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Young patients with congenital aortic valve disease are at risk of left ventricular (LV) diastolic dysfunction (DD). We evaluated LV remodeling and the prevalence of, and risk factors for, DD in patients with aortic stenosis (AS), pure aortic regurgitation (AR), and AS+AR. Patients aged 8 to 39 years with congenital AS (n = 103), AR (n = 36), or AS+AR (n = 107) were identified. Cross-sectional assessment of the LV remodeling pattern and diastolic function was performed. A diastolic function score (DFS; range 0 to 4) was assigned to each patient, with 1 point for an abnormal value in each of 4 categories: mitral inflow (E/A and E-wave deceleration time), tissue Doppler E′, E/E′, and left atrial volume. Patients with a DFS of ≥2 were compared to those with a DFS <2. Concentric hypertrophy was the most common remodeling pattern in those with AS (51%), mixed/physiologic hypertrophy in those with AS+AR (48%) and eccentric hypertrophy in those with AR (49%) predominated. In the entire cohort, 91 patients (37%) had a DFS of ≥2. Patients with AS or AS+AR had greater DFS than those with pure AR (p <0.001). On multivariate analysis, a greater LV mass z-score and previous aortic valve balloon dilation were associated with a DFS of ≥2. In patients with catheterization data (n = 65), E/E′ correlated with LV end-diastolic pressure. Those with a DFS of ≥2 had a greater LV end-diastolic pressure and mean pulmonary artery pressure than those with a DFS <2. In conclusion, DD is common in young patients with AS and AS+AR but not in those with pure AR. A greater LV mass and previous aortic valve dilation were associated with DD.
The effect of chronic pressure and volume loading due to aortic valve disease on left ventricular (LV) remodeling and compliance has been well described in adults. Chronic pressure loading leads to LV remodeling with the development of concentric hypertrophy.
Early in the disease course, concentric hypertrophy allows the wall stress to remain normal and allows preservation of systolic function. Later, the deleterious effects of concentric hypertrophy and associated myocardial fibrosis become apparent, with the development of systolic and diastolic dysfunction (DD).
The myocardial response to chronic pressure load due to congenital aortic valve disease in children is also characterized by concentric hypertrophy, myocardial fibrosis, and impaired diastolic function.
Improvement of heart function after balloon dilation of congenital valvar aortic stenosis: a pilot study with ultrasound tissue Doppler and strain rate imaging.
The effect of LV volume load due to aortic regurgitation (AR) on diastolic function is less clear, with most adult data showing a high incidence of DD,
Left ventricular remodeling early after aortic valve replacement: differential effects on diastolic function in aortic valve stenosis and aortic regurgitation.
The effect of chronic combined pressure and volume load due to AS+AR on diastolic function in younger patients has not been described. In the present cross-sectional study of children and young adults with congenital aortic valve disease, we describe the LV remodeling pattern and prevalence of, and risk factors for, DD in patients with AS, pure AR, and AS+AR.
Methods
The records of all patients age 8 to 39 years evaluated at our institution from January 2005 to May 2011 with moderate or greater congenital AS and/or more than mild AR were retrospectively reviewed. The exclusion criteria included congenital heart disease (with the exception of bicommissural aortic valve and aortic coarctation), previous cardiac surgery with cardiopulmonary bypass, residual aortic arch obstruction (gradient >20 mm Hg), systemic hypertension, chronic renal disease, acquired valve disease, orthotopic heart transplantation, a history of diseases or therapies known to affect diastolic function (coronary artery disease, chemotherapy, Kawasaki disease). Baseline demographics, clinical characteristics, and clinical course, including cardiac interventions, were collected.
The patients were classified into 1 of 3 groups according to the predominant aortic valve disease: AS, pure AR, or AR+AR. The AS group included patients with both moderate or greater AS and mild or less AR. The AS+AR cohort consisted of patients with both greater than mild AR and moderate or greater AS. The pure AR cohort included patients with more than mild AR and no AS (AS gradient <15 mm Hg and no history of balloon aortic valvuloplasty for congenital AS). We defined moderate or greater AS by a Doppler gradient of ≥36 mm Hg using the greater value of the maximum instantaneous gradient from the apical imaging window or mean gradient from the suprasternal notch window and/or a history of balloon aortic valvuloplasty.
Qualitatively grading of AR in our echocardiographic laboratory was performed using a 4-point ordinal scale (0, none; 1, trivial; 2, mild; 3, moderate; and 4, severe) by ½-unit increments and determined by a combination of previously published criteria.
