AF) rhythm control therapy in improving functional mitral regurgitation (MR) and tricuspid regurgitation (TR) and its association with clinical outcomes.

Methods

Among 2,574 patients with AF screened from 2003 to 2023, 817 pairs of patients were selected through propensity matching to compare rhythm control therapy (antiarrhythmic drugs, catheter ablation, or electrical cardioversion) with no rhythm control. MR and TR severity were assessed at baseline and follow-up echocardiography conducted at least 3-month intervals. Clinical outcomes included all-cause mortality and heart failure-related hospitalizations.

Results

Rhythm control was associated with a reduction in moderate or greater MR (7.3% to 4.9%, p=0.008) and attenuation of TR progression (9.1% to 9.3%, p=0.796), contrary to the worsening trends in the no rhythm control group. Sinus restoration was more frequent in the rhythm control group compared to the no rhythm control group (60.2% vs. 48.1%, p<0.001). Patients maintaining sinus rhythm after rhythm control showed the greatest MR improvement (7.3% to 3.5%, p=0.002). Rhythm control was also associated with reverse cardiac remodeling, including reductions in left atrial volume index and improved left ventricular ejection fraction (both p<0.001). Clinical outcomes were more favorable in the rhythm control group, particularly among patients with improved regurgitation or restored sinus rhythm.

Conclusions

AF rhythm control therapy is associated with improved functional MR, attenuated TR progression, enhanced sinus rhythm maintenance, and favorable clinical outcomes. Echocardiography can provide valuable information for identifying the optimal timing of rhythm control intervention and assessing treatment response.

Graphical Abstract

INTRODUCTION

The demographic shift toward an aging population has led to a notable rise in the incidence of atrial fibrillation (AF).¹⁾ AF induces adverse cardiac remodelling, which manifests as chamber dilation, fibrosis, and functional impairment.²⁾,³⁾ This pathophysiological process in AF results in distinct phenotypes of mitral regurgitation (MR) and tricuspid regurgitation (TR), secondary to the remodelling effects of AF.⁴⁾ The progression of functional MR and TR correlates with a poor prognosis in patients with AF.⁵⁾,⁶⁾

The traditional therapeutic approaches for functional MR and TR primarily focus on reducing the degree of regurgitation through volume reduction and enhancement of left ventricular (LV) systolic function.⁷⁾ However, given that many cases involve atrial remodelling with a relatively preserved LV ejection fraction (LVEF), these interventions may have insufficient effects on improving functional regurgitation in AF.⁴⁾,⁵⁾,⁶⁾ Rhythm control therapies in AF have been proposed to alleviate patient symptoms by decreasing the overall AF burden, regulating paroxysmal tachyarrhythmia episodes, and ultimately restoring sinus rhythm.⁸⁾ Previous studies have indicated that AF rhythm control may provide additional benefits by reversing cardiac remodelling and improving functional regurgitation,⁹⁾,¹⁰⁾,¹¹⁾ which need further elucidation in real-world practice in diverse clinical presentation.

The current study comprehensively assessed the efficacy of AF rhythm control therapy in reducing functional MR and TR, and its effects on cardiac remodelling and long-term clinical outcomes. The efficacy of AF rhythm control therapy was specified by its treatment effect on successful sinus restoration. Furthermore, the impact of AF rhythm control therapy was analysed across various clinical presentations, considering echocardiographic features such as regurgitation severity and associated comorbidities.

METHODS

Ethical statement

The Institutional Review Board (IRB) of Seoul National University Bundang Hospital approved the study protocol (IRB No. B-2311-865-102). The requirement for informed consent was waived due to the retrospective and observational nature of the study. All clinical and echocardiographic data were anonymized before analysis. This study complied with the Declaration of Helsinki (2013).

Study population

We screened consecutive patients diagnosed with AF and performed transthoracic echocardiography between 2003 and 2023 at Seoul National University Bundang Hospital. The exclusion criteria were as follows: (1) rheumatic, degenerative (including prolapse), ischemic, or endocarditis-related MR and TR; (2) known history of percutaneous or surgical valvuloplasty or valve replacement in the mitral or tricuspid valves; (3) significant mitral stenosis; (4) presence of a cardiac implantable electronic device; (5) no available follow-up echo; (6) inadequate echocardiographic images to assess MR and TR severity; and (7) prior procedure of catheter ablation or cardioversion for AF (Supplementary Figure 1).

