ABSTRACT
Background
Right ventricular‐to‐pulmonary artery (RV‐PA) coupling is an important predictor of long‐term survival following transcatheter edge‐to‐edge repair. However, its impact on survival in patients undergoing indirect mitral annuloplasty is unknown. The study aimed to assess the impact of baseline RV‐PA coupling on survival following indirect mitral annuloplasty in heart failure patients.
Methods
Patients were classified according to baseline RV‐PA coupling: TAPSE (tricuspid annular plane systolic excursion)/PASP (pulmonary artery systolic pressure) > 0.55 (group 1), ≤ 0.55 ≥ 0.32 (group 2) and ≤ 0.32 (group 3). Clinical follow‐up and RV function were assessed 3 and 12 months following indirect annuloplasty.
Results
A TAPSE/PASP > 0.55 was found in 19 patients, while 47 patients showed a TAPSE/PASP ≤ 0.55 > 0.32 and 26 a TAPSE/PASP ≤ 0.32. A significant reduction in vena contracta and regurgitant volume compared to baseline was found in all groups at 3‐months and 12‐months follow‐up. One‐year mortality was significantly increased in group 3 compared to the other groups (group 1: 0.95, group 2: 0.91, group 3: 0.77; Log‐Rank test p = 0.018). In groups 2 and 3 the TAPSE/PASP significantly improved during the 12‐months follow‐up, while it remained unchanged in group 1 (group 1: baseline = 0.71 ± 0.03, 12‐months = 0.67 ± 0.01; group 2: baseline = 0.43 ± 0.06, 12‐months: 0.56 ± 0.04; group 3: baseline = 0.25 ± 0.06, 12‐months: 0.4 ± 0.03; p < 0.001).
Conclusions
RV‐PA uncoupling before indirect mitral annuloplasty is associated with poor survival. However, Carillon device implantation improved right heart function and RV‐PA coupling in patients with severe RV dysfunction at baseline. Therefore, Carillon device implantation can be a valuable option for transcatheter treatment of patients with FMR and right heart failure.
Keywords: functional mitral regurgitation, indirect mitral annuloplasty, mitral regurgitation, right heart failure, right ventricular to pulmonary artery coupling, transcatheter mitral valve repair
1. Introduction
Indirect mitral annuloplasty using the Carillon Mitral Contour System is one treatment option for patients with functional mitral regurgitation (FMR) and heart failure. It reduces mitral regurgitant volume and leads to left ventricular (LV) and left atrial (LA) reverse remodeling [1, 2, 3, 4]. Furthermore, functional patient outcomes such as NYHA classification are improved [2, 3].
Right ventricular‐to‐pulmonary artery (RV‐PA) coupling is a marker for right ventricular (RV) length‐force relationship and has major prognostic implications for patients with heart failure [5, 6, 7, 8]. It is non‐invasively assessed by transthoracic echocardiography as the ratio of tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) [5]. Impaired TAPSE/PASP ratio (< 0.55 mm/mmHg) is known as RV‐PA uncoupling [9]. Furthermore, a TAPSE/PASP ratio ≤ 0.32 mm/mmHg is associated with poor survival of heart failure patients.
Transcatheter edge‐to‐edge repair (TEER) improves clinical outcome of patients with heart failure and FMR, when heart failure symptoms persist despite guideline directed medical therapy (GDMT) [10]. RV dysfunction is associated with worse outcome in patients with heart failure undergoing TEER. Moreover, RV‐PA uncoupling was shown to be an important predictor of procedural outcome after TEER [11, 12, 13, 14, 15, 16]. Improvement in RV‐PA coupling after successful mitral TEER was found in 66% of the patients [17]. This effect was associated with lower NYHA class, less heart failure hospitalizations and a reduced risk of mortality [17, 18].
The effects of indirect mitral annuloplasty on RV dysfunction and RV‐PA coupling are unknown. One might speculate that a reduction of left atrial pressure leads to decreased RV afterload and improves RV‐PA coupling. Therefore, we aimed to evaluate the impact of RV‐PA coupling and RV dysfunction on the procedural outcome of Carillon device implantation in patients with FMR. Furthermore, changes in RV‐PA coupling induced by indirect mitral annuloplasty should be analyzed in regards of their prognostic value.
