Does Lipoprotein(a) Impair Endothelial Function?

Objectives. This study was undertaken to test the hypothesis that lipoprotein(a) [Lp(a)] impairs endothelial function. Background. Elevated Lp(a) plasm levels have been demonstrated to be associated with an increased risk of coronary heart disease. In atherosclerosis, endothelial dysfunction is known to be an early indicator of vascular changes. However, the effect of Lp(a) on nitric oxide (NO)-dependent vasodilator response has not yet been determined. We therefore examined the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm vascular bed. Methods. Strain gauge plethysmography was used to measure changes in forearm blood flow produced by intraarterial infusion of increasing doses of acetylcholine (3, 12, 24 and 48 μg/min), sodium nitroprusside (200, 800 and 3,200 ng/min) and N-monomethyl image-arginine (image-NMMA) (1, 2 and 4 μmol/min) in 57 white subjects (mean age ± SD 37 ± 14 years). Lp(a) plasm concentrations were determined by rocket immunoelectrophoresis. Results. Endothelium-dependent vasodilation tested by intraarterial acetylcholine and endothelium-independent vascular relaxation tested by intraarterial sodium nitroprusside were not correlated with Lp(a). Similarly, no significant differences in forearm blood flow changes were observed when patients were classified into tertiles according to their individual Lp(a) concentration. In contrast, changes in forearm blood flow after intraarterial image-NMM indicating basal production and release of NO differed significantly among tertiles. Patients in the highest Lp(a) tertile (49.2 ± 20.3 mg/dl) had much greater vasoconstrictive response to image-NMM than patients in the lowest Lp(a) tertile (4.8 ± 2.5 mg/dl): 2 μmol/min of image-NMMA, −23.6 ± 22.5% vs. −10.4 ± 9.1% (p < 0.02); 4 μmol/min of image-NMMA, −27.8 ± 10.3% vs. −17.6 ± 9.9% (p < 0.03). Lp(a) plasm level consistently correlated negatively with the forearm blood flow responses to 4 μmol/min of intraarterial image-NMM (r = −0.38, p < 0.01). Multiple stepwise regression analysis of variables, including total and high and low density lipoprotein cholesterol, further confirmed that plasm Lp(a) remained significant independent determinant of forearm blood flow changes in response to image-NMM (p < 0.02). Conclusions. The endothelium-dependent vasoconstrictive response to image-NMM was enhanced in subjects with relatively high Lp(a) plasm levels, suggesting an increased basal production and release of NO. This response seemed to reflect compensatory mechanism of the endothelium to yet unknown Lp(a)-induced atherosclerotic effects.