Aortic stiffness and diastolic function are abnormal in adults with repaired coarctation of the aorta (CoA). The goal of this study was to determine the relation between aortic stiffness and left ventricular (LV) diastolic impairment in children who had undergone CoA repair very early in life. This is a retrospective review of echocardiograms in children with isolated repaired CoA (group CoA; n = 24) and healthy matched controls (group Normal; n = 24). We analyzed systolic and LV diastolic functions, proximal and distal ascending aortic stiffness indices (SIs), distensibility, and strain. Age range was 0.3 to 21 (median 9) years. Age at time of CoA repair was 0 to 24 (median 0.5) months. Median time since CoA repair was 6 years. There was no significant difference in blood pressure, LV size, and systolic function between the groups. LV diastolic function was impaired in group CoA compared with group Normal (septal E′: CoA 10.3 ± 1.6 cm/s and Normal 13.4 ± 1.9 cm/s, p <0.001). All parameters of proximal and distal ascending aortic elasticities were abnormal in group CoA versus Normal (SI of proximal ascending aorta: CoA 4.9 ± 1.6 and Normal 2.7 ± 0.6, p <0.001). Across all patients, there was a strong correlation between septal E′ and proximal ascending aortic SI (r = −0.72, p <0.001). In conclusion, even children who underwent CoA repair at a very young age have abnormal LV diastolic function and aortic elasticity compared with controls and there is a linear relation between the 2. LV diastolic dysfunction in patients with repaired CoA may be due to chronically increased afterload.
Patients with coarctation of the aorta (CoA) are known to have intrinsic aortic wall abnormalities. These abnormalities cause increased ascending aortic stiffness, which persist even after neonatal CoA repair. Others have shown a correlation of aortic stiffness with age at intervention in adult patients. Left ventricular (LV) diastolic dysfunction is common in adults who have had a successful intervention for CoA. It has been shown that age at intervention and aortic stiffness are independent predictors of LV diastolic impairment and that there is a negative correlation between diastolic function and aortic stiffness in adults with repaired CoA. Therefore, it has been suggested that earlier repair might ameliorate those changes. However, even normotensive children who underwent CoA repair during childhood were recently found to have evidence of impaired relaxation. It is unclear if impaired LV relaxation in children who underwent CoA repair very early in life develops secondary to increased aortic stiffness or if it is due to an intrinsic myocardial abnormality, which could be related to a common genetic variant. It is the hypothesis of this study that both aortic elasticity and diastolic function are abnormal in children and adolescents after successful intervention for CoA at a very young age and that there is a relation between the 2.
Methods
This is a retrospective cohort study of 24 patients (age 0 to 21 years) with repaired CoA (group CoA) and 24 age-, gender-, and weight-matched control subjects (group Normal). Echocardiograms were performed from September 2010 to August 2012.
Inclusion criteria for the CoA group were age at time of CoA repair of ≤24 months, echocardiography at least 3 months after the last intervention, and no clinical or echocardiographic evidence of re-CoA (i.e., mean continuous wave Doppler gradient of <20 mm Hg across the aortic isthmus, nonconcerning abdominal aortic pulse Doppler tracing, and normal femoral pulses). Exclusion criteria for the CoA group were more than mild aortic stenosis (mean >20 mm Hg), more than mild aortic regurgitation, associated repaired or nonrepaired cardiac anomalies (e.g., ventricular septal defect), LV hypertrophy, systolic dysfunction, and a known genetic diagnosis (e.g., Turner syndrome). The control subjects were selected from normal echocardiograms performed for evaluation of a heart murmur, chest pain, palpitations, and/or syncope. Patients with known genetic disorders, hematologic, oncologic, or rheumatologic diagnoses were excluded. Baseline characteristics such as gender, age, weight, height, body surface area (BSA), blood pressure, and heart rate were recorded. For the CoA group, age at initial repair, type of repair, time since repair, and need for reintervention were documented as well. The Institutional Review Board approved this retrospective data review.
