Lori A. Hunter

Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension

Pulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at‐risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 ± 1 months) decreased the estimated pulmonary artery systolic pressure [50 ± 4 to 41 ± 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0·3–17, P = 0·043] and increased the 6‐min walk distance (384 ± 30 to 462 ± 28 m; difference 78 m, 95% CI: 40–117, P = 0·0012). Transient headaches occurred in two patients and transient eye‐lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction. In conclusion: (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6‐min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted.

Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality

Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium‐derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end‐organ disease, we found that higher levels of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule‐1 (sICAM‐1), sE‐selectin and sP‐selectin levels indicated partially overlapping associations with sVCAM‐1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM‐1, ICAM‐1, and E‐selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.

Severity of pulmonary hypertension during vaso‐occlusive pain crisis and exercise in patients with sickle cell disease

Pulmonary hypertension is associated with sudden death and is a risk factor for mortality in adult patients with sickle cell disease. The high mortality despite only mild‐to‐moderate increases in pulmonary vascular resistance remains an unresolved paradox. Accordingly, little is known about the cardiovascular effects of stressors, such as vaso‐occlusive pain crisis (VOC) and exercise, which may acutely increase pulmonary pressures and impair right heart function. We therefore evaluated pulmonary artery pressures by echocardiogram in 25 patients with sickle cell disease in steady‐state and during VOC, and by right heart catheterisation with exercise in a second cohort of 21 patients to determine whether pulmonary hypertension worsens during acute cardiopulmonary stress. TRV increased during VOC (P < 0·001), and the increased pulmonary pressures during VOC were associated with decreases in haemoglobin levels (P < 0·001), and increases in lactate dehydrogenase (P < 0·001) and plasma haemoglobin levels (P = 0·03). During exercise stress performed during cardiac catheterisation, mean pulmonary artery pressures (P < 0·001) and pulmonary vascular resistance increased (P < 0·001) in all subjects. These data suggest that acute elevations in pulmonary pressures during VOC or exercise may contribute to morbidity and mortality in patients with sickle cell disease.

Circulating endothelial progenitor cells in adults with sickle cell disease.

We appreciated the quality of the project by Anjum et al.,[1] concerning circulating endothelial progenitor cells (EPCs) in patients with sickle cell disease. An increasing body of data indicates that intravascular hemolysis contributes to a state of vascular dysfunction in sickle cell disease, especially involving diminished nitric oxide (NO) bioavailability. This vascular dysfunction is detected on venous occlusion plethysmography blood flow physiology studies as a relative blunting of NOinduced vasodilation[2-4] and this state of NO resistance has also been observed in sickle cell mouse models.[5,6] This vascular dysfunction may play a role in the development of pulmonary hypertension in sickle cell disease.[7]