Effect of antioxidant vitamins on low density lipoprotein oxidation and impaired endothelium-dependent vasodilation in patients with hypercholesterolemia

OBJECTIVES: The aims of this study were to determine whether antioxidant vitamins could reduce the susceptibility of low density lipoprotein (LDL) to oxidation and improve endothelium-dependent vasodilator responsiveness in patients with hypercholesterolemia. BACKGROUND: Animals and humans with hypercholesterolemia have exhibited impaired endothelium-dependent vasodilation. In vitro studies suggest that oxidatively modified LDL can impair nitric oxide production. METHODS: Forearm blood flow was measured with strain gauge plethysmography and brachial artery drug infusions in 19 patients, aged 52 +/- 9 years, with hypercholesterolemia (mean +/- SD total cholesterol 283 +/- 22 mg/dl, LDL 197 +/- 31 mg/dl) and in 14 subjects, aged 48 +/- 8 years, with normal cholesterol levels (total cholesterol 169 +/- 20 mg/dl, LDL 102 +/- 25 mg/dl). Acetylcholine (7.5, 15 and 30 micrograms/min) was utilized as an endothelium-dependent vasodilator, and sodium nitroprusside (0.8, 1.6 and 3.2 micrograms/min) was used to test endothelium-independent vasodilation. Oxidative susceptibility of LDL was measured by a spectrophotometric assay of conjugated diene production after the addition of copper chloride. Hypercholesterolemic patients then received daily antioxidant vitamin supplements (beta-carotene [30 mg], ascorbic acid [vitamin C] [1,000 mg], vitamin E [800 IU]) for 1 month, with repeat measurement of both forearm blood flow responsiveness to the same agonists and LDL oxidizability. RESULTS: The maximal flow in response to acetylcholine was impaired in patients compared with that in normal subjects (9.8 +/- 7.8 vs. 15.9 +/- 8.1 ml/min per 100 ml, p = 0.03), with similar maximal flow responses to sodium nitroprusside (9.5 +/- 4.2 vs. 9.0 +/- 2.8 ml/min per 100 ml, p = 0.72). After 1 month of vitamin therapy, the onset of LDL oxidation was prolonged over baseline measurements by 71 +/- 67%, and the maximal rate of oxidation was decreased by 26 +/- 25% (both p < 0.001). However, the maximal forearm blood flow response to acetylcholine remained unchanged from baseline values (maximal flow after acetylcholine 9.0 +/- 6.2 vs. 9.8 +/- 7.8 ml/min per 100 ml, p = 0.57). This study had 80% power (alpha = 0.05) to exclude a 45% increase over baseline value in acetylcholine-stimulated flow during vitamin therapy. CONCLUSIONS: Although 1 month of administration of antioxidant vitamin supplements in hypercholesterolemic patients reduced the susceptibility of LDL to oxidation, impairment in endothelial function remained unaltered. The use of nonvitamin antioxidants or concomitant reduction in LDL levels, as well as more sensitive techniques for measuring vascular responsiveness, may be required to show a beneficial effect on endothelial vasodilator function.