Niacin to Improve Blood Flow in People With Sickle Cell Disease

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.