Background
Echocardiographic measures of left ventricular (LV) dyssynchrony in pediatric patients with heart failure (HF) have not been adequately evaluated. The aim of this study was to evaluate LV systolic dyssynchrony in pediatric patients with HF and normal children.
Methods
Among a total of 68 patients, 22 had HF and 46 were normal. Doppler tissue imaging, M-mode echocardiography, and pulsed-wave Doppler echocardiography were performed. Intraventricular dyssynchrony using the maximal difference in time to peak myocardial systolic contraction (Ts), the standard deviation of Ts of 12 LV segments, septal–to–posterior wall motion delay, and interventricular dyssynchrony by measuring aortic and pulmonary pre-ejection delays were obtained.
Results
The maximal difference in Ts (patients with HF, 91.27 ± 31.18 msec; controls, 45.93 ± 21.29 msec; P < .001), the standard deviation of Ts (patients with HF, 31.05 ± 10.68 msec; controls, 15.60 ± 7.70 msec; P < .001), septal–to–posterior wall motion delay (patients with HF, 117.14 ± 45.18 msec; controls, 48.69 ± 16.63 msec; P < .001) and interventricular dyssynchrony (patients with HF, 21.60 ± 16.27 msec; controls, 11.56 ± 9.38 msec; P = .03) were significantly prolonged in the HF group. Defining systolic dyssynchrony as a standard deviation of Ts > 31 msec (+2 standard deviations of normal controls) and a maximal difference in Ts > 89 msec in normal controls and 18 patients with HF due to dilated cardiomyopathy was included for analysis of systolic dyssynchrony; it was present in three (6.5%) and two (4.3%) controls and in nine (50%) and 10 (55%) patients with HF due to dilated cardiomyopathy, respectively. Low ejection fraction, elevated LV end-diastolic volume, and elevated LV end-systolic volume had significant correlations with systolic dyssynchrony. QRS duration was not significantly correlated with measures of dyssynchrony.
Conclusions
Systolic mechanical dyssynchrony is common in pediatric patients with HF. QRS duration is not a determinant of systolic dyssynchrony in pediatric patients. Echocardiographic measurements of systolic dyssynchrony are feasible in pediatric patients.
Pediatric heart failure (HF) embraces a wide range of ages and diverse causes, leading to intractable symptoms, poor quality of life, and limited survival. Cardiac diseases leading to HF affect myocardial function, primarily due to impairment of systolic and diastolic function. In addition, disturbance in ventricular coordination causing ineffective and asynchronous ventricular contraction may occur. In adult patients with HF, left ventricular (LV) dyssynchrony in the presence of apparent electrical delay on surface electrocardiography with wide QRS complex, left bundle branch block, and interventricular conduction delay are very well established. Furthermore, quite a few studies have shown the presence of systolic and diastolic dyssynchrony and normal QRS duration in adult patients with HF. Adult patients with end-stage HF with systolic dyssynchrony who undergo cardiac resynchronization therapy (CRT) using biventricular pacing show reduced cardiac symptoms and improved heart function, as well as reverse LV remodeling. In addition to significant differences in etiology, most pediatric patients with HF do not have prolonged QRS durations. There are no definitive criteria for selecting pediatric patients with HF for CRT. The presence of mechanical delay resulting in asynchronous ventricular contraction has not been adequately evaluated in children with HF. Establishing the presence of ventricular dyssynchrony will potentially help in considering CRT for pediatric patients with HF. We hypothesized that pediatric patients with HF with structurally normal hearts or congenital heart disease have ventricular mechanical dyssynchrony irrespective of QRS duration. To test this hypothesis, we used conventional echocardiography and Doppler tissue imaging (DTI) to accurately assess regional myocardial contraction and mechanical delay in normal controls and in children with HF.
