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Published in final edited form as: J Am Soc Echocardiogr. 2011 Aug 27;24(11):1285–1290. doi: 10.1016/j.echo.2011.07.009

Abnormalities in Cardiac Structure and Function in Adults with Sickle Cell Disease are not Associated with Pulmonary Hypertension

Jessica E Knight-Perry 2, Lisa de las Fuentes 1,2, Alan D Waggoner 1,2, Raymond G Hoffmann 3, Morey A Blinder 2,4, Victor G Dávila-Román 1,2, Joshua J Field 5
PMCID: PMC3200507  NIHMSID: NIHMS313751  PMID: 21873028

Abstract

Background

In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/s) is associated with increased mortality. The relationships between TRJ velocity, left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD.

Design and Methods

Prospective study of 53 ambulatory SCD adults (age, mean: 34 years; range 21-65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity by use of echocardiography.

Results

SCD subjects had larger left and right atrial volumes and increased LV mass compared to controls. When SCD cases were compared to controls, LV and RV relaxation (i.e., E’) were similar. Among SCD subjects, pulmonary hypertension (TRJ ≥ 2.5 m/s) was present in 40% of cases. Higher TRJ velocity was correlated with larger LA volumes and areas in SCD cases. Additionally, some measures of LV (peak A, lateral and septal annulus E/E’) and RV compliance (TV E/E’) were correlated with TRJ velocity. No other measures of LV/RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity.

Conclusions

Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared to the control group. In SCD subjects, few abnormalities of LV and RV structure/function were associated with TRJ velocity.

Keywords: Pulmonary hypertension, diastolic dysfunction, sickle cell disease

INTRODUCTION

In adult patients with sickle cell disease (SCD), a tricuspid regurgitant jet (TRJ) velocity ≥ 2.5 m/s is associated with increased mortality (risk ratio of 10.1).1 The reported prevalence of increased TRJ velocity (≥ 2.5 m/s) is approximately 30% of adults with SCD.1,2 It is known that reduced nitric oxide (NO) bioavailability in SCD results in endothelial dysfunction and pulmonary vasoconstriction.3,4 Reduced NO availability due to increased arginase and scavenging of NO by cell-free hemoglobin released following hemolysis of sickle erythrocytes has been postulated as a mechanism for development of pulmonary hypertension. In a subset of adults with SCD, chronic thromboembolic disease5,6 and interstitial lung disease7 may also contribute to pulmonary hypertension.

Abnormal left ventricular (LV) diastolic function is a well-established cause of pulmonary venous hypertension in the general population, particularly in subjects with cardiovascular disease.8-11 One study has reported that abnormal LV diastolic function was present in adults with SCD, despite normal LV systolic function, and was an independent predictor of mortality.12 The hypotheses of the present study were that in adults with SCD: 1) indices of LV and right ventricular (RV) systolic function, relaxation and compliance are abnormal compared to those without SCD; and 2) abnormal indices of LV and RV systolic function, relaxation and compliance are associated with TRJ velocity. This study prospectively assessed LV and RV structure and function by echocardiography (2D, pulsed-wave Doppler, and tissue Doppler imaging) in adults with SCD and in normal controls.

METHODS

Patient Population

Subjects greater than 18 years of age with SCD, confirmed by hemoglobin analysis, were recruited from the Adult SCD Clinic at Washington University. A cohort of non-SCD African American controls was identified from an ongoing research study at Washington University. Exclusion criteria for the control group were: 1) history of hypertension and/or use of antihypertensive medications, 2) type 2 diabetes and/or fasting plasma glucose of > 125 mg/dl, 3) history of infection with the human immunodeficiency virus (HIV), 4) history of coronary artery disease, 5) echocardiographic abnormality (i.e., regurgitation/stenosis greater than mild, hypertrophic cardiomyopathy, pericardial disease, ventricular wall motion abnormalities, depressed global systolic function), 6) body mass index (BMI) > 35 kg/m2 and 7) serum creatinine > 2.5 mg/dl. SCD subjects with hypertension, use of anti-hypertensive medications, type 2 diabetes, HIV and coronary artery disease were also excluded to maintain similar eligibility criteria between cases and controls. This study was approved by the Institutional Review Board (IRB) at Washington University School of Medicine in St. Louis, and informed consent was obtained from all participants.

