Although the volume overload of pulmonary circulation improves after atrial septal defect (ASD) closure, the increasing left ventricular preload may contribute to mitral regurgitation (MR) deterioration. We aimed to evaluate the impact of MR after transcatheter ASD closure on clinical outcomes in adults. A total of 288 consecutive patients who underwent transcatheter ASD closure were enrolled. Changes in MR were assessed at 1 month after the procedure. The end point was defined as cardiovascular events. After the procedure, MR ameliorated in 3 patients and unchanged in 253, whereas MR deteriorated in 32. During a median follow-up of 24 months, patients with MR deterioration had no cardiovascular events, and the event-free survival rate was not different between patients with MR deterioration and those with MR amelioration or no-change (p = 0.355). Even in patients with MR deterioration, the New York Heart Association functional class improved after the procedure, with no cases of worsening functional class. Multivariate logistic regression analysis showed that MR deterioration was independently related to advanced age and female gender. The degree of enlargement of mitral valve annulus diameter after the procedure was greater in patients with MR deterioration than in those with MR amelioration or no-change, and it was correlated with the degree of MR deterioration. In conclusion, MR deterioration occurs in a minority of adult patients after transcatheter ASD closure; however, it is not linked with adverse outcomes. MR deterioration may be provoked by geometric changes in mitral valve annulus, especially in women with advanced age.
Transcatheter closure of atrial septal defect (ASD) has been established as an effective treatment for secundum-type ASD. Although the volume overload of pulmonary circulation improves after transcatheter ASD closure, the increasing left ventricular preload may contribute to mitral regurgitation (MR) because of the elevation of left ventricular filling pressure. The alterations of atrial function, including atrial stiffness because of the device, may be associated with MR. Additionally, the configuration change of the mitral ring or the device itself touching the ring may cause MR. However, limited information is available regarding MR related to ASD closure. Hence, the effect of MR after ASD closure on clinical outcomes and the potential mechanisms of the changes in MR remain unknown. Therefore, we aimed to evaluate the fate of MR after transcatheter ASD closure in adult patients and its impact on clinical outcomes and to identify factors related to MR deterioration, including cardiac geometry.
Methods
We investigated 337 consecutive adult patients (>18 years) who underwent transcatheter ASD closure in our institution from April 2008 to November 2012. Of those patients, 7 who had mitral valve (MV) prolapse and 42 who did not receive transthoracic echocardiography in our institution at 1 month after the procedure were excluded. The remaining 288 patients constituted our study population. All patients gave written informed consent for the procedure. The study was approved by the ethics committee of our institution. Indications for transcatheter ASD closure were a hemodynamically significant left-to-right shunt on cardiac catheterization and echocardiography and/or clinical symptoms of heart failure or paradoxical embolism. Exclusion criteria included pulmonary hypertension with pulmonary vascular resistance >8 Wood units and other concomitant congenital heart diseases.
Transcatheter ASD closure was performed as described previously, using the Amplatzer Septal Occluder (St. Jude Medical, St. Paul, Minnesota). All patients received aspirin 100 mg/day at least 48 hours before the procedure, and this was continued for 6 months. Clopidogrel was administered at a dose of 50 to 75 mg/day for 1 month after the procedure. Other medications, such as diuretics and antihypertension drugs, were continued.
Transthoracic echocardiography (iE33; Philips Medical Systems, Andover, Massachusetts, and Atrida; Toshiba Medical Systems, Tokyo, Japan) was scheduled before and at 1, 3, and ≥6 months after the procedure. The color Doppler jet area of MR and left atrial area at the time of midsystole were measured by the area trace method in the apical 4-chamber view, and the ratio of MR jet area to left atrial area was calculated. The grade of MR was determined by the ratio, where 0% to 10% was none/trivial, 10% to 20% was mild, 20% to 40% was moderate, and >40% was severe. MV annulus diameter was measured in the apical 4-chamber and 2-chamber views during systole using the frame-by-frame technique. Left and right ventricular diameters were measured in 2-dimensional parasternal long-axis views. Left ventricular ejection fraction was derived using Teichholz’s formula. Early diastolic MV flow velocity and early diastolic septal mitral annular velocity were measured by pulsewave Doppler and tissue Doppler imaging, respectively. The changes in MR were assessed at 1 month after the procedure in this study because the considerable changes in cardiac geometry occurred within 1 month after the procedure, and the influence of other factors, including medications for MR, was considered to be less at this time. The amelioration or deterioration of MR was defined as the change in at least 1 grade after the procedure.
