Abstract
Background
Severe aortic stenosis (AS) often coexists with mitral regurgitation (MR). This study evaluated the significant evolution of MR in patients undergoing transcatheter aortic valve replacement (TAVR) for AS.
Methods
This multi-center China Degenerative Valve Disease II Cohort (China-DVD2) Study enrolled patients undergoing TAVR for AS from January 2020 to October 2023. MR severity was assessed at baseline and 12 months post-TAVR. Composite endpoints included all-cause death, heart failure rehospitalization, myocardial infarction, and angina.
Results
Among 424 enrolled patients, 130 (31%) had significant MR at baseline. At 12 months, MR improved in 56 (70%) of 80 patients with follow-up, and greater improvement in left ventricular ejection fraction (LVEF) was associated with MR improvement [odds ratios (OR) = 0.97, 95% confidence interval (CI): 0.95–1.00, p = 0.04)]. Patients with MR improvement showed significant New York Heart Association (NYHA) functional class improvement at 12-month follow-up. No survival benefit disparity was observed between patients with and without significant baseline MR, but a trend toward lower composite endpoint rate (12.5% vs. 20.8%, log-rank p = 0.49) was observed in patients with MR improvement. Older age [hazard ratios (HR) = 1.12, 95% CI: 1.01–1.24, p = 0.04)] and higher systolic pulmonary arterial pressure (SPAP) (HR = 1.05, 95% CI: 1.00–1.09, p = 0.04) were linked to worse outcomes.
Conclusions
Most patients with significant MR experienced improvement of NYHA class and MR post TAVR. Baseline significant MR was not linked to worse outcomes, but MR improvement showed a trend toward better prognosis. Older age and higher SPAP predicted worse outcomes.
Keywords: aortic stenosis, mitral regurgitation, transcatheter aortic valve replacement, percutaneous therapy, echocardiography
Graphical abstract
Introduction
Mitral regurgitation (MR) is present in up to one-third of patients with severe aortic stenosis (AS), most commonly as functional MR due to elevated left ventricular–left atrial pressure gradients [1, 2]. A minority of cases involve organic MR from leaflet degeneration, prolapse, or mitral annulus calcification (MAC) [3]. Surgical double-valve procedures carry high periprocedural risk without clear prognostic benefit [1]. Transcatheter aortic valve replacement (TAVR) has become the preferred treatment for elderly or high-risk AS patients.
Severe AS with MR is commonly observed in patients with AS undergoing TAVR, while significant MR accounts for nearly 20% of patients undergoing TAVR [4]. However, current practice predominantly adopts the strategy of isolated treatment for severe AS with TAVR, and significant MR is usually left untreated at the time of TAVR, following the assumption that the MR severity might decrease following TAVR [5]. Recent transcatheter MR therapies allow for staged intervention, beginning with TAVR and reassessment of MR. However, data on the characteristics and evolution of concomitant MR after isolated TAVR are limited. We aimed to characterize the evolution of concomitant MR in patients with AS following TAVR and investigate the potential clinical and imaging prognostic predictors for the development of concomitant MR in patients with severe AS undergoing TAVR.
Methods
Study population
This was a post-hoc analysis of the prospective multi-center China Degenerative Valve Disease II Cohort Study (China-DVD2 Study), and it has been registered with ClinicalTrials.gov (NCT05044338). The study protocol complied with the guidelines of the Declaration of Helsinki and relevant national regulations and was approved by the Ethics Committee of Beijing Hospital (2021BJYYEC-167-01). Moreover, this work conformed to the STROCSS criteria [6]. A total of 424 patients who underwent TAVR for severe AS between January 2020 and October 2023 were consecutively enrolled from five TAVR centers, including Beijing Hospital (n = 77), The Second Affiliated Hospital of Nanchang University (n = 45), The First Affiliated Hospital of Zhengzhou University (n = 28), Guangdong Provincial People’s Hospital (n = 101), The Second Affiliated Hospital, and Zhejiang University School of Medicine (n = 173). All patients were eligible candidates for TAVR as evaluated by the structural heart team. Severe AS was defined as transvalvular velocity exceeding 4 m/s, mean transvalvular gradient ≥ 40 mmHg, and aortic valve area < 1 cm2 [7]. Dobutamine stress echocardiography was performed in cases of suspected severe low-flow low-gradient AS, which was assumed if the following were present: aortic valve area < 1 cm2, mean transvalvular gradient < 35 mmHg, and left ventricular ejection fraction (LVEF) ≤ 40% [8]. Clinical data, transthoracic echocardiography before TAVR, and echocardiographic evaluation at 12-month follow-up were collected.
