Pulmonary Hipertention

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Am J Cardiol. 2009 September 1; 104(5): 713720. doi:10.1016/j.amjcard.2009.04.034.
Prospective Echocardiography Assessment of Pulmonary

Hypertension And Its Potential Etiologies In Children With Sickle
Cell Disease
Niti Dham, MDa, Gregory Ensing, MDb, Caterina Minniti, MDc, Andrew Campbell, MDd,
Manuel Arteta, MDe, Sohail Rana, MDf, Deepika Darbari, MDg, Mehdi Nouraie, MD, PhDh,
Onyinye Onyekwere, MDh, Malgorzata Lasota, RDCSa, Gregory J. Kato, MDc, Mark T.
Gladwin, MDi, Oswaldo Castro, MDh, Victor Gordeuk, MDh, and Craig Sable, MDa
aDepartment of Cardiology, Childrens National Medical Center, Washington, DC
bDepartment
cPulmonary
of Pediatrics-Pediatric Cardiology Division, University of Michigan, Ann Arbor, MI
and Vascular Medicine Branch, National Heart, Lung and Blood Institute, Bethesda,
MD
dDepartment
of Pediatrics-Hematology Division, University of Michigan, Ann Arbor, MI
eDepartment
of Pediatrics-Pulmonary Division, University of Michigan, Ann Arbor, MI
fDepartment
of Pediatrics and Child Health, Howard University, Washington, DC
gDepartment
of Hematology, Childrens National Medical Center, Washington, DC
hCenter
for Sickle Cell Disease, Howard University College of Medicine, Washington, DC
iDepartment
of Pulmonary, Allergy, and Critical Care Medicine and Hemostasis and Vascular
Biology Research Institute, University of Pittsburgh Medical Center; Pittsburgh, PA
Abstract
Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle cell
disease (SCD) but its importance in children is less clear. We define the incidence and etiologies
of PH in pediatric patients with SCD. Children with SCD (n = 310) and matched controls (n = 54)
were prospectively enrolled under basal conditions. Participants underwent echocardiography,
pulse oximetry, 6-minute walk, and hematologic testing. Echocardiographic measures were
compared between SCD and control subjects before and after adjusting for hemoglobin.
Correlation of echocardiographic and clinical parameters was performed. Tricuspid regurgitation
velocity (TRV) was elevated compared to controls (2.28 vs. 2.10 m/s, p <0.0001). Increased TRV
was associated with left ventricular diastolic diameter, hemoglobin, and estimated left atrial
pressure. TRV remained elevated when controlled for left ventricular diameter and left atrial
pressure. An echocardiography-derived pulmonary resistance was not significantly different
between SCD and control patients, although it was elevated in the SCD subgroup with elevated
2009 Excerpta Medica, Inc. Published by Elsevier Inc. All rights reserved.
Correspondence to: Craig Sable, MD, Childrens National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, Tel:
202-476-2020, Fax: 202-476-5700, Email: csable@cnmc.org.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing
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content, and all legal disclaimers that apply to the journal pertain.
Disclosures: Victor Gordeuk, MD - Grants from Biomarin and Actelion pharmaceutical companies and Consulting for Ikaria
Pharmaceutical Company; Other Authors No disclosures/conflict of interest
Dham et al.
Page 2
TRV. When controlled for hemoglobin, TRV was no longer statistically different, but pulmonary
insufficiency velocity, septal wall thickness and estimated pulmonary resistance were statistically
higher. TRV, pulmonary insufficiency end diastolic velocity, and markers of increased cardiac
output correlated with indicators of adverse functional status including history of acute chest
syndrome, stroke, transfusions, and 6-minute walk. In conclusion, children with SCD have mildly
increased TRV that correlated with increased cardiac output and left ventricular filling pressures.
Hemoglobin adjusted analysis also suggests contribution of primary vascular changes.
Keywords
Pulmonary hypertension; Tricuspid regurgitation; Pulmonary vascular resistance; Sickle cell
In the present report, we compare multiple echocardiographic variables between children
with sickle cell disease (SCD) and age and gender matched controls to assess relative
contributions of potential determinants of pulmonary artery pressure in this population. We
also examine the relations among TRV, other echocardiographic measurements and clinical
parameters among children with SCD to better elucidate the physiology and consequences
of echocardiographic abnormalities in this population of children.
METHODS
This is an NIH (Grant # 1 R01 HL079912-01) supported observational, prospective, and
multi-center study of children and adolescents with SCD and matched controls. The centers
