Niacin Therapy to Improve Endothelial Function in 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.