Assessment of MR severity using transthoracic echocardiography
Transthoracic echocardiography was performed at baseline and 12-month follow-up. Images were assessed by two experienced readers as per prespecified protocols, with discrepancies resolved by a third reviewer. The degree of MR was graded using a multiparametric approach integrating color Doppler flow, such as mitral inflow pattern and velocity, vena contracta width, regurgitant fraction, regurgitant volume, and effective regurgitation orifice area, as previously described (Fig. 1) [9]: 0, none/trace; 1+, mild; 2+, moderate; 3+, moderate-to-severe; and 4+, severe. According to the MR severity, MR < 2+ (moderate) was suggested to be nonsignificant MR, and MR ≥ 2+ (moderate) was significant MR. In addition, MR was further classified as organic (primary) and functional (secondary). Abnormalities of the valvular apparatus itself, such as mitral valve prolapse or rheumatic heart disease with MAC, are attributed to organic (primary) MR. In contrast, restricted leaflets, mostly caused by left ventricular dilatation and dysfunction in ischemic cardiomyopathy, annular dilatation and left atrial enlargement secondary to atrial fibrillation (AF), and chronic pressure overload related to aortic stenosis, are collectively regarded as functional (secondary) MR [10]. Echocardiographic quantification of aortic regurgitation (AR) and mitral stenosis (MS) followed an integrated approach that considered all qualitative, semi-quantitative, and quantitative parameters, and assessed AR and MS as mild (1+), moderate (2+), and severe (3+) levels [10].
Figure 1.
Representative example of a TAVR patient with MR. Significant mitral regurgitation (MR) at baseline in parasternal long-axis view (A) and apical four-chamber view (B). The multiparametric approach used to grade MR includes vena contracta width (VCW) and proximal isovelocity surface area (PISA). Representative of a patient with MR improvement after TAVR in parasternal long axis view (C) and apical four-chamber view (D). LV — left ventricle; LA — left atrium; VCW — vena contracta width; PISA — proximal isovelocity surface area
Follow-up at 12 months
MR evolution was assessed at 12 months post TAVR using a transthoracic echocardiogram. Improvement was defined as any decrease in the MR grade of patients with MR ≥ 2+ compared to pre-TAVR, while persistence was noted if there was no change or worsening. Composite endpoints of all-cause death, rehospitalization for heart failure, myocardial infarction, or angina were tracked, with cardiovascular deaths recorded. Follow-up was conducted via clinic visits, medical records, and phone interviews.
Statistical analysis
Categorical variables were reported as frequencies/percentages, and continuous variables as means ± SD or medians (IQR). Group differences were analyzed using chi-square tests for categorical data and t-tests or Mann–Whitney U tests for continuous data. Stepwise logistic regression assessed predictors of MR improvement, with results expressed as ORs with 95% CIs. Characteristics associated with the outcome of interest with p < 0.1 in the univariate analysis were considered as candidate variables and underwent multivariate analysis. Kaplan–Meier curves and log-rank tests compared composite endpoint rates, with Cox proportional hazards models used for adjusted HRs. Statistical significance was set at p < 0.05, and all analyses were performed using R version 4.3.1.
Results
Baseline clinical and echocardiographic characteristics
Our registry included 424 consecutive patients who underwent TAVR for severe AS at five centers. Of the total, 130 (30.7%) patients had significant MR at baseline. The median age of the patients was 74 years (IQR = 70–79 years), and 191 (45%) were female. The median LVEF was 60% (IQR = 51–65%), and 235 patients (55.4%) had NYHA functional class III to IV heart failure. Patients with significant MR were more likely be female (53.8% vs. 41.2%, p = 0.021), had lower body mass index (BMI) (22.4 kg/m2 vs. 23.1 kg/m2, p = 0.01), and had a higher prevalence of AF (24.6% vs. 12.6%, p = 0.003). Baseline STS scores were higher in patients with significant MR than in those with non-significant MR (13.00 vs. 11.90, p = 0.001). Pre-frailty was more common in the non-significant MR group (65.3% vs. 50%, p = 0.004), while frailty was more prevalent in the significant MR group (40.8% vs. 25.5%, p = 0.002). These baseline characteristics did not differ between the MR improvement and non-improvement groups. In terms of baseline echocardiographic variables, patients with significant MR exhibited more dilated left atrial diameter (LAD) and left ventricular end-diastolic diameter (LVEDD), a higher SPAP, and a lower LVEF, and smaller aortic valve area (AVA). Regional wall motion abnormalities and moderate-to-severe AR were more common in patients with significant MR (Tab. 1).
Table 1.