included are Childrens National Medical Center in Washington, DC, Howard University in
Washington, DC, National Institution of Health in Bethesda, MD, and University of
Michigan in Ann Arbor, MI (ClinicalTrials.gov identifier NCT00495638). The study was
approved by the institutional review boards of all participating institutions. Assent and
consent was obtained from each patient and a family member from each patient (for patients
under 18).
Subjects ranged from the age of 3 to 20 years old. Subjects with SCD in this study had to
have been previously identified and documented as having a variant of SCD (SS, SC, or S
thalassemia). Subjects were excluded if they were not in a steady state condition, previously
defined as being free of any hospitalization, emergency room visit, or doctors office visit
for pain crisis, acute chest syndrome, infection, or other complications of SCD for at least
three weeks.
For every 6 SCD patients recruited, 1 healthy control subject matched by sex, age ( 2
years), and center of recruitment was enrolled. Children with hemoglobin A only phenotype,
sickle trait, or hemoglobin C trait were eligible to serve as control subjects. Each patient and
control subject underwent a clinical evaluation, 6-minute-walk, echocardiogram, and
hematologic testing.
Patients underwent medical history, physical examination, and measurement of oxygen
saturation by pulse oximetry (at baseline and during 6-minute-walk). Venous blood was
drawn for complete blood count, reticulocyte count, and serum chemistries. An unencouraged 6-minute-walk test was conducted in a predetermined course, at least 6 feet
wide, as per the guidelines of the American Thoracic Society [1].
Transthoracic echocardiograms were obtained using the Philips Sonos 5500/7500 or iE33
(Philips Medical Systems, Best, Holland), Acuson Sequoia (Siemens Medical Systems,
Mountain View, CA), or General Electric VIVID 7 or VIVID I (General Electric,
Milwaukee, WI). All images were obtained by a licensed sonographer or pediatric
Dham et al.
Page 3
cardiologist and were recorded digitally and subsequently reviewed on an offline digital
work station. Each study was interpreted by one of two pediatric cardiologists (CAS or GJE)
who were blinded to the subjects classification. The first 20 studies in each city were also
blindly interpreted by the other pediatric cardiologist for quality control. There were no
significant differences in qualitative or quantitative interpretations between the two sites.
Cardiac images were obtained, measurements were performed, and the studies were
interpreted according to the guidelines of the American Society of Echocardiography [2]. To
standardize across the spectrum of ages and body size, dimensions were compared to those
of a large cohort of normal infants and children described by Pettersen et al [3] and
expressed as a standard deviation below or above the mean for body surface area (z score).
Left ventricular mass [4], stroke volume, and cardiac output were indexed to body surface
area. Left ventricular stroke volume was calculated from apical four chamber images (single
plane Simpsons rule) [2,5].
TRV was assessed in the parasternal long and short-axis and apical four-chamber views.
Continuous-wave Doppler of the peak regurgitant velocity was used to estimate the right
ventricular to right atrial pressure gradient with the use of the modified Bernoulli equation
[6,7]. Pulmonary artery systolic pressure was quantified by adding the Bernoulli-derived
pressure gradient to the estimated mean right atrial pressure [8]. Estimated pulmonary artery
end diastolic pressure was estimated by applying the modified Bernoulli equation to the
pulmonary insufficiency end diastolic velocity Doppler signal and assuming the estimated
end diastolic right ventricular pressure was equal to the estimated right atrial pressure. Mean
pulmonary artery pressure was calculated from estimated pulmonary artery systolic and
diastolic pressure.
Left ventricular systolic function was assessed by calculating M-mode derived shortening
and Simpson single plane estimated volumes and ejection fractions. Left ventricular
diastolic function was assessed by measuring the peak velocities of the mitral inflow E wave
and A wave, calculating the ratio of the E wave to the A wave, and the tissue Doppler E
wave at the basilar segments of the left ventricular free wall and interventricular
septum[7,9,10]. Left atrial pressure was estimated by calculating the ratio of the mitral
inflow E wave to the tissue Doppler E wave [7,9]. Tissue Doppler recordings from the
basilar right ventricular free wall were also obtained.
An echocardiography derived pulmonary vascular resistance index was calculated from