2. Methods
2.1. Study Population
The study was conducted in accordance with the Helsinki declaration and good clinical practice standards. All patients provided written informed consent for the use of their data. The present study was approved by the ethical committee of the University of Witten‐Herdecke (approval number: S‐246/2023). We performed a single‐center retrospective analysis of our patient database including 92 consecutive patients with FMR treated by indirect mitral valve annuloplasty between January 2016 and January 2023 (Carillon Mitral Contour System, Cardiac Dimensions, Kirkland, WA, USA). A local multidisciplinary heart team decision was made before Carillon device implantation. These patients were stratified into three treatment groups according to baseline right ventricular function using the TAPSE/PASP‐ratio (group 1 TAPSE/PASP > 0.55, group 2 TAPSE/PASP ≤ 0.55 > 0.32, group 3 TAPSE/PASP ≤ 0.32) [9, 14, 19, 20]. In these three cohorts, we obtained baseline characteristics, 3‐months and 12‐months clinical follow‐up including NYHA‐classification as well as transthoracic echocardiography follow‐up including RV function and quantitative mitral valve regurgitation assessment. A TAPSE/PASP ≤ 0.55 was considered as RV‐PA uncoupling. Figure 1 illustrates the study flow diagram. Clinical follow‐up was conducted through consultations that included a structured interview and transthoracic echocardiography at 3 months and at 12 months. If patients missed their scheduled follow‐up appointments, the study center contacted either the patient or their general practitioner.
Figure 1.
Study flow chart. CS, coronary sinus; FMR, functional mitral regurgitation; PASP, pulmonary artery systolic pressure; TAPSE, tricuspid annular plane systolic excursion.
2.2. Carillon Mitral Contour System
Eligibility criteria for coronary sinus (CS) based percutaneous annuloplasty using the Carillon Mitral Contour System included symptomatic (≥ NYHA II) heart failure patients with at least moderate FMR [21]. All patients were on stable heart failure medication according to the current guidelines [22]. Patients with primary or mixed mitral regurgitation were excluded.
Indirect mitral annuloplasty was performed by two experienced and certified implanters. The Carillon device consists of two self‐expanding nitinol anchors connected by a nitinol curvilinear segment. Via right transjugular access, a 10 French delivery catheter is placed in the right atrium directly in front of the CS. After unsheathing and fixation of the distal anchor in the CS, tension is applied to the system. Thus, anterior movement of the posterior part of the mitral annulus and the posterior mitral valve leaflet leads to a better coaptation and consecutive reduction of FMR. The last step consists of deploying the proximal anchor near the CS ostium to fix the tension. To prevent device‐related coronary artery compression, coronary angiography is performed repetitively throughout the procedure. If coronary artery compression occurs, the Carillon device can be retrieved [23]. Continuous transesophageal echocardiography is performed during the procedure for mitral valve assessment.
2.3. Echocardiography
Baseline and follow‐up transthoracic echocardiographic measurements were performed using a Philips iE 33 or EPIQ echocardiography system (Philips, Amsterdam, Netherlands). The echocardiographic parameters for quantitative mitral valve assessment (Vena contracta, proximal isovelocity surface area (PISA), effective regurgitant orifice area (EROA) and regurgitant volume (RegVol)) were evaluated according to current recommendations [24]. A standard classification was used to grade the severity of mitral regurgitation [25]. Quantitative right ventricular (RV) function measurements (Tricuspid Annular Plane Systolic Excursion (TAPSE), Pulmonary Artery Systolic Pressure (PASP), Right Ventricular Enddiastolic Diameter (RVEDD), Right Atrial area (RA area), Right Ventricular Fractional Area Change (RV FAC)) were conducted in accordance with current recommendations [26, 27].
2.4. Statistical Analysis
Statistical analysis was performed using PASW statistics 18 software (SPSS, Chicago, USA). The Kolmogorov‐Smirnov test was used to test all variables for normal distribution. Results are given as mean ± standard error (SEM) in case of normal distribution. The Kruskal‐Wallis test was used for discrete variables and one‐way ANOVA with Tukey posthoc testing for continuous variables to evaluate differences between groups and subgroups. The Mann‐Whitney‐U test was performed for ordinal data. Kaplan‐Meier curves were used for visualizing long‐term survival. In this setting, the Log‐Rank test was used to evaluate statistical significance. Therefore, 1‐year event rates were calculated as product‐limit estimator. Multivariate analysis was performed using a cox regression analysis. A p‐value < 0.05 was considered as statistically significant.
