Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low

Background—Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for familial hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these familial hypoalphalipopro-teinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results—In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and-independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase NG-monomethyl-L-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.40.2 mmol/L; P0.05), and their forearm blood flow responses to both 5HT (maximum, 49.010.4%) and L-NMMA (maximum, 22.822.9%) were blunted compared with control subjects (both P0.005). Infusion of apoA-I/PC disks increased plasma HDL to 1.30.4 mmol/L in ABCA1 heterozygotes, which resulted in complete restoration of vasomotor responses to both 5HT and L-NMMA (both P0.001). Endothelium-independent vasodilation remained unaltered throughout the protocol. Conclusions—In ABCA1 heterozygotes, isolated low HDL is associated with endothelial dysfunction, attested to b