Background
Sickle cell disease (SCD) is a hemoglobinopathy that is common worldwide. It usually presents with cardiac involvement, although data on systolic function are somewhat controversial. The aim of this study was to investigate the value of speckle-tracking strain, a deformation index, in detecting ventricular dysfunction in SCD.
Methods
Ninety adult patients with SCD were compared with 20 healthy controls. Doppler echocardiography with Doppler tissue imaging was performed in all, and the left and right ventricles were analyzed by the use of two-dimensional speckle-tracking strain.
Results
The mean age of the patients with SCD was 26 years, and 43% were men. Left ventricular (LV) dimensions and mass were higher in patients with SCD, whereas LV ejection fraction did not differ from the controls. E and A waves, as well as E/e′ ratio, were also higher in patients with SCD. Two-dimensional speckle-tracking strain of both ventricles in the patients with SCD was not different from that of controls. The factors independently associated with LV longitudinal strain were age ( P = .009), oximetry ( P = .001), lactate dehydrogenase ( P = .014), LV ejection fraction ( P < .001), and right ventricular systolic annular velocity ( P = .010).
Conclusions
Ventricular enlargement with normal ventricular function was a frequent finding in SCD. Two-dimensional speckle-tracking strain of both ventricles was similar in patients and controls, suggesting normal myocardial contractility in patients with SCD. LV global longitudinal strain was associated with age, intensity of hemolysis, and ventricular function.
Sickle cell disease (SCD) is a frequent inherited hemoglobinopathy that affects approximately 100,000 individuals in the United States, with a prevalence of 1 in 365 African Americans. Cardiovascular complications are increasingly identified in patients with SCD and have been associated with mortality. Several mechanisms have been proposed to explain cardiac involvement in SCD, including chronic anemia, progressive dysplasia or thrombotic occlusion of coronary vessels, intrinsic cardiomyopathy, and pulmonary hypertension.
Pulmonary hypertension represents a serious complication of SCD associated with increased morbidity and mortality. Both left ventricular (LV) systolic and diastolic dysfunction may occur in adults and children with SCD, but LV systolic dysfunction is not common and is usually observed in older patients and in those with associated disorders such as systemic hypertension and renal failure. Although most studies in adults show abnormalities of LV diastolic function, LV ejection fraction (LVEF) and/or other conventional indices of systolic function have usually been reported to remain normal. It is well known that conventional indices of LV systolic function are limited in identifying and measuring early ventricular dysfunction because of the volume-expanded high–cardiac output state present in chronic anemia. Strain, a parameter that seems to be independent of ventricular geometry and, to a lesser extent, of ventricular loading conditions, has been used to detect incipient LV and right ventricular (RV) systolic dysfunction in several heart diseases. However, only a few studies, with small numbers of patients, have addressed the role of strain in detecting subclinical changes in ventricular function in SCD, and their results are somewhat controversial.
Thus, the purpose of the present study was to use two-dimensional (2D) speckle-tracking strain to evaluate RV and LV function to determine if incipient ventricular systolic dysfunction in SCD can be detected, despite a normal LVEF. In addition, we investigated the associations between demographic, clinical, laboratory, and echocardiographic parameters and LV longitudinal strain.
Methods
Study Group
Adult outpatients ranging from 18 to 40 years of age, homozygous for hemoglobin S (HbSS) or who had Sβ 0 thalassemia attended at Hemominas Foundation, a referral center for SCD in Belo Horizonte, Brazil, were included. Patients were prospectively enrolled if the diagnosis of SCD had been previously documented by hemoglobin electrophoresis on cellulose acetate and on acid citrate agar showing an absence of hemoglobin A and positive results for sickling. Individuals with HbSS and hemoglobin Sβ 0 were selected because they present a very similar clinical course. The control group consisted of patients without any histories of cardiac disease who were seen at the echocardiography laboratory and had normal results on Doppler echocardiography.
Patients outside the age range or who presented with associated conditions (hypertension, diabetes, alcohol or drug abuse, pregnancy, chronic obstructive lung disease, rheumatic heart disease, and other cardiomyopathies) were excluded.
The study was approved by the institutional research ethics committee of the Hemominas Foundation and Universidade Federal de Minas Gerais, and written informed consent was obtained from all patients.
Clinical Evaluation
At entry, a complete clinical evaluation and routine laboratory examinations were carried out on all patients. Only patients clinically stable for ≥4 weeks were included, and functional status was determined using the New York Heart Association classification on the basis of functional capacity and dyspnea.
