Pulmonary arterial hypertension and left‐sided heart disease in sickle cell disease: Clinical characteristics and association with soluble adhesion molecule expression

Abstract

Pulmonary hypertension (PH), a risk factor for mortality in sickle cell disease (SCD), has pathologic features of both pulmonary arterial hypertension (PAH) and PH related to left-sided heart disease (LHD) suggesting a link between these two entities. We hypothesized that both are characterized by endothelial dysfunction and increased adhesion molecule expression. SCD patients and normal volunteers underwent a screening questionnaire, echocardiogram, and blood donation for preparation of platelet-poor plasma. PAH was defined as a tricuspid regurgitant jet (TRJ) velocity ≥ 2.5 m/sec and/or the presence of isolated right ventricular hypertrophy or decreased systolic function. LHD was defined as either left-sided systolic/diastolic dysfunction or significant valvular disease. Plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-and E-selectin, nitric oxide (NO x ), erythropoietin, and vascular endothelial growth factor (VEGF) levels were assayed by enzyme-linked immunoassay. Forty-three percent of sickle cell anemia (HbSS) and 28% of hemoglobin SC disease (HbSC) disease patients had PAH. Additionally, 10-15% of SCD patients had LHD. VCAM-1 levels were significantly increased in HbSS patients compared with HbSC patients and normal volunteers. VCAM-1 and P-selectin levels correlated positively with TRJ velocity in HbSS patients (r 5 0.45, P 5 0.03, r 5 0.2, P 5 0.05, respectively). ICAM-1, E-selectin, NO x , erythropoietin, and VEGF levels were similar across subject groups. PH is common in SCD and, at times, due to LHD. Increased VCAM-1 and P-selectin expression was associated with TRJ elevation regardless of etiology suggesting a similar effect on endothelial gene expression and possibly providing a pathologic link between PAH and PH related to LHD in SCD. Am. J. Hematol. 83:547-553, 2008. V

Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease

“…22,23 In a study of 124 adults with sickle cell disease, no relationship between erythropoietin and pulmonary hypertension was detected. 24 We, however, observed that serum erythropoietin concentration is associated with higher tricuspid regurgitation velocity in sickle cell disease patients even after adjustment for the degree of hemolysis and other significant covariates, providing evidence for the concept that erythropoietin may be related to the development of pulmonary hypertension. Circulating erythropoietin concentrations reflect the degree of tissue hypoxia, and are known to increase with lower hemoglobin concentrations and hemoglobin oxygen saturations.…”

Pulmonary hypertension in sickle cell disease: diagnosis and management

“…SCD patients may present a diagnostic conundrum because early symptoms of PH in these patients are nonspecific and may not differ from those experienced by SCD patients without PH. 25 Dyspnea is a fairly nonspecific finding in patients with SCD, observed in up to 50% of HbSS and 40% of HbSC adults, 26 and often occurs without coexistent PH. However, a history of progressive dyspnea on exertion or limitations of exercise capacity should raise concern for the presence of PH, particularly when observed in conjunction with exertional hypoxemia.…”

High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension

“…Pulmonary hypertension (PH) occurs in 10% to 30% of patients with sickle cell disease (SCD) [1][2][3] and is associated with a 17% 2-year mortality in adults. 1 Factors implicated in SCD PH include endothelial dysfunction, pulmonary vasoconstriction, and remodeling, all mechanistically associated with chronic hemolysis, hypoxia, hemostatic activation, and inflammation.…”