To evaluate (1) whether right ventricular (RV) dysfunction, evaluated using tricuspid annular plane systolic excursion (TAPSE) is associated with a worse outcome in patients with the Eisenmenger syndrome, (2) which variables are related to RV dysfunction, and (3) whether differences exist among simple pretricuspid, simple post-tricuspid, and combined shunt lesions. Patients with Eisenmenger syndrome, aged >18 years, who underwent echocardiography, were selected from the Belgian Eisenmenger registry and prospectively followed up using a Web-based registry. Cox regression analysis was performed to evaluate the relation to outcomes, defined as all-cause mortality, transplantation, and hospitalization for cardiopulmonary causes. Comparative and bivariate analysis was performed, where applicable. A total of 58 patients (mean age 35.1 ± 13.2 years, 32.8% men) were included. During a mean follow-up of 3.2 years, 22 patients (37.9%) reached the predefined end point. Only TAPSE (hazard ratio 0.820, 95% confidence interval 0.708 to 0.950; p = 0.008) was related to the adverse outcomes on multivariate analysis. Patients with pretricuspid shunt lesions were older (p <0.0001) had greater left (p <0.0001) and right atrial (p <0.0001) dimensions, greater RV dimensions (p = 0.002), and more tricuspid regurgitation (p = 0.012) compared to patients with post-tricuspid lesions. Lower TAPSE was related to the presence of pulmonary artery thrombosis (R = −0.378; p = 0.006). In conclusion, in patients with Eisenmenger syndrome, RV dysfunction, evaluated using TAPSE, is related to worse outcomes. Patients with Eisenmenger syndrome with pretricuspid shunt lesions were older and had greater left atrial, right atrial, and RV dimensions compared to patients with post-tricuspid lesions, indicating a difference in the RV response. Lower TAPSE was associated with the presence of pulmonary artery thrombosis.
The present study aimed at evaluating (1) whether right ventricular (RV) dysfunction, evaluated using tricuspid annular plane systolic excursion (TAPSE), is associated with worse outcomes in patients with the Eisenmenger syndrome, (2) which variables are related with RV dysfunction, and (3) whether differences exist among simple pretricuspid, simple post-tricuspid, and combined shunt lesions.
Methods
Patients with the Eisenmenger syndrome were selected from the Belgian Eisenmenger registry, previously described. According to present guidelines, the patients were divided into those with simple pretricuspid lesions (atrial septal defect, [ASD]), simple post-tricuspid lesions (ventricular septal defect [VSD] and patent ductus arteriosus [PDA]), and combined shunt lesions (atrioventricular septal defect). Patients with complex underlying pathologic findings were excluded. The institutional review board of each participating center approved the registry, and all patients gave written informed consent before inclusion.
The demographic data, medical history (type of congenital heart defect, presence of Down syndrome, surgical procedures, and noncardiac history), clinical baseline characteristics (New York Heart Association class), and treatment were retrieved at inclusion into the registry.
Standard 2-dimensional gray-scale and Doppler examinations were performed. All echocardiographic studies were performed with the participant in the left lateral decubitus position. Two consecutive heartbeats were analyzed, with data presented as the mean values. Left ventricular function was assessed from parasternal 2-dimensional M-mode measurements using the Teichholz formula: (end-diastolic volume = 7/2.4 + end-diastolic diameter) × (end-diastolic diameter). In the parasternal view, the interventricular septal thickness and left atrial dimension were measured using M-mode according to the criteria of the American Society of Echocardiography. The superoinferior dimensions of the left and right atrium were measured at end-systole in the apical 4-chamber view. Similarly, the transverse dimensions of the left and right ventricles at end-diastole were obtained in the apical 4-chamber view. The eccentricity index was defined as the ratio of the RV to left ventricular short-axis dimensions. The RV function was assessed qualitatively (on a scale from 1 [normal] to 4 [severely depressed RV function]) and quantitatively using TAPSE from the M-mode recordings. Using Doppler echocardiography, the systolic pulmonary artery pressure using the modified Bernoulli equation (four times tricuspid regurgitation peak systolic velocity squared) and pulmonary acceleration time (interval between the onset of systolic pulmonary arterial flow and peak flow velocity) were determined. The peak velocity during early diastole (E) and atrial contraction (A) and the E/A ratio were obtained from the mitral inflow patterns. Regurgitation of the mitral, tricuspid (TR), and aortic valve was graded semiquantitatively using color Doppler flow mapping on a scale from 0 to 4. For patients with atrioventricular septal defect, atrioventricular valve regurgitation was graded on as scale from 0 to 4. Moderate to severe regurgitation was defined as 3 or 4 of 4.
The follow-up consisted of evaluations in the participating centers. At every visit, information on death, transplantation, and the need for hospitalization was included in the registry. Data were included to the last follow-up visit.
The composite end point was defined as all-cause mortality, transplantation, or hospitalization for cardiopulmonary causes.