Management of atrial fibrillation

AF management was conducted at the discretion of the attending physicians following standardized approaches.⁸⁾,¹²⁾ Patients received medical therapies for heart rate management and anticoagulation based on the estimated thromboembolic risk. The AF chronicity was indirectly assessed by left atrial (LA) enlargement and the type of AF (paroxysmal vs. persistent). Persistent AF was defined as AF episodes lasting ≥7 days and not self-terminating, in accordance with the global guideline criteria.¹²⁾ In the rhythm control group, class Ic or III antiarrhythmic agents were chosen for medical rhythm control. Referral for advanced rhythm control therapy was determined based on clinical discretion, persistent symptoms, and refractoriness to antiarrhythmic medication. The patients referred for advanced rhythm control therapy underwent AF catheter ablations or elective direct current (DC) cardioversion. AF catheter ablation procedures include cryoballoon ablation and radiofrequency catheter ablation under 3-dimensional electro-anatomical mapping systems. Achievements of electrical isolation of all pulmonary veins were the primary target of the procedures. Additional substrate modifications, including cavotricuspid isthmus ablation and other trigger or linear ablations, were conducted at the operators’ discretion. Among patients who underwent advanced rhythm control therapy, no repeat catheter ablation or DC cardioversion was performed between the baseline and follow-up echocardiographic assessments. No rhythm control group was defined as patients who did not receive any form of rhythm control therapy during the follow-up periods.

Echocardiographic evaluations for functional regurgitation and cardiac remodeling

Baseline echocardiography was defined as the closest examination conducted after the initial AF diagnosis. For patients referred for advanced rhythm control therapy, baseline echocardiography was designated as examination performed prior to the procedures. Follow-up echocardiographic data were obtained at least 3 months after the baseline examinations. The 3-month interval was selected to account for the blanking period associated with the treatment effect of advanced rhythm control therapy and was extrapolated to patients receiving medical rhythm control therapy and those in the no rhythm control group.

All echocardiographic studies were conducted by trained echocardiographers or cardiologists and interpreted by board-certified cardiologists specialized in echocardiography, according to the recent guidelines⁷⁾ as part of routine clinical practice. The severities of functional MR and TR at baseline and follow-up periods were acquired from the final clinical reports, determined based on the MR and TR Doppler images supplemented with quantitatively measured hemodynamic parameters when available, including peak velocity, effective orifice area, and regurgitation volume. The severity of functional regurgitation was graded as trivial, mild, moderate, or severe. Although a recent report recommended subcategorizing severe TR into severe, massive, and torrential grades, we did not apply this method due to the inclusion of patients diagnosed in the early 2000s. LA volume and LVEF were measured as echocardiographic indices for cardiac remodeling and function. LA volume was calculated using the biplane method at the LV end-systolic phase using apical 4- and 2-chamber views and expressed as indexed values (left atrial volume index [LAVI]) for body surface areas. LVEF was derived based on the modified Simpson’s method using the apical 4- and 2-chamber views.

Ascertainment of clinical information and outcome definition

The baseline clinical data, including demographics, clinical risk factors, medications, and outcome events, were obtained through a dedicated review of the electronic health records at the study institution.¹³⁾ The clinical outcome was defined as a composite endpoint of all-cause death and hospitalization for heart failure (HF), collected from the time of follow-up echocardiography. Death events were identified through linkage with national death registries. HF hospitalization was determined based on documented symptoms, signs of congestion, and objective findings from diagnostic tests, as well as the final diagnosis made by a cardiologist as documented in medical records.

Statistical analysis

Clinical data are presented as median with interquartile range (IQR) for continuous variables and as frequency with percentage for categorical variables. Baseline clinical and echocardiographic characteristics were compared between the rhythm control and no rhythm control groups using the Mann-Whitney U test for continuous variables and the χ² test for categorical variables, as appropriate.