Methods
Pediatric patients with HF seen at the Children’s Hospital of the Cleveland Clinic between January 2005 and June 2007 were prospectively evaluated. Twenty-two patients with clinical signs and symptoms of HF and ventricular dysfunction (ejection fraction [EF] < 50%) were identified and selected consecutively. Patients were assigned symptom scores on the basis of the modified New York Heart Association classification for use in children. Eighteen patients had structurally normal hearts with dilated cardiomyopathy (DCM), one had undergone orthotopic heart transplantation, and three had unrepaired congenital heart defects ( Table 1 ). These patients underwent 12-lead electrocardiography, conventional echocardiography, and DTI as part of regular HF evaluation. Among the participants, QRS durations were defined as narrow (96.2%) and wide in four of 68 (5.8%), per standard age-based normative data. Echocardiographic and DTI studies performed 2 to 6 weeks after stabilization with medical treatment were also evaluated. The normal cutoffs of the four echocardiographic systolic dyssynchrony measures are defined as the mean + 2 standard deviations. Any value above this limit was considered abnormal, and accordingly, patients with HF were classified as presenting with significant intraventricular and/or interventricular mechanical dyssynchrony compared with the control group. Patients’ echocardiograms were compared with those of 46 normal children who underwent cardiac evaluation to rule out congenital heart disease. The normal controls were age and gender matched. They had no significant histories of cardiovascular or systemic diseases and had normal results on cardiac physical examination, electrocardiography, and echocardiography. The study was approved by the Cleveland Clinic institutional review board.
| Variable | Value |
|---|---|
| Age (y) (range) | 9.8 (0.1–16) |
| Male/female | 11/11 |
| QRS duration | |
| Wide | 3 |
| Narrow | 19 |
| Causes of heart failure ( n = 22) | |
| DCM ( n = 18) | |
| Idiopathic | 8 |
| Myocarditis | 6 |
| LV noncompaction | 2 |
| Mitochondrial disorder | 2 |
| Congenital heart disease (unrepaired) ( n = 3) | |
| Severe coarctation of aorta | 2 |
| Anomalous left coronary artery from pulmonary artery | 1 |
| Other ( n = 1) | |
| Orthotopic heart transplantation, acute rejection | 1 |
| Modified New York Heart Association class | |
| IV | 18 |
| III | 4 |
| Medications | |
| Diuretics | 21 |
| Angiotensin-converting enzyme inhibitors | 17 |
| β-blockers | 4 |
| Calcium antagonists | 2 |
| Aspirin | 6 |
| Heparin | 1 |
| Intravenous inotropes | 4 |
| Digoxin | 12 |
Echocardiography
Standard transthoracic echocardiographic and Doppler studies were performed (System 5; GE Vingmed Ultrasound AS, Horten, Norway). LV dimensions were measured using two-dimensionally guided M-mode imaging according to American Society of Echocardiography guidelines. EF was measured using two-dimensional echocardiography using the modified Simpson’s method. The advantage of this model is that it is independent of ventricular geometry. DTI was performed in the apical views (four chamber, two chamber, and long axis) for the long-axis motion of the left ventricle, as previously described. Validation of DTI has been performed in physical models, animal models, and human subjects, and it has been found to be accurate in assessing regional velocity and timing of cardiac events. For detailed assessment of regional myocardial function, the sample volume was placed at the middle of the basal and mid segmental portions of the septal, anteroseptal, anterior, lateral, inferior, and posterior walls. Gain and filter settings were adjusted as needed to eliminate background noise and to allow a clear tissue signal. At least three consecutive beats were stored, and the images were digitized and analyzed offline using EchoPAC version 6.3 (GE Vingmed Ultrasound AS). The beginning of the QRS complex was used as the reference point from which the time to peak myocardial systolic contraction (Ts) was quantified. For the assessment of intraventricular dyssynchrony, the standard deviation of Ts (Ts-SD) of 12 LV segments and the maximal difference in Ts (Max-ΔTs) between two LV segments were assessed. Intraobserver and interobserver reliability for these parameters in 10 patients were 0.95 and 0.97, respectively. Septal–to–posterior wall motion delay (SPWMD) was obtained using M-mode echocardiography at the papillary muscle level. SPWMD was calculated as the shortest interval between the maximal posterior displacement of the septum and the maximal displacement of the posterior wall using a short-axis view. Interventricular dyssynchrony was assessed using pulsed-wave Doppler imaging and defined as the difference between the aortic and pulmonary pre-ejection delays (interventricular mechanical delay [IVMD]) and determined as the time from the onset of the QRS complex to the beginning of each respective systolic ejection. This measurement was used as an indicator of interventricular synchrony of right ventricular and LV contraction.