Echocardiography

Subjects with SCD underwent echocardiography during scheduled, well visits to the outpatient clinic when they reported no illness or increased pain, and were not within 2 weeks of a hospitalization or emergency room visit for any reason. Comprehensive echocardiography including 2-dimensional, M-mode, pulsed-wave Doppler (PWD), and tissue Doppler imaging (TDI) was performed in all of the study participants by use of commercially-available ultrasound equipment (Sequoia C512, Acuson-Siemens, Mountain View, CA). Two-dimensional echocardiographic measurements included LV end-diastolic and end-systolic volumes; LV ejection fraction (LVEF) calculated by the method of discs (modified Simpson’s method).13 Left atrial volume was measured at end systole in the apical 4-chamber view.13,14 Stroke volume was calculated by the LV outflow tract time velocity integral determined by pulsed-wave Doppler multiplied by the LV outflow tract cross-sectional area.15 LV mass was measured by the M-Mode-derived cubed method and indexed to height2.7 (LVM/Ht2.7).13 LV diastolic function was assessed using pulsed-wave Doppler-derived peak early-diastolic mitral inflow (E-wave) velocity, late-diastolic mitral inflow (A-wave) velocity, E-wave to A-wave velocity ratio (E/A), E-wave deceleration time (DT), and isovolumic relaxation time (IVRT).16 TDI-derived myocardial early diastolic (E’) tissue velocities were obtained from the apical four-chamber view at the lateral and septal annulus; the mitral E/E’ ratios were determined as a surrogate for LV filling pressures.17,18 LV septal and LV lateral tissue Doppler velocities were averaged from 3 cardiac cycles at end expiration. Diastolic dysfunction was graded as: 1) mild: E/A < 1.0 and/or a deceleration time >240 ms12 and E/E’ ≤ 10; 2) moderate: E/A ≥ 1.0 and/or E/E’ >10; and 3) severe: E/A ratio greater than 95% for age19 or deceleration time <140 ms20 and E/E’ >10.

Right atrial volume was measured at end systole in the apical 4-chamber view.13 Right ventricular areas at end-diastole and end-systole were determined in the apical 4-chamber view. RV fractional area change was calculated as: (RV end diastolic area-RV end systolic area)/RV end diastolic area × 100. RV systolic and diastolic function was assessed by TDI-derived peak systolic (S’) and early-diastolic velocity (E’) at the lateral tricuspid annulus in the apical 4-chamber view at end expiration.21-24 The peak tricuspid E-wave velocity was determined by pulsed-wave Doppler at the tricuspid leaflet tips; RV filling pressure was calculated as TV E/E’.

The myocardial performance index (MPI) was derived by pulsed-wave Doppler. The time intervals from valve closure to valve opening for the mitral and tricuspid values were used to determine total systolic duration (TSD) for the LV and RV, respectively. The LV and RV ejection time (ET) was measured from the onset to end of LV and pulmonary outflow, respectively. MPI was calculated as TSD-ET/ET for each ventricle.

The TRJ velocity was examined in the apical 4-chamber (standard or modified) and parasternal views; the view yielding good-quality Doppler envelopes with the highest velocities were reported (Figure 1). The average of three TRJ velocities was used to report the peak TRJ.

Figure 1A.

Figure 1A

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Continuous wave Doppler of the tricuspid regurgitant jet in a 34 year-old female with sickle cell disease and without pulmonary hypertension. 1B. Continuous wave Doppler of the tricuspid regurgitant jet in a 35 year-old female with sickle cell disease and pulmonary hypertension.

All measurements were performed in accordance to published guidelines or prior studies13,15,16,19,20,25,26 and represent the average of three consecutive cardiac cycles obtained by a single observer blinded to all clinical parameters.

Clinical and laboratory data collection

Standardized data extraction forms were used to perform a review of individual medical records. Laboratory data were collected at scheduled, well visits to an outpatient clinic. No laboratory studies were performed within 2 weeks of a SCD subject reporting illness or increased pain, or hospitalization for any reason.

Statistical analysis

Clinical characteristics were compared between adults with SCD and the control population using a Student’s t test. To compare echocardiographic parameters between SCD subjects and controls, a general linear model was used. Differences in echocardiographic parameters [dependent variables] between cases and controls were adjusted for age, BMI, gender and gender by case/control interaction [independent variables]. Echocardiographic parameters were normally distributed with the exception of TRJ velocity which was subsequently log-transformed for all analyses. Correlations of echocardiographic parameters and TRJ velocity among subjects with SCD were assessed using Pearson’s correlation. The p-values were adjusted for multiple testing using the false discovery rate (FDR) method.27 The SAS Multtest procedure (version 9.1.3, SAS Institute, Cary, NC) was used for the adjustment.

