Whether the relief of chronic right atrial (RA) volume load by device closure of an atrial septal defect (ASD) normalizes RA size is unknown. The present study evaluated the prevalence and determinants of incomplete RA reverse remodeling (RAR) after ASD closure in adults. Transthoracic echocardiography was performed in 44 consecutive patients with secundum ASD (age 43 ± 17 years, 10 men) without a history of atrial arrhythmia shortly before and at 3 months after device closure of ASD. The pulmonary/systemic flow ratio was derived using invasive oximetry. The RA size had significantly decreased at 3 months of follow-up (RA volume index [RAVI] 52 ± 29 to 27 ± 17 ml/m ^{2 }, p <0.001). Incomplete RAR (defined as a RAVI of ≥21 ml/m ^{2 }) was detected in 25 patients (57%) after closure. They were older, had a larger pulmonary/systemic flow ratio, a higher pulmonary arterial systolic pressure, more tricuspid regurgitation, and larger RA, left atrial, and right ventricular sizes before closure than those with a normalized right atrium. Before closure, RAVI was the only independent determinant for incomplete RAR (odds ratio 1.115, 95% confidence interval 1.019 to 1.220; p = 0.018). A cutoff value of RAVI of ≥40 ml/m ^{2 }has a sensitivity of 84% and specificity of 72% in the receiver operating characteristic curve. The preclosure RAVI correlated moderately with the shunt-duration index, calculated by multiplying the age to pulmonary/systemic flow ratio ( *r *= 0.64, p <0.01). In conclusion, incomplete RAR occurred in >1/2 of the adult patients at 3 months after ASD device closure and was related to excessive preclosure RA dilation.

The transcatheter approach has largely replaced conventional surgery for closure of secundum atrial septal defects (ASDs) since the past decade. Plenty of data have shown that device closure of an ASD could lead to improvement in biventricular function and reduction of the right atrial (RA) size. These hemodynamic changes are possibly related to improvement of the symptoms and quality of life scores observed in patients with ASD who have undergone device closure. However, the development of late-onset atrial arrhythmia (atrial fibrillation or flutter), which carries significant morbidity and, occasionally, death, has been reported in these patients despite apparently successful surgical or device closure. Although atrial enlargement has been consistently shown to be an important determinant of atrial arrhythmia, prospective studies to address whether relief of chronic RA volume loading by transcatheter closure of the ASD leads to a normalization of the RA size are lacking. Therefore, the aims of the present study were to characterize the pattern of RA remodeling and to evaluate the prevalence and determinants of incomplete RA reverse remodeling (RAR) after device closure of an ASD.

## Methods

From June 2006 to April 2010, 44 consecutive adult patients with successful device closure of isolated secundum ASD received transthoracic echocardiography shortly before and at 3 months after closure. The exclusion criteria included patients with a history of atrial arrhythmia, left ventricular (LV) ejection fraction of <50%, suboptimal echocardiographic windows, a significant residual shunt after closure (defined as 2-dimensional color flow Doppler width >3 mm at 3 months of follow-up), more than mild mitral or aortic valve disease or other concomitant congenital cardiac defects, such as ventricular septal defect, patent ductus arteriosus, pulmonary valve stenosis, and complete or partial anomalous pulmonary venous connection. The clinical information collected included demographics, the presence of co-morbidities or symptoms, systemic blood pressure, and heart rate readings. All participants provided written informed consent, and the ethics committee of the institution approved the study.

Hemodynamic assessment was performed using cardiac catheterization with the patient under sedation and local anesthesia. The pulmonary arterial systolic pressure was measured with standard fluid-filled catheters, and the pulmonary/systemic flow (Qp/Qs) ratio was calculated with oximetry using Fick’s principle, as previously reported. The presence of a large shunt was defined as a Qp/Qs ratio of ≥1.5:1. The shunt duration index was calculated by multiplying the patient’s age at closure with the Qp/Qs ratio. Device closure of ASD was performed under continuous guidance of intracardiac echocardiography (Acunav, Acuson, Mountain View, California). Amplatzer septal occluders (AGA Medical Corporation, Golden Valley, Minnesota) with appropriate sizes were implanted, as previously described. Oral aspirin and clopidogrel were prescribed for 6 months after ASD closure.

Two-dimensional transthoracic echocardiography (Vivid 7, Vingmed-General Electric, Horten, Norway) was performed at 1 day before and 3 months after ASD closure and all echocardiographs with ≥5 consecutive beats in sinus rhythm were digitally recorded for quantitative off-line analysis (EchoPac PC, version 7.0.0, Vingmed-General Electric). The RA volumes were assessed at different phases of the cardiac cycle using the monoplane area–length method at the apical 4-chamber view. Incomplete RAR was defined as the RA volume measured at end-systole indexed to the body surface area (RAVI) ≥21 ml/m ^{2 }. The left atrial volumes were evaluated using a similar method with the biplane area–length method. The total emptying fraction of both atria was calculated using the following formula : total emptying fraction = (maximum volume − minimum volume)/maximum volume × 100%.