3. Results
Patients baseline clinical, laboratory and echocardiographic parameters are illustrated in table 1. Patients were classified to normal, impaired and severely impaired RV‐PA coupling according to their TAPSE/PASP ratio. A TAPSE/PASP > 0.55 (group 1) was found in 19 patients, while 47 patients showed a TAPSE/PASP ≤ 0.55 > 0.32 (group 2) and 26 patients a TAPSE/PASP ≤ 0.32 (group 3). Mean age was 73.6 ± 2.3 years in group 1, 76.9 ± 1.3 years in group 2 and 75.8 ± 1.3 years in group 3 (p = 0.397). The majority of patients in the three groups were male (group 1 n = 13, group 2 n = 30, group 3 n = 18; p = 0.876). Cardiovascular risk factors including arterial hypertension, diabetes mellitus, smoking status, coronary artery disease and previous heart surgery were comparable in all three groups (Table 1). Furthermore, 57.9% of the patients in group 1 (n = 19), 80.9% of group 2 (n = 47) and 84.6% of group 3 (n = 26) had atrial fibrillation (p = 0.077). Baseline left ventricular ejection fraction (LVEF) and left ventricular enddiastolic diameter (LVEDD) determined by transthoracic echocardiography was similar in the three groups (group 1: 39.7 ± 2.6%, 55.3 ± 1.9 mm; group 2: 40.5 ± 2.0%, 53.3 ± 1.1 mm; group 3: 37.7 ± 2.2%, 56.3 ± 1.4 mm; p = 0.065 and p = 0.244). Baseline echocardiographic right heart parameters (TAPSE, PASP, RVEDD, and TAPSE/PASP) were significantly different for all TAPSE/PASP groups (Table 1). In accordance, right ventricular fractional area change (RVFAC) was significantly reduced according to RV‐PA uncoupling (group 1: 41.5 ± 2.2%, group 2: 38.2 ± 1.4%, group 3: 28.6 ± 1.8%; p < 0.001). No difference in baseline right atrial (RA) area was found (group 1: 23.2 ± 2.0 cm2, group 2: 24.0 ± 1.1 cm2, group 3: 26.5 ± 1.5 cm2; p = 0.322).
Table 1.
Patients characteristics.
| RVPA > 0.55 n = 19 | RVPA ≤ 0.55 > 0.32 n = 47 | RVPA ≤ 0.32 n = 26 | |||||
|---|---|---|---|---|---|---|---|
| n | % or Mean ± SEM | n | % or Mean ± SEM | n | % or Mean ± SEM | p‐value | |
| Age | 19 | 73.6 ± 2.3 | 47 | 76.9.0 ± 1.3 | 26 | 75.8 ± 1.3 | 0.397 |
| Male | 13 | 68.0 | 30 | 64.0 | 18 | 69.0 | 0.876 |
| Patients history | |||||||
| Arterial hypertension | 18 | 95.0 | 41 | 91.0 | 25 | 96.0 | 0.722 |
| Diabetes mellitus | 4 | 21.0 | 9 | 19.5 | 11 | 42.0 | 0.086 |
| Smoker | 4 | 21.0 | 6 | 13.0 | 3 | 12.0 | 0.700 |
| Coronary artery disease | 14 | 73.7 | 31 | 66.0 | 15 | 47.7 | 0.536 |
| PCI | 11 | 57.9 | 22 | 46.7 | 11 | 42.3 | 0.583 |
| Previous heart surgery | 5 | 26.3 | 7 | 14.9 | 8 | 30.8 | 0.254 |
| Coronary artery bypass grafting | 2 | 10.5 | 7 | 14.9 | 8 | 30.8 | 0.153 |
| Aortic Valve Replacement | 2 | 10.5 | 1 | 2.1 | 1 | 3.8 | 0.321 |
| Mitral Valve Surgery | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1.000 |
| TAVR | 1 | 5.3 | 1 | 2.1 | 0 | 0.0 | 0.498 |
| Atrial fibrillation | 11 | 57.9 | 38 | 80.9 | 22 | 84.6 | 0.077 |