echocardiographic parameters described above [11,12]. Cardiac index was calculated from
apical four chamber derived stroke volume using the Simpsons single plane formula and
heart rate. The echocardiography derived pulmonary vascular resistance index was assumed
to be zero if it was calculated to be a negative value.
The continuous variables were assessed for normality. The best transformation was then
used to change to a normal distribution. The student t-test and the Kruskal-Wallis test
(whichever appropriate) were used to compare continuous variables between patients with
SCD and control subjects, and the Pearson chi square test was used to compare dichotomous
variables. Stepwise linear regression was used to assess the relationship between
echocardiogram parameters and clinical variables in patients with SCD. A pvalue less than
0.05 was considered significant.
RESULTS
Demographic and clinical variables of 310 SCD patients and 54 control subjects are
summarized in Table 1 and echocardiographic measurements are presented in Table 2. The
median age of SCD and controls was 13 years old. SCD patients had significantly higher
Dham et al.
Page 4
TRV (2.28 m/sec vs. 2.10 m/sec, p <0.0001, Figure 1A). TRV was measurable in 290/310
(94%) SCD subjects and 48/54 (89%) controls. Thirty-two of 290 (11%) patients with SCD
had a TRV above 2.60 m/sec and 1 SCD patient had a TRV above 3.0 m/sec. One control
had a TRV above 2.60 m/sec (2.7 m/sec). Nine of 290 (3%) SCD patients and no control
subjects had an estimated right to left ventricular pressure ratio greater than 33%. There was
still a significant difference between SCD patients and control subjects for TRV (p=0.004)
after adjusting for the effects of left ventricular diastolic dimension z-score, cardiac index,
and mitral E wave/tissue Doppler E wave (2.3 vs. 2.1 m/sec).
The mean echocardiography derived pulmonary vascular resistance index was not
significantly different between SCD patients (1.75 units m2) and control subjects (1.50
units m2, p = 0.20, Figure 2A). We defined the estimated pulmonary vascular resistance
upper limit of normal based (95%) on our control population as 3.7 units m2. Two of the
38 (5%) controls and 16/226 (7%) SCD patients had an estimated pulmonary vascular
resistance index over 3.7 units m2. There was enough information to calculate the
estimated pulmonary vascular resistance index in 23 of the 32 SCD patients with TRV > 2.6
m/sec. Estimated pulmonary vascular resistance was < 3.7 u m2 in 14 and > 3.7 u m2 in 9 of
these subjects. The distribution of the estimated pulmonary vascular resistance index based
on TRV less than or greater than 2.6 m/sec is shown in Figure 3.
Bivariate analyses results are shown in Table 3. TRV correlated strongly with left
ventricular end diastolic dimension z-score (p <0.0001; Figure 4), mitral E/Etdi (p = 0.006,
Figure 5), left ventricular mass index, and tricuspid valve Etdi. Although our subjects ranged
from 320 years old, there was no correlation of TRV and age.
To determine which echocardiographic changes might reflect pathophysiologic processes
intrinsic to SCD independent of chronic anemia, we also compared echocardiographic
measurements in analyses that adjusted for the degree of anemia as reflected in hemoglobin
concentration. TRV (p = 0.31, Figure 1B), left ventricular end diastolic dimension z-score (p
= 0.07) and cardiac index (p = 0.7) were no longer significantly different between patients
with SCD and controls after this adjustment. Pulmonary insufficiency end diastolic velocity
(p = 0.01), diastolic interventricular septal thickness (p = 0.001), and calculations for
pulmonary end diastolic pressure, mean pulmonary artery pressure, and left ventricle mass
index remained significantly higher in patients with SCD and the calculation for pulmonary
vascular resistance (p = 0.004, Figure 2B) became significantly higher.
Table 4 and Table 5 highlight the correlations between echocardiographic variables and
clinical variables and outcomes.
DISCUSSION
This cohort of patients represents the largest prospective evaluation of echocardiography
findings in children with SCD and includes only patients remote from any acute illness or
event. Children with SCD in the non acute state had higher TRV and higher estimated
pulmonary artery systolic, diastolic, and mean pressures as compared to a similar population
without SCD. These findings are similar to several previous reports of TRV elevations in
children [1317]. Pulmonary hypertension (PH) is prevalent in adults with SCD and is
associated with a significant increase in mortality rate [1820]. In the pediatric population
however, death and major morbidity is much less common and this association has not been
well defined. In our study, TRV correlated with lower oxygen saturation during 6-minutewalk (potentially due to ventilation-perfusion mismatch), acute chest syndrome history, and
need for chronic transfusion.
Dham et al.
Page 5
Elevated pulmonary artery pressure in SCD is sometimes assumed to be due to elevated