Baseline clinical and echocardiographic characteristics for the study population
| Overall (n = 424) | Significant MR (n = 130) | Nonsignificant MR (n = 294) | P-value | |
|---|---|---|---|---|
| Clinical variables | ||||
| Age, years | 73.8 [69.7, 79.0] | 74.8 [70.4, 79.8] | 73.3 [69.2, 78.1] | 0.074 |
| Female | 191 (45.0) | 70 (53.8) | 121 (41.2) | 0.021 |
| BMI, kg/m2 | 22.9 [20.5, 25.6] | 22.4 [20.1, 24.6] | 23.1 [20.8, 26.0] | 0.010 |
| STS score, % | 11.9 [9.5, 14.2] | 13.0 [10.4, 15.4] | 11.9 [9.1, 13.6] | 0.001 |
| FRAIL scale | ||||
| Non-frail | 39 (9.2) | 12 (9.2) | 27 (9.2) | 1.000 |
| Pre-frail | 257 (60.6) | 65 (50.0) | 192 (65.3) | 0.004 |
| Frail | 128 (30.2) | 53 (40.8) | 75 (25.5) | 0.002 |
| Current smokers | 41 (9.7) | 11 (8.5) | 30 (10.2) | 0.703 |
| Prior heart failure | 78 (18.4) | 31 (23.8) | 47 (16.0) | 0.073 |
| NYHA functional class III/IV | 235 (55.4) | 157 (53.4) | 78 (60.0) | 0.248 |
| Atrial fibrillation | 69 (16.3) | 32 (24.6) | 37 (12.6) | 0.003 |
| Coronary artery disease | 95 (22.4) | 37 (28.5) | 58 (19.7) | 0.063 |
| Prior myocardial infraction | 9 (2.1) | 5 (3.8) | 4 (1.4) | 0.203 |
| Prior PCI | 28 (6.6) | 10 (7.7) | 18 (6.1) | 0.698 |
| Prior CABG | 5 (1.2) | 3 (2.3) | 2 (0.7) | 0.345 |
| Prior PPM implantation | 10 (2.4) | 5 (3.8) | 5 (1.7) | 0.320 |
| Hypertension | 228 (53.8) | 74 (56.9) | 154 (52.4) | 0.448 |
| Diabetes mellitus | 90 (21.2) | 26 (20.0) | 64 (21.8) | 0.778 |
| Aortic disease | 24 (5.7) | 11 (8.5) | 13 (4.4) | 0.152 |
| Peripheral arterial disease | 33 (7.8) | 7 (5.4) | 26 (8.8) | 0.303 |
| Prior cerebrovascular accident | 32 (7.5) | 15 (11.5) | 17 (5.8) | 0.062 |
| COPD | 26 (6.1) | 10 (7.7) | 16 (5.4) | 0.502 |
| CKD | 21 (5.0) | 10 (7.7) | 11 (3.7) | 0.137 |
| Cancer | 19 (4.5) | 6 (4.6) | 13 (4.4) | 1.000 |
| AS etiology | ||||
| Rheumatic | 16 (3.8) | 7 (5.4) | 9 (3.1) | 0.378 |
| Degenerative | 374 (88.2) | 115 (88.5) | 259 (88.1) | 1.000 |
| Congenital | 32 (7.5) | 8 (6.2) | 24 (8.2) | 0.601 |
| Other | 2 (0.5) | 0 (0.0) | 2 (0.7) | 0.862 |
| Echocardiographic variables | ||||
| LAD, mm | 40.7 [36.4, 45.0] | 43.0 [38.0, 47.7] | 39.8 [35.9, 44.0] | < 0.001 |
| LVEDD, mm | 48.7 [43.6, 54.0] | 52.0 [47.0, 58.0] | 47.0 [43.0, 52.0] | < 0.001 |
| IVSd, mm | 13.0 [11.8, 14.0] | 12.9 [11.0, 14.0] | 13.0 [12.0, 14.0] | 0.107 |
| LVPWd, mm | 12.0 [11.0, 13.0] | 12.0 [11.0, 13.0] | 12.0 [11.0, 13.0] | 0.817 |
| LVEF, % | 60.0 [51.0, 65.0] | 57.0 [44.0, 62.0] | 61.9 [55.0, 66.9] | < 0.001 |
| SPAP, mmHg | 46.0 [33.0, 62.5] | 46.0 [38.0, 60.8] | 42.0 [31.0, 63.5] | 0.015 |
| Aortic valve area, cm2 | 0.57 [0.40, 0.77] | 0.50 [0.40, 0.68] | 0.60 [0.40, 0.80] | 0.002 |
| Aortic peak velocity, m/s | 4.55 [4.16, 5.20] | 4.56 [4.10, 5.21] | 4.54 [4.18, 5.19] | 0.584 |
| Aortic mean gradient, mmHg | 51.0 [41.0, 67.0] | 50.5 [40.0, 66.8] | 52.0 [41.0, 67.0] | 0.538 |
| Pericardial effusion | 61 (14.4) | 24 (18.5) | 37 (12.6) | 0.150 |
| Wall motion abnormalities | 40 (9.4) | 23 (17.7) | 17 (5.8) | < 0.001 |
| Aortic regurgitation ≥ 2+ | 152 (35.8) | 63 (48.5) | 89 (30.3) | < 0.001 |
| Mitral stenosis ≥ 2+ | 22 (5.2) | 9 (6.9) | 13 (4.4) | 0.405 |
Values are mean ± SD or median [IQR] or n (%). BMI — body mass index; CABG — coronary artery bypass grafting; CKD — chronic kidney disease; COPD — chronic obstructive pulmonary disease; IVSd — interventricular septal end-diastolic thickness; LAD — left atrial diameter; LVEDD — left ventricular end-diastolic diameter; LVEF — left ventricular ejection fraction; LVPWd — left ventricular posterior wall end-diastolic thickness; PCI — percutaneous coronary intervention, PPM — permanent pacemaker; SPAP — systolic pulmonary arterial pressure
Change in MR grade following TAVR
On assessing the change in MR grade among the 130 patients with AS and baseline significant MR (MR grade ≥ 2+), 80 patients had available echocardiographic follow-up data at 12 months following TAVR. There were significant changes observed in the MR grades at 12-month follow-up, and the prevalence of concomitant MR grade ≥ 3+ significantly decreased from 23% to 7% following TAVR (p = 0.002). Of the 80 patients with baseline MR grade ≥ 2+, 56 (70%) patients experienced MR improvement, while MR persistence occurred in 24 (30%) patients. In patients with baseline MR grade ≥ 2+, marked reduction in the aortic mean gradient, LAD, and LVEDV were observed after TAVR, while LVEF experienced a significant increase (Fig. 2).