Power calculation

A power analysis was performed to determine whether the available SCD subject and control sample size was sufficient to detect medium to large effect sizes between measures of LV diastolic function and TRJ velocity (r≥0.4).28 Although our sample size may not have detected small associations between measures of LV diastolic dysfunction and TRJ velocity, our analyses were powered to identify associations with effect sizes likely to be clinically meaningful. To detect a correlation coefficient of 0.4 or greater with β=0.8 and α=0.05, a sample size of at least 50 cases and 30 controls is required.

RESULTS

Clinical characteristics of study population

The study population included 53 adults with SCD (mean age 34 ± 11 years; range 21-65) and 33 healthy, African American controls (mean age 39 ± 10 years; range 18-53). The SCD cohort was comprised of adults with HbSS (68%), HbSC (19%), HbSβ-thalassemia0 (7%) and HbSβ-thalassemia+ (6%). When compared to controls, subjects with SCD had a higher systolic blood pressure, lower diastolic blood pressure and a higher heart rate. Subjects with SCD also had lower body weight (Table 1). Among subjects with SCD, mean hemoglobin was 9.0 (range 5.8-13.3). When compared to historical data from the Cooperative Study of Sickle Cell Disease, the current SCD group had a higher rate of hospitalization for pain (1.2 vs. 0.8/yr) and acute chest syndrome (0.2 vs. 0.13/yr).29

Table 1.

Sample characteristics and hemodynamics in individuals with sickle cell disease (SCD) compared to healthy controls.

Controls
n=33		 SCD
n=53		 P
Sample characteristics
Age (years) 39 ± 10 34 ± 11 0.02
Gender, male (%) 18 53 0.001
Height (cm) 167 ± 7 170 ± 12 0.09
Weight (kg) 78 ± 16 70 ± 15 0.03
BMI (kg/m2) 28 ± 5 25 ± 6 0.003
Hemodynamics
Heart rate (beats/min) 66 ± 9 71 ± 11 0.04
Systolic BP (mm Hg) 112 ± 11 119 ± 15 0.02
Diastolic BP (mm Hg) 76 ± 6 71 ± 7 0.004
Pulse Pressure (mm Hg) 36 ± 7 47 ± 12 <0.001
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Results are reported as the mean ± the standard deviation unless otherwise noted.

Abbreviations: BP = blood pressure; BMI = body mass index

Echocardiographically-derived parameters of cardiac structure and function Right and left cardiac structures

Measurements of cardiac structure including left atrial (LA) volumes, right atrial (RA) volumes, LV mass and end-systolic volume were significantly higher in the SCD group compared with the control group (Table 2). The right ventricular (RV) end-diastolic area was larger in SCD group compared to controls.

Table 2.

Cardiac structure and function in adult subjects with sickle cell disease (SCD) compared to normal controls and within SCD groups determined by the tricuspid regurgitant jet (TRJ) velocity.

