American Journal of Cardiology
Volume 104, Issue 5 , Pages 713-720, 1 September 2009

Prospective Echocardiography Assessment of Pulmonary Hypertension and Its Potential Etiologies in Children With Sickle Cell Disease†

  • Niti Dham, MD

      Affiliations

    • Department of Cardiology, Children's National Medical Center, Washington, District of Columbia
    • ,
  • Gregory Ensing, MD

      Affiliations

    • Pediatric Cardiology Division, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
    • ,
  • Caterina Minniti, MD

      Affiliations

    • Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
    • ,
  • Andrew Campbell, MD

      Affiliations

    • Hematology Division, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
    • ,
  • Manuel Arteta, MD

      Affiliations

    • Pulmonary Division, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
    • ,
  • Sohail Rana, MD

      Affiliations

    • Department of Pediatrics and Child Health, Howard University, Washington, District of Columbia
    • ,
  • Deepika Darbari, MD

      Affiliations

    • Department of Hematology, Children's National Medical Center, Washington, District of Columbia
    • ,
  • Mehdi Nouraie, MD, PhD

      Affiliations

    • Center for Sickle Cell Disease, Howard University College of Medicine, Washington, District of Columbia
    • ,
  • Onyinye Onyekwere, MD

      Affiliations

    • Center for Sickle Cell Disease, Howard University College of Medicine, Washington, District of Columbia
    • ,
  • Malgorzata Lasota, RDCS

      Affiliations

    • Department of Cardiology, Children's National Medical Center, Washington, District of Columbia
    • ,
  • Gregory J. Kato, MD

      Affiliations

    • Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
    • ,
  • Mark T. Gladwin, MD

      Affiliations

    • Department of Pulmonary, Allergy and Critical Care Medicine and Hemostasis and Vascular Biology Research Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
    • ,
  • Oswaldo Castro, MD

      Affiliations

    • Center for Sickle Cell Disease, Howard University College of Medicine, Washington, District of Columbia
    • ,
  • Victor Gordeuk, MD

      Affiliations

    • Center for Sickle Cell Disease, Howard University College of Medicine, Washington, District of Columbia
    • ,
  • Craig Sable, MD

      Affiliations

    • Department of Cardiology, Children's National Medical Center, Washington, District of Columbia
    • Corresponding Author InformationCorresponding author: Tel: 202-476-2020; fax: 202-476-5700

Received 17 February 2009; received in revised form 26 April 2009; accepted 26 April 2009. published online 26 June 2009.

Article Outline

Pulmonary hypertension (PH) is associated with adverse outcomes in adults with sickle-cell disease (SCD), but its importance in children is less clear. The aim of this study was to define the incidence and causes 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 tests, and hematologic testing. Echocardiographic measures were compared between patients with SCD and control subjects before and after adjusting for hemoglobin. Correlations of echocardiographic and clinical parameters were determined. 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 controlling for left ventricular diameter and left atrial pressure. Echocardiographically derived pulmonary resistance was not significantly different between patients with SCD and controls, although it was elevated in the SCD subgroup with elevated TRV. When controlling 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 were correlated with indicators of adverse functional status, including history of acute chest syndrome, stroke, transfusions, and 6-minute walk distance. In conclusion, children with SCD had mildly increased TRV that was correlated with increased cardiac output and left ventricular filling pressures. Hemoglobin-adjusted analysis also suggested a contribution of primary vascular changes.

 

In the present study, we compared multiple echocardiographic variables between children with sickle-cell disease (SCD) and age- and gender-matched controls to assess the relative contributions of potential determinants of pulmonary artery pressure in this population. We also examined the relations among tricuspid regurgitation velocity (TRV), other echocardiographic measurements, and clinical parameters in children with SCD to better elucidate the physiology and consequences of echocardiographic abnormalities in this population of children.

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Methods 

This observational, prospective, and multicenter study of children and adolescents with SCD and matched controls was supported by the National Institutes of Health, Bethesda, Maryland (Grant 1 R01 HL079912-01). The centers included were the Children's National Medical Center, Washington, District of Columbia; Howard University, Washington, District of Columbia; the National Institutes of Health; and the University of Michigan, Ann Arbor, Michigan (ClinicalTrials.gov identifier NCT00495638). The study was approved by the institutional review boards of all participating institutions. Assent and consent were obtained from each patient and a family member of each patient (for patients aged <18 years).