Figure 2.
Changes of echocardiographic variables after TAVR. Paired comparisons of aortic mean gradient (A), left atrial diameter (LAD) (B), left ventricular end-diastolic volume (LVEDV) (C), and left ventricular ejection fraction (LVEF) (D) between baseline and 12 months following TAVR in 80 patients with available echocardiograms. TAVR — transcatheter aortic valve replacement
The main clinical and echocardiographic factors associated with MR improvement at 12 months are summarized in Table 2. The patients with MR improvement had smaller LAD and greater LAD reduction after TAVR compared to patients with MR persistence. Except for LAD, patients with MR improvement also showed more significant reduction of aortic mean gradient and increase of LVEF (Tab. 2). In the multivariate logistic regression model, only greater increase of LVEF was independently associated with MR improvement (OR = 0.97, 95% CI: 0.95–1.00, p = 0.04; Tab. 3).
Table 2.
Factors associated with MR evolution
| Overall (n = 80) | MR improvement (n = 56) | MR persistence/worsening (n = 24) | P-value | |
|---|---|---|---|---|
| Clinical variables | ||||
| Age, years | 75.9 ± 7.3 | 75.0 ± 7.61 | 78.0 ± 6.12 | 0.090 |
| Female | 45 (56.2) | 33 (58.9) | 12 (50.0) | 0.623 |
| BMI [kg/m2] | 22.9 ± 3.5 | 23.0 ± 3.5 | 22.6 ± 3.5 | 0.617 |
| STS score [%] | 13.0 [8.2, 16.1] | 12.5 [5.1, 15.8] | 14.1 [11.4, 16.5] | 0.123 |
| FRAIL Scale | ||||
| Non-frail | 7 (8.8) | 4 (7.1) | 3 (12.5) | 0.730 |
| Pre-frail | 40 (50.0) | 26 (46.4) | 14 (58.3) | 0.464 |
| Frail | 33 (41.2) | 26 (46.4) | 7 (29.2) | 0.234 |
| Current smokers | 5 (6.2) | 4 (7.1) | 1 (4.2) | 1.000 |
| Prior heart failure | 22 (27.5) | 15 (26.8) | 7 (29.2) | 1.000 |
| NYHA functional class III/IV | 45 (56.2) | 35 (62.5) | 10 (41.7) | 0.140 |
| Atrial fibrillation | 8 (10.0) | 4 (7.1) | 4 (16.7) | 0.371 |
| Coronary artery disease | 27 (33.8) | 18 (32.1) | 9 (37.5) | 0.836 |
| Prior myocardial infraction | 4 (5.0) | 2 (3.6) | 2 (8.3) | 0.737 |
| Prior PCI | 8 (10.0) | 4 (7.1) | 4 (16.7) | 0.371 |
| Prior CABG | 3 (3.8) | 2 (3.6) | 1 (4.2) | 1.000 |
| Prior PPM implantation | 5 (6.2) | 2 (3.6) | 3 (12.5) | 0.313 |
| Hypertension | 48 (60.0) | 31 (55.4) | 17 (70.8) | 0.296 |
| Diabetes mellitus | 18 (22.5) | 13 (23.2) | 5 (20.8) | 1.000 |
| Prior cerebrovascular accident | 13 (16.2) | 10 (17.9) | 3 (12.5) | 0.791 |
| COPD | 9 (11.2) | 7 (12.5) | 2 (8.3) | 0.877 |
| CKD | 5 (6.2) | 2 (3.6) | 3 (12.5) | 0.313 |
| AS etiology | ||||
| Rheumatic | 4 (5.0) | 2 (3.6) | 2 (8.3) | 0.737 |
| Degenerative | 69 (86.2) | 48 (85.7) | 21 (87.5) | 1.000 |
| Congenital | 7 (8.8) | 6 (10.7) | 1 (4.2) | 0.604 |
| MR etiology | ||||
| Organic | 45 (56.2) | 27 (48.2) | 18 (75.0) | 0.049 |
| Functional | 14 (17.5) | 12 (21.4) | 2 (8.3) | 0.275 |
| Mixed | 21 (26.2) | 17 (30.4) | 4 (16.7) | 0.318 |
| Echocardiographic variables | ||||
| Baseline | ||||