AR was considered more than mild if ≥1 of the following criteria were met: pandiastolic flow reversal in the descending abdominal aorta, vena contracta width/body surface area >3.1 mm/m2, LV end-diastolic volume z-score >2. The Committee for Clinical Investigation at Children's Hospital Boston approved the use of the patient medical records for this review.
The most recent complete echocardiogram that included a full interrogation of diastolic function was reviewed. The AS gradient and AR grade were collected from reports produced at the time of the study. The following LV parameters were recorded: end-diastolic volume, mass, mass:volume, and ejection fraction and the z-scores for these variables. The LV end-diastolic volume was calculated using the 5/6 area-length formula and LV mass using volumetric 2-dimensional measurements.
Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council.
: normal ventricle (normal mass, volume, and mass:volume), concentric remodeling/hypertrophy (normal LV volume, high LV mass, and/or mass:volume), eccentric remodeling/hypertrophy (high volume, normal mass, and low or normal mass:volume), or mixed/physiologic hypertrophy (high mass, high volume with normal or high mass:volume).
All measurements of diastolic variables were retrospectively remeasured by a single echocardiographer (K.F.) from images obtained at the echocardiogram. Standard mitral valve inflow pulsed-Doppler indexes of diastolic function, including peak early (E) and late (A) diastolic transmitral velocities, E/A, and E-wave deceleration time, were measured. Pulsed wave tissue Doppler imaging velocities were obtained from the lateral mitral annulus and the interventricular septum from the apical 4-chamber view. Only tracings that demonstrated a clear E′ were used. Each tissue Doppler imaging velocity was measured on 3 consecutive cardiac cycles, and the average value was used. The peak early mitral inflow velocity/early mitral tissue Doppler imaging velocity (E/E′) was calculated. The left atrial volumes were calculated using the prolate-ellipse formula.
were used, and a z-score of >2 or <−2 was considered abnormal. Examinations were performed using commercially available ultrasound equipment (Philips iE33, Koninklijke Philips Electronics, NV, Amsterdam, The Netherlands).
The diastolic parameters were grouped into 1 of 4 categories for analysis: (1) pulsed-wave Doppler mitral inflow (E/A, E-wave deceleration time), (2) tissue Doppler imaging velocities (mitral annular and septal E′), (3) E/E′, and (4) left atrial volume. The patients were assigned a diastolic function score (DFS) of 0 to 4, with 1 point for an abnormal value in each category.
For patients who underwent catheterization within 3 months of the echocardiogram, the hemodynamic data were collected from reports produced at the catheterization (n = 65). For cases in which interventions were performed (e.g., balloon aortic valvuloplasty), the preintervention hemodynamic data were included in the analysis.
The demographic and clinical and testing data are reported as counts for categorical variables and as the median and interquartile range for continuous variables. The comparisons of the demographic, clinical, and echocardiographic data among the patients with AS, AS+AR, and AR were made using Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous variables. To evaluate the risk factors for DD, patients with a DFS <2 were compared to those with a DFS ≥2. The associations between the demographic, clinical, and echocardiographic risk factors and a DFS ≥2 were assessed. Multivariate analysis with stepwise logistic regression was used to assess for factors associated with DFS of ≥2.
For the subset of patients with catheterization data, the associations between echocardiographic markers of left heart filling pressures (E/E′), and invasively measured hemodynamic data were evaluated using Pearson's correlation coefficients. Receiver operating characteristic curves were constructed to assess the ability of E/E′ to predict elevated LV end-diastolic pressure. All statistical analyses were 2-sided, and a type I error was controlled at a level of 0.05. Analyses were performed with SPSS, version 16.0 (SPSS, Chicago, Illinois).
Results
The cohort consisted of 246 patients: 103 with AS, 107 with AS+AR, and 36 with pure AR. Patients with AS and AS+AR were older (p = 0.003) and were more likely to have undergone balloon aortic valvuloplasty than those with pure AR (p <0.001; Table 1).
Most patients with AS had concentric hypertrophy (51%) or normal ventricle (39%; Figure 1). Patients with AS+AR disease most commonly had mixed/physiologic hypertrophy (48%) or concentric hypertrophy (25%), while in those with pure AR, eccentric hypertrophy (49%) and a normal ventricle (32%) predominated.
Figure 1Bar chart showing remodeling pattern for patients with AS, mixed aortic valve disease, and AR.
The LV end-diastolic volume was greater in those with AS+AR and AR than in those with AS (p <0.001; Table 2). The LV mass z-score was greatest in the patients with AS+AR followed by those with AR and then patients with AS (p <0.001). However, the LV mass:volume was greatest in patients with AS, intermediate in those with AS+AR, and lowest in those with AR (p <0.001).