Subjects ranged in age from 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 Sβ 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 doctor's office visit for pain crisis, acute chest syndrome, infection, or other complications of SCD for ≥3 weeks.

For every 6 patients with SCD recruited, 1 healthy control subject matched by gender, 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 test, echocardiographic study, and hematologic testing.

Patients underwent medical histories, physical examinations, and measurements of oxygen saturation using pulse oximetry (at baseline and during the 6-minute walk test). Venous blood was drawn for complete blood count, reticulocyte count, and serum chemistries. An unencouraged 6-minute walk test was conducted on a predetermined course, ≥6 feet wide, as per the guidelines of the American Thoracic Society.1

Transthoracic echocardiograms were obtained using the Philips Sonos 5500 or 7500 or iE33 (Philips Medical Systems, Best, The Netherlands), Acuson Sequoia (Siemens Medical Solutions USA, Inc., Mountain View, California), or GE Vivid 7 or Vivid I (GE Healthcare, Milwaukee, Wisconsin). All images were obtained by a licensed sonographer or pediatric cardiologist and were recorded digitally and subsequently reviewed on an off-line digital workstation. Each study was interpreted by 1 of 2 pediatric cardiologists (C.S. or G.E.) who were blinded to the subject's 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 2 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 sizes, dimensions were compared to those of a large cohort of normal infants and children described by Pettersen et al3 and expressed as standard deviations less than or greater than the mean for body surface area (z scores). Left ventricular mass,4 stroke volume, and cardiac output were indexed to body surface area. Left ventricular stroke volume was calculated from apical 4-chamber images (single-plane Simpson's rule).2, 5

TRV was assessed in the parasternal long- and short-axis and apical 4-chamber views. Continuous-wave Doppler of the peak regurgitant velocity was used to estimate the right ventricular–to–right atrial pressure gradient using the modified Bernoulli's equation.6, 7 Pulmonary artery systolic pressure was quantified by adding the Bernoulli-derived pressure gradient to estimated mean right atrial pressure.8 Estimated pulmonary artery end-diastolic pressure was estimated by applying the modified Bernoulli's equation to the pulmonary insufficiency end-diastolic velocity Doppler signal and assuming that 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 pressures.

Left ventricular systolic function was assessed by calculating M-mode-derived shortening and Simpson's 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 measuring 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 echocardiographically derived pulmonary vascular resistance index was calculated from echocardiographic parameters described previously.11, 12 Cardiac index was calculated from apical 4-chamber–derived stroke volume using the Simpson's single-plane formula and heart rate. The echocardiographically derived pulmonary vascular resistance index was assumed to be zero if it was calculated to be a negative value.

Continuous variables were assessed for normality. The best transformation was then used to change to a normal distribution. Student's t test and the Kruskal-Wallis test (whichever was appropriate) were used to compare continuous variables between patients with SCD and control subjects, and Pearson's chi-square test was used to compare dichotomous variables. Stepwise linear regression was used to assess the relation between echocardiographic parameters and clinical variables in patients with SCD. A p value <0.05 was considered significant.

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Results 

Demographic and clinical variables of 310 patients with SCD and 54 control subjects are listed in Table 1, and echocardiographic measurements are listed in Table 2. The median age of patients with SCD and controls was 13 years. Patients with SCD had significantly higher TRV (2.28 vs 2.10 m/s, p <0.0001; Figure 1). TRV was measurable in 290 of 310 subjects with SCD (94%) and 48 of 54 controls (89%). Thirty-two of 290 patients with SCD (11%) had TRVs >2.60 m/s, and 1 patient with SCD had a TRV >3.0 m/s. One control had a TRV >2.60 m/s (2.7 m/s). Nine of 290 patients with SCD (3%) and no control subjects had estimated ratios of right ventricular to left ventricular pressure >33%. There was still a significant difference between patients with SCD 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 ratio (2.3 vs 2.1 m/s).