| Aortic annulus [mm] | 22.2 [19.9, 24.4] | 22.1 [19.9, 24.4] | 22.2 [19.8, 24.6] | 0.966 |
| LVOT diameter [mm] | 21.1 [19.9, 23.8] | 21.3 [20.0, 23.8] | 21.1 [18.0, 23.8] | 0.323 |
| LAD [mm] | 44.3 [40.1, 48.0] | 43.7 [39.9, 48.0] | 45.3 [41.5, 48.5] | 0.614 |
| LVEDD [mm] | 52.4 ± 8.4 | 53.2 ± 8.8 | 50.4 ± 7.2 | 0.167 |
| LVESD [mm] | 40.2 ± 10.8 | 40.0 ± 10.6 | 40.8 ± 11.5 | 0.760 |
| IVSd [mm] | 12.6 [11.0, 13.9] | 12.6 [11.0, 13.9] | 12.5 [11.0, 13.6] | 0.971 |
| LVPWd [mm] | 12.0 [11.0, 13.0] | 12.0 [10.8, 13.0] | 12.0 [11.1, 13.0] | 0.764 |
| LVEF [%] | 57.0 [43.6, 60.0] | 53.3 [44.4, 60.0] | 58.0 [42.6, 60.5] | 0.528 |
| SPAP [mmHg] | 48.0 [38.0, 70.0] | 49.5 [38.0, 70.3] | 44.0 [39.0, 57.5] | 0.198 |
| LVEDV [mL] | 123.5 [88.0, 162.5] | 127.0 [91.5, 162.5] | 108.5 [84.9, 158.0] | 0.459 |
| Aortic valve area [cm2] | 0.60 [0.42, 0.86] | 0.61 [0.40, 0.86] | 0.50 [0.49, 0.73] | 0.570 |
| Aortic peak velocity [m/s] | 4.5 [4.0, 5.0] | 4.5 [4.1, 5.1] | 4.4 [3.8, 4.9] | 0.237 |
| Aortic mean gradient [mmHg] | 52.3 ± 20.4 | 53.3 ± 19.6 | 50.1 ± 22.4 | 0.521 |
| Pericardial effusion | 14 (17.5) | 8 (14.3) | 6 (25.0) | 0.404 |
| Wall motion abnormalities | 16 (20.0) | 13 (23.2) | 3 (12.5) | 0.428 |
| Follow-up at 12 months | ||||
| LAD [mm] | 41.2 ± 6.6 | 40.3 ± 6.8 | 43.4 ± 5.9 | 0.048 |
| LVEDD [mm] | 47.2 ± 6.9 | 47.2 ± 7.2 | 47.3 ± 6.3 | 0.917 |
| LVESD [mm] | 31.7 [28.0, 37.6] | 31.1 [28.1, 36.4] | 34.0 [27.9, 41.0] | 0.233 |
| LVEF [%] | 62.0 [55.0, 66.3] | 62.0 [55.8, 66.3] | 60.0 [52.0, 65.5] | 0.514 |
| LVEDV [mL] | 101.0 [76.6, 124.0] | 99.0 [73.9, 124.0] | 101.5 [80.5, 127.0] | 0.655 |
| Aortic mean gradient [mmHg] | 7.5 [2.9, 13.0] | 5.5 [2.0, 11.3] | 10.0 [6.0, 14.8] | 0.037 |
| Delta LAD [mm] | 2.8 ± 5.7 | 3.6 ± 5.8 | 0.7 ± 5.0 | 0.034 |
| Delta LVEDD [mm] | 3.5 [−0.1, 10.0] | 4.5 [1.0, 10.7] | 0.9 [−1.0, 8.3] | 0.084 |
| Delta LVESD [mm] | 6.0 ± 12.8 | 6.3 ± 13.5 | 5.5 ± 11.2 | 0.814 |
| Delta LVEF [%] | −4.5 [−15.2, 3.0] | −5.9 [−19.0, 0.2] | −2.4 [−8.1, 12.2] | 0.028 |
| Delta LVEDV [mL] | 21.6 ± 47.5 | 27.5 ± 48.6 | 7.0 ± 42.0 | 0.102 |
| Delta Aortic mean gradient [mmHg] | 44.8 ± 21.3 | 45.3 ± 20.2 | 43.3 ± 24.5 | 0.722 |
Values are mean ± SD or median [IQR] or n (%). BMI — body mass index; CABG — coronary artery bypass grafting; COPD — chronic obstructive pulmonary disease; CKD — chronic kidney disease; IVSd — interventricular septal end-diastolic thickness; LAD — left atrial diameter; LVEDD — left ventricular end-diastolic diameter; LVESD — left ventricular end-systolic diameter; LVEDV — left ventricular end-diastolic volume; LVEF — left ventricular ejection fraction; LVPWd — left ventricular posterior wall end-diastolic thickness; PPM — permanent pacemaker; SPAP — systolic pulmonary arterial pressure; Delta LAD/LVEED/LVESD/LVEF/LVEDV/Aortic mean gradient — the difference of these echocardiographic variables between pre and post TAVR.
