Niacin to Improve Blood Flow in People With Sickle Cell Disease
Niacin to Improve Blood Flow in People With Sickle Cell Disease
This study will determine whether niacin can improve blood flow in people with sickle cell
 disease, in which abnormal red blood cells interfere with blood flow to cause the disease
 symptoms. Niacin, a drug that has been used to increase HDL (good cholesterol) levels,
 improves blood flow in people without sickle cell disease. This study will see if it can do
 the same in people with the disease.

 Patients with sickle cell disease between 18 and 65 years of age may be eligible for this
 study.

 Candidates are screened with a medical history, physical examination, blood tests,
 echocardiogram and 6-minute walk test of exercise capacity.

 Participants have the following baseline blood flow studies:

 -  Flow-mediated dilation (FMD): An ultrasound picture of the artery in the forearm is
 obtained. A blood pressure cuff is then placed on the upper arm and inflated for 5
 minutes. After the pressure cuff is released, the ultrasound is repeated.

 -  Peripheral artery tonometry (PAT): A sensor is placed on the subject s finger. The
 sensor puts pressure on the finger and measures blood flow.

 -  Standard forearm blood flow test: Small tubes are placed in the artery of the forearm at
 the inside of the elbow. Saline is infused into one tube. Pressure cuffs are applied to
 the wrist and upper arm. A strain gauge (rubber band device) is placed around the
 forearm. When the cuffs are inflated, blood flows into the arm, stretching the strain
 gauge, and the flow measurement is recorded. Blood samples are collected from the tube
 in the artery to measure blood counts, proteins and other chemicals. At various times,
 small doses of the following drugs are administered through the tube in the vein:

 -  Sodium nitroprusside causes blood vessels to dilate and increases blood flow to the
 heart.

 -  Acetylcholine causes blood vessels to dilate and slows heart rate.

 -  LNMMA decreases blood flow by blocking the production of nitric oxide.

 Blood flow is measured after each dose of the different drugs. There are rest periods between
 injections of the different drugs. Pictures of the forearm are taken during the studies using
 an infrared camera and computer.

 -Drug Treatment. Participants are assigned to take three 4-week courses of niacin or placebo.
 They return to the Clinical Center at the following intervals from the time they start the
 test drug for followup:

 -  Weeks 2, 6 and 10: Brief medical history, review of medication side effects and blood
 tests.

 -  Weeks 4 and 8: Physical examination, brief medical history, review of medication side
 effects and blood tests, repeat FMD and PAT blood flow studies and 6-minute walk test.

 -  Week 12: Same as weeks 4 and 8 plus standard blood flow studies and echocardiogram.
Sickle cell disease is an autosomal recessive disorder and the most common genetic disease
 affecting African-Americans. Approximately 0.15 percent of African-Americans are homozygous
 for sickle cell disease, and 8 percent 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 percent of sickle cell patients have
 vascular dysfunction due to impaired bioavailability of endogenous nitric oxide, due in large
 part to scavenging of nitric oxide by cell-free hemoglobin. We recently have completed
 studies that directly demonstrate endothelial dysfunction in patients with sickle cell
 disease, characterized by decreased ACh dependent vasorelaxation in forearm blood flow
 studies, distinct from the nitric oxide resistance above. Further, we have found in sickle
 cell patients a new association between low levels of apoA-I, pulmonary hypertension and
 endothelial dysfunction. Raising levels of HDL, and therefore apoA-1, could have the effect
 of ameliorating the endothelial dysfunction characteristic of sickle cell disease by
 affecting endothelium dependent vasorelaxation. Therapies directed at restoring HDL in these
 patients may be beneficial.

 HDL is thought to promote vascular health in a variety of ways, some of which are unrelated
 to lipid transport. One of the best-known mechanisms relates to efflux of cholesterol from
 atherosclerotic plaque, yet HDL is thought to have several antithrombotic and
 anti-inflammatory effects. In vitro HDL attenuates formation of oxidized LDL and inhibits
 endothelial cell expression of inflammatory cell adhesion molecules. It is also thought to
 mediate NO production via stimulation of eNOS, thereby modulating endothelial function. In a
 study of subjects with atherosclerosis, low HDL levels correlated with impaired vasomotor
 relaxation via brachial artery FMD. Another study utilizing recombinant HDL cholesterol
 infused into brachial arteries of hypercholesterolemic men resulted in increased
 acetylcholine mediated blood flow that was inhibited by the infusion of L-NAME, an eNOS
 inhibitor, suggesting that HDL increased blood flow via an eNOS dependent mechanism. This may
 have implications not only for subjects with atherosclerosis, but also for those with sickle
 cell disease and endothelial dysfunction.

 We propose that niacin therapy could improve vascular reactivity in response to
 acetylcholine. Several options for increasing HDL levels have been previously utilized in
 forearm flow studies using venous occlusion plethysmography or flow-mediated dilation.
 Reconstituted HDL (rHDL), apoA-1 mimetics and niacin therapy were all shown to improve
 endothelial dysfunction, and proved safe and effective.

 This trial will aim to 1) establish the effects of niacin treatment on raising HDL levels in
 subjects with sickle cell disease, 2) investigate whether niacin treatment would result in
 improvement of endothelial-dependent relaxation via venous occlusion plethysmography, and 3)
 compare the efficacy of peripheral arterial tonometry measurements to venous occlusion
 plethysmography and flow-mediated dilation as indicators of vascular dysfunction.
-  INCLUSION CRITERIA:

 -  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 greater than 5.5 grams per deciliter

 -  Absolute reticulocyte count greater than 95,000 microliters if hemoglobin is less than
 9.0 grams per deciliter.

 -  An apoA-1 level lower than 99 milligrams per deciliter (median value among sickle cell
 subjects), or HDL-C level below 39 milligrams per deciliter (median value amongst our
 sickle cell cohort).

 EXCLUSION CRITERIA:

 -  Acute pain crisis requiring intravenous analgesics within the last week.

 -  Current pregnancy or lactation.

 -  Hemoglobin SC disease, or hemoglobin A greater than 20%

 -  Conditions that may independently affect endothelial function:

 1. Diabetes mellitus

 2. Cigarette smoking within one month

 3. Uncontrolled hypertension

 -  Serum creatinine greater than 2.0 milligram per deciliter

 -  Serum alanine aminotransferase (ALT) greater than 3 times the upper limit of normal.
 (AST elevation will not be used as an exclusion criterion, since this is elevated in
 normal sickle cell subjects due to red cell lysis, even without liver injury)

 -  Uric acid level greater than 8 or history of gout

 -  History of GI bleeding within the past 6 months

 -  Active peptic ulcer disease

 -  Hemoglobin less than or equal to 5.5 grams per deciliter; however, subjects may return
 for evaluation at a later date.

 -  No aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) for 1 week prior to
 forearm blood flow assessment and no caffeine the day of each forearm blood flow
 study. Subjects on opiates or acetaminophen will not be excluded.

 -  Subjects taking sildenafil, vardenafil, tadalafil, 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,
 simvastatin, rosuvastatin) within the last four weeks will be excluded from the study.

 -  Subjects taking prostaglandins such as epoprostenol or treprostinil will be excluded
 from the study.

 -  Subjects with significant cardiac disease and/or known peripheral Arterial disease.

 -  Subjects with significant hypotension.

 -  Women who do not use birth control while participating in this study.