Table 1. Demographic and clinical data
VariablenPatients With SCDnControlsp Value
Age (years)31011.9(11.4–12.5)5412.4(8–17)0.57
Female310151(48%)5428(52%)0.97
Children's National Medical Center310150(48%)5429(54%)
Howard University31087(28%)5412(22%)
University of Michigan31073(24%)5413(24%
Hemoglobin SS295214(72.5%)460—
Hemoglobin Sβ0 thalassemia2955(1.7%)460—
Hemoglobin SD LA2952(0.7%)460—
Hemoglobin SC29561(20.7%)460—
Hemoglobin Sβ+ thalassemia29513(4.4%)460—
Height (cm)310145(142–147)54151(138–166)0.09
Body surface area3101.30(1.26–1.35)541.44(1.33–1.56)0.032
Heart rate26881(79–82)4776(71–80)0.07
Systolic blood pressure (mm Hg)310113(111–114)54116(112–120)0.19
Diastolic blood pressure (mm Hg)31064(63–65)5467(65–70)0.02
Mean blood pressure (mm Hg)31080(79–81)5484(81–86)0.045
Pulse pressure (mm Hg)31048(47–50)5448(46–51)0.9
Hemoglobin (g/dl)3019.4(9.2–9.6)5312.9(12.6–13.3)<0.0001
Lactate dehydrogenase (u/L)295376(354–395)51185(174–196)<0.0001
Oxygen saturation (%)30098(97–98)5299(99–100)<0.0001
6-min walk distance (m)245449(439–459)49491(466–515)0.003⁎

Data are expressed as mean (95% confidence interval) or as number (percentage).

⁎Adjusted for height.

Table 2. Echocardiographic data
VariableUnadjusted ComparisonComparison Adjusted for Hemoglobin Concentration
Patients With SCDControlsp ValuePatients With SCDControlsp Value
TRV (m/s)2.28(2.24to2.32)†2.10(2.02to1.80)∥<0.00012.26(2.22to2.30)†2.22(2.12to2.32)∥0.31
Right ventricular systolic pressure (mm Hg)26(25to27)†23(22to24)∥<0.000126(25to27)†25(23to27)∥0.31
Ratio of right ventricular systolic pressure to left ventricular systolic pressure0.23(0.22to0.23)†0.20(0.19to21)∥<0.00010.23(0.22to0.24)†0.23(0.21to0.25)0.65
Pulmonary insufficiency end-diastolic velocity (m/s)0.96(0.94to0.98)†0.88(0.82to0.94)∥0.0050.96(0.94to0.98)†0.85(0.77to0.93)∥0.010
Pulmonary artery end-diastolic pressure (mm Hg)9.0(8.8to9.2)†8.2(7.8to8.6)∥0.0049.0(8.8to9.2)†8.0(7.4to8.6)∥0.004
Mean pulmonary artery pressure (mm Hg)14.7(14.4to15.0)†13.2(12.7to13.7)∥<0.000114.6(14.3to14.9)†13.7(12.9to14.5)∥0.044
Tricuspid valve inflow tissue Doppler (cm/s)17(17to18)‡17(16to18)0.4117(17to18)‡17(16to18)0.91
Pulmonary vascular resistance (U × m2)1.77(1.61to1.93)‡1.50(1.14to1.86)0.191.81(1.65to1.97)‡1.09(0.65to1.53)0.004
Left atrial z score1.8(1.1to2.7)‡0.7(−0.2to1.3)<0.00011.7(1.5to1.9)‡1.3(0.8to1.8)∥0.09
Left ventricular end-diastolic diameter z score1.2(0.2to2.1)⁎−0.5(−1.4to0.3)§<0.00011.0(0.9to1.1)⁎0.6(0.2to1.0)§0.07
Interventricular septum diastolic diameter z score0.73(0.62to0.84)‡−0.27(−0.49to−0.05)<0.00010.63(0.52to0.74)‡0.07(−0.23to0.37)0.001
Left ventricular posterior wall diastolic diameter z score0.45(0.34to0.58)‡−0.44(−0.66to−0.23)<0.00010.36(0.23to0.49)‡−0.02(−0.36to0.33)0.06
Left ventricular mass index (g/m2)88(85to91)‡58(54to62)<0.000185(81to88)‡,#56(53to60),#0.001
Stroke volume index (ml/m2)39.9(38.4to41.4)⁎29.7(27.3to32.1)§<0.000138.7(37.3to40.1)⁎37.0(33.2to40.9)§0.45
Cardiac index (L/min/m2)3.2(3.0to3.3)†2.2(0.2to4.3)∥<0.00013.0(2.9to3.2)†3.0(2.6to3.3)∥0.72
Ejection fraction (%)64(63to64)⁎65(64to66)§0.1264(63to65)⁎65(64to67)§0.06
Shortening fraction (%)36(35to37)⁎36(35to37)§0.7136(36to37)⁎36(35to37)§0.84
Mitral valve inflow ratio2.11(2.05to2.17)⁎1.99(1.87to2.11)§0.182.11(2.05to2.17)⁎1.98(1.80to2.15)§0.17
Mitral valve inflow/tissue Doppler ratio6.6(6.4to6.8)⁎6.4(6.0to6.8)§0.356.5(6.3to6.7)⁎6.9(6.4to7.4)§0.13
Left atrial pressure10.0(9.8to10.2)⁎9.8(9.2to10.4)§0.469.9(9.7to10.1)⁎10.5(9.8to11.2)§0.16