Table 3.
Risk factors for prognosis of the study population
| Univariate logistic regression | Multivariate logistic regression | |||
|---|---|---|---|---|
|
| ||||
| OR 95% CI | P-value | OR 95% CI | P-value | |
| Variables associated with MR improvement following TAVR | ||||
| Age [years] | 0.94 (0.88–1.01) | 0.09 | 0.94 (0.87–1.00) | 0.08 |
| Delta LAD [mm] | 1.10 (1.00–1.20) | 0.04 | 1.07 (0.97–1.18) | 0.17 |
| Delta LVEF [%] | 0.97 (0.95–0.99) | 0.02 | 0.97 (0.95–1.00) | 0.04 |
| Variables associated with the composite endpoint of patients with baseline significant MR | ||||
| MR improvement | 1.48 (0.48–4.57) | 0.49 | ||
| Age [years] | 1.09 (1.01–1.18) | 0.04 | 1.12 (1.01–1.24) | 0.04 |
| LVOT diameter [mm] | 1.01 (1.01–1.02) | 0.03 | 1.01 (1.00–1.02) | 0.16 |
| SPAP [mmHg] | 1.04 (1.00–1.07) | 0.03 | 1.05 (1.00–1.09) | 0.04 |
MR — mitral regurgitation; TAVR — transcatheter aortic valve replacement; LAD — left atrial diameter; LVEF — left ventricular ejection fraction; LVOT — left ventricular outflow tract; SPAP — systolic pulmonary arterial pressure
Clinical outcomes
The changes in the NYHA functional class over time are shown in Figure 3. In patients with non-significant MR, NYHA functional class III or IV decreased from 53% to 4%, and from 60% to 12% in those with significant MR (p = 0.058). In patients with significant MR improvement, the percentage of NYHA functional class III or IV decreased from 63% to 7%, whereas in the remaining patients with MR persistence, the percentage decreased from 42% to 29% (p < 0.001).
Figure 3.
Evolution of NYHA functional class. Evolution of NYHA functional class in patients with baseline nonsignificant and significant MR (A), patients with MR improvement and MR persistence/worsening (B) following TAVR. MR — mitral regurgitation; TAVR — transcatheter aortic valve replacement
During a follow-up of 12 months, the overall mortality was 3.5% (n = 15), and eight patients died of cardiovascular causes. Forty-one patients (9.7%) were readmitted due to CHF, MI, or angina, with a composite endpoint incidence of 8.7% (n = 56). Among the 80 patients with concurrent significant MR, 5 (6.3%) died at the 12-month follow-up, and cardiovascular death occurred in 3 patients. There were no significant differences in the all-cause mortality or the probability of composite endpoints between patients with and without significant baseline MR (6.2% vs. 2.4%, log-rank p = 0.053; 12.3% vs. 13.6%, log-rank p = 0.57) (Fig. 4A, B). The Kaplan–Meier curves showing the change in the 80 patients with concurrent significant MR are shown in Figures 4C and 4D. Patients with MR improvement following TAVR did not show a significant difference in all-cause mortality compared to patients with MR persistence (3.5% vs. 12.5%, log-rank p = 0.12); however, a trend toward a lower composite endpoint rate was observed (12.5% vs. 20.8%, log-rank p = 0.49). It was noticeable that there was also no significant difference in the 12-month all-cause mortality and probability of composite endpoints between patients with MR improvement and baseline non-significant MR (Fig. 4E, F). We also assessed the relationship between MR etiology and prognosis, finding that the mixed MR group had a higher 1-year all-cause mortality compared to the organic and functional MR groups (19.0% vs. 2.2% vs. 0%, log-rank p = 0.016), while there were no differences in the incidence of the composite endpoint among the three groups (Fig. 4G, H).
Figure 4.
