Atorvastatin Therapy to Improve Endothelial Function in Sickle Cell Disease

ELIGIBILITY: All volunteer subjects must be at least 18 years of age and have provided informed, written consent for participation in this study. Eligibility in the study is determined prior to enrollment on the basis of the following inclusion and exclusion criteria. INCLUSION CRITERIA FOR CONTROLS: For each enrolled study patient with sickle cell disease, we will recruit an African-American healthy control subject of the same gender, within 3 years of age older or younger than the matched patient. INCLUSION CRITERIA FOR SICKLE CELL COHORT: Males or females 18 to 65 years of age. Diagnosis of sickle cell disease (electrophoretic or HPLC documentation of hemoglobin S only phenotype is required). Hemoglobin must be 6-9 g/dL with an absolute reticulocyte count greater than 95,000/microL, or hemoglobin greater than 9 g/dL with no requirement for reticulocyte count. Plasma soluble VCAM level above median value for sickle cell patients defined by assays performed in our laboratory on the blood of sickle cell patients seen in our program or tricuspid regurgitant jet velocity (determined by Doppler echocardiography) greater than 2.4 m/sec or has had a subnormal response to L-NMMA or sodium nitroprusside infusion on a previous forearm blood flow study. EXCLUSION CRITERIA FOR SICKLE CELL COHORT: Clinically unstable sickle cell disease defined as having an acute pain crisis within the last week. Current pregnancy or lactation. Conditions that may independently affect endothelial function: Diabetes mellitus or fasting blood sugar greater than 120 mg/dL Cigarette smoking within one month Hypertension (diastolic blood pressure greater than 90 mmHg) Serum creatinine greater than 1.5 mg/dL Serum alanine aminotransferase (ALT) greater than 3 times the upper limit of normal. (AST elevation will not be used as an exclusion criteria, since this is elevated in normal sickle cell patients due to red cell lysis, even without liver injury) Hemoglobin less than or equal to 6 g/dL; however, patients may return for evaluation at a later date. Recent transfusion (last 4 weeks). No aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) for one week and no caffeine the day of the study. Patients on opiates or acetaminophen will not be excluded. Subjects taking sildenafil, vardenafil, L-arginine, fibrates (e.g., clofibrate, gemfibrozil, or fenofribrate) or inhaled nitric oxide within the last week will be excluded from the study. Subjects taking any statin drug (e.g., fluvastatin, lovastatin, pravastatin, or simvastatin) within the last four weeks will be excluded from the study. Subjects taking drugs with known clinically significant metabolic interactions with statins (via metabolism through cytochrome P450 3A4): Ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, azithromycin, cyclosporine, tacrolimus, fibric acid derivatives, niacin (nicotinic acid). Subjects who have obstructive or vasospastic vascular disease. Subjects with significant cardiac disease and/or ECG abnormalities. Subjects with significant hypotension. Women who do not use two forms of birth control while participating in this study. EXCLUSION CRITERIA FOR CONTROLS: Current pregnancy or lactation. Conditions that may independently affect endothelial function: Diabetes mellitus or fasting blood sugar greater than 120 mg/dL Cigarette smoking within one month Hypertension (diastolic blood pressure greater than 90 mmHg) Serum creatinine greater than 1.5 mg/dL Serum alanine aminotransferase (ALT) greater than 3 times the upper limit of normal. Hemoglobin less than 12 g/dL; however, patients may return for evaluation at a later date. No aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) for one week and no caffeine the day of the study. Patients on opiates or acetaminophen will not be excluded. Subjects taking sildenafil, vardenafil, L-arginine, fibrates (e.g., clofibrate, gemfibrozil, or fenofribrate) or inhaled nitric oxide within the last week will be excluded from the study. Subjects taking any statin drug (e.g., fluvastatin, lovastatin, pravastatin, or simvastatin) within the last four weeks will be excluded from the study. Subjects who have obstructive or vasospastic vascular disease. Subjects with significant cardiac disease and/or ECG abnormalities. Subjects with significant hypotension. Subjects with any known form of hemolytic anemia, including sickle cell disease (Hb SS, SC, S-beta-thalassemia, or other known sickling syndromes; sickle trait will NOT be excluded).