SCD
Controls SCD Correlation with TRJ velocity
n=33 n=53 P* FDR R P FDR
LV structure
 LV ES volume (ml) 34 ± 10 41 ± 16 0.02 0.03 0.09 0.52 0.66
 LV ED volume (ml) 92 ± 26 106 ± 33 0.09 0.12 0.06 0.66 0.74
 LV mass (g) 143 ± 38 219 ± 67 <0.001 0.002 0.30 0.03 0.06
 LV mass/Ht2.7
(g/m2.7)		 36 ± 8 52 ± 13 <0.001 0.002 0.30 0.03 0.06
RV structure
 RV ES area (cm2) 9.8 ± 2.3 11.8 ± 3.2 0.28 0.37 0.26 0.11 0.22
 RV ED area (cm2) 15.6 ± 3.1 19.4 ± 4.6 0.02 0.03 0.24 0.14 0.22
LA/RA structure
 LA volume (ml) 43 ± 14 80 ± 30 <0.001 0.002 0.50 <0.001 0.005
 LA volume/BSA
(ml/m2)		 23 ± 6 45 ± 17 <0.001 0.002 0.49 <0.001 0.005
 RA volume (ml) 42 ± 13 63 ± 22 <0.001 0.002 0.31 0.03 0.06
LV systolic function
 Stroke volume (ml) 62 ± 13 86 ± 19 <0.001 0.002 0.09 0.54 0.66
 Ejection fraction (%) 63 ± 4 60 ± 6 0.03 0.048 −0.003 0.98 0.99
 LV MPI 0.47 ± 0.10 0.41 ± 0.14 0.07 0.10 0.02 0.91 0.98
RV systolic function
 RV fractional area
 change		 0.36 ± 0.12 0.39 ± 0.10 0.04 0.06 0.002 0.99 0.99
 RV MPI 0.28 ± 0.09 0.25 ± 0.11 0.43 0.52 0.22 0.14 0.22
 RV S’ 13.2 ± 2.5 9.9 ± 2.0 <0.001 0.002 −0.08 0.58 0.68
LV diastolic function
 Peak E (m/s) 0.73 ± 0.14 0.90 ± 0.24 0.001 0.002 0.21 0.14 0.22
 Peak A (m/s) 0.48 ± 0.12 0.54 ± 0.16 0.002 0.004 0.35 0.01 0.04
 E/A 1.6 ± 0.5 1.8 ± 0.7 0.82 0.87 −0.17 0.22 0.32
 DT (ms) 192 ± 30 184 ± 33 0.66 0.77 0.13 0.35 0.47
 IVRT (ms) 79 ± 10 77 ± 20 0.86 0.87 0.21 0.13 0.22
 Lateral E’ (cm/s) 15.6 ± 4.0 16.8 ± 4.4 0.87 0.87 −0.33 0.02 0.06
 Lateral E/E’ 4.9 ± 1.2 5.6 ± 2.0 0.008 0.02 0.35 0.01 0.04
 Septal E’ (cm/s) 11.5 ± 2.5 12.0 ± 2.6 0.75 0.84 −0.17 0.23 0.32
 Septal E/E’ 6.5 ± 1.3 7.6 ± 1.8 <0.001 0.002 0.34 0.01 0.04
RV diastolic function
 RV E’ (cm/s) 13.2 ± 2.5 14.5 ± 3.4 0.37 0.47 −0.30 0.03 0.06
 TV E/E’ 4.4 ± 0.9 6.4 ± 1.8 <0.001 0.002 0.40 0.004 0.03
TRJ velocity
 TRJ velocity (m/s) 2.1 ± 0.2 2.5 ± 0.5 0.001 0.002 NA NA
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Results are reported as the mean ± SD.

Abbreviations: A = atrial filling velocity; DT = deceleration time; E = early filling velocity; E’ = early diastolic myocardial velocity; ED = end-diastolic; ES = end-systolic; FDR = false discovery rate; IVRT = isovolumic relaxation time; LA = left atrial; LV = left ventricular; LVMI = left ventricular mass index; MPI=myocardial performance index; RA = right atrial; RV = right ventricular; S’ = systolic myocardial velocity; TRJ=tricuspid regurgitant jet.

*

Adjusted for age, gender, gender/case, body mass index

LV and RV systolic function

Parameters of global LV function, including LV ejection fraction and LV MPI, were normal in both groups; the LV ejection fraction was slightly lower in SCD subjects compared to controls. The SCD group had greater Doppler-derived LV stroke volume compared to controls. The SCD group also had a lower TDI-derived RV S’ velocity compared to controls.

LV diastolic function

The PWD-derived transmitral E- and A-wave velocities were higher in SCD subjects compared to the controls. Mitral DT and IVRT, including TDI measures of LV relaxation (E’) were similar, however, between the groups. Thirteen percent of SCD subjects had mild diastolic dysfunction, 4% had moderate diastolic dysfunction and none had severe diastolic dysfunction.

RV diastolic function

RV E/E’, a surrogate of RV filling pressures, was higher in SCD subjects compared to controls; however, TDI-derived TV E’ did not differ between groups.

TRJ velocity

The TRJ velocity was higher in SCD subjects compared to controls. A TRJ velocity ≥ 2.5 m/s was present in 40% of subjects with SCD compared to 6% of controls. Among SCD subjects, the mean TRJ velocity was 2.5 m/s (range 1.8-4.0). Six SCD subjects (11%) had a TRJ velocity ≥ 3.0 m/s. In subjects with SCD, LA volume correlated moderately with TRJ velocity. Conventional Doppler-derived measurements of LV diastolic filling (i.e., mitral E, E/A, DT or IVRT) did not correlate with TRJ velocity. However, mitral E/E’ ratios at the lateral and septal annulus and TV E/E’ correlated minimally with TRJ velocity.

DISCUSSION

In this prospective study, 2D echocardiography, pulsed wave Doppler-derived mitral and tricuspid inflow velocities, combined with tissue Doppler imaging, were used to assess cardiac structure and function in ambulatory adults with SCD and in race-matched controls. Compared to the control group, subjects with SCD had larger left- and right-heart chambers and higher estimated LV and RV filling pressures, whereas measures of TDI-derived measures of LV and RV relaxation were similar between groups. In SCD subjects, the TRJ velocity correlated modestly with 2D-derived LA volume and non-invasive estimated LV and RV filling pressures (mitral E/E’ and TV E/E’, respectively), but not with LV mass, systolic function, relaxation (i.e. TDI-derived E’ velocity), or measurements of RV size or systolic function. The results suggest that chronic anemia and increased intravascular volume in adult SCD subjects is a primary contributing factor to alterations in cardiac structure and function.

