Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Mortality rates of sickle cell patients with pulmonary hypertension are significantly increased as compared to patients without pulmonary hypertension. We have enrolled 603 subjects and 87 controls in a study of the prevalence and prognosis of subjects with sickle cell disease and pulmonary hypertension. All subjects were screened with transthoracic echocardiograms and the tricuspid regurgitant jet velocity (TRV) used to estimate the pulmonary artery systolic pressure. Elevated estimated pulmonary artery pressure was prospectively defined by a TRV >= 2.5 m/sec and highly elevated TRV defined by a TRV >= 3.0 m/sec. Subjects have been followed for a mean of 6 years and censored at time of death or loss to follow-up. We performed and analyzed Doppler echocardiographic assessments of pulmonary systolic pressure in 492 consecutive patients (mean age=33.0 years). Elevated estimated pulmonary artery pressure occurred in 31 percent of patients. Diastolic dysfunction was present in 18% of patients. A combination of diastolic dysfunction and pulmonary hypertension was present in 11% of patients, and diastolic dysfunction accounted for only 10% to 20% of the variability in TR jet velocity. Diastolic dysfunction, as reflected by a low E/A ratio, was associated with mortality with a risk ratio of 3.5 (95% confidence interval 1.5 to 8.4, p<0.001), even after adjustment for TR jet velocity. The presence of both diastolic dysfunction and pulmonary hypertension conferred a risk ratio for death of 12.0 (95% confidence interval 3.8 to 38.1, p <0.001). Right heart catheterization was performed under a separate protocol in consenting patients with TRV >= 2.8 m/sec (based on the results of the screening echo). Based on these data, approximately 10% of adults with sickle cell disease have pulmonary hypertension proven by right heart catheterization, about half pulmonary arterial hypertension and half pulmonary venous hypertension, the latter most likely due to left ventricular diastolic dysfunction. Additional analyses have identified increasing age, increased serum biomarkers (LDH, total bilirubin) and arginine/ornithine ratio as significant independent predictors of pulmonary hypertension. The patients diagnosed with pulmonary hypertension had significantly greater mortality. These studies suggest that secondary pulmonary hypertension is common in adult patients with sickle cell disease, appears to have no association with hydroxyurea therapy, while there are positive associations with biomarkers suggestive of hemolysis and with earlier mortality. These data suggest that all patients should be screened for this complication and considered for therapeutic trials with oxygen, anticoagulation, transfusion and/or selective pulmonary vasodilators. There have been 79 new subjects enrolled at the NIH during this year;16 were controls and 63 were subjects with sickle cell disease. There were no new subjects enrolled at the Howard University site during this period. The total enrolled at Howard University is 131 and the total enrolled at NIH is 624. Total enrollment for all sites is 755. Subjects continue to be enrolled in this trial and referred for treatment studies if identified with pulmonary hypertension. We conducted 2, 4, 6, and 8 year follow-up visits for comprehensive data collection. We also completed comprehensive survival update on all subjects enrolled to date. Sample analysis from this protocol found that endothelin-1 appears to be a mediator of elevated pulmonary artery pressures as estimated by echocardiography in patients with SCD. This finding lends support to our published case series report of clinical efficacy of the endothelin-1 receptor antagonists bosentan and ambrisentan in SCD adults with PH and identified erythrocyte arginase release as a significant contributing factor to PH severity and patient mortality in SCD. Decreased arginine bioavailability and a shift of metabolism towards ornithine-dependent pathways are novel mechanisms that play a role in PH of various etiologies. Studies currently underway also show the power of combining epidemiological analysis of biomarkers with basic bench science investigation. We have found that serum markers of iron overload are statistically associated with levels of placenta growth factor, with echocardiographic markers of elevated pulmonary artery pressure, and ultimately with mortality in adults with sickle cell disease. We are currently characterizing the molecular regulatory pathways involved in mediating the effect of excess iron on expression of placenta growth factor in human and mouse erythroid cells. Demonstration of a pathophysiological link between iron and pulmonary hypertension in sickle cell disease would support renewed diligence in utilizing clinically available iron chelation drugs to relieve the iron overload state in recurrently transfused patients with sickle cell disease. Additional exploratory biomarker screens have been imitated with Dr. Darryl Zeldins group in the National Institute of Environmental Health Sciences, leveraging trans-institute resources and expertise.

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