Data are expressed as mean (95% confidence interval).

⁎n = 300 to 310.

†n = 253 to 299.

‡n = 226 to 241.

§n = 52 to 54.

∥n = 45 to 48.

n = 34 to 38.

#Geometric mean.

  • View full-size image.
  • Figure 1. 

    Distribution of TRV in controls and patients with SCD in unadjusted analysis (left) and analysis adjusted for hemoglobin (right). Crosses indicate mean values.

The mean echocardiographically derived pulmonary vascular resistance index was not significantly different between patients with SCD (1.75 U × m2) and control subjects (1.50 U × m2, p = 0.20; Figure 2). We defined the estimated pulmonary vascular resistance upper limit of normal based (95%) on our control population as 3.7 U × m2. Two of the 38 controls (5%) and 16 of 226 patients with SCD (7%) had estimated pulmonary vascular resistance indexes >3.7 U × m2. There was enough information to calculate estimated pulmonary vascular resistance indexes in 23 of the 32 patients with SCD with TRVs >2.6 m/s. 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 on the basis of TRV <2.6 m/s or >2.6 m/s is shown in Figure 3.

  • View full-size image.
  • Figure 2. 

    Distribution of pulmonary vascular resistance in controls and patients with SCD in unadjusted analysis (left) and analysis adjusted for hemoglobin (right). Crosses indicate mean values.

Bivariate analysis results are listed in Table 3. TRV was strongly correlated with left ventricular end-diastolic dimension z score (p <0.0001; Figure 4), mitral E wave/tissue Doppler E wave ratio (p = 0.006; Figure 5), left ventricular mass index, and tricuspid valve tissue Doppler E wave. Although our subjects ranged in age from 3 to 20 years, there was no correlation of TRV and age.

Table 3. Pearson's correlations between echocardiographic measurements in patients with sickle cell disease
VariableTRVPIEDVMV E/Etdi⁎LVIDZLVMI⁎
TRV 0.13(0.047)§0.16(0.006)§0.25(<0.0001)∥0.24(0.0002)∥
Pulmonary insufficiency end-diastolic velocity0.13(0.047)§ 0.02(0.74)§−0.04(0.54)§−0.004(0.96)
Tricuspid valve inflow tissue Doppler0.18(0.007)∥0.03(0.69)0.02(0.81)∥0.04(0.54)∥0.11(0.09)∥
Mitral valve inflow/tissue Doppler ratio⁎0.16(0.006)§0.02(0.74)§ 0.25(<0.0001)‡0.14(0.03)∥
Mitral valve inflow ratio⁎−0.05(0.39)§−0.02(0.78)§0.21(0.0003)§0.17(0.004)‡0.08(0.56)∥
Left ventricular end-diastolic diameter z score0.25(<0.0001)∥−0.04(0.54)§0.25(<0.0001)‡ †
Interventricular septum diastolic diameter z score0.20(0.019)0.01(0.86)∥0.08(0.22)∥0.21(0.001)∥†
Left ventricular mass index⁎0.24(0.0002)∥−0.004(0.96)0.14(0.03)∥0.76(<0.0001)∥
Cardiac index⁎0.09(0.16)§0.01(0.89)∥0.17(0.007)§0.49(<0.0001)§0.45(<0.0001)∥
Ejection fraction (%)⁎0.09(0.14)§0.06(0.34)§0.07(0.22)‡−0.02(0.68)§−0.06(0.36)∥