In the entire cohort, 186 patients (73%) had a DFS of ≥1 and 91 (37%) had a DFS ≥2 (Figure 2). The percentage of patients with abnormal diastolic indexes was similar between the AS+AR and AS and both groups had a greater DFS than the AR group (p <0.001 for a DFS of ≥1 and ≥2).
Figure 2Bar graph showing DFS (0, 1, or ≥2) for entire cohort and those with AS, AS+AR, and AR. DFS from 0 to 4 was calculated, with 1 point for abnormal value in each of following 4 categories: (1) Pulsed Doppler mitral inflow (E/A, E-wave deceleration time), (2) tissue Doppler velocities (mitral and septal E′), (3) E/E′, and (4) left atrial volume.
The left atrial volume and pulsed Doppler mitral inflow parameters did not vary among the groups, although significant differences in the tissue Doppler imaging value and E/E′ were present (Table 3). The mitral annular and septal E′ were similar between patients with AS and AS+AR and were lower than those with AR (p <0.001). The E/E′ values and the percentage of patients with an E/E′ z-score of ≥2 were similar between those with AS and AS+AR and greater than in those with AR (p <0.001).
In the AS group, concentric hypertrophy/remodeling was associated with a DFS ≥2 compared to mixed/physiologic hypertrophy or a normal ventricle (50%, 30%, and 15%, respectively, p <0.001). In the AS+AR and AR remodeling pattern was not associated with the DFS. Subgroup analysis of patients with AS comparing patients with mild or less residual AS (n = 37) and those with more than residual mild AS (n = 66) showed a lower LV mass z-score (median 0.84, interquartile range −1.8 to 3.8 vs median 1.52, interquartile range −0.8 to 10.2, p = 0.026) and lower LV mass:volume (median 0.9, interquartile range 0.7 to 1.6, vs median 1.2, interquartile range 0.8 to 1.8, p = 0.001) in patients with lower gradients. However, no difference was found in the demographics, cardiac interventions, or diastolic function parameters.
The results of univariate analysis of factors associated with a DFS of ≥2 is listed in Table 4. On multivariate analysis, only a greater LV mass z-score and previous balloon aortic valvuloplasty were associated with a DFS of ≥2.
Table 4Univariate and multivariate risk factors for diastolic function score ≥2
Factor
OR (95% CI)
p Value
Demographic variables
Male gender
2.02 (1.09–3.63)
0.03
Age (yrs)
1.01 (0.98–1.04)
0.44
Age ≥20 yrs
2.10 (1.20–3.70)
0.01
Weight (kg)
1.00 (0.99–1.01)
0.91
Clinical variables
Balloon aortic valvuloplasty
3.21 (1.87–5.49)
<0.001
Balloon aortic valvuloplasty within first year of life
Catheterization data were available for 65 patients: 28 with AS and 37 with AS+AR. The median LV end-diastolic pressure was 18 mm Hg (range 9 to 33), with 43 patients (66%) having a LV end-diastolic pressure of ≥15 mm Hg. The mean pulmonary artery pressure was ≥35 mm Hg in 5 patients (8%). Pulmonary vascular resistance was ≥2 Woods units in 19 patients (29%). E/E′ correlated with the LV end-diastolic pressure (r = 0.58, p <0.001) and mean pulmonary artery pressure (r = 0.63, p <0.001; Figure 3). An E/E′ >9.5 predicted LV end-diastolic pressure of ≥15 mm Hg, with 84% sensitivity and 76% specificity (Figure 4). Patients with a DFS of ≥2 had a greater LV end-diastolic pressure and mean pulmonary artery pressure than those with those with a DFS <2 (Table 5).
Figure 3Scatter plot of LV end-diastolic pressure (mm Hg) versus E/ E′ (A) (r = 0.58, p <0.001) and mean pulmonary artery pressure (mm Hg) versus E/E′ (B) (r = 0.63, p <0.001) for patients with catheterization data (n = 65).
Figure 4Receiver operating characteristic curve for E/E′ predicting LV end diastolic pressure ≥15. An E/E′ >9.5 is 84% sensitive and 76% specific for LV end-diastolic pressure ≥15 (area under the curve 0.85).
In the present study, we evaluated LV diastolic function in children and young adults with aortic valve disease and found that DD is common in patients with AS and AS+AR and uncommon in those with pure AR. DD was associated with a greater LV mass and previous need for balloon aortic valvuloplasty. These findings suggest that the pressure load on the left ventricle leads to concentric hypertrophy and likely myocardial fibrosis and subsequent DD in AS and AS+AR. Volume loading in AR leads to eccentric hypertrophy and was rarely associated with DD. In patients with AS, the pattern of LV remodeling, in particular, the presence of concentric hypertrophy, was associated with a greater risk of DD. Concentric hypertrophy and associated myocardial fibrosis have been identified, along with impaired relaxation due to alterations in calcium handling, as the etiology of DD in older adults with AS.
