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 hypothesized to be significantly increased as compared to patients without pulmonary hypertension. We have enrolled 374 patients in a study of the prevalence and prognosis of patients with sickle cell disease and pulmonary hypertension. All patients 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. Patients were followed for a mean of 18 months and censored at time of death or loss to follow-up. 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, 32% of patients with sickle cell disease have elevated pulmonary artery systolic pressures (TRV >= 2.5 m/sec) and 9% have severely elevated pressures. Multiple-regression analysis identified increasing age, increased serum markers of hemolysis (LDH, total bilirubin) and arginine/ornithine ratio as significant independent predictors of pulmonary hypertension. Fetal hemoglobin levels did not predict pulmonary hypertension nor did hydroxyurea therapy modify pulmonary pressures. Left ventricular dysfunction was rarely observed (< 2% of patients) and calculated pulmonary artery systolic pressures based on TRV accurately predicted measured values during right heart catheterization (r=0.98; p=0.001). 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 be resistant to hydroxyurea therapy, is linked to hemolysis and is associated with a high 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. Patients continue to be enrolled in this trial and referred for treatment studies if identified with pulmonary hypertension. We have also enrolled 52 African American controls to determine the normal range of tricuspid regurgitant jet velocity who serve as a comparison for the sickle cell population being studied.
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