Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks

OBJECTIVES We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. BACKGROUND Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. METHODS In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 ± 11 yrs) with low density lipoprotein cholesterol ≥160 mg/dl (196 ± 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 μg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 μg/min). RESULTS Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin −33 ± 4% vs. placebo + 2 ± 4%, x ± SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 μg/min: + 22.3 ± 5.2 vs. + 11.2 ± 1.9 ml/min/100 ml, p < 0.01; ACh 48 μg/min: +31.2 ± 6.3 vs. +19.1 ± 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 μg/min: +12.9 ± 3.6 vs. +9.0 ± 1.9 ml/min/100 ml, NS; ACh 48 μg/min: +20.7 ± 3.7 vs. 19.4 ± 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 μg/min: +203 ± 85% [cerivastatin] vs. −26 ± 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 μg/min + N(G)-monomethyl-L-arginine 4 μmol/min −48 ± 85% [cerivastatin]). CONCLUSIONS Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.