Patients with pure AR had little evidence of DD in our study, in contrast to most previous studies of adults with AR, which have reported that DD is common.
One possible explanation for this discrepancy is less severe and a shorter duration of volume load in this cohort compared to previous data, which has generally evaluated older adults undergoing aortic valve replacement. Another potential explanation is that the normal decrease in ventricular compliance with age might be accelerated in older patients with AR, who are likely to have additional co-morbidities that could affect diastolic function.
Previously reported data on diastolic function in younger patients with AR are scant. Future studies evaluating the relationship between DD and LV volume load in younger patients are needed to clarify this issue.
Risk factors for DD in our study included greater LV mass and previous balloon aortic valvuloplasty. These factors suggest diastolic function is worse in patients with a longer duration and severity of LV pressure load. The cross-sectional design of the study and lack of longitudinal diastolic data limited our ability to directly assess the effect of duration and timing of the pressure load on DD. The pressure and volume load at the latest follow-up visit were not associated with DD, but previous balloon aortic valvuloplasty and greater LV mass were, likely indicating that cumulative pressure load is an important an factor in the development of DD. This was also reflected in the AS group in which concentric hypertrophy, regardless of current gradient, was a risk factor for DD compared to other remodeling patterns. In the AS and AS+AR cohort, a substantial number of patients had DD, despite having undergone previous balloon aortic valvuloplasty and having a low residual AS gradient. This suggests that the LV pressure load at vulnerable periods, possibly during the fetal or neonatal period, or that the peak pressure load might play a role in the development of DD, in addition to the cumulative pressure load.
Data from patients who have undergone in utero aortic valvuloplasty for evolving hypoplastic left heart syndrome support the concept that patients with LV pressure load in utero frequently develop DD even if the pressure load has been effectively reduced postnatally.
In adults undergoing aortic valve replacement, a subset of patients have ongoing progression of DD, despite the elimination of pressure load, suggesting that myocardial changes, including fibrosis, can progress in the absence of an ongoing pressure load.
Our data show that noninvasive measures or left atrial pressure, primarily E/E′, correlate well with invasively measured LV end-diastolic pressure and mean pulmonary artery pressure. Although considerable data exist demonstrating tissue Doppler imaging indexes to be relatively load-independent measures of LV diastolic function and correlates of LV end-diastolic pressure in normal elderly patients and a variety of adult disease states,
this relationship has not been previously reported in children with aortic valve disease. Additionally, we found an association between an elevation in E/E′ and elevated pulmonary artery pressure, which has been reported in adults with AS in whom E/E′ has been shown to be the best noninvasive predictor of elevated pulmonary artery pressure.
Recognition of the ability of noninvasive measures to predict LV end-diastolic pressure and pulmonary artery pressure might add useful information in surgical timing and perioperative management of younger patients undergoing aortic valve surgery.
Future studies are needed to evaluate the proposed mechanisms of DD, including myocardial fibrosis, in children and young adults. Quantification of fibrosis with cardiac magnetic resonance imaging and evaluation for biomarkers indicating fibrosis might be helpful in identifying reversible and irreversible myocardial damage and help with optimal timing of interventions.
Long-term, clinical, echocardiographic, and exercise data are needed to determine how frequently progressive symptoms attributable to diastolic heart failure or significantly decreased exercise capacity develop in this patient population.
The limitations of the present study included the cross-sectional, retrospective design, which limited our ability to evaluate the effect of the timing and duration of pressure and volume load on LV function. To avoid the confounding effect cardiopulmonary bypass might have on diastolic function, patients who had undergone cardiac surgery were excluded. Eliminating patients with a history of aortic valve surgery might have biased our cohort toward having less DD, because patients who had undergone surgery might have had more severe aortic valve disease than those who had not. Within the AS, AS+AR, and pure AR groups, significant variation was found between patients in the duration and severity of valve disease. Finally, the lack of a diastolic function grading system designed and validated for younger patients, including patients with congenital heart disease, was a major limitation of the present study and for the field in general.
Disclosures
The authors have disclosed no conflicts of interest.
References
Gaasch W.H.
Zile M.R.
Left ventricular structural remodeling in health and disease: with special emphasis on volume, mass, and geometry.
Improvement of heart function after balloon dilation of congenital valvar aortic stenosis: a pilot study with ultrasound tissue Doppler and strain rate imaging.
Left ventricular remodeling early after aortic valve replacement: differential effects on diastolic function in aortic valve stenosis and aortic regurgitation.
Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council.
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