Atorvastatin Therapy to Improve Endothelial Function in Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will examine the effects of oral atorvastatin on the linings of blood vessels in
      patients with sickle cell disease, plus the agent's effect on blood markers of inflammation
      and blood vessel function. Sickle cell disease is a recessive genetic disorder and the most
      common genetic disease affecting African Americans. Inherited are abnormal genes that make
      hemoglobin, the substance within red blood cells that carries oxygen from the lungs to the
      body. In the disease, sickle hemoglobin leads to rigidity or hardness of the red cells,
      causing obstruction in small blood vessels, inflammation, and injury to organs when the flow
      of blood to them is blocked. Some medications already prescribed for other diseases, such as
      atorvastatin, which is used for lowering cholesterol levels, can improve blood flow.

      Patients 18 to 65 years of age who have sickle cell disease, who have not had an acute pain
      episode within the previous week, and who are not pregnant or lactating may be eligible for
      this study. They will undergo a complete medical history; physical examination; baseline
      blood tests; and echocardiogram, in which an ultrasound wand is placed against the chest wall
      to get images inside the heart and blood vessels.

      In addition, patients will have blood flow studies. During the procedure, they will lie in an
      adjustable reclining chair for 5 to 6 hours. There will be 20- to 30-minute rests between
      specific activities and blood samples will be drawn intermittently for testing. Small tubes
      will be placed in the artery of the forearm at the inside of the elbow. Normal saline will be
      infused into one tube. A small pressure cuff will be applied to the wrist and a larger cuff
      to the upper arm. Both cuffs will be attached to an inflation device. A device like a rubber
      band, a strain gauge, will be placed around the widest part of the forearm. When the pressure
      cuffs are inflated, blood will flow into the arm, stretching the gauge proportion to blood
      flow, and information will be recorded. Then light reflected from the patients' hand and the
      blood flow in the forearm will be measured. Activity of the genes in the white blood cells
      will be measured as well. Small amounts of sodium nitroprusside, widely used to reduce blood
      pressure in people with dangerously high blood pressure, will be injected and blood flow will
      be measured. Later, small amounts of acetylcholine will be injected. It usually causes blood
      vessels to expand. After that, small amounts of L-NMMA will be injected. It usually decreases
      local blood flow by blocking the production of nitric oxide in the cells lining the arm's
      blood vessels. Then acetylcholine combined with L-NMMA will be injected. After that,
      oxypurinol, an agent taken by many patients to prevent gout, will be injected. The procedures
      will be repeated, with oxypurinol given along with each of the agents, and the measurement of
      blood flow in the forearm will be measured after each drug combination.

      Afterward, patients will be treated for 4 weeks at home with oral atorvastatin. They will be
      asked to visit the Clinical Center every 2 weeks for collection of blood samples and an
      examination. After 4 weeks of taking atorvastatin orally, they will be asked to return to
      repeat the blood flow studies, but only the first half will be conducted. The part using
      oxypurinol will not be needed. Regarding some of the blood samples collected during the
      study, there will be an examination of the genes found in the white blood cells. Specific
      attention will go to those genes that make proteins for cell-to-cell interaction and
      inflammation, plus those that cause blood cells to stick to the lining of blood vessels.
    

Detailed description: 
      Sickle cell disease is an autosomal recessive disorder and the most common genetic disease
      affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for
      sickle cell disease, and 8% have sickle cell trait. Hemoglobin S polymerization leads to red
      cell rigidity, microvascular obstruction, inflammation, and end-organ ischemic injury. Our
      published data indicate that up to 50% of sickle cell patients have endothelial dysfunction
      due to impaired bioavailability of endogenous nitric oxide. Our studies indicate that this is
      due in large part to scavenging of nitric oxide by cell-free hemoglobin, with additional
      nitric oxide inactivation by superoxide. This suggests that therapies directed at restoring
      NO bioavailability might be beneficial. In patients with atherosclerotic vascular disease,
      the statin family of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors significantly
      reduce stroke and myocardial infarction and restore endothelial-dependent relaxation of
      conducting arteries. Furthermore, statin therapy has now been clearly shown to reduce
      C-reactive protein levels and clinical events in patients with coronary artery disease
      independent of the effects on lipoproteins. The ability of statins to correct vascular
      inflammation and endothelial dysfunction makes this class of agents attractive to attempt to
      reverse these features of sickle cell pathobiology. This trial will aim to 1) establish the
      effects of oral atorvastatin treatment on endothelial-dependent relaxation in patients with
      sickle cell disease and endothelial dysfunction; 2) establish the effect of therapy on
      peripheral blood markers of inflammation and vascular function, and peripheral blood proteome
      and transcriptome profiles; and 3) investigate whether superoxide produced through xanthine
      oxidase limits nitric oxide bioavailability in patients with sickle cell disease.

      In order to control for the possibility that advancing age, gender and ethnicity may
      influence vascular reactivity, we will also enroll age and gender-matched African-American
      controls in the baseline forearm blood flow portion of this study.
    

Intervention name(s): Oxypurinol; L-NMMA; Acetylcholine
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Acetylcholine; Oxypurinol
Primary purpose: Treatment
Keywords: 3-hydroxy-3-methlglutaryl (HMG); Inhibitors; Endothelial Function; Leukocyte Gene Expression; Statins; Atorvastatin; Sickle Cell Disease