To account for baseline differences between the groups, we performed a propensity score matching (PSM) analysis. Propensity scores were estimated using a logistic regression model that included variables showing significant differences between groups in the original cohort (p<0.05). These covariates comprised demographic factors (age, sex, body mass index), clinical risk factors (hypertension, HF, AF type, CHA₂DS₂-VASc score), concomitant medications (beta-blockers, diuretics), and echocardiographic parameters (LVEF, LA diameter, LAVI, MR severity, TR severity). Patients were matched in a 1:1 ratio using the greedy nearest-neighbor method. The balance of baseline characteristics after matching was assessed using the absolute standardized difference, with values less than 0.1 indicating adequate balance between groups.

Trajectories in severity of functional MR and TR were visualized using the Sankey diagram according to the AF rhythm control therapy. Due to variability in the intervals between baseline and follow-up echocardiographic examinations among patients, a linear mixed-effects model was employed to analyze longitudinal changes in MR and TR severity.¹⁴⁾ In this model, MR and TR severity were modeled as a function of the echocardiographic time point as a fixed effect, while patient-specific intercepts were included as random effects to account for within-subject correlations associated with repeated measurements. Detailed statistical methods for the model configuration were provided in the Supplementary Data 1. We further evaluated the interval change in moderate or greater MR and TR to reveal the association of AF rhythm control therapy with a reduction in significant regurgitation. These results were stratified by the achievement of sinus rhythm at follow-up echocardiography to evaluate the treatment effect associated with successful rhythm restoration. Subgroup analysis was conducted among patients with LA enlargement (LAVI ≥40 mL/m²) and those with persistent AF to analyze whether the AF rhythm control therapy demonstrates a beneficial effect in these progressed stages by reducing functional regurgitation and promoting cardiac reverse remodeling, as assessed by echocardiographic parameters including LAVI and LVEF. The association between AF rhythm control therapy and subsequent changes in functional regurgitation was further stratified based on treatment modality as advanced rhythm control therapy and medication-only approach with antiarrhythmic agents.

A mediation analysis was performed to investigate whether improvements in MR and TR severity, along with sinus rhythm restoration, mediated the association between AF rhythm control therapy and clinical outcomes.¹⁵⁾ This exploratory analysis was conducted at a hypothesis-generating level, prior to the outcome risk assessment. The model was specified to estimate both the direct effect of rhythm control therapy on clinical outcomes and the indirect effects mediated through MR/TR improvement and sinus rhythm restoration. Model fit was evaluated using the standardized root mean square residual, which indicated an acceptable fit with a value of 0.07 (<0.08).¹⁶⁾ Detailed statistical methods for mediation analysis are provided in Supplementary Data 2. Improved regurgitation status was defined as cases where moderate or greater regurgitation improved to mild or less, or where regurgitation remained stable at mild or less without worsening.

Event curves for clinical outcomes were plotted based on rhythm control therapy, further stratified by regurgitation improvement status and sinus restoration. Cox regression analysis was conducted to assess the association between rhythm control therapy and clinical outcomes, stratified by improvement in functional regurgitation and restoration of sinus rhythm. A sensitivity analysis was performed for clinical outcomes collected within 1 year after follow-up echocardiography to evaluate the early outcome benefit of rhythm control therapy. Subgroup analyses were further performed to assess the impact of rhythm control therapy on clinical outcomes across diverse clinical presentations, considering baseline severity of functional regurgitation, AF chronicity, cardiac remodeling characteristics, and associated comorbidities.

All statistical analyses were performed using R software, V.4.3.2 (R Development Core Team, Vienna, Austria). Two-sided p values <0.05 were considered statistically significant.

RESULTS

Baseline characteristics

Overall, 2,574 patients were included in the study population, with 958 of them undergoing rhythm control therapy (Supplementary Figure 1). After 1:1 PSM, a total of 817 pairs of patients were included in the analysis, with baseline characteristics well-balanced between groups (Table 1, Supplementary Figure 2). Advanced rhythm control was employed in 56.3% of the rhythm control group, with 10% undergoing DC cardioversion only.

Table 1. Baseline characteristics in matched population.