Electrocardiography and comprehensive Doppler echocardiography, with color flow mapping, tissue Doppler imaging, and speckle-tracking (2D strain) of both left and right ventricles, were also performed in all patients.
Doppler Echocardiography
Doppler echocardiography with color flow mapping was performed using a Vivid 7 system (GE Healthcare, Milwaukee, WI) with multifrequency transducers. M-mode measurements were performed according to the American Society of Echocardiography recommendations. LV mass was calculated using Devereux’s formula.
LV diastolic function was assessed by pulsed Doppler of the mitral inflow and by tissue Doppler imaging measurements, obtained at the medial and lateral border of the mitral annulus in the apical four-chamber view. Systolic tissue Doppler velocity (S′) and early (e′) and late (A′) diastolic tissue velocities were acquired, and the ratio of the mitral E velocity to the mean e′ was calculated (E/e′). Measurements were averaged over three beats.
Right atrial area was measured in end-systole in the apical four-chamber view. RV areas at end-systole and end-diastole were obtained in the apical four-chamber view, and fractional area change was calculated as (RV end-diastolic area − RV end-systolic area)/RV end-diastolic area × 100. RV tissue Doppler imaging was performed at the lateral tricuspid annulus in the apical four-chamber view, where peak systolic (S′) and early (e′) and late (A′) diastolic velocities were measured.
The presence and severity of valvular regurgitation was evaluated by integrating several parameters, as recommended. Maximal tricuspid regurgitation velocity (TRv) was obtained in the four-chamber or parasternal view.
RV and LV 2D Strain
Images of the left ventricle in the apical four-, two-, and three-chamber views were obtained for analysis, as previously described. The left ventricle was divided into 18 segments and, by using a dedicated software package (EchoPAC PC version 7.0.X; GE Healthcare, Fairfield, CT), 2D LV longitudinal strain was obtained for each segment. Longitudinal strain was assessed in all six LV walls in the three apical views, and the average value of each wall on each view was used for comparisons with the controls ( Figure 1 ). RV longitudinal strain was also measured in a modified four-chamber view, aiming at the right ventricle and using the same software provided for the left ventricle ( Figure 2 ). Both septal and free RV walls were measured and the mean value of the six segments was used to calculate RV global longitudinal strain.
Radial and circumferential strain were assessed in the six LV walls in the parasternal LV short-axis view at the levels of the papillary muscles and mitral valve, and their average values were used for comparison with the controls. Global longitudinal, radial, and circumferential strains were obtained by dividing the sum of the strain from all LV walls segments by the number of segments.
Statistical Analysis
Categorical data are presented as numbers and percentages and continuous data as mean ± SD or median (interquartile range). The variables of patients with SCD and controls were compared using χ 2 tests, unpaired Student’s t tests, or Mann-Whitney tests as appropriate. A multivariate linear regression model was performed to estimate the association between clinical, demographic, laboratory, and echocardiographic variables with LV global longitudinal strain. The reproducibility of three types of LV strain and RV strain was assessed by the intraclass correlation coefficients for repeated measures in a random sample of 15 patients. P values < .05 were considered significant. SPSS version 18 (SPSS, Inc, Chicago, IL) was used for all analyses.
Results
Study Group
A total of 106 patients with SCD who were referred to the Hemominas Foundation were initially considered for the study. On the basis of exclusion criteria, 16 patients (15%) were not eligible for the study. A total of 90 adults with SCD, genotype HbSS (86 patients) or Sβ 0 thalassemia (four patients), ranging from 18 to 40 years of age, were included. The control group consisted of 20 age- and gender-balanced control patients. Their clinical and demographic characteristics, as well as Doppler echocardiographic data, are presented in Table 1 .