| Transthoracic echocardiography | |||||||
| LVEF (%) | 19 | 39.7 ± 2.6 | 47 | 40.5 ± 2.0 | 26 | 37.7 ± 2.2 | 0.065 |
| LVEDD (mm) | 19 | 55.3 ± 1.9 | 47 | 53.3 ± 1.1 | 26 | 56.3 ± 1.4 | 0.244 |
| Mitral annulus diameter (cm) | 19 | 4.2 ± 0.1 | 47 | 4.4 ± 0.3 | 26 | 4.4 ± 0.1 | 0.634 |
| PASP (mmHg) | 19 | 29.9 ± 1.6 | 47 | 45.3 ± 1.4 | 26 | 52.3 ± 2.5 | < 0.001 |
| TAPSE (mm) | 19 | 20.7 ± 1.0 | 47 | 19.2 ± 0.6 | 26 | 12.8 ± 3.1 | < 0.001 |
| RVEDD (mm) | 19 | 38.8 ± 1.6 | 47 | 41.3 ± 0.9 | 26 | 44.1 ± 1.2 | 0.028 |
| RA area (cm2) | 19 | 23.2 ± 2.0 | 47 | 24.0 ± 1.1 | 26 | 26.5 ± 1.5 | 0.322 |
| RVFAC (%) | 19 | 41.5 ± 2.2 | 47 | 38.2 ± 1.4 | 26 | 28.6 ± 1.8 | < 0.001 |
| TAPSE/PASP (mm/mmHg) | 19 | 0.7 ± 0.03 | 47 | 0.4 ± 0.01 | 26 | 0.2 ± 0.04 | < 0.001 |
| FMR Grading | |||||||
| FMR 1+ | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1.000 |
| FMR 2+ | 1 | 5.3 | 0 | 0.0 | 0 | 0.0 | 0.146 |
| FMR 3+ | 8 | 42.1 | 18 | 38.3 | 12 | 46.2 | 0.777 |
| FMR 4+ | 10 | 52.6 | 29 | 61.7 | 14 | 53.8 | 0.777 |
| Vena contracta (mm) | 19 | 5.9 ± 0.3 | 47 | 6.0 ± 0.2 | 26 | 6.0 ± 0.2 | 0.978 |
| EROA (cm2) | 19 | 0.2 ± 0.02 | 47 | 0.3 ± 0.01 | 26 | 0.2 ± 0.02 | 0.858 |
| PISA (mm) | 19 | 7.0 ± 0.3 | 47 | 7.4 ± 0.2 | 26 | 7.1 ± 0.3 | 0.513 |
| Regurgitant Volume (ml) | 19 | 34.4 ± 2.9 | 47 | 35.5 ± 2.4 | 26 | 35.6 ± 3.1 | 0.962 |
| Right heart catheterization | |||||||
| Pulmonary Hypertension (mPAP > 20 mmHg) | 42.9 (6/14) | 78.0 (32/41) | 100 (17/17) | < 0.001 | |||
| Pre‐Capillary PH | 0.0 | 0.0 | 0.0 | 1.000 | |||
| Post‐Capillary PH | 42.9 | 78.0 | 100.0 | 0.004 | |||
| Combined Pre‐/Postcapillary PH | 0.0 | 0.0 | 0.0 | 1.000 | |||
| PASP (mmHg) | 14 | 28.9 ± 2.0 | 41 | 45.2 ± 1.7 | 17 | 65.6 ± 3.4 | < 0.001 |
| mPAP (mmHg) | 14 | 18.7 ± 1.3 | 41 | 30.0 ± 1.3 | 17 | 39.4 ± 2.1 | < 0.001 |
| PAWP (mmHg) | 14 | 20.1 ± 2.2 | 41 | 22.5 ± 1.2 | 17 | 29.1 ± 2.5 | 0.031 |
| Dyspnea | |||||||
| NYHA II | 2 | 10.5 | 4 | 8.5 | 1 | 3.8 | 0.671 |
| NYHA III | 11 | 57.9 | 32 | 68.0 | 18 | 69.2 | 0.684 |
| NYHA IV | 6 | 31.6 | 11 | 23.5 | 7 | 27.0 | 0.788 |
| Laboratory results | |||||||
| NT‐proBNP (pg/ml) | 19 | 5326.4 ± 915.7 | 46 | 5103.9 ± 564.3 | 25 | 7135.5 ± 961.2 | 0.153 |
| Creatinine (mg/dl) | 19 | 1.4 ± 0.1 | 47 | 1.3 ± 0.1 | 26 | 1.5 ± 0.1 | 0.443 |
| Hemoglobin (g/dl) | 19 | 12.8 ± 0.4 | 47 | 12.7 ± 0.2 | 26 | 12.7 ± 0.5 | 0.962 |
| Baseline medication | |||||||
| Beta blocker | 18 | 94.7 | 46 | 97.9 | 26 | 100.0 | 0.493 |
| ACEI or ARB or ARNI | 17 | 89.5 | 41 | 87.2 | 24 | 92.3 | 0.801 |
| MRA | 8 | 42.1 | 19 | 40.4 | 11 | 42.3 | 0.985 |
| Diuretic | 19 | 100.0 | 44 | 93.6 | 26 | 100.0 | 0.230 |
