Conventional 2-dimensional, M-mode, and spectral Doppler echocardiographic techniques have documented abnormal ventricular function in adults with sickle cell disease (SCD), but assessments in children are conflicting. Tissue Doppler echocardiography (TDE) provides additional information about myocardial function. Two-dimensional, M-mode, tricuspid regurgitation jet velocity (TRJV) data, and tissue Doppler echocardiographically derived myocardial velocity measurements of left ventricular (LV) and right ventricular function were taken from children with SCD compared to those of similar healthy historical controls and correlated with clinical characteristics and hemoglobin levels. Compared to 55 controls, 54 children with SCD (mean age 14.2 years, range 6 to 21) had a larger left ventricle, greater LV mass, and higher LV fractional shortening; 30% had increased pulmonary artery pressure (TRJV ≥2.5 m/s). Conventional echocardiographic measurements of LV systolic function and spectral Doppler measurements of LV and right ventricular diastolic function were essentially normal, but TDE indicated that 31% of SCD children had evidence of LV diastolic dysfunction (peak early diastolic velocity of LV inflow Doppler/peak early diastolic velocity at lateral mitral valve annulus >8), a finding that correlated with lower hemoglobin levels. Although decreasing hemoglobin levels in children with SCD correlated with LV hypertrophy, LV dilation, and LV diastolic dysfunction, long-term transfusion or hydroxyurea therapy did not affect these measurements. In conclusion, 1/3 of children with SCD had tissue Doppler echocardiographic evidence of LV diastolic dysfunction, which was correlated with hemoglobin levels. Adding serial assessments of ventricular function with TDE to conventional echocardiography may detect early cardiac changes, especially in children with severe anemia.
Sickle cell disease (SCD) is the most common inherited hematologic disorder in the United States, affecting 1 in 365 African-Americans. Left ventricular (LV) diastolic dysfunction and pulmonary hypertension are common in adults with SCD and associated with increased mortality. Abnormal systolic and diastolic ventricular functions occur in adults with SCD. However, in children with SCD, assessments of ventricular function are conflicting. Although tissue Doppler echocardiography (TDE) has not been widely applied to children with SCD, it may detect subclinical myocardial dysfunction often not evident on conventional 2-dimensional, M-mode, or spectral Doppler studies. Findings from TDE may be less affected by preload variation, as seen in chronic anemia. LV filling pressures can be estimated by TDE, which helps assess ventricular function in myocardial disease. We hypothesized that TDE would be a sensitive ventricular function marker to complement conventional echocardiography in children with SCD. The purposes of this study were to assess echocardiographic findings in children with SCD and analyze biventricular systolic and diastolic functions using conventional Doppler and TDE.
Methods
The institutional review board of the University of Miami and Holtz Children’s Hospital approved the study. Children with SCD were eligible for the study if they were treated at the University of Miami/Holtz Children’s Hospital from July 2006 through December 2008.
All children had echocardiography and TDE performed during a follow-up visit while their disease was stable. Children were excluded if they had SCD-related acute chest syndrome within 1 month before being evaluated. Demographics, blood pressures, and hemoglobin values obtained on the day of echocardiographic examination were abstracted from medical records. To identify possible confounding clinical factors, we also collected information on the presence of concomitant reactive airway disease, systemic arterial hypertension, and treatment with long-term blood transfusions or hydroxyurea. We selected a healthy group of historical controls with age and sex distributions similar to those of the SCD group and for whom tissue Doppler echocardiographic data had been collected for another study at our center. We compared conventional and tissue Doppler echocardiographic findings of the SCD group to those of the control group. All 2-dimensional, M-mode, and spectral Doppler echocardiographic variables were measured according to recommendations of the American Society of Echocardiography. Surveillance transthoracic echocardiograms were acquired using a Vivid 7 system (General Electric Medical Systems, Milwaukee, Wisconsin). M-mode parasternal short-axis measurements were obtained at end-diastole for interventricular septal thickness, LV posterior wall thickness, LV end-systolic diameter, and LV end-diastolic diameter. LV fractional shortening was calculated from these data. LV mass was calculated using the Devereux formula and indexed to body surface area. LV ejection fraction was obtained using the biplane Simpson method. Tricuspid regurgitation jet velocity (TRJV) was measured from different views, with the maximal peak velocity reported. Spectral Doppler flow velocities were obtained for peak early (E M ) and late diastolic flows at the LV inflow and right ventricular inflow. Tissue Doppler measurements ( Table 1 ) of lateral mitral and tricuspid valve annulus excursions were recorded from the apical 4-chamber view ( Figure 1 ). The ratio of E M to peak velocity of early diastolic excursion of lateral mitral valve annulus (E m ) is used as a surrogate for LV diastolic filling pressure. In adults ratios ≤8 indicate normal LV filling pressure and therefore normal LV diastolic function. Ratios >8 suggest increased LV filling pressure or diastolic dysfunction. All measurements of tissue Doppler echocardiographic and spectral Doppler velocities were averaged over 3 consecutive heartbeats.