pulmonary vascular resistance and treatment with pulmonary vasodilators proposed for even
a mild degree of pulmonary pressure elevation [19]. However, the impact of SCD on the
cardiovascular system goes beyond the pulmonary vascular bed. Increased cardiac output
associated with anemia alone will potentially elevate pulmonary artery pressure in the
presence of normal pulmonary vascular resistance. Many patients with elevations in TRV
also have systemic hypertension, left-sided volume overload, and abnormal diastolic
function [2123], all of which lead to elevated left ventricular filling pressures and
secondary elevation of pulmonary artery pressures. Finally, abnormalities of blood viscosity
will elevate pulmonary artery pressure and calculated pulmonary vascular resistance. This
study investigates the relative contribution of the additional etiologies for PH in SCD
including increased pulmonary flow volume (cardiac output), increased left ventricular
filling pressures, increased blood viscosity and increased pulmonary vascular resistance
(assessed non-invasively).
Our SCD subjects had multiple measures of increased pulmonary blood flow. This is
consistent with previous studies which have shown significant correlation between left
ventricular size and mass and degree of anemia [22,24]. A substantial portion of pulmonary
artery pressure elevation is likely a consequence of increased cardiac output and stroke
volume. However, the difference in TRV in our cohort remained significant after adjusting
for left ventricular size and measures of diastolic pulmonary artery pressure remained
significant after controlling for hemoglobin.
Patients with elevated left ventricular filling pressure (and elevated left atrial pressure) may
develop secondary PH related to pulmonary venous hypertension. Several recent
publications have assessed the importance of diastolic function in children and adults with
SCD [21,23,25]. The relative contributions of increased flow volume and diastolic function
abnormalities remain difficult to differentiate. In our cohort, ejection and shortening fraction
were not significantly different between SCD patients and controls. However, the presence
of increased preload suggests elevated preload is necessary to provide normal left ventricle
shortening. These findings are similar to other studies in SCD [21,22,26,27]. Previous
studies have reported that children with SCD have lower load independent measures of
systolic function such as velocity of circumferential fiber shortening [24,27].
TRV was still higher in SCD patients after adjusting for volume loading and diastolic filling
pressure, suggesting that the pulmonary vascular bed also plays a role. To assess this noninvasively, we compared an echocardiography derived pulmonary vascular resistance.
Though incorporating many assumptions, the index used is similar to previously established
echocardiography estimates and each component was validated in prior studies
[2,6,9,11,12]. We found no significant difference between SCD patients and controls in
estimated pulmonary vascular resistance. Even though TRV was used in the pulmonary
vascular resistance calculation, many patients with elevated TRV still had normal estimated
pulmonary vascular resistance. This finding of normal pulmonary vascular resistance with
SCD, even in the presence of elevated pulmonary artery pressure, is consistent with
catheterization data in adults [18].
Our hemoglobin adjusted echocardiography comparisons between patients and controls may
contribute insights to the pathophysiology of systemic and pulmonary vasculopathy that is
postulated to occur in SCD. The only measurements that remained significantly greater in
patients with SCD were septal wall thickness and pulmonary diastolic Doppler velocity.
Calculations for left ventricular mass index and pulmonary vascular resistance were
significantly higher in SCD after adjustment for hemoglobin concentration. We postulate
that these findings provide evidence to support an anemia independent process that likely
Dham et al.
Page 6
represents the effect of hemolysis on the systemic and pulmonary vascular beds
[19,20,22,28,29]. Hemolysis and hemoglobin were independent predictors of TRV in our
prior analysis [30].
Although the use of TRV to assess pulmonary pressure by echocardiography has been well
validated, there are several pitfalls. The absence of a TRV signal does not exclude the
patient from having an elevated pulmonary pressure [20]. Additionally, if proper alignment
is not obtained, a true TRV may be underestimated. The estimation of right atrial pressure
adds another source of error. Higher cardiac output likely predisposes to a higher likelihood
of an optimal TRV measurement being obtained. It is possible that this technical issue could
explain some of the difference in TRV between SCD patients and control subjects in our
cohort. Echocardiography estimates of left ventricular filling pressure and pulmonary
vascular resistance are based primarily on studies of adults. Additional measurements of
diastolic function such as indexed left atrial volume could provide additional information.
Nonetheless, comparisons between SCD and control subjects and correlations still provide
useful information.
Our study demonstrated only small differences in TRV between SCD and control subjects.
Our exclusion of acutely ill patients partially explains why other pediatric studies report a
higher prevalence and more significant degree of TRV elevation. It is likely that patients
with SCD are predisposed to more significant elevations in pulmonary artery pressure
during acute illnesses and it may be difficult to predict which patients will have the most
adverse response to acute airway and pulmonary complications.
Acknowledgments
Supported in part by grant nos. 2 R25 HL003679-08 and 1 R01 HL079912-02 from NHLBI, by Howard University
GCRC grant number 2MOI RR10284-10 from NCRR, NIH, Bethesda, MD, and by the intramural research program
of the National Institutes of Health.
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Figure 1.
Distribution of tricuspid regurgitation velocity in control and sickle cell subjects in