Follow-up information was obtained by medical records, contact with the patient’s physicians, or interview with the patient or, if deceased, with family members. The end point was defined as cardiovascular events, including cardiovascular death, hospitalization because of heart failure or stroke, or new onset of atrial arrhythmias. Patients were followed from the date of the procedure until the date of first documentation of cardiovascular events or the latest of follow-up. The New York Heart Association functional class and plasma B-type natriuretic peptide levels were also assessed before and at the latest follow-up after the procedure.
Data are shown as mean ± SD for continuous variables and as number and percentage for categorical variables. Statistically significant differences were analyzed by the t test and Mann-Whitney U test for continuous variables and the χ 2 test for categorical variables. Univariate and multivariate logistic regression analyses were performed to identify factors related to MR deterioration after the procedure. Variables for univariate analysis included age, gender, ASD diameter, pulmonary-to-systemic blood flow ratio, pulmonary artery pressure, New York Heart Association functional class, diuretics use, MR grade, early diastolic septal mitral annular velocity, left ventricular end-diastolic diameter, and MV annulus diameter before the procedure. Odds ratios are shown with 95% confidence intervals. The relations between the changes in the ratio of MR jet area to left atrial area after the procedure and the changes in cardiac geometry after the procedure were evaluated by Pearson’s correlation coefficients. The event-free survival rate was estimated by Kaplan-Meier analysis and compared by the log-rank test. Statistical analysis was performed with JMP, version 8.0 (SAS Institute Inc., Cary, North Carolina), and significance was defined as a value of p <0.05.
Results
A total of 288 patients were enrolled in this study. Mean ASD diameter was 18 ± 7 mm. New York Heart Association functional class I was found in 149 patients, class II in 118, and class III in 21. Thirty patients had a history of hospitalization because of heart failure, and 66 were treated with diuretics before the procedure. Two hundred thirty-two patients had none/trivial MR, 44 had mild MR, and 12 had moderate MR. No patients had severe MR.
At 1 month after the procedure, 209 patients had none/trivial MR, 58 had mild MR, and 21 had moderate MR. MR ameliorated in 3 patients (1%) and unchanged in 253 (88%), whereas MR deteriorated in 32 (11%). Comparisons of baseline characteristics between patients with MR deterioration and those with MR amelioration or no-change are listed in Table 1 . Patients with MR deterioration were older and more likely to be women. Plasma B-type natriuretic peptide levels and the frequency of diuretics use were higher in patients with MR deterioration than in those with MR amelioration or no-change. Additional treatments of diuretics after the procedure were initiated in 3 patients with MR deterioration and in 12 with MR amelioration or no-change because high pulmonary artery pressure was observed during the procedure, and this frequency was not different between the 2 groups. Multivariate logistic regression analyses showed that MR deterioration was independently related to advanced age and female gender ( Table 2 ).
| Variable | All (n = 288) | MR amelioration or no-change (n = 256) | MR deterioration (n = 32) | p |
|---|---|---|---|---|
| Age (years) | 53 ± 17 | 52 ± 17 | 61 ± 15 | 0.007 |
| Female | 180 (63%) | 153 (60%) | 27 (84%) | 0.007 |
| ASD diameter (mm) | 18 ± 7 | 18 ± 7 | 18 ± 7 | 0.889 |
| Device size (mm) | 22 ± 6 | 22 ± 6 | 21 ± 7 | 0.796 |
| Pulmonary to systemic blood flow ratio | 2.6 ± 0.9 | 2.6 ± 0.9 | 2.6 ± 1.1 | 0.762 |