		No rhythm control (n=817)	Rhythm control (n=817)	pdifference
Clinical features
	Age (years)	66 (58–74)	65 (57–72)	0.497
	Male	532 (65.1)	558 (68.3)	0.189
	Body mass index (kg/m2)	24.7 (22.7–26.8)	25.0 (23.0–27.1)	0.178
	Hypertension	304 (37.2)	315 (38.6)	0.610
	Diabetes	134 (16.4)	143 (17.5)	0.598
	History of heart failure	79 (9.7)	81 (9.9)	0.934
	History of stroke	37 (4.5)	52 (6.4)	0.127
	History of myocardial infarction	41 (5.0)	39 (4.8)	0.909
	CHA2DS2-VASc score	3 (2–4)	3 (2–4)	0.352
Classification of AF
	Paroxysmal AF	393 (48.1)	419 (51.3)	0.216
	Persistent AF	424 (51.9)	398 (48.7)
AF management
	Beta-blockades	435 (53.2)	458 (56.1)	0.274
	RAS blockades	381 (46.6)	373 (45.7)	0.728
	Diuretics	125 (15.3)	114 (14.0)	0.484
Antiarrhythmic drug
	Class Ic	-	378 (46.3)
	Class III	-	415 (50.8)
Radiofrequency ablation		-	164 (20.0)
Cryo-balloon ablation		-	215 (26.3)
DC cardioversion only		-	82 (10.0)
Echocardiography
	LVEDD (mm)	48 (44–53)	48 (45–52)	0.528
	LVEDV (mL)	77 (61–99)	79 (65–98)	0.273
	LVEF (%)	59 (50–64)	58 (51–63)	0.565
	LAVI (mL/m2)	47 (36–63)	47 (37–61)	0.764
	LA diameter (mm)	43 (38–49)	43 (39–48)	0.647
	TR Vmax	2.4 (2.2–2.6)	2.4 (2.1–2.6)	0.111
MR severity				0.627
	None or trivial	584 (71.5)	622 (76.1)
	Mild	176 (21.5)	135 (16.5)
	Moderate	43 (5.3)	45 (5.5)
	Severe	14 (1.7)	15 (1.8)
TR severity				0.670
	None or trivial	564 (69.0)	546 (66.8)
	Mild	176 (21.5)	197 (24.1)
	Moderate	58 (7.1)	55 (6.7)
	Severe	19 (2.3)	19 (2.3)

Values are presented as number (range) or number (%).

AF = atrial fibrillation; DC = direct current; LA = left atrium; LAVI = left atrial volume index; LVEDD = left ventricle end-diastolic dimension; LVEDV = left ventricle end-diastolic volume; LVEF = left ventricular ejection fraction; MR = mitral regurgitation; RAS = renin-angiotensin system; TR = tricuspid regurgitation; TR V_max = maximal tricuspid regurgitation velocity.

Baseline echocardiographic features showed preserved LVEF in both the no rhythm control and rhythm control groups (median 58% and 59%, respectively). Both groups exhibited increased LAVI (median 47 mL/m²) and LA diameter (43 mm). Moderate or greater MR was present in 7.0% and 7.3% of patients, while moderate or greater TR was observed in 9.4% and 9.0% of patients in the no rhythm control and rhythm control groups, respectively. The interval from baseline to follow-up echocardiography was slightly longer in the no rhythm control group (median 25.3 months; IQR, 17.8–32.0) compared to the rhythm control group (median 21.5 months; IQR, 13.5–29.7; p<0.001). At follow-up echocardiography, the rhythm control group showed a higher rate of sinus rhythm status than the no rhythm control group (60.2% vs. 48.1%, p<0.001).

Trajectories in functional regurgitation associated with atrial fibrillation rhythm control therapy

The interval changes in functional MR and TR, stratified by rhythm control therapy, are illustrated using Sankey diagrams (Figure 1). The overall distribution of MR severity showed no significant difference in both groups. However, in the no rhythm control group, a numeric increase in moderate or greater MR was observed (7.0% to 7.7%, p=0.439), whereas in the rhythm control group, a significant reduction in moderate or greater MR was noted (7.3% to 4.9%, p=0.008). The difference in trends between the 2 groups was statistically significant (p_trend=0.017). For TR, the no rhythm control group showed a significant worsening in the overall severity distribution (p_trend<0.001), with a notable increase in the prevalence of moderate or greater TR (9.4% to 12.6%, p=0.003). In contrast, the rhythm control group showed no significant change in moderate or greater TR (9.1% to 9.3%, p=0.796). Such trends in TR severity differed significantly between the groups (p=0.039).