We analyzed the data using Statistical Package for Social Sciences for Windows, version 19 (SPSS, Chicago, Illinois). The Kolmogorov-Smirnov test was used to test for normality. Descriptive data for continuous variables are presented as the mean ± SD or medians (ranges), as appropriate. Descriptive data for discrete variables are presented as frequencies or percentages. For comparative statistics, continuous variables were evaluated between subgroups using 1-way analysis of variance with Tukey’s honestly significant difference post hoc testing, if normally distributed. The proportions were evaluated between subgroups using Fischer’s exact test. Cox regression analysis was performed with the composite end point as a dependent variable. Patients were censored after the first event. Echocardiographic variables were used as independent variables. For patients with ASD, VSD, or PDA, TR and MR were considered. For patients with atrioventricular septal defect, atrioventricular valve regurgitation was considered in the analysis. After univariate analysis, multivariate Cox regression analysis was performed. However, because of the inherent heterogeneity, valve regurgitation was not included in the multivariate regression analysis but reported separately. If the univariate variables correlated highly with each other (R >0.60), only 1 was entered into the multivariate analysis. The level of significance for the multivariate model was set at 0.05. Kaplan-Meier analysis and the log-rank test were performed. For associative statistics, the Spearman rho correlation coefficient was used. All tests were 2-sided, and the level of significance was set at 0.05.
Results
A total of 58 patients with the Eisenmenger syndrome (mean age 35.6 ± 13.0, 32.8% men) who underwent transthoracic echocardiography were selected, 9 with ASD, 23 with atrioventricular septal defect, 20 with VSD, and 6 with PDA. The patient characteristics and echocardiographic variables are summarized in Tables 1 and 2 , respectively.
| Variable | Total Population | Simple Pretricuspid (n = 9) | Simple Post-Tricuspid (n = 26) | Combined Shunt (n = 23) | p Value ⁎ |
|---|---|---|---|---|---|
| Age (years) | 35.6 ± 13.0 | 51.1 ± 9.2 † ‡ | 37.3 ± 12.1 † | 27.6 ± 8.6 | <0.0001 |
| Male gender | 19 (33%) | 1 (11%) † | 5 (19%) † | 13 (57%) | 0.007 |
| Down syndrome | 35 (60%) | 0 (0%) | 14 (54%) | 23 (100%) | — |
| Oxygen saturation (%) | 84.1 ± 6.8 | 85.7 ± 6.6 | 84.1 ± 7.2 | 83.5 ± 6.6 | 0.723 |
| New York Heart Association class ≥3 | 25 (43%) | 6 (67%) | 8 (31%) | 11 (48%) | 0.154 |
| Iron deficiency | 17 (29%) | 5 (56%) | 7 (27%) | 5 (22%) | 0.244 |
| Specific pulmonary arterial hypertension therapy | 21 (36%) | 9 (100%) † ‡ | 9 (35%) | 3 (13%) | <0.0001 |
| Follow-up (years) | 3.2 ± 1.8 | 2.6 ± 1.9 | 3.4 ± 1.7 | 3.2 ± 1.8 | 0.480 |
| Follow-up to first event (years) | 2.6 ± 1.8 | 1.4 ± 1.8 ‡ | 3.2 ± 1.7 | 2.4 ± 1.8 | 0.032 |
† p <0.05 vs atrioventricular septal defect;
| Variable | Total Population | Simple Pretricuspid (n = 9) | Simple Post Tricuspid (n = 26) | Combined (n = 23) | p Value ⁎ |
|---|---|---|---|---|---|
| Left atrium parasternal (mm) | 33.6 ± 9.8 † ‡ | 46.9 ± 8.5 | 31.9 ± 6.7 | 30.0 ± 8.6 | <0.0001 |
| Left atrium apical (mm) | 45.0 ± 9.5 † ‡ | 56.2 ± 9.1 | 42.8 ± 8.2 | 42.6 ± 7.9 | <0.0001 |
| Right atrium apical (mm) | 47.3 ± 8.9 † ‡ | 59.4 ± 7.1 | 44.1 ± 7.9 | 45.7 ± 6.4 | <0.0001 |
| Left ventricle transverse (mm) | 36.6 ± 7.7 | 38.4 ± 9.9 | 36.3 ± 7.7 | 36.1 ± 7.0 | 0.744 |