unadjusted (left) and adjusted for hemoglobin(right) Crosses show mean values.
Abbreviations: TRV - tricuspid regurgitation velocity

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Figure 2.
Distribution of pulmonary vascular resistance in control and sickle cell subjects in

unadjusted (left) and adjusted for hemoglobin (right) Crosses show mean values.

Dham et al.
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Figure 3.
Frequency distribution of pulmonary vascular resistance in sickle cell disease grouped by

tricuspid regurgitation velocity category. Abbreviation: TRV tricuspid regurgitation
velocity

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Figure 4.
Correlation between left ventricular end diastolic dimension Z score and tricuspid valve
regurgitation velocity in sickle cell disease Abbreviation: LVIDd left ventricular internal
dimension in diastole.
Dham et al.
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Figure 4.
Correlation between mitral inflow E wave/tissue Doppler E wave ratio and tricuspid
regurgitation velocity in sickle cell disease Abbreviation: E/Etdi mitral inflow E wave/
tissue Doppler imaging E wave

295
295
295
310
310
268
310
310
310
310
301
295
300
245
Hemoglobin SD Los Angeles*
Hemoglobin SC*
Hemoglobin Sbeta+ thal*
Height (cm)
Body Surface Area
Heart rate
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
Mean blood pressure (mm Hg)
Pulse pressure (mm Hg)
Hemoglobin (g/dL)
Lactate dehydrogenase (u/l)
Oxygen Saturation (%)
Six minute walk (m)
Adjusted for the height
Number (%)
***
295
Hemoglobin Sbeta0 thal*
Geometric mean
**
295
310
Howard University
310
310
Childrens National Medical Center
Hemoglobin SS*
310
Female*
University of Michigan
310
Age (years)
449 (439459)
98 (9798)
376 (354395)
9.4 (9.29.6)
48 (4750)
80 (7981)
64 (6365)
113 (111114)
81 (7982)
1.30 (1.261.35)
145 (142147)
13 (4.4%)
61 (20.7%)
2 (0.7%)
5 (1.7%)
214 (72.5%)
73 (24%)
87 (28%)
150 (48%)
151 (48%)
11.9 (11.412.5)
Sickle Cell
49
52
51
53
54
54
54
54
47
54
54
46
46
46
46
46
54
54
54
54
54
491 (466515)
99 (99100)
185 (174196)
12.9 (12.613.3)
48 (4651)
84 (8186)
67 (6570)
116 (112120)
76 (7180)
1.44 (1.331.56)
151 (138166)
13 (24%
12 (22%)
29 (54%)
28 (52%)
12.4 (817)
Control
Demographic and Clinical Data , Mean (95% CI)
0.003***
<0.0001
<0.0001
<0.0001
0.9
0.045
0.02
0.19
0.07
0.032
0.09
--
--
--
--
--
0.97
0.57
p Value
Table 1
Dham et al.
Page 14
N, = 226241
N, = 253299
N = 300310
10.0 (9.810.2)1