Figure 1. Trajectories in MR and TR severity stratified by AF rhythm control therapy. Trends in functional MR and TR, stratified by rhythm control therapy, were visualized using the Sankey diagram. Interval changes in moderate or greater MR and TR were further analysed according to the rhythm control therapy.

AF = atrial fibrillation; MR = mitral regurgitation; TR = tricuspid regurgitation.

When the patients with moderate or greater regurgitation were subdivided into the rhythm status at follow-up echocardiography, the greatest reduction in moderate or greater MR was observed in patients who achieved sinus restoration after rhythm control therapy (7.1% to 3.5%, p=0.002) (Figure 2). In contrast, patients in the no rhythm control group who remained AF demonstrated a worsening of MR, with an increasing trend in moderate or greater MR from 9.4% to 11.8% (p=0.113), and TR, with a significant increase from 13.4% to 20.8% (p<0.001). Patients with persisting AF despite rhythm control therapy presented no significant interval change in MR and TR.

Figure 2. Interval changes in moderate or greater regurgitation according to AF rhythm control therapy and follow-up rhythm status. The impact of rhythm control therapy on subsequent changes in moderate or greater functional regurgitation was analysed according to the rhythm status at follow-up echocardiography.

AF = atrial fibrillation; MR = mitral regurgitation; SR = sinus rhythm; TR = tricuspid regurgitation.

The beneficial effects of rhythm control therapy on functional regurgitation were consistently observed in patients with progressed disease status, such as LA enlargement and persistent AF, showing a trend toward MR reduction and a stationary TR (Figure 3). Among patients with LA enlargement, the rhythm control group demonstrated a significant decrease in LAVI (from 56 [IQR, 46–68] to 52 [42–66], p<0.001), whereas no significant change was observed in the no rhythm control group (from 57 [48–74] to 58 [46–75], p=0.266). In the persistent AF subgroup, LAVI remained stable in the rhythm control group (from 54 [IQR, 43–66] to 53 [42–67], p=0.781), but significantly increased in the no rhythm control group (from 56 [44–75] to 60 [48–77], p<0.001). LVEF showed a modest improvement in both groups across subgroups, with no significant intergroup difference.

Figure 3. Interval changes in moderate or greater regurgitation and echocardiographic features according to AF rhythm control therapy in patients with progressed AF status. The impact of AF rhythm control therapy on functional regurgitation and cardiac remodelling was analysed in patients with progressed AF status, characterized by enlarged LV volume, and in those with persistent AF.

AF = atrial fibrillation; EF = ejection fraction; LA = left atrial; LAVI = left atrial volume index; LVEF = left ventricular ejection fraction; MR = mitral regurgitation; TR = tricuspid regurgitation.

When the rhythm control group was stratified based on treatment modality, the rates of sinus rhythm restoration were similar between the medical rhythm control group and the advanced rhythm control group (60.1% vs. 60.3%, p for difference=0.997). The reduction in moderate or greater MR tended to be more prominent in the advanced rhythm control group, although the between-group differences in regurgitation improvement were not statistically significant (Supplementary Figure 3).

Clinical outcomes associated with atrial fibrillation rhythm control therapy

Over a median follow-up of 3.1 years (IQR, 1.3–5.5), 152 composite endpoint events were observed, including 59 deaths and 108 HF hospitalizations. Mediation analysis evaluating the association between rhythm control therapy and clinical outcomes demonstrated both a direct effect of rhythm control therapy (coeff=−0.035 [standard error 0.012], p=0.008) and indirect effects mediated by improvements in valvular regurgitation (coeff=−0.006 [0.003], p=0.031) and restoration of sinus rhythm (coeff=−0.003 [0.002], p=0.046) (Figure 4). Patients who underwent rhythm control therapy and subsequently showed improvement in MR/TR or achieved sinus rhythm had the lowest risk of clinical outcomes. Conversely, the highest risks were observed in patients who did not receive rhythm control therapy and showed no improvement in MR/TR (hazard ratio [HR], 5.54; 95% confidence interval [CI], 3.52–8.72; p<0.001), as well as in those who remained AF (HR, 2.36; 95% CI, 1.49–3.74; p<0.001) (Figure 5). These trends were consistently observed across individual clinical outcomes (Supplementary Table 1). Subgroup analyses demonstrated that the rhythm control therapy was associated with favorable clinical outcomes across diverse clinical subgroups (Figure 6).

