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. Pulmonary hypertension was prospectively defined by a TRV >= 2.5 m/sec and severe pulmonary hypertension 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). Doppler-defined pulmonary hypertension 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 ony 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, 60% of patients with sickle cell disease have elevated pulmonary artery systolic pressures (TRV >= 2.8 m/sec) and 9% have severely elevated pressures. Multiple-regression analysis identified increasing age, increased serum biomarkers (LDH, total bilirubin) and arginine/ornithine ratio as significant independent predictors of pulmonary hypertension. Fetal hemoglobin levels did not predict pulmonary hypertension nor did a history of hydroxyurea treatment. Left ventricular dysfunction was rarely observed (<2% of patients). 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. As part of this protocol, adult patients were assessed for depression using the Beck Depression Inventory II (BDI-II). The findings of these tests suggest that there is a correlation between severity of depressive symptoms and reported sleep quality. Further planned analyses will look to elucidate the nature of this correlation and examine the association of severity of depressive symptoms and pain scores, reliance on analgesics, measures of treatment adherence, and genetic factors. These findings suggest that screening and treatment of depression are important components of routine care for persons with SCD. Sample analysis from this protocol found that ET-1 appears to be a mediator of elevated pulmonary artery pressures as estimated by echocardiography in patients with SCD. This finding lends support to clinical efficacy of the ET-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. However, decreased Arg bioavailability and a shift of metabolism towards ornithine-dependent pathways are novel mechanisms that play a role in PH of various etiologies. Variants in the GCH1 gene, which have previously been identified as modulators of pain in other disease populations, are associated with increased risk of severe vaso-occlusive pain crises in a case control study. GCH1 is the rate limiting step for the synthesis of BH4 (tetrahydrobiopterin) which is an essential co-factor for the synthesis of nitric oxide, catecholamines, serotonin, and phenylalanine metabolism. In vitro, this GCH1 haplotype is associated with increased gene expression. We believe that this result indicates that this is a unique African haplotype associated with increased BH4 and increased pain. Surprisingly, this haplotype is not associated with pulmonary hypertension in SCD despite the biological suggestion that the African haplotype might promote nitric oxide production. Variants in the MYH9 gene are associated with decreased glomerular filtration rate in SCD. Genetic markers in the region of MYH9 on chromosome 22 have been identified as major risk factors for focal segmental glomerular sclerosis (FSGS) in African American populations. This association study extends this work to a disease specific patient population that is at high risk for renal insufficiency. Genetic association studies highlighted vaso-occlusive pain crises resulting in hospitalization as a phenotype of sickle cell anemia. Accordingly, the epidemiology of severe acute pain crises resulting in hospitalization has been reviewed in this cohort. One quarter of subjects with sickle cell anemia are not frequently hospitalized for pain (<1 per year), and more frequent pain crises are associated with low hemoglobin, low HDL, and higher LDH. Despite modern therapy for sickle cell anemia, more frequent pain crises remain a risk factor for early mortality. This mortality risk is independent of the previously described risk of death with an elevated TRV on echocardiogram. A genome wide association study of this pain phenotype in sickle cell anemia is in progress using an ancestry informative markers that were identified from the HapMap project. The phenotype defining cases in this study is >1 severe pain crisis per year which provides >80% statistical power to detect genome wide associations with a relative risk of 2 or higher.

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