| Ventricle | Systolic Function Measurements | Diastolic Function Measurements |
|---|---|---|
| Left | peak systolic velocity at lateral mitral valve annulus (lowered by systolic dysfunction) | peak early diastolic velocity at lateral mitral valve annulus (lowered by diastolic dysfunction) |
| peak early diastolic velocity of left ventricular inflow Doppler/peak early diastolic velocity at lateral mitral valve annulus (higher ratio is associated with higher left ventricular filling pressure or higher degree of diastolic dysfunction) | ||
| Right | peak systolic velocity at lateral tricuspid valve annulus (lowered by systolic dysfunction) | peak early diastolic velocity at lateral tricuspid valve annulus (lowered by diastolic dysfunction) |
Continuous data are reported as mean ± SD, and discrete data are reported as frequency and percentage. Continuous variables are also often expressed as z scores, which indicate, in units of SD, how far an individual or mean value from the sample population is from that of the mean of a normal distribution. Analysis of covariance was used to compare healthy control children to those with SCD, adjusting for effects of age and sex. Adjusted mean ± SE is reported for this analysis. The t tests for independent samples were used for comparisons made within the SCD group. Relations among hemoglobin levels, LV dimensions, and tissue Doppler echocardiographic measurements were assessed with the Pearson correlation coefficient. Effects of long-term transfusion and hydroxyurea were also analyzed with t tests. All data met assumptions of the data used to analyze them. SAS statistical software (SAS Institute, Cary, North Carolina) was used for all statistical analyses. Alpha was set at 0.05 and all tests were 2-tailed.
Results
Fifty-four children with SCD were enrolled. Of these, 33 (61%) were boys; the study age range was 6 to 21 years (mean ± SD 14.2 ± 4.4). Of these, 50 had sickle cell anemia (hemoglobin SS disease), 2 had sickle cell hemoglobin–β thalassemia, and 2 had hemoglobin SC disease. The control group consisted of 55 healthy children (37 boys, 67%) whose ages ranged from 10 to 19 years (mean ± SD 13.3 ± 2.0). Groups did not differ significantly by age or sex.
Children with SCD had a larger left ventricle (increased LV end-diastolic diameter z scores), larger LV mass (increased LV mass z scores), and higher LV fractional shortening than healthy children ( Table 2 ). LV posterior wall thickness, interventricular septal thickness, and LV end-systolic dimension z scores were similar to those in the control group. In children with SCD, 40 (74%) had a TRJV measurable by Doppler. These velocities ranged from 1.7 to 3.2 m/s. Of these 40 children, 12 (30%) had a TRJV ≥2.5 m/s, indicating increased pulmonary artery systolic pressure. No child with SCD had moderate or severe pulmonary artery hypertension as estimated by TRJV measurement. Mean LV ejection fraction did not differ significantly between the SCD and control groups.