Statistical Analysis
Data were analyzed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Control subjects were included in the study to characterize the range of intraventricular and interventricular electromechanical delays in the population with normal cardiac function. The Shapiro-Wilk test was used to verify that the distribution of the control data followed a Gaussian curve. Two-sample t tests and Fisher’s exact tests were used to compare patient characteristics between the two study groups (controls and patients with HF). Interobserver and intraobserver reliability were evaluated by means of interclass correlation coefficients. Correlations between various patient characteristics and the four systolic dyssynchrony measures were assessed using Pearson’s correlation coefficients and multiple regression analysis to identify potential predictors of systolic dyssynchrony. P values < .05 were considered to be statistically significant.
Results
The etiology of HF, New York Heart Association class, and the use of medications in the 22 patients are summarized in Table 1 . DCM was the most prevalent cause of HF (81%). Baseline demographics as well as clinical and echocardiography characteristics of the patients with HF and normal controls are shown in Table 2 . There was no difference in age between patients with HF and controls (7.56 ± 6.3 and 9.82 ± 5.77 years, respectively, P = NS). Gender distribution, weight, and body surface area were also comparable. Heart rates were faster in the patient group (110.9 ± 26.4 vs 86.4 ± 27.3 beats/min, P = .001). However, age and heart rate were not confounders of systolic dyssynchrony according to analysis of covariance, and hence unadjusted P values are presented. LV diastolic and systolic volumes were adjusted for body surface area. The HF group had larger LV diastolic (134.7 ± 96.4 vs 84.09 ± 49.2 mL/m 2 , P = .003) and LV systolic (102.3 ± 78.0 vs 36.9 ± 24.15 mL/m 2 , P = .002) volumes compared with controls. The mean LV EF was lower in the HF group compared with controls (26.4 ± 8.1% vs 61.1 ± 7.0%, P < .0001). In the HF group, only patients with idiopathic DCM ( n = 18) were analyzed for dyssynchrony, and predominantly HF patients had systolic ventricular dyssynchrony compared with normal controls (50% vs 6.5%; Figure 1 A). The HF group had prolonged QRS durations compared with controls (82.7 ± 27.5 vs 66.1 ± 14.5 msec, P = .02). However, only three patients in the HF group with DCM ( n = 18) had wide QRS complexes. Of these, one had systolic dyssynchrony. The remaining 15 patients with HF had narrow QRS durations, and eight of these (53%) had systolic ventricular dyssynchrony ( Figure 1 B). Forty-five of 46 patients in the normal group had narrow QRS durations, of whom three had ventricular dyssynchrony. The remaining subject had a wide QRS complex, and this patient did not have ventricular dyssynchrony.
