Published Online
on May 2, 2005

A more recent version of this article appeared on May 10, 2005

This Article Full Text (PDF) All Versions of this Article: 111/18/2356    most recent 01.CIR.0000164260.82417.3Fv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Landmesser, U. Articles by Drexler, H. Search for Related Content PubMed PubMed Citation Articles by Landmesser, U. Articles by Drexler, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ASCORBIC ACID SODIUM ASCORBATE Related Collections Congestive Endothelium/vascular type/nitric oxide Related Article

Submitted on October 5, 2004
Revised on January 23, 2005
Accepted on January 26, 2005

Simvastatin Versus Ezetimibe. Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans

Ulf Landmesser MD^*, Ferdinand Bahlmann MD, Maja Mueller BS, Stephan Spiekermann MD, Nina Kirchhoff BS, Svenja Schulz BS, Costantina Manes MD, PhD, Dieter Fischer MD, Kirsten de Groot MD, Danilo Fliser MD, Günter Fauler MD, Winfried März MD, and Helmut Drexler MD

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.

^* To whom correspondence should be addressed. E-mail: Landmesser.Ulf{at}MH-Hannover.de.

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

Related Article:

Clinical Significance of Statin Pleiotropic Effects: Hypotheses Versus Evidence

Michael H. Davidson
Circulation 2005 111: 2280-2281. [Full Text]

This article has been cited by other articles:

				M. Settergren, F. Bohm, L. Ryden, and J. Pernow Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease Eur. Heart J., July 2, 2008; 29(14): 1753 - 1760. [Abstract] [Full Text] [PDF]

				S. Kinlay Vascular form and function: two mechanisms for cardiovascular prevention Eur. Heart J., July 2, 2008; 29(14): 1711 - 1713. [Full Text] [PDF]

				L. G. Mikael and R. Rozen Homocysteine modulates the effect of simvastatin on expression of ApoA-I and NF-{kappa}B/iNOS Cardiovasc Res, July 1, 2008; (2008) cvn157v2. [Abstract] [Full Text] [PDF]

				A. Kourliouros, A. De Souza, N. Roberts, A. Marciniak, A. Tsiouris, O. Valencia, J. Camm, and M. Jahangiri Dose-related effect of statins on atrial fibrillation after cardiac surgery. Ann. Thorac. Surg., May 1, 2008; 85(5): 1515 - 1520. [Abstract] [Full Text] [PDF]

				B. A. Golomb, J. E. Dimsdale, H. L. White, J. B. Ritchie, and M. H. Criqui Reduction in Blood Pressure With Statins: Results From the UCSD Statin Study, a Randomized Trial Arch Intern Med, April 14, 2008; 168(7): 721 - 727. [Abstract] [Full Text] [PDF]

				J. J.P. Kastelein, F. Akdim, E. S.G. Stroes, A. H. Zwinderman, M. L. Bots, A. F.H. Stalenhoef, F. L.J. Visseren, E. J.G. Sijbrands, M. D. Trip, E. A. Stein, et al. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia N. Engl. J. Med., April 3, 2008; 358(14): 1431 - 1443. [Abstract] [Full Text] [PDF]

				S. Yagi, K.-i. Aihara, Y. Ikeda, Y. Sumitomo, S. Yoshida, T. Ise, T. Iwase, K. Ishikawa, H. Azuma, M. Akaike, et al. Pitavastatin, an HMG-CoA Reductase Inhibitor, Exerts eNOS-Independent Protective Actions Against Angiotensin II Induced Cardiovascular Remodeling and Renal Insufficiency Circ. Res., January 4, 2008; 102(1): 68 - 76. [Abstract] [Full Text] [PDF]

				K. M. Maki-Petaja, A. D. Booth, F. C. Hall, S. M.L. Wallace, J. Brown, C. M. McEniery, and I. B. Wilkinson Ezetimibe and Simvastatin Reduce Inflammation, Disease Activity, and Aortic Stiffness and Improve Endothelial Function in Rheumatoid Arthritis J. Am. Coll. Cardiol., August 28, 2007; 50(9): 852 - 858. [Abstract] [Full Text] [PDF]