| Variable | Value | z Score ⁎ | p Value |
|---|---|---|---|
| End-diastolic septal wall thickness (mm) | 8.9 ± 1.9 | 0.05 ± 1.1 | 0.73 |
| End-diastolic left ventricular diameter (mm) | 49.3 ± 7.5 | 0.99 ± 1.4 | <0.001 |
| End-diastolic left ventricular posterior wall thickness (mm) | 8.2 ± 1.7 | −0.23 ± 1.4 | 0.23 |
| End-systolic left ventricular diameter (mm) | 31.1 ± 5.5 | 0.30 ± 1.4 | 0.11 |
| Left ventricular fractional shortening (%) | 37.1 ± 4.4 | 1.34 ± 1.8 | <0.001 |
| Left ventricular mass (g) | 149.8 ± 62.4 | ||
| Left ventricular mass index (g/m 2 ) | 102.3 ± 26.6 | 0.67 ± 1.3 | 0.001 |
⁎ The z scores are based on the distribution of these measurements in healthy children, a distribution that has a standard normal distribution with a mean z score of 0 and a SD of 1. The p value is from a 2-sided 1-sample test (z test) of a normally distributed variable with a known variance of 1.
Lateral mitral annular peak systolic and diastolic velocities (including E m ) were significantly lower in SCD children than in controls ( Table 3 ). Mean E M /E m ratio, a marker of LV filling pressures, was significantly higher in children with SCD. All controls had E M /E m ratios <8. Of the 54 children with SCD, 17 (31%) had an E M /E m ratio >8, suggesting the presence of LV diastolic dysfunction. Lateral tricuspid annular velocities (peak velocities of systolic, early diastolic, and late diastolic excursions of lateral tricuspid valve annulus) were significantly higher in children with SCD than in controls. The E M /E m ratio was correlated with interventricular septal thickness z scores, LV posterior wall thickness z scores, and LV mass z scores ( Table 4 ). Patients with E M /E m ratios >8 had higher LV mass z scores (p = 0.007), interventricular septal thickness z scores (p = 0.003), and TRJV (p = 0.02) and lower hemoglobin (p = 0.03), lateral mitral annular peak systolic velocity (p = 0.08), E m (p <0.001), and lateral mitral annular peak diastolic velocity (p = 0.003) than patients with an E M /E m ratio ≤8.
| Measurement | Healthy Controls (n = 55) | SCD (n = 54) | p Value |
|---|---|---|---|
| Peak systolic velocity at lateral mitral valve annulus (cm/s) | 10.3 ± 0.3 | 9.1 ± 0.2 | 0.001 |
| Peak systolic velocity at lateral tricuspid valve annulus (cm/s) | 12.5 ± 0.3 | 15.7 ± 0.3 | <0.001 |
| Peak early diastolic velocity of left ventricular inflow Doppler (cm/s) | 91 ± 3 | 113 ± 02 | <0.001 |
| Peak late diastolic velocity of left ventricular inflow Doppler (cm/s) | 41 ± 2 | 52 ± 2 | <0.001 |
| Peak early/late diastolic velocity of left ventricular inflow Doppler | 2.3 ± 0.1 | 2.3 ± 0.1 | 0.887 |
| Peak early diastolic velocity at lateral mitral valve annulus (cm/s) | 18.4 ± 0.4 | 16.0 ± 0.4 | <0.001 |
| Peak late diastolic velocity at lateral mitral valve annulus (cm/s) | 7.0 ± 0.3 | 5.7 ± 0.3 | <0.001 |
| Peak early/late diastolic velocity at lateral mitral valve annulus | 2.8 ± 0.1 | 3.0 ± 0.1 | 0.139 |
| Peak early diastolic velocity of left ventricular inflow Doppler/peak early diastolic velocity at lateral mitral valve annulus | 4.8 ± 0.3 | 7.5 ± 0.3 | <0.001 |
| Peak early diastolic velocity of right ventricular inflow Doppler (cm/s) | 57 ± 2 | 65 ± 2 | 0.001 |
| Peak late diastolic velocity of right ventricular inflow Doppler (cm/s) | 31 ± 2 | 40 ± 1 | <0.001 |
| Peak early/late diastolic velocity of right ventricular inflow Doppler | 1.9 ± 0.1 | 1.8 ± 0.1 | 0.055 |
| Peak early diastolic velocity at lateral tricuspid valve annulus (cm/s) | 15.0 ± 0.4 | 16.9 ± 0.4 | 0.001 |