Data are expressed as r value (p value).

LVIDZ = left ventricular end-diastolic diameter z score; LVMI = left ventricular mass index; MV E/Etdi = mitral valve inflow E wave/tissue Doppler E wave ratio; PIEDV = pulmonary insufficiency end-diastolic velocity.

⁎Natural log transformed

†Not computable.

‡n = 300 to 310.

§n = 253 to 299.

∥n = 226 to 241.

n = 189 to 214.

  • View full-size image.
  • Figure 4. 

    Correlation between left ventricular end-diastolic dimension z score and TRV in patients with SCD. CI = confidence interval; LVIDd = left ventricular internal dimension in diastole.

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 1), 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 ventricular mass index remained significantly higher in patients with SCD, and the calculation for pulmonary vascular resistance (p = 0.004; Figure 2) became significantly higher.

Table 4, Table 5 list the correlations between echocardiographic variables and clinical variables and outcomes.

Table 4. Pearson's correlation coefficients for echocardiographic measures with clinical variables in children with sickle cell disease
VariableTRVPIEDVMV E/Etdi⁎LVIDZLVMI⁎
Hemoglobin−0.27(<0.0001)‡0.03(0.61)‡−0.21(0.0004)‡−0.50(<0.0001)†−0.45(<0.0001)§
Lactate dehydrogenase⁎0.35(<0.0001)‡0.02(0.71)‡0.27(<0.0001)‡0.53(<0.0001)‡0.49(<0.0001)§
Systolic blood pressure0.15(0.012)‡0.13(0.034)‡0.009(0.88)†−0.04(0.50)†0.07(0.26)§
Diastolic blood pressure−0.07(0.3)‡0.01(0.8)‡−0.15(0.008)†−0.17(0.004)†−0.05(0.4)§
Mean arterial pressure0.02(0.7)‡0.07(0.3)‡−0.10(0.07)†−0.13(0.019)†−0.01(0.9)§
Pulse pressure0.23(0.0001)‡0.13(0.03)‡0.14(0.013)†0.10(0.07)†0.14(0.028)§
Oxygen saturation−0.20(0.001)‡−0.07(0.24)‡−0.11(0.06)‡−0.33(<0.0001)‡−0.39(<0.0001)§

Data are expressed as r value (p value).

Abbreviations as in Table 3.

⁎Natural log transformed.

†n = 300 to 310.

‡n = 248 to 299.

§n = 226 to 244.

Table 5. Correlations between echocardiographic measures and clinical outcomes in patients with sickle cell disease
VariableTRVPIEDVMV E/Etdi⁎LVIDZCardiac Index⁎LVMI⁎
6-min walking distance (m)0.03(0.69)∥0.08(0.21)∥0.04(0.54)∥0.02(0.75)∥−0.16(0.026)−0.07(0.33)
Oxygen desaturation0.22(0.001)∥−0.01(0.9)∥−0.13(0.038)∥0.15(0.04)∥0.14(0.049)−0.18(0.012)
Acute chest syndrome (no. of episodes in life)†0.23(<0.0001)‡0.01(0.84)§−0.02(0.71)‡0.15(0.001)‡0.12(0.06)§0.15(0.023)∥
Stroke†−0.02(0.76)§−0.02(0.77)§0.07(0.20)§0.04(0.55)§0.12(0.07)§0.06(0.38)∥
No. of blood transfusions in lifetime†0.18(0.003)§−0.005(0.94)§−0.03(0.61)§0.19(0.0008)§−0.01(0.83)§0.31(<0.0001)∥

Data are expressed as r value (p value).

