Sickle Cell Disease Clinical Trial
Official title:
Atorvastatin Therapy To Improve Endothelial Function in Sickle Cell Disease
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.
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.
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