| Right ventricle transverse (mm) | 38.3 ± 10.5 † ‡ | 48.7 ± 11.3 | 37.8 ± 9.9 | 34.6 ± 8.1 | 0.002 |
| Eccentricity index | 1.0 ± 0.3 | 0.9 ± 0.4 | 1.0 ± 0.4 | 1.1 ± 0.3 | 0.248 |
| Interventricular septum (mm) | 11.2 ± 2.9 | 11.1 ± 1.8 | 10.5 ± 3.1 | 12.0 ± 2.8 | 0.195 |
| Left ventricular ejection fraction (%) | 65.6 ± 9.2 | 65.3 ± 10.6 | 63.4 ± 7.4 | 68.2 ± 10.2 | 0.191 |
| Right ventricular function | 1.6 ± 0.8 | 2.0 ± 1.0 | 1.6 ± 0.8 | 1.4 ± 0.5 | 0.111 |
| Mitral inflow E/A ratio | 1.1 ± 0.4 ‡ | 0.77 ± 0.25 | 1.17 ± 0.41 | 1.41 ± 0.36 | 0.001 |
| Pulmonary acceleration time (ms) | 75.9 ± 20.3 | 73.2 ± 19.0 | 72.4 ± 22.3 | 81.4 ± 18.0 | 0.337 |
| Tricuspid annular plane systolic excursion (mm) | 18.2 ± 4.1 | 18.0 ± 4.0 | 17.2 ± 4.1 | 19.3 ± 4.0 | 0.222 |
| Mitral regurgitation (n/4) | 1.1 ± 0.9 | 1.3 ± 0.5 | 1.1 ± 1.0 | — | 0.459 |
| Tricuspid regurgitation (n/4) | 2.0 ± 1.0 | 2.7 ± 0.9 | 1.7 ± 0.9 | — | 0.012 |
| Atrioventricular valve regurgitation (n/4) | 1.7 ± 1.2 | — | — | 1.7 ± 1.2 | — |
| Aortic regurgitation (n/4) | 0.2 ± 0.4 | 0.1 ± 0.3 | 0.3 ± 0.5 | 0.1 ± 0.2 | 0.132 |
| Pulmonary regurgitation (n/4) | 1.1 ± 0.7 | 1.4 ± 0.5 | 1.1 ± 0.8 | 0.9 ± 0.7 | 0.187 |
| Systolic pulmonary artery pressure (mm Hg) | 85.5 ± 25.6 | 86.0 ± 18.3 | 91.6 ± 31.6 | 74.7 ± 16.4 | 0.259 |
Of the 58 patients, 22 (37.9%) reached the composite end point. During a mean follow-up of 3.2 years, 9 patients (15.5%) died, 2 (3.4%) underwent transplantation, and 18 (31%) were hospitalized for cardiopulmonary causes. Univariate Cox regression analysis showed that left atrial dimensions (p = 0.003), right atrial dimensions (p <0.0001), qualitative RV function assessment (p <0.0001), TAPSE (p = 0.001), TR (p = 0.013), and atrioventricular valve regurgitation (p = 0.004) were related to the adverse outcome ( Table 3 ). According to multivariate analysis, only TAPSE (hazard ratio 0.820, 95% confidence interval 0.708 to 0.950; p = 0.008) independently predicted adverse outcome ( Table 4 ). TAPSE was divided into tertiles. Kaplan-Meier analysis showed that patients with TAPSE of ≤15.9 mm had lower event-free survival ( Figure 1 ) . TAPSE of ≤15.9 mm was also related to greater mortality ( Figure 2 ) .
| Variable | HR (95% CI) | p Value |
|---|---|---|
| Left atrium parasternal (mm) | 1.074 (1.025–1.127) | 0.003 |
| Left atrium apical (mm) | 1.075 (1.025–1.127) | 0.003 |
| Right atrium apical (mm) | 1.090 (1.041–1.140) | <0.0001 |
| Left ventricle transverse (mm) | 1.017 (0.955–1.083) | 0.602 |
| Right ventricle transverse (mm) | 1.037 (0.998–1.079) | 0.066 |
| Eccentricity index | 0.444 (0.112–1.760) | 0.248 |
| Interventricular septum (mm) | 1.119 (0.959–1.305) | 0.154 |
| Left ventricular ejection fraction (%) | 0.997 (0.931–1.025) | 0.346 |
| Right ventricular function | 2.688 (1.605–4.502) | <0.0001 |
| Mitral inflow E/A ratio | 0.682 (0.222–2.099) | 0.505 |
| Pulmonary acceleration time (ms) | 0.982 (0.957–1.007) | 0.164 |
| Tricuspid annular plane systolic excursion (mm) | 0.805 (0.705–0.918) | 0.001 |
| Mitral regurgitation (n/4) | 1.383 (0.754–2.537) | 0.294 |
| Tricuspid regurgitation (n/4) | 2.266 (1.185–4.333) | 0.013 |
| Atrioventricular valve regurgitation (n/4) | 2.180 (1.277–3.720) | 0.004 |
| Aortic regurgitation (n/4) | 1.035 (0.360–2.974) | 0.949 |
| Pulmonary regurgitation (n/4) | 1.443 (0.779–2.671) | 0.243 |
| Systolic pulmonary artery pressure (mm Hg) | 0.998 (0.977–1.019) | 0.852 |
⁎ Composite end point of all-cause mortality, hospitalization, and transplantation.
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