Abbreviations as in Table 3.

⁎Natural log transformed.

†Spearman's correlation coefficient.

‡n = 300 to 310.

§n = 248 to 299.

∥n = 221 to 244.

n = 189 to 210.

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Discussion 

This cohort of patients represents the largest prospective evaluation of echocardiographic findings in children with SCD and included only patients remote from any acute illness or event. Children with SCD in the nonacute state had higher TRVs and higher estimated pulmonary artery systolic, diastolic, and mean pressures compared to a similar population without SCD. These findings are similar to those in several previous reports of TRV elevations in children.13, 14, 15, 16, 17 Pulmonary hypertension is prevalent in adults with SCD and is associated with a significant increase in mortality rate.18, 19, 20 In the pediatric population, however, death and major morbidity are much less common, and this association has not been well defined. In our study, TRV was correlated with lower oxygen saturation during 6-minute walk testing (potentially because of ventilation-perfusion mismatch), acute chest syndrome history, and need for chronic transfusion.

Elevated pulmonary artery pressure in SCD is sometimes assumed to be due to elevated pulmonary vascular resistance, and treatment with pulmonary vasodilators is 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,21, 22, 23 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. In this study, we investigated the relative contribution of the additional causes of pulmonary hypertension in SCD, including increased pulmonary flow volume (cardiac output), increased left ventricular filling pressures, increased blood viscosity, and increased pulmonary vascular resistance (assessed noninvasively).

Our subjects with SCD had multiple measures of increased pulmonary blood flow. This is consistent with previous studies that have shown significant correlations 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 pulmonary hypertension related to pulmonary venous hypertension. Several recent studies 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, the ejection and shortening fractions were not significantly different between patients with SCD and controls. However, the presence of increased preload suggests that elevated preload is necessary to provide normal left ventricular shortening. These findings are similar to other studies of 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 patients with SCD 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 echocardiographically derived pulmonary vascular resistance. Although incorporating many assumptions, the index used is similar to previously established echocardiographic estimates, and each component was validated in previous studies.2, 6, 9, 11, 12 We found no significant difference between patients with SCD and controls in estimated pulmonary vascular resistance. Although 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 echocardiographic comparisons between patients and controls may contribute insights to the pathophysiology of systemic and pulmonary vasculopathy that is postulated to occur in patients with SCD. The only measurements that remained significantly greater in patients with SCD were septal wall thickness and pulmonary diastolic Doppler velocity. Calculations of left ventricular mass index and pulmonary vascular resistance were significantly higher in patients with SCD after adjustment for hemoglobin concentration. We postulate that these findings provide evidence to support an anemia-independent process that likely represents the effect of hemolysis on the systemic and pulmonary vascular beds.19, 20, 22, 28, 29 Hemolysis and low hemoglobin oxygen saturation were independent predictors of TRV in our previous 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 a patient from having elevated pulmonary pressure.20 Additionally, if proper alignment is not obtained, 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 patients with SCD and control subjects in our cohort. Echocardiographic 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 patients with SCD and control subjects and correlations still provide useful information.

Our study demonstrated only small differences in TRV between patients with SCD and control subjects. Our exclusion of acutely ill patients partially explains why other pediatric studies have reported a higher prevalence and more significant degrees 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.

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  • † Conflicts of interest: Dr. Gordeuk has received grants from BioMarin Pharmaceutical Inc., Novato, California, and Actelion Pharmaceuticals Ltd., Allschwil, Switzerland, and is a consultant for Ikaria Holdings, Clinton, New Jersey.

 This study was supported in part by Grants 2 R25 HL003679-08 and 1 R01 HL079912-02 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland; by Howard University General Clinical Research Center Grant 2MOI RR10284-10 from the National Center for Research Resources, National Institutes of Health, Bethesda, Maryland; and by the Intramural Research Program of the National Institutes of Health.

PII: S0002-9149(09)01002-9

doi:10.1016/j.amjcard.2009.04.034

American Journal of Cardiology
Volume 104, Issue 5 , Pages 713-720, 1 September 2009

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