| Oral anticoagulation | 13 | 68.4 | 35 | 74.5 | 22 | 84.6 | 0.427 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; EF, ejection fraction; EROA, effective regurgitant orifice area; FMR, functional mitral regurgitation; LV, left ventricle; LVEDD, left ventricular enddiastolic diameter; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PASP, systolic pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PCI, percutaneous coronary intervention; PH, pulmonary hypertension; PISA, proximal isovelocity surface Area; RA, right atrial; RVEDD, right ventricular enddiastolic diameter; RVFAC, right ventricular fractional area change; RVPA, TAPSE/PASP; SEM, standard error of the mean; TAPSE, tricuspid annular plane systolic excursion; TAVR, transcatheter aortic valve replacement.
All patients had at least moderate FMR before indirect mitral annuloplasty. Quantitative echocardiographic mitral regurgitation assessment using the parameters vena contracta, effective regurgitant orifice area (EROA), proximal isovelocity surface area (PISA) and regurgitant volume were similar in the RV‐PA coupling groups (Table 1). Baseline New York Heart Association (NYHA) classification was not different between the groups (Table 1).
Procedural complications related to Carillon device implantation were rare regardless of RV‐PA coupling. Only one minor bleeding and one coronary sinus perforation, which was managed by successful balloon occlusion of the CS, occurred. Compression of left circumflex artery due to the Carillon Mitral Contour System could be addressed by resheathing and repositioning the device in five cases and no procedure was aborted without successful implantation.
Quantitative echocardiographic MR assessment showed a significant reduction in vena contracta compared to baseline in all three treatment groups at 3‐months and 12‐months follow‐up (Figure 2A). Additionally, EROA and regurgitant volume (RegVol) were significantly decreased following indirect mitral annuloplasty in all groups at 3‐months and 12‐months follow‐up (Figure 2B,C). In group 2 as well group 3, mitral annulus diameter was significantly reduced at 3‐months and 12‐months follow‐up, while group 1 showed no significant reduction (Figure 2D).
Figure 2.
Echocardiographic assessment following indirect mitral annuloplasty in functional mitral regurgitation. Quantitative echocardiographic assessment determining vena contracta (A), effective regurgitation orifice area (EROA, B), Regurgitant Volume (RegVol, C) and mitral annulus diameter (D) at baseline, 3‐Months Follow‐Up (3Mo‐FU) and 12‐Months Follow‐Up (12Mo‐FU) in functional mitral regurgitation (FMR). Mean ± SEM. §, #, * versus baseline (color indicating TAPSE/PASP group), p < 0.05. PASP, pulmonary artery systolic pressure; TAPSE, tricuspid annular plane systolic excursion.
Qualitative mitral valve assessment revealed improved FMR class following indirect mitral annuloplasty (Figure 3A). Furthermore, NYHA classification was improved at 3‐months and at 12‐months follow‐up compared to baseline (Figure 3B).
Figure 3.