Figure 4. Path diagrams of relationship between AF rhythm control therapy, improved regurgitation status or sinus restoration, and clinical outcome. The path diagrams illustrated the associations between rhythm control therapy, improved regurgitation status or sinus restoration, and clinical outcomes. The direct and indirect effects of rhythm control therapy were represented by coefficients along each path, serving as effect estimates.

AF = atrial fibrillation; HF = heart failure; MR = mitral regurgitation; SE = standard error; TR = tricuspid regurgitation.

Figure 5. Clinical outcome according to AF RC therapy and associated functional regurgitation and rhythm status. The event curves for clinical outcomes were displayed based on RC therapy, with additional stratification by improved regurgitation status and sinus restoration at follow-up echocardiography.

AF = atrial fibrillation; HR = hazard ratio; MR = mitral regurgitation; NRC = no rhythm control; RC = rhythm control; SR = sinus rhythm; TR = tricuspid regurgitation.

Figure 6. Subgroup analysis of outcome risk associated with AF rhythm control therapy. The outcome risk associated with the rhythm control therapy was examined across diverse clinical presentations, considering baseline MR and TR severity, AF chronicity, cardiac remodelling features, and associated comorbidities.

AF = atrial fibrillation; BMI = body mass index; CI = confidence interval; HR = hazard ratio; LAVI = left atrial volume index; LVEF = left ventricular ejection fraction; MR = mitral regurgitation; TR = tricuspid regurgitation.

Sensitivity analysis focusing on 1-year clinical outcomes demonstrated similar results for the association between rhythm control therapy and clinical benefit as main analysis. Mediation analysis for 1-year outcomes illustrated both a direct association between rhythm control therapy and clinical outcomes, as well as indirect associations mediated through improvements in valvular regurgitation and restoration of sinus rhythm (Supplementary Figure 4). Patients who received rhythm control therapy and subsequently presented improvement in MR/TR or sinus rhythm restoration exhibited the lowest risk of adverse 1-year outcomes. In contrast, the highest risks were observed in patients who neither received rhythm control therapy nor demonstrated improvement in MR/TR (HR, 6.85; 95% CI, 3.59–13.08; p<0.001), as well as in those with sustained AF (HR, 3.95; 95% CI, 1.95–8.01; p<0.001) (Supplementary Figure 5, Supplementary Table 1).

DISCUSSION

In this study, we investigated the impact of AF rhythm control therapy on functional MR and TR, cardiac remodeling, and clinical outcomes. Rhythm control therapy—including antiarrhythmic drugs, catheter ablation, and electrical cardioversion—was associated with significant improvement in functional MR and attenuation of TR progression. Furthermore, patients undergoing rhythm control were more likely to achieve sinus rhythm, which was associated with a greater degree of improvement in functional regurgitation. Improvement in functional regurgitation and restoration of sinus rhythm associated with rhythm control therapy were also linked to favorable clinical outcomes.

As the aging population increases, the prevalence and duration of AF have risen, leading to a higher incidence of functional MR and TR.¹⁾,²⁾ The pathophysiology of functional MR and TR in the context of AF is complex and bidirectional.³⁾,⁴⁾,¹⁷⁾ The occurrence and persistence of AF promote atrial dilation, structural remodeling, and dysfunction, which in turn lead to annular enlargement, impaired leaflet coaptation, and functional regurgitation. Conversely, progressive regurgitation can exacerbate atrial and ventricular remodeling, creating a vicious cycle.¹⁸⁾ In this context, isolating the effect of rhythm control interventions, such as antiarrhythmic drugs or catheter ablation, is indeed challenging, akin to the “chicken-or-egg” dilemma. However, the treatment of functional MR and TR related to AF has not been firmly established.⁷⁾ The only treatment modality for treating secondary MR with class I indication is guideline-directed medical therapy for HF, limited to sodium glucose co-transporter 2 inhibitors in HF with preserved ejection fraction. The treatment of secondary TR has class II indications for surgery, typically performed simultaneously with left heart surgery. Recently, percutaneous strategies, such as transcatheter edge-to-edge repair and percutaneous valvular replacement, have been attempted in advanced stages of functional MR and TR. These interventions have shown reductions in functional MR¹⁹⁾ and TR²⁰⁾; however, studies demonstrating the benefits of rhythm control therapy in mortality or HF admissions are still lacking.