				J. Afilalo, A. A Majdan, and M. J Eisenberg Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials Heart, August 1, 2007; 93(8): 914 - 921. [Abstract] [Full Text] [PDF]

				M. Piorkowski, S. Fischer, C. Stellbaum, M. Jaster, P. Martus, A. J. Morguet, H.-P. Schultheiss, and U. Rauch Treatment With Ezetimibe Plus Low-Dose Atorvastatin Compared With Higher-Dose Atorvastatin Alone: Is Sufficient Cholesterol-Lowering Enough to Inhibit Platelets? J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1035 - 1042. [Abstract] [Full Text] [PDF]

				C H Strey, J M Young, J H Lainchbury, C M Frampton, M G Nicholls, A M Richards, and R S Scott Short-term statin treatment improves endothelial function and neurohormonal imbalance in normocholesterolaemic patients with non-ischaemic heart failure Heart, November 1, 2006; 92(11): 1603 - 1609. [Abstract] [Full Text] [PDF]

				D. Hilfiker-Kleiner, U. Landmesser, and H. Drexler Molecular Mechanisms in Heart Failure: Focus on Cardiac Hypertrophy, Inflammation, Angiogenesis, and Apoptosis J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A56 - A66. [Abstract] [Full Text] [PDF]

				T. Lenderink, E. Boersma, A. K. Gitt, U. Zeymer, L. Wallentin, F. Van de Werf, D. Hasdai, S. Behar, and M. L. Simoons Patients using statin treatment within 24 h after admission for ST-elevation acute coronary syndromes had lower mortality than non-users: a report from the first Euro Heart Survey on acute coronary syndromes Eur. Heart J., August 1, 2006; 27(15): 1799 - 1804. [Abstract] [Full Text] [PDF]

				P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen Statins in the treatment of chronic heart failure: Biological and clinical considerations Cardiovasc Res, August 1, 2006; 71(3): 443 - 454. [Abstract] [Full Text] [PDF]

				S. Fichtlscherer, C. Schmidt-Lucke, S. Bojunga, L. Rossig, C. Heeschen, S. Dimmeler, and A. M. Zeiher Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for 'pleiotropic' functions of statin therapy Eur. Heart J., May 2, 2006; 27(10): 1182 - 1190. [Abstract] [Full Text] [PDF]

				R. Paumelle, C. Blanquart, O. Briand, O. Barbier, C. Duhem, G. Woerly, F. Percevault, J.-C. Fruchart, D. Dombrowicz, C. Glineur, et al. Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator-Activated Receptor-{alpha} via Inhibition of the Protein Kinase C Signaling Pathway Circ. Res., February 17, 2006; 98(3): 361 - 369. [Abstract] [Full Text] [PDF]

				Y. Rikitake and J. K. Liao Rho GTPases, Statins, and Nitric Oxide Circ. Res., December 9, 2005; 97(12): 1232 - 1235. [Abstract] [Full Text] [PDF]

				2nd International Symposium on Triglycerides and HDL: Lipid abnormalities and their treatment Diabetes Care, November 1, 2005; 28(11): 2795 - 2802. [Full Text] [PDF]

				H. Zhang, A. Zhang, D.E. Kohan, R.D. Nelson, F.J. Gonzales, T. Yang, C. Schmidt-Lucke, L. Rossig, S. Fichtlscherer, M. Vasa, et al. Edema and Congestive Heart Failure from Thiazolidone Insulin Sensitizers--Excess Sodium Reabsoption in the Collecting Duct: Collecting Duct-Specific Deletion of Peroxisome Proliferator-Activated Receptor {gamma} Blocks Thiazolidinedione-Induced Fluid Retention. Proc Nat Acad Sci U S A 102: 9406-9411, 2005 J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3139 - 3142. [Full Text] [PDF]

				M. H. Davidson Clinical Significance of Statin Pleiotropic Effects: Hypotheses Versus Evidence Circulation, May 10, 2005; 111(18): 2280 - 2281. [Full Text] [PDF]