Clinical and echocardiographic assessment following indirect mitral annuloplasty in functional mitral regurgitation. Functional mitral regurgitation (FMR) class (A) and New York Heart Association (NYHA) classification (B) at baseline, 3‐Months Follow‐Up (3Mo‐FU) and 12‐Months Follow‐Up (12Mo‐FU). PASP, pulmonary artery systolic pressure; TAPSE, tricuspid annular plane systolic excursion.
The Kaplan‐Meier curves visualize long‐term survival according to RV‐PA coupling (Central Illustration illustration 1, 4). 1‐year mortality was significantly increased in group 3 compared to group 1 and 2 (Log‐Rank test p = 0.018). At 12‐months follow‐up, one death occurred in group 1, three deaths in group 2, while six patients died in group 3. Following a multivariate analysis of the baseline parameters, only the TAPSE/PASP ratio was identified as an independent predictor of 1‐year mortality, whereas age, gender, atrial fibrillation, and LVEF were not (Table 2).
Central illustration 1.
Kaplan‐Meier curves of 1‐year survival following indirect mitral annuloplasty in functional mitral regurgitation. Kaplan‐Meier curve for 1‐year survival in patients with functional mitral regurgitation (FMR) undergoing indirect mitral annuloplasty. PA, pulmonary artery; PASP, pulmonary artery systolic pressure; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion.
Figure 4.
Echocardiographic right ventricular function assessment following indirect mitral annuloplasty in functional mitral regurgitation. Quantitative echocardiographic right ventricular function assessment determining tricuspid annular plane systolic excursion (TAPSE, A), pulmonary artery systolic pressure (PASP, B), TAPSE/PASP‐ratio (C), right atrial (RA) area (D), right ventricular enddiastolic diameter (RVEDD, E) and right ventricular fractional area change (RVFAC, F) at baseline, 3‐Months Follow‐Up (3Mo‐FU) and 12‐Months Follow‐Up (12Mo‐FU). Mean ± SEM. # versus TAPSE/PASP > 0.55, § versus TAPSE/PASP ≤ 0.32, * versus baseline (color of the star corresponding to TAPSE/PASP group color), p < 0.05.
Table 2.
Multivariate baseline predictors of 1‐year mortality (cox regression analysis).
| Baseline parameters | Adjusted Hazard Ratio (95% Confidence Interval) | p‐value |
|---|---|---|
| Age | 0.95 (0.89–1.02) | 0.148 |
| Sex | 1.32 (0.41–4.23) | 0.646 |
| TAPSE/PASP ratio | 0.1 (0.05–0.60) | 0.030 |
| Atrial fibrillation | 1.55 (0.32–7.62) | 0.590 |
| LVEF | 1.03 (0.98–1.08) | 0.142 |
Abbreviations: LVEF, Left Ventricular Ejection Fraction; PASP, Pulmonary Artery Systolic Pressure; TAPSE, Tricuspid Annular Plane Systolic Excursion.
Echocardiographic parameters of right heart function at baseline and following indirect mitral annuloplasty for all groups were analyzed and are shown in Figure illustration 1, 4. TAPSE was significantly reduced in group 3 at baseline, at 3‐months follow‐up and at 12‐months follow‐up compared to group 1 (Figure illustration 1, 4). Furthermore, TAPSE was not different for group 1 and 2 at baseline, 3‐months and 12‐months follow‐up (Figure illustration 1, 4). In group 3 TAPSE improved significantly following indirect mitral annuloplasty at 3‐ and 12‐months follow‐up compared to baseline (Figure illustration 1, 4). PASP was significantly lower at baseline, 3‐months and 12‐months follow‐up in group 1 compared to group 3 (Figure illustration 1, 4). At baseline PASP was significantly higher in group 3 compared to group 2 (Figure illustration 1, 4).
At baseline TAPSE/PASP was significantly higher in group 1 compared to group 2 and 3 (Figure illustration 1, 4). In both groups 2 and 3 the TAPSE/PASP significantly improved during the 12‐months follow‐up, while it remained unchanged in group 1 (Figure illustration 1, 4). At 3‐months and 12‐months follow‐up TAPSE/PASP was significantly higher in group 1 compared to group 2 and 3 (Figure 4C).