| Variable | Patients with HF ( n = 22) | Normal controls ( n = 46) | P |
|---|---|---|---|
| Age (y) | 9.82 (0.1–16) | 7.56 (0.1−17) | .1467 |
| Male/female | 11/11 | 26/20 | .6106 |
| QRS duration (msec) | 82.76 ± 27.5 | 66.11 ± 16.07 | .0228 |
| Weight (kg) | 34.58 ± 29.57 | 41.75 ± 27.8 | .3369 |
| Body surface area (m 2 ) | 1.02 ± 0.67 | 1.29 ± 0.62 | .1222 |
| Heart rate (beats/min) | 110.90 ± 26.4 | 86.43 ± 27.6 | .0014 |
| EF (%) | 26.45 ± 8.09 | 61.17 ± 6.5 | <.0001 |
| LV end-diastolic volume index (mL/m 2 ) | 150.23 ± 112.50 | 63.12 ± 19.27 | .0030 |
| LV end-systolic volume index (mL/m 2 ) | 112.74 ± 87.13 | 26.9 ± 10.02 | .0002 |
Systolic Ventricular Dyssynchrony
Systolic ventricular dyssynchrony was apparent in the patients with HF with DCM. Figures 2 A and 2 B illustrate regional myocardial velocity curves and simultaneous time to peak systolic contraction obtained by DTI at the basal anterior, mid anterior, basal inferior, and mid inferior segments in a single patient, a normal control ( Figure 2 A) and a patient with HF ( Figure 2 B). The measures of intraventricular dyssynchrony (Ts-SD, Max-ΔTs, and SPWMD) were all prolonged in patients with HF compared with normal controls ( P < .001). Similarly, IVMD measured using pulsed Doppler echocardiography was prolonged in patients with HF compared with normal controls ( P = .03; Table 3 ). Table 4 summarizes systolic dyssynchrony from various echocardiographic measures in normal controls and demonstrates the normal cutoff values. Table 5 illustrates the presence of systolic dyssynchrony in normal controls and patients with HF due to DCM. Patients with HF with various causes were analyzed separately ( Table 6 ). DCM represented the major etiology of HF (81%) in our cohort. Therefore, using Ts-SD > 31 msec and Max-ΔTs > 89 msec as markers of significant systolic dyssynchrony, it was found in nine of 18 (50%) and 10 of 18 (55%) patients with HF due to DCM and in two (4.3%) and three (6.5%) controls, respectively. Similarly, defining dyssynchrony as SPWMD > 82 msec, a total of 14 of 17 patients with HF (82%) had dyssynchrony, compared with only two normal controls (4.6%). There was no evidence of dyssynchrony in both these measures in patients with unrepaired congenital heart disease. However, using IVMD > 30 msec as an indicator of interventricular dyssynchrony, only one control (2.4%) had dyssynchrony, compared with three of 14 patients with HF (21%) ( Tables 4 and 5 ).
| Variable | Patients with HF ( n = 22) | Normal controls ( n = 47) | P |
|---|---|---|---|
| Max-ΔTs | 91.27 ± 31.18 | 45.93 ± 21.29 | <.0001 |
| Ts-SD | 31.05 ± 10.68 | 15.60 ± 7.70 | <.0001 |
| SPWMD | 117.14 ± 45.18 | 48.69 ± 16.63 | <.0001 |
| IVMD | 21.60 ± 20.5 | 11.56 ± 9.38 | .0334 |
| Variable | n | Mean ± SD | Mean + 2 SDs |
|---|---|---|---|
| Ts-SD | 46 | 15.60 ± 7.70 | 31.01 |
| Max-ΔTs | 46 | 46.17 ± 21.23 | 88.64 |
| SPWMD | 43 | 48.69 ± 16.63 | 81.96 |
| IVMD | 41 | 11.56 ± 9.38 | 30.30 |
| Variable | Normal controls ( n = 46) | Patients with HF with DCM ( n = 18) |
|---|---|---|
| Ts-SD > 31 msec | 3/46 (6.5%) | 9/18 (50%) |
| Max-ΔTs > 89 msec | 2/46 (4.3%) | 10/18 (55%) |
| SPWMD > 82 msec | 2/43 (4.6%) | 14/17 (82%) |
| IVMD > 30 msec | 1/41 (2.4%) | 3/14 (21%) |
| Cause of HF | Measures of ventricular dyssynchrony | |
|---|---|---|
| Ts-SD > 31 msec | Max-ΔTs > 89 msec | |
| DCM | 9/18 (50%) | 10/18 (55%) |
| Idiopathic | 4/8 (50%) | 4/8 (50%) |
| Myocarditis | 3/6 (50%) | 4/6 (33%) |
| Mitochondrial | 0/2 (0%) | 0/2 (0%) |
| LV noncompaction | 2/2 (100%) | 2/2 (100%) |
| Other | ||
| Orthotopic heart transplantation | 1/1 (100%) | 0/1 (0%) |
| Congenital heart disease | 0/3 (0%) | 0/3 (0%) |
| Coarctation of aorta | 0/2 (0%) | 0/2 (0%) |
| Anomalous origin of left coronary artery from pulmonary artery | 0/2 (0%) | 0/2 (0%) |
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