12-month Kaplan–Meier curves for all-cause mortality and probability of composite endpoint. 12-month Kaplan–Meier curves for all-cause mortality (6.2% vs. 2.4%, log-rank p = 0.053) (A) and probability of composite endpoint (12.3% vs. 13.6%, log-rank p = 0.57) (B) comparing patients with and without baseline significant MR; all-cause mortality (3.5% vs. 12.5%, log-rank p = 0.12) (C) and probability of composite endpoints (12.5% vs. 20.8%, log-rank p = 0.49) (D) comparing patients with MR improvement to patients with MR persistence/worsening; all-cause mortality (3.5% vs. 2.4%, log-rank p = 0.62) (E) and probability of composite endpoints (12.5% vs. 13.6%, log-rank p = 0.78) (F) comparing patients with MR improvement to patients without baseline significant MR; all-cause mortality (2.2% vs. 0% vs. 19.0%, log-rank p = 0.016) (G) and probability of composite endpoints (13.3% vs. 14.3% vs. 19.0%, log-rank p = 0.83) (H) comparing patients with organic MR, functional MR, and mixed MR. MR — mitral regurgitation
In patients with baseline significant MR, older age (HR = 1.09, 95% CI: 1.01–1.18, p = 0.04), higher LVOT diameter (HR = 1.01, 95% CI: 1.01–1.02, p = 0.03), and higher SPAP (HR = 1.04, 95% CI: 1.00–1.07, p = 0.03) were associated with increased probability of the composite endpoint in the univariate analysis. In the multivariate analysis, older age was associated with poor prognosis (HR = 1.12, 95% CI: 1.01–1.24, p = 0.04), and higher SPAP remained independently associated with increased probability of the composite endpoint, with an adjusted HR of 1.05 (95% CI: 1.00–1.09, p = 0.04; Tab. 3).
Discussion
This study aimed to evaluate the changes and prognostic implications of concomitant significant MR in patients with severe AS undergoing TAVR. Nearly one-third of patients had significant MR at baseline, and 70% experienced MR improvement post TAVR. Smaller LAD and LVEDV, and greater improvement in LVEF and aortic mean gradient after TAVR were observed during the follow-up period in patients with significant MR, with a greater increase in LVEF linked to MR improvement. At 12-month follow-up, patients with MR improvement had significantly better improvement of NYHA class compared to those with persistent MR. No survival benefit disparity was demonstrated between patients with and without significant baseline MR, though a trend toward a lower composite endpoint rate was observed in those with MR improvement. Neither the presence of significant baseline MR nor MR improvement after TAVR correlated with clinical outcomes, while older age and higher SPAP were independently associated with worse outcomes after TAVR in patients with significant MR.
The prevalence of moderate-to-severe MR in AS patients undergoing TAVR, as seen in our study (31%), aligns with prior findings of 15–20% in other trials like PARTNER [11]. The mechanisms of MR in patients undergoing TAVR have been characterized as organic or functional [12, 13]. MR in these patients is mainly functional [8], caused by an imbalance in the closure of the mitral valve and mitral valve tethering due to left ventricular geometric changes from chronic pressure overload in AS. This leads to ventricular remodeling and sustained regurgitation from the ventricle to the atrium, often associated with left atrial enlargement and atrial fibrillation (AF). Our study also found a higher prevalence of AF and enlarged LAD and LVEDD in patients with significant MR, consistent with prior studies. In our study, organic MR was the most common etiology among patients with significant MR, followed by mixed MR. Patients with persistent or worsening MR after TAVR more often had organic MR than those with improvement. Additionally, patients with mixed MR showed the highest 1-year all-cause mortality in the overall cohort. The most frequent etiology of organic MR in patients undergoing TAVR is MAC, which is generally associated with increased age and cardiovascular risk factors [14]. Organic MR is less likely to improve after TAVR due to fixed structural lesions. Mixed MR may indicate both primary valve disease and adverse cardiac remodeling, contributing to poorer outcomes and higher mortality.
Previous studies have shown that concomitant MR improves in approximately 50–60% of patients after TAVR [15, 16]. In the PARTNER trial, MR improvement was reported in 58% of patients who underwent TAVR at 30 days [11]. In our study, we saw higher rates of improvement from baseline significant MR following TAVR. Of the 80 patients with baseline MR grade ≥ 2+, 70% of patients with moderate-to-severe MR experienced at least a one-grade improvement in the MR severity during the 12-month follow-up after TAVR. The prevalence of concomitant MR grade ≥ 3+ decreased from 23% to 7%. Improvement in MR following correction of severe AS using TAVR may be associated with a series of hemodynamic changes post TAVR. In the short term, MR improvement after the procedure may be related to a decrease in the left ventricular afterload and improved mitral leaflet tethering [17]. Intraventricular pressure significantly decreased after TAVR, leading to a reduction in the trans-mitral pressure gradient between the ventricle and atrium. In the long term, TAVR can lead to reverse cardiac remodeling, resulting in the restoration of ventricular geometry [18]. Several morphological and hemodynamic changes are involved in this process, including the subsequent gradual reversal of left ventricular concentric hypertrophy, regression of enlarged left ventricular cavities and diffuse fibrosis, reduction in LVEDV and mitral tethering forces, LVEF improvement, and normalization of diastolic function [19, 20]. Our study observed marked reductions in LAD and LVEDV, alongside significant LVEF improvement in patients with MR ≥ 2+, which indicated the potential occurrence of reverse cardiac remodeling. These changes likely contributed to better NYHA class in those with MR improvement.