| Pulmonary artery pressure (mm Hg) | 16 ± 6 | 16 ± 5 | 18 ± 6 | 0.075 |
| Permanent atrial fibrillation | 26 (9%) | 21 (8%) | 5 (16%) | 0.168 |
| New York Heart Association functional class I/II | 267 (93%) | 240 (94%) | 27 (84%) | 0.055 |
| New York Heart Association functional class III | 21 (7%) | 16 (6%) | 5 (16%) | |
| B-type natriuretic peptide (pg/ml) | 70 ± 127 | 58 ± 98 | 162 ± 247 | <0.001 |
| Diuretics use before the procedure | 66 (23%) | 54 (21%) | 12 (38%) | 0.037 |
| Ratio of MR jet area to left atrial area (%) | 5.9 ± 6.7 | 5.9 ± 6.8 | 5.7 ± 5.4 | 0.851 |
| MR grade none or trivial/mild/moderate | 232/44/12 | 207/37/12 | 25/7/0 | 0.152 |
| Left ventricular end-diastolic diameter (mm) | 42 ± 4 | 42 ± 5 | 41 ± 4 | 0.520 |
| Left ventricular end-systolic diameter (mm) | 26 ± 4 | 26 ± 4 | 25 ± 5 | 0.328 |
| Left ventricular ejection fraction (%) | 69 ± 6 | 69 ± 6 | 70 ± 8 | 0.407 |
| Right ventricular end-diastolic diameter (mm) | 35 ± 6 | 35 ± 6 | 37 ± 6 | 0.102 |
| e’ (cm/s) | 10.2 ± 3.2 | 10.4 ± 3.2 | 9.1 ± 2.5 | 0.037 |
| E/e’ ratio | 7.8 ± 2.8 | 7.7 ± 2.8 | 8.6 ± 2.9 | 0.077 |
| Left atrial volume index (ml/m 2 ) | 41 ± 17 | 41 ± 16 | 42 ± 18 | 0.407 |
| MV annulus diameter in the apical 4-chamber view (mm) | 28 ± 4 | 28 ± 4 | 28 ± 3 | 0.484 |
| MV annulus diameter in the apical 2-chamber view (mm) | 29 ± 3 | 29 ± 3 | 29 ± 3 | 0.814 |
| Variable | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| OR (95% CI) | p | OR (95% CI) | p | |
| Age >60 years | 2.73 (1.30-5.99) | 0.008 | 2.78 (1.10-7.45) | 0.031 |
| Female | 3.64 (1.47-11.0) | 0.004 | 2.78 (1.08-8.30) | 0.034 |
| ASD diameter | 0.98 (0.93-1.02) | 0.335 | ||
| Pulmonary to systemic blood flow ratio | 0.86 (0.61-1.22) | 0.380 | ||
| Pulmonary artery pressure | 1.04 (0.99-1.09) | 0.108 | ||
| New York Heart Association functional class III | 2.78 (0.86-7.75) | 0.085 | 1.10 (0.25-4.29) | 0.893 |
| Diuretics use before the procedure | 2.24 (1.01-4.82) | 0.048 | 1.88 (0.68-4.96) | 0.217 |
| MR mild or moderate | 1.18 (0.45-2.76) | 0.716 | ||
| e’ | 0.90 (0.80-0.99) | 0.041 | 0.93 (0.82-1.05) | 0.240 |
| Left ventricular end-diastolic diameter | 0.96 (0.89-1.03) | 0.244 | ||
| MV annulus diameter in the apical 4-chamber view | 0.96 (0.88-1.03) | 0.260 | ||
During a median follow-up of 24 months (range 1 to 72 months), 7 (2%) of the 288 patients had cardiovascular events. Three patients were hospitalized because of heart failure, 1 had stroke, and 3 developed new onset of atrial arrhythmias. All cardiovascular events were observed in patients with MR amelioration or no-change, and no events were observed in those with MR deterioration. Kaplan-Meier analysis showed that the event-free survival rate was not different between the 2 groups (log-rank test, p = 0.355). The New York Heart Association functional class improved after the procedure, and no cases with worsening functional class were observed in the 32 patients with MR deterioration. Plasma B-type natriuretic peptide levels did not change at a median follow-up of 28 months in the 32 patients with MR deterioration (162 ± 247 to 101 ± 119 pg/ml, p = 0.218).
Echocardiographic parameters before and at 1 month after the procedure are listed in Table 3 . MV annulus diameter increased in patients with MR deterioration, whereas it unchanged in those with MR amelioration or no-change. The degree of enlargement of MV annulus diameter was greater in patients with MR deterioration than in those with MR amelioration or no-change (4-chamber view: 3.0 ± 1.9 vs −0.1 ± 2.0 mm, p <0.001; 2-chamber view: 2.3 ± 1.9 vs −0.6 ± 1.8 mm, p <0.001). The degree of enlargement of MV annulus diameter in the apical 4-chamber view was correlated with the degree of deterioration of the ratio of MR jet area to left atrial area (r = 0.350, p <0.001, Figure 1 ).