Increased circulating blood volume due to chronic anemia is documented in SCD subjects.30-32 The larger LA and LV volumes, RA volumes and RV end-diastolic areas in SCD subjects were likely an adaptive response to the increased blood volume. In addition, the higher transmitral LV filling velocities and surrogate measures of LV filling pressure (i.e., E/E’ ratios), that remained within the normal ranges, were likely due to increased preload. Furthermore, non-invasive measures of LV ventricular relaxation or stiffness or compliance (i.e., IVRT, and E’ velocities, mitral E/A ratio and DT,) did not differ between SCD cases and controls, suggesting that the intrinsic myocardial properties in SCD subjects remain preserved, consistent with other investigators.12 Thus, our data suggest measurements of LV and RV size and function in patients with SCD are primarily related to increased preload due to chronic anemia.

In the SCD group, only a few LV indices were associated with TRJ velocity (i.e., mitral A-wave and E/E’ lateral and septal). Prior investigators reported a relationship between LV relaxation (i.e., E/A, DT) and TRJ velocity in adults with SCD.12 However, measures of LV relaxation explained only 10-20% of the variation in TRJ velocity. The authors concluded that abnormal LV relaxation did not contribute significantly to the pathogenesis of pulmonary hypertension in SCD. The results of the present investigation are consistent with this observation.

Despite larger LA and RA volumes, indices of LV relaxation including the mitral E/A ratio, DT, IVRT and TDI-derived E’ velocities were similar between SCD and control groups. The findings that mitral A wave velocity and E/E’ were greater in SCD patients than in the control group was likely related to the increased LA volume. Although increased LA volume is an index of diastolic dysfunction in the general population,33-36 it is postulated that in SCD patients, the increased LA volume, mitral A wave velocity, and E/E’ ratios are likely secondary to chronic anemia.

RV systolic function was similar in SCD subjects and controls when determined by 2D-derived fractional area change. However, the TDI-derived S’ velocity was lower compared to controls. It may be that the larger RV chamber areas and slightly higher TRJ velocities in SCD subjects may have resulted in decreased RV systolic myocardial velocities and increased surrogate measures of RV filling pressure (i.e., TV E/E’) compared to controls. The relative absence of significant pulmonary hypertension in the SCD subjects (only 11% with a TRJ velocity > 3.0 m/s) likely explains why RV systolic function remained normal. Thus, the results of the present study suggest that hemolysis and associated increased in blood volume may contribute to pulmonary hypertension in SCD.

Limitations of the present study

First, the small sample size increases the risk of type II error. Second, the number of tests performed to determine associations with echocardiographic measurements increases the risk of type I error. To address this limitation, our statistical analyses were adjusted for multiple testing using FDR.27 Third, the SCD subjects either had no pulmonary hypertension or mild pulmonary hypertension and therefore the results may not be applicable to SCD subjects with moderate to severe pulmonary hypertension. Fourth, 2D-Doppler derived LV and RV strain and strain rate were not obtained in this study. These alternative methods require further studies in SCD subjects. Finally, Doppler and TDI-based measurements are only surrogate markers to characterize diastolic function. Invasive measures (i.e., conductance and pressure tipped catheters) would be useful to determine the relationship between LV diastolic function and elevated TRJ velocity but were not clinically indicated in SCD subjects.

Conclusions

Adults with SCD have larger LV and LA volumes, increased LV mass and higher estimated LV and RV filling pressures compared to controls. LA volumes and estimated LV and RV filling pressures were associated with TRJ velocity. The lack of significant pulmonary hypertension in most subjects with SCD resulted in preserved RV systolic function. Structural and functional cardiac abnormalities present in SCD subjects are related to chronic anemia and intravascular volume overload. Taken together, our data suggest that chronic anemia and intravascular volume overload results in increased cardiac chamber stretch or stiffness contributing to increased filling pressures and pulmonary artery pressure in SCD.

Acknowledgments

Grant Support: Supported in part by the National Heart, Lung, and Blood Institute awards K12HL08710 (JJF), KL2RR024994 (LdlF) and UL1RR024992 (JJF and LdlF), and the Doris Duke Charitable Foundation award 2004061 (JKP).

Footnotes

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