Successful sinus rhythm restoration is associated with improvement in symptoms and performance in AF patients, as well as enhanced underlying cardiac function.¹⁰⁾ Previous studies have suggested important clues for mechanistic insights for AF rhythm control therapy in functional regurgitation. Catheter ablation has been shown to induce reverse remodeling of the LA and improve LA reservoir and conduit function, resulting in a reduction of mitral annular dimension and improved leaflet coaptation, thereby reducing functional MR.²¹⁾ Similarly, AF ablation has been associated with RA size reduction and tricuspid annular contraction, which may alleviate functional TR.²²⁾ Moreover, recovery of RA electrical and structural changes was observed following restoration of sinus rhythm.²³⁾ Recent molecular insights also suggest that rhythm control therapy, particularly sinus rhythm restoration, may interrupt a self-perpetuating cycle of atrial electrical, structural, and inflammatory remodeling. Ca²⁺-loading of both cardiomyocytes and fibroblasts, oxidative stress, and low-grade local inflammation can promote the progression of AF. By maintaining sinus rhythm, rhythm control can potentially reverse these maladaptive cascades, improving atrial synchrony and mitral/tricuspid valve coaptation.²⁴⁾

Of note, we observed a consistent effect of rhythm control therapy on the progression of MR and TR and cardiac remodeling among patients with LA enlargement and persistent AF. In real-world practice, such patients are considered as progressed state and having high risk for AF recurrence.²⁵⁾ The primary goal of rhythm control therapy is to manage AF-related symptoms,⁸⁾,¹²⁾ which may not be very evident in long-standing persistent AF stages.¹⁰⁾ Our results suggest that, even in progressed AF status, rhythm control therapy in AF may still have a beneficial role not only in the restoration of sinus rhythm but also in the improvement of cardiac remodeling and functional valvular regurgitation. Downstream analysis of rhythm control modalities demonstrated that the reduction in functional regurgitation was more pronounced in patients who underwent advanced rhythm control strategies, such as catheter ablation, compared to those managed with antiarrhythmic medications alone. Catheter ablation, through LA substrate modification, was associated with lower rates of AF recurrence and subsequent reverse LA remodeling.¹⁰⁾ These findings support a mechanistic link between rhythm control and structural remodeling, highlighting that rhythm control therapy may contribute to the improvement of functional regurgitation beyond mere rhythm modulation in the context of the bi-directional relationship between AF and valvular dysfunction.

Since the publication of the AFFIRM study, rate control therapy has been a cornerstone in the management of AF, given the lack of observed survival benefit with rhythm control strategies.²⁶⁾ Consequently, the primary aim of rhythm control therapy has traditionally focused on symptom relief and improvement in quality of life. Recently, the survival benefit of rhythm control therapy has been demonstrated in AF patients with HF with reduced ejection fraction,²⁷⁾ acquiring the class I indication in these patients.⁸⁾,¹²⁾ Rhythm control therapy has also been linked to improvement in biventricular function, particularly in patients with advanced HF. As demonstrated in the CASTLE-HTx trial, rhythm control via ablation therapy significantly reduced the composite outcome of death, LV assist device implantation, or heart transplantation.²⁸⁾ Recent mechanistic data from the EAST-AFNET 4 substudy revealed that sinus rhythm maintenance at 12 months explained over 80% of the benefit associated with early rhythm control on major cardiovascular outcomes, including cardiovascular death, stroke, HF hospitalization, and acute coronary syndrome.²⁹⁾ However, the benefits of rhythm control therapy are still controversial in asymptomatic AF, where atrial remodeling dominates but a relatively preserved LV function.⁴⁾,⁵⁾

Our study evaluated the effects of AF rhythm control therapy on clinical outcomes from the perspectives of functional regurgitation and rhythm control status. Mediation analysis demonstrated that rhythm control therapy was associated with clinical outcomes through both direct and indirect pathways. Patients who exhibited improvement in functional regurgitation and achieved sinus rhythm following rhythm control therapy experienced the lowest risk of adverse clinical outcomes. Although hypothesis-generating, these findings suggest that the beneficial effects of rhythm control therapy may be partially mediated through improvements in functional regurgitation and maintenance of sinus rhythm, which together may synergistically contribute to a favorable prognosis.

