Niacin therapy to improve endothelial function in Sickle Cell Disease

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Over the last few years, data has been published by several groups, including our own, indicating that vascular smooth muscle is dysfunctional in patients with sickle cell disease. The etiology of this vascular dysfunction is undoubtedly multifactorial, though our group has demonstrated considerable evidence for a mechanism involving consumption of nitric oxide by cell-free plasma hemoglobin released during intravascular hemolysis. We recently have completed studies that directly demonstrate endothelial dysfunction in patients with sickle cell disease, a dysfunction characterized by decreased ACh dependent vasorelaxation in forearm blood flow studies, and that is distinct from the nitric oxide resistance mechanism mentioned above. Further, we have found in sickle cell patients a new association between low levels of apoA-l, pulmonary hypertension and endothelial dysfunction. Raising levels of HDL and therefore apoA-l, 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. We propose a forearm blood flow physiology study with Niaspan, a slow release form of niacin, previously reported to increase high density lipoprotein (HDL) and apo A-l levels. The specific aims of this study are: (1) To determine whether orally administered Niaspan significantly increases HDL levels in patients with sickle cell disease (primary endpoint). (2) To determine whether orally administered Niaspan significantly increases acetylcholine-stimulated blood flow in patients with sickle cell disease (secondary endpoint), and (3) To determine whether plasma markers of endothelial dysfunction are significantly changed by orally administered Niaspan. Thirty-five adult patients with Hb SS or SbO-thalassemia will be enrolled. To increase the likelihood that subjects will have endothelial dysfunction at study entry, we will try to recruit subjects found by previous studies to have a lower than average apoA-l level of < 89 mg/dL or HDL < 39 mg/dL. After baseline forearm blood flow measurements patients will be started on a 3 month course of niacin therapy, and have scheduled clinic visits for history and physicals, dose titration (to a maximum of 1500 mg Niacin-ER daily), pill counts, and laboratory tests. After 3 months of this treatment, blood sampling to determine the primary endpoint (increased HDL), and forearm blood flow testing will be repeated.