2.11 (2.052.17)1
Mitral valve inflow ratio
Left atrial pressure
36 (3537)1
Shortening fraction (%)
6.6 (6.46.8)1
64 (6364)1
Ejection fraction (%)
Mitral valve inflow / tissue Doppler ratio
3.2 (3.03.3)2
39.9 (38.441.4)1
Cardiac index (l/min/m2)
Stroke volume index (ml/m2)
88 (8591)3
0.45 (0.340.58)3
Left ventricular posterior wall diastolic diameter z-score
Left ventricular mass index (gm/m2)
0.73 (0.620.84)3
1.2 (0.22.1)1
Left ventricular end diastolic diameter z-score
Interventricular septum diastolic diameter z-score
1.8 (1.12.7)3
1.77 (1.611.93)3
17 (1718)3
14.7 (14.415.0)2
Left atrial z-score
Pulmonary vascular resistance (units m2)
Tricuspid valve inflow tissue Doppler (cm/sec)
Mean pulmonary artery pressure (mm Hg)
9.0 (8.89.2)2
0.96 (0.940.98)2
Pulmonary insufficiency end diastolic velocity (m/sec)
Pulmonary artery end diastolic pressure (mm Hg)
0.23 (0.220.23)2
26 (2527)2
Right ventricle systolic pressure (mmHg)
Ratio of right ventricle systolic pressure to left ventricle systolic pressure
2.28 (2.242.32)2
<0.0001
<0.0001
0.27 (0.49 0.05)6

0.44 (0.66 0.23)6
9.8 (9.210.4)4
6.4 (6.06.8)4
1.99 (1.872.11)4
36 (3537)4
65 (6466)4
2.2 (0.24.3)5
29.7 (27.332.1)4
0.46
0.35
0.18
0.71
0.12
<0.0001
<0.0001
<0.0001
<0.0001
0.5 (1.40.3)4
58 (5462)6
<0.0001
0.19
0.41
<0.0001
0.004
0.005
<0.0001
<0.0001
<0.0001
p Value
0.7 (0.21.3)6
1.50 (1.141.86)6
17 (1618)6
13.2 (12.713.7)5
8.2 (7.88.6)5
0.88 (0.820.94)5
0.20 (0.1921)5
23 (2224)5
2.10 (2.021.80)5
Control
Unadjusted comparison
Tricuspid Regurgitation Velocity (m/sec)
Sickle Cell
Echocardiography Data, Mean (95% CI)
9.9 (9.710.1)1
6.5 (6.36.7)1
2.11 (2.052.17)1
36 (3637)1
64 (6365)1
3.0 (2.93.2)2
38.7 (37.340.1)1
85 (8188)3**
0.36 (0.230.49)3
0.63 (0.520.74)3
1.0 (0.91.1)1
1.7 (1.51.9)3
1.81 (1.651.97)3
17 (1718)3
14.6 (14.314.9)2
9.0 (8.89.2)2
0.96 (0.940.98)2
0.23 (0.220.24)2
26 (2527)2
2.26 (2.222.30)2
Sickle Cell
10.5 (9.811.2)4
6.9 (6.47.4)4
1.98 (1.802.15)4
36 (3537)4
65 (6467)4
3.0 (2.63.3)5
37.0 (33.240.9)4
56 (5360)6**
0.02 (0.360.33)6
0.07 (0.230.37)6
0.6 (0.21.0)4
1.3 (0.81.8)5
1.09 (0.651.53)6
17 (1618)6
13.7 (12.914.5)5
8.0 (7.48.6)5
0.85 (0.770.93)5
0.23 (0.210.25)
25 (2327)5
2.22 (2.122.32)5
Control
0.16
0.13
0.17
0.84
0.06
0.72
0.45
0.001
0.06
0.001
0.07
0.09
0.004
0.91
0.044
0.004
0.010
0.65
0.31
0.31
p Value
Comparison adjusted for hemoglobin concentration
Table 2
Dham et al.
Page 15
Geometric mean
Page 16
**
N=3438
6
N=4548
5
N, = 5254
Dham et al.


