BACKGROUND:Cholesterol-lowering therapy can improve cardiovascular morbidity and mortality in patients with atherosclerosis. Although the mechanisms responsible are unclear, these benefits precede macroscopic changes in the vasculature. Emerging evidence that improvement in endothelial function may occur requires substantiation; in particular, it is unclear how early any such improvement would be detectable after initiation of therapy. METHODS AND RESULTS: This randomized, double-blind, placebo-controlled crossover study evaluated the effect of simvastatin (20 mg daily for 4 weeks) on endothelium-dependent and endothelium-independent vasodilation and on the response to the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (L-NMMA), in the forearm vasculature of subjects with moderate elevation of total serum cholesterol (6.0 to 10.0 mmol/L) by use of strain-gauge plethysmography. Studies were repeated after 3 more months of open therapy. When the results are expressed as percentage changes in flow in the infused arm relative to the noninfused arm, the vasodilator response to acetylcholine was significantly increased after 4 weeks of treatment with simvastatin (P < .0005), and this improvement was further enhanced after 3 months (P < .005). Concurrently, simvastatin augmented the vasoconstrictor response to L-NMMA, an effect that was maintained at 3 months (P < .0005). The response to the endothelium-independent vasodilator sodium nitroprusside was unaltered. CONCLUSIONS: These observations indicate that within 1 month of treatment with simvastatin, both the stimulated and basal nitric oxide dilator functions of the endothelium are augmented, and the benefits of this HMG-coenzyme A reductase inhibitor persist with continued therapy.
RCT Entities:
BACKGROUND:Cholesterol-lowering therapy can improve cardiovascular morbidity and mortality in patients with atherosclerosis. Although the mechanisms responsible are unclear, these benefits precede macroscopic changes in the vasculature. Emerging evidence that improvement in endothelial function may occur requires substantiation; in particular, it is unclear how early any such improvement would be detectable after initiation of therapy. METHODS AND RESULTS: This randomized, double-blind, placebo-controlled crossover study evaluated the effect of simvastatin (20 mg daily for 4 weeks) on endothelium-dependent and endothelium-independent vasodilation and on the response to the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (L-NMMA), in the forearm vasculature of subjects with moderate elevation of total serum cholesterol (6.0 to 10.0 mmol/L) by use of strain-gauge plethysmography. Studies were repeated after 3 more months of open therapy. When the results are expressed as percentage changes in flow in the infused arm relative to the noninfused arm, the vasodilator response to acetylcholine was significantly increased after 4 weeks of treatment with simvastatin (P < .0005), and this improvement was further enhanced after 3 months (P < .005). Concurrently, simvastatin augmented the vasoconstrictor response to L-NMMA, an effect that was maintained at 3 months (P < .0005). The response to the endothelium-independent vasodilator sodium nitroprusside was unaltered. CONCLUSIONS: These observations indicate that within 1 month of treatment with simvastatin, both the stimulated and basal nitric oxide dilator functions of the endothelium are augmented, and the benefits of this HMG-coenzyme A reductase inhibitor persist with continued therapy.