For more than a century, evidence has continued to accumulate supporting the pivotal role of cholesterol in the pathogenesis of atherosclerotic cardiovascular disease (CVD). The fi nding of a curvilinear relationship between systemic levels of LDL cholesterol (LDL-C) and prospective cardiovascular risk in population studies ( 1 ) and unequivocal clinical benefi t of therapies that lower LDL-C ( 2 ) have prompted its central role in the approach to risk prediction and preventive strategies. However, the fi nding that many patients with established CVD have normal LDL-C levels and no identifi able risk factor suggests that additional factors are likely to play a contributory role in promoting cardiovascular risk.A number of additional lipid risk factors have been proposed to be independently associated with CVD. Lipoprotein (a) [Lp(a)] contains apolipoprotein (apo)B-100, linked by a disulfi de bond to apo(a). Data supports the idea that Lp(a) possesses potent atherogenic and thrombogenic properties ( 3-6 ). This is likely to be derived not only from the presence of apoB-100, but also due to the presence of a kringle structure with remarkable homology to plasminogen, which may alter hemostatic activity. Although epidemiologic studies have reported variable fi ndings with regard to the relationship between Lp(a) levels and cardiovascular risk ( 7-18 ), it was recently reported that genetic polymorphisms associated with elevated Lp(a) levels are associated with an excessive rate of myocardial infarction (19)(20)(21)(22). This implicates a direct role for Lp(a) in acute thrombotic/ischemic events. In addition, accumulating evidence suggests a relationship between apo(a) isoform size and both Lp(a) levels and cardiovascular risk ( 23 ). Supplementary key words atherosclerosis • risk factor • coronary angiographyThis study was supported

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Through bound apolipoprotein A-I (apoA-I), high density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD)have low apoA-I andendothelial dysfunction,we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C, and improves vascular function in SCD. Twenty-seven SCD patientswith HDL-C <39 mg/dL or apoA-I <99 mg/dL were randomized to 12 weeks of niacin-ER, increased in 500mg increments to a maximum of 1500mg daily, or placebo. The primary outcome was the absolute change in HDL-C after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C compared with placebo treatment at 12 weeks (5.1±7.7 vs. 0.9±3.8 mg/dL, one-tailed p=0.07), associated with significantly greater, improvements in the ratios of low-density lipoprotein to HDL-C (1.24 vs. 1.95, p = 0.003), and apolipoprotein B to apoA-I (0.46 vs. 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in three independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C.