0.25 (<0.0001)1
0.02 (0.78)2
0.04 (0.54)2
0.05 (0.39)2
0.25 (<0.0001)3
0.20 (0.019)
0.24 (0.0002)3
0.09 (0.16)2
0.09 (0.14)2
Mitral valve inflow ratio*
Left ventricular end diastolic diameter z-score
Interventricular septum diastolic diameter z score
Left ventricular mass index*
Cardiac index*
Ejection fraction %*
Not computable

0.06 (0.34)2
0.07 (0.22)1
0.17 (0.007)2
0.14 (0.03)3
0.004 (0.96)4
0.01 (0.89)3
0.08 (0.22)3
0.01 (0.86)3
0.45 (<0.0001)3
0.06 (0.36)3
0.02 (0.68)2
**
**
0.08 (0.56)3
0.14 (0.03)3
0.49 (<0.0001)2
0.76 (<0.0001)3
0.21 (0.001)3
0.17 (0.004)1
0.25 (<0.0001)1
0.11 (0.09)3
0.004 (0.96)4
0.04 (0.54)2
0.04 (0.54)3
0.24 (0.0002)3
LVMI*
0.25 (<0.0001)3
LVIDZ
Abbreviations: LVIDZ Left ventricular end diastolic diameter z-score; LVMI Left ventricular mass index; MV E/Etdi Mitral valve inflow/tissue Doppler ratio; PIEDV Pulmonary insufficiency end
diastolic velocity; TRV Tricuspid regurgitation velocity
N = 189214
N = 226241
N = 253299
N = 300310
**
Natural Log transformed
0.21 (0.0003)2
0.02 (0.74)2
0.16 (0.006)2
0.02 (0.81)3
Mitral valve inflow/tissue Doppler ratio*
0.03 (0.69)4
0.18 (0.007)3
Tricuspid valve inflow tissue Doppler
0.02 (0.74)2
0.16 (0.006)2
MV E/Etdi*
0.13 (0.047)2
0.13 (0.047)2
PIEDV
Pulmonary insufficiency end diastolic velocity
Tricuspid regurgitation velocity
TRV
Pearson Correlation Between Echocardiogram Measurements in Patients with Sickle Cell Disease - R (p value)
Table 3
Dham et al.
Page 17

0.13 (0.034)2
0.01 (0.8)2
0.13 (0.03)2
0.07 (0.24)2
0.35 (<0.0001)2
0.15 (0.012)2
0.07 (0.3)2
0.02 (0.7)2
0.23 (0.0001)2
0.20 (0.001)2
Lactate dehydrogenase*
Systolic blood pressure
Diastolic blood pressure
Mean arterial pressure
Pulse pressure
O2 saturation
0.07 (0.3)2
0.11 (0.06)2
0.14 (0.013)1
0.33 (<0.0001)2
0.10 (0.07)1
0.13 (0.019)1
0.10 (0.07)1
0.39 (<0.0001)3
0.14 (0.028)3
0.01 (0.9)3
0.05 (0.4)3
0.07 (0.26)3
0.04 (0.50)1
0.17 (0.004)1
0.49 (<0.0001)3
0.45 (<0.0001)3
LVMI*
0.53 (<0.0001)2
0.50 (<0.0001)1
LVIDZ
0.15 (0.008)1
0.009 (0.88)1
0.27 (<0.0001)2
0.21 (0.0004)2
MV E/Etdi*
Abbreviations: LVIDZ Left ventricular end diastolic diameter z-score; LVMI Left ventricular mass index; MV E/Etdi Mitral valve inflow/tissue Doppler ratio; PIEDV Pulmonary insufficiency end
diastolic velocity; TRV Tricuspid regurgitation velocity
N, = 226244
N, = 248299
N = 300310
0.03 (0.61)2
0.27 (<0.0001)2
Hemoglobin
0.02 (0.71)2
PIEDV
TRV
Pearson Correlation Coefficient of Echocardiogram Measures with Clinical Variables in Children with Sickle Cell Disease- R (P value)
Table 4
Dham et al.
Page 18