| Variable | Patients | Controls | P |
|---|---|---|---|
| Age (yrs) | 26.5 (22–33) | 27.5 (24–35) | .162 |
| Men | 39 (43%) | 9 (45%) | .542 |
| BSA (m 2 ) | 1.6 ± 0.2 | 1.8 ± 0.2 | .017 |
| Heart rate (beats/min) | 72 (63–78) | 65 (60–70) | .122 |
| Systolic pressure (mm Hg) | 110 (105–120) | 110 (110–120) | .680 |
| Diastolic pressure (mm Hg) | 70 (60–80) | 70 (70–80) | .166 |
| LVEDd (mm) | 52 (49–57) | 46 (41–49) | <.001 |
| LVEDd/BSA (mm) | 33 (30–36) | 26 (24–28) | <.001 |
| LVESd (mm) | 34 (31–37) | 30 (26–32) | <.001 |
| LVEF (%) | 63 (59–66) | 63 (60–65) | .928 |
| VS (mm) | 11 (10–12) | 9.5 (8–10) | <.001 |
| PW (mm) | 11 (10–12) | 9 (8–10) | <.001 |
| Indexed LV mass (g/m 2 ) | 147.9 ± 42.7 | 79.9 ± 17.8 | <.001 |
Forty-two patients with SCD (47%) were on hydroxyurea, and 16 individuals (18%) with the genotype HbSS who had histories of stroke were under hypertransfusion (i.e., periodic transfusion at regularly scheduled intervals to maintain the percentage HbSS < 30% of total hemoglobin). The patients on hydroxyurea or on hypertransfusion regimen had higher hemoglobin values (9.5 ± 1.7 vs 8.2 ± 1.2 g/dL, P < .001), lower reticulocyte counts (0.8 ± 0.6% vs 1.4 ± 0.5%, P < .01), and better oxygen saturation (95% vs. 92%, P = .010) than those not undergoing these treatment modalities. Body surface area was lower in the patients, while both blood pressure and heart rate were similar to those of the controls. LV dimensions and indexed mass were higher in patients with SCD, and LVEFs was equal in patients and controls ( Table 1 ). Both septal and lateral mitral annular velocities were similar between patients with SCD and control subjects.
Ventricular Function
Mitral E and A waves were higher in patients with SCD, while septal and lateral e′ were similar to those of the controls. As a consequence, E/e′ ratios were also higher in patients, but they still remained within the normal range. Left atrial (LA) diameter and indexed volume were higher in patients with SCD ( Table 2 ).
| Variable | Patients | Controls | P |
|---|---|---|---|
| E (cm/sec) | 109.4 ± 20.8 | 89.1 ± 14.0 | <.001 |
| A (cm/sec) | 60.8 ± 15.3 | 49.6 ± 9.7 | .002 |
| DT (cm/sec) | 224.0 ± 37.9 | 236.9 ± 43.0 | .186 |
| IVRT (msec) | 75.2 ± 9.5 | 76.2 ± 9.5 | .656 |
| E/A | 1.9 ± 0.5 | 1.9 ± 0.5 | .872 |
| Septal e′ (cm/sec) | 12.3 ± 2.2 | 12.7 ± 2.1 | .452 |
| Lateral e′ (cm/sec) | 16.8 ± 2.7 | 16.3 ± 2.6 | .374 |
| E/e− ratio | 5.4 ± 1.3 | 4.3 ± 0.7 | <.001 |
| LAd (mm) | 38 (36–44) | 32 (30–36.5) | <.001 |
| LA volume index (mL/m 2 ) | 35.8 ± 12.1 | 18.7 ± 5.2 | <.001 |
| LV longitudinal strain (%) | −19.4 ± 2.2 | −18.9 ± 2.0 | .377 |
| LV radial strain (%) | 35.5 ± 11.1 | 38.2 ± 13.8 | .427 |
| LV circumferential strain (%) | −18.4 ± 4.0 | −18.1 ± 2.4 | .772 |
Diastolic and systolic RV areas were both higher in patients with SCD, while RV fractional area change remained normal and similar to that of the controls ( Table 3 ), as well as RV strain. The other conventional RV function indices were similar between the groups.
| Variable | Patients | Controls | P |
|---|---|---|---|
| RV end-diastolic area (cm 2 ) | 14.1 ± 3.5 | 11.2 ± 3.2 | <.001 |
| RV end-systolic area (cm 2 ) | 7.9 ± 2.1 | 6.1 ± 2.0 | .001 |
| RV FAC (%) | 44.2 ± 10.2 | 45.1 ± 8.6 | .722 |
| Maximal TRv (m/sec) ∗ | 2.51 ± 0.23 | 2.15 ± 0.21 | <.001 |
| TAPSE (mm) | 23.7 ± 3.8 | 22.9 ± 2.0 | .286 |
| RV e′ (cm/sec) | 15.9 ± 3.0 | 14.7 ± 3.0 | .096 |
| RV A′ (cm/sec) | 12.2 ± 3.3 | 12.3 ± 3.6 | .954 |
| RV S (cm/sec) | 15.8 ± 2.8 | 14.2 ± 2.3 | .024 |
| RV e′/A ratio | 1.4 ± 0.4 | 1.3 ± 0.4 | .271 |
| RV global longitudinal strain (%) | 21.6 ± 3.1 | 22.0 ± 4.1 | .679 |
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