Baseline moderate or severe MR is not linked to worse outcomes, which is consistent with our study [7]. Current evidence suggests that the key determinant for predicting prognosis in the concurrent AS with MR population is the change in MR grade after TAVR rather than the MR severity pre-TAVR [21, 22]. Therefore, identifying the predictors of MR improvement post TAVR is essential for adopting comprehensive treatment strategies for concurrent valve diseases. In the multivariate analysis, greater LVEF improvement remained an independent predictor of MR improvement, but other variables like pre-TAVR LVEDD, LVESD [8], LVEF [23], transaortic mean gradient, and pulmonary hypertension [24] described in previous study did not significantly differ between patients with MR improvement and persistence. This reflects the complex and heterogeneous nature of MR in TAVR patients, as organic and functional MR respond differently to TAVR. Patients with concurrent AS and MR represent a unique population, and the hemodynamic interaction between AS and MR could cause an overestimation of the MR grade due to the increase in end-systolic pressure in the presence of AS, which further complicates the pathophysiology of the disease. Predicting MR evolution based solely on echocardiographic parameters is challenging, and further investigation into factors like mitral valve tenting and annular dimensions is needed to better assess MR changes.
The effect of MR improvement on clinical outcomes in patients undergoing TAVR remains inconsistent. Cortes et al. [25] found no disparity in the overall or cardiovascular mortality between patients with improved MR and patients with persistent MR post TAVR. In contrast, Mauri et al. and Freitas-Ferraz et al. reported improved survival in patients who experienced MR improvement post TAVR [2, 8, 26]. While no significant reduction in all-cause mortality was found in patients with MR improvement, a trend toward lower composite endpoint rates was observed. Older age and SPAP were independently associated with worse outcomes post TAVR. This highlights the importance of identifying multi-factorial contributors to outcomes beyond MR improvement alone. Understanding the complex interaction between AS and MR, and exploring more objective measures, will aid in better stratification and treatment strategies for this patient population.
Study limitations
This study has several limitations. First, as a post-hoc analysis of the China-DVD2 cohort, key data such as detailed MR etiology and procedural details (e.g., valve type, pre/post-dilation) were unavailable due to the lack of prospective collection. Second, all patients were Chinese, limiting generalizability, especially given the higher prevalence of bicuspid valves in Asia. Third, echocardiographic assessments were site-reported without core lab review, introducing inter-center variability; although two experienced echocardiographers retrospectively reviewed key cases, limited image quality restricted detailed etiological analysis. Fourth, the COVID-19 pandemic affected follow-up, with echocardiographic data missing in 38.5% of patients with baseline significant MR. However, baseline characteristics were comparable, minimizing selection bias. The small sample size also limited the statistical power of subgroup analyses. Fifth, MR was graded semi-quantitatively as per current guidelines; future studies will include detailed anatomical and hemodynamic parameters (e.g., annular diameter, EROA). Lastly, no patients underwent mitral intervention during the 12-month follow-up, possibly due to short follow-up duration and limited procedural adoption in China. Ongoing follow-up and cohort expansion will help clarify the role and timing of such interventions.
Conclusions
Concomitant baseline MR grade ≥ 2+ was a frequent entity in the TAVR population, wherein most patients experienced MR improvement after TAVR and improved NYHA functional class. Baseline significant MR was not associated with worse clinical outcomes, and a trend toward improved prognosis was observed in patients with MR improvement. Older age and higher SPAP were predictors of worse outcomes in patients with AS and concurrent significant MR following TAVR. Patients with moderate or severe MR should be closely followed up after TAVR, while considering the multi-pathophysiological process involved in reverse cardiac remodeling after pressure overload correction. Evaluation of quantitative changes in MR and ventricular remodeling using reasonable methods is needed in the concurrent AS with MR population, which warrants validation through cohort studies with larger sample sizes.
Supplementary Information
Acknowledgments
Authors are deeply appreciative of the support from the clinical teams and patients at each of these centers in the China Degenerative Valve Disease II Cohort Study (China-DVD2 Study). This prospective multi-center study was made possible through the efforts and dedication of the following institutions: Beijing Hospital, The Second Affiliated Hospital of Nanchang University, The First Affiliated Hospital of Zhengzhou University, Guangdong Provincial People’s Hospital, The Second Affiliated Hospital, Zhejiang University School of Medicine, and Fuwai Hospital, China National Center for Cardiovascular Diseases.
Footnotes
Ethics statement: This study was approved by the institutional Ethics Committee (Approval No. 2021BJYYEC-167-01), and all patients provided informed consent to participate in this study and underwent the intervention procedure.
Authors’ contributions: H.P.Z. designed the research study; X.H.Z., R.S.Z., and H.P.Z. performed the research; X.H.Z., Y.G., X.W., and H.P.Z. collected, measured, and analyzed the data; X.H.Z. and H.P.Z. wrote, reviewed, and/or revised the manuscript; H.P.Z. supervised the study. All authors read and approved the final manuscript.
Funding: This research was funded by the National Key R&D Program of China, grant number 2020YFC2008100, and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, grant number 2024-JKCS-04.
Conflict of interest: The authors have no competing interest to declare.
Supplementary material: Suppl. Table 1. (available on Journal’s website)
ClinicalTrials.gov Identifier: NCT05044338.
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