Nonsedated echocardiographies were performed using the Philips IE33 (Philips Medical Systems, Andover, Massachusetts) and the GE Vivid 9 (General Electric, Milwaukee, Wisconsin) equipments. Probe frequency was selected according to patient size. Echocardiograms were performed according to the pediatric guidelines of the American Society of Echocardiography. Measurements were performed offline (Synapse Cardiovascular version 4.0.9; FUJIFILM Medical Systems U.S.A., Inc., Stamford, Connecticut) and averaged over 3 cardiac cycles. All measurements were performed by 1 of 2 investigators (KCL and CGW). Interobserver variability was assessed for all parameters in 16 patients (8 from each group). The second observer (CGW) was blinded to the measurements of the first observer (KCL).
LV end-diastolic and end-systolic dimensions, shortening fraction, end-diastolic interventricular septal and posterior wall thicknesses were determined from M-mode in the parasternal short-axis view, and BSA-based Z scores were documented. Pulmonary venous pulse-wave (PW) Doppler velocities of the right upper pulmonary vein were measured from apical 4-chamber view with the sector placed in the pulmonary vein (S-, D-, and A-wave velocities and A-wave duration). Mitral inflow parameters (E- and A-wave velocities and A-wave duration) were measured with the PW Doppler sample volume positioned at the tips of the valve leaflets during diastole. PW tissue Doppler evaluation was performed at the septal and lateral mitral valve annuli from apical 4-chamber view, and peak systolic velocity (S′) as well as early and late diastolic velocities (E′ and A′) were recorded. Morphology of the aortic valve was assessed by 2-dimensional echocardiography. For the CoA group, mean gradients across the aortic valve and aortic isthmus and degree of aortic insufficiency were collected.
Two-dimensional measurements of the ascending aorta were obtained at 2 sites using the trailing edge-to-leading edge method. Diastolic dimension (DD) was obtained at the onset of the QRS complex of the simultaneously recorded electrocardiogram. Systolic dimension (SD) was measured at the point of maximum aortic wall distension. Three separate measurements of consecutive cardiac cycles were averaged. Proximal ascending aortic measurements were made from a parasternal long-axis view at the level of the right pulmonary artery. The distal ascending aortic dimension was recorded just proximal to the origin of the innominate artery. A right arm blood pressure was obtained at the time of the echocardiography (systolic blood pressure: SBP and diastolic blood pressure: DBP). From those measurements, aortic distensibility (DI), stiffness index (SI), and strain were derived as previously described : DI = 2 (SD − DD)/[DD (SBP − DBP)] 10 −6 cm 2 /dyne; SI = ln (SBP/DBP) × (DD)/(SD − DD); and strain = (SD − DD)/DD.
For statistical analysis, continuous variables are expressed as mean values and standard deviations. Differences between groups were compared using the Mann-Whitney U test. Differences between related samples were compared using the Wilcoxon signed rank test. Categorical variables are expressed as frequency and compared using the Fisher’s exact test. Variables were associated using Spearman correlation coefficient (r). Where appropriate, Bonferroni correction of α level was used to adjust for multiple comparisons (e.g., we used 3 outcomes to look at aortic elasticity; therefore, α = 0.05/3 = 0.017). To assess interobserver reliability, intraclass correlation coefficient for average measurements was performed for all variables. Statistical analysis was performed using Statistical Package for Social Sciences, version 19 (IBM SPSS, Chicago, Illinois).
Results
The age of patients with CoA (n = 24) and control subjects (n = 24) ranged from 3 months to 21 years (mean 8.8 ± 5.9 years). There was no significant difference in age, gender distribution, weight, height, BSA, heart rate, and blood pressure between the 2 groups ( Table 1 ). In the CoA group, patients had their initial intervention from 0 to 24 months of life (mean 5.8 ± 2.9 months; median 0.5 months). Most (n = 16; 67%) had their initial intervention in the neonatal period (15 end-to-end anastomosis and 1 subclavian flap) and 4 of those subsequently required a catheter-based intervention for re-CoA (3 balloon angioplasties and 1 stent). The remaining 8 patients (33%) had their initial intervention beyond 1 month of age. Of this group, 6 patients underwent surgical repair with end-to-end anastomosis, 1 had primary balloon angioplasty and stent implantation, and 1 had balloon angioplasty alone. None of the patients who had their initial intervention beyond the neonatal period required a reintervention. Average time since repair was 6.7 ± 8.1 years (median 5.9). Sixteen patients (67%) had associated bicuspid aortic valves, all of them with fusion of the right and left coronary cusps. None of the patients had other associated congenital heart defects, and no one had required cardiopulmonary bypass in the past.