Right atrial (RA) area was similar in all treatment groups at baseline and remained unchanged during the 12‐months follow‐up in all groups (Figure illustration 1, 4). Right ventricular enddiastolic diameter (RVEDD) was significantly increased in group 3 compared to group 1 at baseline, 3‐ and 12‐months follow‐up, while right ventricular fractional area change (RVFAC) was significantly decreased in group 3 compared to group 1 at baseline, 3‐ and 12‐months follow‐up (Figure illustration 1, 4). However, in all groups RVEDD remained unchanged during the follow‐up, while RVFAC improved at 12‐months follow‐up in group 3 (Figure illustration 1, 4).
4. Discussion
RV dysfunction is associated with worse clinical outcome in heart failure patients undergoing TEER. In this setting, RV‐PA uncoupling was independently related to reduced survival rate after TEER [5, 6, 7, 8]. To date, no clinical trial had been published comparing changes in RV function in heart failure patients undergoing indirect mitral annuloplasty. In our Carillon registry, we compared survival and echocardiographic right heart parameters in patients undergoing indirect mitral valve annuloplasty using the Carillon Mitral Contour System according to baseline RV‐PA coupling. Mortality was significantly increased after Carillon implantation in severe RV‐PA uncoupling (TAPSE/PASP ≤ 0.32). Thus, our analysis demonstrated impaired survival following indirect mitral annuloplasty in patients with RV‐PA uncoupling. Furthermore, TAPSE/PASP ratio was found as an independent predictor of 1‐year mortality in patient undergoing Carillon device implantation following a multivariate analysis. These findings are in accordance with the results of current clinical trials on RV‐PA coupling in patients undergoing TEER [11, 12, 13, 14, 15, 16, 28]. However, impaired baseline right heart function leads to RV remodeling, dysfunction, and consecutive worsening of heart failure [29]. This is associated with reduced survival regardless of interventional mitral valve repair. Therefore, we found RV‐PA uncoupling to be a marker of reduced long‐term survival in patients undergoing indirect mitral annuloplasty. Therefore, adequate patient selection in regard of right heart function is important for mitral TEER and Carillon device implantation.
Right heart function could be assessed by transthoracic echocardiography in clinical routine. It has major prognostic implications for patients with heart failure and FMR. Our study revealed a significant improvement in TAPSE and PASP following indirect mitral annuloplasty in patients with severe RV‐PA uncoupling (TAPSE/PASP ≤ 0.32) during 12‐months follow‐up. This positive effect on major right heart echocardiographic parameters could not be confirmed for patients with a TAPSE/PASP ≤ 0.55 > 0.32. However, there was a trend for improved TAPSE and PASP without reaching statistical significance in this group of patients. Our results indicate that the extend of improvement in RV function following indirect mitral annuloplasty depends on baseline RV dysfunction. This theory is further strengthened by the fact, that TAPSE/PASP as a marker of RV‐PA coupling significantly increases following indirect mitral annuloplasty in patients with impaired baseline right heart function. Other studies have demonstrated similar results in the setting of TEER [17, 28]. The effect of improved RV function after transcatheter mitral valve repair in the setting of impaired baseline RV function might be explained by a reduction in pulmonary congestion and RV afterload [30].
As previously reported in the setting mitral TEER the proportion of AF is higher when RV‐PA coupling is impaired [16]. A multivariate analysis did not reveal AF as an independent predictor of mortality. However, atrial arrhythmias and RV‐PA coupling are strongly linked to each other. Atrial dilatation as a consequence of RV dysfunction promotes the initiation of atrial fibrillation. On the other hand, atrial fibrillation is associated with further right ventricular deterioration and enhances RV‐PA uncoupling. Therefore, rhythm control in heart failure patients with relevant FMR might play a crucial role in preventing RV‐PA uncoupling, while transcatheter mitral valve repair before RV‐PA uncoupling could impact the onset of atrial fibrillation [31, 32].
Indirect mitral annuloplasty is known for LV reverse remodeling and reduction of LVEDD and left ventricular volume during follow‐up [1]. One might speculate that Carillon device implantation might lead to right ventricular reverse remodeling. However, we obtained no reduction in RVEDD at 3‐ and 12‐months follow‐up indicating no effect of indirect mitral annuloplasty on right ventricular remodeling. Furthermore, left atrial volumes were reduced following Carillon device implantation [4]. In our Carillon registry we found no improvement in RA area following indirect mitral annuloplasty. The absence of RA area and RVEDD reduction due to indirect mitral annuloplasty might be explained by the small sample size of each cohort. However, we found a significant improvement in RVFAC in the TAPSE/PASP ≤ 0.32 group at 12‐months follow‐up. This late improvement in RV function might be due to reverse RV remodeling, since similar effects are known for the left ventricle after Carillon device implantation [1].