Determining the optimal timing for initiating rhythm control therapy in AF remains challenging. Current guidelines suggest that younger age and shorter AF duration may favor rhythm control therapy; however, these criteria are limited to apply as objective cues.¹²⁾ Moreover, the association between subjective symptoms and AF chronicity is often inconsistent,³⁰⁾ making it particularly difficult to define the appropriate timing for intervention in asymptomatic patients. In this study, rhythm control therapy was associated not only with sinus rhythm restoration but also with improvements in functional regurgitation and reverse cardiac remodeling. These findings highlight the potential utility of echocardiography in AF management—beyond clinical assessment alone—by enabling the monitoring of functional regurgitation progression and cardiac structural changes. These advantages allow echocardiography to be effectively utilized in identifying the optimal timing for rhythm control intervention and in evaluating therapeutic response, ultimately contributing to improved clinical outcomes.

This study was conducted in a single-center, retrospective setting. Although covariate adjustment was performed using PSM, unmeasured clinical factors influencing the decision to initiate AF rhythm control therapy may have affected its observed impact on functional regurgitation and sinus rhythm restoration. Findings from mediation analysis remain hypothesis-generating and do not support causal inference. The current study lacks data on AF recurrence, progression of MR and TR, and the use of advanced rhythm control strategies beyond follow-up echocardiography. Consequently, further prospective cohort studies or randomized clinical trials are needed to validate the long-term therapeutic efficacy of AF rhythm control, including its potential mechanistic associations with valvular regurgitation and rhythm status. Relatively small proportion of patients with moderate or greater MR and TR may have limited the statistical power to detect significant benefits of rhythm control on functional regurgitation. Nonetheless, by including patients with milder degrees of regurgitation, this study offers real-world insight into the broader disease course. Due to the long study period, both the assessment of MR and TR severity and the approaches to AF rhythm control—including antiarrhythmic medications and ablation techniques—evolved over time, which may have influenced the study outcomes. However, all patients were managed according to the standard practices of the time. Although we evaluated patients with progressed AF based on LA size and AF subtype, the duration of AF at baseline could not be reliably determined, limiting generalizability to those with chronic or long-standing AF. The predominance of patients with preserved LVEF also restricts extrapolation to populations with advanced LV dysfunction. Lastly, while echocardiographic assessments followed ASE guidelines, quantitative parameters of MR/TR severity and right heart function were not consistently available, limiting detailed evaluation. These gaps highlight the need for future prospective studies with comprehensive imaging and long-term rhythm control strategies.

AF rhythm control therapy is associated with a significant reduction in moderate or greater MR and attenuation of TR progression. It is also linked to successful restoration of sinus rhythm. These effects, through improvement in functional regurgitation and maintenance of sinus rhythm, may contribute to reverse cardiac remodeling and favorable clinical outcomes. Echocardiography can provide valuable information for identifying the optimal timing of rhythm control intervention and assessing treatment response in AF management.

SUPPLEMENTARY MATERIALS

Supplementary Data 1

Model configuration for longitudinal changes in MR and TR

Supplementary Data 2

Mediation analysis model configuration

Supplementary Table 1

Individual clinical outcomes

Supplementary Figure 1

Study flow.

Supplementary Figure 2

Covariate balance after propensity score matching.

Supplementary Figure 3

Interval changes in significant regurgitation stratified based on RC modality. Interval changes in moderate or greater MR and TR were stratified among patients undergoing RC therapy, comparing advanced RC therapy with medication-only treatment using antiarrhythmic drugs. This analysis was performed for the overall patient cohort (A) and subgroups with progressed AF status, such as those with enlarged left atrium (B) or persistent AF type (C).

Supplementary Figure 4

Path diagrams of relationship between atrial fibrillation rhythm control therapy, improved regurgitation status or sinus restoration, and 1-year clinical outcome.

Supplementary Figure 5

One-year clinical outcome according to atrial fibrillation RC therapy and associated functional regurgitation and rhythm status.