The right ventricular (RV) and LV volumes and ejection fractions were assessed using the biplane Simpson method. The degree of tricuspid regurgitation was assessed by tracing the regurgitant jet area within the right atrium using 2-dimensional color Doppler echocardiography. The minimum and maximum inferior vena cava diameters were measured from subcostal M-mode echocardiograms, and the collapse index was defined as the ratio of the difference between the maximum and minimum diameter to the maximum diameter. Two experienced investigators who were unaware of the clinical data performed the off-line analyses independently, with the echocardiographic examinations scrambled in a random order.

The inter- and intraobserver variability was assessed in 20 randomly chosen patients. The variability was calculated as the percentage error, derived as the absolute difference between 2 sets of measurements, divided by the mean of the observations.

Statistical software of SPSS version 17 (SPSS Inc, Chicago, Illinois) was used to analyze all the data. All continuous variables are expressed as the mean ± SD and Kolmogorov-Smirnov test was applied to test the normality. The paired *t *test and independent *t *test were used to compare the mean value of the parametric values, as appropriate. The categorical variables are expressed as the frequency and were compared using the Pearson chi-square test or Fisher’s exact test, as appropriate. Pearson’s correlation was performed to test the correlations among the age at closure, Qp/Qs ratio, shunt duration index, the degree of tricuspid regurgitation, and the preclosure RAVI. Univariate and multivariate logistic regression analyses were performed to identify potential clinical and echocardiographic predictors of incomplete RAR at 3 months. Receiver operating characteristic curve was performed to determine the cutoff value of the potential parameter that predicted incomplete RAR. A significant difference was defined as p <0.05 (2-tailed).

## Results

A total of 44 consecutive adult patients underwent successful device closure of ASD (age 43 ± 17 years, 10 men), most of them with a large shunt. Of the 44 patients, 11 (25%) had co-morbidities (nonobstructive coronary heart disease in 2, hypertension in 9, and diabetes mellitus in 4) and 15 patients (34%) had symptoms. The ASD size measured by intracardiac echocardiography, the occluder size, the Qp/Qs calculated by oximetry, and the pulmonary arterial systolic pressure are also listed in Table 1 .

Demographic Data | Whole Group |
---|---|

Age at closure (years) | 43 ± 17 |

Men | 10 (23%) |

Body surface area (m ^{2 }) |
1.60 ± 0.16 |

Heart rate (beats/minute) | 72 ± 11 |

Blood pressure (mm Hg) | |

Systolic | 117 ± 17 |

Diastolic | 69 ± 10 |

Co-morbidities | 11 (25%) |

Symptoms | 15 (34%) |

Pulmonary-to-systemic flow ratio | 2.27 ± 0.69 |

Large shunt | 42 (95%) |

Pulmonary arterial systolic pressure (mm Hg) | 41 ± 11 |

Atrial septal defect size (mm) | 17 ± 7 |

Occluder size (mm) | 21 ± 7 |

The changes in atrial and ventricular volumes and functions after ASD closure are listed in Table 2 . Abolition of the interatrial shunt resulted in significant reduction of both RV and RA sizes, and improvement in RA function, as measured by the total emptying fraction, was observed at 3 months of follow-up ( Table 2 ). The diameters of the inferior vena cava had decreased significantly, and the collapse index remained unchanged. However, no significant change was seen in the left atrial and LV sizes or function.

