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 449 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. We performed and analyzed Doppler echocardiographic assessments of pulmonary artery systolic pressure in 235 consecutive patients (mean age=37.11 years). Doppler-defined pulmonary hypertension occurred in 32 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, 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. 491 subjects have enrolled in this study to date and we continue to enroll approximately 8 new subjects per month. Subjects continue to be enrolled in this trial and referred for treatment studies if identified with pulmonary hypertension. We have also enrolled 66 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. The two tests below were added and are currently being performed on all initial visits and on follow-up visits occurring at 2, 4, 6, etc. years: (1) Peripheral Arterial Tonometry (PAT) (ENDO-PAT 2000, Itamar Medical) is a relatively new, FDA-approved noninvasive technology that captures a beat-to-beat plethysmographic recording of the finger arterial pulse wave activity with pneumatic probes. The PAT score (ratio of finger blood flow amplitude before and after blood flow occlusion) will be analyzed for correlation with tricuspid regurgitant jet velocity, as well as other clinical laboratory and research markers obtainned in this study. This is a hypothesis generating analysis for future potential studies. (2) The passive infrared photography may be administered to subjects enrolled in this protocol. A non-invasive, real-time, in vivo imaging system has been developed for directly determining the spatial distributions of blood flow, by measuring the emission infrared emission from the skin of an individual. During Infrared (IR) photography images will be collected during 7-20 min and analyzed using imaging software. The software is capable of extracting temperature variations from collected 3D image cube and to identify for any chosen region of interest the low frequency temperature oscillations (0.017 Hz) using Fast Fourier Transformation and Wavelet analysis. Calculated power spectrum will reflect frequencies at which blood flow oscillates. At the end of analysis, a synthesized image will represent the spatial distribution and amplitude of oscillations at a given frequency. Such very low frequency oscillations have been characterized by laser Doppler flowmetry (point measurement) as related to endothelial function, NO dependent, increased with cholinergic stimulation, and potential to be a noninvasive marker for NO-dependent microvascular reactivity. IR photography is a passive method, provides a new information on spatial extend of flow oscillation and more safe and easy to use in the clinic. This year we added the Pittsburgh Sleep Quality Index and Beck Depression Inventory: This is being used to assess the co-morbidity of depression and sleep disturbances of subjects with and without pulmonary hypertension. The subjects receive both The Pittsburgh Sleep Quality Index (PSQI) questionnaire and the Beck Depression Inventory questionnaire upon initial evaluation or their scheduled follow-up visit every 2 years. They are asked to complete the BDI questionnaire in clinic and return it to a member of the study team. That questionnaire is then scored while the subjects are in clinic and Dr. Jeffrey Schulden is in clinic to see any subject whose responses indicate tendency toward depression or suicidal ideation. The PSQI questionnaire may be completed in clinic or taken home, completed and returned to us by mail.
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