| Variable | CoA (n = 24) | Normal (n = 24) |
|---|---|---|
| Men/Women | 19 (79)/5 (21) | 19 (79)/5 (21) |
| Age (yrs) | 8.4 ± 6.9 | 9.3 ± 4.8 |
| Weight (kg) | 35 ± 27 | 38 ± 21 |
| Height (cm) | 124 ± 41 | 136 ± 35 |
| Body surface area (m 2 ) | 1.1 ± 0.6 | 1.2 ± 0.5 |
| Heart rate (beats/min) | 89 ± 26 | 84 ± 17 |
| Systolic blood pressure (mm Hg) | 108 ± 12 | 105 ± 11 |
| Diastolic blood pressure (mm Hg) | 62 ± 12 | 59 ± 8 |
| Bicuspid aortic valve (n) | 16 | N/A |
| Aortic valve mean gradient (mm Hg) | 6.7 ± 4.7 | N/A |
| Aortic regurgitation (n) | 2 mild, 5 trace | N/A |
| CoA mean gradient (mm Hg) | 10 ± 3.4 | N/A |
The CoA and Normal groups had comparable absolute values and Z scores for LV end-diastolic and end-systolic dimensions, shortening fraction, and end-diastolic interventricular septal and posterior wall thicknesses ( Table 2 ). Although the proximal ascending aortic dimension was equal in both groups, the distal ascending aorta was significantly smaller in the CoA group compared with the Normal group.
| Variable | CoA (n = 24) | Normal (n = 24) | ||
|---|---|---|---|---|
| Absolute Value (cm) | Z Score | Absolute Value (cm) | Z Score | |
| LV end-diastolic dimension | 3.8 ± 1 | −0.2 ± 1.2 | 3.9 ± 0.8 | −0.4 ± 1.3 |
| LV end-systolic dimension | 2.3 ± 0.6 | −0.5 ± 1.1 | 2.4 ± 0.5 | −0.5 ± 1.1 |
| Interventricular septal thickness in diastole | 0.6 ± 0.2 | 0 ± 0.8 | 0.6 ± 0.8 | −0.1 ± 0.8 |
| Posterior wall thickness in diastole | 0.6 ± 0.2 | 0.2 ± 0.9 | 0.6 ± 0.1 | 0.3 ± 0.9 |
| Shortening fraction (%) | 39 ± 4 | 40 ± 2.6 | ||
| Proximal ascending aortic dimension in systole | 2 ± 0.7 | 2 ± 0.5 | ||
| Distal ascending aortic dimension in systole | 1.5 ± 0.4 | 1.9 ± 0.4 | ||
The CoA group compared with the Normal group had significantly higher mitral E- and A-wave velocities and a lower E/A ratio ( Table 3 ). Tissue Doppler was significant for lower septal and lateral mitral valve annular E′ velocities and a higher corresponding E/E′ ratios in the CoA group compared with the Normal group ( Table 3 ). There was a trend toward increased left atrial volume indexed to BSA and pulmonary venous A-wave velocity in the CoA group compared with the Normal group but those parameters did not reach statistical significance. Likewise, left atrial volume indexed to BSA had a weak positive correlation with septal E/E′ ratio (r = 0.3, p = 0.05). All parameters of aortic elasticity, that is, DI, SI, and strain, were highly abnormal in our patients with repaired CoA ( Table 3 ) compared with the control group. This pertained to both proximal and distal ascending aortic measurements. Across all patients, there was a linear relation between parameters of diastolic function and aortic elasticity ( Table 4 ). Correlation was strongest between proximal ascending aortic SI and septal E′ velocity ( Table 4 and Figure 1 ) or septal E/E′ ratio.