Parameter | Before Closure | 3 mo After Closure | p Value |
---|---|---|---|

Right atrial maximal volume (ml) | 83 ± 45 | 43 ± 28 | <0.001 |

Right atrial volume index (ml/m ^{2 }) |
52 ± 29 | 27 ± 17 | <0.001 |

Right atrial total emptying fraction (%) | 46 ± 21 | 57 ± 19 | 0.003 |

Right ventricular end-diastolic volume (ml) | 84 ± 37 | 38 ± 13 | <0.001 |

Right ventricular end-systolic volume (ml) | 40 ± 18 | 20 ± 9 | <0.001 |

Right ventricular ejection fraction (%) | 52 ± 14 | 46 ± 15 | 0.061 |

Left atrial maximal volume (ml) | 66 ± 35 | 64 ± 28 | 0.654 |

Left atrial volume index (ml/m ^{2 }) |
41 ± 23 | 40 ± 19 | 0.647 |

Left atrial total emptying fraction (%) | 56 ± 16 | 50 ± 18 | 0.166 |

Left ventricular end-diastolic volume (ml) | 64 ± 19 | 68 ± 18 | 0.117 |

Left ventricular end-systolic volume (ml) | 24 ± 8 | 23 ± 7 | 0.746 |

Left ventricular ejection fraction (%) | 63 ± 7 | 65 ± 5 | 0.070 |

Maximum diameter of inferior vena cava (cm) | 1.7 ± 0.7 | 1.3 ± 0.3 | 0.005 |

Minimum diameter of inferior vena cava (cm) | 0.9 ± 0.6 | 0.6 ± 0.2 | 0.007 |

Collapse index of inferior vena cava | 0.5 ± 0.2 | 0.6 ± 0.2 | 0.085 |

All patients had an enlarged right atrium (i.e., RAVI ≥21 ml/m ^{2 }) before closure, and incomplete RAR was detected in 25 (57%) of 44 patients at 3 months after ASD closure (chi-square = 54.5 vs before closure, p <0.001; Table 3 ). As a group, these patients were older, had a larger Qp/Qs ratio, a higher pulmonary arterial systolic pressure, more severe tricuspid regurgitation, more dilated inferior vena cava, and larger left atrial, RA, and RV sizes before closure compared to patients in whom the RA size had normalized. At 3 months, 2 patients were developing atrial fibrillation, and both were in the incomplete RAR group (chi-square = 1.59, p = 0.317).

Parameter | RAR at 3 mo of Follow-Up | Chi-Square; p Value | |
---|---|---|---|

Yes (n = 19) | No (n = 25) | ||

Demographics | |||

Age at closure (years) | 36 ± 12 | 47 ± 18 | —; 0.034 |

Men | 5 (26%) | 5 (25%) | 0.031; 0.575 |

Co-morbidities | 3 (16%) | 8 (32%) | 1.151; 0.191 |

Symptoms | 6 (32%) | 9 (28%) | 0.094; 0.508 |

Invasive parameters | |||

Pulmonary/systemic flow ratio | 1.95 ± 0.53 | 2.44 ± 0.69 | —; 0.016 |

Large shunt | 17 (90%) | 25 (100%) | 2.694; 0.101 |

Pulmonary arterial systolic pressure (mm Hg) | 37 ± 12 | 43 ± 10 | —; 0.049 |

Size of atrial septal defect (mm) | 16 ± 7 | 17 ± 6 | —; 0.404 |

Size of occluder (mm) | 19 ± 7 | 22 ± 5 | —; 0.199 |

Preclosure echocardiographic parameter | |||

Right atrial maximal volume (ml) | 57 ± 26 | 102 ± 47 | —; 0.001 |

Right atrial volume index (ml/m ^{2 }) |
35 ± 17 | 64 ± 30 | —; 0.001 |

Right atrial total emptying fraction (%) | 50 ± 18 | 47 ± 22 | —; 0.276 |

Right ventricular end-diastolic volume (ml) | 71 ± 40 | 94 ± 32 | —; 0.049 |

Right ventricular end-systolic volume (ml) | 36 ± 23 | 43 ± 15 | —; 0.242 |

Right ventricular ejection fraction (%) | 51 ± 12 | 54 ± 15 | —; 0.567 |

Left atrial maximal volume (ml) | 44 ± 15 | 73 ± 37 | —; 0.003 |

Left atrial volume index (ml/m ^{2 }) |
18 ± 9 | 46 ± 24 | —; 0.001 |

Left atrial total emptying fraction (%) | 61 ± 14 | 57 ± 15 | —; 0.354 |

Left ventricular end-diastolic volume (ml) | 61 ± 20 | 65 ± 18 | —; 0.414 |

Left ventricular end-systolic volume (ml) | 22 ± 8 | 25 ± 7 | —; 0.254 |

Left ventricular ejection fraction (%) | 63 ± 7 | 62 ± 6 | —; 0.531 |

Tricuspid regurgitation (cm ^{2 }) |
2.9 ± 3.4 | 7.0 ± 6.4 | —; 0.027 |

Maximum diameter of inferior vena cava (cm) | 1.3 ± 0.6 | 1.9 ± 0.5 | —; 0.013 |

Minimum diameter of inferior vena cava (cm) | 0.6 ± 0.5 | 1.1 ± 0.5 | —; 0.013 |

Collapse index of inferior vena cava | 0.6 ± 0.2 | 0.4 ± 0.2 | —; 0.076 |

The univariate predictors were age at closure, Qp/Qs ratio, pulmonary arterial systolic pressure, degree of tricuspid regurgitation, and preclosure left atrial and RA sizes ( Table 4 ). On multivariate analysis, it was observed that only the preclosure RAVI remained an independent determinant (odds ratio 1.115; 95% confidence interval 1.019 to 1.220; p = 0.018) of incomplete RAR at 3 months of follow-up. The receiver operating characteristic curve revealed that a cutoff value of RAVI of ≥40 ml/m ^{2 }was 84% sensitive and 72% specific in predicting incomplete RAR, with an area under the curve of 0.82 (p <0.01; Figure 1 ). Bivariate correlation analysis showed both age at closure ( *r *= 0.51, p <0.001) and Qp/Qs ratio ( *r *= 0.51, p <0.001) correlated significantly with the preclosure RAVI. A closer correlation was found between the preclosure RAVI and shunt duration index, a parameter incorporating age at closure and the degree of shunting ( *r *= 0.64, p <0.001; Figure 2 ). In addition, a positive correlation was found between the degree of tricuspid regurgitation and the preclosure RAVI ( *r *= 0.75, p <0.001).