In the treatment of FMR indirect mitral valve annuloplasty using the Carillon Mitral Contour System has shown to be effective and safe [1, 2, 3]. Echocardiographic MR parameters such as EROA, regurgitant volume and vena contracta are improved, while adverse event rate is low [1, 2, 3, 32, 33, 34]. Furthermore, following Carillon device implantation NYHA classification is significantly reduced during long‐term follow‐up [1, 2, 3]. In our l Carillon registry, we confirmed this improvement in qualitative and quantitative echocardiographic MR parameters and NYHA classification during a 12‐months follow‐up regardless of RV‐PA coupling. Also, mitral annulus diameter was reduced due to indirect mitral annuloplasty as previously described [1, 2, 3, 33].
Our registry confirmed a low procedural complication rate with no procedural death in a cohort of 92 patients. Therefore, Carillon device implantation is safe and compared to transcatheter edge‐to edge repair complications such as stroke or pericardial tamponade are rare [10].
In summary we showed for the first time that RV‐PA coupling is associated with long‐term survival following indirect mitral annuloplasty using the Carillon Mitral Contour System. Especially in severe RV‐PA uncoupling an increased 1‐year mortality was found. However, indirect mitral annuloplasty improves RV‐PA coupling and right heart function during a 12‐months follow‐up in the setting of impaired RV function. Therefore, Carillon device implantation is an option for transcatheter treatment of selected patients with FMR and right heart failure.
5. Study Limitations
This study has potential limitations due to its retrospective, non‐randomized and single‐center study design. TAPSE/PASP thresholds defining RV‐PA coupling vary among the studies in structural heart disease. Severe RV‐PA coupling was found to be < 0.32 mm/mmHg in patients with pulmonary hypertension [9] and TAVR populations [19, 20]. For FMR patients treated by mitral TEER a cut‐off of 0.274 mm/mmHg or 0.36 mm/mmHg was obtained [14, 16]. Severe RV‐PA coupling was defined as 0.32 mm/mmHg in this study. This threshold showed a significant impact on patient mortality across multiple studies [14, 19, 20]. Normal RV‐PA coupling is not yet defined for patients with FMR due to left heart disease. Therefore, a TAPSE/PASP ratio of > 0.55 mm/mmHg, as established in transcatheter aortic valve replacement studies, was used in this study [19, 20]. No additional cardiac imaging, such as cardiac magnetic resonance or computed tomography, was performed apart from echocardiography. Moreover, the study has a limited follow‐up period of 12 months. Three‐dimensional chamber volumes were not assessed using transthoracic echocardiography, and measurements like RVEDD, which rely on end‐diastolic diameters, have limitations in accurately evaluating reverse remodeling. Therefore, the results should be regarded as hypothesis generating and need to be supported by prospective multi‐center trials.
6. Conclusion
Indirect mitral annuloplasty improved echocardiographic parameters of right heart function and RV‐PA coupling in patients with RV dysfunction. In heart failure patients RV‐PA uncoupling has a negative impact on 1‐year mortality following indirect mitral annuloplasty using the Carillon Mitral Contour system. Therefore, Carillon device implantation is an option for transcatheter treatment of selected patients with FMR and right heart failure.
Conflicts of Interest
Dennis Rottländer received educational grants from Abbott. Milad Golabkesh received receipt of Honoria from Shockwave Medical. Hubertus Degen is a consultant for Biotronik and Cardiac Dimensions. Michael Haude is a consultant for Biotronik, Orbus Neich, Robocath, Shockwave Medical and Cardiac Dimensions. He received institutional grants and lecture fees from Biotronik, Cardiac Dimensions, Orbus Neich, SMT and Philips. The other authors have no conflicts of interest to declare.
Dennis Rottländer and Milad Golabkesh contributed equally.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. The data of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request. The data of this study are available from the corresponding author upon reasonable request.