| Peak late diastolic velocity at lateral tricuspid valve annulus (cm/s) | 8.3 ± 0.3 | 9.7 ± 0.3 | 0.002 |
| Peak early/late diastolic velocity at lateral tricuspid valve annulus | 1.9 ± 0.1 | 1.9 ± 0.1 | 0.720 |
| Echocardiographic Measurement | IVSd z score | LVDd z score | LVPWd z score | LVDs z score | LVM z score | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| r | p Value | r | p Value | r | p Value | r | p Value | r | p Value | |
| Peak systolic velocity at lateral mitral valve annulus | 0.02 | 0.89 | −0.27 | 0.05 | 0.16 | 0.24 | −0.18 | 0.18 | −0.11 | 0.42 |
| Peak early diastolic velocity at lateral mitral valve annulus | −0.20 | 0.14 | −0.11 | 0.42 | −0.06 | 0.64 | −0.10 | 0.45 | −0.21 | 0.13 |
| Peak late diastolic velocity at lateral mitral valve annulus | −0.17 | 0.21 | 0.01 | 0.95 | −0.01 | 0.96 | 0.05 | 0.7 | −0.08 | 0.55 |
| Peak early/late diastolic velocity at lateral mitral valve annulus | 0.04 | 0.75 | −0.09 | 0.54 | 0.03 | 0.81 | −0.13 | 0.35 | −0.02 | 0.88 |
| Peak early diastolic velocity of left ventricular inflow Doppler/peak early diastolic velocity at lateral mitral valve annulus | 0.41 | <0.01 | 0.15 | 0.29 | 0.32 | 0.02 | 0.05 | 0.74 | 0.44 | <0.01 |
Twelve patients (22%) had current mild-to-moderate chronic reactive airway disease. These patients had lower peak velocity of late diastolic excursion of lateral tricuspid valve annulus and peak velocity of early/late diastolic excursion of lateral tricuspid valve annulus ratios. The importance of this finding is unclear. Eight patients (15%) were taking long-term antihypertensive medications for systemic hypertension. At the echocardiographic study, all had normal blood pressures. None of the patients with SCD had clinical heart failure. Systolic blood pressure percentile (using blood pressure measurement obtained during the clinic visit) was positively correlated with the E M /E m ratio (r = 0.36, p <0.01) and negatively correlated with E m (r = −0.34, p <0.01).
The mean ± SD hemoglobin level of the 54 patients with SCD was 8.86 ± 1.32 g/dl. Hemoglobin levels in SCD were negatively correlated with interventricular septal thickness z scores, LV end-diastolic diameter z scores, LV end-systolic diameter z scores, LV mass z scores, and E M /E m ( Table 5 ).
| Echocardiographic Measurement | Pearson r | p Value |
|---|---|---|
| End-diastolic septal wall thickness z score | −0.32 | 0.02 |
| End-diastolic left ventricular diameter z score | −0.33 | 0.02 |
| End-diastolic left ventricular posterior wall thickness z score | −0.2 | 0.15 |
| End-systolic left ventricular diameter z score | −0.26 | 0.05 |
| Left ventricular mass z score | −0.48 | <0.01 |
| Peak systolic velocity at lateral mitral valve annulus | −0.05 | 0.71 |
| Peak early diastolic velocity at lateral mitral valve annulus | 0.15 | 0.28 |
| Peak late diastolic velocity at lateral mitral valve annulus | 0.13 | 0.33 |
| Peak early/late diastolic velocity at lateral mitral valve annulus | −0.02 | 0.89 |
| Peak early diastolic velocity of left ventricular inflow Doppler/peak early diastolic velocity at lateral mitral valve annulus | −0.48 | <0.01 |
| Peak systolic velocity at lateral tricuspid valve annulus | −0.1 | 0.48 |
| Peak early diastolic velocity at lateral tricuspid valve annulus | 0.03 | 0.82 |
| Peak late diastolic velocity at lateral tricuspid valve annulus | −0.14 | 0.30 |
| Peak early/late diastolic velocity at lateral tricuspid valve annulus | 0.16 | 0.24 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