| Variable | CoA (n = 24) ∗ | Normal (n = 24) | p |
|---|---|---|---|
| Left atrium | |||
| Volume (ml/m 2 ) | 21 ± 6 | 17 ± 4 | 0.02 |
| Right pulmonary vein Doppler | |||
| S (cm/s) | 47 ± 10 | 49 ± 10 | NS |
| D (cm/s) | 56 ± 11 | 61 ± 9 | NS |
| A (cm/s) | 24 ± 4 | 21 ± 4 | 0.03 |
| Mitral valve Doppler | |||
| E (cm/s) | 113 ± 17 | 98 ± 10 | <0.001 |
| A (cm/s) | 78 ± 21 | 52 ± 18 | <0.001 |
| E/A ratio | 1.6 ± 0.4 | 2.1 ± 0.6 | 0.002 |
| ΔA duration (ms) | −28 ± 49 | −16 ± 27 | NS |
| Tissue Doppler, septal | |||
| S′ (cm/s) | 7.4 ± 1.1 | 7.8 ± 1 | NS |
| E′ (cm/s) | 10.3 ± 1.6 | 13.4 ± 1.9 | <0.001 |
| A′ (cm/s) | 6.6 ± 1.7 | 6.2 ± 1.3 | NS |
| E/E′ | 11.1 ± 2.3 | 7.5 ± 1.3 | <0.001 |
| Tissue Doppler, lateral | |||
| S′ (cm/s) | 8 ± 2.2 | 9.1 ± 1.8 | NS |
| E′ (cm/s) | 13.9 ± 3.4 | 17.7 ± 4.2 | 0.006 |
| A′ (cm/s) | 6.5 ± 2.3 | 6.1 ± 1.4 | NS |
| E/E′ | 8.7 ± 3 | 5.9 ± 1.5 | <0.001 |
| Ascending aorta, proximal | |||
| SI | 4.9 ± 1.6 | 2.7 ± 0.6 | <0.001 |
| DI (10 −6 cm 2 /dyne) | 5.6 ± 1.9 | 10.3 ± 2.8 | <0.001 |
| Strain (%) | 12.9 ± 3.8 | 23 ± 5 | <0.001 |
| Ascending aorta, distal | |||
| SI | 4 ± 1.4 | 2.7 ± 0.5 | <0.001 |
| DI (10 −6 cm 2 /dyne) | 6.9 ± 2.5 | 9.7 ± 2.2 | <0.001 |
| Strain (%) | 15.7 ± 5.5 | 21.7 ± 3.5 | <0.001 |
∗ Data sets are incomplete for a few patients in the CoA group. This reduced the number of measurements included (n) for the following variables: pulmonary vein Doppler (n = 19), tissue Doppler data (n = 20), and proximal ascending aorta (n = 22).
| Variable | Tissue Doppler, Septal | Tissue Doppler, Lateral | ||
|---|---|---|---|---|
| E′ | E/E′ | E′ | E/E′ | |
| Ascending aorta, proximal | ||||
| SI | −0.72 (<0.001) | 0.72 (<0.001) | −0.36 (0.02) | 0.41 (0.007) |
| DI (10 −6 cm 2 /dyne) | 0.67 (<0.001) | −0.67 (<0.001) | 0.25 (NS) | −0.31 (0.04) |
| Strain (%) | 0.71 (<0.001) | −0.71 (<0.001) | 0.38 (0.01) | −0.43 (0.004) |
| Ascending aorta, distal | ||||
| SI | −0.4 (0.008) | 0.41 (0.006) | −0.05 (NS) | 0.12 (NS) |
| DI (10 −6 cm 2 /dyne) | 0.4 (0.007) | −0.38 (0.01) | 0.01 (NS) | −0.07 (NS) |
| Strain (%) | 0.53 (<0.001) | −0.46 (0.002) | 0.23 (NS) | −0.25 (NS) |
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