Abstract

Background: Echocardiography (ECHO)-determined tricuspid regurgitation jet velocity (TRV) ≥2.5 m/s occurs in about 30% of adults with sickle cell disease(SCD)and is associated with increased mortality. The frequency and significance of high TRV in children is not known. We determined the prevalence and risk factors of elevated estimated systolic pulmonary artery pressures in 228 patients with SCD and 39 controls.

Methods: Patients with SCD (Hb SS, SC, SB thalassemia or other major sickling phenotypes) aged 3 to 20 years were evaluated clinically and with ECHO and six minute walk tests at their steady state. Healthy, non-SCD controls, matched for ethnicity, sex and age, were also evaluated.

Results: A comparison of patients and controls is summarized in Table 1. 184 patients (81%) had hemoglobin SS phenotype and 28 (12%) had hemoglobin SC. TRV was measurable in 214 (94%) of the patients and 34 (87%) of the controls. In a multivariate logistic regression model, each 10 mm Hg increase in systolic blood pressure was associated with an estimated 2.0-fold increase in the odds of TRV≥2.5 m/sec (P = 0.002) and a 10-fold increase in LDH with a 25-fold increase in the odds (P = 0.015).

Conclusion: This study of children with SCD who have limited iron overload and limited renal dysfunction compared with the aging SCD population provides a unique window into the early pathogenesis of PH in SCD. TRV and LVMI are significantly higher in children and adolescents with SCD at steady state than age-matched control participants. Among children with SCD, TRV elevation is independently associated with systolic BP and LDH concentration. In this analysis we find a strong association with hemolysis and systemic hypertension and surprisingly no associations with vaso-occlusive events or biomarkers (VOC, ACS, HU use, WBC and platelet counts).

Table I.

Comparison of SCD and control subjects. Results in mean (SD) unless otherwise stated.

SCD(n=228)Control (n=39)p
Age in years 12 (5) 12 (5) 0.7 
Female (%) 48% 46% 0.8 
Systolic BP (mm Hg) 112 (11) 116 (15) 0.1 
Diastolic BP (mm Hg) 64 (9) 68 (10) 0.040 
Six minute walk in meters 454 (76) 498 (84) 0.006 
TRV in m/sec 2.3 (0.3) 2.1 (0.3) 0.003 
TRV 2.5 m/sec (%) 21% 3% 0.012 
LV intern. diastolic diam Z-score 1.2(1.4) −0.3(1.2) <0.001 
LV mass index 88 (25) 59 (13) <0.001 
SCD(n=228)Control (n=39)p
Age in years 12 (5) 12 (5) 0.7 
Female (%) 48% 46% 0.8 
Systolic BP (mm Hg) 112 (11) 116 (15) 0.1 
Diastolic BP (mm Hg) 64 (9) 68 (10) 0.040 
Six minute walk in meters 454 (76) 498 (84) 0.006 
TRV in m/sec 2.3 (0.3) 2.1 (0.3) 0.003 
TRV 2.5 m/sec (%) 21% 3% 0.012 
LV intern. diastolic diam Z-score 1.2(1.4) −0.3(1.2) <0.001 
LV mass index 88 (25) 59 (13) <0.001 
Table II.

Comparison of SCD patients according to TRV category. Results in mean (SD) unless otherwise stated.

VariablesTRV <2.5 (n= 169)TRV ≥2.5 (n=45)p
History of acute chest syndrome (%) 20% 40% 0.034 
Hydroxyurea therapy 42% 44% 0.8 
Hemoglobin in g/dl 9.3 (1.8) 8.9 (1.7) 0.071 
LDH in U/L 393 (163) 474 (170) 0.009 
Total Bilirubin in mg/dL 2.7 (1.9) 3.8 (2.2) 0.004 
VariablesTRV <2.5 (n= 169)TRV ≥2.5 (n=45)p
History of acute chest syndrome (%) 20% 40% 0.034 
Hydroxyurea therapy 42% 44% 0.8 
Hemoglobin in g/dl 9.3 (1.8) 8.9 (1.7) 0.071 
LDH in U/L 393 (163) 474 (170) 0.009 
Total Bilirubin in mg/dL 2.7 (1.9) 3.8 (2.2) 0.004 

Author notes

Disclosure:Research Funding: Investigator in the Novartis Sponsored Phase II study of ICL-670(Exjade) in Sickle Cell Iron Overload Study.