0.03 (0.61)2
0.005 (0.94)2
0.18 (0.003)2
Number of blood transfused in lifetime**
0.19 (0.0008)2
0.04 (0.55)2
0.15
(0.001)1
0.15 (0.04)3
0.02 (0.75)3
LVIDZ
0.01 (0.83)2
0.12 (0.07)2
0.12
(0.06)2
0.14 (0.049)4
0.16 (0.026)
Cardiac Index*
0.31 (<0.0001)3
0.06 (0.38)3
0.15 (0.023)3
0.18 (0.012)4
0.07 (0.33)4
LVMI*
Abbreviations: Abbreviations: LVIDZ Left ventricular end diastolic diameter z-score; LVMI Left ventricular mass index; MV E/Etdi Mitral valve inflow/tissue Doppler ratio; PIEDV Pulmonary
insufficiency end diastolic velocity, TRV Tricuspid regurgitation velocity
Sample size: 1: 300310, 2: 248299, 3: 221244, 4: 189210
Spearman correlation coefficient
**
0.07 (0.20)2
0.02 (0.77)2
0.02 (0.76)2
0.02
Stroke**
0.01
0.23
Acute chest syndrome (# episodes in life)**
(0.71)1
0.13 (0.038)3
(0.84)2
0.01 (0.9)3
0.22 (0.001)3
Oxygen desaturation
(<0.0001)1
0.04 (0.54)3
0.08 (0.21)3
MV E/Etdi*
0.03 (0.69)3
PIEDV
Distance (m)
Six-minute-walk
TRV
Correlation Between Echocardiogram Measures and Clinical Outcomes in Patients with Sickle Cell Disease- R (p value)
Table 5
Dham et al.
Page 19

Pulmonary Hipertention

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Published in final edited form as:

Prospective Echocardiography Assessment of Pulmonary

of Pediatrics-Pediatric Cardiology Division, University of Michigan, Ann Arbor, MI

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of Pediatrics-Hematology Division, University of Michigan, Ann Arbor, MI

of Pediatrics-Pulmonary Division, University of Michigan, Ann Arbor, MI

of Pediatrics and Child Health, Howard University, Washington, DC

of Hematology, Childrens National Medical Center, Washington, DC

for Sickle Cell Disease, Howard University College of Medicine, Washington, DC

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An echocardiography derived pulmonary vascular resistance index was calculated from

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Am J Cardiol. Author manuscript; available in PMC 2011 October 19.

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Elevated pulmonary artery pressure in SCD is sometimes assumed to be due to elevated

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Distribution of tricuspid regurgitation velocity in control and sickle cell subjects in

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Distribution of pulmonary vascular resistance in control and sickle cell subjects in

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Frequency distribution of pulmonary vascular resistance in sickle cell disease grouped by

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Am J Cardiol. Author manuscript; available in PMC 2011 October 19.

Hemoglobin SD Los Angeles*

Hemoglobin Sbeta+ thal*

Body Surface Area

Systolic blood pressure (mm Hg)

Diastolic blood pressure (mm Hg)

Mean blood pressure (mm Hg)

Pulse pressure (mm Hg)

Lactate dehydrogenase (u/l)

Oxygen Saturation (%)

Six minute walk (m)

Adjusted for the height

Hemoglobin Sbeta0 thal*

Childrens National Medical Center