Published online before print May 2, 2005, doi: 10.1161/01.CIR.0000164260.82417.3F
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(Circulation. 2005;111:2356-2363.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Simvastatin Versus Ezetimibe
Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans
From Abteilung Kardiologie und Angiologie (U.L., M.M., S.S., N.K., S.S., C.M., D. Fischer, H.D.) and Abteilung Nephrologie (F.B., K.d.G., D. Fliser), Medizinische Hochschule Hannover, Hannover, Germany, and Clinical Institute of Medical and Chemical Laboratory Diagnostics (G.F., W.M.), Medical University of Graz, Graz, Austria.
Correspondence to Ulf Landmesser, MD, Medizinische Hochschule Hannover, Abteilung Kardiologie und Angiologie, Carl Neuberg Str 1, 30625 Hannover, Germany. E-mail Landmesser.Ulf{at}MH-Hannover.de
Received October 5, 2004; revision received January 23, 2005; accepted January 26, 2005.
Background— Statins may exert important pleiotropic effects, ie, improve endothelial function, independently of their impact on LDL cholesterol. In humans, however, pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels. We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe, a novel cholesterol absorption inhibitor, result in different effects on endothelial function.
Methods and Results— Twenty patients with chronic heart failure were randomized to 4 weeks of simvastatin (10 mg/d) or ezetimibe (10 mg/d) treatment. Flow-dependent dilation (FDD) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals (
FDD-VC). Activity of extracellular superoxide dismutase, a major vascular antioxidant enzyme system, was determined after release from the endothelium by a heparin bolus injection. Endothelial progenitor cells were analyzed with an in vitro assay. Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent (15.6% versus 15.4%; P=NS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (mevalonate-simvastatin, –1.04±0.62 versus mevalonate-ezetimibe, 1.79±0.94 ng/mL; P<0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5±0.6% versus 5.1±0.7%; P<0.01) but not after ezetimibe treatment (5.6±0.5% versus 5.8±0.6%; P=NS). FDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by >100% (P<0.05) after simvastatin but not ezetimibe treatment. Simvastatin treatment increased the number of functionally active endothelial progenitor cells, whereas ezetimibe had no effect.
Conclusions— Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering, at least in part by reducing oxidant stress. Simvastatin may thereby exert important pleiotropic effects in humans.
Key Words: endothelium • stem cells • heart failure • statins • superoxide dismutase
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